Anesthesia and

Uncommon Diseases
SI X T H E D IT IO N

Anesthesia and
Uncommon Diseases

LEE A. FLEISHER, MD
Robert D. Dripps Professor and Chair
Department of Anesthesiology and Critical Care
Professor of Medicine
Perelman School of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

ANESTHESIA AND UNCOMMON DISEASES ISBN: 978-1-4377-2787-6

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Notices
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This book is dedicated to my wife, Renee, who is my true partner in life, an outstanding
example to our children, and a sounding board.
To my many teachers over the years, from professors during my residency to faculty
colleagues and the many residents and medical students who taught me through their
questions.
I particularly want to acknowledge one teacher, Stanley Rosenbaum, an internist,
anesthesiologist, and intensivist at Yale University. Stanley, who was one of my first
attendings, taught me the art and science of caring for patients with complex medical
comorbidities and became an important collaborator in my early research efforts.
—Lee A. Fleisher
PR E FAC E
It was a pleasure to edit the sixth edition of Anesthesia and
Uncommon Diseases, following the traditions of Drs. Katz,
Benumof, and Kadis from previous publications. When I was
a resident at Yale New Haven Hospital, the third edition of this
book was always an important component of my planning for
the next day's anesthetic. In developing the sixth edition, I have
asked the authors to include tables and key points that high-
light significant management practices for the various diseases
to complement the comprehensive reviews in the text. Given
the quality of the chapters from the previous edition, I invited
many of the same authors to contribute some new chapters
and ensured that all chapters have been updated to reflect the
newest information available on these complex diseases.
In putting together a multiauthor text, numerous people must
be acknowledged. I would like to thank my executive assistant,
Eileen O'Shaughnessy, for managing a diverse group of authors.
I would also like to thank Natasha Andjelkovic and Executive
Content Strategist William Schmitt, my publishers at Elsevier, for
their patience and support, and Content Development Manager
Lucia Gunzel, whose guidance was very valuable.
Lee A. Fleisher, MD
Editor
vii
F OR E WO R D
What are uncommon diseases? The Oxford English Dictionary
defines “uncommon” as not possessed in common, not com-
monly (to be) met with, not of ordinary occurrence, unusual,
rare. “Rare” has various meanings, such as few in number and
widely separated from each other (in space or time), though
also including unusual and exceptional. Another synonym for
uncommon is “infrequent,” the definition of which includes
not occurring often, happening rarely, recurring at wide inter-
vals of time. The chapter titled Respiratory Diseases in this
edition aims to review “less common” pulmonary conditions,
rather than “uncommon.” None of these definitions includes
quantification.
Why do we need a separate text to help us conduct the anes-
thetics of illnesses that do not happen often, if that is indeed
the case? The simplest answer, congruent with the present
obsession with the wisdom of the market, might be that the
need has been already proven by the fact that the anesthetic
community has bought sufficient copies of the p ­ revious five
editions of this book to warrant a sixth. Nevertheless, it seems
an intriguing question. Are the readers of the book residents
studying arcane facts in order to pass certification examina-
tions? Are they investigators searching for relevant questions to
research? Are they isolated clinicians faced with the n ­ ecessity
of ­managing patients with unusual conditions the clinicians
encounter so infrequently that they do not recall (or never
knew) the most relevant facts requisite for providing safe care?
Do the many uncommon conditions, even though each might
occur infrequently, happen sufficiently often in the aggregate
that we would ignore them to the peril of our patients?
To begin to approach this question, we need to consider the
practice of medicine and the fact that medicine is a profession.
Professions are occupations in which groups of individuals are
granted a monopoly by society to learn and apply advanced
knowledge in some area for the benefit of that society. The pro-
fession has the obligation to transmit that knowledge to others
who will join that profession, to develop new knowledge, and
to maintain standards of practice by self-regulation. There is
a moral covenant with society to behave altruistically—that is,
for the professional to subsume her or his own personal inter-
ests for the benefit of the society. These characteristics trans-
late into an obligation to provide competent care for all who
entrust themselves into our hands, no matter how rare or
­esoteric their condition may be. In the practice of anesthesiology
(and of all of medicine, for that matter), it is not possible for
any one individual to know everything necessary to fulfill that
responsibility. Thus, we are dependent on rapid access to gain
sufficient knowledge to approach that duty.
In the preface to the first edition of Anesthesia and
Uncommon Diseases (1973), editors Jordan Katz and Leslie B.
Kadis stressed their intention to present disease entities whose
underlying pathophysiologic processes might profoundly
affect normal anesthetic management. They noted that, “In
general, the information we wanted to present has never been
published.” This resulted in “a compendium of what is and is
not known about unusual diseases as they may or may not
relate to anesthesia.” The authors expressed the hope that their
work would stimulate others to publish their experiences.
The subsequent three decades have seen a remarkable growth
and development of knowledge in biomedical science, includ-
ing anesthesiology and its related disciplines. Many others have
indeed published their experiences with conditions covered in
editions of this book. This has resulted in understanding the
physiology and safe anesthetic management of many of these
diseases, so that recommendations for their management can
be provided with confidence. It has also been accompanied by
recognition of other, not previously recognized, illnesses that
have joined the ranks of “uncommon diseases.” An example
of the former is the present virtually complete understanding
of succinylcholine-associated hyperkalemia in certain muscle
­diseases; an example of the latter is the entire field of mitochon-
drial diseases, which was added in the fifth edition.
Anesthesiology has been characterized as hours of bore-
dom interspersed with moments of terror. I would argue
strongly that this is an incomplete and misleading character-
ization, but will not expand on that here. However, as a recov-
ering clinician who spent decades (unsuccessfully) attempting
to make every anesthetic as “boring” as possible, I can vouch
that terror is indeed an inevitable component of the specialty.
Knowledge—technical, experiential, judgmental, didactic—
is the most effective deterrent to these vexing episodes and
the best tool to successfully confront them when they occur.
This book is a single source of extremely useful and provoc-
ative knowledge for trainees, practitioners, and investigators
alike. I suspect this is why the previous editions of this book
have been so successful, why this updated and much changed
edition, with new topics and new contributors, will also be a
success, and why we will need further new editions in future.
Edward Lowenstein, MD
Henry Isaiah Dorr Distinguished Professor
of Anaesthesia and Professor of Medical Ethics,
Harvard Medical School; Provost, Department of
Anesthesia, Critical Care and Pain Medicine,
Massachusetts General Hospital, Boston, Massachusetts
ix
C O N T R IB U TO R S

Shamsuddin Akhtar, MBBS Rafael Cartagena, MD

Associate Professor Medical Director of the Operating Room
Department of Anesthesiology Henrico Doctor's Hospital
Yale University School of Medicine President, Total Anesthesia
New Haven, Connecticut Richmond, Virginia
Chapter 13: Diseases of the Endocrine System Chapter 4: Respiratory Diseases

Dean B. Andropoulos, MD, MHCM Maurizio Cereda, MD

Chief of Anesthesiology Assistant Professor
Texas Children's Hospital Department of Anesthesiology and Critical Care
Professor, Anesthesiology and Pediatrics Perelman School of Medicine
Baylor College of Medicine University of Pennsylvania
Houston, Texas Philadelphia, Pennsylvania
Chapter 3: Congenital Heart Disease Chapter 7: Renal Diseases

Amir Baluch, MD Franklyn P. Cladis, MD

Research Associate Assistant Professor of Anesthesiology
Louisiana State University School of Medicine Director of Pediatric Anesthesia Fellowship
New Orleans, Louisiana Program
Attending Anesthesiologist University of Pittsburgh School of Medicine
Baylor Surgicare Attending Anesthesiologist
Dallas, Texas Children's Hospital of Pittsburgh of UPMC
Chapter 15: Psychiatric and Behavioral Disorders Pittsburgh, Pennsylvania
Chapter 16: Mineral, Vitamin, and Herbal Supplements Chapter 21: The Pediatric Patient

Dimitry Baranov, MD Bruce F. Cullen, MD

Assistant Professor of Clinical Anesthesiology and Critical Care Professor Emeritus
Department of Anesthesiology and Critical Care Department of Anesthesiology
Perelman School of Medicine University of Washington School of Medicine
University of Pennsylvania Seattle, Washington
Philadelphia, Pennsylvania Chapter 18: Burns
Chapter 8: Neurologic Diseases
Peter J. Davis, MD, FAAP
Paul X. Benedetto, MD Professor of Anesthesiology and Pediatrics
Chief Resident University of Pittsburgh
Department of Dermatology Anesthesiologist-in-Chief
Cleveland Clinic Foundation Children's Hospital of Pittsburgh of UPMC
Cleveland, Ohio Pittsburgh, Pennsylvania
Chapter 10: Skin and Bone Disorders Chapter 21: The Pediatric Patient

Sanjay M. Bhananker, MD, FRCA Anahat Dhillon, MD

Associate Professor Assistant Clinical Professor
Department of Anesthesiology and Pain Medicine Department of Anesthesiology
University of Washington School of Medicine David Geffen School of Medicine at UCLA
Seattle, Washington Los Angeles, California
Chapter 18: Burns Chapter 5: Liver Diseases

xi
 xii Contributors
Richard P. Dutton, MD, MBA
Clinical Associate
University of Chicago
Chicago, Illinois
Executive Director
Anesthesia Quality Institute
Park Ridge, Illinois
Chapter 17: Trauma and Acute Care
Gregory W. Fischer, MD
Associate Professor of Anesthesiology
Department of Anesthesiology
Associate Professor of Cardiothoracic Surgery
Mount Sinai School of Medicine
Mount Sinai Medical Center
New York, New York
Chapter 11: Hematologic Diseases
Lee A. Fleisher, MD
Robert D. Dripps Professor and Chair
Department of Anesthesiology and Critical Care
Professor of Medicine
Perelman School of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
Charles Fox, MD
Vice Chairman of Academics
Department of Anesthesiology
Tulane University School of Medicine
New Orleans, Louisiana
Chapter 15: Psychiatric and Behavioral Disorders
Erin A. Gottlieb, MD
Attending Pediatric Cardiovascular
Anesthesiologist
Texas Children's Hospital
Assistant Professor of Anesthesiology and
Pediatrics
Baylor College of Medicine
Houston, Texas
Chapter 3: Congenital Heart Disease
Thomas E. Grissom, MD, FCCM
Associate Professor
Department of Anesthesiology
University of Maryland School of Medicine
R Adams Cowley Shock Trauma Center
Baltimore, Maryland
Chapter 17: Trauma and Acute Care
David L. Hepner, MD
Associate Professor of Anesthesia
Harvard Medical School
Staff Anesthesiologist
Department of Anesthesiology, Perioperative and Pain Medicine
Associate Director, Weiner Center for Preoperative Evaluation
Brigham and Women's Hospital
Boston, Massachusetts
Chapter 19: Pregnancy and Obstetric Complications
Caron M. Hong, MD, MSc
Assistant Professor
Department of Anesthesiology and Surgery
University of Maryland School of Medicine
Baltimore, Maryland
Chapter 4: Respiratory Diseases
Jiri Horak, MD
Assistant Professor
Department of Anesthesiology and Critical Care
Perelman School of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
Chapter 7: Renal Diseases
Joel A. Kaplan, MD
Professor of Anesthesiology
University of California, San Diego
San Diego, California
Chapter 2: Cardiac Diseases
Adam M. Kaye, PharmD, FASCP, FCPhA
Associate Clinical Professor
Department of Pharmacy Practice
Thomas J. Long School of Pharmacy and Health Sciences
University of the Pacific
Stockton, California
Chapter 16: Mineral, Vitamin, and Herbal Supplements
Alan D. Kaye, MD, PhD
Professor and Chairman
Department of Anesthesiology
Professor
Department of Pharmacology
Louisiana State University School of Medicine
Director of Anesthesia
Director of Interventional Pain Services
Louisiana State University Interim Hospital
Chapter 15: Psychiatric and Behavioral Disorders
Chapter 16: Mineral, Vitamin, and Herbal Supplements
 Contributors xiii

Bhavani Shankar Kodali, MD Kathryn E. McGoldrick, MD

Associate Professor and Vice Chair Professor and Chair
Department of Anesthesiology, Perioperative, and Pain Medicine Department of Anesthesiology
Harvard Medical School New York Medical College
Brigham and Women's Hospital Valhalla, New York
Boston, Massachusetts Chapter 1: Eye, Ear, Nose, and Throat Diseases
Chapter 19: Pregnancy and Obstetric Complications
Alexander Mittnacht, MD
Corry J. Kucik, MD, DMCC, FCCP Associate Professor of Anesthesiology
Assistant Professor of Anesthesiology and Critical Care Director of Pediatric Cardiac Anesthesia
University of Southern California Mount Sinai School of Medicine
Anesthesiology Program Director New York, New York
Navy Trauma Training Center Chapter 2: Cardiac Diseases
Los Angeles, California
Chapter 17: Trauma and Acute Care Patrick Neligan, MA, MD, FCAI
Honorary Senior Lecturer in Anaesthesia and Intensive Care
Jonathan Leff, MD National University of Ireland
Assistant Professor of Anesthesiology Consultant Anaesthetist in Intensive Care
Albert Einstein College of Medicine Galway University Hospitals
Chief of Cardiothoracic Anesthesia Galway, Ireland
Director Cardiothoracic Anesthesia Fellowship Chapter 7: Renal Diseases
Montefiore Medical Center Chapter 12: Infectious Diseases and Biologic Weapons
Bronx, New York
Chapter 11: Hematologic Diseases Anthony N. Passannante, MD
Professor of Anesthesiology
Richard J. Levy, MD University of North Carolina at Chapel Hill
Associate Professor of Anesthesiology and Critical Care Professor and Vice-Chair for Clinical Operations
Medicine, Pediatrics, and Integrative Systems Biology University of North Carolina Health System
The George Washington University School of Medicine and Chapel Hill, North Carolina
Health Sciences Chapter 4: Respiratory Diseases
Director of Cardiac Anesthesia
Vice Chief of Anesthesiology and Pain Medicine Srijaya K. Reddy, MD
Children’s National Medical Center Assistant Professor of Anesthesiology and Pediatrics
Washington, DC Division of Anesthesiology and Pain Medicine
Chapter 14: Mitochondrial Disease Children's National Medical Center
George Washington University School of Medicine and
Henry Liu, MD Health Sciences
Associate Professor of Anesthesiology Washington, DC
Tulane University School of Medicine Chapter 14: Mitochondrial Disease
Staff Anesthesiologist
Director of Cardiothoracic and Vascular Anesthesia David L. Reich, MD
Tulane University Medical Center Horace W. Goldsmith Professor and Chair of
New Orleans, Louisiana Anesthesiology
Chapter 15: Psychiatric and Behavioral Disorders Mount Sinai School of Medicine
New York, New York
Maureen McCunn, MD, MIPP, FCCM Chapter 2: Cardiac Diseases
Assistant Professor
Department of Anesthesiology and Critical Care Amanda J. Rhee, MD
Perelman School of Medicine Assistant Professor of Anesthesiology
University of Pennsylvania Mount Sinai School of Medicine
Philadelphia, Pennsylvania New York, New York
Chapter 17: Trauma and Acute Care Chapter 2: Cardiac Diseases
 xiv Contributors

Peter Rock, MD, MBA, FCCM Ashish C. Sinha, MBBS, MD, PhD, DABA
Martin Helrich Professor and Chair President, International Society for the Perioperative Care of
Department of Anesthesiology the Obese Patient (ISPCOP)
Professor of Anesthesiology, Medicine and Surgery Professor and Vice Chairman of Research
The University of Maryland School of Medicine Director of Clinical Research
Baltimore, Maryland Anesthesiology and Perioperative Medicine
Chapter 4: Respiratory Diseases Drexel University College of Medicine
Hahnemann University Hospital
Steven J. Schwartz, MD Philadelphia, Pennsylvania
Assistant Professor Chapter 6: Obesity and Nutrition Disorders
Anesthesiology and Adult Critical Care
Johns Hopkins Bayview Medical Center Doreen Soliman, MD
Johns Hopkins Medical Institutions Assistant Professor of Anesthesiology
Baltimore, Maryland Director of Pediatric Anesthesia Residency Program
Chapter 20: The Geriatric Patient University of Pittsburgh School of Medicine
Attending Anesthesiologist
Benjamin K. Scott, MD Children's Hospital of Pittsburgh of UPMC
Assistant Professor Pittsburgh, Pennsylvania
Department of Anesthesiology Chapter 21: The Pediatric Patient
University of Colorado
Denver, Colorado Randolph H. Steadman, MD
Chapter 8: Neurologic Diseases Professor and Vice Chair
Chief, Anesthesia for Liver Transplant
Scott Segal, MD, MHCM Department of Anesthesiology
Professor and Chair David Geffen School of Medicine at UCLA
Department of Anesthesiology Los Angeles, California
Tufts University School of Medicine Chapter 5: Liver Diseases
Tufts Medical Center
Boston, Massachusetts Patricia B. Sutker, PhD
Chapter 19: Pregnancy and Obstetric Complications Professor
Department of Anesthesiology
Michael G.S. Shashaty, MD, MSCE Louisiana State University School of Medicine
Instructor, Division of Pulmonary, Allergy, and Critical Care New Orleans, Louisiana
Faculty Fellow, Center for Clinical Epidemiology and Chapter 15: Psychiatric and Behavioral Disorders
Biostatistics
Perelman School of Medicine John E. Tetzlaff, MD
University of Pennsylvania Professor of Anesthesiology
Philadelphia, Pennsylvania Cleveland Clinic Lerner College of Medicine of Case
Chapter 7: Renal Diseases Western Reserve University
Staff, Department of General Anesthesia
Linda Shore-Lesserson, MD, FASE Anesthesiology Institute
Professor of Anesthesiology Cleveland Clinic
Albert Einstein College of Medicine Cleveland, Ohio
Bronx, New York Chapter 10: Skin and Bone Disorders
Chapter 11: Hematologic Diseases
Joshua M. Tobin, MD
Frederick E. Sieber, MD Assistant Professor
Professor and Director of Anesthesia Division of Trauma Anesthesiology
Johns Hopkins Bayview Medical Center University of Maryland School of Medicine
Johns Hopkins Medical Institutions R Adams Cowley Shock Trauma Center
Baltimore, Maryland Baltimore, Maryland
Chapter 20: The Geriatric Patient Chapter 17: Trauma and Acute Care
 Contributors xv
Michael K. Urban, MD, PhD
Associate Professor of Clinical Anesthesiology
Weil Medical College of Cornell University
Medical Director PACU/SDU
Hospital for Special Surgery
New York, New York
Chapter 9: Muscle Diseases
Ian Yuan, MEng, MD
Resident
Department of Anesthesiology and Critical Care
Perelman School of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
Chapter 6: Obesity and Nutrition Disorders
 C H
Eye, Ear, Nose, and Throat Diseases
Eye Diseases: General Considerations
Corneal Pathology and Systemic Disease
Lens Pathology and Systemic Disease
Glaucoma and Systemic Disease
Retinal Complications of Systemic Disease
Eye Diseases: Specific Considerations
Marfan's Syndrome
Graves’ Disease
Homocystinuria
Hemoglobinopathies: Sickle Cell Disease
Acquired Immunodeficiency Syndrome (AIDS)
Retinopathy of Prematurity
Incontinentia Pigmenti
Retinitis Pigmentosa
Eye Trauma
Ear, Nose, and Throat Considerations
Sleep Apnea
Recurrent Respiratory Papillomatosis
Cystic Hygroma
Wegener's Granulomatosis
Acromegaly
Ludwig's Angina
Conclusion
KEY POINTS
n During ophthalmic surgery, the anesthesiologist is often
positioned away from the patient's face, preventing imme-
diate access to the airway, and during many laryngologic
surgeries, must share the airway with the surgeon. These
logistical exigencies can compromise patient safety.
n Patients with eye conditions are often at the extremes of
age and may have extensive associated systemic processes
or metabolic diseases.
n Patients requiring ENT surgery may have preoperative air-
way compromise from edema, infection, tumor, or trauma;
effective anesthesiologist-surgeon communication is vital
A P T E R
1
KATHRYN E. MCGOLDRICK, MD  n
for optimal patient outcome. Contingency planning is crit-
ical for patient safety.
n Few ocular/ENT conditions have isolated ophthalmic or
otorhinolaryngologic pathology. Multisystem involvement
is common, and the anesthesiologist needs to have a com-
prehensive understanding of the disease process, surgical
requirements, and effects of anesthetic interventions on
both patient and proposed surgery.
n In Lowe’s (oculocerebrorenal) syndrome, cataract is often
the presenting sign, with other abnormalities such as men-
tal retardation, renal tubular dysfunction, and osteoporo-
sis appearing later. Drugs excreted by the kidney should
be given cautiously and nephrotoxins avoided. Meticulous
attention must be paid to gentle intraoperative positioning.
n The primary areas of concern for the anesthesiologist
caring for a patient with Graves’ disease involve the con-
sequences of chronic corticosteroid use, side effects of anti-
thyroid drugs, possible perioperative thyroid storm, and a
potentially difficult intubation owing to tracheal deviation
associated with a large neck mass.
n In determining whether a patient with obstructive sleep apnea
(OSA) is a candidate for outpatient surgery, it is imperative to
consider the patient’s BMI and neck circumference, severity of
OSA, presence or absence of associated cardiopulmonary dis-
ease, nature of the surgery, anticipated postoperative analgesic
requirement, and the resources of the ambulatory facility.
n Wegener’s granulomatosis is a systemic disease of unknown
etiology characterized by necrotizing granulomas and vascu-
litis that affect the upper and lower airways and the kidneys.
The anesthesiologist must anticipate a host of potential prob-
lems including the side effects of chronic corticosteroid and
aggressive immunosuppressive therapy as well as the pres-
ence of underlying pulmonary and renal disease. Midline
necrotizing granulomas of the airway are often present, and
subglottic or tracheal stenosis should also be expected.
Many patients presenting for relatively “simple” ophthalmic
or otorhinolaryngologic procedures suffer from complex
1
 2 ANESTHESIA AND UNCOMMON DISEASES
s­ ystemic diseases. Although the surgeon may have the luxury
of being able to focus on one specific aspect of the patient's
condition, the anesthesiologist must be knowledgeable about
the ramifications of the entire disease complex and the ger-
mane implications for anesthetic management. Issues of safety
often are complicated by the logistic necessity for the anesthe-
siologist to be positioned at a considerable distance from the
patient's face, thus preventing immediate access to the airway
for certain types of ophthalmic surgery. Additionally, during
many laryngologic surgeries, the anesthesiologist must share
the airway with the surgeon. Moreover, many of these patients
with complex disease undergo surgical procedures that are
routinely performed on an ambulatory basis, further challeng-
ing the anesthesiologist to provide a rapid, smooth, problem-
free recovery.
This chapter focuses on several eye diseases as well as ear,
nose, and throat (ENT) conditions, many of which are rela-
tively rare. Nonetheless, the anesthesiologist needs to under-
stand the complexities involved, because failure to do so may
be associated with preventable morbidity and mortality.
EYE DISEASES: GENERAL
CONSIDERATIONS
Patients with eye conditions are often at the extremes of
age, ranging from fragile infants with retinopathy of pre-
maturity or congenital cataracts to nonagenarians with
submacular hemorrhage. These patients also may have
­ although rarely a ­b alanced translocation of chromosome
extensive associated systemic processes or metabolic dis-
eases.1 Moreover, the increased longevity in developed
nations has produced a concomitant increase in the longi-
tudinal prevalence of major eye diseases. A study of elderly
Medicare beneficiaries in the United States followed for 9
years during the 1990s documented a dramatic increase
in the prevalence of major chronic eye diseases associated
with aging.2 For example, the prevalence of diabetes melli-
tus increased from 14.5% at baseline in the study patients to
25.6% nine years later, with diabetic retinopathy among per-
sons with diabetes mellitus increasing from 6.9% to 17.4%
of the subset. Primary open-angle glaucoma increased from
4.6% to 13.8%, and glaucoma suspects increased from 1.5%
to 6.5%. The prevalence of age-related macular degenera-
tion increased from 5% to 27.1%. Overall, the proportion of
subjects with at least one of these three chronic eye diseases
increased significantly, from 13.4% to 45.4% of the elderly
Medicare population.
Ophthalmic conditions typically involve the cornea, lens,
vitreoretinal area, intraocular pressure–regulating appara-
tus, or eye muscles and adnexa. These patients may present
for, respectively, corneal transplantation, cataract extraction,
vitrectomy for vitreous hemorrhage, scleral buckling for ret-
inal detachment, trabeculectomy and other glaucoma filtra-
tion procedures for glaucoma amelioration, or rectus muscle
recession and resection for strabismus. Conversely, they may
require surgery for a condition entirely unrelated to their ocu-
lar pathology. Nonetheless, their ocular disease may present
BOX 1-1   n OPHTHALMIC CONDITIONS OFTEN
ASSOCIATED WITH COEXISTING DISEASE
Aniridia Macular hypoplasia
Cataracts Nystagmus
Colobomata Optic nerve hypoplasia
Corneal dystrophies Retinal detachment
Ectopia lentis Retinopathy
Glaucoma Strabismus
issues for anesthetic management, or the eye pathology may
be only one manifestation of a constellation of systemic condi-
tions that constitute a syndrome with major anesthetic impli-
cations (Box 1-1).
Other, less common eye defects frequently linked with
coexisting diseases include aniridia, colobomas, and optic
nerve hypoplasia. Aniridia, a developmental abnormality
characterized by striking hypoplasia of the iris, is a mis-
nomer because the iris is not totally absent. The term
describes only one facet of a complex developmental dis-
order that features macular and optic nerve hypoplasia
as well as associated cataracts, glaucoma, ectopia lentis,
progressive opacification, and nystagmus. Type I aniridia
involves autosomal dominant transmittance of a gene
thought to be on chromosome 2. Type II aniridia u ­ sually
appears sporadically and is associated with an intersti-
tial deletion on the short arm of c­ hromosome 11 (11p13),
11 may produce familial type II. In addition to the typical
ocular lesions, children with type II aniridia frequently are
mentally retarded and have genitourinary anomalies—the
“ARG triad.” Individuals with the chromosome 11 defect
and this triad may develop Wilms’ tumor3 and should be
followed with regular abdominal examinations and fre-
quent renal ultrasonography at least until they are 4 years
old. Chromosomal analysis is indicated in all infants with
congenital aniridia.
Coloboma denotes an absence or defect of some ocular
tissue, usually resulting from malclosure of the fetal intraoc-
ular fissure, or rarely from trauma or disease. The two major
types are chorioretinal or fundus coloboma and isolated optic
nerve coloboma. The typical fundus coloboma is caused by
malclosure of the embryonic fissure, resulting in a gap in
the retina, retinal pigment epithelium, and choroid. These
defects may be unilateral or bilateral and usually produce a
visual field defect corresponding to the chorioretinal defect.
Although colobomas may occur independent of other
abnormalities, they also may be associated with microph-
thalmos, cyclopia, anencephaly, or other major central ner-
vous system aberrations. They frequently are linked with
chromosomal abnormalities, especially the trisomy 13 and
18 syndromes. Colobomas may be seen with the CHARGE
syndrome (congenital heart disease, choanal atresia, men-
tal retardation, genital hypoplasia, and ear anomalies) or
the VATER association (tracheoesophageal fistula, con-
genital heart disease, and renal anomalies). Rarely, isolated
 Chapter 1  Eye, Ear, Nose, and Throat Diseases 3

c­ olobomas of the optic nerve occur. They may be familial as erythema multiforme and pemphigus have corneal mani-
and associated with other ocular pathology as well as sys- festations (see Chapter  10). Finally, mandibulo-­oculofacial
temic defects, including cardiac conditions. dyscephaly (Hallermann-Streiff syndrome) is of interest to anes-
Optic nerve hypoplasia is a developmental defect char- thesiologists because of anticipated difficulty with intubation.
acterized by deficiency of optic nerve fibers. The anomaly
may be unilateral or bilateral, mild to severe, and associ-
Lens Pathology and Systemic Disease
ated with a broad spectrum of ophthalmoscopic find-
ings and clinical manifestations. Visual impairment may A cataract is defined as a clouding of the normally clear crys-
range from minimal reduction in acuity4 to blindness. talline lens of the eye. The different types of cataracts include
Strabismus or nystagmus secondary to visual impairment nuclear-sclerotic, cortical, posterior subcapsular, and mixed.
is common. Although optic nerve hypoplasia may occur Each type has its own location in the lens and risk factors
as an isolated defect in otherwise normal children, the for development, with nuclear-sclerotic cataracts being the
lesion can be associated with aniridia, microphthalmos, most common type of age-related cataract. The leading cause
coloboma, anencephaly, hydrocephalus, hydranencephaly, of blindness worldwide, cataracts affect more than 6 million
and encephalocele. Optic nerve hypoplasia may occur in individuals annually.8 Indeed, cataract surgery is the most
a syndrome termed septo-optic dysplasia or de Morsier's ­frequently p­ erformed surgical procedure in the United States,
syndrome. There may be coexisting hypothalamic condi- with more than 1.5 million operations annually.9 More than
tions and extremely variable endocrine aberrations.5,6 An half the population older than 65 develop age-related cata-
isolated deficiency of growth hormone is most common, but racts with associated visual disability.10 Despite extensive
multiple hormonal imbalances, including diabetes insipi- research into the pathogenesis and pharmacologic prevention
dus, have been reported. The etiology of optic nerve hypo- of ­cataracts, however, there are no proven means to prevent
plasia remains unknown. However, it has been observed age-related cataracts.
to occur with slightly increased frequency in infants of Although age-related cataracts are most frequently encoun-
­diabetic ­mothers,4 and the prenatal use of drugs such as tered, cataracts may be associated with dermatologic diseases
LSD (lysergic acid diethylamide), meperidine, phenytoin, such as incontinentia pigmenti, exogenous substances, genetic
and quinine has been implicated sporadically. diseases, hematologic diseases, infections, and metabolic per-
turbations (Box 1-3).
Exogenous substances that can trigger cataracts include
Corneal Pathology and Systemic Disease
corticosteroids,11–13 phenothiazines, naphthalene, ergot,
A vast spectrum of conditions may be associated with cor- parachlorobenzene, and alcohol.14 Metabolic conditions
neal pathology7 (Box  1-2). Associated inflammatory diseases ­associated with cataracts include diabetes mellitus, Fabry's dis-
include rheumatoid arthritis, Reiter's syndrome, Behçet's syn- ease, galactosemia, hepatolenticular degeneration (Wilson's
drome, and sarcoidosis. Connective tissue disorders such as disease), hypoparathyroidism, hypothyroidism, phenylketon-
ankylosing spondylosis, scleroderma, Sjögren's syndrome, and uria, Refsum's disease, and xanthomatosis. Another metabolic
Wegener's granulomatosis have been associated with corneal
disturbances. Associated metabolic diseases include cystinosis,
disorders of carbohydrate metabolism, gout, hyperlipidemia,
BOX 1-3   n CONDITIONS ASSOCIATED WITH
and Wilson's disease. Also, such conditions as Graves’ hyper- CATARACTS
thyroid disease, leprosy, chronic renal failure, and tuberculosis
may have associated corneal disease. Even skin diseases such Aging Galactosemia
Hypoparathyroidism
Chromosomal Anomalies
Hypothyroidism
Trisomy 13
Lowe's syndrome
Trisomy 18
Phenylketonuria
BOX 1-2   n SYSTEMIC DISEASES ASSOCIATED WITH Trisomy 21
Refsum's disease
CORNEAL PATHOLOGY Turner's syndrome
Wilson's disease
Dermatologic Disease Xanthomatosis
Connective Tissue Metabolic Diseases
Incontinentia pigmenti
Disorders Carbohydrate metabolism Infectious Diseases
Ankylosing spondylosis disorders Exogenous Substances Herpes
Scleroderma Chronic renal failure Alcohol Influenza
Sjögren's syndrome Cystinosis Ergot Mumps
Wegener's granulomatosis Gout Naphthalene Polio
Graves’ disease Parachlorobenzene Rubella
Inflammatory Diseases
Wilson's disease Phenothiazines Toxoplasmosis
Behçet's syndrome
Vaccinia
Reiter's syndrome Skin Disorders Metabolic Conditions
Varicella-zoster
Rheumatoid arthritis Erythema multiforme Diabetes mellitus
Sarcoidosis Pemphigus Fabry's disease
 4 ANESTHESIA AND UNCOMMON DISEASES
disorder important in the differential diagnosis of congeni-
tal cataracts is Lowe's (oculocerebrorenal) syndrome. In this
X-linked disorder, cataract is frequently the presenting sign,
with other abnormalities appearing later. These anomalies
include mental and growth retardation, hypotonia, renal aci-
dosis, aminoaciduria, proteinuria, and renal rickets, requir-
ing calcium and vitamin D therapy.15,16 Other concomitants
include osteoporosis and a distinctive facies (long with fron-
tal bossing). Although lens changes may also be seen in het-
erozygous female children, affected male children usually
have obvious, dense, bilateral cataracts at birth. They may also
be afflicted with associated glaucoma. Interestingly, carrier
females in their second decade of life have significantly higher
numbers of lens opacities than age-related controls; however,
absence of opacities is no guarantee that an individual is not
a carrier. Anesthetic management includes careful attention
to acid-base balance and to serum levels of calcium and elec-
trolytes. Renal involvement of oculocerebrorenal syndrome of
Lowe comprises tubular dysfunction characterized by protein-
uria and generalized aminoaciduria progressing to the renal
Fanconi's syndrome. Bicarbonate wasting and hyperkaluria
result from a proximal tubule transport defect, with later glo-
merular disease.17 The administration of drugs excreted by
the kidney should be observed carefully and nephrotoxins
avoided. The patient with osteoporosis should be positioned
on the operating table gently and carefully.
Infectious causes of cataracts include herpesvirus, influ-
enza, mumps, polio, rubella, toxoplasmosis, vaccinia, and
varicella-zoster virus.18 Chromosomal anomalies associated
with cataracts include trisomy 13 (Patau's syndrome), trisomy
18 (Edward's syndrome), and trisomy 21 (Down syndrome).
In Patau's and Edward's syndromes, congenital cataracts fre-
quently occur in conjunction with other ocular anomalies,
such as coloboma and microphthalmia. Cataracts have also
been reported with Turner's syndrome (XO).
An additional type of lens abnormality that can be asso-
ciated with major systemic disease is ectopia lentis (Fig.  1-1
and Box  1-4). Displacement of the lens can be classified
FIGURE 1-1  Ectopia lentis. Displaced lens of the eye is common
in patients with Marfan's syndrome.  (Courtesy American Academy
of Ophthalmology, 2011, aao.org.)
BOX 1-4  n CONDITIONS ASSOCIATED WITH
ECTOPIA LENTIS
Ocular Conditions
Aniridia
Congenital glaucoma
High myopia
Intraocular tumor
Trauma
Uveitis
Systemic Diseases
Homocystinuria
Hyperlysinemia
Marfan's syndrome
Sulfite oxidase deficiency
Weill-Marchesani syndrome
t­opographically as subluxation or luxation. Luxation denotes
a lens that is dislocated either posteriorly into the vitreous cav-
ity or, less often, anteriorly into the anterior chamber. In sub-
luxation, some zonular attachments remain, and the lens stays
in its plane posterior to the iris, but tilted. The most common
cause of lens displacement is trauma, although ectopia lentis
may also result from other ocular disease, such as intraocular
tumor, congenital glaucoma, uveitis, aniridia, syphilis, or high
myopia. Inherited defects and serious systemic diseases, such
as Marfan's syndrome, homocystinuria, Weill-Marchesani
syndrome, hyperlysinemia, and sulfite oxidase deficiency, are
also associated with ectopia lentis. Indeed, lens displacement
occurs in approximately 80% of patients with Marfan's syn-
drome (see later discussion).
Glaucoma and Systemic Disease
Glaucoma is a condition characterized by elevated intraocu-
lar pressure (IOP), resulting in impairment of capillary blood
flow to the optic nerve and eventual loss of optic nerve tissue
and function. Two different anatomic types of glaucoma exist:
open-angle (or chronic simple) glaucoma and closed-angle (or
acute) glaucoma. (Other variations of these processes occur
but are not especially germane to anesthetic management.
Glaucoma is actually many diseases, not one.)
With open-angle glaucoma, the elevated IOP exists in con-
junction with an anatomically patent anterior chamber angle.
Sclerosis of trabecular tissue is thought to produce impaired
aqueous filtration and drainage. Treatment consists of medi-
cation to produce miosis and trabecular stretching. Common
eyedrops include epinephrine, echothiophate iodide, timolol,
dipivefrin, and betaxolol. Carbonic anhydrase inhibitors such
as acetazolamide can also be administered by various routes
to reduce IOP by interfering with the production of aqueous
humor. All these drugs are systemically absorbed and thus can
have anticipated side effects.
It is important to appreciate that maintenance of IOP is
determined primarily by the rate of aqueous formation and
the rate of aqueous outflow. The most important influence on
 Chapter 1  Eye, Ear, Nose, and Throat Diseases 5

formation of aqueous humor is the difference in osmotic pres-

sure between aqueous and plasma, as illustrated by the follow- BOX 1-5   n CONDITIONS ASSOCIATED WITH
GLAUCOMA
ing equation:
Ocular Conditions
IOP = K[(OPaq − OPpl) + CP] Aniridia
Anterior cleavage syndrome
where K = coefficient of outflow, OPaq = osmotic pressure of
Cataracts
aqueous humor, OPpl = osmotic pressure of plasma, and CP = Ectopia lentis
capillary pressure. Because a small change in solute concen- Hemorrhage
tration of plasma can dramatically affect the formation of Mesodermal dysgenesis
aqueous humor and thus IOP, hypertonic solutions such as Persistent hyperplastic primary vitreous
Retinopathy of prematurity
mannitol are administered to reduce IOP.
Spherophakia
Fluctuations in aqueous outflow can also greatly change Trauma
IOP. The primary factor controlling aqueous humor outflow Tumor
is the diameter of Fontana's spaces, as illustrated by the fol-
Systemic Diseases
lowing equation: Chromosomal anomalies
4 Congenital infection syndromes (TORCH*)
A = [r × (Piop − Pv)] ÷ 8 ηL
Hurler's syndrome
where A = volume of aqueous outflow per unit of time, r = radius Marfan's syndrome
Refsum's disease
of Fontana's spaces, Piop = IOP, Pv = venous pressure, η = vis-
Sarcoidosis
cosity, and L = length of Fontana's spaces. When the pupil dilates, Stickler's syndrome
Fontana's spaces narrow, resistance to outflow is increased, and Sturge-Weber syndrome
IOP rises. Because mydriasis is undesirable in both closed- Von Recklinghausen's disease
angle and open-angle glaucoma, miotics such as pilocarpine are
applied to the conjunctiva in patients with glaucoma. *Toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex.
The previous equation describing the volume of aque-
ous outflow per unit of time clearly underscores that outflow
is exquisitely sensitive to fluctuations in venous pressure.
Because an elevation in venous pressure results in an
BOX 1-6   n GLAUCOMA PATIENTS: ANESTHETIC
increased volume of ocular blood as well as decreased aque- OBJECTIVES
ous outflow, IOP increases considerably with any maneu-
ver that increases venous pressure. Therefore, in addition Perioperative instillation of miotics to enhance aqueous humor
to preoperative instillation of miotics, other anesthetic outflow
Avoidance of venous congestion/overhydration
objectives for the patient with glaucoma include periop- Avoidance of greatly increased venous pressure (e.g., coughing,
erative avoidance of venous congestion and of overhydra- vomiting)
tion. Furthermore, hypotensive episodes should be avoided Avoidance of hypotension that may trigger retinal vascular thrombosis
because these patients are purportedly vulnerable to retinal
vascular thrombosis.
Although glaucoma usually occurs as an isolated disease, it
may also be associated with such conditions as Sturge-Weber
TABLE 1-1  n Comparison of Open-Angle and
syndrome and von Recklinghausen's disease (neurofibro- Closed-Angle Glaucoma*
matosis) (Box  1-5). Ocular trauma, corticosteroid therapy,
sarcoidosis, some forms of arthritis with uveitis, and pseudo- Open-Angle Glaucoma Closed-Angle Glaucoma
exfoliation syndrome can also be associated with secondary Anatomically patent Shallow anterior chamber
glaucoma. anterior chamber angle
Primary closed-angle glaucoma is characterized by a shal-
Trabecular sclerosis Narrow iridocorneal angle
low anterior chamber and a narrow iridocorneal angle that
impedes the egress of aqueous humor from the eye because Ten times more common Iris covers trabecular meshwork
the trabecular meshwork is covered by the iris (Box  1-6). than closed-angle
Relative pupillary block is common in many angle-closure Painless Painful
episodes in which iris-lens apposition or synechiae impede
Initially unaccompanied by Red eye with corneal edema
the flow of aqueous from the posterior chamber. In the
visual symptoms Blurred vision; fixed, dilated pupil
United States, angle-closure glaucoma (ACG) is one-tenth
as c­ ommon as open-angle glaucoma (Table  1-1). In acute Can result in blindness if Can cause irreversible optic
ACG, if the pressure is not reduced promptly, permanent chronically untreated nerve injury within 24-48 hours
Requires emergency treatment
visual loss can ensue as a result of optic nerve damage.
Because irreversible optic nerve injury can occur within *Also called angle-closure glaucoma (ACG).
 6 ANESTHESIA AND UNCOMMON DISEASES
24 to 48 hours, treatment should be instituted immedi-
ately after making the diagnosis of acute ACG. Signs and
symptoms include ocular pain (often excruciating), red
eye, corneal edema, blurred vision, and a fixed, mid-dilated
pupil. Consultation with an ophthalmologist should be
sought immediately. Topical pilocarpine 2% is adminis-
tered to cause miosis and pull the iris taut and away from
the trabecular meshwork. A topical beta-adrenergic blocker
(β-blocker) also should be considered. If a prompt reduc-
tion in IOP does not ensue, systemic therapy with an agent
such as mannitol should be considered, but its poten-
tially adverse hemodynamic effects should be weighed in a
patient with cardiovascular disease.
If medical therapy is effective in reducing IOP to a safe
level and the angle opens, an iridotomy/iridectomy can be
performed immediately, or delayed until the corneal edema
resolves and the iris becomes less hyperemic.
Retinal Complications of Systemic Disease
Retinal conditions such as vitreous hemorrhage and reti-
nal detachment are most frequently associated with diabetes
mellitus and hypertension (Box 1-7), although patients with
severe myopia (unaccompanied by any systemic disease) are
vulnerable to retinal detachment. In addition, collagen dis-
orders and connective tissue diseases, such as systemic lupus
erythematosus, scleroderma, polyarteritis nodosa, Marfan's
syndrome, and Wagner-Stickler syndrome, are often asso-
ciated with retinal pathology. Serious retinal complications
have been reported with skin conditions (e.g., incontinentia
pigmenti). Moreover, such conditions as sickle cell anemia,
macroglobulinemia, Tay-Sachs disease, Niemann-Pick dis-
ease, and hyperlipidemia can result in vitreoretinal disorders.
During the past three decades, cytomegalovirus retinitis has
been reported in AIDS patients, sometimes causing retinal
detachment.
BOX 1-7   n CONDITIONS ASSOCIATED WITH
VITREORETINAL PATHOLOGY
Collagen/connective tissue disorders
Marfan's syndrome
Polyarteritis nodosa
Scleroderma
Systemic lupus erythematosus
Wagner-Stickler syndrome
Diabetes mellitus
Hypertension
Human immunodeficiency virus/acquired immunodeficiency
syndrome
Hyperlipidemia
Incontinentia pigmenti
Macroglobulinemia
Niemann-Pick disease
Tay-Sachs disease
EYE DISEASES: SPECIFIC
CONSIDERATIONS
This section shifts focus from systemic to specific disease enti-
ties associated with serious ocular pathology and the anes-
thetic management of these patients.
Marfan's Syndrome
Marfan's syndrome is a disorder of connective tissue, involv-
ing primarily the cardiovascular, skeletal, and ocular systems.
However, the skin, fascia, lungs, skeletal muscle, and adi-
pose tissue may also be affected. The etiology is a mutation
in FBNI, the gene that encodes fibrillin-1, a major component
of extracellular microfibrils, which are the major components
of elastic fibers that anchor the dermis, epidermis, and ocu-
lar zonules.19 Connective tissue in these patients has decreased
tensile strength and elasticity. Marfan's syndrome is inherited
as an autosomal dominant trait with variable expression.
Ocular manifestations of Marfan's syndrome include
severe myopia, spontaneous retinal detachments, displaced
lenses (see Fig. 1-1), and glaucoma. Cardiovascular manifesta-
tions include dilation of the ascending aorta and aortic insuffi-
ciency. The loss of elastic fibers in the media may also account
for dilation of the pulmonary artery and mitral insufficiency
resulting from extended chordae tendineae. Myocardial isch-
emia caused by medial necrosis of coronary arterioles as well
as dysrhythmias and conduction disturbances have been well
documented. Heart failure and dissecting aortic aneurysms or
aortic rupture can occur.
Marfan's patients are tall, with long, thin extremities and
fingers (arachnodactyly). Joint ligaments are loose, resulting
in frequent dislocations of the mandible and hip. Possible cer-
vical spine laxity can also occur. Kyphoscoliosis and pectus
excavatum can contribute to restrictive pulmonary disease.
Lung cysts have also been described, increasing the risk of
pneumothorax. A narrow, high-arched palate is typical.
The early manifestations of Marfan's syndrome may be
subtle, and therefore the patient presenting for initial surgery
may be undiagnosed. The anesthesiologist, however, should
have a high index of suspicion when a tall young patient with a
heart murmur presents for repair of a spontaneously detached
retina. These young patients should have a chest radiograph
as well as an electrocardiogram (ECG) and echocardiogram
before surgery. Antibiotics for subacute bacterial endocardi-
tis prophylaxis should be considered, as well as β-blockers to
mitigate increases in myocardial contractility and aortic wall
tension (dP/dT).
ANESTHETIC MANAGEMENT
If general anesthesia is elected in the Marfan's patient, the anes-
thesiologist should be prepared for a potentially difficult intu-
bation (Box 1-8). Laryngoscopy should be carefully performed
to circumvent tissue damage and especially to avoid hyperten-
sion with its attendant risk of aortic dissection. The patient
should be carefully positioned to avoid cervical spine or other
 Chapter 1  Eye, Ear, Nose, and Throat Diseases 7
BOX 1-8   n MARFAN'S SYNDROME: ANESTHETIC
CONCERNS
Difficult intubation
Lung cysts
Restrictive pulmonary disease
Dysrhythmias and/or conduction disturbances
Dilation of aorta and pulmonary artery; dissecting/ruptured aortic
aneurysms
Aortic and/or mitral insufficiency
Consider antibiotic prophylaxis for subacute bacterial endocarditis.
Myocardial ischemia; heart failure
Consider beta blockade.
Propensity to mandibular/cervical/hip dislocation
joint injuries, including dislocations. The dangers of hyperten-
sion in these patients are well known. Presence of significant
aortic insufficiency clearly warrants that the blood pressure
(BP, especially diastolic) should be high enough to provide
adequate coronary blood flow, but not be so high as to risk dis-
section of the aorta. Maintenance of the patient's normal BP is
typically a good plan. No single intraoperative anesthetic agent
or technique has demonstrated superiority. If pulmonary cysts
are present, however, positive-pressure ventilation may lead to
pneumothorax.20 At extubation, clinicians should take care to
avoid sudden increases in BP or heart rate. Adequate postop-
erative pain management is vitally important to avoid the det-
rimental effects of hypertension and tachycardia.
In appropriate patients having ophthalmic surgery, regional
anesthesia may be a viable option. Retrobulbar or peribulbar
block may be inadvisable in these patients because of the ocu-
lar perforation risk in the presence of high myopia. However,
a catheter-based, sub–Tenon's capsule approach using 5 mL of
a 50:50 mixture of 4% lidocaine and 0.75% bupivacaine has
been as effective as retrobulbar block in controlling intraop-
erative pain during vitreoretinal surgery.21
Graves’ Disease
Graves’ disease is the most common cause of both pediat-
ric and adult hyperthyroidism. Graves’ disease encompasses
hyperthyroidism, goiter, pretibial myxedema, and often but
not inevitably, exophthalmos. The condition occurs in con-
junction with the production of excess thyroid hormone and
affects approximately 3 in 10,000 adults (usually women), typ-
ically age 25 to 50. Graves’ ophthalmopathy includes corneal
ulcerations and exophthalmos that can be severe. Retro-orbital
tissue and the extraocular muscles are infiltrated with lympho-
cytes, plasma cells, and mucopolysaccharides. The extraocular
muscles often are swollen to 5 to 10 times their normal size. If
proptosis secondary to infiltrative ophthalmopathy is severe
and if muscle function or visual acuity deteriorates, cortico-
steroid therapy (usually prednisone, 20-40 mg/day for adults)
is initiated, especially if retrobulbar neuritis develops. Patients
who fail to respond to corticosteroid therapy require surgical
intervention. Lateral (Krönlein's) or supraorbital (Naffziger's)
decompression is performed.
Graves’ disease is thought to be autoimmune in origin,
with thyroid-stimulating immunoglobulins directed against
thyroid antigens that bind to thyroid-stimulating hormone
(TSH, thyrotropin) receptors on the thyroid gland. Soft, mul-
tinodular, nonmalignant enlargement of the thyroid is typi-
cal. There is a strong hereditary component with Graves’
disease, and the condition is likely exacerbated by emotional
stress. These patients may have other signs of autoimmune
involvement, including myositis and occasionally myasthe-
nia gravis. Symptoms include weakness, fatigue, weight loss,
tremulousness, and increased tolerance to cold. Proptosis, dip-
lopia or blurred vision, photophobia, conjunctival chemosis,
and decreased visual acuity may be noted. Cardiac symptoms
include a hyperdynamic precordium, tachycardia, and ele-
vated systolic BP, decreased diastolic BP, and widened pulse
pressure. Atrial fibrillation, palpitations, and dyspnea on exer-
tion may also occur.
The differential diagnosis of Graves’ disease includes other
causes of hyperthyroidism such as pregnancy that may be asso-
ciated with the production of an ectopic TSH-like substance,
autoimmune thyroiditis, thyroid adenoma, choriocarcinoma, a
TSH-secreting pituitary adenoma, and surreptitious ingestion
of tri-iodothyronine (T3) or thyroxine (T4).22 The goals of drug
therapy in the hyperthyroid patient are to control the major
manifestations of the thyrotoxic state and to render the patient
euthyroid. The most frequently used agents are the thiourea
derivatives propylthiouracil (PTU) and methimazole, which
act by inhibiting synthesis of thyroid hormone. (PTU may also
inhibit the conversion of T4 to T3.) Because of the large glan-
dular storage of hormone, 4 to 8 weeks is usually required to
render a patient euthyroid with these drugs. Therapy typically
lasts several months, after which thyroid reserve and suppres-
sive response to thyroid hormone are re-evaluated. The major
complication of this therapy is hypothyroidism, and the dos-
age is usually adjusted to the lowest possible once a euthyroid
state is attained.23 Other side effects encountered in patients
taking these antithyroid drugs include leukopenia, which
may be therapy limiting, as well as agranulocytosis, hepatitis,
rashes, and drug fever. Beta-receptor numbers are reportedly
increased by hyperthyroidism,24 and β-blockers are used to
control the effects of catecholamine stimulation rapidly, such
as tachycardia, tremor, and diaphoresis.25
ANESTHETIC MANAGEMENT
The main areas of concern for the anesthesiologist in the
patient with Graves’ disease involve chronic corticosteroid use,
possible perioperative thyroid storm, and a potentially diffi-
cult intubation because of tracheal deviation from a large neck
mass26 (Box 1-9). When surgery is planned, it is imperative to
determine if the Graves’ patient is euthyroid because the euthy-
roid state will diminish the risks of life-threatening thyroid
storm and of perioperative cardiovascular complications by
more than 90%. Achievement of the euthyroid state is assessed
by clinical signs and symptoms, plasma hormone levels, and
evidence of gland shrinkage. The patient should also be evalu-
ated for associated autoimmune diseases. A chest r­ adiograph,
 8 ANESTHESIA AND UNCOMMON DISEASES
BOX 1-9   n GRAVES’ DISEASE: ANESTHETIC
CONCERNS
Difficult intubation secondary to tracheal deviation or compression
Side effects of antithyroid drugs, including leukopenia and hepatitis
Effects of chronic steroid consumption
Meticulous intraoperative eye protection and temperature monitoring
Perioperative thyroid storm
Determine euthyroid state.
Associated autoimmune disease(s)
Weakened tracheal rings
lateral neck films, and computed tomography (CT) of the neck
and thorax will determine tracheal displacement or compres-
sion. If there is a question about the adequacy of the airway
or tracheal deviation or compression, awake fiberoptic intu-
bation is a prudent approach. An armored tube or its equiva-
lent is also useful if any tracheal rings are weakened. Liberal
hydration is advised if the patient's cardiovascular status will
permit this intervention. High-dose corticosteroid coverage is
indicated, and continuous temperature monitoring is essen-
tial. The eyes must be meticulously protected.
No single anesthetic drug or technique has proved superior
in the management of hyperthyroid patients. However, anti-
cholinergic drugs are not recommended, and ketamine should
be avoided, even in the patient who has been successfully ren-
dered euthyroid.27 Sudden thyroid storm secondary to stress or
infection is always a possibility, and the clinician must be alert
for even mild increases in the patient's temperature or heart rate.
Other early signs of thyroid storm include delirium, confusion,
mania, or excitement. The differential diagnosis of these symp-
toms includes malignant hyperthermia, pheochromocytoma cri-
sis, and neuroleptic malignant syndrome. Treatment of thyroid
storm is supportive, including infusion of cooled saline solu-
tions, β-blocker therapy, antithyroid drugs, and corticosteroids.
Homocystinuria
Although rare, homocystinuria is generally considered the sec-
ond most common inborn error of amino acid metabolism (inci-
dence ~1:200,000),28 after phenylketonuria (~1:25,000).29 An
error of sulfur amino acid metabolism, homocystinuria is char-
acterized by the excretion of a large amount of urinary homo-
cystine, which can be detected by the cyanide-­nitroprusside
test. A host of assorted genetic aberrations may be linked with
homocystinuria, but the most common is a deficiency of cys-
tathionine β-synthase, with accumulation of methionine and
homocystine. The disorder is autosomal recessive. Disease
occurs in the homozygote, but the heterozygote is without risk
of developing the potentially life-threatening complications of
the condition. Although one third of homocystinuric patients
have normal intelligence, most are mentally retarded.
Ectopia lentis occurs in at least 90% of persons with homo-
cystinuria (see Fig.  1-1). Frequently there is subluxation of
the lens into the anterior chamber, causing pupillary block
­glaucoma, necessitating surgical correction. Other o ­ cular
BOX 1-10   n HOMOCYSTINURIA PATIENTS:
PERIOPERATIVE CONCERNS
Restrictive lung disease
Positioning-induced fractures associated with osteoporosis
Thrombotic complications
Hypoglycemic convulsions
findings reported in homocystinuria include pale irides,
­retinoschisis, retinal detachment, optic atrophy, central retinal
artery occlusion, and strabismus.
Because of abnormal connective tissue, the skeletal find-
ings are similar to those of Marfan's syndrome. Most homo-
cystinuric patients have arachnodactyly, kyphoscoliosis, and
sternal deformity. They also may have severe osteoporosis.
Kyphoscoliosis and pectus excavatum may be associated with
restrictive lung disease.
It is imperative to appreciate that patients with homocys-
tinuria are extremely vulnerable to thrombotic complications
associated with high mortality30 (Box  1-10). An untreated
homocystinuric patient may have a perioperative mortality rate
as high as 50%. Elevated concentrations of homocystine irri-
tate the vascular intima, promoting thrombolic nidus forma-
tion and presumably increasing the adhesiveness of platelets.31
Other possible causes of the thrombotic tendency include
increased platelet aggregation, Hageman factor activation, and
enhanced platelet consumption as a result of endothelial dam-
age. Patients with homocystinuria are also at risk for hypogly-
cemic convulsions secondary to hyperinsulinemia, which is
thought to be provoked by hypermethioninemia.32
Preoperative measures include a low-methionine, high-
cystine diet and vitamins B6 and B12 and folic acid to regulate
homocystine levels, as well as acetylsalicylic acid (aspirin) and
dipyridamole to prevent aberrant platelet function. Besides
appropriate dietary and drug therapy, proper perioperative
care involves prevention of hypoglycemia and maintenance of
adequate circulation. Patients with osteoporosis must be care-
fully positioned on the operating table. Glucose levels should
be monitored perioperatively. Low-flow, hypotensive states
must be assiduously avoided. The patients must be kept well
hydrated and well perfused.33 Anesthetic agents selected should
promote high peripheral flow by reducing vascular resistance,
maintain cardiac output, and foster rapid recovery and early
ambulation. Postoperative vascular support stockings that pre-
vent stasis thrombi in leg veins are indicated.
Hemoglobinopathies: Sickle Cell Disease
Hemoglobinopathies are inherited disorders of hemoglobin
synthesis. There may be structural derangements of globin
polypeptides or, as in thalassemia, abnormal synthesis of glo-
bin chains. In hemoglobin (Hb) S, for example, a single amino
acid (valine) is substituted for glutamic acid in the β chain. This
substitution has no effect on oxygen (O2) affinity or molecular
stability. Nonetheless, in the setting of low O2 tension, it causes
 Chapter 1  Eye, Ear, Nose, and Throat Diseases 9
an intermolecular reaction, producing insoluble structures
within the erythrocytes that result in sickling.34 These atypical
red blood cells lodge in the microcirculation, causing painful
vaso-occlusive crises, infarcts, and increased susceptibility to
infection. Low O2 tension and acidic environments are major
triggers and determinants of the degree of sickling. Sickled cells
are thought to produce a rightward shift (P50 = 31 mm Hg) of
the oxyhemoglobin dissociation curve to enhance O2 delivery.
Although ophthalmic pathology such as proliferative reti-
nopathy can occur in all sickling diseases, it is more common
in adults with Hb SC or Hb S thalassemia than in those with
Hb SS. Proliferative retinopathy usually appears in the third or
fourth decades of life and is the result of vascular occlusion.
This occlusion of retinal vessels eventually produces ischemia,
neovascularization, vitreous hemorrhage, fibrosis, traction,
and retinal detachment or atrophy. Prophylactic laser photoco-
agulation has helped reduce the incidence of these conditions.
The severity of the anemia depends on the amount of Hb S
present. In homozygous SS disease, the Hb S content is 85% to
90%, the remainder being Hb F. Sickle cell thalassemia (Hb SF) is
characterized by an Hb S content of 67% to 82% and causes some-
what less severe problems. Indeed, patients with Hb SC and Hb S
thalassemia typically have a much more benign course than those
individuals with Hb SS and usually have only mild anemia and
splenomegaly. Heterozygous persons with Hb SA (sickle trait)
rarely have serious clinical problems. However, some increased
risk of stroke and pulmonary emboli or infection has been sug-
gested, but not well quantitated, after the stress of hypothermic,
low-flow cardiopulmonary bypass in patients with sickle trait.35
Sickle cell disease (Hb SS) is an autosomal recessive con-
dition that occurs most frequently in individuals of African
ancestry, although the gene for Hb S also occurs in persons
with ancestors from areas endemic for falciparum malaria.
From 8% to 10% of American blacks are heterozygous carriers
of Hb S; approximately 0.5% of blacks are homozygous for Hb
S disease. Patients with homozygous sickle cell disease have
chronic hemolytic anemia (Box 1-11). Organ damage results
from vaso-occlusive ischemia because sickled cells are unable
to traverse narrow capillary beds. Also, sickled cells tend to
adhere to the endothelium and cause release of vasoactive
substances. Chronic pulmonary disease gradually progresses
as a result of recurrent pulmonary infection and infarction.
Eventually, these individuals develop pulmonary hyperten-
sion, cardiomegaly, and heart failure, as well as renal failure.
BOX 1-11   n SICKLE CELL DISEASE PATIENTS:
PERIOPERATIVE CONCERNS
Anemia
Chronic pulmonary disease
Pulmonary hypertension
Cardiomegaly and heart failure
Renal failure
Extreme vulnerability to dehydration, hypothermia, hypoxia, and
acidosis
Hemolytic transfusion reaction resulting from alloimmunization
Multiple problems place these patients at high periop-
erative risk, including anemia, underlying cardiopulmonary
disease, and extreme vulnerability to dehydration, hypother-
mia, hypoxia, and acidosis. Preoperative management should
include correction of anemia. In the past, controversy sur-
rounded whether patients with sickle cell disease should
receive a preoperative exchange transfusion with Hb A. Data
now suggest, however, that preoperative transfusion to an Hb
level of 10 g/dL, independent of the Hb S percentage, is equally
effective in preventing perioperative complications as transfu-
sion designed to establish a level of 10 g/dL and an Hb S level
below 30%.36 Controversy also surrounds the issue of the rela-
tive risks of transfusion for simple, brief surgical procedures
in patients who are minimally symptomatic and considered
at low risk for intraoperative vaso-occlusive crises. Clearly, all
blood transfusion in these patients carries a high risk of hemo-
lytic transfusion reaction because of alloimmunization from
previous exposure.
ANESTHETIC CONCERNS
In providing intraoperative management, clinicians should
appreciate that no difference in morbidity or mortality has
been shown among assorted anesthetic agents or between
regional and general anesthetic techniques.37 Factors that
precipitate sickle crises, such as dehydration, hypoxia, aci-
dosis, infection, hypothermia, and circulatory stasis, should
be meticulously prevented. Intraoperative normothermia
should be maintained with fluid warmers, breathing-circuit
humidification, warming blankets, forced-air warmers, and
a well-heated operating room (OR). Adequate perioperative
volume replacement is critical; aggressive hydration with crys-
talloid or colloid is indicated, except in the patient with con-
gestive heart failure (CHF). Supplemental oxygen and mild
hyperventilation are desirable to prevent hypoxemia and aci-
dosis. Although possibly valid with Hb S, pulse oximetry is
extremely unreliable in the presence of deoxygenated, polym-
erized Hb S because aggregation of sickled cells interferes with
the light-emitting diode. After surgery, O2 therapy, liberal
hydration, and maintenance of normothermia should be con-
tinued for a minimum of 24 hours, because crises may occur
suddenly postoperatively. Additionally, adequate analgesia,
early ambulation, and pulmonary toilet, including incentive
spirometry, are important in preventing serious complica-
tions. Postoperative pneumonia in the patient with hemoglo-
binopathy can be fatal.
Acquired Immunodeficiency Syndrome (AIDS)
First described in the United States in 1981, the human immu-
nodeficiency virus/acquired immunodeficiency syndrome
(HIV/AIDS) epidemic is one of the most devastating to have
afflicted humankind. Although ongoing research continues to
improve the quality of life for the millions of people affected,
there is still no cure. Thus, anesthesiologists must be ­prepared to
manage the AIDS patient's numerous and complex challenges.
 10 ANESTHESIA AND UNCOMMON DISEASES
Patients with AIDS frequently develop cytomegalovirus ret-
initis,38 a condition treated by the insertion of a slow-release
antiviral drug packet into the vitreous. Occasionally, the reti-
nitis will produce a retinal detachment that requires surgical
correction.
Many patients with AIDS are extremely ill with cachexia,
anemia, and residual respiratory insufficiency from previous
episodes of Pneumocystis jiroveci (formerly P. carinii) pneu-
monia, tuberculosis, or aspergillosis (Box 1-12). In addition to
reduced pulmonary reserve, these patients often have limited
myocardial reserve because of the debilitating effects of their
underlying disease. AIDS is strongly associated with the devel-
opment of cardiomyopathy, hypertension, right ventricular
dysfunction, myocarditis, pericardial effusion, and coronary
artery disease.39 The preoperative assessment must reflect that
AIDS is a complex, multiorgan disease requiring risk strati-
fication. Disease severity may be staged by considering the
peripheral blood CD4 counts and the clinical manifestations.
CD4 cell counts range from relatively normal (>500/mm3) to
severe depletion (<200/mm3). The clinical manifestations are
typically placed in strata based on the level of immunologic
dysfunction, ranging from “minimal” to “AIDS-defining” con-
ditions. The presence of neurologic, pulmonary, cardiovascu-
lar, and hematologic abnormalities is of particular concern.
Although antiretroviral therapy has greatly prolonged
the lives of AIDS patients, these drugs can have disturbing
side effects and notable drug interactions. The antiretrovi-
ral drugs fall into four categories: nucleoside analog reverse-­
transcription inhibitors, nonnucleoside reverse-transcription
inhibitors, protease inhibitors, and fusion inhibitors. Although
extremely effective in managing AIDS, the protease inhibitors
inhibit cytochrome P450 enzymes, with the greatest effect on
drugs metabolized by the CYPA4 enzyme. A strong interac-
tion between ritonavir and fentanyl metabolism suggests
that the dose of fentanyl should be reduced in patients taking
ritonavir.40
Severely debilitated patients may require invasive moni-
toring, depending greatly on the type of surgical procedure
being performed, and strict attention must be paid to ­aseptic
BOX 1-12   n AIDS PATIENTS: PERIOPERATIVE
CONCERNS
Anemia
Respiratory insufficiency
Hypertension
Cardiomyopathy, myocarditis, right ventricular dysfunction, and
coronary artery disease
Pericardial effusion
Vulnerability to infection and pressure sores
Altered drug requirements secondary to hypoglobulinemia and
cytochrome P450 inhibition
Transmission of HIV or other drug-resistant pathogens
AIDS, Acquired immunodeficiency syndrome; HIV, human
immunodeficiency virus.
technique. Hypoglobulinemia is extremely common in AIDS
patients and will reduce drug requirements. Therefore, anes-
thetic medications must be carefully selected and titrated.
Moreover, supplemental oxygen should be provided to pre-
vent perioperative episodes of desaturation. Additionally,
these cachectic patients require special precautions to prevent
pressure sores. Pre-emptive pain management may offer pro-
tection against additional immune suppression.41
It cannot be overemphasized that, because of the risk of
infection, strict hygienic practices are critical with AIDS
patients. Moreover, medical personnel must protect them-
selves against the hazard of transmission of HIV and other
drug-resistant pathogens by scrupulous adherence to the
Universal Precautions.
Retinopathy of Prematurity
Although Terry42 first described the pathologic condition
in 1942, the neologism “retrolental fibroplasia” was coined
in 1944 by Harry Messenger (Boston ophthalmologist and
Greek/Latin scholar).43 However, the term retinopathy of pre-
maturity now has gained widespread acceptance because it
describes the late, cicatricial phase of the disease as well as the
earlier acute changes.
Retinopathy of prematurity (ROP) is usually associated
with extremely low-birth-weight (LBW) (1000-1500 g) pre-
term infants and “micropremies” (<750 g) who require O2
therapy. Hyperoxia is thought to trigger blood vessel con-
striction in the developing retina, causing areas of periph-
eral ischemia, poor vascularization, and neovascularization
(proliferation of network of abnormal retinal vessels), which
produces fibrosis, scarring, and retinal detachment. Because
advances in neonatology have led to greater than 85% survival
rates for extremely LBW infants and to approximately 75%
survival rates for extremely preterm babies (born at 24-27
weeks’ gestation), it is not surprising that the prevalence of
ROP increased in recent decades. Moreover, the assumption
that ROP is caused exclusively by excess oxygen in this pop-
ulation is incorrect, because ROP has a multifactorial ori-
gin.44–46 The factors associated with the development of ROP
are highly interrelated, but Flynn established that low birth
weight was the most significant predictor of risk.47 Common
problems of prematurity include respiratory distress syn-
drome (traditionally managed with antenatal corticosteroids,
postnatal surfactant therapy, and effective ventilation), apnea,
bronchopulmonary dysplasia (BPD), persistent pulmonary
hypertension, patent ductus arteriosus, necrotizing entero-
colitis, gastroesophageal reflux, anemia, jaundice, hypogly-
cemia and hypocalcemia, intraventricular hemorrhage, and
ROP (Box 1-13).
Recent trials have shown, however, that the less invasive
strategy of nasal continuous positive airway pressure (CPAP)
in extremely preterm babies, compared with immediate intu-
bation followed by surfactant therapy, has important benefits
and no serious side effects.48,49 Mortality and BPD rates were
similar in both approaches. Predicting which babies would
 Chapter 1  Eye, Ear, Nose, and Throat Diseases 11
BOX 1-13   n COMMON PROBLEMS WITH
PREMATURITY
Anemia
Apnea
Bronchopulmonary dysplasia
Gastroesophageal reflux
Hypoglycemia/hypocalcemia
Intraventricular hemorrhage
Jaundice
Necrotizing enterocolitis
Patent ductus arteriosus
Persistent pulmonary hypertension
Respiratory distress syndrome
Retinopathy of prematurity
have an inadequate response to treatment with CPAP and who
should therefore receive early intubation/ventilation and sur-
factant should be a future goal.50 Targeting oxygen saturation
levels is extremely challenging, and a recommended O2 satura-
tion that is effective yet safe remains elusive. Analysis of retro-
spective data from the 1960s found that the standard practice
of limiting the fraction of inspired oxygen (Fio2) to less than
0.5 resulted in 16 excess deaths for every one case of blind-
ness prevented.51 The arbitrary limiting of Fio2 disappeared
as a practice when the arrival of continuous pulse oximetry
allowed neonatologists to deliver only the O2 amount neces-
sary to maintain a safe level of oxygenation. This advance,
however, has forced the question of what defines a “safe” oxy-
genation level.
The Surfactant, Positive Pressure, and Oxygenation
Randomized Trial (SUPPORT) showed that a lower target
level of oxygenation (85%-89%), compared with a higher
range (91%-95%), was associated with a substantial decrease
in severe ROP in survivors, but at the cost of increased mor-
tality.49 However, analysis of the raw pulse oximetry data
showed considerable overlap, and the target ranges achieved
in terms of O2 saturation were not those sought in the study
design. Moreover, no data on neurodevelopmental problems
are yet available, which will be important in the long term.
Considering these limitations, no major change in clinical
practice seems warranted based on the SUPPORT results. The
lowest Fio2 that maintains O2 saturation above 90% may be the
best available compromise based on current data.
ANESTHETIC CONCERNS
Postoperative apnea is the most common problem associated
with anesthesia in premature infants.52 Almost 20% of prema-
ture infants can be expected to develop this life-­threatening
complication, with the greatest risk for infants at 50 weeks’
postconceptual age (gestational age plus chronologic age) and
earlier.53 Apnea may result from prolonged effects of anesthetic
agents, a shift of the carbon dioxide (CO2) response curve, or
fatigue of respiratory muscles. Recommendations for continu-
ous cardiopulmonary monitoring in patients less than 46 weeks’
postconceptual age54 were extended to include monitoring
for infants less than 60 weeks’ postconceptual age for at least
12 apnea-free hours after surgery.55 Although the incidence of
postoperative apnea is inversely related to postconceptual age,
even full-term infants occasionally have postoperative apnea.53
In addition to prematurity as a risk factor, infants with a his-
tory of anemia,56 neonatal apnea spells, respiratory distress
syndrome, and pulmonary disease have approximately twice
the risk of developing postoperative apnea.
Chronic lung disease, also known as BPD, remains the pri-
mary long-term pulmonary complication among premature
infants, associated with pulmonary hypertension, abnormal-
ities of postnatal alveolarization, and neovascularization.57
Infants with BPD have impaired growth58 and may have poor
long-term cardiopulmonary function, an increased vulnera-
bility to infection,59 and a greatly increased risk of abnormal
neurologic development.60 A University of Chicago investiga-
tion, however, reported that administration of nitric oxide to
premature infants with respiratory distress syndrome reduced
the incidence of chronic lung disease and death.61
Although lacking a widely accepted definition, many neo-
natologists define BPD as a condition requiring supplemental
O2 after 36 weeks’ postmenstrual age.62 Conditions associ-
ated with BPD include prematurity, persistent ductus arterio-
sus, and prolonged ventilation with high inspiratory pressure
and O2 concentration. Affected patients have abnormali-
ties in lung compliance and airway resistance that may per-
sist for several years. They also have chronic hypercarbia and
hypoxemia. Abnormal findings on chest radiograph include
hyperexpanded lungs, small radiolucent cysts, increased inter-
stitial markings, and peribronchial cuffing. Treatment of BPD
patients typically is bronchodilators to reduce airway resis-
tance and diuretics to decrease pulmonary edema. Air trap-
ping during assisted ventilation may be minimized using a
prolonged expiratory time.
When undergoing anesthesia and surgery, premature
infants must be kept warm because they defend their core
temperature at considerable metabolic cost (Box  1-14). The
brown fat cells begin to differentiate at 26 to 30 weeks’ ges-
tation and thus are absent as a substrate buffer in extremely
premature infants.63 Also, infants have a greater surface area
per volume compared with adults and therefore tend to lose
body heat rapidly in a cold environment. Metabolic acidosis
is produced by cold stress. The acidosis causes myocardial
depression and hypoxia, exacerbating the metabolic acidosis.
Warming the OR (86° F, or 30° C) and using warming units
BOX 1-14   n PREMATURE INFANTS: ANESTHETIC
MANAGEMENT
Normothermia critical
Reduced anesthetic requirement
Intraoperatively, maintain preductal oxygen saturation at 93% to 95%.
Prolonged expiratory time often helpful
Extubate only when infant is vigorous and fully awake.
Postoperative cardiopulmonary monitoring for 12 hours or longer
 12 ANESTHESIA AND UNCOMMON DISEASES
may help ­maintain the infant's body temperature. Warming
intravenous (IV) and irrigation fluids may also be beneficial.
Standard monitoring equipment includes electrocardiograph,
stethoscope, BP monitor, temperature probe, pulse oximeter,
and capnograph. A pulse oximeter probe placed in a preduc-
tal position on the right hand to reflect the degree of oxygen-
ation in blood flowing to the retina can be compared with
one located in a postductal position on the left foot to deter-
mine the severity of ductal shunting. Although pulse oxim-
etry findings can be used to diagnose hypoxemia, hyperoxia
in this vulnerable population cannot be detected by pulse
oximetry. Maintaining O2 saturation intraoperatively at 93%
to 95% (preductal) places most premature infants on the steep
portion of the oxyhemoglobin dissociation curve and avoids
severe hyperoxia.64 Reported levels of expired CO2 may not
accurately reflect arterial pressure (Paco2) if the infant has
congenital heart disease or major intrapulmonary shunting. In
infants, changes in BP, heart rate, and intensity of heart sounds
are helpful indicators of cardiac function, intravascular volume
status, and depth of anesthesia. Hepatic and renal function
in premature infants is immature and suboptimal, and their
anesthetic requirement is considerably less than that of more
mature and robust infants.
The combination of ventilatory depression from residual
anesthetic drugs with immature development of respiratory
control centers can cause postoperative hypoventilation and
hypoxia as well as apnea. Therefore, these infants with ROP
must be wide awake and vigorously responsive before they
are extubated. When indicated by clinical circumstances, they
should be carefully monitored postoperatively for at least 12
hours for signs of apnea, hypoxia, or bradycardia. The margin
of safety for premature infants is narrow. They have minimal
pulmonary reserve and rapidly become hypoxic.
Incontinentia Pigmenti
Bloch-Sulzberger syndrome, also known as incontinen-
tia ­pigmenti, is a rare hereditary disease with dermatologic,
­neurologic, ocular, dental, and skeletal manifestations (Box 1-15).
Inherited as either an autosomal dominant gene or a sex-linked
dominant gene, the condition is observed predominantly in
female patients because it is usually lethal in males. Skin involve-
ment is typically noted at birth. The dermatopathology begins
with inflammatory linear vesicles or bullae that progress to ver-
rucous papillomata and eventually to splashes of pigmentation
(Fig.  1-2). By adulthood, however, these lesions are replaced
by atrophic, hypopigmented lesions. Patients are retarded, and
BOX 1-15   n INCONTINENTIA PIGMENTI PATIENTS:
ANESTHETIC MANAGEMENT
Control seizures.
Careful airway manipulation because of pegged teeth
Avoid succinylcholine in patients with spastic paralysis.
Autonomic hyperreflexia possible with high spinal cord involvement
FIGURE 1-2  Incontinentia pigmenti. This genetic disorder
affects the skin, hair, teeth, nails, and central nervous system,
often with cataracts and retinal vascular abnormalities.
Excessive deposits of melanin discolor the skin of the trunk and
extremities.  (Courtesy goldbamboo.com.)
spastic paralysis,65 seizures,66 microcephaly, hydrocephalus,
and cortical atrophy have been reported.
Individuals with incontinentia pigmenti are often blind. In
addition to cataracts and strabismus, they may have retinitis
proliferans and other types of retinopathy,67–69 chorioretinitis,
uveitis, optic nerve atrophy, foveal hypoplasia,70 and retinal
tears or detachments. Partial anodontia and pegged or coni-
cal teeth are characteristic of the condition. Assorted skeletal
anomalies are sometimes present.
The major anesthetic concerns involve the teeth and the
central nervous system abnormalities. Because of the dental
pathology, airway manipulation must be performed with care.
Succinylcholine should be avoided in patients with spastic
paralysis, and patients with a high level of spinal cord involve-
ment theoretically could develop autonomic hyperreflexia. No
particular anesthetic technique has been recommended for
patients with incontinentia pigmenti.
Retinitis Pigmentosa
Retinitis pigmentosa consists of a group of diseases, frequently
hereditary, marked by progressive loss of retinal response (as
elicited by ERG). The diseases are characterized by retinal
atrophy, attenuation of the retinal vessels, clumping of pig-
ment, and contraction of the field of vision. Retinitis pigmen-
tosa may be transmitted as a dominant, recessive, or X-linked
trait and is sometimes associated with other genetic defects.
Electroretinography (ERG) is a stimulated reflex response
study to evaluate a patient for retinitis pigmentosa. The test
measures the electrical response of the retina to light stimula-
tion; ERG should not be equated with visual evoked potential
testing, which assesses polysynaptic cortical activity. In young
children, the ophthalmologist may request general anesthe-
sia to perform ERG. Although retinitis pigmentosa, absent
 Chapter 1  Eye, Ear, Nose, and Throat Diseases 13
other genetic abnormalities, presents no anesthetic challenges
related to the patient's medical condition, the conditions of the
test and selection of anesthetic agent are noteworthy.
Dark adaptation is required before recording the electroret-
inogram to obtain accurate responses from the rod photore-
ceptors, so ERG is performed in total darkness. After induction
of anesthesia, contact lens–like electrodes are placed on both
corneas, with reference electrodes on the forehead and both
earlobes. A dome-shaped photostimulator is lowered over
the patient's face, serving as a flashing light source. The anes-
thesiologist frequently must work in cramped quarters, with-
out the usual OR accoutrements, including adequate lighting
and readily accessible emergency equipment. Additionally,
the young patient's face is partially obscured by rather bulky
ophthalmologic equipment, and access to the child's airway
is less than ideal. Anesthesia equipment must include a suc-
tion apparatus and an immediately available light source.
Monitoring should incorporate an electrocardiograph, a pulse
oximeter, and an end-tidal CO2 monitor. The airway should be
secured with an endotracheal tube (ETT) or a laryngeal mask
airway (LMA).
An electroretinogram produces three distinct waveforms
that measure electrical responses of different types of retinal
cells. Electrical responses from the rod and cone photorecep-
tors produce an a wave. The b wave is the result of activity of
the second-order rod and cone bipolar cells. The activity of
amacrine cells is measured by oscillatory potentials. Both the
amplitude and the time to peak (implicit time) can be mea-
sured for these waves.
ANESTHETIC CONCERNS
The choice of anesthetic agents is somewhat traditional
rather than truly evidence based. Although ERG is a simple
rod-cone reflex response study, anesthetic agents may affect
the amplitude and latency of the ERG responses, distorting
the interpretation. Although known to cause nystagmus and
enhanced electroencephalographic activity, ketamine pur-
portedly does not modify ERG responses significantly in rab-
bits.71 Information is sparse about the effects of anesthetic
agents on ERG testing in humans. In pigs, however, propofol
appears to preserve the photoreceptor response better than
thiopental.72 The effect of propofol on the electroretinogram
was studied in 20 children having strabismus surgery, and
under certain conditions, a decrease in the b-wave amplitude
was noted.73 Furthermore, in dogs, halothane and sevoflu-
rane strongly depress the scotopic threshold response while
moderately depressing the b wave and increasing oscillatory
potential amplitudes.74 In rats, photoreceptor and postrecep-
toral responses recorded under the barbiturate pentobarbital
(Nembutal) and the dissociative agent zolazepam (Telazol)
differ significantly.75 Therefore, almost by default, ketamine
became the agent of choice for ERG testing in children.
Recently, however, isoflurane and sevoflurane have been used
successfully in children having ERG,76 as has propofol.77
By way of contrast, a brief discussion of visual evoked
potentials (VEPs) is indicated. The visual pathway includes
the retina, optic nerve, optic chiasm, optic tracts, lateral genic-
ulate nucleus in the thalamus, optic radiation, and occipital
visual cortex. Retinal stimulation produces an evoked elec-
trical response in the occipital cortex, which may be altered
with impairment of the visual apparatus and associated neural
pathways. VEPs are recorded from scalp electrodes positioned
over the occipital, parietal, and central areas. They are cortical
near-field potentials with long latencies.78 More information
is available about the effects of anesthetic agents on VEPs in
humans than when ERG testing is involved. For example, gen-
erally all volatile anesthetics dramatically prolong VEP latency
and decrease amplitude in a dose-dependent manner.79,80 With
IV agents, induction doses of thiopental decrease the ampli-
tude and prolong the latency of VEP waves,81 whereas etomi-
date produces a small increase in latency with no alteration
in amplitude.82 Ketamine has negligible effect on latency but
produces a 60% reduction in amplitude.83 To date, the avail-
able data indicate that opioid and ketamine or propofol-based
anesthetic techniques, as well as regimens using low-dose vola-
tile anesthetics without nitrous oxide, allow satisfactory intra-
operative recordings of VEPs, with the caveat that there may
be a high incidence of false-positive or false-negative results.84
In summary, because these potentials represent polysynap-
tic cortical activity, VEPs are exquisitely sensitive to the effects
of anesthetic agents and physiologic factors. Furthermore,
VEPs are extremely dependent on appropriate stimulation of
the retina and may be adversely affected by narcotic-induced
pupillary constriction.85 In contrast, subcortical potentials,
such as ERG responses, are probably less sensitive to anes-
thetic effects.
Eye Trauma
Eye trauma may be penetrating or blunt. Special anesthetic
considerations apply in the patient with a penetrating eye
injury. As in all cases of trauma, it is axiomatic that other
injuries, such as intracranial trauma and possible thoracic or
abdominal injury, must be excluded before surgically address-
ing the penetrating eye injury.
Open-eye injuries requiring surgical repair vary in severity
from a small corneal leak to a totally disrupted globe with dam-
age to the sclera, cornea, iris, and lens, accompanied by loss of
vitreous, choroidal vessel hemorrhage, and retinal detachment.
Frequently it is difficult to determine the extent of the injury
until the patient has been anesthetized. However, retrobulbar
or peribulbar blocks traditionally had not been recommended
in patients with open globes or extensive ocular trauma; dis-
rupting the eye further is a risk because of concerns about
potential extrusion of intraocular contents from the pressure
generated by local anesthetic administration, as well as other
factors. Recently, however, there have been case reports of suc-
cessful use of ophthalmic blocks in select patients. Scott et al.86
at Bascom Palmer Eye Institute safely blocked patients with
open-globe injuries.86 Eyes selected for regional techniques
typically involved less severe injuries resulting from either
intraocular foreign bodies or dehiscence of cataract or corneal
 14 ANESTHESIA AND UNCOMMON DISEASES
transplant incisions. The eyes tended to have more anterior,
smaller wounds than those repaired under general anesthesia
and were less likely to have a pupillary defect. Indeed, in some
patients the wounds may have been self-sealing.
ANESTHETIC MANAGEMENT
Once the decision has been made to administer general anes-
thesia, it is important to appreciate that any additional damage
to the eye that transpires after the initial trauma is not nec-
essarily the result of anesthetic drugs and manipulations. In
many cases, for example, the patient may have been crying,
coughing, vomiting, rubbing the eye, or squeezing the eye-
lids closed before anesthesia was induced.87 These maneuvers
are known to increase IOP dramatically. Even a normal blink
increases IOP by 10 to 15 mm Hg; forced eyelid closure causes
an increase in IOP of more than 70 mm Hg, an effect that may
be ameliorated by performing a lid block to prevent lid spasm
using the O'Brien technique. Increased IOP also results from
other forms of external pressure, such as face mask application
and from obstructed breathing or Valsalva maneuvers. Also,
IOP is increased by succinylcholine and endotracheal intuba-
tion, especially if laryngoscopy is difficult or prolonged.
Ideal anesthesia for an eye trauma patient with a full stom-
ach requires preoxygenation via a gently applied face mask,
followed by a rapid-sequence induction with cricoid pressure
and a smooth, gentle laryngoscopy and intubation, to ensure a
stable IOP (Box 1-16). Experts disagree, however, on the best
way to accomplish these goals, particularly selection of a mus-
cle relaxant to secure the airway most safely without causing
extrusion of intraocular contents or pulmonary aspiration of
gastric contents.
Nondepolarizing neuromuscular blocking agents relax
the extraocular muscles and reduce IOP. In general, however,
at least 3 minutes must pass before the usual doses of non-
depolarizing drugs given in the traditional manner provide
adequate paralysis for endotracheal intubation. During this
interval, the unconscious patient's airway is unprotected by a
cuffed ETT, and aspiration could occur. Further, if paralysis
is incomplete, the patient may cough or “buck” on the ETT,
causing an increase in IOP of 40 mm Hg. In contrast, the depo-
larizing drug succinylcholine provides an opportunity for
swift intubation, airway protection, and consistently excellent
intubating conditions within 60 seconds. Succinylcholine is
BOX 1-16   n OPEN EYE/FULL STOMACH SETTING:
ANESTHETIC MANAGEMENT
Avoid coughing, vomiting, and direct eye pressure.
Ensure adequate anesthetic depth before attempting laryngoscopy.
Administer appropriate adjuvants and neuromuscular blocker before
laryngoscopy.
Perform gentle and brief laryngoscopy.
Maintain and monitor intraoperative paralysis.
Maintain stable venous and arterial pressures.
Prevent periextubation bucking and coughing.
Extubate only when patient is fully awake.
rapidly cleared, permitting the patient to return to spontane-
ous respiration, which is important if the patient has a difficult
airway. Succinylcholine, however, increases IOP by approxi-
mately 8 mm Hg. This relatively small increase occurs 1 to 4
minutes after IV administration, and within 7 minutes IOP
values return to baseline. Factors contributing to the ocu-
lar hypertensive effect of succinylcholine are incompletely
understood.
Interventions advocated to prevent succinylcholine-
induced increases in IOP include pretreatment with acetazol-
amide, propranolol, lidocaine,88 narcotics,89 clonidine,90 and
nondepolarizing relaxants. None of these interventions, how-
ever, consistently and completely blocks the ocular hyperten-
sive response.91,92 The use of succinylcholine in patients with
open globes has traditionally been considered controversial,
although this philosophy may be based more on anecdote and
“zero tolerance” for a potential anesthesia-related complica-
tion than on incontrovertible scientific evidence.93
If the anesthesiologist elects to use a nondepolarizing agent
instead of succinylcholine, the administration of high-dose
(400 μg/kg) vecuronium94 or enlisting the “priming” tech-
nique95 may accelerate the onset of available nondepolarizing
muscle relaxants. With priming, approximately one tenth of an
intubating dose of muscle relaxant is followed 4 minutes later
by an intubating dose. After an additional 90 seconds, intu-
bation may be accomplished. However, the use of large doses
of nondepolarizing agents and the priming technique have
serious disadvantages, including the risk of aspiration during
the interval when the airway is unsecured and the unpredict-
able onset of sufficient paralysis to permit intubation with-
out coughing. If high doses of such agents as atracurium or
mivacurium are used, histamine release can cause untoward
side effects, including hemodynamic instability. Large doses
(1.2 mg/kg) of rocuronium do not consistently afford condi-
tions for intubation as excellent as provided by succinylcho-
line. Rapacuronium, the nondepolarizing agent with a rapid
onset, showed promise in this setting, but the occurrence of
intractable bronchospasm reported after its administration
resulted in its removal from U.S. markets.
An acceptable option, unless contraindicated by such con-
ditions as hyperkalemia or a susceptibility to malignant hyper-
thermia, is to administer succinylcholine after pretreatment
with a defasciculating dose of a nondepolarizing relaxant and,
if necessary, an appropriate drug to prevent significant BP
increases associated with laryngoscopy. Cases appear in the
literature attesting to the apparent safety of using succinylcho-
line in the open eye/full stomach setting96,97 (see Box 1-16).
After intubation is safely and smoothly accomplished, the
depth of anesthesia and the extent of muscle relaxation must
be adequate to ensure lack of movement and to prevent cough-
ing while the eye is open. This is best determined and followed
by assessing the effects of peripheral nerve stimulation with
a twitch monitor. Moreover, BP should be carefully main-
tained within an acceptable range, because choroidal hemor-
rhage is more likely in open-eye situations when hypertension
and increased venous pressure are also present. Prophylactic
 Chapter 1  Eye, Ear, Nose, and Throat Diseases 15
administration of antiemetics is recommended to prevent
postoperative vomiting. When surgery has been completed
and spontaneous respiration has returned and the patient is
awake with intact reflexes to prevent aspiration, the ETT is
removed. IV lidocaine (1.5 mg/kg) and a small dose of nar-
cotic may be given before extubation to attenuate periextuba-
tion bucking and coughing.
In summary, the decision to administer or avoid succinyl-
choline involves assessing and balancing risks for the individ-
ual patient. The critical factors in this individual calculation
are the airway assessment, extent of ocular damage, and any
potential medical contraindication to a particular approach.98
A patient with a medical contraindication to succinylcholine,
such as malignant hyperthermia susceptibility, whose airway
assessment is reassuring may be managed using sufficiently
large doses of a nondepolarizing neuromuscular blocker to
enable accelerated onset of paralysis and satisfactory intu-
bating conditions. Maintenance could then be accomplished
with a total IV anesthetic technique. When confronted with a
patient whose airway evaluation suggests potential problems,
the anesthesiologist should consult with the ophthalmologist
about the likelihood of salvaging the injured eye. In patients
with minor injury, general anesthesia may be avoided by pro-
ceeding under topical or regional anesthesia. If this approach
is not feasible because of extensive ocular damage, awake
fiberoptic intubation may be the safest choice, realizing that
substantial increases in IOP may ensue from gagging, retch-
ing, and coughing. These risks, however, pale in significance
when balanced against the consequences of a lost airway.
EAR, NOSE, AND THROAT CONSIDERATIONS
Difficulty in managing the airway is a major cause of
­anesthesia-related morbidity and mortality. When the pro-
posed surgical procedure involves the airway, consummate
skill in airway management is required, especially because of
possible airway compromise preoperatively by edema, infec-
tion, tumor, or trauma. Moreover, the anesthesiologist and
the surgeon often must share the patient's airway, so effective
communication is critical to effect an optimal patient outcome.
Sleep Apnea
Sleep patterns disturbed by snoring are thought to occur
in approximately 25% of the population.99 However, most
patients who snore do not have apnea or associated episodes
of significant hypoxemia. Nonetheless, obstructive sleep apnea
(OSA) is a relatively common disorder among middle-aged
adults, especially (obese) Americans. Obesity is a critical inde-
pendent causative/risk factor. The majority of people who have
OSA are obese, and the severity of the condition seems to cor-
relate with the patient's neck circumference100 and abdominal
girth. Not all obese patients have OSA, however, and not all
patients with OSA are obese. In the nonobese minority of OSA
patients, causative risk factors are craniofacial and ­orofacial
bony abnormalities, nasal obstruction, and h ­ypertrophied
tonsils. Young et  al.100 reported that the prevalence of OSA
associated with hypersomnolence was 2% in women and 4%
in men 30 to 60 years old.
Nonetheless, a much higher proportion of patients may
be at risk for OSA, and the vast majority of these patients are
undiagnosed. Because the anesthetic ramifications are impor-
tant, it is critical to take a careful history, including sleep pat-
terns, and harbor a high index of suspicion for the condition.
Obstructive sleep apnea is defined as cessation of airflow
for more than 10 seconds despite continuing ventilatory effort,
five or more times per hour of sleep, and usually associated
with a decrease in arterial oxygen saturation (Sao2) of more
than 4%. Although this review focuses predominantly on
OSA, the three types of sleep apnea are obstructive, central,
and mixed. Unlike OSA, respiratory efforts temporarily stop
in central sleep apnea. Diagnosis is established definitively
during polysomnography.
It is generally accepted that many patients with OSA have
resultant pathologic daytime sleepiness associated with perfor-
mance decrements. Also, patients with severe apnea develop
major health problems; whether patients with less severe apnea
incur the same detrimental consequences remains contro-
versial because of methodologic problems and failure to con-
trol for confounding factors in many relevant investigations.
Clearly, the study design with the greatest methodologic rigor
for the identification of long-term health consequences of
OSA is the prospective, population-based, cohort study.101
Most clinical research in OSA, however, has used less rigor-
ous research designs, such as case-control, cross-sectional, or
case studies, which are more susceptible to problems of bias
and less able to establish causality between adverse health con-
sequences and OSA. Thus, few absolute conclusions can be
drawn at this time about the long-term consequences of mild
to moderate OSA. However, findings from the Sleep Heart
Health Study,102 the Copenhagen City Heart Study,103 and oth-
ers104 demonstrate a firm association between sleep apnea and
systemic hypertension, even after accounting for other impor-
tant patient characteristics, such as age, gender, race, con-
sumption of alcohol, and use of tobacco products.
Few definitive data exist to guide perioperative manage-
ment of patients with OSA (Box 1-17). Not surprisingly, many
anesthesiologists question whether OSA patients are appro-
priate candidates for ambulatory surgery. The risks of car-
ing for these challenging patients in the ambulatory venue are
further amplified by 80% to 95% of people with OSA being
undiagnosed;105 they have neither a presumptive clinical diag-
nosis nor a sleep study diagnosis of OSA. This is of concern
because these patients may suffer perioperatively from life-
threatening desaturation and postoperative airway obstruc-
tion. Moreover, serious comorbidities may be present because
prolonged apnea results in hypoxemia and hypercarbia, which
can lead to increased systemic and pulmonary artery pressures
and dysrhythmias. Cor pulmonale, polycythemia, and CHF
may develop.
Sleep apnea occurs when the negative airway pressure
that develops during inspiration is greater than the muscular
 16 ANESTHESIA AND UNCOMMON DISEASES
BOX 1-17   n SLEEP APNEA PATIENTS: ANESTHETIC
MANAGEMENT
Have high index of suspicion with obesity.
Identify and quantify comorbid disease(s).
Perform meticulous airway assessment.
Have low threshold for awake intubation.
Administer sedative-hypnotics and narcotics sparingly.
Use short-acting anesthetic drugs.
Administer multimodal analgesics.
Extubate only when patient is fully awake.
Recover in sitting position
Be able to administer continuous positive airway pressure.
Admit to telemetry ward when indicated.
­ istending pressure, thereby causing airway collapse. Isono106
d Moreover, whether these unexpected findings are germane to
emphasizes that patients with OSA have narrower, more col-
lapsible airways than age-matched and body mass index
(BMI)–matched, non-OSA patients. Obstruction can occur
throughout the upper airway, above, below, or at the level of the
uvula.107,108 Because of the inverse relationship between obesity
and pharyngeal area, the smaller size of the upper airway in
the obese patient causes a more negative pressure to develop
for the same inspiratory flow.108,109 Also, a neurologic basis has
been postulated for OSA, in that the neural drive to the airway
dilator muscles is insufficient or is not coordinated appropri-
ately with the drive to the diaphragm.108 Indeed, it has been
hypothesized that OSA is associated with complicated neu-
roanatomic interactions. During wakefulness, OSA patients
have augmented basal genioglossus activity to compensate
for their narrower, more collapsible airway. However, neural
compensation for anatomic abnormalities that are operative
during wakefulness is abolished during sleep.110 Pharyngeal
wall collapsibility is exacerbated by the reduced lung volumes
associated with obesity.106 The caudal tracheal traction that
occurs during inspiration is reduced in obese, supine adults.
This traction is thought to enhance longitudinal tension of the
pharyngeal airway wall, thereby stiffening the airway.111 Thus,
it is important to maintain lung volume in patients with OSA,
which is facilitated by the sitting or semisitting position.
Obstruction can occur during any sleep state but is often
noted during rapid eye movement (REM) sleep. Nasal con-
tinuous positive airway pressure (CPAP) can ameliorate the
situation by keeping the pressure in the upper airway positive,
thus acting as a “splint” to maintain airway patency. The site(s)
of obstruction can be determined preoperatively by magnetic
resonance imaging (MRI), CT, and intraluminal pressure
measurements during sleep.112 Some studies suggest that the
major site of obstruction in most patients is at the orophar-
ynx, but obstruction can also occur at the nasopharynx, hypo-
pharynx, and epiglottis.113 If the surgery is designed to relieve
obstruction at one area but a pathologic process extends to
other sites,114 postoperative obstruction is not only possible
but probable, especially when one allows for the edema associ-
ated with airway instrumentation. Technologic advances have
made CPAP devices more tolerable to patients. Weight loss
may improve OSA as well.
French investigators observed that some patients who
received a pacemaker with atrial overdrive pacing to reduce
the incidence of atrial dysrhythmias reported a reduction in
breathing disorders after pacemaker implantation. These car-
diologists therefore initiated a study to investigate the effi-
cacy of atrial overdrive pacing in the treatment of sleep apnea
symptoms in consecutive patients who required a pacemaker
for conventional indications. They found that atrial pacing at
15 beats per minute faster than the mean nocturnal heart rate
resulted in a significant reduction in the number of episodes of
both central sleep apnea and OSA.115 Postulating that enhanced
vagal tone may be associated with (central) sleep apnea, the
investigators acknowledged, however, that the mechanism of
the amelioration of OSA by atrial overdrive pacing is unclear.
the sleep apnea patient with normal cardiac function is uncer-
tain. Gottlieb116 suggests that a central mechanism affecting
both respiratory rhythm and pharyngeal motor neuron activ-
ity would offer the most plausible explanation for the reported
equivalence in the improvement of central sleep apnea and
OSA during atrial overdrive pacing. Do cardiac vagal afferents
also inhibit respiration? Identification of specific neural path-
ways might also advance efforts to develop a pharmacologic
treatment for sleep apnea.
Surgical approaches to treat sleep-related airway obstruc-
tion include classic procedures such as tonsillectomy that
directly enlarge the upper airway. More specialized procedures
to accomplish the same objective include uvulopalatopharyn-
goplasty (UPPP), uvulopalatal flap (UPF), uvulopalatopharyn-
goglossoplasty (UPPGP), laser midline glossectomy (LMG),
linguoplasty (LP), inferior sagittal mandibular osteotomy
and genioglossal advancement (MOGA), hyoid myotomy
(HM) and suspension, and maxillomandibular osteotomy and
advancement (MMO). Another approach is to bypass the pha-
ryngeal part of the airway with a tracheotomy.
Although physicians and surgeons have been treating OSA
for more than 25 years, few long-term, standardized results
on the efficacy of different therapies are available. One report,
however, suggests that at least 50% of patients with sleep apnea
syndrome can be managed effectively with a single therapy or
combination of therapies. Nasal CPAP, tracheotomy, MMO,
and tonsillectomy typically receive high marks for efficacy;117
UPPP showed positive results maintained for at least 1 year.118
Another study, combining UPPP with genioglossus and
hyoid advancement, reported encouraging results in patients
with mild and moderate OSA and multilevel obstruction.119
However, the long-term results of laser-assisted uvulopala-
toplasty (LAUP) for management of OSA have been a con-
cern.120 The favorable, subjective, short-term results of LAUP
apparently deteriorated over time. Postoperative polysom-
nography revealed that LAUP might lead to deterioration of
existing apnea. These findings are probably related to velopha-
ryngeal narrowing and progressive palatal fibrosis caused by
the laser beam.
The debate about whether OSA patients should undergo
surgery as outpatients is ongoing, with no “one size fits all”
 Chapter 1  Eye, Ear, Nose, and Throat Diseases 17
solution.105 Any management strategy must consider the
patient's BMI and neck circumference, severity of OSA, pres-
ence or absence of associated cardiopulmonary disease, nature
of the surgery, and anticipated postoperative opioid require-
ment. The degree of fat accumulation in the intra-abdominal
region is associated with the metabolic syndrome and secre-
tion of hormones and proinflammatory cytokines that may
influence breathing in obese OSA patients.121 Screening tests
for OSA include the Berlin questionnaire, STOP-Bang instru-
ment, American Society of Anesthesiologists (ASA) checklist,
and Kushida morphometric index; these are highly accurate
for identifying only severe OSA and have high false-negative
rates for detecting mild OSA.122 The “gold standard” for iden-
tifying and quantifying the presence and severity of OSA is
polysomnography, but it is expensive, cumbersome to perform,
and not universally available.
It seems reasonable to expect that OSA patients without
multiple risk factors who are having relatively noninvasive pro-
cedures (e.g., carpal tunnel repair, breast biopsy, knee arthros-
copy) typically associated with minimal postoperative pain may
be candidates for ambulatory status. However, those individu-
als with multiple risk factors, or those OSA patients having
airway surgery, most probably will benefit from a more con-
servative approach that includes postoperative admission and
careful monitoring. Indeed, the 2006 ASA guidelines specifi-
cally state that adult airway surgery, tonsillectomy in children
younger than 3 years, and laparoscopic surgery involving the
upper abdomen are inadvisable outpatient procedures for OSA
patients.123 It is imperative to appreciate that these patients are
exquisitely sensitive to the respiratory depressant effects of
opioids. Moreover, the risk of prolonged apnea is increased
for as long as 1 week postoperatively. A recent national (U.S.)
study of inpatients having noncardiac surgery reported that
sleep apnea is an independent risk factor for perioperative pul-
monary complications, including aspiration pneumonia, adult
respiratory distress syndrome, and the need for postoperative
intubation or mechanical ventilation.124
ANESTHETIC MANAGEMENT
Is perioperative risk related to the type of anesthesia (gen-
eral, regional, or monitored care) administered to sleep apnea
patients? The limited evidence suggests that type of sur-
gery probably supersedes selection of anesthetic technique.
Certainly, the use of regional anesthesia, although strongly
recommended by the ASA, may not necessarily obviate the
need for securing the airway and may even require emer-
gency airway intervention if excessive amounts of sedative-
hypnotics or opioids are administered. Regardless of the type
of anesthesia selected, sedation should be administered judi-
ciously. CPAP or noninvasive positive-pressure ventilation
(NIPPV) should be applied as soon as possible after surgery to
patients who were receiving it preoperatively. The supine posi-
tion should be avoided, if feasible, during recovery. The sitting
position fosters improved lung volumes, which tend to mini-
mize pharyngeal collapsibility. In addition, the ASA guidelines
state that OSA patients should be monitored postoperatively
for 3 hours longer than usual, and for 7 hours after the last epi-
sode of obstruction or room-air hypoxemia.123 Patients should
be awake and alert, have O2 saturation within 2% of baseline,
and have minimal pain and postoperative nausea/vomiting at
discharge.
When confronted with an especially challenging OSA
patient requiring general anesthesia, a judicious approach
may include awake fiberoptic intubation; administering very-
low-dose short-acting narcotics, short-acting muscle relax-
ants, and a low-solubility inhalational agent; and infiltrating
the surgical site with a long-acting local anesthetic. Extubation
should be performed only when the patient is without resid-
ual neuromuscular blockade and is fully awake, using a tube
changer or catheter, and CPAP should be administered post-
operatively. These high-risk patients should then be admitted
to a telemetry ward or intensive care unit, because the chal-
lenge of maintaining the airway will extend well into the post-
operative period, and OSA is an independent risk factor for
perioperative pulmonary complications.124 Respiratory events
after surgery in OSA patients may occur at any time.
Anesthetic care of the OSA patient is especially challeng-
ing, and few definitive data are available to guide perioperative
management, with recommendations based more on expert
opinion than on evidence. The anesthesiologist should begin
by having a high index of suspicion for the diagnosis and
then seek to identify and quantify associated comorbidities.
The major focus of the anesthesiologist must be establishing
and maintaining the airway, a challenge that continues post-
operatively, especially if surgery involves the oropharyngeal
or hypopharyngeal area. Depending on the type of surgery,
the anticipated amount of narcotic required postoperatively
to manage pain, and the patient's condition, outpatient sur-
gery may not be prudent. The resources of the facility must
also be considered when deciding whether to accept an OSA
patient. Certain OSA patients might be appropriate for a
hospital-based ambulatory surgery unit, but not for a free-
standing facility or an office. The importance of effective
communication, monitoring, vigilance, judgment, and con-
tingency planning cannot be overemphasized.
Recurrent Respiratory Papillomatosis
Recurrent respiratory papillomatosis (RRP) is a disease of
viral origin caused by human papillomavirus types 6 and 11
(HPV-6 and HPV-11) and associated with exophytic lesions of
the airway that are friable and bleed easily (Fig. 1-3). Although
a benign disease, RRP may have devastating consequences
because of the airway involvement, unpredictable clinical
course, and risk of malignant conversion in chronic invasive
papillomatosis.
In children, RRP is both the most common benign neo-
plasm of the larynx and the second most frequent cause of
hoarseness.125 The disease is frustrating and often resistant to
treatment because it tends to recur and spread throughout the
respiratory tract. Although RRP most frequently affects the
larynx, the condition can involve the entire aerodigestive tract.
 18 ANESTHESIA AND UNCOMMON DISEASES
FIGURE 1-3  Laryngeal papillomatosis. Severe stridor and airway
obstruction can occur.  (Courtesy goldbamboo.com.)
The course of RRP is highly variable; some patients undergo
spontaneous remission, whereas others experience aggressive
papillomatous growth, necessitating multiple surgeries over
many years. The differential diagnosis of the persistent or pro-
gressive stridor and dysphonia associated with RRP in infants
includes laryngomalacia, subglottic stenosis, vocal cord paral-
ysis, or a vascular ring (Box 1-18).
In most pediatric series, RRP is typically diagnosed
between 2 and 4 years of age, with a delay in correct diagnosis
from time of symptom onset of about 1 year.126 The incidence
among U.S. children is estimated at 4.3 per 100,000, translat-
ing into more than 15,000 surgical interventions at a total cost
exceeding $100 million annually.127
Two distinct forms of RRP are recognized: a juvenile or
aggressive form and an adult or less aggressive form. Adult-
onset RRP may reflect either activation of virus present from
birth or an infection acquired in adolescence or adulthood.
HPV-6 and HPV-11, the same types that cause genital warts,
are the most common types of HPV identified in the airway.
Specific viral subtypes may be correlated with disease sever-
ity and clinical course. Children infected with HPV-11, for
example, appear to develop more severe airway obstruction at
a younger age and have a higher incidence of tracheotomy.128
Numerous studies have linked childhood-onset RRP to moth-
ers with genital HPV infections. Nevertheless, few children
exposed to genital warts at birth develop clinical symptoms.129
BOX 1-18   n DIFFERENTIAL DIAGNOSIS OF INFANTILE
PROGRESSIVE STRIDOR/DYSPHONIA
Laryngomalacia
Recurrent respiratory papillomatosis
Subglottic stenosis
Vocal cord paralysis
Vascular ring
Other factors must be operative, such as duration and ­volume
of virus exposure, behavior of the virus, presence of local
trauma, and patient immunity.
Presenting symptoms of RRP include a change in voice,
ranging from hoarseness to stridor to aphonia. The stridor
can be either inspiratory or biphasic. The history may include
chronic cough and frequent respiratory infections. Children
are frequently misdiagnosed initially as having croup, chronic
bronchitis, or asthma. Lesions usually are found in the larynx
but may also occur on the epiglottis, pharynx, or trachea. The
preoperative diagnosis is best made with an extremely small-
diameter, flexible fiberoptic nasopharyngoscope to establish
more fully the extent of airway encroachment.
No single modality has consistently been shown to eradi-
cate RRP. The primary treatment is surgical removal, with a
goal of complete obliteration of papillomas and preservation
of normal structures. However, in patients with anterior or
posterior commissure disease or extremely virulent lesions,
the objective may be revised to subtotal removal with clear-
ing of the airway. It is advisable to “debulk” as much disease
as possible, while preventing the complications of subglottic
and glottic stenosis, web formation, and diminished airway
patency. Whenever possible, tracheostomy is avoided to pre-
vent seeding of papillomas into the distal trachea.
The CO2 laser has been the favored instrument in the eradi-
cation of RRP involving the larynx, pharynx, upper trachea,
and nasal and oral cavities. However, large, bulky accumula-
tions of papillomas may require sharp dissection. Adjuvant
treatments may include interferon alfa-N1,130 indole-3-carbinol,
­acyclovir, ribavirin,131 retinoic acid, and photodynamic ther-
apy.132 Clearly, the objective of all interventions is to remove as
much disease as feasible without causing potentially scarring
permanent damage to underlying mucosa in critical areas.
Although the CO2 laser is the most common laser for laryn-
geal RRP, the KTP (potassium titanyl phosphate) or argon
laser can also be used. Papillomas that extend down the tra-
cheobronchial tree often require the KTP laser coupled to a
ventilating bronchoscope for removal. Moreover, the endo-
scopic microdebrider may cause less laryngeal scarring than
the CO2 laser.133
ANESTHETIC MANAGEMENT
The anesthetic management of patients with RRP is often
challenging and depends on the site of the lesions, degree
of airway obstruction, and age of the patient134 (Table  1-2).
The issues are further complicated by use of a laser and the
anesthesiologist sharing the airway with the surgeon. Several
approaches should be considered, each with advantages and
disadvantages. A thoughtful risk/benefit analysis is essential.
Teamwork and effective communication are critical to opti-
mal outcome; video monitors allow the entire OR staff to view
the surgery. The anesthesiologist and surgeon must communi-
cate throughout the procedure, focusing on the patient's cur-
rent ventilatory status, amount of bleeding, vocal cord motion,
O2 concentration administered, and timing of laser use with
respiration.
 Chapter 1  Eye, Ear, Nose, and Throat Diseases 19
TABLE 1-2  n Anesthetic Options for Recurrent
Respiratory Papillomatosis
Intubation Techniques Nonintubation Techniques
Surgeon gowned and Same pretreatment and
gloved before induction precautions as with
intubation
Preoperative
dexamethasone
Slow, gentle inhalation Insufflation of volatile agents
induction with continuous with spontaneous ventilation
positive airway pressure
Intubate with smaller- Total intravenous anesthesia
than-usual, laser-safe with spontaneous ventilation
endotracheal tube
Eye protection for patient Jet ventilation with muscle
and staff paralysis
Fio2 <0.3*
Awake extubation
*Fraction of inspired oxygen concentration.
The available anesthetic options may be broadly separated
into intubation and nonintubation techniques. When the
lesions are assumed to be partially obstructing the airway, the
best approach is a careful, gentle, smooth induction with sevo-
flurane, preferably with an IV line in place before induction is
initiated. Preoperative IV dexamethasone, 0.5 mg/kg, is rou-
tinely given. The surgeon should be present in the OR, and all
the requisite equipment to deal with total airway obstruction
should be immediately available. Often a jaw thrust combined
with positive pressure in the anesthesia circuit will maintain
airway patency. Should complete airway obstruction occur,
the anesthesiologist may elect to give an appropriate dose of
propofol, if indicated, and attempt intubation with a smaller-
than-usual ETT. If this attempt fails, the surgeon should use
the rigid bronchoscope; as a last resort, a transtracheal needle
should be placed or tracheotomy performed. The anesthesi-
ologist may then choose among several techniques.
An intubation technique has the advantage of allowing the
anesthesiologist to maintain control of the airway and venti-
lation. However, the ETT increases the risk of airway fire and
may impede surgical exposure and access. The smallest pos-
sible laser-safe ETT tube should be used that permits adequate
ventilation. If a cuffed tube is deemed necessary, the cuff should
be filled with methylene blue–colorized saline to provide an
additional warning if the cuff is perforated.135 After the airway
has been secured with a laser-safe ETT, the anesthesiologist
has the option to administer muscle relaxants. The child's eyes
are protected with moist, saline-soaked gauze eye pads placed
over the lids. Additionally, all OR personnel must wear safety
glasses and special laser masks with extremely small pores to
minimize exposure to the laser plume. The Fio2 delivered to
the patient should be as close to a room air mixture as possible
(0.26-0.3). During resection, the surgeon must exercise great
care to avoid injuring the anterior commissure, and at least
1 mm of untreated mucosa should be left so that a web does not
develop. If the surgeon detects disease in the posterior part of
the glottis or in the subglottic region, the ETT obstructs expo-
sure of these areas to the operative field, and an alternative
means of anesthesia is selected. Often the surgeon will prefer
an apneic technique in which the ETT is removed intermit-
tently and surgery performed while the patient's O2 saturation
is monitored. The ETT is periodically reinserted as needed.
Typically, the lungs are reoxygenated for the same period that
they were apneic before proceeding with the next “cycle.”
Alternatively, a nonintubation technique uses spontaneous
ventilation with volatile anesthetic agents.136,137 The patient
is induced as previously detailed, and maintenance of anes-
thesia is continued with sevoflurane, insufflated into the oro-
pharynx by attaching the fresh gas flow hose to a side port on
the suspension laryngoscope. The larynx is anesthetized with
topical lidocaine (not to exceed 4-5 mg/kg) before proceed-
ing with further surgical intervention. This is not an ideal (or
easy) anesthetic technique because the anesthesiologist must
deftly balance the anesthetic depth somewhere between too
light (triggering laryngospasm) and too deep (causing apnea).
Additionally, the OR environment becomes contaminated, but
a vacuum hose is helpful in extracting exhaled gases and virus
particles. Total IV anesthesia with an infusion of propofol and
remifentanil is also appropriate with this nonintubated, spon-
taneous ventilation technique.134 The surgeon, however, may
complain of too much laryngeal movement with total IV anes-
thesia because patients anesthetized with these agents breathe
slowly but very deeply.
Another anesthetic alternative is the use of jet ventilation,
which eliminates the potential for ETT fire and allows good visu-
alization of the vocal cords and distal areas. However, jet ventila-
tion carries the risk of barotrauma and may allow transmission
of HPV particles into the distal airway. The jet cannula can be
positioned above or below the vocal cords; placement of the can-
nula proximal to the end of the laryngoscope decreases the risk
of possible pneumothorax or pneumomediastinum. With large
laryngeal lesions, narrowed airways, and ball-valve lesions, con-
siderable outflow obstruction may develop, leading to increased
intrathoracic pressure and pneumothorax. The anesthesiologist
must carefully observe chest excursion and ensure unimpeded
exhalation. Muscle relaxants are administered to prevent vocal
cord motion. Constant anesthesiologist-surgeon communica-
tion is required on timing of ventilation in relation to surgical
manipulation. Excessive mucosal drying and gastric distention
are other disadvantages of jet ventilation. At the end of the pro-
cedure, the trachea is intubated with a standard ETT.
The trachea is extubated only when the child is fully awake.
High humidity and, occasionally, racemic epinephrine are
administered postoperatively. The patient is closely monitored
for several hours before discharge, and often an overnight stay
is advisable, especially if the disease was extensive and the air-
way was significantly compromised. Continuous pulse oxim-
etry is mandatory and postoperative steroid administration
may be helpful.
 20 ANESTHESIA AND UNCOMMON DISEASES
SUMMARY
The scientific community is aggressively working to improve
knowledge of RRP. A national registry of patients with RRP
has been formed through the cooperation of the American
Society of Pediatric Otolaryngology and the Centers for
Disease Control and Prevention.138 This registry identifies
patients who are suitable for enrollment in multi-institutional
studies of adjuvant therapies and better defines the risk fac-
tors for transmission of HPV and the cofactors that determine
the virulence of RRP. Future projects will refine surgical tech-
niques to minimize laryngeal scarring.
Cystic Hygroma
Cystic hygroma is a rare, multilocular, benign lymphatic mal-
formation, usually involving the deep fascia of the neck, oral
cavity, and tongue, although the axilla may also be affected
(Fig. 1-4). A cystic hygroma in a developing fetus can progress
to hydrops and eventually fetal death. Some cases of congen-
ital cystic hygroma resolve, leading to webbed neck, edema,
and a lymphangioma. In other cases the hygroma can progress
in size to become larger than the fetus. Cystic hygromas can
occur as an isolated finding or in association with other birth
defects and result from environmental, genetic, and unknown
factors.
When a cystic hygroma is diagnosed prenatally, the risk for
a chromosomal abnormality approaches 50%. Cystic hygro-
mas that develop in the third trimester or in the postnatal
period, however, are usually not associated with abnormali-
ties. These lesions are capable of massive growth and can be
quite disfiguring. Almost all known cases of cystic hygroma
FIGURE 1-4  Cystic hygroma. This histologically benign, lymphatic
malformation can produce severe airway encroachment.  (Courtesy
valuemd.com.)
have presented by 5 years of age, with most being observed
in the neonatal period.139 In fact, there are cases of antenatal
diagnosis of cystic hygroma, with fetal airway encroachment
detected by screening ultrasound. The few infants who sur-
vived to delivery were intubated immediately after the head
was delivered, with the placenta functioning as an extracorpo-
real source of oxygenation until the airway was secured.140,141
As the tumor grows, it often encroaches on surrounding
structures such as the pharynx, tongue, or trachea. Dysphagia
and various degrees of airway obstruction can occur. Cystic
hygromas are not responsive to radiation therapy, and multi-
ple surgical resections are often necessary. Because the tumors
are not encapsulated, hygromas easily envelop and grow into
surrounding structures, preventing complete excision. The
ability of cystic hygromas to elude complete extirpation has
led to recrudescence, with injection of sclerosing agents intra-
lesionally as primary or adjunctive therapy.142 This approach
had been abandoned, but the availability of newer, improved
agents has led to better results.
Although sudden enlargement of the tumor can cause a
true airway emergency, most often the children present for
elective resection. Because of mechanical complications, the
young child may be malnourished or dehydrated and may
also have sleep apnea. Stridor is an ominous sign, suggesting
imminent airway decompensation. A chest radiograph should
be reviewed for tracheal deviation or mediastinal extension.
Although CT or MRI will provide more complete information
about the full extent of the lesion, the sedation necessary to
obtain such studies may cause airway obstruction—an exam-
ple of “perfection being the enemy of good.”
ANESTHETIC MANAGEMENT
The patient with cystic hygroma is given an antisialagogue
before anesthesia is administered to minimize secretions
that might complicate anesthetic management (Box  1-19).
The surgeon is present in the OR, gowned and gloved, and
ready to perform a tracheostomy if necessary. The anesthe-
siologist must carefully prepare a variety of difficult airway
equipment in the event of an airway emergency. Clearly, the
safest approach in these children is awake intubation, because
a marginally adequate airway while the patient is awake may
become totally obstructed during induction when the upper
airway muscles relax and the tumor fills the airway.
BOX 1-19   n CYSTIC HYGROMA PATIENTS:
ANESTHETIC MANAGEMENT
Evaluate preoperatively for stridor, tracheal deviation, or mediastinal
extension.
Determine optimally tolerated position.
Administer preoperative antisialagogue.
Have surgeon gowned and gloved before induction/intubation.
Apply topical vasoconstrictor to nares.
Know that fiberoptic nasotracheal intubation is often necessary.
Perform extubation with caution.
 Chapter 1  Eye, Ear, Nose, and Throat Diseases 21
However, because many, if not most, pediatric patients will
not tolerate an awake intubation, children with cystic hygroma
often undergo a slow, meticulous, titrated inhalation induc-
tion of anesthesia, with preservation of spontaneous venti-
lation and application of CPAP. When anesthetic depth is
adequate, fiberoptic intubation is performed. A large, pro-
truding tongue often makes oral intubation impossible, so
the nasal route is chosen after administration of an appropri-
ate vasoconstrictor to the nostrils. (If an unsuccessful direct
laryngoscopy or an attempt at blind nasal intubation is per-
formed initially, these approaches may trigger bleeding that
could hamper subsequent attempts at fiberoptic intubation.)
When the surgery is completed, it is helpful to perform direct
laryngoscopy because the view may have improved signifi-
cantly after the resection.134 This information will prove useful
in the event that reintubation is required postoperatively.
If attempts at fiberoptic intubation are unsuccessful, other
options include passing a retrograde wire after asking the sur-
geon to aspirate fluid from the mass (which the surgeon may
decline to perform because of concern about recurrence from
an incompletely resected, ruptured sac), using a light wand or
Bullard laryngoscope, attempting tactile intraoral tube place-
ment, or trying a blind nasal intubation. In the event that these
attempts fail and mask ventilation becomes inadequate, an
LMA should be inserted. If this fails to open the airway, an
emergency surgical airway should be attempted. In the event
the surgeon is unable to expose the trachea, the only remain-
ing option to save the child may be femoral cardiopulmonary
bypass.134
Wegener's Granulomatosis
Wegener's granulomatosis (WG) is a systemic disease of
unknown etiology characterized by necrotizing granulomas
and vasculitis that classically affects the upper and lower air-
ways and the kidneys (Fig. 1-5). Although the etiology is still
not established, Staphylococcus aureus may play a role in the
pathophysiology.143 WG patients can have a myriad of head
and neck manifestations, including mucosal ulceration of the
nose, palate, larynx, and orbit, as well as deafness and subglot-
tic144 or tracheal stenosis. Ocular disease occurs in 50% to 60%
of adults with WG145 and may include such conditions as nec-
rotizing scleritis with peripheral keratopathy,146 orbital pseu-
dotumor,145 and ocular myositis,145 as well as uveitis, vitreous
hemorrhage, and central retinal artery occlusion.147
Wegener's granulomatosis often starts with severe rhi-
norrhea, cough, hemoptysis, pleuritic pain, and deafness.
However, WG is a truly systemic disease and varies widely
in presentation. Some disease presentations are more subtle
and indolent than the more typical, fulminant presentation.
Indeed, the protean manifestations of WG often produce diag-
nostic delay. Diagnosis is supported by histopathologic studies
showing a vasculitis, parenchymal necrosis, and multinucle-
ate giant cells, but tissue biopsy alone is insufficient to estab-
lish the diagnosis of WG. The most specific test is a positive
antineutrophil cytoplasmic autoantibody test (c-ANCA).148
FIGURE 1-5  Wegener's granulomatosis. This sometimes fatal
vasculitis can cause saddle-nose deformity (perforated nasal
septum, mucosal ulcerations, and underlying bone destruction
of oral cavity) and necrotizing granulomas of the airway.  (From
Aries P, Ullrich S, Gross W: A case of destructive Wegener's
granulomatosis complicated by cytomegalovirus infection, Nat Clin
Pract Rheumatol 2:511-515, 2006.)
However, approximately 10% of patients with clinical phe-
notypes identical to those of ANCA-positive patients may be
ANCA negative and may also respond to all anti-inflammatory
or immunosuppressive therapies shown to be effective for
seropositive patients.149
Wegener's granulomatosis was once fatal. With the advent
of long-term corticosteroid and immunosuppressive therapy,
however, WG patients survive longer, with a broader spectrum
of disease observed in recent years. The incidence of subglot-
tic stenosis in WG ranges from 8.5% to 23%.150 It is a major
cause of morbidity and mortality and typically is unresponsive
to systemic chemotherapy. Other treatments have included
mechanical subglottic dilation (with or without intratracheal
steroid injection) and laser therapy, with variable success.
Subglottic stenosis has been treated with endoscopic inser-
tion of nitinol stents after dilation of the stenotic segment with
bougie dilators.144 Nitinol is a nickel-titanium alloy that has
excellent properties, including biocompatibility, kink resis-
tance, and elasticity, thus resembling the tracheobronchial
tree. These metal stents are expandable, serving as an intralu-
minal support to establish and maintain airway patency. They
are usually permanent but can be removed if necessary. For
the intervention to be successful, however, the diseased seg-
ment must begin at least 1 cm below the vocal cords.
ANESTHETIC CONCERNS
Patients with WG often present for ocular, nasal, or laryngeal
surgery. The anesthesiologist must anticipate a host of poten-
tial problems (Box  1-20). These challenges include address-
ing the side effects of chronic corticosteroid and aggressive
immunosuppressive therapy as well as the presence of under-
lying pulmonary and renal disease. Although several years
 22 ANESTHESIA AND UNCOMMON DISEASES
BOX 1-20   n WEGENER'S GRANULOMATOSIS:
ANESTHETIC CONCERNS
Side effects of steroids and immunosuppressive agents
Bleeding induced by airway manipulation
Subglottic stenosis
Tracheal stenosis
Reduced pulmonary reserve
Impaired renal function
ago cyclophosphamide was credited with prolonging life in
patients with WG, current thinking is that chronic long-term
cyclophosphamide therapy is no longer justified. Remission
maintenance therapies with methotrexate or azathioprine are
as effective as prolonged cyclophosphamide and are much
safer.151 Additionally, midline necrotizing granulomas of
the airway may cause obstruction or bleeding at intubation.
Some degree of subglottic or tracheal stenosis should also be
expected. Chest radiography, CT, or MRI of the airway; arte-
rial blood gas analysis; pulmonary function tests; and blood
urea nitrogen (BUN)/creatinine levels are helpful guides to
optimal anesthetic management. (See also Chapter 4.)
Acromegaly
Acromegaly is a rare chronic disease of midlife caused by
excess secretion of adenohypophyseal growth hormone (GH).
Hypersecretion of GH before epiphyseal closure produces
gigantism in younger individuals. GH acts on a wide variety
of tissues, both directly and through insulin-like growth factor
I (IGF-I), which is released mainly from the liver in response
to GH. In addition to stimulating bone and cartilage growth,
GH and IGF-I promote protein synthesis and lipolysis while
reducing insulin sensitivity and causing sodium retention.
Therefore, acromegaly is characterized by enlargement of the
jaw, hands, feet, and soft tissues, as well as by diabetes mel-
litus and hypertension. Severe, chronic hypertension may
result in cardiomegaly, left ventricular dysfunction, CHF, and
dysrhythmias. Airway soft tissue overgrowth may produce
macroglossia with glossoptosis, vocal cord thickening with
hoarseness, and subglottic narrowing. Vocal cord paralysis has
also been reported occasionally. Approximately 25% of acro-
megalic patients have an enlarged thyroid, which may produce
tracheal compression or deviation. Diagnosis is confirmed by
elevated 24-hour GH levels in conjunction with increased
serum IGF-I levels.
Most pituitary tumors originate in the anterior part of the
gland, and the overwhelming majority are benign adenomas.
Proposed etiologic mechanisms include malfunction of normal
growth-regulating genes, abnormal tumor suppressor genes,
and changes in genes that control programmed cell death.152
The prevalence of pituitary tumors is approximately 200 per
1 million population,153 but random autopsy results indicate
an incidence as high as 27%,154 suggesting that the majority of
pituitary adenomas are asymptomatic. The most common type
of pituitary adenoma causes hyperprolactinemia. Adenomas
producing acromegaly and Cushing's disease are more unusual.
The annual incidence of acromegaly, for example, is said to be 3
to 8 cases per 1 million.
The primary treatment of acromegaly is surgery, with or
without subsequent radiotherapy. However, in the relatively
few patients who respond to treatment with dopamine agonists
such as bromocriptine, surgery can be avoided. Somatostatin
also inhibits GH release, and long-acting analogs of soma-
tostatin, such as octreotide, may be tried in those who fail to
respond to dopamine agonists.155
SURGERY AND ANESTHETIC CONCERNS
Acromegaly is widely recognized as one of many causes of dif-
ficult airway management156,157 (Box 1-21). Careful preopera-
tive airway assessment is therefore indicated, paying special
attention to possible sleep apnea by questioning the patient
about any history of loud snoring, frequent nocturnal awaken-
ing, and daytime hypersomnolence. It is imperative to appre-
ciate that the risk of death from respiratory failure is threefold
greater in patients with acromegaly.158 Hypertension is com-
mon in acromegalic patients but usually responds to antihy-
pertensive therapy. Myocardial hypertrophy and interstitial
fibrosis are also common and may be associated with left
ventricular dysfunction. Thus, indicated preoperative studies
often include a chest radiograph, ECG, and echocardiogram,
in addition to lateral neck radiographs and CT of the neck.
The pituitary fossa can be approached using the trans­
sphenoidal, transethmoidal, or transcranial route. For all
but the largest tumors, the transsphenoidal route is preferred
because of a lower incidence of associated complications.
Otolaryngologists often assist neurosurgeons in performing
transsphenoidal hypophysectomy, gaining access to the pitu-
itary fossa using a sublabial or endonasal approach. Hormone
replacement, including 100 mg of hydrocortisone, is adminis-
tered intravenously at induction, and prophylactic antibiotics
are given. An appropriate vasoconstrictor is applied to the nos-
trils, and care must be taken to prevent hypertension or dys-
rhythmias. Large face masks and long-bladed laryngoscopes
should be prepared and a fiberoptic laryngoscope ­available.
BOX 1-21   n ACROMEGALY PATIENTS: PERIOPERATIVE
CONCERNS
Difficult airway management; suspect sleep apnea
Subglottic narrowing
Tracheal compression or deviation associated with thyroid
enlargement
Hypertension
Cardiomegaly
Dysrhythmias
Left ventricular dysfunction
Congestive heart failure
Diabetes mellitus
Venous air embolism
Postoperative anterior pituitary insufficiency and diabetes insipidus
Postoperative cerebrospinal fluid rhinorrhea, meningitis, sinusitis,
and cranial nerve palsy
 Chapter 1  Eye, Ear, Nose, and Throat Diseases 23
Depending on the airway assessment, awake fiberoptic intu-
bation may be the preferred approach to securing the air-
way. The intubating LMA has also been used successfully in
patients with acromegaly. Equipment for tracheostomy should
be immediately available if airway involvement is extensive.
After intubation, the mouth and pharynx should be packed
before surgery commences to prevent intraoperative bleed-
ing into the laryngeal area, which may cause postextubation
laryngospasm, and into the stomach, which may trigger post-
operative nausea and vomiting.
Some surgeons request that a lumbar drain be inserted in
patients with major suprasellar tumor extension. The inten-
tion is to produce prolapse of the suprasellar part of the tumor
into the operative field by injecting 10-mL aliquots of normal
saline as needed. Additionally, if the dura is perforated intra-
operatively, the lumbar catheter can be left in situ postopera-
tively to control any leakage of cerebrospinal fluid (CSF).159
Transsphenoidal surgery is conducted with the patient
supine with a moderate degree of head-up tilt. Careful moni-
toring for venous air embolism is indicated if the head is ele-
vated more than 15 degrees. Other monitoring should include
direct arterial BP, ECG, O2 saturation, and end-tidal CO2
determination. VEPs have limited usefulness because they are
very sensitive to anesthetic effects.
Any anesthetic approach that is compatible with the exi-
gencies of intracranial surgery is acceptable. Regardless of
whether an inhalational agent or total IV anesthesia is selected,
short-acting agents are administered to allow rapid recovery at
the end of surgery. Drugs such as propofol, sevoflurane, and
remifentanil are excellent agents to accomplish this objective.
At the completion of surgery, pharyngeal packs should
be removed. When the patient is awake with reflexes intact,
extubation should be conducted, taking care not to dislodge
nasal packs or stents. Patients with acromegaly should be
carefully observed postoperatively for airway patency. Those
with sleep apnea should be carefully followed in a monitored
unit, because treatment options such as nasal CPAP cannot
be applied after transsphenoidal surgery. Narcotics should be
administered with special caution to patients with sleep apnea.
Hormone replacement with tapered cortisol therapy is c­ ritical
postoperatively. In addition to anterior pituitary insufficiency,
diabetes insipidus may also develop postoperatively, but most
borderline cases resolve spontaneously in a few days as poste-
rior lobe function recovers.159 Other potential complications
include CSF rhinorrhea, meningitis, sinusitis, and cranial
nerve palsy.
Ludwig's Angina
Ludwig's angina is a potentially lethal, rapidly expanding cel-
lulitis of the floor of the mouth characterized by brawny indu-
ration of the upper neck (Fig.  1-6). Odontogenic infections
account for the majority of cases. Spread of the infection along
the deep cervical fascia can result in mediastinitis, mediastinal
abscess, jugular vein thrombosis, innominate artery rupture,
empyema, pneumothorax, pleural and pericardial effusion,
FIGURE 1-6  Ludwig's angina. This rapidly expanding
cellulitis of the floor of the mouth can be fatal if not managed
appropriately.  (From Dachs R, Tun Y: Painful oral ulcerations in a
51-year-old woman, Am Fam Physician 80:875-876, 2009.)
subphrenic abscess, necrotizing fasciitis, and mandibular or
cervical osteomyelitis. The inflammation is typically caused by
cellulitis, but gangrenous myositis may also be a component.160
Although the symptoms appear in writings dating back to
Hippocrates, Ludwig's angina was best described initially in
1836 by its namesake, Karl Friedrich Wilhelm von Ludwig.
He described this disease as a rapidly progressive, gangre-
nous cellulitis originating in the region of the submandibular
gland that extends by continuity rather than lymphatic spread.
During the late 19th and early 20th centuries, Ludwig's angina
was usually considered a complication of local anesthetics
administered to facilitate extraction of mandibular teeth.161
The actual pathogenesis was not elucidated until later.
In 1943, Tschiassny162 clarified the unique role that the floor
of the mouth played in the development of Ludwig's angina.
He described how periapical dental abscesses of the second
and third mandibular molars penetrate the thin, inner cor-
tex of the mandible. Because these roots extend inferior to the
mandibular insertion of the mylohyoid muscle, infection of
the submandibular space ensues. Because of communication
around the posterior margin of the mylohyoid muscle, rapid
involvement of the sublingual space occurs, followed quickly
by involvement of the contralateral spaces. The unyielding
presence of the mandible, hyoid, and superficial layer of the
deep cervical fascia limits tissue expansion as edema devel-
ops and progresses. This resistance leads to superior and pos-
terior displacement of the floor of the mouth and the base
of the tongue. These patients therefore have an open-mouth
appearance, with a protruding or elevated tongue, and exhibit
marked neck swelling. Soft tissue swelling in the suprahyoid
region, combined with lingual displacement and concomitant
laryngeal edema, can occlude the airway and abruptly asphyx-
iate the patient.
Although the overwhelming preponderance of cases of
Ludwig's angina have an odontogenic origin, other risks
 24 ANESTHESIA AND UNCOMMON DISEASES
include sublingual lacerations, tongue piercing, IV drug abuse,
penetrating injuries to floor of mouth, sialadenitis, compound
mandibular fractures, osteomyelitis of mandible, otitis media,
infected malignancy, and abscesses located under the thyro-
hyoid membrane.163 Patients typically present with fever, as
well as edema of the tongue, neck, and submandibular region.
These symptoms can progress to include dysphagia, inabil-
ity to handle secretions, dysphonia, trismus, and difficulty
breathing. Polymicrobial infections are common; usual organ-
isms include streptococci, staphylococci, and Bacteroides.
In the preantibiotic era, Ludwig's angina was associated
with mortality rates exceeding 50%. Originally, the extremely
sudden manner of death was ascribed to overwhelming sepsis.
The lethal role of mechanical respiratory obstruction leading
to asphyxia was not understood until later.164 In 1942, Taffel
and Harvey165 succeeded in reducing mortality to less than
2% by emphasizing early diagnosis and advocating aggres-
sive treatment with wide surgical decompression of the sub-
mandibular and sublingual spaces with the patient under local
anesthesia. This intervention allowed the elevated base of the
tongue to assume an anteroinferior position, thereby preserv-
ing the patency of the oropharyngeal airway.
The increasing availability of antibiotics in the 1940s
reduced the incidence of and mortality from Ludwig's angina.
Currently, aggressive antibiotic therapy in the early stages of
the disease has reduced the need for surgical decompression
and airway intervention (Box  1-22). Patterson et  al.,166 for
example, reported a series of 20 patients at their institution
in whom only 35% required airway control through tracheot-
omy or endotracheal intubation. The anticipated need for air-
way control may differ among groups, with older patients who
have more comorbidities apparently at greater risk for airway
obstruction.167,168 Additionally, patients who are in poorer con-
dition at presentation may well be in danger of imminent air-
way closure. Stridor, anxiety, cyanosis, and difficulty managing
secretions clearly are late signs of impending obstruction and
should indicate the need for immediate airway intervention.
ANESTHETIC CONCERNS
Airway management may be extremely difficult in patients
with Ludwig's angina, and intervention should occur early in
the course of the disease. IV dexamethasone and nebulized
epinephrine may help alleviate airway obstruction. Often,
BOX 1-22   n LUDWIG'S ANGINA PATIENTS:
ANESTHETIC CONCERNS
Early, aggressive antibiotic therapy may obviate need for airway
intervention/surgical decompression.
IV dexamethasone and nebulized epinephrine may alleviate airway
obstruction.
Older, sicker patients purportedly at increased risk for airway
obstruction.
Anticipate difficult airway management.
Favor awake fiberoptic intubation with an armored tube or
­tracheostomy—under local anesthesia.
­ reliminary tracheostomy using local anesthesia may be the
p
safest option. Depending on the patient's condition, includ-
ing the presence or absence of trismus and the ability of the
patient to cooperate, other options include awake fiberoptic
intubation, or inhalation induction if the case is mild and has
not progressed, preserving spontaneous respiration, followed
by intubation with direct laryngoscopy or fiberoptic assis-
tance. If the oropharynx cannot be visualized by CT, a fiber-
optic nasotracheal approach is advised. A surgeon should be
present and a tracheotomy kit immediately available when the
nonsurgical route to establish the airway is selected. Because
of the potential for continued airway swelling after ETT place-
ment, it seems prudent to insert an armored tube to protect
the airway better.
CONCLUSION
Treatment of many complex ophthalmic and otolaryngologic
conditions has undergone extraordinary progress during the
past three decades. These patients often have complicated
anesthetic issues and are presenting for many diagnostic and
surgical procedures that did not exist a generation ago. The
anesthesiologist must appreciate that few of the conditions
presented here have isolated ophthalmic or ENT pathology,
but rather are frequently associated with multisystem dis-
eases. The anesthetic plan must reflect this reality. Typically,
it is inappropriate to insist dogmatically that one anesthetic
approach is unequivocally superior to all others in the man-
agement of any specific condition, especially the complex
entities discussed here. The key to optimal anesthetic man-
agement and outcome resides in a comprehensive understand-
ing of the disease process, the surgical requirements, and the
effects of anesthetic agents and techniques on both the indi-
vidual patient and the proposed surgery.
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 C H A P T E R
2
Cardiac Diseases
ALEXANDER MITTNACHT, MD; DAVID L. REICH, MD  n
AMANDA J. RHEE, MD; JOEL A. KAPLAN, MD  n

Cardiomyopathies Patients with Transplanted Heart

General Classification The Denervated Heart
Hypertrophic Cardiomyopathy Immunosuppressive Therapy
Arrhythmogenic Right Ventricular Cardiomyopathy/ Anesthetic Considerations
Dysplasia Conclusion
Left Ventricular Noncompaction
Conduction System Disease
Ion Channelopathies
KEY POINTS
Dilated Cardiomyopathy
Restrictive Cardiomyopathies n Even the most uncommon cardiac diseases are c­ haracterized
Human Immunodeficiency Virus and the Heart by common and classifiable patterns of cardiac physiology
Miscellaneous Cardiomyopathies and pathophysiology.
Secondary Cardiomyopathies n Knowledge of disease effects on determinants of cardiac
Cardiac Tumors function allows the practitioner to select appropriate anes-
Benign Cardiac Tumors thetic drugs and techniques based on the common patterns
Malignant Cardiac Tumors of cardiac pathophysiology.
Metastatic Cardiac Tumors n Appropriate hemodynamic monitoring guides treatment
Cardiac Manifestations of Extracardiac Tumors options and allows for early intervention should hemo-
Anesthetic Considerations dynamic instability occur. Intra-arterial blood pressure
Ischemic Heart Disease monitoring and transesophageal echocardiography are
Physiology of Coronary Artery Disease and Modification by frequently helpful in addition to standard monitors.
Uncommon Disease n Central venous catheters are often indicated for the admin-
Uncommon Causes of Ischemic Heart Disease istration of vasoactive drugs. Central venous pressure
Anesthetic Considerations monitoring may be useful in assessing loading conditions.
Pulmonary Hypertension and Cor Pulmonale n Pulmonary artery catheters may be helpful in guiding
Pathophysiology treatment options, especially in patients with pulmonary
Cor Pulmonale hypertension, but have not been shown to improve patient
Anesthetic Considerations outcome.
Pericarditis, Effusion, and Tamponade n In ischemic heart disease, regardless of the underlying etiol-
Constrictive Pericarditis ogy, the key to optimizing myocardial perfusion is increas-
Pericardial Effusion and Cardiac Tamponade ing myocardial oxygen supply and decreasing demand.
Uncommon Causes of Valvular Lesions n Pulmonary hypertension has many etiologies and can be
Stenotic Valvular Lesions present with or without right ventricular dysfunction and
Regurgitant Valvular Lesions cor pulmonale. Pulmonary vasodilators such as inhaled
Anesthetic Considerations nitric oxide may need to be continued or started in the
perioperative period.

28

n Constrictive pericarditis, pericardial effusion, and car-
diac tamponade can lead to diminished ventricular filling
and cardiac output; compensatory mechanisms ameliorate
symptom severity in chronic disease. The effects of anes-
thetic induction may lead to hemodynamic collapse in
patients with cardiac tamponade.
n Valvular lesions can be regurgitant, stenotic, or both in
uncommon cardiac diseases. Hemodynamic goals for ste-
notic lesions are to maintain preload and afterload for ade-
quate perfusion pressure with fixed, low cardiac output;
regurgitant lesions require high preload and relatively low
afterload.
n The newly transplanted heart is denervated, and the effect
of common drugs such as atropine may be altered or abol-
ished; direct-acting sympathomimetics result in more pre-
dictable responses.
The major cardiovascular diseases most often encountered
are atherosclerotic coronary artery disease, degenerative val-
vular disease, and essential hypertension. Experience with
these common diseases helps the anesthesiologist become
familiar with both the pathophysiology and the anesthetic
management of patients with cardiac disease. Although less
common, the diseases discussed in this chapter are usually
analogous to common patterns of physiology and patho-
physiology. The anesthetic management of patients with
uncommon cardiovascular disease is fundamentally no dif-
ferent from the management of the more familiar problems.
The same principles of management apply, including (1) an
understanding of the disease process and its manifestations;
(2) thorough knowledge of anesthetic and adjuvant drugs,
especially cardiovascular effects; (3) proper use of monitor-
ing; and (4) an understanding of the requirements of the sur-
gical procedure.
Because the diseases discussed here are infrequently or
rarely seen, extensive knowledge of their pathophysiology,
particularly in the anesthetic and surgical setting, is largely
lacking. The use of hemodynamic monitoring provides the
best guide to intraoperative and postoperative treatment of
patients with uncommon cardiovascular diseases. Monitoring
is no substitute for understanding physiology and pharmacol-
ogy or for clinical judgment, but rather provides information
that facilitates clinical decisions. Understanding the require-
ments of the surgical procedure and ensuring good commu-
nication between the anesthesiologist and surgeon are also
necessary to anticipate intraoperative problems and thus for-
mulate an anesthetic plan.
This chapter does not provide an exhaustive list or consid-
eration of all the uncommon diseases that affect the cardio-
vascular system, although it covers a wide range. No matter
how bizarre, a disease entity can only affect the cardiovas-
cular ­system in a limited number of ways. It can affect the
­myocardium, coronary arteries, conduction system, pulmonary
circulation, and valvular function, or it can impair cardiac
­filling or emptying. Subsections in this chapter follow this
basic discussion approach.
Chapter 2  Cardiac Diseases 29
CARDIOMYOPATHIES
General Classification
Cardiomyopathies are defined as diseases of the myocar-
dium that are associated with cardiac dysfunction. Classified
in various ways, cardiomyopathies are usually viewed, on an
etiologic basis, as primary myocardial diseases, in which the
disease locus is the myocardium itself, or secondary myocar-
dial diseases, in which the myocardial pathology is associated
with a systemic disorder. On a pathophysiologic basis, myo-
cardial disease can be divided into three general categories:
dilated (congestive), hypertrophic, and restrictive (obstructive)
cardiomyopathies (Fig. 2-1).
Over the past decade, advances in understanding myo-
cardial etiology and diagnosis and the identification of new
diseases have led to updated classifications, notably the 2006
American Heart Association (AHA) contemporary defini-
tions and classification of cardiomyopathies1 (Box  2-1). The
AHA expert consensus panel defines the cardiomyopathies as
“a heterogeneous group of diseases of the myocardium asso-
ciated with mechanical and/or electrical dysfunction that
usually (but not invariably) exhibit inappropriate ventricular
hypertrophy or dilation and are due to a variety of causes that
frequently are genetic. Cardiomyopathies either are confined
to the heart or are part of generalized systemic disorders, often
leading to cardiovascular death or progressive heart failure–
related disability.” This classification scheme divides cardio-
myopathies into two major categories: primary and secondary.
When discussing the anesthetic management of patients with
cardiomyopathies, the pathophysiologic changes often are
more relevant than their etiology. This discussion refers to the
most recent AHA recommended classification of cardiomy-
opathies, although the anesthetic management is discussed on
the basis of the pathophysiologic changes that result from their
underlying etiology.
Normal Congestive Restrictive Hypertrophic
Systole
Diastole
FIGURE 2-1  Fifty-degree left anterior oblique views of the heart in
various cardiomyopathies at end systole and end diastole. (From
Goldman MR, Boucher CA: Value of radionuclide imaging techniques
in assessing cardiomyopathy, Am J Cardiol 46:1232, 1980.)
 30 ANESTHESIA AND UNCOMMON DISEASES
BOX 2-1   n CLASSIFICATION OF CARDIOMYOPATHIES
(PRIMARY CARDIOMYOPATHIES)
Genetic
Hypertrophic cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy/dysplasia
Left ventricular noncompaction
Glycogen storage cardiomyopathy
Conduction defects
Mitochondrial myopathies
Ion channel disorders
Mixed
Dilated cardiomyopathy
Restricted cardiomyopathy
Acquired
Inflammatory disorders
Stress-provoked conditions
Peripartum disorders
Tachycardia-induced conditions
Infants of insulin-dependent diabetic mothers
Modified from Maron BJ, et al: Contemporary definitions and classification
of the cardiomyopathies: an American Heart Association Scientific
Statement, Circulation 113:1807-1816, 2006.
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is an autosomal dom-
inant genetic disease and the most common genetic cardio-
vascular disease, with a prevalence of approximately 1 in 500
young adults in the United States.2 HCM is the most common
cause of sudden cardiac death in young U.S. athletes and an
important cause of heart failure at any age. Morphologically, it
is defined by a hypertrophied, nondilated left ventricle in the
absence of another causative disease for hypertrophy, such as
chronic hypertension or aortic stenosis. The variety of genetic
defects that results in HCM explains the heterogeneity of its
phenotypic presentation.3
Hypertrophic cardiomyopathy usually results from asym-
metric hypertrophy of the basal ventricular septum and occurs
in either an obstructive or a nonobstructive form (Table 2-1).
A dynamic pressure gradient in the left ventricular outflow
tract (LVOT) is present in the obstructive forms.4–7 other con-
ditions also present the picture of an obstructive cardiomy-
opathy, such as massive infiltration of the ventricular wall, as
occurs in Pompe's disease, where an accumulation of cardiac
glycogen in the ventricular wall produces LVOT obstruction.
This is caused by genetic mutations interfering with cardiac
metabolism.
Obstructive HCM, also referred to as hypertrophic
obstructive cardiomyopathy (HOCM), asymmetric septal
hypertrophy (ASH), or idiopathic hypertrophic subaortic ste-
nosis (IHSS), has the salient anatomic feature of basal sep-
tal hypertrophy.8 Obstruction of the LVOT is caused by the
hypertrophic muscle mass and systolic anterior motion (SAM)
of the anterior leaflet of the mitral valve. Hypotheses for the
TABLE 2-1  n Treatment Principles of Dilated
Cardiomyopathies
Clinical Relatively
Problem Treatment Contraindicated
↓ Preload Volume Nodal rhythm
replacement High spinal anesthesia
Positional change
↓ Heart rate Atropine Verapamil
Pacemaker
↓ Contractility Positive inotropes Volatile anesthetics
Digoxin
↑ Afterload Vasodilators Phenylephrine
Light anesthesia
­ echanism of SAM include a Venturi effect of rapidly flow-
m
ing blood in the LVOT.9 Other theories include alteration in
the position of the leaflet coaptation point in relation to the
interventricular septum, and blood flow changes caused by
the bulging septum that cause parts of the anterior mitral valve
tissue and subvalvular apparatus to protrude or to be “pushed”
into the LVOT during systole.10,11 Various degrees of mitral
­regurgitation are typically associated with SAM. The outflow
tract obstruction can result in hypertrophy of the remainder of
the ventricular muscle, secondary to increased pressures in the
ventricular chamber.
The current therapeutic options for patients with hypertro-
phied cardiomyopathy are based on pharmacologic therapy,
surgical interventions, percutaneous transluminal septal myo-
cardial ablation, and dual-chamber pacing.12–16 An automated
implantable cardioverter-defibrillator (AICD) is frequently
implanted to treat arrhythmias so as to prevent sudden car-
diac death.17,18 The pharmacologic therapy of obstructive
HCM has been based on beta-adrenergic blockade, although
it is still unclear whether this prolongs life expectancy. Patients
who do not tolerate β-blockers instead receive verapamil, with
beneficial effects likely resulting from depressed systolic func-
tion and improved diastolic filling and relaxation. Patients
whose symptoms are inadequately controlled with β-blockers
or verapamil receive disopyramide, a type IA antiarrhythmic
agent with negative inotropic and peripheral vasoconstrictive
effects. Amiodarone is administered for the control of supra-
ventricular and ventricular arrhythmias.19
Data are minimal or lacking to support the use of combi-
nation therapy for HOCM.20 Most patients with obstructive
HCM are treated only with medical therapy. Nevertheless,
5% to 30% of patients are surgical candidates. The surgery is
septal myotomy/myectomy, mitral valve repair/replacement
or valvuloplasty, or a combination of the two.21 The potential
complications of surgical correction of the LVOT obstruction
include complete heart block and late formation of a ventricu-
lar septal defect from septal infarction.

Percutaneous transluminal alcohol septal ablation is per-
formed in the catheterization laboratory but requires special
expertise that is limited to experienced centers.22 Although
this may be efficacious for subsets of patients with obstructive
HCM, the procedural complication rate may exceed that of
surgical myectomy.23 Ablation is also associated with the risk
of serious adverse events, such as alcohol toxicity and malig-
nant tachyarrhythmias.24 A relatively new alternative to induce
septal ablation involves percutaneous transluminal septal coil
embolization, which avoids the problem of alcohol toxicity.
Further experience and outcome data are required before this
new technique is considered a standard treatment modal-
ity for HCM.25 Although still controversial, evidence suggests
that atrioventricular sequential (DDD) pacing is beneficial for
patients with obstructive HCM.26,27
ANESTHETIC CONSIDERATIONS
The determinants of the functional severity of the ventricular
obstruction in obstructive HCM are (1) the systolic volume of
the ventricle, (2) the force of ventricular contraction, and (3)
the transmural pressure distending the LVOT.
Large systolic volumes in the ventricle distend the LVOT
and reduce the obstruction, whereas small systolic volumes
narrow the LVOT and increase the obstruction. When ven-
tricular contractility is high, the LVOT is narrowed, increasing
the obstruction. When aortic pressure is high, the increased
transmural pressure distends the LVOT. During periods of
decreased afterload and hypotension, however, the LVOT is
narrowed, resulting in greatly impaired cardiac output often
associated with significant mitral regurgitation. As the ven-
tricle hypertrophies, ventricular compliance decreases, and
passive filling of the ventricle during diastole is impaired. The
ventricle becomes increasingly dependent on the presence of
atrial contraction to maintain an adequate ventricular end-
diastolic volume. Monitoring should be established that allows
continuous assessment of these parameters, particularly in
patients in whom the obstruction is severe.
In patients with symptomatic obstructive HCM present-
ing for surgery, an indwelling arterial catheter for beat-to-
beat observation of ventricular ejection and continuous blood
pressure (BP) monitoring should be placed before anesthesia
induction. Transesophageal echocardiography (TEE) provides
useful data on ventricular function and filling, the severity of
LVOT obstruction, and the occurrence of SAM and mitral
regurgitation. A pulmonary artery catheter (PAC), once more
widely used, has not shown to improve outcome. Its use may
be helpful in guiding treatment options, especially in patients
with obstructive HCM undergoing major surgery with large
fluid shifts.
Special consideration should be given to those features of
the surgical procedure and anesthetic drugs that can p ­ roduce
changes in intravascular volume, ventricular contractility, and
transmural distending pressure of the outflow tract. Decreased
preload, for example, can result from blood loss, sympathec-
tomy secondary to spinal or epidural anesthesia, use of potent
Chapter 2  Cardiac Diseases 31
volatile anesthetics and nitroglycerin, or p ­ ostural changes.
Ventricular contractility can be increased by hemodynamic
responses to tracheal intubation or surgical stimulation.
Transmural distending pressure can be decreased by hypoten-
sion secondary to anesthetic drugs, hypovolemia, or positive-
pressure ventilation. Additionally, patients with obstructive
HCM do not tolerate increases in heart rate. Tachycardia
decreases end-diastolic ventricular volume, resulting in a
narrowed LVOT. As noted earlier, the atrial contraction is
extremely important to the hypertrophied ventricle. Nodal
rhythms should be aggressively treated, using atrial pacing if
necessary.
Halothane, now a historical drug and no longer available
in the United States, had major hemodynamic advantages for
the anesthetic management of patients with obstructive HCM.
Its advantages were to decrease heart rate and myocardial
contractility. Of the inhalational anesthetics, halothane had
the least effect on systemic vascular resistance (SVR), which
tended to minimize the severity of the obstruction when vol-
ume replacement was adequate. Sevoflurane decreases SVR to
a lesser extent than isoflurane or enflurane and thus may be
preferable. Agents that release histamine, such as morphine,
thiopental, and atracurium, are not recommended because
of the resulting venodilation. Agents with sympathomimetic
side effects (ketamine, desflurane) are not recommended
because of the possible tachycardia. High-dose opioid anes-
thesia causes minimal cardiovascular side effects along
with ­bradycardia and thus may be useful in these patients.
Preoperative β-blocker and calcium channel blocker therapy
should be continued. Intravenous (IV) propranolol, esmolol,
or verapamil may be administered intraoperatively to improve
hemodynamic performance. Table 2-2 summarizes the anes-
thetic and circulatory management of obstructive HCM.28
TABLE 2-2  n Treatment Principles of Hypertrophic
Obstructive Cardiomyopathy
Clinical Relatively
Problem Treatment Contraindicated
↓ Preload Volume Vasodilators
Phenylephrine Spinal/epidural
anesthesia
↑ Heart Rate β-Adrenergic Ketamine
blockers β-Adrenergic agonists
Verapamil
↑ Contractility Halothane Positive inotropes
Sevoflurane Light anesthesia
β-Blockers
Disopyramide
↓ Afterload Phenylephrine Isoflurane
Spinal/epidural
anesthesia
 32 ANESTHESIA AND UNCOMMON DISEASES
Anesthesia for management of labor and delivery in the
parturient with obstructive HCM is quite complex. “Bearing
down” (Valsalva maneuver) during delivery may worsen
LVOT obstruction. Beta-blocker therapy may have been
discontinued during pregnancy because of the association
with fetal bradycardia and intrauterine growth retardation.
Oxytocin must be used carefully because of its vasodilating
properties and compensatory tachycardia. Pulmonary edema
has been observed in parturients with HCM, emphasizing the
need for careful fluid management.29 Spinal anesthesia is rela-
tively contraindicated because of the associated vasodilation,
but epidural anesthesia has been used successfully.30 General
anesthesia is preferred by many practitioners. If hypoten-
sion occurs during anesthesia, the use of beta-agonists such
as ephedrine may result in worsening outflow tract obstruc-
tion, and alpha-agonists such as phenylephrine, once thought
to result in uterine vasoconstriction, are now preferred.31,32
However, careful titration of anesthetic agents and adequate
volume loading (most often guided by invasive monitoring) is
essential to safely conducted anesthesia in this clinical setting.
Arrhythmogenic Right Ventricular
Cardiomyopathy/Dysplasia
Arrhythmogenic right ventricular cardiomyopathy/dysplasia
(ARVC/D) is an uncommon (estimated 1:5000 young adults),
newly described, autosomal dominant disease with incomplete
penetrance. ARVC/D is frequently associated with myocardi-
tis but is not considered a primary inflammatory cardiomy-
opathy. It involves predominantly the right ventricle initially,
progressing to affect the left ventricle in later stages. There is
a progressive loss of myocytes, with replacement by fatty or
fibrofatty tissue, which leads to regional (segmental) or global
pathology. It is three times more common in women.
The clinical presentation of ARVC/D usually includes ven-
tricular tachyarrhythmias, such as monomorphic ventricular
tachycardia, syncope, or cardiac arrest, with global or segmen-
tal chamber dilation and regional wall motion abnormalities.
It has been recognized as an important cause of sudden death
in young athletes.33 Diagnosis involves assessment of multiple
facets of cardiac physiology, including electrical, functional,
and anatomic pathology.
ANESTHETIC CONSIDERATIONS
The main therapeutic options are similar to those for other
arrhythmia-prone or heart failure patients. Patients often pres-
ent with AICDs, and antiarrhythmic agents such as β-blockers
or amiodarone may be helpful should arrhythmias occur.34
Catheter ablation of diseased areas of myocardium (acting as
arrhythmogenic foci) can be useful in cases of refractory med-
ical therapy. Cardiac transplantation is also an option as a final
alternative.
As a rarer heart disease, minimal evidence exists for the
optimal anesthetic management of patients with ARVC/D.
It is one of the main causes of sudden, unexpected periopera-
tive death, which can occur in low-risk surgical candidates,
even in patients with a history of successful anesthesia.35,36
The uncommon nature of the disease makes it difficult to
make specific recommendations for anesthetic management.
If the condition is known, invasive continuous arterial BP
monitoring is prudent intraoperatively. A PAC should prob-
ably be avoided, given the tendency toward arrhythmias.
Propofol and etomidate appear to be safe induction agents.34
Neuromuscular blocking agents such as vecuronium, cisa-
tracurium, and rocuronium are probably safe as well. AICDs
should be managed according to the guidelines published and
referred to throughout this text,37 regardless of the presence of
ARVC/D.38
Left Ventricular Noncompaction
Left ventricular (LV) noncompaction of ventricular myocar-
dium is a genetic disorder with familial and nonfamilial types.
LV noncompaction has a distinctive “spongy” appearance
to the LV myocardium, with deep intertrabecular recesses
(sinusoids) that communicate with the LV cavity. LV non-
compaction results in LV systolic dysfunction, heart failure,
thromboemboli, arrhythmias, sudden death, and ventricular
remodeling.1
ANESTHETIC CONSIDERATIONS
Anesthetic management in patients with LV noncompaction
depends on the severity of ventricular dysfunction, which should
be evaluated preoperatively. In patients with impaired cardiac
function, management should be directed toward preserving
contractility and baseline levels of preload and afterload. Up to
80% of patients with LV noncompaction have a neuromuscular
disorder, such as Duchenne's or Becker's muscular dystrophy or
myotonic dystrophy.39 Thus, depolarizing neuromuscular junc-
tion blockers should be avoided or used with caution.40 Patients
may be receiving anticoagulation for thromboembolic prophy-
laxis and may therefore have contraindications for using neur-
axial techniques. AICDs are often inserted for indications such
as arrhythmias or heart failure, and patients should be managed
accordingly.41,42
Data are limited regarding anesthetic management in
patients with LV noncompaction syndrome. In a retrospec-
tive study on 60 patients with noncompaction undergoing 220
procedures, only patients undergoing general anesthesia expe-
rienced complications, compared to regional anesthesia or
sedation/analgesia.43 Because the nature of the surgery often
dictates the need for general anesthesia, patients with non-
compaction syndrome requiring general anesthetics warrant
vigilant monitoring in the perioperative period.
Conduction System Disease
LENÈGRE'S DISEASE
Progressive cardiac conduction defect, also known as Lenègre's
disease, has an autosomal dominant pattern of inheritance
resulting in ion channelopathies, which manifest as con-
duction abnormalities. Lenègre's disease involves primary

­ rogressive development of cardiac conduction defects in the
p contraindicated in WPW patients. Amiodarone, sotalol, ibuti-
His-Purkinje system. This leads to widening QRS complexes,
long pauses, and bradycardia.1,44
WOLFF-PARKINSON-WHITE SYNDROME
Wolff-Parkinson-White (WPW) is a rare pre-excitation syn-
drome that presents often as paroxysmal supraventricular
tachycardia episodes. The presence of accessory anatomic
bypass tracts enables the atrial impulse to activate the His
bundle more rapidly than through the normal atrioventric-
ular (A-V) nodal pathway. If the refractoriness in one of the
pathways increases, a re-entrant tachycardia can be initiated.
The electrocardiogram (ECG) in WPW syndrome demon-
strates a short PR interval (<0.12 msec), a delta wave (slurred
transition between PR interval and R-wave upstroke), and a
widened QRS complex.45–47 The incidence of sudden cardiac
death in patients with WPW syndrome is estimated at 0.15%
to 0.39% over 3 to 10 years of follow-up, and in WPW patients
with a history of cardiac arrest, it is the presenting symptom in
approximately 50%.48
Medications that produce more refractoriness in one of the
pathways can create a window of functional unidirectional
block. This initiates a circle of electrical impulse propagation
that results in a rapid ventricular rate. These patients are usu-
ally treated with drugs that increase the refractory period of
the accessory pathway, such as procainamide, propafenone,
flecainide, disopyramide, ibutilide, and amiodarone.49–51
However, individual patient response will vary depending
on the window of unidirectional block, as well as the differ-
ent effects the same drug has on both pathways. For example,
verapamil and digoxin may perpetuate the arrhythmias, espe-
cially when WPW syndrome is associated with atrial fibrilla-
tion.48,52 A nonpharmacologic approach in the treatment of
patients with pre-excitation syndromes is catheter ablation
of the accessory pathways,53,54 with initial success of approxi-
mately 95% in most series.55
ANESTHETIC CONSIDERATIONS
The current treatment of choice for WPW is ablation of the
accessory pathway, which is usually performed in electrophys-
iology laboratories.56,57 The procedures often involve periods
of programmed electrical stimulation in attempts to provoke
the arrhythmias before and after the ablation of the accessory
pathway. Antiarrhythmic medications are usually discontin-
ued before the procedure. Thus, these patients present for an
anesthetic in a relatively unprotected state. Premedication is
indicated to prevent anxiety, which could increase catechol-
amine levels and precipitate arrhythmias. Electrocardiographic
(ECG) monitoring should be optimal for the diagnosis of atrial
arrhythmias (leads II and V1).
If arrhythmias occur in WPW patients, A-V nodal block-
ing agents such as adenosine, β-blockers, diltiazem, and vera-
pamil, as well as lidocaine, should be used with caution. These
A-V blockers must be avoided if atrial fibrillation is suspected,
because these drugs can promote conductance through the
accessory pathway with rapid ventricular response. Digoxin is
Chapter 2  Cardiac Diseases 33
lide, flecainide, or procainamide is preferable in such cases.48
If general anesthesia is needed, it is reported that opioid-
benzodiazepine or opioid-propofol anesthetic regimens show
no effect on electrophysiologic parameters of the accessory
conduction pathways.58,59 Volatile anesthetics theoretically
increase refractoriness within the accessory and A-V path-
ways; however, modern volatile anesthetic agents are widely
used in patients undergoing ablation procedures under gen-
eral anesthesia.60,61 Dexmedetomidine is frequently used for
radiofrequency ablation procedures performed under seda-
tion, because it is unlikely to exacerbate tachycardias and more
likely to cause bradycardia.62
Ion Channelopathies
There are a variety of ion channelopathies of genetic origin in
which defective ion channel proteins lead to arrhythmias that
can cause sudden death. Diagnosis requires identification of
the pathology on a 12-lead ECG.
LONG QT SYNDROME
Long QT syndrome, the most common of the ion channelo-
pathies, is characterized by prolongation of ventricular repo-
larization and the QT interval (QTc >440 msec). It increases
the risk of developing polymorphic ventricular tachycardia
(torsade des pointes). This can lead to syncope and sudden
cardiac death. The more common pattern of inheritance is
autosomal dominant, referred to as Romano-Ward syndrome.
The rare, autosomal recessive inheritance pattern is associated
with deafness, called Jervell and Lange-Nielsen syndrome.63–65
In untreated patients, mortality approaches 5% per year, quite
remarkable for a population with median age in the 20s. The
severity of the disease is judged by the frequency of syncopal
attacks. These attacks may be caused by ventricular arrhyth-
mias or sinus node dysfunction. The development of tors-
ade de pointes is especially ominous and may be the terminal
event for these patients.66
Torsade de pointes is a malignant variety of ventricular
tachycardia with a rotating QRS axis that is resistant to cardio-
version.67,68 The pathogenesis of this syndrome is theorized to
be an imbalance of sympathetic innervation. Left stellate gan-
glion stimulation lowers the threshold for ventricular arrhyth-
mias, while right stellate ganglion stimulation is protective
against ventricular arrhythmias. Patients receiving β-blockers
and those with high left thoracic sympathectomy had relief of
syncope and decreased mortality.69
BRUGADA'S SYNDROME
Patients with Brugada's syndrome have characteristic ECG
findings of right bundle branch block and ST-segment ele-
vation in the anterior precordial leads (V1-V3). It is inher-
ited in an autosomal dominant pattern. Brugada's syndrome
may present as sudden nocturnal death from ventricular
fibrillation or tachycardia, especially in Southeast Asian
males.1,63,70
 34 ANESTHESIA AND UNCOMMON DISEASES
CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR
TACHYCARDIA
Catecholaminergic polymorphic ventricular tachycardia
(CPVT) has two patterns of inheritance that lead to ventric-
ular tachycardia triggered by vigorous physical exertion or
acute emotion, usually in children and adolescents. This can
lead to syncope and sudden death. The resting ECG is unre-
markable, with the exception of sinus bradycardia and promi-
nent U waves in some cases. The most common arrhythmia
seen in CPVT is a bidirectional ventricular tachycardia with
an alternating QRS axis.1,63,71
SHORT QT SYNDROME
Short QT syndrome is characterized by a short QT interval
(QTc <330 msec) and ECG appearance of tall, peaked T waves.
It is associated with polymorphic ventricular tachycardia and
ventricular fibrillation.1,72,73
IDIOPATHIC VENTRICULAR FIBRILLATION
The literature describes a group of cardiomyopathies desig-
nated as idiopathic ventricular fibrillation. Data are insuffi-
cient, however, to establish this as a distinct cardiomyopathy.
It is likely the summation of multiple etiologies that lead to
arrhythmias, probably caused by ion channel mutations.1,74
ANESTHETIC CONSIDERATIONS
Patients with ion channelopathies may present intraoperatively
or in the postanesthesia care unit with sudden arrhythmias that
warrant vigilant ECG monitoring. Continuous invasive intra-
arterial BP monitoring should be considered in patients with
a history of frequent arrhythmias. Patients should be treated
as any patient prone to arrhythmias; this includes ­avoiding
arrhythmogenic medications and immediate availability of a
­cardioverter-defibrillator device. Few data are available on anes-
thetic recommendations for these cardiomyopathies. Patients
with long QT syndrome will occasionally present for high
left thoracic sympathectomy and left stellate ganglionectomy,
although most patients with these ion channelopathies will most
likely present for surgery unrelated to their primary disorder.
Patients with long QT syndrome seem to be at increased risk
of arrhythmia during periods of enhanced sympathetic activ-
ity, particularly during emergence from general anesthesia with
use of potent volatile agents, and when neuromuscular blocker
reversal drugs were given with ondansetron in children.75 Beta
blockade has been described as the most successful medical
management of patients with congenital long QT syndrome
types I and II, which affect potassium channels. Beta blockade
is contraindicated in type III, which involves sodium channels.76
In patients who receive β-blockers, it is reasonable to continue
beta blockade perioperatively. Intraoperatively and particularly
during long procedures, supplemental IV doses of a β-blocker
or a continuous infusion of esmolol should be considered.
The anesthetic technique should be tailored to mini-
mize sympathetic stimulation. A balanced anesthetic tech-
nique with adequate opioid administration is appropriate for
this purpose, and is effective at suppressing catecholamine
elevations in response to stimuli. Nitrous oxide (N2O) causes
mild sympathetic stimulation and thus should be avoided.
Medications that can further prolong the QT interval should
probably be avoided, including isoflurane, sevoflurane,77
thiopental, succinylcholine, neostigmine, atropine, glycopyr-
­
rolate, metoclopramide, 5HT3 receptor antagonists, and
d
­ roperidol.78 Ketamine is generally not recommended as an
induction agent in patients with congenital long QT s­ yndrome.
Despite the QT-prolonging effect, thiopental has been used
without adverse consequences. Propofol has no effect on or
may actually shorten the QT interval and is theoretically a
good choice of induction agent.79 Anxiolysis with midazolam
has been used successfully.80
In patients with Brugada's syndrome, sodium channel
blockers such as procainamide and flecainide are contraindi-
cated, and medications such as neostigmine, class 1A antiar-
rhythmic drugs, and selective α-adrenoreceptor agonists may
increase ST segment elevation and should also be avoided.
Thiopental, isoflurane, sevoflurane, N2O, morphine, fentanyl,
ketamine, and succinylcholine have been used successfully.81–83
Some report arrhythmias related to propofol administration. In
contrast to patients with long QT syndrome, propofol should
be used with caution in patients with Brugada's syndrome.84,85
Dilated Cardiomyopathy
Dilated cardiomyopathy (DCM) has both genetically derived
and acquired components, as well as inflammatory and non-
inflammatory forms.86 It is a relatively common cause of heart
failure, with a prevalence of 36 per 100,000 people,87 and is a
common indication for heart transplantation. DCM is char-
acterized by ventricular chamber enlargement and systolic
dysfunction with normal left ventricular wall thickness. From
20% to 35% of DCM is familial, with predominantly autosomal
dominant inheritance, but also X-linked autosomal recessive
and mitochondrial patterns.88 The main features of DCM are
left ventricular dilation, systolic dysfunction, myocyte death,
and myocardial fibrosis.89 Evidence indicates genetic simi-
larities between hypertrophic and dilated cardiomyopathy.90
Nonfamilial causes for DCM include infectious agents, par-
ticularly viruses that lead to inflammatory myocarditis, and
toxic, degenerative, and infiltrative myocardial processes.91,92
Although there are different systems for classifying DCM, this
section discusses inflammatory and noninflammatory forms.
INFLAMMATORY CARDIOMYOPATHY (MYOCARDITIS)
There are a wide variety of toxins and drugs that cause inflam-
matory myocarditis (Table  2-3). Infectious myocarditis typi-
cally evolves through several stages of active infection, through
healing, and may ultimately culminate in DCM.
Myocarditis presents with the clinical picture of fatigue,
dyspnea, and palpitations, usually in the first weeks of the
infection, progressing to overt congestive heart failure
(CHF) with cardiac dilation, tachycardia, pulsus alternans,
and pulmonary edema. Between 10% and 33% of patients
with i­nfectious heart diseases will have ECG evidence of
 Chapter 2  Cardiac Diseases 35

­ yocardial involvement. Mural thrombi often form in the

m In the bacterial varieties of myocarditis, isolated ECG
ventricular cavity and may result in systemic or pulmonary
emboli. Supraventricular and ventricular arrhythmias are
common. Fortunately, patients usually have complete recov-
ery from infectious myocarditis, although exceptions include
myocarditis associated with diphtheria or Chagas’ disease.
Occasionally, acute myocarditis may even progress to a recur-
rent or chronic form of myocarditis, resulting ultimately in a
restrictive type of cardiomyopathy caused by fibrous replace-
ment of the myocardium.93,94
changes or pericarditis are common and usually benign,
whereas CHF is unusual. Diphtheritic myocarditis is generally
the worst form of bacterial myocardial involvement; in addi-
tion to inflammatory changes, its endotoxin is a competitive
analog of cytochrome B and can produce severe myocardial
dysfunction.95,96 The conduction system is especially affected
in diphtheria, producing either right or left bundle branch
block, which is associated with 50% mortality. When complete
heart block supervenes, mortality approaches 80% to 100%.

TABLE 2-3  n  Inflammatory Cardiomyopathies (Dilated)

Disease Process Mechanism Associated Circulatory Problems Miscellaneous

BACTERIAL Arrhythmias
ST–T-wave changes

Diphtherial Endotoxin competitive analog of Conduction system, especially BBB; rare Temporary pacing
cytochrome B valvular endocarditis often required

Typhoid Inflammatory changes* with fiber Arrhythmias

degeneration Endarteritis
Endocarditis
Pericarditis
Ventricular rupture

Scarlet fever Inflammatory changes Conduction disturbances

B-Hemolytic strep Arrhythmias

Meningococcus Inflammatory changes and endotoxin, DIC

generalized and coronary thrombosis Peripheral circulatory collapse (Waterhouse-
Friderichsen syndrome)

Staphylococcus Sepsis, acute endocarditis

Brucellosis Fiber degeneration and granuloma Endocarditis, pericarditis

formation

Tetanus Inflammatory changes, cardiotoxin Severe arrhythmias Apnea

Melioidosis Myocardial abscesses

Spirochetal Focal hemorrhage and inflammatory Severe arrhythmias Temporary pacing

leptospirosis changes Endocarditis and pericarditis

Syphilis

Rickettsial ECG changes

Pericarditis

Endemic typhus Inflammatory changes Arrhythmias

Epidemic typhus Symptoms secondary to vasculitis Vasculitis

and hypertension

VIRAL

Human Inflammatory changes Systolic and diastolic dysfunction

immunodeficiency Myocarditis Dilated cardiomyopathy and CHF
virus (HIV) Neoplastic infiltration Pericardial effusion
Endocarditis
Pulmonary hypertension

Coxsackievirus B Inflammatory changes Constrictive pericarditis

A-V nodal arrhythmias

Continued
 36 ANESTHESIA AND UNCOMMON DISEASES

TABLE 2-3  n  Inflammatory Cardiomyopathies (Dilated)—Cont'd

Disease Process Mechanism Associated Circulatory Problems Miscellaneous

Echovirus Inflammatory changes Dysrhythmia

Mumps Primary atypical pneumonia-associated Heart block

Influenza Stokes-Adams attacks Pericarditis

Infectious Herpes simplex-associated with

mononucleosis intractable shock

Viral hepatitis Arbovirus-constrictive pericarditis

is reported sequela

Rubella

Rubeola

Rabies

Varicella

Lymphocytic

Choriomeningitis

Psittacosis

Viral encephalitis

Cytomegalovirus

Variola

Herpes zoster

MYCOSES Usually obstructive symptoms

Cryptococcosis Reported CHF

Blastomycosis

Actinomycosis Valvular obstruction

Coccidioidomycosis Constrictive pericarditis

PROTOZOAL

Trypanosomiasis Inflammatory changes Severe arrhythmia secondary to conduction Pacing often

(Chagas’ disease; Neurotoxin of Trypanosoma cruzi system degeneration required
see text) Mitral and tricuspid insufficiency secondary
to cardiac enlargement

Sleeping sickness Inflammatory changes Unusual disease

manifestations

Toxoplasmosis Inflammatory changes Cardiac tamponade

Leishmaniasis Inflammatory changes Unusual

manifestations

Balantidiasis

HELMINTHIC Inflammatory changes

Trichinosis Usually secondary to adult or ova Arrhythmias

infestation of myocardium or coronary
insufficiency secondary to same

Schistosomiasis Cor pulmonale-secondary pulmonary

hypertension

Filariasis

*Inflammatory type usually associated with myofibrillar degeneration, inflammatory cell infiltration, and edema.
BBB, Bundle branch block; DIC, disseminated intravascular coagulation; ECG, electrocardiogram; CHF, congestive heart failure; A-V, atrioventricular.

Syphilis, leptospirosis, and Lyme disease represent three exam-
ples of myocardial infection by spirochetes.97 Tertiary syphilis
is associated with multiple problems, including arrhythmias,
conduction disturbances, and CHF. Lyme disease myocarditis
usually presents with conduction abnormalities, such as bra-
dycardia and A-V nodal block.98
Viral infections manifest primarily with ECG abnormali-
ties, including PR prolongation, QT prolongation, ST-segment
and T-wave abnormalities, and arrhythmias. However, each
viral disease produces slightly different ECG changes, with
complete heart block being the most significant. Most of
the viral diseases have the potential to progress to CHF if
the viral infection is severe.99 Recent advances in molecular
biologic techniques have allowed for more accurate identifi-
cation of viruses. Previously, coxsackievirus B was the most
common virus identified as producing severe viral heart dis-
ease. Currently, the most prevalent viral genomes detected are
enterovirus, adenovirus, and parvovirus B19.100–102 Although
the pathogenic role of enterovirus in myocarditis and chronic
DCM is well established, whether parvovirus B19 is inciden-
tal or pathogenic in viral myocarditis is still unclear. Epstein-
Barr virus (EBV) and human herpesvirus 6 (HHV-6) have also
been implicated in viral myocarditis. The presence of parvovi-
rus B19, EBV, and HHV-6 is associated with a decline in car-
diac function within 6 months.
Subsequently, there may be an autoimmune phase in
which the degree of the cardiac inflammatory response cor-
relates with a worse prognosis, which may culminate in
DCM.103 The 2009 H1N1 pandemic influenza strain was
associated with myocarditis as well. In one study, patients
with H1N1 influenza associated with myocarditis were pre-
dominantly female, young (mean age 33.2 years), and had
morbidity/mortality of 27%.104,105
Mycotic myocarditis has protean manifestations that
depend on the extent of mycotic infiltration of the myocar-
dium and may present as CHF, pericarditis, ECG abnormali-
ties, or valvular obstruction.
Of the protozoal forms of myocarditis, Chagas’ disease, or
trypanosomiasis, is the most significant, and the most com-
mon cause of chronic CHF in South America. ECG changes
of right bundle branch block and arrhythmias occur in 80%
of patients. In addition to the typical inflammatory changes
in the myocardium that produce chronic CHF, a direct neu-
rotoxin from the infecting organism, Trypanosoma cruzi, pro-
duces degeneration of the conduction system, often causing
severe ventricular arrhythmias and heart block with syncope.
The onset of atrial fibrillation in these patients is often an omi-
nous prognostic sign.106,107
Helminthic myocardial involvement may produce CHF, but
more frequently symptoms are secondary to infestation and
obstruction of the coronary or pulmonary arteries by egg, lar-
val, or adult forms of the worm. Trichinosis, for example, pro-
duces a myocarditis secondary to an inflammatory response
to larvae in the myocardium, even though the larvae them-
selves disappear from the myocardium after the second week
of infestation.
Chapter 2  Cardiac Diseases 37
NONINFLAMMATORY DILATED CARDIOMYOPATHY
The noninflammatory variety of dilated cardiomyopathy also
presents as myocardial failure, but in this case caused by idio-
pathic, toxic, degenerative, or infiltrative processes in the
myocardium108,109 (Table 2-4).
As an example of the toxic cardiomyopathy type, alcoholic
cardiomyopathy is a typical hypokinetic noninflammatory car-
diomyopathy associated with tachycardia and premature ven-
tricular contractions that progress to left ventricular failure
with incompetent mitral and tricuspid valves. This cardiomy-
opathy probably results from a direct toxic effect of ethanol
or its metabolite acetaldehyde, which releases and depletes
cardiac norepinephrine.110 Alcohol may also affect excitation-
contraction coupling at the subcellular level.111 In chronic alco-
holic patients, acute ingestion of ethanol produces decreases
in contractility, elevations in ventricular end-diastolic pres-
sure, increases in SVR and systemic hypertension.112–115
Alcoholic cardiomyopathy is classified into three hemody-
namic stages. In stage I, cardiac output, ventricular pressures,
and left ventricular end-diastolic volume (LVEDV) are nor-
mal, but the ejection fraction (EF) is decreased. In stage II, car-
diac output is normal, although filling pressures and LVEDV
are increased, and EF is decreased. In stage III, cardiac out-
put is decreased, filling pressures and LVEDV are increased,
and EF is severely depressed. Most noninflammatory forms of
DCM undergo a similar progression.
Doxorubicin (Adriamycin) is an antibiotic with broad-
spectrum antineoplastic activities. Its clinical effectiveness,
however, is limited by its cardiotoxicity. Doxorubicin produces
dose-related DCM. Doxorubicin may disrupt myocardial
mitochondrial calcium homeostasis. Patients treated with this
drug must undergo serial evaluations of left ventricular systolic
function.116,117 Dexrazoxane, a free-radical scavenger, may pro-
tect the heart from doxorubicin-associated damage.118
PATHOPHYSIOLOGY
The key hemodynamic features of the DCMs are elevated
filling pressures, failure of myocardial contractile strength,
and a marked inverse relationship between afterload and
stroke volume. Both the inherited and the nonfamilial
forms of inflammatory and noninflammatory DCMs pres-
ent a picture identical to that of CHF produced by severe
coronary artery disease (CAD). In some conditions the pro-
cess that has produced the cardiomyopathy also involves the
coronary arteries. The pathophysiologic considerations are
familiar. As the ventricular muscle weakens, the ventricle
dilates to take advantage of the increased force of contrac-
tion that results from increasing myocardial fiber length. As
the ventricular radius increases, however, ventricular wall
tension rises, increasing both the oxygen consumption of
the myocardium and the total internal work of the muscle.
As the myocardium deteriorates further, the cardiac output
falls, with a compensatory increase in sympathetic activity
to maintain organ perfusion and cardiac output. One fea-
ture of the failing myocardium is the loss of its ability to
maintain stroke volume in the face of increased a­ fterload.
 38 ANESTHESIA AND UNCOMMON DISEASES

TABLE 2-4  n  Noninflammatory Cardiomyopathies (Dilated)

Disease Process Mechanism Associated Circulatory Problems Miscellaneous

NUTRITIONAL DISORDERS

Beriberi Thiamine deficiency Peripheral A-V shunting with low SVR

Inflammatory changes Usually high-output failure with
decreased SVR, but low-output
failure with normal SVR may occur

Kwashiorkor Protein deprivation Degeneration of conduction system

METABOLIC DISORDERS

Amyloidosis Amyloid infiltration Associated with restrictive

of myocardium and obstructive forms of
cardiomyopathy
Valvular lesions
Conduction abnormalities

Pompe's disease α-Glucuronidase deficiency Septal hypertrophy

Glycogen storage disease Glycogen accumulation Decreased compliance

type II in cardiac muscle

Hurler's syndrome Accumulation of glycoprotein Mitral regurgitation

in coronary tissue, heart
parenchyma

Hunter's syndrome Same as for Hurler's Similar to but milder than Hurler's

Primary xanthomatosis Infiltration of myocardium Aortic stenosis

Advanced CAD

Uremia Multiple metastatic coronary Anemia Most cardiac manifestations

calcifications Hypertension dramatically improve after
Hypertension Conduction deficits dialysis
Electrolyte imbalance Pericarditis and cardiac tamponade

Fabry's disease Abnormal glycolipid metabolism Hypertension

secondary to ceramide CAD
trihexosidase with glycolipid
infiltration of myocardium

HEMATOLOGIC DISEASES

Leukemia Leukemic infiltration of Arrhythmias Usually resolves with

myocardium Pericarditis successful therapy

Sickle cell Intracoronary thrombosis with CAD

ischemic cardiomyopathy Cor pulmonale

NEUROLOGIC DISEASE

Duchenne's muscular Muscle fiber degeneration with Conduction defects possibly 50% incidence of cardiac
dystrophy fatty and fibrous replacement secondary to small-vessel CAD involvement

Friedreich's ataxia Similar to Duchenne's with Conduction abnormalities

collagen replacement of ? HOCM
degenerating myofibers

Roussy-Lévy hereditary Similar to Friedreich's ataxia

polyneuropathy

Myotonia atrophica Similar to above Conduction abnormalities, possibly

Stokes-Adams attacks

CHEMICAL AND TOXIC

Doxorubicin (see text)

Zidovudine (see text)

 Chapter 2  Cardiac Diseases 39

TABLE 2-4  n  Noninflammatory Cardiomyopathies (Dilated)­—Cont'd

Disease Process Mechanism Associated Circulatory Problems Miscellaneous

Ethyl alcohol (see text) Myofibrillar degeneration

secondary to direct toxic effect
of ethanol and/or acetaldehyde

Beer drinker's Probably from addition of cobalt Cyanosis Acute onset and rapid course
cardiomyopathy sulfate to beer, with myofibrillar
dystrophy and edema

Cobalt infection Similar to beer drinker's Predominant symptoms:

cardiomyopathy usually CNS, aspiration
pneumonitis

Phosphorus Myofibrillar degeneration Relatively unresponsive

secondary to direct toxic effect to adrenergic agents
of phosphorus, which prevents
amino acid incorporation into
myocardial proteins

Fluoride Direct myocardial toxin

Severe hypocalcemia secondary to
fluoride-binding of calcium ion

Lead Secondary to nephropathic Hypertension

hypertension
Direct toxin

Scorpion venom Sympathetic stimulation with Adrenergic blockade probably

secondary myocardial changes indicated

Tick paralysis ? Toxic myocarditis

Radiation Hyalinization and fibrosis Conduction abnormalities

caused by direct effect secondary to sclerosis of
of x-radiation conduction system; CAD
Constrictive myocarditis
and pericarditis

MISCELLANEOUS AND SYSTEMIC SYNDROMES

Rejection cardiomyopathy Lymphocytic infiltration and Arrhythmias and conduction After heart transplantation
general rejection phenomena abnormalities

Senile cardiomyopathy Unrelated to CAD

Rheumatoid arthritis Rheumatoid nodular invasion Mitral and aortic regurgitation; CAD
From coronary arteritis Constrictive pericarditis

Marie-Strümpell Generalized degenerative Aortic regurgitation

(ankylosing spondylitis) changes

Cogan's syndrome Fibrinoid necrosis of Aortic regurgitation

(nonsyphilitic interstitial myocardium CAD
keratitis)

Noonan's syndrome ? (No detectable chromosome Pulmonary stenosis

(male Turner's) abnormality) Obstructive and nonobstructive
cardiomyopathy

Pseudoxanthoma Connective tissue disorder with Valve abnormality

elasticum* myocardial infiltration and fibrosis CAD

Trisomy 17-18 Diffuse fibrosis ? Viral etiology

Scleroderma of Buschke Myocardial infiltration with acid Self-limited with good

mucopolysaccharides prognosis

Wegener's granulomatosis Panarteritis and myocardial Mitral stenosis (?)

granuloma formation Cardiac tamponade

Continued
 40 ANESTHESIA AND UNCOMMON DISEASES

TABLE 2-4  n  Noninflammatory Cardiomyopathies (Dilated)—Cont'd

Disease Process Mechanism Associated Circulatory Problems Miscellaneous

Periarteritis nodosa Panarteritis Conduction abnormalities

Hypertension changes CAD

Postpartum
cardiomyopathy

NEOPLASTIC DISEASES

Primary mural cardiac Obstructive symptoms

tumors

Metastases: malignant Mechanical impairment

(especially malignant of cardiac function
melanoma)

Sarcoidosis Cor pulmonale secondary Cor pulmonale

to pulmonary involvement ECG abnormalities and conduction
Sarcoid granuloma leading disturbances
to ventricular aneurysms Pericarditis
Valvular obstruction

*Also called nevus elasticus; Grönblad-Strandberg syndrome (and angioid retinal streaks).
A-V, Atrioventricular; CAD, coronary artery disease; CNS, central nervous system; HOCM, hypertrophic obstructive cardiomyopathy; SVR, systemic vascular resistance.

Normal
of mitral regurgitation is the mechanism of the improvement.
Afterload reduction also decreases left ventricular filling
pressure, which relieves pulmonary congestion and should
Moderate ventricular
dysfunction
preserve coronary perfusion pressure.120
The clinical picture of the DCM falls into the two famil-
iar categories of forward and backward failure. The features
Stroke volume

of “forward” failure, such as fatigue, hypotension, and oligu-

Failing ventricle
Afterload
FIGURE 2-2  Stroke volume (SV) as a function of afterload for
normal left ventricle, for left ventricle with moderate dysfunction,
and for failing left ventricle.
Figure 2-2 shows that in the failing ventricle, stroke v­ olume
falls almost linearly with increases in afterload. The increased
sympathetic outflow that accompanies left ventricular failure
initiates a vicious cycle of increased resistance to forward
flow, decreased stroke volume and cardiac output, and fur-
ther sympathetic stimulation in an effort to maintain circu-
latory homeostasis.
Mitral regurgitation is common in severe DCM due to
stretching of the mitral annulus (Carpentier Type I) and dis-
tortion of the geometry of the chordae tendineae, resulting
in restriction of leaflet apposition (Carpentier Type IIIb).119
The forward stroke volume improves with afterload reduc-
tion, even with no increase in EF. This suggests that reduction
ria, are caused by decreases in cardiac output with reduced
organ perfusion. Reduced perfusion of the kidneys results in
activation of the renin-angiotensin-aldosterone system, which
increases the effective circulating blood volume through
sodium and water retention. “Backward” failure is related to
the elevated filling pressures required by the failing ventricles.
As the left ventricle dilates, end-diastolic pressure rises, and
mitral regurgitation worsens. The manifestations of left-sided
failure include orthopnea, paroxysmal nocturnal dyspnea, and
pulmonary edema. The manifestations of right-sided failure
include hepatomegaly, jugular venous distention, and periph-
eral edema.
ANESTHETIC CONSIDERATIONS
Electrocardiographic monitoring is essential in the manage-
ment of patients with DCMs, particularly in those with myo-
carditis. Ventricular arrhythmias are common, and complete
heart block, which can occur from these conditions, requires
rapid diagnosis and treatment. The ECG is also useful in mon-
itoring ischemic changes when CAD is associated with the
cardiomyopathy, as in amyloidosis.
Direct invasive intra-arterial BP monitoring during sur-
gery provides continuous information and a convenient route
for obtaining arterial blood gases (ABGs). Any DCM patient
with a severely compromised myocardium who requires

anesthesia and surgery should have central venous access
for monitoring and vasoactive drug administration. The use
of a PAC is much more controversial. The American Society
of Anesthesiologists (ASA) Task Force on Pulmonary Artery
Catheterization has published practice guidelines.121,122 The
indication for PAC placement depends on a combination of
patient-, surgery-, and practice setting–related factors. Patients
with severely decreased cardiac function from DCM have sig-
nificant cardiovascular disease and are considered at increased
or high risk. With no evidenced-based medicine to support
outcome differences, recommendations for PAC monitoring
were based on expert opinion at that time. Patients with DCM
presenting for surgery who have an overall increased or high-
risk score should probably have hemodynamic parameters
monitored with a PAC. In addition to measuring right- and
left-sided filling pressures, a thermodilution PAC may be used
to obtain cardiac output and calculate SVR and pulmonary
vascular resistance (PVR), which allow for serial evaluation of
the patient's hemodynamic status. PACs with fiberoptic oxim-
etry, rapid-response thermistor catheters that calculate right
ventricular EF, and pacing PAC are available. Pacing PAC and
external pacemakers provide distinct advantages in manag-
ing the patient with myocarditis and associated heart block.
Recent evidence seems to provide further support for clini-
cians who choose not to use PAC monitoring on the basis of
no outcome differences between high-risk surgical patients
who were cared for with and without PAC monitoring and
goal-directed therapy.123–125
Transesophageal echocardiography provides useful data
on ventricular filling, ventricular function, severity of mitral
regurgitation, and response of the impaired ventricle to anes-
thetic and surgical manipulations. Recent guidelines indicate
that hemodynamic decompensation is a class I indication for
TEE monitoring.126–128 With the increased availability of equip-
ment and trained anesthesiologists, TEE will become increas-
ingly important in the perioperative management of patients
with cardiomyopathies.
The avoidance of myocardial depression still remains
the goal of anesthetic management for patients with DCM,
although, paradoxically, beta-adrenergic blockade has been
associated with improved hemodynamics and improved sur-
vival in patients with DCM.129–133 (This may result from an
antiarrhythmic effect.) All the potent volatile anesthetic agents
are myocardial depressants, and therefore high concentrations
of these agents are probably best avoided in these patients.
Low doses are usually well tolerated, however, and frequently
used as part of a balanced anesthetic.
For the patient with severely compromised myocardial
function, the synthetic piperidine narcotics (fentanyl,
sufentanil, remifentanil) are useful because myocardial con-
tractility is not depressed. Bradycardia associated with high-
dose narcotic anesthesia may be prevented by the use of
pancuronium for muscle relaxation, anticholinergic drugs, or
­pacing. Pancuronium, however, should be avoided in patients
with impaired renal function, a common problem in cardio-
myopathy patients. For peripheral or lower abdominal s­ urgical
Chapter 2  Cardiac Diseases 41
procedures, a regional anesthetic technique is a reasonable
alternative, provided filling pressures are carefully controlled
and the hemodynamic effects of the anesthetic are monitored.
A recent study suggests that thoracic epidural used as a ther-
apeutic strategy in addition to medical therapy in patients
with DCM may improve cardiac function and reduce hospi-
tal readmission and mortality.134 One problem is that regional
anesthesia is frequently contraindicated because patients with
cardiomyopathies are frequently treated with anticoagulant and
antiplatelet drugs to prevent embolization of mural thrombi
that develop on hypokinetic ventricular wall segments.
In planning anesthetic management for the patient with
DCM, associated cardiovascular conditions, such as the pres-
ence of CAD, valvular abnormalities, LVOT obstruction, and
constrictive pericarditis should also be considered. Patients
with CHF often require circulatory support intraoperatively
and postoperatively. Inotropic drugs such as dopamine and
dobutamine are effective in low output states and produce
modest changes in SVR at lower dosages. In severe ventric-
ular failure, more potent drugs such as epinephrine may be
required. Phosphodiesterase-III inhibitors, such as milrinone,
with inotropic and vasodilating properties, may improve
hemodynamic performance. As previously noted, stroke vol-
ume is inversely related to afterload in the failing ventricle,
and reduction of left ventricular afterload with vasodilating
drugs such as nicardipine, nitroprusside, and nesiritide are
also effective in increasing cardiac output.
In patients with myocarditis, especially of the viral variety,
transvenous or external pacing may be required should heart
block occur. Intra-aortic balloon counterpulsation, left ven-
tricular assist devices, and cardiac transplantation are further
options to be considered in the case of the severely compro-
mised ventricle. Incidence of supraventricular and ventric-
ular arrhythmias increases in myocarditis and DCM.135,136
These arrhythmias often require extensive electrophysiologic
workup and may be unresponsive to maximal medical ther-
apy. Frequently, patients with DCM present for AICD implan-
tation or ventricular arrhythmia ablation procedures.137
Restrictive Cardiomyopathies
Primary restrictive nonhypertrophied cardiomyopathy is a
rare form of heart muscle disease and heart failure charac-
terized by biatrial enlargement, normal or decreased volume
of both ventricles, normal left ventricular wall thickness and
A-V valves, and impaired ventricular filling with restrictive
pathophysiology. Restrictive (or restrictive/obliterative) car-
diomyopathies are usually the end stage of myocarditis or an
infiltrative myocardial process (amyloidosis, hemochromato-
sis, scleroderma, eosinophilic heart disease) or the result of
radiation treatment138 (Table 2-5). New evidence suggests that
restrictive cardiomyopathy is genetic in origin, with mutations
in sarcomeric contractile protein genes.139,140
Restrictive cardiomyopathy may share characteristics with
constrictive pericarditis. Cardiac output is maintained in the
early stages by elevated filling pressures and an increased
 42 ANESTHESIA AND UNCOMMON DISEASES
TABLE 2-5  n  Restrictive/Obliterative Cardiomyopathies (Including Restrictive Endocarditis)
Disease Process Mechanism
End stage of acute Fibrous replacement
myocarditis of myofibrils
Metabolic Amyloid infiltration of myocardium
Amyloidosis
Hemochromatosis Iron deposition and secondary
fibrous proliferation
Drugs: methysergide Endocardial fibroelastosis
(Sansert)
Restrictive endocarditis Picture very similar to constrictive
pericarditis
Carcinoid Serotonin-producing carcinoid
tumors, but serotonin is apparently
not causative agent for fibrosis.
Endomyocardial fibrosis Fibrous obliteration of ventricular
cavities
Löffler's syndrome Fibrosis of endocardium with
decreased myocardial contraction
Becker's disease Similar to Löffler's
heart rate. However, in contrast to constrictive pericarditis, an
increase in myocardial contractility to maintain cardiac out-
put is usually not possible.141 Thromboembolic complications
are common and may be the initial presentation. Advanced
states can lead to elevated jugular venous pressure, peripheral
edema, liver enlargement, ascites, and pulmonary congestion.
Also, whereas constrictive pericarditis is usually curable surgi-
cally, restrictive cardiomyopathy requires medical therapy and
in some patients, valvular repair or cardiac transplantation.
Imaging techniques such as echocardiographic evaluation
with speckle-track imaging, velocity vector imaging combined
with computed tomography (CT), and cardiac magnetic reso-
nance imaging (MRI) can help differentiate constrictive and
restrictive types of cardiomyopathy.138,142
ANESTHETIC CONSIDERATIONS
Anesthetic and monitoring considerations in patients with
restrictive cardiomyopathies are similar to those of constric-
tive pericarditis and cardiac tamponade, with the additional
feature of poor ventricular function in later stages of the dis-
ease. (See Constrictive Pericarditis later for the physiology
and management of restrictive ventricular filling and earlier
Dilated Cardiomyopathy for the management of impaired
ventricular function.) Anesthetic management depends on
whether restrictive physiology or heart failure is predominant.
Despite normal ventricular function, diastolic dysfunction
in patients with restrictive cardiomyopathy leads to a low car-
diac output state. Monitoring should include at a minimum
invasive intra-arterial BP monitoring, and central venous access
Associated Circulatory Problems Miscellaneous
Valvular malfunction
Coronary artery disease
Conduction abnormalities
Valvular stenosis Similar to changes in
carcinoid syndrome
Pulmonary stenosis
Tricuspid insufficiency and/or stenosis
Right-sided heart failure
Mitral and tricuspid insufficiency
Subendocardial and papillary muscle
degeneration and fibrosis
Similar to Löffler's
should be established in patients with advanced disease. A PAC
offers the advantage of cardiac output measurement and the
assessment of loading conditions, both of which may be helpful
in guiding anesthetic management, even though outcome data
has not been established for this particular group of patients.
When inducing anesthesia, it may be prudent to avoid
medications that produce bradycardia, decreased venous
return, and myocardial depression. Etomidate can be used
for anesthesia induction with little impact on hemodynamics
and myocardial function.143 Ketamine, even though intrinsic
cardiodepressive properties have been described, maintains
SVR and is frequently used in these patients. Anesthesia can
typically be maintained with a balanced anesthesia technique
using lower doses of inhaled potent volatile anesthetics, sup-
plemented with an opioid such as fentanyl or sufentanil.144,145
A high-dose opioid technique, as recommended in the past, is
usually reserved for patients with advanced disease who may
not tolerate inhalational anesthetic agents.
Human Immunodeficiency Virus and the Heart
According to the U.S. Centers for Disease Control and Prevention
(CDC), at the end of 2010, more than 1 million people in the
United States and more than 34 million worldwide may be
infected with the human immunodeficiency virus (HIV).146,147
HIV affects all organ systems, including the cardiovascular sys-
tem. The heart can be affected by the virus directly, by oppor-
tunistic infections related to the immunocompromised state, by
malignancies common to the disease, and by drug therapy.
 Chapter 2  Cardiac Diseases 43

Left ventricular diastolic function is affected early in the Miscellaneous Cardiomyopathies

course of HIV infection. Echocardiographic evaluation of 51
STRESS (TAKOTSUBO) CARDIOMYOPATHY
HIV-positive patients compared with data from age-matched
Stress cardiomyopathy is a relatively recently described clinical
and gender-matched controls found that HIV-positive
entity, also known by its Japanese name, Takotsubo, (“octopus
patients, regardless of the presence of symptomatic disease,
trap”). It is typically characterized by reversible apical left ven-
had impaired LV diastolic function.148 The mechanism of
tricular systolic dysfunction in the absence of atherosclerotic
dysfunction is unclear but may be secondary to viral myo-
CAD that is triggered by profound psychological stress.170,171
carditis; the clinical significance remains to be determined.
Although traditionally the disease is described as “apical bal-
Systolic dysfunction has been reported later in the disease
looning” (resembling an octopus trap), Takotsubo cardiomy-
course. Signs and symptoms of LV failure may also be masked
opathy may manifest as midventricular and basal ventricular
by concurrent pulmonary disease. Pulmonary hypertension
dysfunction.172 The ventricular pathology overall is the result
also has been described in patients with HIV infection.149
of myocardial stunning, leading to transient periods of isch-
Systolic dysfunction in HIV-positive patients may be a side
emia, possibly from coronary artery vasospasm.173 Other pro-
effect of antiviral medications, especially the reverse-transcriptase
posed mechanisms include catecholamine-induced damage,
inhibitor zidovudine (AZT).150 Electron microscopy studies
microvascular endothelial dysfunction, and neurogenically
show that AZT disrupts the mitochondrial apparatus of cardiac
mediated myocardial stunning.174 On ECG, this disease mim-
muscle.151,152 Children infected with HIV who were treated with
ics ST-elevation myocardial infarction.175,176
AZT had a significant decrease in LV ejection fraction compared
Treatment includes providing mechanical ventilatory sup-
with those not receiving AZT; Domanski et al.150 recommended
port, vasopressors to support systemic blood pressure, and
serial evaluation of LV function. Starc et al.153 found that 18%
diuretics as needed.177–179 Fortunately, stress cardiomyopathy is
to 39% of children diagnosed with acquired immunodeficiency
usually transient and resolves with supportive care.
syndrome (AIDS) developed cardiac dysfunction within 5 years
There is no current consensus on how to best deliver anesthe-
of follow-up, and that cardiac dysfunction was associated with
sia to patients with a history of Takotsubo cardiomyopathy. Most
an increased risk of death. The effects of the newer antiviral
case reports describe that adverse events occurred mostly dur-
agents on the heart have not yet been established.
ing general anesthesia, and surgery performed under regional
Heart involvement was found in 45% of patients with AIDS
anesthesia was well tolerated. Such reports are so few, however,
in an autopsy study.154 Pericardial effusion, DCM, aortic root
that recommendations on anesthesia technique cannot be made
dilation and regurgitation, and valvular vegetations were the
at this time.180–186 It seems prudent to make attempts to prevent
more frequent findings.155,156 The pericardium is sometimes
emotional stress or sympathetic surges, which frequently occur
affected by opportunistic infections (e.g., cytomegalovirus)
in the perioperative period. Adequate sedation and anxiolysis
and tumors (e.g., Kaposi's sarcoma, non-Hodgkin's lym-
should therefore be provided preoperatively.
phoma). Additionally, an autonomic neuropathy associated
with HIV infection can cause QT prolongation, which may
predispose these patients to ventricular arrhythmias.157 PERIPARTUM CARDIOMYOPATHY
Peripartum cardiomyopathy typically develops during the
ANESTHETIC CONSIDERATIONS third trimester of pregnancy or within 5 months after deliv-
General anesthesia is considered safe in HIV/AIDS patients, ery.187,188 It is a distinct form of cardiomyopathy and unre-
but drug interactions and their impact on various organ sys- lated to any other cause of heart failure. Symptoms are those
tems and the patient's overall physical status should be consid- of systolic heart failure, including sudden cardiac arrest, and
ered preoperatively. Rarely, patients with advanced disease may develop in the majority of patients within 4 months after
also have pericardial involvement with pericardial effusion and delivery.189 Perioperative cardiomyopathy (HCM) carries
tamponade. An echocardiographic evaluation may provide a significant risk for high morbidity and mortality, but full
useful information in this setting. A preoperative chest radio- recovery is possible.190 Treatment and anesthetic management
graph should be available in all symptomatic patients undergo- of patients with peripartum cardiomyopathy depend on the
ing surgery under general anesthesia to rule out tuberculosis severity of presenting symptoms. The most common form
and acute pulmonary infections. Although general anesthe- of clinical presentation for anesthesiologists is significantly
sia may suppress the immune system, no adverse effects on decreased systolic cardiac function, including cardiogenic
patients with HIV/AIDS have been found.158 Regional anesthe- shock, and should be treated accordingly. The underlying
sia is often the technique of choice, and early concerns regard- pathophysiology is similar to that of a dilated cardiomyopa-
ing neuraxial anesthesia and the potential spread of infectious thy, as discussed earlier.
material intrathecally could not be confirmed.159–164
Drug interactions between antiviral medications and drugs
Secondary Cardiomyopathies
used during anesthesia induction and maintenance have been
described,165–167 but serious side effects are rare. Antiviral Many disease processes lead to myocardial pathology, and the
medications should be continued perioperatively in patients presentation varies with secondary cardiomyopathies. Each
scheduled for surgery.168,169 patient should receive individualized treatment based on the
 44 ANESTHESIA AND UNCOMMON DISEASES

manifestations of their specific disease. Typically the under-

TABLE 2-6  n Primary Neoplasms of the Heart
lying etiology will result in a cardiac manifestation affecting and Pericardium
the myocardium or valvular function, and perioperative care
should be managed accordingly. Type No. Cases Percentage

BENIGN
CARDIAC TUMORS Myxoma 130 29.3
Primary tumors of the heart are unusual. However, the Lipoma 45 10.1
likelihood of encountering a cardiac tumor increases when
Papillary fibroelastoma 42 9.5
metastatic tumors of the heart and pericardium are con-
sidered. For example, breast cancer and lung cancer metas- Rhabdomyoma 36 8.1
tasize frequently to the heart.191 Primary cardiac tumors
Fibroma 17 3.8
may occur in any chamber or in the pericardium and may
arise from any cardiac tissue. Of the benign cardiac tumors, Hemangioma 15 3.4
myxoma is the most common, followed by lipoma, papil- Teratoma 14 3.2
lary fibroelastoma, rhabdomyoma, fibroma, and heman-
gioma192–194 (Table  2-6). The generally favorable prognosis Mesothelioma of A-V node 12 2.7
for patients with benign cardiac tumors is in sharp contrast Granular cell tumor 3 0.7
to the prognosis for those with malignant cardiac tumors.
Neurofibroma 3 0.7
The diagnosis of a malignant primary cardiac tumor is sel-
dom made before extensive local involvement and metas- Lymphangioma 2 0.5
tases have occurred, making curative surgical resection an Subtotal 319 72.0
unlikely event.
MALIGNANT

Benign Cardiac Tumors Angiosarcoma 39 8.8

Rhabdomyosarcoma 26 5.8
Myxomas are most frequently benign tumors. They typically
originate from the region adjacent to the fossa ovalis and project Mesothelioma 19 4.2
into the left atrium. They are usually pedunculated masses that
Fibrosarcoma 14 3.2
resemble organized clot on microscopy and may be gelatinous
or firm. A left atrial myxoma may prolapse into the mitral valve Malignant lymphoma 7 1.6
during diastole. This often results in a ball-valve obstruction to Extraskeletal osteosarcoma 5 1.1
left ventricular inflow that mimics mitral stenosis; it may also
cause valvular damage by a “wrecking-ball” effect. More friable Neurogenic sarcoma 4 0.9
tumors result in systemic or pulmonary embolization, depend- Malignant teratoma 4 0.9
ing on the location and the presence of any intracardiac shunts.
Thymoma 4 0.9
Pulmonary hypertension may result from mitral valve obstruc-
tion or regurgitation caused by a left atrial myxoma, or pulmo- Leiomyosarcoma 1 0.2
nary embolization in the case of a right atrial myxoma. Atrial Liposarcoma 1 0.2
fibrillation may be caused by atrial volume overload. Surgical
therapy requires careful manipulation of the heart before insti- Synovial sarcoma 1 0.2
tution of cardiopulmonary bypass, to avoid embolization, and Subtotal 125 28
resection of the base of the tumor to prevent recurrence, with
444 100
overall very good early and long-term outcomes.195–197 total

Other benign cardiac tumors occur less frequently. In gen-

eral, intracavitary tumors result in valvular dysfunction or
obstruction to flow, and tumors localized in the myocardium
cause conduction abnormalities and arrhythmias. Papilloma
(papillary fibroelastoma) is usually a single, villous connective
tissue tumor that results in valvular incompetence or coronary
ostial obstruction. Cardiac lipoma is an encapsulated collec-
tion of mature fat cells. Lipomatous hypertrophy of the inter-
atrial septum is a related disorder that may result in right atrial
obstruction. Rhabdomyoma is a tumor of cardiac muscle that
occurs in childhood and is associated with tuberous sclerosis.
Fibroma is another childhood cardiac tumor.198
Malignant Cardiac Tumors
Of the 10% to 25% of primary cardiac tumors that are malig-
nant, almost all are sarcomas.199,200 The curative therapy of sar-
comas is based on wide local excision that is not possible in the
heart. Also, the propensity toward early metastasis contributes
to the dismal prognosis. Rhabdomyosarcoma may occur in neo-
nates, but most cardiac sarcomas occur in adults. Sarcomas may
originate from vascular tissue, cardiac or smooth muscle, and
any other cardiac tissue. Palliative surgery may be indicated to

relieve symptoms caused by mass effects.201 Patients with these
tumors respond poorly to radiotherapy and chemotherapy.202
Metastatic Cardiac Tumors
Breast cancer, lung cancer, lymphomas, and leukemia may all
result in cardiac metastases. About one fifth of patients who
die of cancer have cardiac metastases. Thus, metastatic cardiac
tumors are much more common than primary ones. Myocardial
involvement results in CHF and may be classified as a restric-
tive cardiomyopathy. Pericardial involvement results in cardiac
compression from tumor mass or tamponade caused by effu-
sion. Melanoma is particularly prone to cardiac metastasis.203
Cardiac Manifestations of Extracardiac Tumors
Carcinoid is a tumor of neural crest origin that secretes sero-
tonin, bradykinin, and other vasoactive substances.204 Hepatic
carcinoid metastases result in right-sided valvular lesions,
presumably from a secretory product that is metabolized in
the pulmonary circulation. Recently, serotonin itself has been
implicated in the pathogenesis of tricuspid valve dysfunc-
tion.205–207 The end result is thickened valve leaflets that may
be stenotic or incompetent, although regurgitation is more
common.
Pheochromocytoma is a catecholamine-secreting tumor
also of neural crest origin. Chronic catecholamine excess has
toxic effects on the myocardium that may result in a dilated
cardiomyopathy.208
Anesthetic Considerations
The presence of a cardiac tumor requires a careful preoperative
assessment of cardiac morphology and function. Transthoracic
and transesophageal echocardiography, CT, and MRI are all
used for diagnosis and assessment of treatment options. For the
anesthesiologist planning for the appropriate technique, these
imaging results are essential. A right-sided tumor, for exam-
ple, is a relative contraindication to PAC insertion because of
the risk of embolization. Functional mitral stenosis caused by
a large left atrial myxoma may require hemodynamic manage-
ment similar to that of fixed mitral stenosis should the patient
A B
Chapter 2  Cardiac Diseases 45
become hemodynamically unstable. Adequate preload to
maximize ventricular filling in the presence of an obstructing
tumor, slow heart rate, and high afterload to maintain perfu-
sion pressure in the setting of a fixed low cardiac output, are all
goals when planning an appropriate anesthetic technique. The
use of intraoperative TEE can be invaluable in the management
of patients with cardiac tumors (Fig.  2-3). In the 2010 prac-
tice guideline update, use of TEE is recommended for all open-
heart surgery, including removal of intracardiac tumors.126
Carcinoid tumors demand more challenging manage-
ment strategies because the hypotension that can result from
their manipulation may not be responsive to, and may even
be provoked by, certain vasoactive drugs, including epineph-
rine, norepinephrine, and dopamine. Castillo et  al.209 review
the management of patients undergoing surgery for carci-
noid heart disease. Usually, general anesthetic management
includes administration of a preoperative loading dose of the
somatostatin analog octreotide, followed by a continuous infu-
sion. Episodes of hypotension and hypertension are treated
with additional octreotide boluses and vasoactive drugs.
Epinephrine should probably be avoided and has been associ-
ated with higher mortality in a recent study. Weingarten et al.210
acknowledge, however, that patients receiving epinephrine
had worse preoperative New York Heart Association (NYHA)
functional class symptoms, which could partly explain this
finding. The use of vasopressin in the hypotensive patient
with carcinoid is generally considered safe. Most inotropic and
vasoactive drugs have been administered in these patients in
true emergencies and during significant hemodynamic com-
promise when unresponsive to octreotide alone. The periop-
erative administration of octreotide probably decreases the
triggering effect of these drugs. Histamine-releasing medi-
cations (e.g., morphine, meperidine, atracurium) should be
avoided. Induction medications (e.g., etomidate, propofol)
and benzodiazepines (e.g., midazolam) have all been used suc-
cessfully in patients with carcinoid disease.
ISCHEMIC HEART DISEASE
The most important aspects of coronary artery disease remain
the same regardless of the etiology of the obstruction in the
coronary arteries. As with that produced by arteriosclerosis,
FIGURE 2-3  A, Transesophageal
echocardiogram of mass on
right cusp of aortic valve. B,
Photograph of resected aortic
valve from same patient, with
the tumor attached to right cusp.
 46 ANESTHESIA AND UNCOMMON DISEASES
the CAD produced by an uncommon disease retains the key
clinical features. Physiologic considerations remain essentially
the same, as do treatment and anesthetic management.
The preoperative assessment should determine the symp-
toms produced by the CAD. Symptoms in the patient history
are angina, exercise limitations, and those of myocardial fail-
ure, such as orthopnea or paroxysmal nocturnal dyspnea. The
physical examination retains its importance, especially when
quantitative data regarding cardiac involvement are not avail-
able. Physical findings such as S3 and S4 heart sounds are
important, as are auscultatory signs of uncommon conditions
such as cardiac bruits, which might occur in a coronary arte-
riovenous fistula. If catheterization, echocardiography, and
other imaging data are available, the specifics of coronary
artery anatomy and ventricular function, such as end-­diastolic
pressure, ejection fraction, and presence of wall motion abnor-
malities, are all useful in guiding management.211,212
After ascertaining the extent of CAD, the clinician should
consider special aspects of the disease entity producing the
coronary insufficiency. In ankylosing spondylitis, for exam-
ple, coronary insufficiency is produced by ostial stenosis, yet
valvular problems often coexist and even overshadow the
CAD.213 In rheumatoid arthritis, however, airway problems
may be the most significant part of the anesthetic challenge.
Hypertension, which frequently coexists with arteriosclerotic
CAD, is also a feature of the CAD produced by Fabry's dis-
ease. Other features to consider are metabolic disturbances, as
when systemic lupus erythematosus produces both CAD and
renal failure.214
Physiology of Coronary Artery Disease and
Modification by Uncommon Disease
The key to the physiology of CAD is the balance of myocar-
dial oxygen (O2) supply and demand (Fig.  2-4). Myocardial
O2 supply depends on many factors, including the heart rate,
patency of the coronary arteries, hemoglobin concentra-
tion, Pao2, and coronary perfusion pressure. The same fac-
tors determine supply in uncommon diseases, but the specific
manner in which an uncommon disease modifies these fac-
tors should be sought. A thorough knowledge of the anatomy
of the coronary circulation and how the disease process can
affect arterial patency is a useful starting point; this informa-
tion is usually derived from coronary angiography. In assess-
ing the adequacy of coronary perfusion, the viscosity of the
blood should be considered because flow is a function both of
the dimensions of the conduit and the nature of the fluid in the
system. In disease processes such as thrombotic thrombocy-
topenic purpura, sickle cell disease, or polycythemia vera, the
altered blood viscosity can assume critical importance.215–218
Oxygen carrying capacity must also be considered in cer-
tain uncommon disease states. Hemoglobin concentration
is usually not a limiting factor in the O2 supply to the myo-
cardium. However, in diseases such as leukemia, anemia
may be a prominent feature, and the myocardial O2 supply
may be reduced accordingly. Another example is myocardial
Myocardial O2 Balance
O2 Supply O2 Demand
1. Coronary blood flow 1. Blood pressure (afterload)
2. Oxygen delivery 2. Ventricular volume (preload)
a. O2 saturation 3. Heart rate
b. Hematocrit 4. Contractility
FIGURE 2-4  Myocardial oxygen supply and demand balance.
ischemia in carbon monoxide poisoning, where the hemo-
globin, although quantitatively sufficient, cannot carry oxy-
gen. Similarly, the partial pressure of oxygen in arterial blood
(Pao2) is usually not a limiting factor. However, in conditions
where CAD coexists with cor pulmonale, as in schistosomi-
asis or sickle cell disease, the inability to maintain adequate
­oxygenation may limit the myocardial O2 supply. In sickle
cell disease it may be the key feature; failure to maintain an
adequate Pao2, secondary to repeated pulmonary infarctions,
further increases the tendency of cells containing hemoglo-
bin S to sickle, compromising myocardial O2 delivery through
“sludging” in the coronary microcirculation.219
The major factors determining myocardial O2 demand
include heart rate, ventricular wall tension, and myocar-
dial contractility. Tachycardia and hypertension after tra-
cheal intubation, skin incision, or other noxious stimuli are
common causes of increased myocardial O2 demand dur-
ing surgery. Additionally, complicating factors of an unusual
disease may also produce increases in demand. Increases in
rate may occur as a result of tachyarrhythmias secondary to
sinoatrial (SA) or A-V nodal involvement in amyloidosis or
in Friedreich's ataxia. Increases in wall tension may occur in
severe hypertension associated with systemic lupus erythema-
tosus (SLE), periarteritis nodosa, or Fabry's disease. Outflow
tract obstruction with increased ventricular work can occur in
primary xanthomatosis or tertiary syphilis; and diastolic ven-
tricular radius can also increase, with greater wall tension, as
in aortic regurgitation associated with ankylosing spondylitis.
Modern cardiac anesthesia practice should tailor the
anesthetic management to the problems posed by the pecu-
liarities of the coronary anatomy. For example, knowledge
of the presence of a lesion in the left main coronary artery
dictates great care during anesthesia to avoid even modest
hypotension or tachycardia. Lesions of the right coronary
artery are known to be associated with an increased inci-
dence of atrial arrhythmias and heart block, and steps must
be taken either to treat these or to compensate for their car-
diovascular effects.

In diseases such as primary xanthomatosis or Hurler's
syndrome, the infiltrative process that produces CAD usu-
ally involves the coronary arteries diffusely, but some diseases
may have features that can mimic either isolated left main
CAD or right CAD. Bland-White-Garland syndrome, which
is anomalous origin of the left coronary artery from the pul-
monary artery, and coronary ostial stenosis produced by aor-
tic valve prosthesis both behave as left main CAD. A similar
syndrome could be produced by bacterial overgrowth of the
coronary ostia, ankylosing spondylitis, a dissecting aneurysm
of the aorta, or Takayasu's arteritis. Right CAD could be mim-
icked by the syndrome of the anomalous origin of the right
coronary artery from the pulmonary artery, or infiltration of
the SA or A-V nodes in amyloidosis or Friedreich's ataxia.
In small-artery arteritis, which occurs in periarteritis nodosa
or SLE, the small arteries supplying the SA or A-V nodes may
be involved in the pathologic process, producing ischemia of
the conduction system.
The uncommon diseases that produce CAD can be divided
into those that produce CAD associated with good (normal) left
ventricular function and those associated with poor LV func-
tion (Box  2-2). In any of these diseases, ventricular ­function
can regress from good to poor. In some conditions the CAD
progression and ventricular deterioration occur at the same
rate, and LV function is eventually severely depressed. In other
situations, coronary insufficiency is primary, and LV dysfunc-
tion eventually occurs after repeated episodes of ischemia and
thrombosis. Ventricular function must be evaluated by clini-
cal signs and symptoms, echocardiography, nuclear imaging,
MRI, or cardiac catheterization. The converse is severe arte-
rial disease coupled with relatively good LV function. This is
the picture of a cardiomyopathy associated with almost inci-
dental CAD, as occurs in Hurler's syndrome, amyloidosis, or
SLE. Most anatomic lesions, such as Kawasaki's disease, cor-
onary AV fistula, and trauma-induced coronary insufficiency,
are usually associated with good LV function. There is a clini-
cal “gray zone” where CAD and poor LV function coexist, with
neither process predominating, such as with tuberculosis and
syphilis. These diseases can only be characterized by investigat-
ing the extent of involvement of the coronary arteries and the
myocardium in the disease process. The following discussion
focuses on select disease states that affect the coronary arteries.
Uncommon Causes of Ischemic Heart Disease
CORONARY ARTERY SPASM
The luminal narrowing of the coronary arteries second-
ary to spasm has been associated with angina and myocar-
dial infarction (MI).220 The mechanism of coronary artery
spasm remains unclear. The smooth muscle cells of the coro-
nary artery walls may contract in response to various stim-
uli.221 There may be abnormal responses to various vasoactive
substances,222,223 and, in addition, there may be increased
alpha-adrenergic tone.224 Another theory is that vessels with
eccentric atherosclerotic plaques have a segment of disease-free
wall that may be a site for vasospasm, which can convert an
Chapter 2  Cardiac Diseases 47
BOX 2-2   n UNCOMMON CAUSES OF CORONARY
ARTERY DISEASE
Coronary Artery Disease Associated with Cardiomyopathy
(Poor Left Ventricular Function)
A. Pathologic basis: infiltration of coronary arteries with luminal narrowing
1. Amyloidosis: valvular stenosis, restrictive cardiomyopathy
2. Fabry's disease: hypertension
3. Hurler's syndrome: often associated with valvular malfunction
4. Hunter's syndrome: often associated with valvular malfunction
5. Primary xanthomatosis: aortic stenosis
6. Leukemia: anemia
7. Pseudoxanthoma elasticum: valve abnormalities
B. Inflammation of coronary arteries
1. Rheumatic fever: in acute phase
2. Rheumatoid arthritis: aortic and mitral regurgitation,
constrictive pericarditis
3. Periarteritis nodosa: hypertension
4. Systemic lupus erythematosus: hypertension, renal failure,
mitral valve malfunction
C. Embolic or thromboembolic occlusion of coronary arteries
1. Schistosomiasis
2. Sickle cell anemia: cor pulmonale depending on length and
extent of involvement
D. Fibrous and hyaline degeneration of coronary arteries
1. Post transplantation
2. Radiation
3. Duchenne's muscular dystrophy
4. Friedreich's ataxia: possibly associated with hypertrophic
obstructive cardiomyopathy
5. Roussy-Lévy syndrome: hereditary polyneuropathy
E. Anatomic abnormalities of coronary arteries
1. Bland-White-Garland syndrome (left coronary artery arising from
pulmonary artery): endocardial fibroelastosis, mitral regurgitation
2. Ostial stenosis secondary to ankylosing spondylitis: aortic
regurgitation
Coronary Artery Disease Usually Associated with Normal
Ventricular Function
A. Anatomic abnormalities of coronary arteries
1. Right coronary arising from pulmonary artery
2. Coronary arteriovenous fistula
3. Coronary sinus aneurysm
4. Dissecting aneurysm
5. Ostial stenosis: bacterial overgrowth syphilitic aortic
6. Coronary artery trauma: penetrating or nonpenetrating
7. Spontaneous coronary artery rupture
8. Kawasaki's disease: coronary artery aneurysm
B. Embolic or thrombotic occlusion
1. Coronary emboli
2. Malaria and/or malarial infested red blood cells
3. Thrombotic thrombocytopenic purpura
4. Polycythemia vera
C. Infections
1. Miliary tuberculosis: intimal involvement of coronary arteries
2. Arteritis secondary to salmonella or endemic typhus
(associated with active myocarditis)
D. Infiltration of coronary arteries
1. Gout: conduction abnormalities, possible valve problems
2. Homocystinuria
E. Coronary artery spasm
F. Cocaine
G. Miscellaneous
1. Thromboangiitis obliterans (Buerger's disease)
2. Takayasu's arteritis
 48 ANESTHESIA AND UNCOMMON DISEASES
insignificant obstruction into a critical lesion. Patients with
coronary artery vasospasm may respond to nitroglycerin and
calcium channel blockers.
COCAINE ABUSE
Cocaine can affect the heart in several ways, and cocaine use
can result in myocardial ischemia, MI, and sudden death.225–228
Cocaine exerts its effects on the heart mainly by its ability to
block (1) sodium channels, resulting in a local anesthetic or
membrane-stabilizing property, and (2) reuptake of norepi-
nephrine, resulting in increased sympathetic activity. Not sur-
prisingly, therefore, cocaine administered acutely can have
a biphasic effect on LV function, with transient depression
followed by a sustained increase in contractility.229 Cocaine
also induces coronary vasospasm and reduced coronary
blood flow while increasing heart rate and blood pressure.
These effects decrease myocardial O2 supply and increase O2
demand. Cocaine and its metabolites can also induce platelet
aggregation and release platelet-derived growth factor, which
can promote fibrointimal proliferation and accelerated athero-
sclerosis.230,231 Chronic users of cocaine also have an exagger-
ated response to sympathetic stimuli, which may contribute to
the LV hypertrophy frequently observed.
CORONARY ARTERY DISSECTION
When there is separation of the intimal layer from the medial
layer of the coronary artery, there may be obstruction of the
true coronary artery lumen with subsequent distal myocardial
ischemia. Coronary artery dissection may be primary or sec-
ondary. Primary coronary artery dissection may occur during
coronary artery catheterization or angioplasty and in trauma
to the heart. Primary coronary artery dissection may also
occur spontaneously. Spontaneous dissection is usually asso-
ciated with coronary arterial wall eosinophilia, and can also
be seen in the postpartum period232 and with cocaine abuse.233
Secondary coronary artery dissection is more common and is
usually caused by a dissection in the ascending aorta.
INFLAMMATORY CAUSES
Infectious
Infectious coronary artery arteritis may be secondary to hema-
togenous spread or direct extension from infectious processes
of adjacent tissue. The infectious process results in thrombo-
sis of the involved artery with myocardial ischemia. Syphilis
is one of the most common infections to affect the coronary
arteries. Up to 25% of patients with tertiary syphilis have ostial
stenosis of the coronary arteries.234,235 HIV infection has also
been associated with CAD.236
Noninfectious
Polyarteritis Nodosa. This systemic necrotizing vasculitis
involves medium-sized and small vessels. Epicardial coronary
arteries are involved in the majority of cases of polyarteritis
nodosa. After the initial inflammatory response, the coronary
artery may dilate to form small, berrylike aneurysms that may
rupture, producing fatal pericardial tamponade.237,238
Systemic Lupus Erythematosus. The pericardium and myo-
cardium are usually affected in SLE. Patients with SLE, however,
may suffer acute MI in the absence of atherosclerotic CAD.239,240
The hypercoagulable state of SLE together with a predisposition
to premature coronary atherosclerosis has been implicated.
In addition, glucocorticoids used for the treatment of SLE may
also predispose these patients to accelerated atherosclerosis.
Kawasaki's Disease (Mucocutaneous Lymph Node
Syndrome). In this disease of childhood, a vasculitis of the
coronary vasa vasorum leads to weakened walls of the ves-
sels with subsequent coronary artery aneurysm formation.241
Thrombosis and myocardial ischemia can also occur. Patients
with Kawasaki's disease are prone to sudden death from ven-
tricular arrhythmias and occasionally from rupture of a coro-
nary artery aneurysm. Thrombus in the aneurysm may also
embolize, causing myocardial ischemia.242
Takayasu's Disease. This disease leads to fibrosis and lumi-
nal narrowing of the aorta and its branches. The coronary
ostia may be involved in this process.243
METABOLIC CAUSES
Homocystinuria
An increased incidence of atherosclerotic disease is reported in
patients with high levels of homocysteine.244,245 This process may
involve intimal proliferation of small coronary vessels and an
increased risk of MI. Nevertheless, meta-analysis and prospective
studies have not consistently confirmed these findings.246,247
CONGENITAL ABNORMALITIES OF CORONARY
ARTERIAL CIRCULATION
Left Coronary Artery Arising from Pulmonary Artery
In Bland-White-Garland syndrome the right coronary artery
arises from the aorta, but the left coronary arises from the pul-
monary artery. Flow in the left coronary arterial system is ret-
rograde, with severe LV hypoperfusion as well as myocardial
ischemia and infarction. As such, most patients with this defect
present in infancy with evidence of heart failure. Untreated
patients usually die during infancy. Patients who survive child-
hood may present with mitral regurgitation from annular
dilation. The goals of medical therapy are to treat CHF and
arrhythmias. The defect can be corrected surgically by pri-
mary anastomosis of the left coronary artery to the aorta.248,249
In older children, a vein graft or the left internal mammary
artery may be used to establish anterograde flow in the left cor-
onary arterial system. Postoperative improvement in LV func-
tion can be expected if this surgery is performed early.250,251
Coronary Arteriovenous Fistula
There is an anatomic communication between a coronary artery
and a right-sided structure, such as the right atrium, right ven-
tricle, or coronary sinus. The right coronary artery is more fre-
quently affected and is usually connected to the coronary sinus.
Most patients are asymptomatic. These patients are at risk for
endocarditis, myocardial ischemia, and rupture of the fistulous
connection.252 These fistulas should be corrected surgically.253

Anesthetic Considerations
The anesthetic employed in patients with ischemic heart dis-
ease or CAD should be tailored to the degree of myocardial
dysfunction.254 In patients with pure coronary insufficiency
with good LV function, anesthetic management is aimed at
decreasing O2 demand by decreasing myocardial contractility
while preserving O2 supply. Continuous monitoring of hemo-
dynamic parameters extending into the postoperative period
is probably more important for patient outcome than choice of
anesthetic technique. In patients with poor ventricular func-
tion, the anesthetic technique should maintain hemodynamic
stability by avoiding drugs that produce significant degrees
of myocardial depression. A regional technique, if applicable,
may be the preferred anesthetic technique for smaller proce-
dures. A neuraxial technique is not contraindicated as long as
the patient's coagulation status, including potent antiplatelet
medications, is considered, and may actually provide supe-
rior pain control and reduce the stress response to surgery.
However, caution must be exercised to prevent a sudden drop
in blood pressure, and thus a spinal technique is relatively con-
traindicated. For major surgery, most practitioners employ a
balanced general anesthetic technique.
When coronary vasospasm is considered, it is important
to maintain a relatively high coronary perfusion pressure.
Pharmacologic agents, such as nitroglycerin and calcium
channel blockers, may also be used. Patients who are chronic
users of cocaine should be considered at high risk for ischemic
heart disease and arrhythmias. These patients may respond
unpredictably to anesthetic agents and other drugs used in the
perioperative period. Ephedrine and other indirect sympatho-
mimetic drugs should be avoided in cocaine users.
In periarteritis nodosa or Fabry's disease, hypertension
is often associated with poor LV function. In such patients
a vasodilator such as nicardipine, sodium nitroprusside, or
nitroglycerin can be used to control hypertension, rather than
a volatile anesthetic. Milrinone and nesiritide are also options.
The principles for the management of intraoperative arrhyth-
mias remain the same as for the treatment of arrhythmias in
the patient with atherosclerotic CAD.
The degree of functional impairment of the myocardium
and coronary circulation dictates the extent and type of moni-
toring. The selection of ECG leads to monitor depends on the
coronary anatomy involved. Diseases involving left CAD are
best monitored using precordial leads, such as the V5 lead.
In patients with right CAD, ECG leads used to assess the infe-
rior surface of the heart (leads II, III, or aVF), or the posterior
surface (esophageal lead), are preferable.255–257
Arterial blood pressure should be monitored by indwell-
ing catheter in patients with known coronary insufficiency
undergoing major procedures. The clinician should be cau-
tious when using peripheral arterial monitoring in patients
with generalized arteritis and carefully evaluate the adequacy
of collateral blood flow before cannulation of the periph-
eral artery. In occlusive diseases (e.g., Raynaud's, Takayasu's
­arteritis, Buerger's) or in cases of sludging in the microcircula-
tion (e.g., sickle cell disease), the area distal to the c­ annulated
Chapter 2  Cardiac Diseases 49
artery should be checked frequently for signs of arterial insuf-
ficiency. A more central and larger vessel, such as the axillary
artery, should be chosen for arterial catheterization. The use
of a PAC, once routinely deployed in patients with impaired
ventricular function and CAD, has not been shown to improve
outcome. In the absence of convincing evidence of outcome
benefits associated with pulmonary artery catheterization,
decisions regarding this type of monitoring should be made on
a case-by-case basis. Central venous access should be consid-
ered for administration of vasoactive medications in patients
with significant CAD undergoing major procedures.
PULMONARY HYPERTENSION AND
COR PULMONALE
Pulmonary hypertension (PHT) has been defined as mean
pulmonary artery pressure (PAP) greater than 25 mm Hg at
rest or greater than 30 mm Hg during exercise, or pulmonary
vascular resistance (PVR) of 3 Wood units or greater, with a
pulmonary artery occlusion pressure of 15 mm Hg or less.258
More recently, it has been suggested to simplify the definition
of PHT as a mean PAP greater than 25 mm Hg at rest, without
taking exercise or PVR into consideration.259 The 2008 revised
nomenclature on PHT (Dana Point Classification) lists five
main categories: (1) pulmonary arterial hypertension, (2) PHT
caused by left-sided heart disease, (3) PHT caused by lung dis-
ease and/or hypoxia, (4) chronic thromboembolic PHT, and
(5) PHT with unclear multifactorial mechanisms1,260 (Box 2-3).
BOX 2-3   n DIAGNOSTIC CLASSIFICATION OF
PULMONARY HYPERTENSION
1. Pulmonary arterial hypertension (PAH)
1.1 Idiopathic PAH
1.2 Heritable PAH
1.3 Drug- and toxin-induced
1.4 PAH associated with
1.5 Persistent PAH of the newborn
1.6 Pulmonary veno-occlusive disease
2. Pulmonary hypertension caused by left-sided heart disease
2.1 Systolic dysfunction
2.2 Diastolic dysfunction
2.3 Valvular disease
3. Pulmonary hypertension caused by lung disease and/or hypoxia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary diseases
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to altitude
3.7 Developmental abnormalities
4. Chronic thromboembolic pulmonary hypertension
5. Pulmonary hypertension with unclear multifactorial mechanisms
5.1 Hematologic disorders
5.2 Systemic disorders (e.g., sarcoidosis)
5.3 Metabolic disorders
Modified from Simonneau G, et al: Updated clinical classification of
pulmonary hypertension, J Am Coll Cardiol 54:S43-S54, 2009.
 50 ANESTHESIA AND UNCOMMON DISEASES
Pathophysiology
The normal pulmonary vasculature changes from a high-
resistance circuit in utero to a lower-resistance circuit in the
newborn secondary to several concomitant changes: (1) the
relief of hypoxic vasoconstriction that occurs with breathing
air; (2) the stenting effect of air-filled lungs on the pulmonary
vessels, which increases their caliber and decreases their resis-
tance; and (3) the functional closure of the ductus arteriosus,
secondary to an increase in the Pao2. The muscular medial
layer of the fetal pulmonary arterioles normally involutes in
postnatal life, and PAP assumes normal adult values by 2 to
3 months of age. Assuming there is no active vasoconstriction,
PAP remains low even when blood flow across the pulmo-
nary vascular bed is increased, because of the numerous par-
allel vascular channels that distend and lower their resistance
when blood flow is increased. General pathologic conditions,
which are the basis of the PHT classification, will convert this
normally low-resistance circuit into a high-resistance circuit.
A decrease in pulmonary arterial cross-sectional area results
in increased PVR, as dictated by Poiseuille's law, which states
that resistance to flow is inversely proportional to the fourth
power of the radius of the vessels.
There are a number of rarer causes of decreased pulmonary
arterial cross-sectional area. For example, filarial worms, the eggs
of Schistosoma mansoni, or multiple small thrombotic emboli are
typical embolic causes of PHT. Primary deposition of fibrin in the
pulmonary arterioles and capillaries caused by altered hemosta-
sis with prothrombotic mechanisms, especially increased platelet
activation, also decreases cross-sectional area. Pulmonary arterial
medial hypertrophy can occur if there is increased flow or pres-
sure in the pulmonary circulation early in life. In this situation
the muscular media of the pulmonary arterioles undergo hyper-
trophy rather than the normal postnatal involution.261 As the
muscle hypertrophies, reflex contraction increases in response to
PAP elevation. This raises the PAP even higher by further reduc-
ing cross-sectional area. Long-standing PAP elevation results in
intimal damage to the pulmonary arterioles, followed by fibrosis,
thrombosis, and sclerosis, with an irreversible decrease in cross-
sectional area of the arterial bed, as often occurs in long-standing
mitral valve disease or emphysema.
Primary vasoconstrictors, such as the seeds of Crotalaria
plants, or hypoxia associated with high altitude or pulmonary
parenchymal disease can also cause PHT.262 PHT resulting from
increases in pulmonary arterial flow is usually associated with
various congenital cardiac lesions, such as atrial septal defect,
ventricular septal defect (VSD), patent ductus arteriosus, or
in adult life, VSD occurring after a septal MI. Hypoxemia
will aggravate this situation; an increased incidence of PHT is
seen in infants with congenital left-to-right shunting who are
born at high altitudes compared with similar infants born at
sea level. Long-standing increases in flow with intimal dam-
age may result in fibrosis and sclerosis, as previously noted.
An increase in PAP in these patients ultimately may result in
Eisenmenger's syndrome, in which irreversibly increased PAP
results in a conversion of left-to-right shunting to right-to-left
shunting, with the development of tardive cyanosis.
As with systemic arterial hypertension, PHT is character-
ized by a prolonged asymptomatic period. As pulmonary vas-
cular changes occur, an irreversible decrease in pulmonary
cross-sectional area develops, and stroke volume becomes
fixed as a result of the fixed resistance to flow. As such, cardiac
output becomes heart rate dependent, resulting in the symp-
toms of dyspnea, fatigue, syncope, and chest pain. Right ven-
tricular (RV) hypertrophy often occurs in response to PHT,
which may progress to RV dilation and failure.263
Cor Pulmonale
Cor pulmonale (also known as pulmonary heart disease) is
usually defined as an alteration in the structure and function
of the right ventricle, such as RV hypertrophy, dilation, and
right-sided heart failure secondary to increased resistance
or pressure in the lungs. Therefore this excludes RV failure,
which occurs after increases in PAP secondary to increases
in pulmonary blood flow, pulmonary capillary pressure, or
venous pressure. Both increases in pulmonary blood flow
and passive increases in pulmonary venous and capillary
pressure can produce RV failure, but strictly speaking, do
not produce cor pulmonale. The physiologic considerations
in cor pulmonale and in RV failure from other causes are
similar. The many causes of cor pulmonale include pulmo-
nary parenchymal disease, pulmonary embolism, chronic
hypoxia, obstructive sleep apnea, and primary pulmonary
artery disease.264
TYPES
Cor pulmonale is divided into two types: acute and chronic.
Acute cor pulmonale is usually secondary to a massive pul-
monary embolus, resulting in a 60% to 70% decrease in
the pulmonary cross-sectional area, associated with cyano-
sis and acute respiratory distress. With acute cor pulmo-
nale, there is a rapid increase in RV systolic pressure, which
slowly returns toward normal secondary to displacement of
the embolus peripherally, lysis of the embolus, and increases
in collateral blood flow. Massive emboli may be associated
with acute RV dilation and failure, elevated central venous
pressure, and cardiogenic shock. Another feature of massive
pulmonary embolization is the intense pulmonary vasocon-
strictive response.265,266
Chronic cor pulmonale presents with a different picture,
associated with RV hypertrophy and dilation and a change in
the normal crescentic shape of the right ventricle to a more
ellipsoid shape. This configuration is consistent with a change
from volume work that the right ventricle normally performs,
to the pressure work required by a high afterload. LV dys-
function may occur in association with RV hypertrophy. This
dysfunction cannot be related to any obvious changes in the
loading conditions of the left ventricle and is probably caused
by displacement of the interventricular septum. Chronic cor
pulmonale is usually superimposed on long-standing pulmo-
nary arterial hypertension associated with chronic respiratory
disease.267

BRONCHITIS
Chronic bronchitis is probably the most common cause of
cor pulmonale in adults, and its pathophysiology can serve as
a guide to understanding and managing cor pulmonale from
all causes. Initially, the PVR in chronic bronchitis is normal or
slightly increased because cardiac output increases. Later, there
is a further increase in PVR or an inappropriately elevated PVR
for the amount of pulmonary blood flow. Recall that normally
there is a slight decrease in PVR when pulmonary blood flow is
increased that is probably secondary to an increase in pulmo-
nary vascular diameter and flow through collateral channels.
In chronic bronchitis the absolute resistance of the pulmo-
nary circulation may not change, because of the inability of
the resistance vessels to dilate. A progressive loss of pulmonary
parenchyma occurs and, because of dilation of the terminal
bronchioles, an increase in p ­ ulmonary dead space causes pro-
gressively more severe mismatching of ­pulmonary ventilation
and perfusion. In response to the ventilation/perfusion mis-
match, the pulmonary circulation attempts to compensate by
decreasing blood flow to the areas of the lung that have hypoxic
alveoli. This occurs at the cost of decreased pulmonary arteri-
ole cross-sectional area and increased PAP.268
Long-standing chronic bronchitis results in elevations in
PAP, with resulting alterations in the structure and function
of the right ventricle, such as RV hypertrophy. In any form of
respiratory embarrassment, whether infection or progression
of the primary disease, further increases in PVR elevate PAP,
and RV failure supervenes. With the onset of respiratory prob-
lems in the patient with chronic bronchitis, several changes
can make PHT more severe and can precipitate RV failure.
A respiratory infection produces further ABG abnormalities,
with declines in Pao2 and elevations in Paco2. Generally, PAP
is directly proportional to Paco2, although the pulmonary cir-
culation also vasoconstricts in response to hypoxemia. With a
decrease in Pao2, there is usually an increase in cardiac output
in an effort to maintain O2 delivery to tissues. This increased
blood flow through the lungs may result in further PAP eleva-
tions because of the fixed, decreased cross-sectional area of the
pulmonary vascular bed. In addition, patients with chronic
bronchitis and long-standing hypoxemia often have compen-
satory polycythemia. The polycythemic blood of the chronic
bronchitis produces an increased resistance to flow through
the pulmonary circuit because of its increased viscosity.
The patient with chronic bronchitis normally has increased
airway resistance that worsens during acute respiratory infec-
tion because of secretions and edema that further decrease the
caliber of the small airways. These patients also have a loss of
structural support from degenerative changes in the airways
and from a loss of the stenting effect of the pulmonary paren-
chyma. For these reasons, the patient's small airways tend to col-
lapse during exhalation, and airway pressure increases because
of this “dynamic compression” phenomenon. In chronic bron-
chitis and emphysema, the decrease in cross-sectional area of
the pulmonary vessels does not result from fibrotic obliteration
of pulmonary capillaries or arterioles, but rather from hypertro-
phy of the muscular tunica media of the pulmonary a­ rterioles.
Chapter 2  Cardiac Diseases 51
The vessels become compressible but not distensible, so that
with exhalation and an increase in intrathoracic pressure, air-
way compression results in a further increase in PVR and an
increase in PAP. The hypertrophied muscular tunica media
vasorum prevents the resulting PAP increase from distend-
ing the pulmonary vessels and maintaining a normal pressure.
With the onset of respiratory embarrassment in the patient with
chronic bronchitis, there are increases in PAP, afterload, and RV
work requirement that may result in RV failure.
A similar pattern may be observed in other forms of pul-
monary disease, because the compensatory mechanisms are
much the same as in chronic bronchitis. Chronic bronchi-
tis, however, is somewhat more amenable to therapy because
the acute pulmonary changes are often reversible. Relief of
hypoxemia, for example, may be expected to ameliorate the
PHT. In PHT and cor pulmonale secondary to pulmonary
fibrosis, relief of hypoxia probably has little to offer the pul-
monary circulation; the PVR increase is not caused by vaso-
constriction of muscular pulmonary arterioles, but rather by
a fibrous obliteration of the pulmonary vascular bed.
Anesthetic Considerations
Monitoring for patients with significant PHT, and in patients
with right-sided heart failure, should provide a continuous
assessment of PAP, RV filling pressure, RV myocardial O2
supply/demand balance, and some measure of pulmonary
function. The ECG allows for the monitoring of arrhythmias.
In the setting of RV hypertrophy, with an increased risk of coro-
nary insufficiency, ECG monitoring allows observation of the
development of ischemia or acute strain of the right ventricle,
seen in the inferior or right precordial leads. PAP monitoring
provides an estimate of the severity of PHT, and in patients
with right-sided heart failure, an indication of the workload
imposed on the right ventricle. The PAC permits monitoring
of PAP as well as central venous pressure, as an indication of
RV filling pressure. Most anesthesiologists would choose PAP
monitoring in patients with significant PHT, as well as in those
with right-sided heart failure undergoing major surgical pro-
cedures associated with major fluid shifts, even without doc-
umented benefits in patient outcome. The PAC can also help
distinguish between LV failure and respiratory failure. In LV
failure, elevated PAP occurs with elevated pulmonary capillary
wedge pressure (PCWP), whereas in respiratory failure, PAP is
often elevated with a normal PCWP. The PAC also allows for
the determination of cardiac output and PVR. It is important to
follow the PAP in these patients; an increase in PAP is often the
cause of acute cor pulmonale, and serial measurements of PAP
and PVR allow evaluation of the effects of therapeutic interven-
tions. Perioperative TEE is increasingly useful in this patient
population because of the increasing numbers of trained indi-
viduals and equipment. Two-dimensional imaging of biventric-
ular function and noninvasive estimates of RV systolic pressure
(using tricuspid regurgitant jet and modified Bernoulli equa-
tion), as well as the severity and mechanism of tricuspid regur-
gitation, which is often seen with RV failure, are examples of
applications of TEE monitoring for patients with PHT.
 52 ANESTHESIA AND UNCOMMON DISEASES
Pulse oximetry and ABG sampling are simple ways of
assessing pulmonary function. Capnography is not an accu-
rate method of assessing Paco2 when significant “dead space”
ventilation is present. The use of an indwelling arterial cath-
eter facilitates arterial blood sampling and continuous arterial
BP monitoring. Calculation of intrapulmonary venous admix-
ture by using mixed venous blood samples obtained from the
pulmonary artery, however, is a more sensitive indicator of
pulmonary dysfunction than Pao2 values alone.
In the anesthetic management of patients with PHT or cor
pulmonale, special consideration must be given to the degree
of PHT and the functional state of the right ventricle. Possible
scenarios include isolated PHT with or without right-sided
heart failure and acute or chronic cor pulmonale with or with-
out right-sided heart failure. The anesthetic management may
differ accordingly, ranging from vigilant monitoring to acute
cardiopulmonary resuscitation (CPR). Some general prin-
ciples apply. Hypoxia, hypercarbia, acidosis, and hypother-
mia should be avoided because they increase PVR.258 The use
of a high inspired fraction of oxygen (Fio2) is often advised,
but pulmonary vascular reactivity and the underlying eti-
ology will often determine if a patient benefits from pulmo-
nary vasodilator (including O2) administration. For example, if
PHT is coexistent with hypoxia in a patient with chronic bron-
chitis, O2 administration may afford significant relief of the
PHT. If the PHT is secondary to massive pulmonary fibrotic
changes or acute mechanical obstruction from thromboembo-
lism, however, little relief of PHT would be expected with O2
administration.
The type of anesthetic and anesthesia technique is proba-
bly less important to patient outcome than the severity of PHT,
associated right-sided heart failure, and surgery with expected
hemodynamic instability. In 156 children with PHT undergoing
256 procedures, the incidence of complications increased with
the severity of PHT, and complications were not associated with
the type of anesthetic or airway management.269 This was con-
firmed in another retrospective analysis of children with PHT
undergoing general anesthesia.270 The type of agents used for
induction or maintenance of anesthesia was not associated with
periprocedural complications. Major surgery, however, was a
predictor of adverse events. Traditionally, it has been taught that
nitrous oxide might increase PAP and should be used cautiously
in this setting, even though scant data support this.271
When PHT coexists with cor pulmonale, the anesthetic
technique should attempt to preserve RV function. The pri-
mary concern is the maintenance of RV function in the face of
an elevated RV afterload. In this setting, a balanced anesthesia
technique employing opioids, such as fentanyl or sufentanil, in
combination with sedative-hypnotic drugs, such as propofol
or midazolam, or low doses of a potent inhalational agent will
usually provide cardiovascular stability.272 Inotropic support
is often required in the patient with RV failure with chronic
cor pulmonale. An inotropic agent should be selected only
after considering its pulmonary effects, and the effects of the
inotropic intervention should be monitored. As in LV failure,
where the reduced LV afterload can increase stroke volume
and cardiac output, in RV failure the reduction in RV afterload
can produce similar effects.
Dobutamine or milrinone tend to reduce PAP and PVR
and probably are the inotropic drugs of choice in RV fail-
ure without systemic hypotension. If RV perfusion pressures
need to be maintained, or when RV contractility is severely
impaired, norepinephrine or ­epinephrine is the preferred
catecholamine, even in patients with PHT.273,274 Furthermore,
vasopressin is particularly effective for systemic ­hypotension
in patients with RV failure.275 Vasodilators found effective in
reducing RV afterload include sodium nitroprusside, nitro-
glycerin, milrinone, adenosine, nifedipine, amlodipine, and
prostaglandin E1.276,277 Inhaled nitric oxide (NO) selectively
dilates the pulmonary vasculature and has been used to treat
PHT in various clinical settings.278–280
Prostacyclin acts via specific prostaglandin receptors and
has also been shown to reduce PHT.281 However, the vasodi-
lation is not selective for the pulmonary vasculature, and sys-
temic hypotension may ensue. Prostacyclin analogs, such as
epoprostenol, are given for chronic PHT and may also be use-
ful for intraoperative use. One caveat is that inadvertent dis-
continuation of chronic IV epoprostenol therapy may lead
to a fatal pulmonary hypertensive crisis. The administration
of prostacyclin, nitroglycerin, and milrinone by inhalation
is one strategy to reduce systemic side effects.282,283 Inhaled
prostaglandins are replacing inhaled NO in some institutions
because of cost considerations. Selective p ­ hosphodiesterase-5
inhibitors (e.g., sildenafil) are becoming the mainstay of
chronic PHT therapy. Preoperative optimization of patients
with severe PHT using sildenafil has been described.284,285
Endothelin receptor (ET-1)–A antagonists (e.g., bosen-
tan, sitaxsentan, ambrisentan) are newer drugs that have been
approved by the U.S. Food and Drug Administration (FDA)
for the use in patients with PHT.286,287 Table 2-7 summarizes
the hemodynamic effect on the systemic as well as pulmonary
circulation of some of the more common drugs used in the
anesthesia setting. Furthermore, medications used for treat-
ment of chronic PHT should not be discontinued perioper-
atively because of the expected acute exacerbation of PHT.
Since systemic hypotension is a side effect of some of these
drugs, appropriate monitoring as previously outlined should
be established before anesthesia induction. An anesthetic tech-
nique associated with a sudden drop in arterial blood pressure,
such as a spinal anesthetic, is relatively contraindicated, except
with careful preparation and monitoring. A balanced general
anesthesia or epidural technique is preferred.
PERICARDITIS, EFFUSION,
AND TAMPONADE
Constrictive Pericarditis
The pericardium is not essential to life, as demonstrated by
the benign effects of pericardiectomy. Nevertheless, the peri-
cardium has several important functions. The intrapericardial
pressure reflects intrapleural pressure and is a determinant of
 Chapter 2  Cardiac Diseases 53

TABLE 2-7  n  Select Pulmonary Vascular Pharmacopeia

Drug PAP PCWP QP SAP HR PVR

ALPHA (a)- AND BETA (b)-ADRENERIGIC ANTAGONISTS

Norepinephrine, 0.05-0.5 μg/kg/min ↑↑ ↑ to ↑↑ — ↑↑ NC or ↑ ↑*

Phenylephrine, 0.15-4 μg/kg/min ↑↑ — ↓ ↑↑ ↓ ↑*

Epinephrine, 0.05-0.5 μg/kg/min ↑ NC or ↓ ↑ ↑↑ ↑ ↑

Dopamine, 2-10 μg/kg/min NC or ↑ NC or ↓ ↑ NC or ↑ ↑ ↓

Dobutamine, 5-15 μg/kg/min ↑ ↓ ↑↑ NC or ↑ ↑ ↓

Isoproterenol, 0.015-0.15 μg/kg/m SL ↓ ↓ ↑↑ ↓ ↑↑ ↓

Vasopressin, 2-8 units/hr NC or ↑ ↑ —† ↑↑ NC or ↓ ↑

b-ANTAGONISTS

Propranolol, 0.5-2 mg — NC to ↑ NC or ↓ NC or ↓ ↓↓ NC or ↑

Esmolol, 50-300 μg/kg/min — NC to ↑ NC or ↓ NC or ↓ ↓↓ NC or ↑

a-ANTAGONIST

Phentolamine, 1-3 μg/kg/min ↓ ↓ ↑ ↓ ↑ ↓

SMOOTH MUSCLE DILATORS

Sodium nitroprusside, 0.5-3 μg/kg/min ↓ ↓ ↑↑ ↓↓ ↑ ↓

Nitroglycerin, 0.5-5 μg/kg/min ↓↓ ↓ NC to ↑ ↓ ↑ ↓

Prostaglandin E1, 0.05-0.1 μg/kg/min ↓↓ ↓ ↑ ↓ ↑ ↓

Adenosine, 50-200 μg/kg/min ↓ ↑ ↑ NC or ↓ ↑ or ↓ ↓

PHOSPHODIESTERASE-III INHIBITOR

Milrinone, 0.375-0.75 μg/kg/m ↓ ↓ ↑ ↓ ↑ ↓

OTHER DRUGS

Nitric oxide, 1-80 ppm ↓↓ ↑ ↑↑ NC NC ↓↓

Epoprostenol (prostacyclin), 2-5 ng/kg/min IV ↓ NC ↑ ↓ ↑ ↓

Iloprost (stable prostacyclin analog), ↓↓ NC ↑↑ NC NC ↓↓

10-50 μg via nebulizer

*Data not consistent; either NC or ↑ or ↓; most studies show less increase in PVR with norepinephrine compared with phenylephrine.
†Vasopressin significantly decreases cardiac output.
NC, No change; —, data unavailable; SL ↓, slight decrease.
HR, Heart rate; PAP, Pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, peripheral vascular resistance; QP, pulmonary blood flow; SAP,
systemic arterial pressure.

ventricular transmural filling pressure. During spontaneous
ventilation, the pericardium serves to transmit negative pleu-
ral pressure, which maintains venous return to the heart.288
Constrictive pericarditis results from fibrous adhesion of
the pericardium to the epicardial surface of the heart. Table 2-8
lists conditions associated with constrictive pericarditis. With
the key feature of increased resistance to normal ventricular
filling, constrictive pericarditis is a chronic condition usually
well tolerated by the patient until well advanced. Constrictive
pericarditis often resembles a restrictive cardiomyopathy
and occasionally presents a diagnostic dilemma.289–292 Unlike
restrictive cardiomyopathy, however, ventricular relaxation
is usually preserved in patients with constrictive pericarditis.
It restricts ventricular diastolic filling, so normal ventricular
end-diastolic volumes are not obtained, and stroke volume is
decreased. Compensatory mechanisms include an increase in
heart rate and contractility, usually secondary to an increase
in endogenous catecholamine release. This maintains cardiac
output in the face of the restricted stroke volume until the
decrease in ventricular diastolic volume is quite severe. As car-
diac output falls, there is decreased renal perfusion, resulting in
increased levels of aldosterone and thus increased extracellular
 54 ANESTHESIA AND UNCOMMON DISEASES

TABLE 2-8  n Conditions Causing Pericarditis and TABLE 2-8  n Conditions Causing Pericarditis and
Cardiac Tamponade Cardiac Tamponade—Cont'd

Pericarditis/Tamponade Associated Conditions Pericarditis/Tamponade Associated Conditions

CONSTRICTIVE PERICARDITIS Collagen disease

Idiopathic causes Uremia

Infectious causes Myxedema Low cardiac output

Can be sequela of most acute Myocarditis Hemorrhagic diatheses

bacterial infections that produce Cardiomyopathy
pericarditis Genetic coagulation defects;
anticoagulants
Tularemia Valve malfunction
Drugs
Tuberculosis
Hydralazine, procainamide
Viral: especially arbovirus, Valvular obstruction (Pronestyl), phenytoin (Dilantin)
coxsackievirus B
Physical causes
Mycotic: histoplasmosis,
coccidioidomycosis Radiation Cardiomyopathy, CAD
Constrictive pericarditis
Neoplasia
Trauma (perforation): surgical
Primary mesothelioma of manipulation, intracardiac
pericardium catheters, pacing wires

Secondary to metastases: Neoplasia

especially malignant melanoma
Primary: mesothelioma, juvenile
Physical causes xanthogranuloma

Radiation Cardiomyopathy Metastatic disease

Posttraumatic CAD Miscellaneous

Postsurgical Postmyocardial infarction:

ventricular rupture
Systemic syndromes
Pancreatitis
Systemic lupus erythematosus Cardiomyopathy, CAD
Reiter's syndrome Aortic regurgitation
Rheumatoid arthritis Cardiomyopathy, CAD
Aortic stenosis Behçet's syndrome

Uremia Cardiomyopathy Löffler's syndrome: endocardial Restrictive

Cardiac tamponade fibroelastosis with eosinophilia cardiomyopathy

CARDIAC TAMPONADE Long-standing congestive heart

failure
Infectious causes
CAD, Coronary artery disease.
Viral (most) Myocarditis
Cardiomyopathy
Valve malfunction

Bacterial: especially tuberculosis

Protozoal: amebiasis,
toxoplasmosis
Mycotic infection
Systemic/metabolic causes
Systemic lupus erythematosus
Acute rheumatic fever
Rheumatoid arthritis
volume. The greater extracellular volume increases RV filling
pressure, which eventually becomes essential for maintaining
ventricular diastolic volume in the presence of severe pericar-
Valvular obstruction dial constriction.
A number of characteristic hemodynamic features accom-
pany constrictive pericarditis as well as pericardial tampon-
Cardiomyopathy, CAD
ade. Rather than the slight respiratory variation in blood
Constrictive pericarditis
pressure seen in normal patients, dramatic respiratory varia-
tions in BP (pulsus paradoxus) are present. Kussmaul's sign
Cardiomyopathy, CAD (jugular venous distention during inspiration) may also be
Aortic stenosis seen. With adequate blood volume, right atrial pressure in

constrictive pericarditis is usually 15 mm Hg or greater and
usually equals left atrial pressure. Both constrictive pericar-
ditis and cardiac tamponade demonstrate a diastolic “pres-
sure plateau” or “equalization of pressures,” in which the
right atrial pressure equals the right ventricular end-diastolic
pressure, pulmonary artery diastolic pressure, and left atrial
pressure.
ANESTHETIC CONSIDERATIONS
Monitoring should assess the compensatory mechanisms in
constrictive pericarditis. The ECG should be observed for
heart rate and ischemic changes, because the myocardial O2
supply/demand ratio can be altered by the pathologic process
and therapeutic interventions. An indwelling arterial catheter
for continuous BP monitoring should be established before
anesthesia induction. A central venous pressure catheter is
often indicated for venous access in patients with constrictive
pericarditis undergoing more than minor procedures. The use
of a PAC is controversial, however, and has not been shown
to improve outcome. In patients with advanced disease, use
of a PAC may provide useful information about cardiac func-
tion, loading conditions, and cardiac output, particularly in
the postoperative period when echocardiography is often not
readily available. The intraoperative use of TEE can be help-
ful in patients with constrictive pericarditis undergoing non-
cardiac surgery, when hemodynamic compromise can be
expected based on the planned surgery, or when circulatory
instability persists despite attempted therapy.126
The main anesthetic goals are to minimize any effects of
anesthetic techniques and drugs on the compensatory mecha-
nisms that maintain hemodynamic stability in patients with
constrictive pericarditis. Accordingly, bradycardia and myo-
cardial depression must be avoided, and preload and afterload
need to be maintained in the face of a fixed, low cardiac output.
It is reasonable to induce general anesthesia using IV ketamine
or etomidate titrated to effect. Propofol is relatively contrain-
dicated because it may produce hypotension. Thiopental is
best avoided because of venodilation and cardiac depression.
A high-dose opioid anesthesia will not depress myocardial
contractility, but the associated bradycardia may not be tol-
erated. In patients who rely on sympathetic tone for compen-
sation, even the use of high-dose opioids may cause sudden
hemodynamic compromise during anesthetic induction and
must be immediately treated, preferably with epinephrine and
norepinephrine. The use of a spinal/epidural technique is not
recommended in symptomatic patients with constrictive peri-
carditis because of the sympathectomy.
Pericardial Effusion and Cardiac Tamponade
As with constrictive pericarditis, pericardial effusion and
cardiac tamponade also restrict ventricular diastolic filling,
although from extrinsic compression of the ventricular wall by
fluid in the pericardium. Symptoms seen with pericardial effu-
sion depend on the rate and volume of fluid accumulation.292
Chronic pericardial effusion may be well tolerated for some
Chapter 2  Cardiac Diseases 55
time. In contrast, acute cardiac tamponade is a syndrome with
a rapid and dramatic onset of symptoms.293–296 With a more
gradual accumulation of fluid, the pericardium stretches, and
larger pericardial volumes are tolerated before symptoms
occur. Once symptoms begin, however, they proceed rapidly
because of the sigmoidal relationship between pressure and
volume in the pericardial sac. As the limit of pericardial disten-
sibility is reached, small increases in volume produce dramatic
increases in intrapericardial pressure. As such, the removal of
small volumes of pericardial fluid in a situation of severe car-
diac tamponade can produce dramatic relief of symptoms as a
result of a rapid fall in intrapericardial pressure.297
The clinical features of cardiac tamponade result from
restriction of diastolic ventricular filling and increased
pericardial pressure. The increased pericardial pressure
is transmitted to the ventricular chamber. This decreases
the atrioventricular pressure gradient during diastole and
impedes ventricular filling. Thus, despite an increase in dia-
stolic ventricular pressure, there is a decrease in the end-
diastolic ventricular volume and stroke volume. Similar to
advanced constrictive pericarditis, equilibration of right
atrial pressure, right ventricular end-diastolic pressure, pul-
monary artery diastolic pressure, and left atrial pressure can
be seen. Pulsus paradoxus is another nonspecific sign, also
seen in patients with constrictive pericarditis. It consists of
a decline in systolic pressure during inspiration of more than
12 mm Hg. Additionally, increased diastolic ventricular pres-
sure decreases coronary perfusion pressure and results in
early closure of the mitral and tricuspid valves, limiting dia-
stolic flow and reducing ventricular volume (Fig. 2-5).
The compensatory mechanisms in cardiac tamponade
are similar to those in constrictive pericarditis. A decrease
in cardiac output results in an increase in endogenous cate-
cholamines. The consequent increases in heart rate and con-
tractility help maintain cardiac output in the face of a decreased
stroke volume. Increased contractility increases the ejection
fraction, allowing more complete ventricular emptying.
Pericardial
pressure
Ventricular Ventricular
pressure volume
Gradient to Coronary Stroke
ventricular filling perfusion volume
pressure
Cardiac
output
Heart rate Contractility Volume
retention
by kidneys
FIGURE 2-5  Physiology of tamponade.
 56 ANESTHESIA AND UNCOMMON DISEASES
ANESTHETIC CONSIDERATIONS
Monitoring in patients with pericardial effusion is simi-
lar to patients with constrictive pericarditis and depends
on the acuteness of the case. At a minimum, an indwell-
ing arterial catheter for continuous BP monitoring should
be established before anesthetic induction. The first step
in the anesthetic management of patients with pericardial
effusion or cardiac tamponade is to assess its severity. The
anesthesiologist must decide whether induction of anesthe-
sia can be tolerated. If the patient is tachycardic, hypoten-
sive, and unable to assume a supine position, with distended
jugular veins indicative of high filling pressures, then peri-
cardiocentesis or a small pericardial window performed
under local anesthesia should be considered before induction
of general anesthesia. Any patient with a significant pericar-
dial effusion, however, should be expected to deteriorate
suddenly at any time. In the presence of restricted ventricu-
lar diastolic filling, the initiation of positive-­pressure venti-
lation (PPV) may severely decrease venous return and cause
sudden hemodynamic collapse. If time permits, placement of
a central venous catheter in an awake, spontaneously breath-
ing patient may be indicated before anesthesia induction for
central administration of vasoactive drugs. Many institutions
require the surgical team to be present in the room prior to
anesthesia induction. Hemodynamically unstable patients
should be prepped and draped with a surgeon ready to per-
form pericardial drainage immediately after the patient has
been induced.
Similar to patients with constrictive pericarditis, bra-
dycardia and myocardial depression must be avoided, and
preload and afterload need to be maintained in the face of a
fixed, low cardiac output. IV ketamine or etomidate titrated
to effect are good choices. The onset of PPV may decrease
venous return and cardiac output further, resulting in sud-
den cardiovascular collapse. Thiopental and propofol are
relatively contraindicated because of possible hypoten-
sion; thiopental is known to cause venodilation and cardiac
depression. Again, high-dose opioid may not be well tol-
erated in patients who rely on sympathetic activation as a
compensatory mechanism. Hypotension during anesthetic
induction must be treated immediately, preferably with epi-
nephrine and norepinephrine. The use of a spinal/epidural
technique is best avoided in symptomatic patients with peri-
cardial effusion or tamponade.298–300
UNCOMMON CAUSES OF VALVULAR
LESIONS
This section considers the pathophysiology of uncommon
causes of valvular lesions and how these diseases affect car-
diac compensatory mechanisms. Anesthetic management of
valvular lesions is directed at preserving the compensatory
mechanisms, so it is essential to understand how these dis-
eases interfere with compensation and how anesthetic manip-
ulations interact with them.
Stenotic Valvular Lesions
VALVULAR AORTIC STENOSIS
Aortic stenosis results from narrowing of the aortic valve ori-
fice, resulting in a pressure gradient across the aortic valve.
The obstruction to flow is proportional to the decrease in
cross-sectional area of the obstructed outlet. The left ventricle
compensates by increasing the transvalvular pressure to main-
tain flow. The ventricle undergoes concentric hypertrophy
in order to force blood across the stenotic valve, but compli-
ance decreases resulting in increased LV filling pressure that
is required to maintain adequate preload and cardiac output.
As a result of hypertrophy, ventricular wall tension per unit
area is partially decreased toward a more normal range, but
total ventricular O2 demand is increased because of an increase
in LV mass. As ventricular compliance falls, passive filling of
the ventricle during diastole is decreased, and the ventricle
becomes increasingly dependent on atrial augmentation of
ventricular diastolic volume. In this setting the atrial “kick”
may contribute as much as 30% to 50% to the LV end-diastolic
volume. Diastolic subendocardial blood flow is also decreased
as a result of an increase in LV diastolic pressure. Aortic dia-
stolic pressure must remain high to maintain adequate myo-
cardial blood flow.301,302
Uncommon disease processes can affect compensatory
mechanisms to the progressively narrowing of the ­aortic
valve orifice or LVOT by several mechanisms. First, a disease
could potentially interfere with the compensatory mecha-
nism of concentric hypertrophy and increased ventricular
contractility. In Pompe's disease, LV hypertrophy occurs but
is only secondary to massive myocardial glycogen accumu-
lation. Ventricular strength is not increased to compen-
sate for the typical outflow tract obstruction that occurs in
Pompe's disease. In amyloidosis, aortic stenosis is coupled
with a restrictive cardiomyopathy; as in Pompe's disease,
the heart is unable to increase ventricular muscle mass or
contractility. A disease process may also interfere with the
critical atrial augmentation of LV end-diastolic volume, as
in sarcoidosis or Paget's disease. Diseases of this type infil-
trate the cardiac conduction system, resulting in arrhyth-
mias or heart block, with the loss of synchronous atrial
­contraction. The requirement for elevated ventricular dia-
stolic filling pressure may be compromised in methysergide
toxicity, which can produce mitral stenosis coupled with
­aortic stenosis. This reduces both passive ventricular filling
and ventricular filling resulting from atrial contraction.
Table  2-9 lists causes of aortic stenosis and key features of
their pathophysiology that can adversely affect cardiac com-
pensatory mechanisms.
MITRAL STENOSIS
The primary defect in mitral stenosis is restriction of nor-
mal LV filling across the mitral valve. As in other ste-
notic lesions, the area of the valve orifice is the key to
flow, and as the orifice becomes smaller, turbulence across
 Chapter 2  Cardiac Diseases 57

TABLE 2-9  n  Uncommon Causes of Valvular Lesions: Aortic Stenosis

FEATURES AFFECTING COMPENSATORY MECHANISMS

Atrial Transport and

Disease Rhythm Contractility and Hypertrophy Associated Problems

1. Congenital and degenerative

  a. Congenital

  (1) Valvular
   (2) Discrete subvalvular
  (3) Supravalvular

  b. Bicuspid valve Coarctation of aorta

Polycystic kidneys

  c. Degenerative

   (1) Senile calcification

   (2) Mönckeberg's sclerosis

2. Infectious

  a. Syphilis Dilated cardiomyopathy and

outflow obstruction

  b. Actinomycosis Dilated cardiomyopathy and

outflow obstruction

3. Infiltrative

  a. Amyloidosis Sinoatrial and 1. Dilated cardiomyopathy

atrioventricular nodal 2. CAD
infiltration

  b. Pompe's disease 1. Hypertrophic cardiomyopathy

2. Dilated cardiomyopathy

  c. Fabry's disease Cardiomyopathy Hypertension

  d. Primary xanthomatosis Atrial arrhythmias with 1. Dilated cardiomyopathy

rapid rate 2. CAD

4. Miscellaneous

  a. Sarcoid Arrhythmias and 1. LV dyssynergy with aneurysm

inflammation of 2. LV infiltration and
conduction system cardiomyopathy

  b. Endocardial fibroelastosis 1. Restriction of ventricular filling 1. M itral valve malfunction with

2. Interference with stenosis, poor ventricular
subendocardial blood flow filling
with decreased oxygen 2. Regurgitation decreasing LV
delivery to myocardium pressure development

  c. Methysergide toxicity Restriction of ventricular filling Similar to endocardial fibrosis

secondary to endocardial
fibrosis

  d. Paget's disease 1. Arrhythmias with Possible mitral stenosis and

loss of atrial kick poor ventricular filling
2. Complete heart block

CAD, Coronary artery disease; LV, left ventricular.

 58 ANESTHESIA AND UNCOMMON DISEASES

the valve increases, and total resistance to flow increases.
The ­compensatory mechanisms in mitral stenosis include
(1) dilation and hypertrophy of the left atrium, (2) increases
in atrial filling pressures, and (3) a slow heart rate to allow
sufficient time for diastolic flow with minimal turbulence.303
Decompensation in rheumatic mitral stenosis usually occurs
when there is atrial fibrillation with a rapid ventricular rate.
This causes a loss of the atrial contraction and decreased
time for ventricular filling, which results in pulmonary vas-
cular engorgement. Thus, altered LV function is almost
never the limiting factor in the ability of the heart to com-
pensate for mitral stenosis.304
As in other valvular lesions produced by uncommon dis-
eases, coexistent cardiovascular problems that interfere with
compensatory mechanisms are very important. Diseases such
as sarcoidosis or amyloidosis can infiltrate ventricular muscle,
preventing LV filling by decreasing compliance. Amyloidosis,
gout, and sarcoidosis can also affect the conduction system of
the heart, resulting in heart block, tachyarrhythmias, or atrial
fibrillation (Table 2-10).
TRICUSPID STENOSIS
Isolated tricuspid stenosis is rare, and the etiology is either
carcinoid or congenital (Table  2-11). The problems in tri-
cuspid stenosis are similar to those in mitral stenosis. There
is a large, right atrial–right ventricular diastolic gradi-
ent, and flow across the stenotic tricuspid valve is related
to valve area.305,306 The compensatory mechanisms in tricus-
pid stenosis are also similar to those in mitral stenosis.
An increase in right atrial pressure maintains flow across
the stenotic valve and is associated with hepatomegaly, jug-
ular venous distention, and peripheral edema. The implica-
tions of slow heart rate in tricuspid stenosis are the same as
in mitral stenosis. Right ventricular contractility is usually
well maintained. The onset of atrial fibrillation in tricuspid
stenosis may produce symptoms such as increased periph-
eral edema, whereas in mitral stenosis it results in signs of
left-sided failure.307
Diseases can interfere with cardiac compensation for tri-
cuspid stenosis in much the same way as for mitral stenosis.
Further restriction of RV filling may occur in conditions such

TABLE 2-10  n  Uncommon Causes of Valvular Lesions: Mitral Stenosis

FEATURES AFFECTING COMPENSATORY MECHANISMS

Disease Rhythm Atrial Transport LV Function Associated Conditions

1. Inflammatory

  a. Rheumatic fever

  b. Rheumatoid Heart block 1. P

 ericardial Dilated cardiomyopathy 1. A
 ortic stenosis and
arthritis constriction insufficiency
2. Cardiac tamponade 2. Mitral insufficiency

2. Infiltrative

  a. Amyloidosis 1. Heart block Atrial dilation and Dilated and restrictive Malfunctioning of other
2. Infiltration of hypertrophy cardiomyopathy valves
conduction system

  b. Sarcoidosis Infiltration of Dilated cardiomyopathy 1. Pulmonary hypertension

conduction system 2. Cor pulmonale

  c. Gout Infiltration of
conduction system

3. Miscellaneous*

  a. Left atrial myxoma

  b. Parachute mitral valve

  c. Concentric ring of left atrium

  d. Methysergide Endocardial fibrosis Mitral insufficiency

toxicity

  e. Wegener's Arrhythmias secondary Myofibrillar degeneration Dilated cardiomyopathy

granulomatosis to myocardial
vasculitis

*Normal compensatory mechanisms. LV, Left ventricular.

 Chapter 2  Cardiac Diseases 59

TABLE 2-11  n  Uncommon Causes of Valvular Lesions: Tricuspid Stenosis

FEATURES AFFECTING COMPENSATORY MECHANISMS

Disease Rhythm Atrial Transport LV Function Associated Conditions

1. Inflammatory

a. Rheumatic fever Usually associated with

other valvular lesions

b. SLE Arrhythmias from 1. CAD

pericarditis 2. Cardiomyopathy

2. Fibrotic

a. C
 arcinoid Fibrosis evolving to 1. P
 ulmonary hypertension Pulmonic stenosis
syndrome hypertrophy and with increased RV afterload
dilation 2. Endocardial fibrosis

b. E
 ndocardial Similar to carcinoid
fibroelastosis syndrome

c. Methysergide Similar to carcinoid Mitral and aortic

toxicity syndrome valvular abnormality

3. Miscellaneous

a. Hurler's syndrome Infiltration of Infiltration of atrial Dilated cardiomyopathy Aortic stenosis

conduction system wall

b. M
 yxoma of right Usually normal compen­
atrium satory mechanisms

CAD, coronary artery disease; LV, Left ventricular; RV, right ventricular; SLE, systemic lupus erythematosus.

as malignant carcinoid syndrome that produce endocardial
fibrosis, reducing RV compliance. Tricuspid stenosis frequently
coexists with pulmonic stenosis in patients with carcinoid syn-
drome, resulting in severely restricted cardiac output.308
PULMONIC STENOSIS
As in aortic stenosis, the valve area is the critical determi-
nant of transvalvular blood flow. Pulmonic stenosis produces
symptoms that are similar to the classic clinical features of
aortic stenosis: fatigue, dyspnea, syncope, and angina. The
compensatory mechanisms in pulmonic stenosis are similar
to those in aortic stenosis, including RV hypertrophy, and RV
dilation, with a change from a crescent-shaped chamber best
suited to handle volume loads to an ellipsoid chamber best
suited to handle pressure loads. The hypertrophied and dilated
right ventricle also interferes with LV function, and LV fail-
ure may supervene. Angina occurs occasionally in pulmonic
stenosis and should be especially noted. Normally, the right
ventricle is a thin-walled chamber with low intraventricular
pressures, resulting in a high transmural perfusion pressure
and good subendocardial blood flow that limits development
of RV ischemia. Concentric hypertrophy increases both RV
mass and RV pressures, increasing the potential for ischemia
of the right ventricle, since RV O2 requirements are increased
and coronary perfusion may be decreased. Cyanosis can
occur with severe pulmonic stenosis accompanied by a fixed,
low cardiac output. When RV pressure rises, a patent fora-
men ovale may produce right-to-left interatrial shunting.
Usually, isolated pulmonic stenosis is well tolerated for long
periods until compensatory mechanisms fail. When a second
valvular lesion coexists with pulmonic stenosis, the potential
effects of this lesion on compensatory mechanisms should be
considered.309
Compensatory mechanisms in pulmonic stenosis can be
altered in much the same way as in aortic stenosis. Decreases
in RV contractility occur in infiltrative diseases of the myo-
cardium, such as Pompe's disease and sarcoidosis. The loss
of the atrial “kick” and the development of tachyarrhyth-
mias have the same implications for cardiac function in pul-
monic stenosis as in aortic stenosis. In subacute bacterial
endocarditis, or with geometric changes resulting in tricus-
pid annular dilation, tricuspid insufficiency may coexist with
pulmonic stenosis, impairing pressure development in the
right ventricle, especially when RV failure supervenes. With
the increase in RV mass and the increased requirement for
O2 delivery to the right ventricle, RV O2 supply may be com-
promised, as in the coronary artery pathology of Pompe's
disease (Table 2-12).
Many patients with pulmonic stenosis are candidates for
balloon valvuloplasty of the pulmonic valve. A balloon cath-
eter is placed percutaneously and the tip guided across the
pulmonic valve. The balloon is inflated, tearing the fused
 60 ANESTHESIA AND UNCOMMON DISEASES

TABLE 2-12  n  Uncommon Causes of Valvular Lesions: Pulmonic Stenosis

FEATURES AFFECTING COMPENSATORY MECHANISMS

Disease Atrial Transport and Rhythm Contractility and Hypertrophy Associated Problems

1. Congenital

  a. Valvular

  b. Infundibular

  c. Supravalvular with peripheral coarctation

2. Genetic: Noonan's Hypertrophic cardiomyopathy:

syndrome obstructive and nonobstructive Aortic regurgitation

3. Infiltrative

  a. Pompe's Arrhythmias from conduction Dilated cardiomyopathy Aortic stenosis and outflow
system infiltration tract obstruction

  b. Lentiginosis Massive atrioventricular septal

hypertrophy

  c. Sarcoid Arrhythmias from conduction Cardiomyopathy Cor pulmonale

system involvement

4. Infectious

  a. Subacute bacterial Heart block Tricuspid insufficiency

endocarditis

  b. Tuberculosis Pulmonary insufficiency

  c. Rheumatic fever Usually associated with other

valvular lesions

5. Neoplastic

  a. Mediastinal tumors

  b. Primary tumors

  (1) Sarcoma Rhythm or cardiomyopathic

  (2) Myxoma complications will depend on
extent of wall involvement in
neoplastic process.

  c. Malignant carcinoid Endocardial fibrosis 1. Pulmonary hypertension

syndrome 2. Pulmonary regurgitation
2. Tricuspid regurgitation
and/or stenosis

6. Physical: extrinsic
causes

  a. Aneurysm of ascen­
ding aorta or sinus
of Valsalva

  b. Constrictive Picture of restrictive

pericarditis cardiomyopathy but usually
with good ventricular function

  c. Postsurgical Often associated with other

banding congenital cardiac abnormalities
 Chapter 2  Cardiac Diseases 61

leaflets apart.310 Various degrees of pulmonic regurgitation
are invariably produced, but this is typically well tolerated
for a long time.
Regurgitant Valvular Lesions
AORTIC INSUFFICIENCY
The primary problem in aortic insufficiency is a decrease
in net forward blood flow from the left ventricle caused by
diastolic regurgitation of blood back into the LV chamber.
Acute aortic insufficiency is poorly tolerated and represents
an acute volume overload of the LV chamber, resulting in
increased wall tension, end-diastolic pressure, acute mitral
regurgitation, pulmonary edema, and cardiogenic shock. In
chronic aortic insufficiency, however, a number of compen-
satory changes apply, and depending on the severity of aortic
regurgitation, patients may be asymptomatic for years. The LV
chamber size increases, causing an eccentric hypertrophy. The
LV compliance is increased, able to accommodate large dia-
stolic volumes at relatively low filling pressures. The increase
in ventricular volume allows full use of the Frank-Starling
mechanism, whereby the strength of ventricular contraction
is increased with increasing fiber length. Ejection fraction
is maintained, because both stroke volume and ventricular
end-diastolic volume increase together. Despite these com-
pensatory mechanisms, however, studies have shown that ven-
tricular contractility is not normal, and eventually symptoms
of heart failure develop.311 Nevertheless, the onset of clinical
symptoms of aortic insufficiency does not necessarily corre-
late with ventricular function status.312
The increase in chamber size and eccentric hypertrophy,
which help maintain cardiac function in aortic insufficiency,
can be compromised in such conditions as ankylosing spondy-
litis in which myocardial fibrosis limits the increase in cham-
ber size to the degree that this disease produces a restrictive
picture. Cogan's syndrome produces a generalized cardiomy-
opathy with CAD and can alter the compensatory mechanism
by decreasing both the ability of the left ventricle to hypertro-
phy and the ability of the coronary arteries to deliver oxygen to
the ventricle. Increases in LV compliance could be prevented in
situations such as aortic insufficiency caused by methysergide,
which produces an endocardial fibrosis and thus decreased
ventricular compliance. The usual ability of the left ventricle
to maintain the ejection fraction in aortic insufficiency could
be compromised by the cardiomyopathy of amyloidosis. The
aortic insufficiency produced by acute bacterial endocarditis
is occasionally associated with complete heart block, result-
ing in a slow heart rate with ventricular overdistention and a
decrease in cardiac output. Aortic insufficiency caused by con-
ditions (e.g., SLE) associated with increased PVR can increase
the regurgitant fraction in the face of the incompetent aortic
valve.313,314 Table  2-13 lists causes of aortic insufficiency and
key features of their pathophysiology that can adversely affect
cardiac compensatory mechanisms.

TABLE 2-13  n  Uncommon Causes of Valvular Lesions: Aortic Insufficiency

FEATURES AFFECTING COMPENSATORY MECHANISMS

LV Compliance and Heart Rate and Related Cardiac

Disease Contractility Rhythm Vascular Resistance Abnormalities

1. Infiltrative

  a. Amyloidosis Dilated and restrictive Arrhythmias, 1. CAD

cardiomyopathy infiltration of 2. Stenosis or insufficiency
conduction system of other valves

  b. Morquio's Usually isolated aortic insufficiency with mild

  c. Scheie's mucopolysaccharides

  d. Pseudo-xanthoma Dilated cardiomyopathy

elasticum

2. Infectious

  a. Bacterial endocarditis Complete heart block Insufficiency of other valves

  b. Syphilis Dilated or restrictive Infiltration of 1. Aortic stenosis

cardiomyopathy conduction system 2. Aortic aneurysm

  c. Rheumatic fever

3. Congenital valve disease

  a. Bicuspid aortic valve Usually intact compensatory mechanisms

  b. Aneurysm of sinus of Valsalva
  c. Congenital fenestrated cusp

Continued
 62 ANESTHESIA AND UNCOMMON DISEASES

TABLE 2-13  n  Uncommon Causes of Valvular Lesions: Aortic Insufficiency—Cont'd

FEATURES AFFECTING COMPENSATORY MECHANISMS

LV Compliance and Heart Rate and Related Cardiac

Disease Contractility Rhythm Vascular Resistance Abnormalities

4. Degenerative

  a. Marfan's Normal Normal Cystic medial Pulmonic insufficiency

necrosis of aorta
with dissection

  b. O
 steogenesis Normal Normal Cystic medial Mitral regurgitation
imperfecta necrosis

5. Inflammatory Mitral regurgitation

  a. R
 elapsing
polychondritis

  b. S
 ystemic lupus Pericarditis and effusion Hypertension Mitral regurgitation
erythematosus secondary to renal
disease

  c. Reiter's syndrome

  d. Rheumatoid arthritis Congestive Complete heart 1. Aortic stenosis

cardiomyopathy block 2. Mitral stenosis/
insufficiency
3. Constrictive pericarditis
4. Cardiac tamponade

6. Systemic syndromes

  a. A
 nkylosing Complete heart Aortic dissection
spondylitis block

  b. Cogan's 1. CAD Generalized angiitis

2. Dilated cardiomyopathy

  c. Noonan's Cardiomyopathy Pulmonic stenosis

  d. Ehlers-Danlos Spontaneous vascular

dissection

7. Miscellaneous

  a. Aortic dissection Interference with

compensation depends
on cause, e.g., syphilis,
Marfan's, traumatic

  b. Methysergide toxicity Endocardial fibrosis: Mitral valve stenosis/

restriction of LV filling insufficiency

  c. Traumatic rupture Acute dilation and failure

CAD, coronary artery disease; LV, Left ventricular.

MITRAL REGURGITATION regurgitation represents a volume overload of both the left

As with aortic regurgitation, mitral regurgitation results from
failure of the affected valve to maintain competence during
the cardiac cycle. Mitral regurgitation occurs by one of three
basic mechanisms: (1) damage to the valve apparatus itself,
(2) inadequacy of the chordae tendineae-papillary muscle
support of the valvular apparatus, or (3) left ventricular dila-
tion and stretching of the mitral valve annulus with loss of the
structural geometry required for valvular closure.315 Mitral
atrium and the left ventricle. In mitral regurgitation, ventricu-
lar ejection appears to be well preserved because of the parallel
unloading circuit through the open mitral valve, which allows
a rapid reduction of wall tension and change in volume dur-
ing systole. However, the chronic volume overload results in
an i­rreversible decrease in contractility, which is often appar-
ent only after the mitral valve function has been restored, by
repairing or replacing the mitral valve.316,317

Compensatory mechanisms in mitral regurgitation include
ventricular dilation, elevations in ventricular filling pressure,
and the maintenance of low PVR. As in aortic insufficiency,
ventricular dilation allows maximum advantage to be gained
from the Frank-Starling mechanism. A low PVR maintains
forward flow, whereas increases in PVR increase the degree of
regurgitant flow through the mitral valve. In mitral regurgita-
tion, the heart benefits from a relatively rapid heart rate; a slow
rate is associated with an increased ventricular diastolic diam-
eter, which may distort the mitral valve apparatus even further
and result in increased regurgitation.
A number of diseases can be cited that interfere with the
compensatory mechanisms in mitral regurgitation. When
mitral regurgitation is secondary to amyloid infiltration of
the mitral valve, ventricular dilation is compromised by coin-
cident amyloid infiltration of the ventricular myocardium,
which restricts ventricular diastolic filling.318 Amyloid infil-
tration of the conduction system can cause heart block and
bradycardia, resulting in increased mitral regurgitation for
reasons previously noted (Table 2-14).
TRICUSPID INSUFFICIENCY
Tricuspid insufficiency is mechanically similar to mitral insuf-
ficiency. The most common cause of tricuspid insufficiency is
right ventricular failure.319 Carcinoid disease can cause defor-
mation and insufficiency of the tricuspid valve,320 and endocar-
ditis affecting the tricuspid valve can be seen in IV drug users.
Tricuspid insufficiency represents a volume overload of both
the right ventricle and the right atrium. Isolated tricuspid regur-
gitation is often well tolerated, unless RV dysfunction develops
or coexists. In this situation the loss of integrity of the RV cham-
ber from the incompetent tricuspid valve increases regurgitant
flow at the expense of forward flow through the pulmonary cir-
culation, decreasing the volume delivered to the left ventricle,
with a resulting decrease in cardiac output (Table 2-15).
PULMONIC INSUFFICIENCY
Pulmonic insufficiency usually occurs in the setting of PHT
or cor pulmonale but may exist as an isolated lesion, as in
acute bacterial endocarditis in IV drug users. Pulmonic insuf-
ficiency may also be iatrogenic, frequently a sequela of pul-
monary valvuloplasty procedures or tetralogy of Fallot repair
involving a transannular patch. It is well tolerated for long
periods. As with aortic insufficiency, pulmonic insufficiency
represents a volume overload on the ventricular chamber, but
the crescentic RV geometry is such that volume loading is eas-
ily handled. The right ventricle is normally a highly compli-
ant chamber, and with its steep filling pressure–stroke volume
curve, it functions well in the presence of volume increases.
Disease states can interfere with the compensatory mecha-
nisms of the right ventricle in several ways. Diseases that pro-
duce pulmonic insufficiency, such as the malignant carcinoid
syndrome, also produce an endocardial fibrosis that decreases
the ability of the RV chamber to dilate in response to volume
loading. Increases in RV afterload increase the regurgitant
fraction. This is especially true when pulmonic insufficiency
Chapter 2  Cardiac Diseases 63
is secondary to PHT. Hypoxemia can increase PVR, as occurs
with the hypoxemia that results from pulmonary vascular dys-
function in carcinoid syndrome. It is unusual for a cardiomy-
opathy to coexist with isolated pulmonic insufficiency; thus
the potential for eccentric hypertrophy usually remains intact.
However, syphilis could allow a cardiomyopathy to coex-
ist with pulmonic insufficiency, although this would depend
on the extent of syphilitic involvement of the myocardium
(Table 2-16).
Anesthetic Considerations
Perioperative problems will arise from valvular lesions
when compensatory mechanisms acutely fail. Monitoring
should be selected to give a continuing assessment of the
status of these compensatory mechanisms. Standard moni-
toring that includes an ECG is essential for monitoring car-
diac rhythm and ischemic changes.321 In moderate or severe
valvular lesions, blood pressure is best monitored continu-
ously with an indwelling arterial catheter, which also allows
for the monitoring of ABGs. TEE is useful for assessing the
changes in preload and contractility that result from anes-
thetic and surgical manipulations. Pulsed-wave Doppler
and color flow mapping are useful for determining the flow
characteristics of valvular lesions and their response to phar-
macologic or surgical manipulations.322 The insertion of a
central venous catheter for vasoactive drug administration,
as well as for monitoring right-sided filling pressures, is
indicated in patients with moderate to severe valvular dis-
ease. The value of a PAC is controversial; it may be contra-
indicated in patients with tricuspid stenosis and difficult to
deploy in patients with severe tricuspid regurgitation. In
patients with significant left-sided valvular disease, accurate
assessment of loading conditions can be difficult or mislead-
ing because of the underlying valvular disease. Cardiac out-
put determination using a PAC can be inaccurate in patients
with severe tricuspid regurgitation. The decision to employ
a PAC in patients with valvular disease should be made on
an ­individual basis, considering surgery-related factors and
practitioner experience as well.
The anesthetic management in patients with valvular
lesions varies significantly, depending on the severity of the
valvular disease, the underlying etiology, and the planned pro-
cedure. In patients with uncommon diseases, these are the
primary considerations in the choice of anesthetic drugs and
techniques. With increasing severity of the valvular lesion,
patient management depends on the type of valvular lesion
rather than underlying disease, particularly in stenotic val-
vular disease. In patients with fixed, low cardiac output from
a stenotic valvular lesion, afterload should be maintained at
all times to allow adequate perfusion of vital organs, includ-
ing coronary perfusion. Therefore, an intrathecal technique is
often contraindicated in patients with significant stenotic val-
vular lesions. If a neuraxial technique is chosen, an epidural
technique is preferred, with careful monitoring and inter-
vention to maintain sympathetic tone. Many ­practitioners,
 64
ANESTHESIA AND UNCOMMON DISEASES
TABLE 2-14  n  Uncommon Causes of Valvular Lesions: Mitral Regurgitation

FEATURES AFFECTING COMPENSATORY MECHANISMS

Disease Rate LV Function/Compliance Vascular Resistance Associated Conditions

1. Conditions producing annular dilation

  a. Aortic regurgitation Usually in failure at this stage Elevated with low output

  b. LV failure Usually elevated

2. Conditions affecting chordae tendineae cordis and papillary muscles

  a. Myocardial ischemia Associated arrhythmias, Often poor Normal or elevated if cardiac

especially bradyarrhythmias output decreased

  b. Chordal rupture

  c. Hypertrophic obstructive Hyperkinetic with low ventricular Usually elevated

cardiomyopathy compliance

3. Conditions affecting the valve leaflets

  a. Marfan's syndrome Usually intact; also affect

  Ehlers-Danlos syndrome connective tissue of chordae
  Osteogenesis imperfecta tendineae

  b. Rheumatic fever

  c. Rheumatoid arthritis Heart block Dilated cardiomyopathy Other associated valve

abnormalities

  d. Ankylosing spondylitis Atrioventricular dissociation Aortic regurgitation

  e. Amyloidosis Sinoatrial and atrioventricular Restrictive and dilated Coronary artery disease
nodal infiltration cardiomyopathy

  f. Gout Urate deposits in conduction Usually normal Coronary artery disease

system

LV, Left ventricular.

 Chapter 2  Cardiac Diseases 65

TABLE 2-15  n  Uncommon Causes of Valvular Lesions: Tricuspid Regurgitation

FEATURES AFFECTING COMPENSATORY MECHANISMS

Disease Rate LV Function/Compliance Vascular Resistance Associated Conditions

1. Annular dilation

  a. RV failure Often from pulmonary

hypertension

  b. Pulmonic RV failure or extreme RV Often from pulmonary

insufficiency dilation hypertension

2. Leaflets, chordae, papillary muscles

  a. Ebstein's anomaly

  b. Acute bacterial endocarditis

  c. Rheumatic fever Compensation intact

LV, Left ventricular; RV, right ventricular.

TABLE 2-16  n  Uncommon Causes of Valvular Lesions: Pulmonic Insufficiency

FEATURES AFFECTING COMPENSATORY MECHANISMS

LV Compliance
Disease Contractility Heart Rate Rhythm Vascular Resistance Associated Abnormalities

1. Congenital

  a. Isolated

  (1) Hypoplastic Usually tolerated as

isolated lesion

  (2) Aplastic

  (3) Bicuspid

  b. Associated with other Toleration of pulmonic insufficiency depends on

congenital cardiac degree of myocardial dysfunction induced by
lesions other cardiac lesions

2. Acquired

  a. Syphilitic aneurysm Dilated cardiomyopathy Infiltration of Luminal narrowing

of pulmonary artery conduction system

  b. Rheumatic Tolerated well in isolation

  c. Bacterial endocarditis Complete heart block Endocarditis of other valves

 d. Echinococcus cyst Endocardial fibrosis Tricuspid valve malfunction

3. Malignant carcinoid Endocardial fibrosis Tricuspid valve

syndrome malfunction

4. Physical

  a. Traumatic

  b. After valvotomy/ Decreased ventricular

valvuloplasty for compliance if right
pulmonic stenosis ventricle is hypertrophic
from pulmonic stenosis

5. Functional: secondary Ventricular hypertrophy Elevated pulmonary 1. COPD

to pulmonary with decreased resistance secon­ 2. Mitral stenosis
hypertension compliance dary to pulmonary 3. Primary pulmonary
hypertension hypertension

COPD, chronic obstructive pulmonary disease; LV, Left ventricular.

 66 ANESTHESIA AND UNCOMMON DISEASES
however, choose a balanced general anesthetic technique
with invasive hemodynamic monitoring in patients with sig-
nificant valvular disease. For anesthesia induction, etomidate
is well tolerated by patients with valvular lesions,323 whereas
thiopental and propofol must be administered slowly and
titrated to effect.324 Neuromuscular blocking agents should be
selected according to their autonomic properties. In stenotic
lesions, cisatracurium, rocuronium, and vecuronium will not
result in significant increases in heart rate and are preferred
over pancuronium.325,326 In the past, a high-dose opioid tech-
nique was often used to maintain anesthesia in patients with
significant valvular heart disease, providing stable hemody-
namics. Consequently, prolonged mechanical ventilation was
frequently required. In current practice, a balanced anesthe-
sia technique using low doses of a potent inhalational volatile
anesthetic supplemented with shorter-acting opioids is pre-
ferred by most practitioners aiming to achieve immediate or
early extubation after surgery.
PATIENTS WITH TRANSPLANTED HEART
The first human heart transplantation was performed in the
late 1960s, but this practice was limited by early experiences
with organ rejection and opportunistic infections. Since 1980,
with the introduction of more effective immunosuppression
and improved survival, the procedure has emerged as a widely
acceptable treatment modality for end-stage heart disease.327
These recipients of heart transplants may present for noncar-
diac surgery, and therefore the physiology of the denervated
heart and the side effects of the immunosuppressive agents
must be considered.
The Denervated Heart
The recipient atrium (which may remain after transplanta-
tion) maintains its innervation, but this has no effect on the
transplanted heart. Therefore, the transplanted heart is com-
monly referred to as being “denervated.” The efferent (to the
heart) and afferent (away from the heart) limbs of the para-
sympathetic and sympathetic nervous systems are disrupted
during cardiac transplantation. This has significant impact on
the physiology of the transplanted heart and the response to
common pharmacologic agents in the perioperative period.
Some degree of sympathetic reinnervation of the transplanted
heart has been documented, although this reinnervation is
delayed and incomplete.328,329
Immunosuppressive Therapy
The main agents used for chronic immunosuppression are
calcineurin inhibitors, azathioprine, rapamycins (everolimus/
sirolimus), tacrolimus, mycophenolate mofetil, corticoste-
roids, and azathioprine.330,331 These drugs may interact with
anesthetic agents and have side effects with anesthetic implica-
tions. Cyclosporine is nephrotoxic and hepatotoxic. Another
important side effect associated with the use of ­cyclosporine
is hypertension. Cyclosporine can also lower the seizure
threshold. Tacrolimus is nephrotoxic and can lead to diabe-
tes and high blood pressure. Chronic corticosteroid therapy
is associated with glucose intolerance and osteoporosis, and
azathioprine is toxic to the bone marrow. The immunosup-
pressive agents should be considered in the anesthetic plan,
and organ systems that could be affected must be evaluated
preoperatively.332,333
Anesthetic Considerations
The physiology and response to pharmacologic agents are dif-
ferent in the denervated heart. The vagal innervation of the
heart is disrupted, and there is a lack of heart rate variability
with respiration, vagal maneuvers, and exercise. Cholinesterase
inhibitors, such as neostigmine and edrophonium, do not usu-
ally produce bradycardia, although case reports have linked
cardiac arrest and bradycardia to neostigmine administration,
even in the transplanted heart.334,335 However, the effects on
other organ systems (e.g., salivary glands) remain, and these
drugs must still be used in combination with anticholinergic
agents.336 Similarly, anticholinergic agents, such as atropine, do
not increase the heart rate, so that bradycardia is treated with
direct acting agents, such as isoproterenol, or with pacing.
A paradoxical response with the development of A-V block
or sinus arrest was reported after administration of atropine
in patients with transplanted hearts.337 Drugs with vagolytic
side effects, such as pancuronium, do not produce tachycar-
dia. The denervated sinus and A-V nodes have been shown to
be supersensitive to adenosine and theophylline.338
Sympathetic stimulation can originate from two sources:
neuronal or humoral. In the denervated heart the neuronal
input is initially disrupted and only partially restored, but
increases in circulating catecholamines will increase heart
rate. Because of the denervation, indirect-acting cardiovascu-
lar agents have unpredictable effects. The response of the cor-
onary circulation may also be affected.339,340
The normal, innervated heart responds to an increase in
aerobic demand mainly by an increase in heart rate. However,
the initial response of the denervated heart to an increased
demand is through the Frank-Starling mechanism: increasing
stroke volume through preload augmentation. The increase
in heart rate by the humoral pathway or circulating catechol-
amines is delayed. Overall, the response of the denervated heart
to exercise or increased metabolic demand is subnormal.341–343
Sensory fibers in the heart play an important role in main-
taining systemic vascular resistance. With rapid changes in
SVR, the denervated heart may not respond appropriately,
and these patients tolerate hypovolemia poorly. Sensory fibers
in the heart are also important in the manifestations of myo-
cardial ischemia. As such, the patient with a denervated heart
may not experience angina, although there are reports to the
contrary.
Another factor that must be considered in the anesthetic
management of these patients is that the transplanted heart
is also predisposed to accelerated coronary artery disease.

Fibrous proliferation of the intima of epicardial vessels may
result from a chronic rejection process, and within 5 years
of transplantation, many patients have developed signifi-
cant occlusion of the coronary arteries.344,345 Therefore, these
patients must be evaluated for CAD.
CONCLUSION
Although the main focus of these discussions is the cardiovas-
cular pathology encountered in uncommon cardiac diseases,
the clinician should remember that these diseases seldom
have isolated cardiovascular pathology. Many of the diseases
discussed are severe multisystem diseases, and an anesthetic
plan must also consider the needs of monitoring dictated by
other systemic pathology (e.g., measurements of blood sugar
in diabetes secondary to hemochromatosis) and the potential
untoward effects of drugs in unusual metabolic disturbances
(e.g., use of drugs with histamine-releasing properties, such
as thiopental or morphine, in malignant carcinoid syndrome).
One anesthetic technique never is absolutely superior to all
others in the management of any particular lesion, particularly
those caused by uncommon cardiac conditions. The key to the
proper anesthetic management of any uncommon disease lies
in an understanding of the disease process, particularly the
compensatory mechanisms involved in maintaining cardio-
vascular homeostasis, the cardiovascular effects of anesthetic
drugs, and appropriate monitoring of the effects of anesthetic
and therapeutic interventions.
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 C H
Congenital Heart Disease
General Principles
Classification
Pathophysiology
Hemodynamic Management
Ventilatory Management
Anesthetic Agents and Hemodynamic Effects
Volatile Anesthetics
Opioids and Benzodiazepines
Propofol
Ketamine
Etomidate
Dexmedetomidine
Pharmacokinetics and Intracardiac Shunts
Preanesthetic Assessment and Planning
History and Physical Examination
Premedication and Monitoring
Airway and Ventilation Management
Anesthetic Techniques
Postoperative Care Plan and Disposition
Infective Endocarditis Prophylaxis
Patients at Greatest Anesthetic Risk
Specific Cardiac Lesions
Left-to-Right Shunt Lesions
Patent Ductus Arteriosus
Aortopulmonary Window
Atrial Septal Defect
Ventricular Septal Defect
Atrioventricular Canal
Double-Outlet Right Ventricle
Truncus Arteriosus
Anomalous Pulmonary Venous Return
Left-Sided Obstructive Lesions
Right-Sided Obstructive Lesions
Single Ventricle
Coronary Artery Anomalies
Regurgitant Valvar Lesions
Vascular Rings
A P T E R
3
DEAN B. ANDROPOULOS, MD, MHCM  n
ERIN A. GOTTLIEB, MD  n
Other Cardiac Disease
Pulmonary Hypertension
Dilated Cardiomyopathy and Myocarditis
Pericardial Effusion and Tamponade
Pacemakers and Defibrillators
The Post–Cardiac Transplant Patient
Conclusion
KEY POINTS
n Congenital heart disease (CHD) is the most common birth
defect requiring invasive treatment.
n With improved medical, surgical, and perioperative care, about
1 million children and 1 million adults now live with CHD.
n Although relatively uncommon in the general population,
anesthesiologists must understand which CHD patients
are at higher anesthetic risk and plan perioperative care
accordingly.
n The patient with CHD is classified by anatomic lesion, state
of cardiac surgical repair, and residual defects.
n Anesthesiologists determine the pathophysiologic effects of
the patient's lesion, set hemodynamic goals for anesthetic
care, and then plan drug administration and the ventilation
and preload/afterload strategies to achieve these goals.
n Outcome studies of noncardiac and cardiac anesthetics
show that the highest-risk patients have left-sided obstruc-
tive lesions, pulmonary hypertension, single functional
ventricle, or dilated cardiomyopathy.
n For individual CHD lesions, see key points listed in the
chapter boxes.
Congenital heart disease (CHD) occurs in 8 to 9 per 1000
live births, making it the most common birth defect requir-
ing invasive treatment. Surgical mortality is now less than
5% in high-quality centers, and as a result of improvements
in medical, surgical, and perioperative care, the number of
75
 76 ANESTHESIA AND UNCOMMON DISEASES

children and adults with CHD is increasing. In the United
States, about 1 million children and 1 million adults are living
with CHD.1 About 55% of these patients have simple lesions,
30% have moderately complex lesions, and 15% have complex
CHD. An increasing number of patients with complex CHD
survive in the modern era, and these children will present for
anesthetic care for noncardiac procedures more frequently
than in the past. More adult patients with simple and com-
plex congenital heart defects will present for surgery and pro-
cedures that require anesthetic care. Thus, although CHD is a
relatively uncommon disease in the general population, it is
essential that the anesthesiologist understand which patients
are at higher anesthetic risk and plan their perioperative care
accordingly.
Pediatric and adult patients with CHD may present for
surgery or a diagnostic procedure at a pediatric, adult, mater-
nity, or community hospital or outpatient center. The anesthe-
siologist caring for the pediatric or adult patient with CHD
needs to understand the cardiac lesion and physiology, stage of
repair or palliation, the patient's current physiologic state, and
effects of CHD on anesthetic care. In addition, the anesthesi-
ologist needs to assess the appropriateness of caring for these
often-complicated patients at a proposed venue. This chap-
ter discusses the preoperative assessment and planning, gen-
eral principles of intraoperative care, and postoperative care
for the patient with CHD undergoing anesthesia. Key CHD
lesions are reviewed, with prevalence, anatomy, corrective
approaches, pathophysiology, and anesthetic considerations
discussed for each lesion.
GENERAL PRINCIPLES
Classification
The myriad of classification and nomenclature schemes for
CHD make consensus difficult regarding the best methods
to organize these lesions. The following classification scheme
for the anesthesiologist to categorize CHD, as well as some
acquired forms of pediatric heart disease, is useful:
n Left-to-right shunt lesions: two ventricles
n Right-to-left shunt lesions: two ventricles
n Complete-mixing two-ventricle lesions
n Complete-mixing single-ventricle lesions
n Obstructive lesions without shunting
n Regurgitant lesions without shunting
n Cardiomyopathies
Another useful approach to CHD involves the stage of
repair: unrepaired, palliated, completely repaired with residual
defects, or completely repaired with no residual defects.2
Table  3-1 summarizes the major lesions in these categories.
The anatomy, pathophysiology, and approach to anesthesia
are detailed in the sections addressing the individual lesions.

TABLE 3-1  n  Classification of Congenital Heart Disease (CHD) for Anesthesiologists*

Category Examples Characteristics

Left-to-right shunt lesions: VSD, ASD, PDA; aortopulmonary window; partial atrioventricular Acyanotic
two ventricles canal; partial anomalous pulmonary venous return

Right-to-left shunt lesions: Tetralogy of Fallot; pulmonary atresia with VSD, pulmonary Cyanotic
two ventricles atresia with intact ventricular septum; double-outlet right
ventricle; Ebstein's anomaly

Complete-mixing two- Dextrotransposition of the great arteries; total anomalous Cyanotic; level of cyanosis depends on
ventricle lesions pulmonary venous return; truncus arteriosus; complete communications at atrial, ventricular,
atrioventricular canal and great vessel levels

Complete-mixing single- HLHS, tricuspid atresia, other forms of univentricular heart Cyanotic; complete mixing of pulmonary and
ventricle lesions systemic venous return; level of cyanosis
depends on systemic/pulmonary blood
flow ratio and degree of mixing

Obstructive lesions without Aortic stenosis, mitral stenosis, pulmonic stenosis;

shunting coarctation of aorta; interrupted aortic arch; cor
triatriatum; hypertrophic cardiomyopathy

Regurgitant lesions without Aortic insufficiency, mitral insufficiency, pulmonic

shunting insufficiency, tricuspid insufficiency

Cardiomyopathy Dilated cardiomyopathy, myocarditis, anomalous origin of Anatomically “normal” with decreased
left coronary artery from pulmonary artery; post–cardiac ventricular function
transplant coronary artery vasculopathy

*Some lesions may fall into more than one category depending on exact anatomy. For example, double-outlet right ventricle without pulmonary stenosis is a left-to-
right shunt lesion; most have some pulmonary stenosis and are right-to-left shunts. Ebstein's anomaly often has an ASD with right-to-left shunting; with no ASD, this is
a two-ventricle regurgitant lesion without shunting.
ASD, Atrial septal defect; PDA, patent ductus arteriosus; HLHS, hypoplastic left heart syndrome; VSD, ventricular septal defect.
 Chapter 3  Congenital Heart Disease 77

When considering patients with two ventricles without

Pathophysiology
When approaching the patient with congenital heart dis-
ease, after classification into the scheme previously noted, the
anesthesiologist should determine the pathophysiologic con-
sequences of the patient's lesion, then construct a set of hemo-
dynamic goals for the anesthetic care of that patient. After
these goals are decided, the anesthesiologist can plan anes-
thetic and vasoactive drug administration, ventilation strate-
gies, and strategies for preload and afterload management to
achieve these goals (Fig. 3-1).
obstructive or shunting lesions, the four major determi-
nants of cardiac output are preload, afterload, heart rate,
and contractility. The patient with CHD has additional
dimensions for consideration. Because of the frequent pres-
ence of mixing lesions resulting in arterial desaturation,
additional parameters are addressed to optimize cardiac
output and oxygen (O2) delivery, including hemoglobin
(Hb) concentration. Many cyanotic patients depend on
increased Hb levels for O2-carrying capacity (14-17 g/dL).
A “normal” Hb level for an infant or young child of 11 g/dL

Shunts

Right-to-left Left-to-right

• Pulmonary flow • Systemic perfusion

Hemodynamic • Hypoxemia • Low cardiac output
consequences • LV volume load • Hypotension
• LV dysfunction • LV failure
• LV volume load

• Avoid decrease in SVR • Avoid increase in SVR

Hemodynamic • Decrease PVR • Avoid decrease in PVR
goals • Hyperoxia • Fio2 (hypoxic gas mixtures if needed)
• Hyperventilation • Avoid hyperventilation
A
Obstructive lesions

Right-sided Left-sided

• Pulmonary flow • Systemic perfusion

Hemodynamic • Hypoxemia • Low cardiac output
consequences • RV hypertrophy • Hypotension
• RV dysfunction • LV failure
• Tricuspid regurgitation • Coronary perfusion

• Avoid increase in PVR • Avoid decrease in SVR

Hemodynamic • Avoid decrease in SVR • Avoid decrease in PVR
goals • Hyperoxia • Maintain preload
• Avoid hypoventilation • Maintain ductal patency*
• Maintain preload (R L shunt)
• Maintain ductal patency*
(L R shunt)

B * In ductus arteriosus-dependent CHD lesions

FIGURE 3-1  General approach to pathophysiology in patients with congenital heart disease (CHD). A, Hemodynamic
consequences and goals for intracardiac and extracardiac shunting lesions. Hypoxic gas mixtures are used infrequently, and risk/benefit
should be assessed carefully. LV, Left ventricular; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; Fio2, fraction
of inspired oxygen. B, Obstructive lesions. RV, Right ventricular; L → R, left-to-right; R → L, right-to-left.
Continued
 78 ANESTHESIA AND UNCOMMON DISEASES

Regurgitant lesions

Right-sided Left-sided

• RV volume load • LV volume load

Hemodynamic • RV enlargement • LV enlargement
consequences • RV dysfunction • LV dysfunction
• Elevated CVP • Low systemic perfusion
• Potential for • Pulmonary hypertension
R L atrial shunt • Elevated LAP, PCWP
with high CVP/RAP

• Decrease RV afterload/ • Decreased LV afterload/

Hemodynamic lower PVR lower SVR
goals • Hyperoxia • Increase heart rate
• Avoid hypoventilation • Enhance LV function
• Increase heart rate
• Enhance RV function

C
Mixing lesions

• Hypoxemia (varying degrees)

Hemodynamic • Qp/Qs very dependent on
consequences PVR and SVR
• Elevated hematocrit and
hyperviscosity

• Adjust PVR/SVR for optimal

Hemodynamic Qp/Qs and oxygen saturations
goals • Fio2 and↑ PaCO2if Qp/Qs is
high
• Improve mixed venous saturation
• Optimize tissue O2 delivery

D
FIGURE 3-1—Cont'd  C, Regurgitant lesions. CVP, central venous pressure; RAP, right atrial pressure; LAP, left atrial pressure; PCWP,
pulmonary capillary wedge pressure. D, Mixing lesions. Qp/Qs, pulmonary/systemic blood flow ratio; paco2, arterial carbon dioxide partial
pressure. (Data from Andropoulos DB: Hemodynamic management. In Andropoulos DB, et al, editors: Anesthesia for congenital heart
disease, ed 2, Oxford, UK, 2010, Wiley-Blackwell.)

is often too low for these patients. Also, the mixed venous
oxygen saturation (Svo2) is important because, of neces-
sity, Svo2 is lower in patients with arterial desaturation
with the same O2 extraction. Therefore, raising Svo2 is a
way to increase arterial oxygen saturation (Sao2, Spo2) in
the patient with right-to-left (R-L) shunting or mixing
lesions. Besides increasing Hb, decreasing O2 consumption
by using deeper anesthetic levels, lowering temperature, or
lowering myocardial O2 consumption are also important to
increase Svo2 (Fig. 3-2).
Avoiding any introduction or entrainment of air bubbles
into the venous circulation is an important consideration in
all patients with CHD, particularly those with obligatory R-L
shunting or complete intracardiac mixing. In these patients,
even a small amount of air may rapidly pass into the arterial
circulation and lodge in a coronary artery, causing myocar-
dial ischemia and possibly ventricular fibrillation, or into the
cerebral circulation, causing cerebral ischemia. However, even
in patients with predominantly left-to-right (L-R) shunting,
Valsalva maneuvers and other conditions can cause paradoxical

Preload
Contractility 
Oxygen delivery
Oxygen extraction
FIGURE 3-2  Determinants of cardiac output and oxygen delivery in congenital heart disease. (Data from Andropoulos DB:
Hemodynamic management. In Andropoulos DB, et al, editors: Anesthesia for congenital heart disease, ed 2, Oxford, UK, 2010, Wiley-Blackwell.)
air embolus. Techniques for infusion of intravenous (IV) fluids
and injection of drugs must meticulously avoid this problem.
Hemodynamic Management
Patients with congenital heart disease undergoing an anesthetic
procedure may require inotropic, lusitropic (improving dia-
stolic ventricular function), and vasodilator or vasoconstrictor
support to achieve the optimal hemodynamic state. Tables 3-2
and 3-3 list currently available agents and their dosages.2 With
many choices but few data, the anesthesiologist often is unable
to choose one drug over another from similar classes. Therefore
it is often preferable to become familiar with a limited number
of agents to use for hemodynamic management.
Two of the most common drugs in modern practice for
inotropic support are milrinone and epinephrine. Milrinone
is a phosphodiesterase-III inhibitor that prolongs the actions
of cyclic adenosine monophosphate (cAMP), and has ino-
tropic, lusitropic, and mild pulmonary and systemic vasodi-
lator ­properties. Therefore, milrinone is particularly useful
in patients with normal or high systemic vascular resis-
tance (SVR) and failing ventricles with a degree of pulmo-
nary hypertension. Single-ventricle patients in need of such
hemodynamic support are particularly responsive to milri-
none. A loading dose of 50 to 75 μg/kg, given over 30 min-
utes, rapidly achieves therapeutic plasma levels; this can be
problematic because of milrinone's vasodilating properties.
For this reason, the infusion is often initiated without a load-
ing dose. Infusion rates of 0.375 to 0.75 μg/kg/min are effec-
tive. Risk of tachycardia or atrial and ventricular arrhythmias
is minimal for milrinone.
Chapter 3  Congenital Heart Disease 79
Afterload
Cardiac output / Heart rate
Hemoglobin
 Arterial O2 content
Mixing lesions/
R-to-L shunts
Venous saturation
For patients in need of significant inotropic support, epi-
nephrine, at low dose of 0.02 to 0.04 μg/kg/min, moderate
dose of 0.05-0.09 μg/kg/min, or high dose of 0.1-0.2 μg/kg/
min is effective. Patients requiring high-dose epinephrine
for longer than several hours are candidates for mechani-
cal support of the circulation. For hypotension, vasopressin
at 0.02 to 0.04 units/kg/hr is effective in increasing SVR;
again, patients requiring vasopressin for more than several
hours should be evaluated for other means of circulatory
support.
ARRHYTHMIAS
Maintaining normal sinus rhythm, or at least atrioven-
tricular synchrony to allow for complete ventricular fill-
ing and optimize stroke volume, is an important goal for
every patient with CHD receiving anesthesia. Generally,
the incidence of arrhythmias increases with increasing
age, and the potential severity and hemodynamic effect
of the arrhythmia (i.e., ventricular arrhythmias or signifi-
cant atrial arrhythmias) are observed more often in older
patients.
The anesthesiologist must understand the patient's
underlying cardiac rhythm, any drug or other therapy,
symptoms of the arrhythmia, and recent data (e.g., 24 hour
Holter monitoring, electrophysiologic studies) to plan the
anesthetic procedure. In the operating room (OR), ade-
quate electrocar­diographic (ECG) monitoring, preferably
a ­f ive-lead ­system (right/left arms/legs, V lead) capable of
displaying up to eight leads simultaneously and recording
episodes of ­arrhythmia, is important for any patient with
 80 ANESTHESIA AND UNCOMMON DISEASES

TABLE 3-2  n  Inotropic Drugs

Drug Dose* Receptors INY HR SVR PVR RVR

Epinephrine 0.02-0.2
Lower β1, β2 > α1 ↑ ↑ ↔, ↓ ↔, ↓ ↓
Higher α1 > β1, β2 ↑ ↑ ↑ ↑ ↑

Norepinephrine 0.02-0.2 α1 > β1, β2 ↑ ↑ ↑ ↑ ↓

Dopamine 2-5 DA1, DA2 ↔ ↔ ↔ ↔ ↓

5-10 β1, β2 > α1 ↑ ↑ ↔, ↓ ↔ —
>10 α1 > β1, β2 ↑ ↑ ↑ ↑ ↑

Dobutamine 2-20 β1 > β2, α1 ↑ ↑ ↓ ↓ ↔

Isoproterenol 0.01-0.2 β1, β2 ↑ ↑ ↓ ↓ ↓

Milrinone Loading: PD-III inhibitor ↑ ↑ ↓ ↓ ↓

25-100 μg/kg ↑ cAMP
Infusion:
0.25-0.75

Calcium chloride IV bolus: Contractile proteins ↑ ↔, ↓ ↑ ↔, ↑ ↔

5-10 mg/kg
Infusion:
10 mg/kg/hr

Nesiritide 1-μg/kg load BNP ↔ ↔ ↓ ↓ ↑

0.1-0.2

Levosimendan Loading: Troponin C; increasing ↑ ↔ ↓ ↓ ↓

6-12 μg/kg Ca++ sensitivity;
0.05-0.1 ATP-sensitive
K+ channels for vasodilation

*Micrograms per kilogram body weight per minute (μg/kg/min), unless otherwise noted.
ATP, Adenosine triphosphate; BNP, brain (B-type) natriuretic peptide; cAMP, cyclic adenosine monophosphate; DA, dopamine; ↑, increase; ↓, decrease; ↔, no effect;
HR, Heart rate; INY, inotropy; PD-III, phosphodiesterase type III; PVR, Pulmonary vascular resistance; RVR, Renal vascular resistance; SVR, Systemic vascular resistance.

TABLE 3-3  n  Vasoactive Drugs

Drug Dose Receptors INY HR SVR PVR RVR

Vasopressin 0.01-0.05 U/kg/hr V1, V2 ↔ ↔, ↓ ↑ ↑ ↑

Phenylephrine 0.02-0.3 μg/kg/min α1 (Agonist) ↔ ↓ ↑ ↑ ↑

Nitroglycerin 0.2-10 μg/kg/min Vascular myocyte/ ↔ ↔, ↑ ↓ ↓ ↓

guanylyl cyclase
↑ cGMP

Nitroprusside 0.2-5 μg/kg/min Vascular myocyte/ ↔ ↔, ↑ ↓ ↓ ↓

guanylyl cyclase
↑ cGMP

Inhaled nitric 10-40 ppm Vascular myocyte/ ↔ ↔ ↔ ↓ ↔

oxide ↑ cGMP

Prostaglandin E1 0.01-0.2 μg/kg/min Vascular myocyte/ ↔ ↔, ↑ ↓ ↓ ↓

↑ cAMP

Fenoldopam Initial dose: 0.025-0.3 μg/ DA1, α2 ↔ ↔ ↓ ↔ ↓

kg/min; titrate to max
dose of 1.6 μg/kg/min

Nicardipine 0.1-0.3 mg/kg/hr; max Calcium channel ↔ ↑ ↓ — ↓

dose of 15 mg/hr antagonist

cAMP, Cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; DA, dopamine; HR, Heart rate; INY, inotropy; PVR, Pulmonary vascular resistance;
RVR, Renal vascular resistance; ↑, increase; ↓, decrease; ↔, no effect; SVR, Systemic vascular resistance; V, vasopressin.
 Chapter 3  Congenital Heart Disease 81

TABLE 3-4  n  Pharmacologic Therapy for CHD Patients with Acute, Hemodynamically Significant Arrhythmias

Drug Dose Indications Comments

Adenosine 100 μg/kg rapid bolus, double if Supraventricular tachycardia May cause sinus pauses, bradycardia, and
ineffective, max: 300 μg/kg A-V block

Amiodarone Load: 5 mg/kg over 30-60 Atrial tachycardia, atrial flutter, May cause sinus bradycardia, A-V block,
minutes; may repeat twice atrial fibrillation or hypotension; drug interactions with
Infusion: 15-20 mg/kg/24 hr JET; VT and VF procainamide and β-blockers

Atropine 10-20 μg/kg Sinus bradycardia —

A-V block

Epinephrine 1-5 μg/kg Sinus bradycardia —

A-V block

Esmolol Load: 250-500 μg/kg over 1-2 Sinus tachycardia; atrial and May cause negative inotropy, bradycardia,
minutes ventricular tachyarrhythmias sinus pauses, and A-V block
Infusion: 50-500 μg/kg/min

Isoproterenol 0.01-0.03 μg/kg/min Sinus bradycardia in denervated β2 effects may decrease diastolic BP

heart; complete A-V block

Lidocaine Load: 1-2 mg/kg over 1 minute; Premature ventricular Toxicity from hepatic/renal failure
may repeat contractions
Infusion: 20-50 μg/kg/min VT, VF

Magnesium Load: 25-50 mg/kg over 30 VT (torsade de pointes) May cause muscle weakness and sedation
sulfate minutes Prevention of JET

Procainamide Load: 10-15 mg/kg over Atrial tachycardia Monitor procainamide, N-acetylprocainamide

30-45 min JET, VT levels; may cause hypotension; synergistic
Infusion: 20-40 μg/kg/min adverse effects with amiodarone

A-V, Atrioventricular; JET, junctional ectopic tachycardia; VF, ventricular fibrillation; VT, ventricular tachycardia.

the potential for hemodynamically significant arrhythmia.
Pharmacologic, pacing, and cardioversion-defibrillation
therapy must be available for CHD patients (Tables  3-4
and 3-5).3
Ventilatory Management
Management of ventilation in patients with congenital heart
disease often has exaggerated effects on cardiac function,
pulmonary vascular resistance (PVR), and cardiopulmo-
nary interaction not seen in patients with normal hearts.
Appropriate ventilatory management during anesthesia can
help achieve hemodynamic goals, or if used inappropriately,
can be harmful to the patient with CHD.4 Therefore, plan-
ning ventilation strategy is as important as the anesthetic or
vasoactive agents when attempting to achieve a set of hemo-
dynamic goals.
For example, the neonate's pulmonary vasculature is exqui-
sitely sensitive to fraction of inspired oxygen concentration
(Fio2), arterial carbon dioxide partial pressure (Paco2), and
pH; maintenance of these parameters is the cornerstone of
achieving the goals for PVR. Many neonates will need a higher
PVR to shunt blood away from the lungs, toward the systemic
circulation through a patent ductus arteriosus (PDA) before
surgical repair, to lower pulmonary/systemic blood flow ratio
(Qp/Qs). Low Fio2, often 0.21, along with lowering min-
ute ventilation to elevate Paco2, is often used to achieve this
goal. Conversely, in the infant with elevated PVR causing R-L
shunting or poor cardiac output, high Fio2 and hyperventila-
tion to produce mild to moderate hypocarbia is effective at
lowering PVR.
Positive-pressure ventilation (PPV) often has detrimen-
tal effects on single-ventricle patients who have undergone
the Fontan operation. The absence of a right ventricular
pumping chamber means that flow through the Fontan cir-
cuit depends significantly on negative intrathoracic pressure
from spontaneous respiration creating a pressure gradient
from the extrathoracic veins; positive pressure decreases
this gradient and reduces flow. In contrast, PPV may actu-
ally improve ventricular function in patients with a failing
left or systemic ventricle. The intrathoracic positive pres-
sure is transmitted to the pericardial space, which reduces
the transmural wall tension across the ventricle, compared
to spontaneous ventilation with negative intrathoracic pres-
sure. This decreased wall tension reduces the work of the
ventricle, resulting in more efficient contraction. These
examples illustrate the importance of careful planning of
ventilatory strategy in patients with CHD.
 82 ANESTHESIA AND UNCOMMON DISEASES

TABLE 3-5  n Pacing, Cardioversion, and Defibrillation for CHD Patients with Acute, Hemodynamically Significant
Arrhythmias

Treatment Dose Indications Comments

Atrial overdrive pacing with temporary Rate: 10%-20% faster than SVT rate SVT —
wires/permanent pacemaker for up to 15 seconds

Atrial pacing with temporary wires Desired rate for optimal Sinus or junctional Output double the
hemodynamics bradycardia capture threshold
JET

Atrioventricular (A-V) sequential Desired rate for optimal A-V block Output double the
pacing with temporary wires hemodynamics capture threshold

Synchronized cardioversion 0.5-1 joules/kg SVT, atrial flutter, atrial Sedation/analgesia

fibrillation needed

Defibrillation 3-5 joules/kg VT, VF —

External transcutaneous pacing Increase output until capture; desired Sinus bradycardia Temporary therapy in
rate for optimal hemodynamics A-V block emergencies only
Junctional bradycardia

Esophageal pacing Desired rate for optimal Sinus bradycardia, SVT Not effective for A-V
hemodynamics; overdrive for SVT block

Transvenous pacing Desired rate for optimal A-V block Temporary therapy;
hemodynamics; increase output Sinus or junctional ineffective in single-
until capture bradycardia ventricle patients

JET, Junctional ectopic tachycardia; SVT, supraventricular tachycardia; VF, ventricular fibrillation; VT, ventricular tachycardia.

comparing halothane, isoflurane, and sevoflurane in 54 chil-

ANESTHETIC AGENTS AND HEMODYNAMIC
EFFECTS
Anesthetic agents can have profound effects on hemody-
namics in patients with congenital heart disease, much more
than in patients with normal hearts. The usual doses of typi-
cal agents (e.g., induction dose of propofol) are well tolerated
in patients with normal hearts and vascular systems but may
lead to severe hemodynamic compromise in some patients
with CHD (Box 3-1).
Volatile Anesthetics
Although halothane is no longer available in the United States
because of its profound myocardial depressant effects, it is use-
ful to review studies in CHD patients comparing new agents
to halothane. A study using transthoracic echocardiography
BOX 3-1   n ANESTHETIC MANAGEMENT PRINCIPLES
IN CONGENTIAL HEART DISEASE
Understand hemodynamic consequences of patient's lesion and
state of repair.
Construct a set of hemodynamic goals for each patient.
Plan anesthetic agents and techniques, ventilatory management, and
inotropic/vasoactive drug support based on these goals.
Although no anesthetic agent or technique is contraindicated, avoid
agents or doses counter to hemodynamic goals, and use agents
that promote these goals.
dren with two-ventricle CHD reported that halothane at
1 and 1.5 minimum alveolar concentration (MAC) caused sig-
nificant myocardial depression, resulting in a decline in mean
arterial pressure (MAP decline of 22% and 35%), ejection frac-
tion (EF decline of 15% and 20%), and cardiac output (CO
decline of 17% and 21%), respectively, in patients age 1 month
to 13 years undergoing cardiac surgery (Fig. 3-3).5 Sevoflurane
maintained both CO and heart rate (HR) and had less pro-
found hypotensive effects (MAP decrease 13% and 20% at
1 and 1.5 MAC) and negative inotropic effects (EF preserved at
1 MAC, 11% decrease at 1.5 MAC) compared with halothane.
Isoflurane, in concentrations as high as 1.5 MAC, preserved
CO and EF, had less suppression of MAP (22% and 25%) than
halothane, increased HR (17% and 20%), and decreased SVR
(20% and 22%).
The effects of volatile anesthetics on pulmonary (Qp) and
systemic (Qs) blood flow in 30 biventricular patients and in
L-R shunts has also been assessed. Halothane, isoflurane,
and sevoflurane did not change Qp/Qs as measured by echo-
cardiography.6 Russell et al.7 compared halothane with sevo-
flurane in the prebypass period in 180 children with a variety
of cardiac diagnoses, including 14 with single-ventricle phys-
iology and 40 with tetralogy of Fallot. The incidence of sig-
nificant hypotension, bradycardia, and arrhythmia requiring
drug treatment with atropine, phenylephrine, epinephrine,
or ephedrine was higher with halothane (two events per
patient vs. one). Serum lactate also increased slightly with
halothane.
 Chapter 3  Congenital Heart Disease 83

Ejection fraction Cardiac output

110 140
Percent change from baseline

Percent change from baseline

100
120

90
100
80

80
70 H H
S S
I I
60 F/M 60 F/M

0 1 1.5 0 1 1.5
MAC MAC
Change from baseline, p  .05 Change from baseline, p  .05
H vs I, p  .05 F/M vs S, p  .05
H vs I, F/M p  .05
A B
FIGURE 3-3  Hemodynamic changes assessed by echocardiography. In 54 patients with CHD with two ventricles: A, ejection fraction;
B, cardiac output. H, Halothane; S, sevoflurane; I, isoflurane; F/M, fentanyl/midazolam; MAC, minimal alveolar concentration. See text for
details. (Data from Rivenes SM, et al: Anesthesiology 94:223-229, 2001.)

Patients with a single functional ventricle constitute an
increasing proportion of patients undergoing anesthesia for both
cardiac and noncardiac surgery, and studies of hemodynamic
effects of anesthetic agents are limited. Ikemba et  al.8 studied
30 infants with a single functional ventricle immediately before
their bidirectional cavopulmonary connection, randomized to
receive sevoflurane at 1 and 1.5 MAC, or fentanyl/midazolam
at equivalent doses. Myocardial performance index (MPI), a
transthoracic echocardiographic measurement of ventricular
function that can be applied to single-ventricle patients, was
unchanged with any of these regimens compared with baseline,
indicating that either sevoflurane or fentanyl/midazolam can be
used in this population to maintain hemodynamic stability.
In normal children, desflurane usually produces tachycar-
dia and hypertension during the induction phase, followed by a
slight reduction in HR and systolic blood pressure (BP) during
steady state at 1 MAC anesthetic level.9,10 There are no reports
of its hemodynamic profile in patients with congenital heart
disease.
In summary, isoflurane and sevoflurane have had some study
in the CHD population, and both maintain normal cardiac out-
put at anesthetic concentrations in patients with normal, or only
slightly compromised, ventricular function. There have been no
published studies of these agents in patients specifically with
significantly depressed myocardial function; these volatile anes-
thetics should be used with caution in these patients.
Opioids and Benzodiazepines
Midazolam is often used with fentanyl anesthesia to provide
sedation and amnesia, as a substitute for low-dose volatile
anesthetics, particularly in hemodynamically unstable patients
and young infants, in whom the myocardial depressant effects
of volatile agents are more pronounced. Fentanyl and mid-
azolam combinations have been studied in two different
clinical dose regimens to simulate 1 and 1.5 MAC of volatile
agents: fentanyl, 8- to 18-μg bolus followed by 1.7 to 4.3 μg/
kg/hr infusion, then repeat bolus at 50% of original doses fol-
lowed by 50% increase in infusion, depending on age; and
midazolam, 0.29-mg/kg bolus followed by 139 μg/kg/hr infu-
sion, then repeat bolus at 50% of original dose, followed by
50% increase in infusion, for all ages; for induction and the
prebypass period in congenital heart surgery in biventricular
patients (see Fig. 3-3).5 Vecuronium was used for muscle relax-
ation to isolate the effects of the other two agents on hemo-
dynamics. Measurements of cardiac output and contractility
were made by echocardiography. Fentanyl/midazolam caused
a significant decrease (22%) in CO despite preservation of
contractility, predominantly from a decrease in HR.
Propofol
Williams et al.11 measured the hemodynamic effects of propo-
fol (50-200 μg/kg/min) in 31 patients age 3 months to 12 years
undergoing cardiac catheterization. Propofol significantly
decreased MAP and SVR; however systemic CO, HR, and
mean pulmonary artery pressure (PAP), as well as PVR, did not
change. In patients with cardiac shunts, the net result was a sig-
nificant increase in the R-L shunt, a decrease in the L-R shunt,
and decreased Qp/Qs, resulting in a significant decrease in Pao2
and Sao2, as well as reversal of the shunt from L-R to R-L in
two patients. Another study of cardiac catheterization showed
that patients could experience a 20% decrease in HR or MAP.12
These effects of propofol, causing venodilation and vasodila-
tion, decreased HR, and possibly decreased contractility with
significant induction doses, mandate caution with this agent in
 84 ANESTHESIA AND UNCOMMON DISEASES
patients who are preload and afterload dependent. Such patients
include those with dilated cardiomyopathy and coronary artery
lesions requiring higher coronary perfusion pressures.
Ketamine
Despite the potential adverse effects of dysphoria, halluci-
nations, excessive salivation, tachycardia, and hypertension,
ketamine has been a mainstay in the induction of gen-
eral anesthesia in patients with congenital heart disease.13,14
Administered intravenously (IV) or intramuscularly (IM),
ketamine will reliably maintain HR, BP, and systemic CO at an
induction dose of 1 to 2 mg/kg IV or 5 to 10 mg/kg IM, with a
maintenance dose of 1 to 5 mg/kg/hr in patients with a variety
of congenital diseases, including tetralogy of Fallot.15,16
Several studies addressed exacerbation of pulmonary
hypertension (PH). Morray et al.17 demonstrated that in car-
diac catheterization patients, 2 mg/kg of ketamine caused a
minimal (<10%) increase in mean PAP, and pulmonary/sys-
temic vascular resistance ratio (Rp/Rs), with no change in
direction of shunting or Qp/Qs. Hickey et al.18 studied postop-
erative cardiac surgery patients with normal Paco2 and found
that ketamine at 2 mg/kg had no effect on PAP or calculated
PVR, in patients with normal or with elevated baseline PVR.
Ketamine, 2-mg/kg load followed by 10 μg/kg/min infusion,
did not change PVR in 15 children with severe PH, when
breathing spontaneously with a baseline of 0.5 MAC sevoflu-
rane.19 Recent reports indicate that ketamine is effective and
safe for patients with CHD and with PH receiving noncardiac
anesthetics, as long as the airway is managed properly to avoid
significant hypercarbia or hypoxemia.19,20
Etomidate
Etomidate is an imidazole derivative and sedative-hypnotic
induction agent thought to be devoid of cardiovascular effects,
thus achieving widespread use in patients with limited cardio-
vascular reserve. Few reports address the hemodynamic effects
of etomidate in children with congenital heart disease. In 20
patients with a variety of congenital defects studied in the car-
diac catheterization laboratory (CCL), etomidate (0.3-mg/kg
bolus followed by 26 μg/kg/min infusion) had similar effects as
ketamine (4 mg/kg followed by 83 μg/kg/min infusion): a slight
increase in HR but no change in MAP during induction or the
60-minute infusion.21 Sarkhar et  al.22 studied etomidate (0.3-
mg/kg bolus) in 12 children undergoing cardiac catheterization
for device closure of atrial septal defect (ASD) or radiofre-
quency ablation of atrial arrhythmias. There were no signifi-
cant changes in any hemodynamic parameter (HR, MAP, filling
pressures, SVR or PVR, Qp/Qs, Svo2). A case report of stable
hemodynamics with etomidate induction in a pediatric patient
with e­ nd-stage cardiomyopathy receiving a second anesthetic
4 weeks after cardiovascular collapse with ketamine induc-
tion demonstrates the utility of this drug in this population.23
Etomidate has been used for induction of anesthesia in adults
with congenital cardiac conditions such as ruptured aneurysm
of the sinus of Valsalva, as well as for cesarean section in a patient
with uncorrected coronary artery–to–pulmonary artery fistula,
with no cardiovascular effects in these patients.24,25
Thus, etomidate seems best utilized in patients with the
most limited cardiac reserve. It appears particularly useful in
teenagers or adults with poorly compensated, palliated CHD
presenting for cardiac transplantation or revision of previ-
ous surgeries. Temporary adrenal suppression will occur with
even one induction dose of etomidate.
Dexmedetomidine
Dexmedetomidine has been studied as an adjunct agent
in general anesthesia for pediatric cardiac surgery. Dex­
medetomidine, 0.5-μg/kg load followed by 0.5 μg/kg/hr infu-
sion, with an isoflurane-fentanyl-midazolam anesthetic,
significantly reduced HR, MAP, and cortisol, blood glucose,
and serum catecholamine response in children age 1 to
6 years undergoing cardiac surgery with bypass, compared
with the baseline anesthetic.26 Chrysostomu et  al.27 studied
38 pediatric patients (average age 8 years) after biventricu-
lar repair with c­ ardiopulmonary bypass; 33 were extubated.
Dexmedetomidine infusion rate varied from 0.1 to 0.75 μg/kg/hr
(mean 0.3), and desired sedation was achieved in 93% and
analgesia in 83% of patients. There was no respiratory depres-
sion, but hypotension was observed in 15% of patients.27
Pharmacokinetics and Intracardiac Shunts
The presence of a right-to-left intracardiac shunt decreases the
rate of rise of the concentration of inhaled anesthetic in
the arterial blood, as a portion of the systemic cardiac output
bypasses the lungs and then dilutes the anesthetic concentra-
tion in the systemic arterial blood. The anesthetic concentra-
tion in the blood thus never equals the exhaled concentration.
Inhaled induction is noticeably slower in cyanotic CHD
patients. Huntington et  al.28 studied six children with R-L
shunts from a fenestrated Fontan operation whose average
Qp/Qs was 0.58. These patients achieved an arterial anesthetic
concentration (Fa) of only 55% of inspired halothane concen-
tration (Fi) after 15 minutes during wash-in of 0.8% halothane.
After closure of R-L shunt (occlusion of Fontan fenestration
in CCL), the Fa of halothane equaled the Fi. This difference
between Fa and Fi is greater during induction or washout
and greater with less soluble drugs (sevoflurane, desflurane,
nitrous oxide) than with more soluble drugs (halothane).
In the face of significant R-L intracardiac shunting, IV
agents given by bolus may pass directly into the left side of
the heart with less dilution by systemic venous blood and pas-
sage through the pulmonary vascular system. This may result
in transiently high arterial, brain, and cardiac concentrations
of drugs such as lidocaine.29 IV induction agents and muscle
relaxants may also achieve sufficient arterial and brain con-
centrations more rapidly with R-L intracardiac shunts.30
Left-to-right intracardiac shunts have minimal effect on
the speed of induction with inhaled anesthetic agents.31 The

recirculation of blood through the lungs results in increased
uptake of anesthetic and in a higher blood anesthetic concentra-
tion in the pulmonary capillaries, reducing anesthetic uptake.
The two effects cancel each other. Only in severe congestive
heart failure from L-R shunt, with significant interstitial and
alveolar edema, would L-R intracardiac shunting be expected
to slow inhalation induction, from the combined effects of dif-
fusion limitation and ventilation/perfusion mismatch, resulting
in alveolar dead space ventilation with no uptake of any new
anesthetic agent.
PREANESTHETIC ASSESSMENT AND
PLANNING
Patients with congenital heart disease often have complicated
histories, including operative and CCL reports, echocardio-
graphic images, computed tomography (CT) and magnetic
resonance imaging (MRI) studies, and extensive clinic visits.
The modern electronic medical record has greatly facilitated
the gathering of pertinent information in these complicated
patients and should be used whenever possible. A common
question is whether cardiology consultation is necessary before
anesthesia. Any patient with poor cardiac compensation should
have cardiology consultation before anesthesia, including patients
with significant cyanosis, poor ventricular function, uncon-
trolled arrhythmias, and significant PH. Optimization of med-
ical management and postponement of elective surgery may be
necessary in some cases. Occasionally, a very ill patient with
CHD surgery is cancelled permanently after a thorough assess-
ment of operative risks and benefits along with anesthetic risks.
Patients with good cardiac compensation but with complex
disease should receive cardiology consultation and echocar-
diography within 6 months of anesthesia. Well-compensated
patients with simple or moderately complex disease do not
usually require cardiology consultation in this period.
History and Physical Examination
Preoperative assessment should include a detailed descrip-
tion of the patient's cardiac anatomy, cardiac surgery his-
tory, and catheter-based interventions. Residual defects
after surgery are important because many patients and par-
ents assume these are completely repaired after complex
surgery. All diagnostic echocardiographic and catheter-
ization studies should be reviewed with careful attention
to ventricular function, atrioventricular valve compe-
tency, and PVR measurement32 (Figs. 3-4 and 3-5). Cardiac
MRI and CT angiographic images and data should also be
reviewed, particularly in delineating extracardiac anatomy
such as the aorta and its branches33 (Figs.  3-6 and 3-7).
A history of thrombosis or occlusion of veins or arteries will
help guide invasive catheter placement, and knowledge of
previous interventions helps determine appropriate loca-
tions (e.g., avoidance of left radial arterial line in patients
who had aortic coarctation repaired with left subclavian flap
technique). The patient or caregiver should be questioned
Chapter 3  Congenital Heart Disease 85
about the patient's functional status, limitations on activity,
and other cardiac symptomatology.
Chronic medication use should also be reviewed. Many
patients with CHD are taking medications for afterload reduc-
tion (angiotensin-converting enzyme [ACE] inhibitors), diure-
sis (furosemide, other diuretics), pulmonary hypertension
(endothelin receptor antagonists, prostacyclins, phosphodies-
terase inhibitors), arrhythmias (β-blockers, amiodarone), and
systemic anticoagulation (aspirin, low-molecular-weight hep-
arin, warfarin). The anesthetic implications of all medications
should be considered. In general, all cardiac medications should
be continued up to and including the day of surgery, with the
exception of anticoagulants. Aspirin use is common in infants
with systemic-to-pulmonary artery and other shunts and is
often safe to continue for peripheral surgery. Other agents (e.g.,
heparin, warfarin) must be addressed with the surgeon and car-
diologist, depending on the indication and the procedure.
On physical examination, signs of poor cardiac output and
long-standing cyanosis may include peripheral vasoconstric-
tion and clubbing, respectively. Pulse oximetry readings on
room air or baseline O2 delivery should be noted. In addi-
tion, the volar aspect of the wrists should be examined for
scars indicating previous arterial cutdown that may compli-
cate arterial line placement. A careful airway examination is
necessary because of the association of CHD with a number of
craniofacial syndromes that may complicate airway manage-
ment. Pulmonary examination to assess degree of respiratory
distress is important. The major examination findings are dis-
cussed later for each lesion.
Depending on the severity of cardiovascular disease,
comorbidities, and the proposed procedure, extensive preop-
erative testing may be warranted. Common laboratory tests
include hemoglobin and hematocrit, platelet count, coagula-
tion studies, and electrolytes. Exercise stress testing, electro-
cardiogram (ECG), and Holter study may also be indicated.
Table 3-6 summarizes important preanesthetic considerations
in the CHD population.
Premedication and Monitoring
Premedication plays a significant role in allaying anxiety
in patients with congenital heart disease. Many patients,
both pediatric and adult, have undergone multiple procedures,
and providing a comfortable separation from family members
and transfer to the OR can enhance the perioperative experi-
ence. Anxiolysis can also reduce myocardial O2 consumption
and sympathetic stimulation. However, excessive sedation
can also be detrimental in the CHD patient. Hypoxemia and
hypercarbia from hypoventilation can decrease pulmonary
blood flow in patients with systemic-to-pulmonary arterial
shunts or passive pulmonary blood flow (Fontan) and can
cause cardiovascular collapse in patients with PH.
Common premedications in CHD children include oral or
IV midazolam, ketamine, and pentobarbital. Common anx-
iolytics in adults include oral diazepam and IV diazepam,
midazolam, and ketamine. Patients with CHD receiving
 86 ANESTHESIA AND UNCOMMON DISEASES

LA
LA
RA RA

LV
LV
* RV
RV

A B

d-TGA

AO
PA
LA

RV LV

RA

RV LV

C
FIGURE 3-4  Preoperative echocardiographic findings in CHD. A, Perimembranous ventricular septal defect (VSD). Color flow Doppler
image depicts left-to-right shunting through defect in membranous septum (arrow). B, Complete atrioventricular canal, transesophageal view.
Four-chamber view demonstrates ostium primum atrial septal defect (ASD; arrow) and inlet VSD (arrow with asterisk). C, Cor triatriatum.
Obstructive membrane in left atrium (LA) (arrowheads) divides cavity into proximal and distal portions. RA, right atrium. D, Dextrotransposition
of the great arteries (d-TGA). Pulmonary artery (PA) arises from left ventricle (LV), and aorta (AO) arises from right ventricle (RV). Associated
perimembranous VSD is seen (arrow). (Modified from Russell IA, Miller-Hance WC: Transesophageal echocardiography in congenital heart
disease. In Andropoulos DB, et al, editors: Anesthesia for congenital heart disease, ed 2, Oxford, UK, 2010, Wiley-Blackwell.)

premedication should be monitored closely for signs of respi-
ratory depression and poor CO, with pulse oximetry and ECG
monitoring.
The use of invasive monitoring depends on the patient's
physiology, the procedure, and the need for close BP control
and frequent arterial blood gases (ABGs). Sites for arterial
catheter placement depend on previous surgery. For example,
patients with classic or modified Blalock-Taussig shunts will
often have spuriously low BP when monitored on the ipsilat-
eral upper extremity. In addition, patients with left subclavian
flap repair of aortic coarctation will have unreliable BP mea-
surements on the left upper extremity. Arterial cutdown for
previous surgeries can also complicate percutaneous arterial
catheter placement.
Central venous pressure (CVP) monitoring can also be
helpful, but it is important to understand the patient's venous
anatomy before placement. Depending on the stage of pallia-
tion, the superior vena cava (SVC) may be connected to the
pulmonary artery, and pressure measurement in the SVC
reflects PAP, not true CVP. Measurement of CVP in the patient
with a superior cavopulmonary connection requires a catheter
in the inferior vena cava (IVC). After the Fontan operation,
both the SVC and the IVC are connected to the pulmonary
arteries, and pressure measured in these locations is not
equivalent to atrial pressure. In addition, CVP catheter place-
ment in the internal jugular vein of an infant with a planned
­single-ventricle palliation is discouraged because a stenosis or
thrombosis of the SVC can preclude further palliation.
 Chapter 3  Congenital Heart Disease 87

14/16 16/16
49 45
m=15 m=15

n=13
100 v=18 100 FIGURE 3-5  Hypoplastic left heart syndrome
m=11 87
(HLHS). Catheterization diagram of infant with HLHS
after stage I palliation and bidirectional cavopulmonary
n=12 anastomosis (Glenn anastomosis). This one-page
v=16 63
document summarizes history, anatomy, and physiology
m=11
and contains a wealth of information necessary to
118/12 plan anesthetic care. Numbers in circles are oxygen
saturations, numbers without circles are pressures;
arrows indicate catheter course; a, a-wave pressure;
106/52
79 v, v-wave pressure; m, mean pressure; ABG, arterial
m=73
ABG on 100% 7.3/53/57/26/–1 blood gas; BSA, body surface area; LSVC, presence of
left superior vena cava; Qp, pulmonary blood flow; Qs,
systemic blood flow; PAR, pulmonary artery resistance;
Ht 48 cm Wt 4.3 kg BSA 0.22 m2 Hgb 14.3 Hct – % LSVC –
U, Wood units; Rp:Rs, pulmonary-to-systemic vascular
Qp 1.47 L/min/m2 Qs 2.57 L/min/m 2
Qp:Qs 0.6:1 PAR 2.72 U·m 2
Rp:RS –
resistance ratio; VO2, oxygen consumption.
(Fick) (Fick)
VO2 cons 160 ml/min/m2
(assumed)

DIAGNOSIS:
1. Hypoplastic left heart syndrome (mitral and aortic stenosis)
2. Norwood procedure with a 3.5 mm Blalock-Taussig (BT) shunt
3. Right subclavian artery occlusion
4. Right ventricular dysfunction
5. Bidirectional Glenn
6. Poorly controlled atrial tachycardia

FIGURE 3-6  Magnetic resonance

angiograms of coarctation. A, Severe
coarctation (arrows) of the aorta in
15-year-old male patient, just distal
to left subclavian artery. B, Large
collateral arterial vessels are seen in
posterosuperior aspect of thorax, and
a large internal mammary artery is
present (arrowheads). (From Mossad
EB, Joglar JJ: Preoperative evaluation
and preparation. In Andropoulos DB,
et al, editors: Anesthesia for congenital
heart disease, ed 2, Oxford, UK, 2010,
Wiley-Blackwell.)

A B
 88 ANESTHESIA AND UNCOMMON DISEASES
FIGURE 3-7  Severe aortic coarctation. This 19-year-old male
patient was diagnosed with aortic coarctation using narrow-
collimation contrast-enhanced multislice computed tomography
(CT). Axial CT image shows severe aortic coarctation. The main
pulmonary artery is seen branching into the right and left pulmonary
arteries. The ascending aorta is imaged in cross-section alongside
the pulmonary artery. In comparison, the black arrow indicates the
severely narrowed proximal descending thoracic aorta. Enlarged
internal mammary arteries (double white arrows) and numerous
enlarged collateral vessels (arrowheads) are also present. (From
Mossad EB, Joglar JJ: Preoperative evaluation and preparation.
In Andropoulos DB, et al, editors: Anesthesia for congenital heart
disease, ed 2, Oxford, UK, 2010, Wiley-Blackwell.)
Cerebral oximetry monitoring using near-infrared spec-
troscopy (NIRS) is often considered routine during cardiac
surgery, but it can also be used during noncardiac surgery to
trend O2 delivery and CO. Somatic oximetry with the same
device, using a probe placed on the flank at the tenth thoracic–
first lumbar vertebral (T10-L1) level, is an important monitor
of systemic O2 delivery in single-ventricle infants and may be
considered for major noncardiac surgery in these patients.34,35
Transesophageal echocardiography (TEE) can be used to
monitor function and filling intraoperatively and assist the
anesthesiologist in adjusting pharmacologic therapy and fluid
administration during major surgery in patients with complex
CHD.36
Airway and Ventilation Management
Depending on the type of procedure planned and patient
selection, a natural airway, laryngeal mask airway (LMA), or
endotracheal tube (ETT) can all be used safely. Knowledge
of the patient's cardiac lesion and function and the goals for
ventilation and oxygenation are critical. Pulmonary hyperten-
sion is exacerbated by hypoxemia and hypercarbia, so airway
and ventilation management should be planned accordingly.
Left-to-right shunt lesions such as ventricular septal defects,
truncus arteriosus, and systemic-to-pulmonary arterial shunts
can become unstable with the administration of high concen-
trations of inspired O2 and with hypocarbia.
Anesthetic Techniques
When delivered with care, any anesthetic drug can be used
in the patient with congenital heart disease. Myocardial
depressants should be avoided in patients with poor ventricu-
lar function and who would poorly tolerate a BP decrease.
Regional anesthetic techniques are also used in many patients
with CHD, but careful assessment, including knowledge of
anticoagulant therapy, is important for planning these tech-
niques. Plans for emergence and tracheal extubation should
also be considered. Tracheal extubation with deep levels of
anesthesia can avoid the increased PVR that can accom-
pany light planes of anesthesia and straining against an ETT.
However, use of tracheal extubation must be weighed against
the potential for airway obstruction, which can be disastrous
in patients with PH.
Postoperative Care Plan and Disposition
Before anesthetizing a CHD patient for a procedure, the clini-
cian should have a postoperative care plan. Depending on the
lesion, preoperative status, and procedure, it is often necessary
to reserve a bed in an intensive care unit (ICU) or a patient
floor. Patients with delicate physiology (e.g., systemic shunt-
dependent pulmonary flow, poor ventricular function) are
usually admitted to the ICU or cardiology ward after admin-
istration of most anesthetics. At a minimum, these patients
need a period of observation (4-6 hours) to ensure that they
are hemodynamically stable in their baseline cardiac rhythm,
maintaining stable So2 without airway or pulmonary prob-
lems, and can take oral fluids before discharge home.
Although procedures can be performed in CHD patients
at freestanding outpatient surgical facilities, careful preop-
erative evaluation must occur. If there is any potential for
instability or need for hospital admission, the lack of prox-
imity to skilled help, drugs, and equipment precludes safe
anesthesia care in these facilities, and the procedure should
be performed in a hospital setting with adequate backup
provisions.
Infective Endocarditis Prophylaxis
Infective endocarditis (IE) is a serious cause of morbidity and
mortality, and patients with congenital heart disease have an
increased incidence of IE, 1.1 per 1000 patient-years, com-
pared with the general population, 1.7 to 6.2 per 100,000
patient-years.37
The American Heart Association (AHA) published new
guidelines for IE prevention in 2007.38 The committee found
that very few cases of IE could be prevented by the admin-
istration of antimicrobial endocarditis prophylaxis. As a
result, the indications were narrowed considerably over

TABLE 3-6  n  Preanesthetic Considerations for CHD Patients
Evaluation
History
Physical examination
Chest radiography
Electrocardiography;
including 24-hour Holter
monitoring
Hemoglobin
Oxygen saturation (SpO2)
Echocardiography
Computed tomography
(CT) angiography
Cardiac magnetic
resonance imaging (MRI)
Cardiac catheterization
PDA, Patent ductus arteriosus; NYHA, New York Heart Association; BP, blood pressure; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; PAP,
pulmonary artery pressure; RV, right ventricular; PA, pulmonary artery; Qp/Qs, pulmonary/systemic blood flow ratio.
Chapter 3  Congenital Heart Disease 89
Findings Anesthetic Implications
Cardiac lesion: cyanotic or acyanotic, one or two ventricles Overall anesthetic planning
Septated, or intra-atrial or ventricular communications
Surgery or catheter interventions:
  Palliated or corrected
  Residual defects
Source of pulmonary blood flow:
  PDA, shunt, native, collaterals
Ventricular function
Coronary anatomy
Outflow tract obstruction
Exercise tolerance, feeding, NYHA functional class
Medical therapy
General appearance Degree of compensation and physiologic
BP: normal, elevated, low for age reserve to tolerate anesthesia and surgery
Cyanosis, clubbing Anesthetic drugs and doses
Tachypnea, retractions Arterial and central venous catheterization
Peripheral perfusion and pulses Airway and ventilatory management
Precordium, heart sounds, murmurs Need for central venous access
Hepatomegaly, jugular venous distention
Diaphoresis
Adequacy of peripheral veins and arterial pulses
Heart size and configuration: normal or small heart; Functional degree of left-to-right or right-to-
cardiomegaly left shunting
Pulmonary vasculature: normal, increased, or decreased Plan ventilatory management.
Pulmonary parenchymal disease Adequacy of medical therapy (e.g., diuretics)
Rhythm: normal sinus vs. atrial or ventricular arrhythmias; Plan antiarrhythmic and pacemaker therapy.
paced rhythm Degree of ventricular hypertrophy
Rate General condition of myocardium
ST segments
Axis deviation
Normal, low, or elevated for age and gender Relative degree and duration of cyanosis
Need for blood transfusion
Normal: 95%-100% Establish normal ranges for patient
Mild desaturation: 85%-95% Plan ventilatory, hemodynamic, and
Moderate cyanosis: 75%-85% transfusion management
Severe cyanosis: <75%
Cardiac anatomy, residual defects, ventricular function Plan hemodynamic goals for anesthesia:
Outflow tract obstruction   BP/SVR (afterload-vasodilator)
Valvar regurgitation   PVR/PAP (RV afterload)
Atrial/ventricular communication   HR, contractility (inotropic support)
  Ventricular filling (preload)
  Diastolic function (lusitropy)
Anatomy of extracardiac structures: aorta, pulmonary Detailed anatomy of extracardiac structures:
arteries and veins Aortic, PA, or pulmonary venous obstruction
Anatomy of intracardiac/extracardiac structures, ventricular Detailed anatomy
function, Qp/Qs Plan ventilatory management, inotropic/
vasodilator support
Detailed anatomy Most detailed hemodynamic information;
Hemodynamics, including pressures in all vessels/ plan hemodynamic goals
chambers
SVR/PVR and Qp/Qs, PVR reactivity
 90 ANESTHESIA AND UNCOMMON DISEASES

previous versions of the guidelines. Patients must first have

a cardiac indication; these are now limited to the presence BOX 3-2   n HIGH-RISK CARDIAC CONDITIONS IN
ENDOCARDITIS PATIENTS FOR WHOM
of a prosthetic valve, previous endocarditis, and some forms DENTAL PROPHYLAXIS IS REASONABLE
of CHD. The CHD indications include unrepaired cyanotic
CHD, complete repair with a prosthetic patch or material Prosthetic cardiac valve or prosthetic material used for cardiac
valve repair
but only in the first 6 months after the procedure, and those
Previous infective endocarditis (IE)
with residual defects near the site of a patch. Transplant Congenital heart disease*
patients with valvulopathy are also included. In addition, a ● Unrepaired cyanotic CHD, including palliative shunts and conduits
procedural indication must exist for IE prophylaxis. These ● Completely repaired congenital heart defect with prosthetic

include dental work with disruption of gums or mucosa; air-
way procedures such as tonsillectomy; and gastrointestinal
(GI), genitourinary (GU), or skin, soft tissue, and orthope-
dic procedures involving infected tissue. Simple GI, GU, or
other procedures without infection are no longer indications
for prophylaxis. Box 3-2 and Table 3-7 summarize the major
recommendations involving dental procedures and antibi-
otic regimens.38
The American College of Obstetrics and Gynecology
(ACOG) and AHA do not recommend IE prophylaxis for
uncomplicated vaginal or cesarean deliveries, regardless of the
type of maternal cardiac disease. The maternal cardiac con-
ditions associated with the highest risk of adverse outcome
from IE are appropriate for antibiotic administration only
if the patient has an established infection that could cause
bacteremia.39
Patients at Greatest Anesthetic Risk
Patients with congenital heart disease are known to be at much
higher risk for perioperative cardiac arrest and death than
those without cardiac disease. A Mayo Clinic study of 92,881
pediatric anesthetic procedures from 1988 to 2005 revealed
that 88% of the 80 arrests involved patients with CHD. The rate
material or device, whether placed by surgery or by catheter
intervention, during the first 6 months after the procedure†
● Repaired CHD with residual defects at the site or adjacent to
the site of a prosthetic patch or prosthetic device (which inhibit
endothelialization)
Cardiac transplantation recipients who develop cardiac valvulopathy
Data from Wilson W et al: Prevention of infective endocarditis, Circulation
116:1736-1754, 2007.
*Except for the conditions listed above, antibiotic prophylaxis is no longer
recommended for any other form of CHD.
†Prophylaxis is reasonable because endothelialization of prosthetic material
occurs within 6 months postoperatively.
of cardiac arrest was several hundred–fold higher for patients
with CHD.40 Recent data also show which CHD patients are at
the highest risk for cardiac arrest and death during or shortly
after anesthesia (Box 3-3).
The Pediatric Perioperative Cardiac Arrest Registry evalu-
ated 393 pediatric patients (127 with heart disease) who had
anesthetic-related cardiac arrest from 1994 to 2005.41 About
59% of these patients were unrepaired, and 26% were palli-
ated, so only 15% had undergone reparative surgery. Single-
ventricle diagnosis was most common (19%), with hypoplastic
left heart syndrome (HLHS) in the most patients. Mortality

TABLE 3-7  n  Endocarditis Prophylaxis: Dental Regimens for CHD Surgical Patients

Regimen*

Situation Agent Adults Children

Oral Amoxicillin 2 g 50 mg/kg

Unable to take oral medication Ampicillin 2 g IM or IV 50 mg/kg IM or IV

or
Cefazolin or ceftriaxone 1 g IM or IV 50 mg/kg IM or IV

Allergic to penicillins or ampicillin Cephalexin†‡ 2 g 50 mg/kg

(oral) or
Clindamycin 600 mg 20 mg/kg
or
Azithromycin or clarithromycin 500 mg 15 mg/kg

Allergic to penicillins or ampicillin and Cefazolin or ceftriaxone† 1 g IM or IV 50 mg/kg IM or IV

unable to take oral medication or
Clindamycin 600 mg IM or IV 20 mg/kg IM or IV

Data from Wilson W et al: Prevention of infective endocarditis, Circulation 116:1736-1754, 2007.
*Single dose, 30 to 60 minutes before procedure.
†Or other first- or second-generation oral cephalosporin in equivalent adult or pediatric dosage.
‡Cephalosporins should not be used in patients with a history of anaphylaxis, angioedema, or urticaria with penicillins or ampicillin.
IM, Intramuscularly; IV, intravenously.
 Chapter 3  Congenital Heart Disease 91

Melbourne, Australia, revealed 10 anesthetic-related deaths,

BOX 3-3   n HIGHEST-RISK CHD LESIONS FOR PATIENT
ANESTHESIA
Left-sided obstructive lesions
Pulmonary hypertension (PH)
Single-ventricle (SV) lesions
Dilated cardiomyopathy (DCM)
was only 25% after cardiac arrest in this group. Left-to-right
shunt lesions were the next most common diagnosis, with 18%,
but mortality was low (17%) after arrest. Left-sided obstruc-
tive lesions were seen in 16%, but with high mortality (45%).
Aortic stenosis had the single highest mortality rate after car-
diac arrest under anesthesia (62%). Data on anesthetic-related
24-hour and 30-day mortality for 101,885 pediatric anesthetic
patients from 2003 to 2008 at Royal Children's Hospital in
five in patients with PH with or without CHD; eight had com-
plex CHD, PH, or both.42
SPECIFIC CARDIAC LESIONS
Left-to-Right Shunt Lesions
Left-to-right shunt lesions are among the most common CHD
lesions that the anesthesiologist will encounter. The level of
shunting can occur at any location between intracardiac cham-
bers (i.e., ventricular septal defect [VSD] or atrial septal defect
[ASD]), or extracardiac structures (i.e. patent ductus arterio-
sus [PDA]). The pathophysiologic consequences of L-R shunt
depend on several factors: the size of the defect, pressure gra-
dient between chambers or arteries, the pulmonary/systemic
vascular resistance (PVR/SVR) ratio, the relative compliance of
right and left ventricles, and blood viscosity43 (Fig 3-8).

Left-to-right shunts

Atrial Ventricular or
level great artery level

Relative Blood Size of Pressure Ratio of

compliance viscosity defect gradient PVR to SVR
Right vs left (hemoglobin) between
ventricle chambers/
arteries
Degree of shunting affected by these factors

Atrial or Atrial, ventricular, or great artery shunts Great

ventricular artery shunts
shunts

RV filling Pulmonary blood flow LA and LV blood flow Diastolic BP

RVEDV and RVEDP Pulmonary edema Pulmonary LVEDV and LVEDP Coronary
venous perfusion pressure
congestion

RV failure PVR LV failure Myocardial

ischemia

Pulmonary hypertension

RV hypertrophy Pressure Shunt reversal Eisenmenger’s

RV  LV R L syndrome

FIGURE 3-8  Pathophysiology of left-to-right shunting lesions. Flow diagram depicts factors that affect left-to-right shunting at atrial,
ventricular, and great artery level and pathophysiology produced by these shunts. A large shunt will result in left ventricular (LV) failure,
right ventricular (RV) failure, and pulmonary edema. Increased pulmonary blood flow and pulmonary artery pressures lead to pulmonary
hypertension and eventually Eisenmenger's syndrome. These final common outcomes are highlighted in bold. PVR, Pulmonary vascular
resistance; SVR, systemic vascular resistance; LA, left atrial; BP, blood pressure; RVEDV, right ventricular end-diastolic volume; RVEDP,
right ventricular end-diastolic pressure; LVEDP, left ventricular end-diastolic pressure; LVEDV, left ventricular end-diastolic volume; R →
L, right to left. (Data from Walker SG: Anesthesia for left-to-right shunt lesions. In Andropoulos DB, et al, editors: Anesthesia for congenital
heart disease, ed 2, Oxford, UK, 2010, Wiley-Blackwell.)
 92 ANESTHESIA AND UNCOMMON DISEASES
In general, atrial-level shunting produces the least degree
of change, resulting in increased right ventricular (RV) filling
and mild increases in RV end-diastolic volume and pressure.
Symptoms are minimal, and these shunts may be tolerated for
decades. Ventricular-level shunting is often more problematic,
and if the defect is large and unrestrictive, RV pressure is close
to left ventricular (LV) pressure, also elevating pulmonary
artery (PA) pressure and flow significantly. Qp/Qs greater than
3:1 will produce significant increases in left atrial (LA) and LV
blood flow, LV end-diastolic pressure (LVEDP) and volume
(LVEDV), and can lead to pulmonary venous congestion, pul-
monary edema, and respiratory distress. Smaller, restrictive
ventricular defects, where RV pressure is significantly lower
than LV pressure, produce lesser elevations in Qp/Qs, and pul-
monary congestion is less severe.
Shunts at the great artery level, if large, are the most problem-
atic. In young infants, these lesions can produce a “steal” of blood
flow away from the aorta to the PA, lowering diastolic BP and
causing coronary ischemia, heralded by global LV dysfunction
and dilation, poor CO, and ST-segment changes on ECG. Any
L-R shunt that is large enough, particularly at the ventricular or
great artery levels, produces pulmonary hypertension, which,
if left untreated over years, may become irreversible. This syn-
drome results from increased shear stress and circumferential
stretch on the pulmonary arterioles causing endothelial dys-
function and vascular remodeling. Smooth muscle cells prolifer-
ate, extracellular matrix increases, and intravascular thrombosis
occurs in the smaller arterioles. This increases PVR, and even-
tually the shunt inverts, resulting in cyanosis (Eisenmenger's
syndrome).44 Although encountered less frequently in contempo-
rary practice, patients with Eisenmenger's syndrome are always
at high risk under anesthesia and require careful assessment and
planning (see later discussion).
Ventilatory management during general anesthesia will
affect pathophysiology, especially with large L-R shunts in
small infants, whose pulmonary vasculature will respond vig-
orously to changes in Fio2 and Paco2. Hyperoxygenation and
hyperventilation usually lower PVR greatly and increase the
L-R shunt, which may cause lower diastolic pressure, coronary
steal, and large increases in both RV and LV volumes, lead-
ing to acute myocardial dysfunction. Generally, lower Fio2 and
normocarbia are the goal during anesthesia in these infants,
to limit increases in pulmonary blood flow. Positive end-
expiratory pressure (PEEP) also limits increases in Qp/Qs.
Any anesthetic regimen can be used in these patients; most
agents are pulmonary vasodilators, and none, even ketamine,
is a pulmonary vasoconstrictor (Box 3-4; see also Pulmonary
Hypertension).
BOX 3-4   n  LARGE LEFT-TO-RIGHT (L-R) SHUNTS
Controlling pulmonary/systemic blood flow ratio (Qp/Qs) is an
important goal.
Limiting Fio2 prevents large decreases in pulmonary vascular resistance.
Avoiding hyperventilation and adding PEEP help balance Qp/Qs.
Patent Ductus Arteriosus
The patent ductus arteriosus (PDA) is the connection between
the pulmonary artery and lesser curve of the arch of the aorta,
which during fetal life carries blood from the PA to the aorta,
bypassing the lungs so that only 5% to 10% of the fetal car-
diac output passes through the lungs45,46 (Fig. 3-9). Normally,
patency is maintained by low fetal oxygen tension (Po2), low
levels of circulating prostanoids produced by the placenta,
and lack of prostanoid metabolism by the lungs. At birth, with
onset of respiration and expansion of the lungs, oxygenation,
and decreased levels of prostanoids, the PDA constricts, and
normally is functionally closed by 48 to 72 hours of life, and
anatomically closed by 2 weeks, producing the ligamentum
arteriosum. However, some PDAs never close, and it is one of
the most common, simple CHD lesions.
Isolated PDA incidence is 1:2000 to 1:5000 live births and
accounts for 3% to 7% of congenital heart disease.1 PDA is
more common in premature infants but may be encountered
at any age, including adults. It is also a component of many
more complex cardiac diseases, and early neonatal survival
depends on the PDA for many lesions, including stenosis or
atresia of the pulmonary or aortic valves (e.g., pulmonary atre-
sia, HLHS). Maintaining ductal patency with prostaglandin E1
(PGE1) for such lesions is mandatory until surgical or catheter
palliation or correction can be performed.
Ductus arteriosus
Aorta
Pulmonary
artery
Left
atrium
Right
atrium
Left
ventricle
Right
ventricle
FIGURE 3-9  Patent ductus arteriosus with resultant left-to-
right shunting. Some of the blood from the aorta crosses ductus
arteriosus and flows into pulmonary artery (arrows). (Modified from
Brickner ME, Hillis LD, Lange RA: N Engl J Med 342:256-263, 2000.)

Flow through the PDA is normally left to right (i.e., aorta to
PA). The amount of flow depends on the diameter, length, and
tortuosity of the PDA and the relative pressure and resistances
in the aorta and PA. Anatomic variations range from a tiny
PDA with almost no flow to large, aneurysmal, calcified PDA
in adults, with very high pressures from years of exposure to
aortic pressure and flows. The pathophysiologic consequences
of a PDA range from minimal through significant increases
in Qp/Qs (>2:1), causing increases in RV volume and pres-
sure and possible increases in LA and LV flow to the point that
LVEDV and LVEDP are elevated, which can increase pulmo-
nary venous pressure and cause transudation of fluid through
pulmonary capillaries into the interstitial and alveolar spaces.
This is particularly common in premature infants, who may be
ventilator dependent solely as a result of the PDA. In addition,
patients with very large PDA may have a large steal of flow
from the aorta to the PA, lowering diastolic BP and potentially
causing coronary ischemia. Over time, patients with a large,
long-standing PDA may develop irreversible elevations in PA
pressure, leading to reversal of the shunt and Eisenmenger's
syndrome. Many patients with small PDA are asymptomatic,
with increasing symptomatology according to the PDA size
and Qp/Qs. Recurrent respiratory infections, difficulty feed-
ing, diaphoresis, and impaired growth are seen in infants with
large PDA. Occasionally, congestive heart failure (CHF) is
seen.
Physical examination in isolated PDA usually reveals
an acyanotic child, with Spo2 of 95% to 100% on room air.
Peripheral pulses are easily palpable because of the increased
pulse pressure resulting from lowered diastolic BP. Precordial
examination yields a vigorous cardiac impulse, with the LV
apex often displaced to the left. A compensatory tachycardia
at rest is often present. With a small shunt, there may only
be a soft grade I-II/VI systolic murmur over the left infracla-
vicular area. With increasing shunt, the murmur will become
louder and longer, and with very large PDA there is a con-
tinuous, machinery-like murmur, loudest just after the second
heart sound (S2), which is often accentuated. Examination of
the lungs may reveal tachypnea, retractions, and fine rales if
there is significant pulmonary congestion.
Diagnostic testing in patients with PDA includes an ECG,
which often reveals evidence of LA and LV enlargement and
in more severe cases, RV enlargement as well. Rhythm is nor-
mally sinus, although adults may develop atrial fibrillation
from long-standing atrial enlargement. Chest radiograph find-
ings range from near-normal to cardiomegaly with increased
pulmonary vascular markings in larger PDA. Transthoracic
echocardiogram is the most useful diagnostic modality and
is often sufficient to make an accurate diagnosis as to size,
tortuosity, direction of shunting, and enlargement of cardiac
chambers and any associated defects. Both two-dimensional
and color Doppler images, as well as pulsed and continuous-
wave Doppler studies, are obtained for a complete picture of
anatomy and physiology. The PDA is often larger than the
aorta and the branch PAs in premature infants. In PDA with
complex or questionable anatomy, additional studies (e.g., CT
Chapter 3  Congenital Heart Disease 93
angiography, MRI) are performed. These studies are partic-
ularly useful if a coarctation of the aorta is suspected, often
present in the juxtaductal position. Cardiac catheterization is
performed only in particularly difficult cases or when PDA is
associated with device closure in the CCL.
Closure of the PDA is performed by one of three methods:
thoracotomy with ligation or ligation/division, video-assisted
thoracoscopy (VATS) with ligation, or endovascular closure
with coils, plugs, or other devices in the CCL.47 Robotic-
assisted VATS has also been reported.48 Choice of closure
method depends on the size of the patient, anatomy of the
PDA, and institutional practice, including surgeon and car-
diologist preference. In general, premature and other small
infants will have left thoracotomy with extrapleural dissection
and closure of the PDA; larger infants can undergo thoracot-
omy or VATS repair. Surgical closure is used for large or tor-
tuous PDAs or when coarctation of the aorta may be present.
In the modern era, most small to moderate PDAs in larger
infants and children are occluded in the CCL. Adult patients
with large, aneurysmal PDAs may require cardiopulmonary
bypass (CPB) or even deep hypothermic circulatory arrest
(DHCA) through a thoractomy or sternotomy.49
Anesthetic considerations in PDA patients include thor-
ough preoperative evaluation with complete examination and
assessment of all diagnostic studies, to assess the degree of L-R
shunting and pathophysiologic severity. Packed red blood cells
must be available in the OR or CCL, in case of tearing or rup-
ture of the PDA, which although rare, can cause catastrophic
bleeding. Standard monitors are applied before induction, and
inhalational induction with sevoflurane or IV induction with
various agents can be accomplished. An arterial line, prefer-
ably in the right radial artery, is indicated for small infants
undergoing surgery, as well as other patients with significant
pathophysiology. In the CCL the cardiologist will acquire fem-
oral arterial access for monitoring and approach to the PDA. A
central venous catheter is needed only for large PDAs accom-
panied by significant pathophysiology. For thoracotomy or
VATS in small infants, single-lung ventilation (SLV) is usu-
ally unnecessary; the technical difficulty and time required
often are significant. Insufflation of CO2 with lung retraction
for VATS, or simple retraction and packing for thoracotomy
in small infants, is usually sufficient for surgical exposure.
Alternately, the endotracheal tube may be advanced into the
right main bronchus in a small infant; the problem with this
approach is that the right upper-lobe bronchus is often close to
the carina and is occluded by the ETT. In larger patients, SLV
can be provided by bronchial blockers, or in larger patients
(>30 kg), a small, left-sided double-lumen ETT, and will assist
with surgical exposure, particularly in VATS.
Any combination of inhaled or IV agents may be used for
maintenance of anesthesia, keeping in mind the severity of
pathophysiology. Severely ill neonates with large PDA will be
intolerant of the myocardial depressant and hypotensive effects
of significant concentrations of halogenated anesthetics. Nitrous
oxide (N2O) should be avoided because of its potential to
expand closed air spaces. In small infants with large L-R shunts,
 94 ANESTHESIA AND UNCOMMON DISEASES
high Fio2 accompanied by hyperventilation to lower Paco2
will often excessively lower PVR, resulting in large increases in
Qp/Qs, more diastolic steal of systemic blood flow, and large
increases in both LV and RV volumes, all of which may lead to
acute myocardial failure. Inotropic support with dopamine or
epinephrine may be needed in some patients, particularly the
premature infant. Precise ventilation, with a microprocessor-
controlled anesthesia ventilator capable of delivering small tidal
volumes, or hand ventilation, may be required.
Premature infants often undergo thoracotomy at the bedside
in the neonatal ICU, to avoid the stresses of transport to a dis-
tant OR. A complete anesthesia setup, with all necessary equip-
ment and drugs, is brought to the bedside. Normally the infant's
NICU ventilator is used, and anesthesia is provided with fen-
tanyl (30-50 μg/kg) and small doses of midazolam, along with
neuromuscular blockade with vecuronium, pancuronium, or
other nondepolarizing agent. This approach provides suffi-
cient anesthesia to prevent hemodynamic response to surgery,
while allowing hemodynamic stability in these fragile patients.50
During PDA ligation, particularly in premature infants, the
anesthesiologist must have a method to monitor lower-extremity
perfusion, such as pulse oximeter probe on the toe or foot. The
PDA is often larger than the descending thoracic aorta, and the
aorta has been mistakenly ligated in some cases; disappearance
of pulse oximeter signal on the lower extremity must immedi-
ately be noted, and the surgeon must ensure that the correct
structure has been occluded. Ligation of the left PA is also pos-
sible in small infants. Method of occlusion can be with vascular
clips; however, many surgeons believe the most secure method
is ligation at both ends of the PDA with heavy silk sutures or
oversewing, followed by ligation to ensure permanent occlu-
sion. A thoracostomy tube is typically placed, although some
surgeons do not place these tubes in premature infants. A post-
operative chest radiograph is obtained in all patients.
In small infants with significant pathophysiology, the trachea
is left intubated to allow recovery from both the cardiac and the
pulmonary effects of a large PDA. In almost all other patients,
the trachea can be extubated at the end of the procedure.
Postoperative analgesia can include thoracic nerve blocks or
wound infiltration by the surgeon, or possibly thoracic epidural
analgesia (not usually used because recovery is typically rapid).
Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs)
are used for postoperative pain. Postoperative stay for uncom-
plicated PDA ligation is short, usually 24 to 48 hours; CCL
closure is usually followed by discharge home the same day.
According to the latest AHA infective endocarditis guide-
lines, acyanotic patients with unrepaired or repaired PDA do
not require prophylaxis.38
Aortopulmonary Window
Aortopulmonary (AP) window is an abnormal connection
between the intrapericardial components of the aorta and pul-
monary artery. AP window is a rare lesion, only 0.1% to 0.6%
of congenital heart defects.51 About half of patients also have
associated cardiac defects (e.g., PDA, VSD). The AP window
can range from small, circular communication to total absence
of the septum between the aorta and PA. Some AP window
defects have a tubular communication. The pathophysiol-
ogy of an AP window is similar to that of a large PDA and
depends on size of the communication and relative SVR and
PVR. AP window is usually diagnosed in early infancy, with
the presence of a systolic or continuous murmur similar to
that of a PDA, with pulmonary overcirculation, tachypnea,
poor feeding and growth, and signs of CHF. Diastolic coro-
nary steal may impair ventricular function. Diagnosis is by
echocardiography. Repair is most often done in early infancy,
almost always with CPB; the AP window is repaired by patch-
ing if large, or by direct suture ligation if small. Older children
with suitable defects may have an AP window occluded in the
CCL with various closure devices. Anesthetic management is
the same as for the patient with a large PDA, with the same
approach to pathophysiologic derangements. Approach to the
infant undergoing repair with CPB is the same as for any com-
plex case.
Atrial Septal Defect
Atrial septal defects (ASD) represent 5% to 10% of congenital
heart defects and are classified as secundum (80% of defects),
primum, sinus venosus, or coronary sinus ASDs52 (Fig. 3-10).
The secundum ASD is in the middle of the atrial septum, in the
fossa ovalis, and results from lack of proper formation of the
secundum septum. A primum ASD is low in the atrial septum,
just above the tricuspid valve, a result of abnormal formation
of the septum primum. It is often associated with a cleft mitral
valve or with partial or complete atrioventricular (A-V) canal
defects. Sinus venosus ASDs are usually found just below the
SVC orifice but may also be found just above the IVC orifice.
This lesion is often associated with partial anomalous pulmo-
nary venous return (PAPVR; see later).1,43,53 A coronary sinus
ASD, or “unroofed coronary sinus,” results from lack of a par-
tition between the coronary sinus and left atrium, allowing
LA blood to drain into the right atrium. This defect is usually
associated with a persistent left SVC. Finally, a probe-patent
foramen ovale (PFO) is present in up to one third of normal
individuals, resulting from failure of fusion of the overlap-
ping primum and secundum septae. As long as LA pressure is
higher than right atrial (RA) pressure, ASD is asymptomatic;
however, paradoxical embolus and stroke or transient isch-
emic attack may occur if RA exceeds LA pressure, as during a
Valsalva maneuver.
Flow through the ASD is left to right, and symptomatol-
ogy depends on the size of the shunt. Because of the low
pressure in the atria and small interatrial pressure gradients,
the magnitude of the shunt is usually 2:1 or less. Ventricular
compliance also affects degree of shunting; the relatively stiff
right ventricle in the first few months of life prevents sig-
nificant shunt. Symptoms are often minimal, and may go
undetected for many years, even decades. Exercise intoler-
ance is one of the usual symptoms; more severe symptoms
(e.g., CHF, atrial flutter/fibrillation) are late signs and usually
 Chapter 3  Congenital Heart Disease 95

RAA
SVC
PT
SVC

3
ASD

1
2 RV
TV
RV CS
IVC

4
B

IVC
A
FIGURE 3-10  Atrial septal defects. A, Atrial septal anatomy. Schematic diagram shows the location of atrial septal defects, numbered
in decreasing order of frequency: 1, secundum; 2, primum; 3, sinus venosus; 4, coronary sinus type. IVC, Inferior vena cava; PT,
pulmonary trunk; RV, right ventricle; SVC, superior vena cava. B, Secundum atrial septal defect (ASD), right atrial view. SVC, Superior vena
cava; RAA, right atrial appendage; CS, coronary sinus; TV, tricuspid valve; RV, right ventricle. (Modified from Porter CJ, Feldt RH, Edwards
WD, et al: Atrial septal defects. In Emmanouilides GC, Riemenschneider TA, Allen HD, Gutgesell HP, editors: Moss and Adams heart disease
in infants, children, and adolescents: including the fetus and young adult, Baltimore, 1995, Williams & Wilkins.)

in patients over age 40. Pulmonary hypertension during child-
hood is rare but occurs in about 20% of patients age 20 to 40
and half of patients over 40. Rarely, fixed pulmonary pressures
result in Eisenmenger's syndrome. LV and RV sizes and func-
tion remain normal, but right atrium and right ventricle are
enlarged with the added volume load. Systemic CO and Sao2
are normal (Box 3-5).
Physical examination reveals an acyanotic child, usually
in no distress. Patients with ASD often have no symptoms
until later in life. Cardiac examination is usually abnormal,
with a fixed, split S2 the most consistent finding. This results
from increased RV volume, delaying full ejection and keeping
the pulmonary valve open later, and eliminating the respira-
tory variation. The murmurs are soft, I-II/VI, systolic, and at
the left upper sternal border. A soft ­mid-diastolic murmur
may be present with large shunts. In many ASD patients the
physical examination findings are subtle, resulting in delayed
diagnosis. ECG normally reveals sinus rhythm; biatrial
enlargement, right-axis deviation, and first-degree A-V
block may be seen in some patients. As noted, atrial fibril-
lation or flutter is a late sign usually seen only in unrepaired
adults. Chest radiograph reveals cardiomegaly, increased PA
size, and increased pulmonary vascular markings in patients
with moderate to large L-R shunts.
Diagnostic modalities for ASD include transthoracic echo-
cardiography, the most useful test, which typically is sufficient
to make the diagnosis and plan treatment. Two-dimensional
(2D) echocardiography defines the size, position, and mor-
phology of the defect, ventricular size and function, and any
associated intracardiac lesions (e.g., PAPVR). Color flow
Doppler defines the direction of blood flow and its velocity, to
assess the relative LA and RA pressures. Agitated saline con-
trast injection during a Valsalva maneuver can diagnose an
R-L shunt through a PFO by the early appearance of micro-
bubbles in the left atrium. Cardiac MRI and CT are not used
for ASD diagnosis, except in cases of complex or uncertain
anatomy, with associated defects not well defined by echocar-
diography. Cardiac catheterization is only used in conjunction
with planned device closure of the ASD.
Most patients with an unrepaired ASD will tolerate anesthe-
sia well without hemodynamic compromise. The usual tech-
niques and drug doses used for patients without heart disease
can be employed. Air bubbles must be avoided in any IV flu-
ids; paradoxical embolization can occur during Valsalva-type
maneuvers. Patients with CHF, atrial arrhythmias, or PH must
be carefully evaluated and the anesthetic planned accordingly.
Infective endocarditis prophylaxis for ASD patients is only
indicated after patch repair in the first 6 months.38
Secundum ASDs with adequate rims of tissue in all dimen-
sions or PFOs are normally closed in the CCL, with various
devices deployed by large sheaths introduced via the femoral
vein.54 For children, general anesthesia is normally employed,
and the device is positioned with the aid of fluoroscopy and
TEE necessitating a general anesthetic. In older patients, it is
possible to use sedation without endotracheal intubation, if an
intracardiac echo catheter technique is used.55 These proce-
dures usually are not accompanied by major hemodynamic
instability or blood loss. Larger defects, or other types of ASDs
(sinus venosus, primum, coronary sinus) are closed surgi-
cally with CPB; minimally invasive techniques with tiny ster-
notomy incisions can be used. Most patients have short CPB
and aortic cross-clamp times, and repair is with autologous
 96 ANESTHESIA AND UNCOMMON DISEASES

BOX 3-5   n  ATRIAL SEPTAL DEFECT (ASD)

Three major types of ASD are secundum, primum, and sinus

venosus.
Symptoms are usually mild.
Pulmonary vascular disease does not develop until the fourth or fifth
decade of life.

pericardial patch or direct suture closure. The majority of

these patients can be extubated in the OR and do not experi-
ence much bleeding or hemodynamic instability.56
A

Ventricular Septal Defect

C
Ventricular septal defect (VSD) is the most common form of con- B
genital heart disease; up to 20% of patients have this lesion as an D
isolated defect. In addition, as many as 40% to 50% of all patients
have a VSD as some component of their CHD.1,43,57 VSD anatomy
is highly variable, but four main types are encountered, as follows: E

1. Perimembranous VSD is the most common form (75%-80%

of VSDs) is found in the middle of the ventricular septum,
underneath the septal leaflet of the tricuspid valve.
2. Subarterial or outlet VSD (5%-15%) is high in the outlet
septum, underneath the aortic and pulmonary valves.
3. Muscular VSD (2%-7%) can be found anywhere in the
muscular septum.
4. Inlet-type VSD (5%) is located in the inlet septum under-
neath the tricuspid valve.
Many other variations and combinations of VSD range
from tiny muscular VSDs that close spontaneously to very
large and multiple defects58 (Fig. 3-11).
Left-to-right shunt through the VSD depends on the
size of the defect, the relative pressures in the right and
left ventricles, and the relative ventricular compliances, as
well as the PVR and SVR. If the VSD is small and restric-
tive, there is significant resistance to flow, the pressure
drop across the VSD is large, and Qp/Qs is less than 2:1. As
the VSD size increases, resistance is less and flow greater,
until the defect is termed unrestrictive; LV and RV pres-
sures are similar, Qp/Qs increases significantly to 3:1 or
greater, and relative PVR/SVR ratio becomes the impor-
tant determinant of flow. In clinical practice, Qp/Qs ranges
from essentially 1:1 with a tiny VSD to extreme elevations
of 5:1 or greater in infants with very large VSD and low
PVR. Certainly, elevated PVR may develop with months
or years of high pressure and flows into the pulmonary
arteries. If left untreated, the increased PVR can become
fixed and suprasystemic, and flow direction can reverse
to produce an R-L shunt, cyanosis, and Eisenmenger's
syndrome. Although unusual before several years of life,
Eisenmenger’s syndrome can occur as early as 1 to 2 years
in patients with large VSDs (Box 3-6).
Physical examination findings range from asymptomatic
patients to those with severe CHF. Infants with large VSD are
F
G
FIGURE 3-11  Anatomic position of ventricular septal defects.
A, Subarterial or outlet defect; B, papillary muscle of the conus; C,
perimembranous defect; D, marginal muscular defects; E, central
muscular defects; F, inlet defect; G, apical muscular defects.
(Redrawn from Graham TP Jr, Gutgesell HP: Ventricular septal
defects. In Emmanouilides GC, et al, editors: Moss and Adams
heart disease in infants, children, and adolescents: including the
fetus and young adult, Baltimore, 1995, Williams & Wilkins.)
BOX 3-6   n  VENTRICULAR SEPTAL DEFECT (VSD)
Three major types of VSD are perimembranous, subarterial, and
muscular.
The Qp/Qs ratio varies from near-normal to greater than 3:1.
The Qp/Qs depends on size of the defect, left/right ventricular
pressures, and pulmonary vascular resistance.
Pulmonary vascular disease may develop early in life in patients with
large VSD.
normally acyanotic with Spo2 of 95% to 100%. Tachypnea is
common, reflecting the pulmonary congestion, and a com-
pensatory tachycardia to maintain systemic CO in the face of
a large L-R shunt is often present. Feeding is often tiring for
these infants, and growth is often poor, both from inadequate
caloric intake and from a very high metabolic rate accom-
panying increased myocardial work. CHF is heralded by

retractions, fine rales, hepatomegaly, jugular venous disten-
tion, and diaphoresis. Cardiac examination reveals an active
precordium, displacement of the ventricular apex to the left,
and a murmur, which is usually a grade II-III/VI pansystolic
murmur between the second and third left intercostal spaces.
Smaller, restrictive defects produce more turbulent flow and
may be accompanied by a grade IV/VI murmur. Large VSD in
young infants whose PVR has not yet experienced its physi-
ologic fall may have minimal or no murmur, explaining why
some of these patients are diagnosed late. Qp/Qs greater than
3:1 will also produce a mid-diastolic flow murmur at the
cardiac apex. Heart sounds are normal unless PVR is signifi-
cantly elevated. ECG findings are not specific for VSD, are usu-
ally sinus rhythm, and may exhibit right-axis deviation with
significant shunts. Chest radiography normally reveals cardio-
megaly and increased pulmonary vascular markings, in pro-
portion to the size of the L-R shunt. Echocardiography is the
mainstay of diagnosis, with 2D echocardiography revealing
the size, position, and shape of the defect, ventricular size and
function, and associated intracardiac defects (see Fig. 3-4, A).
MRI, CT, and cardiac catheterization are required only for
complicated VSD with associated defects or for hemodynamic
catheterization if PVR is a concern.
Patients with an unrepaired small VSD are relatively asymp-
tomatic and will tolerate any of the common anesthetic tech-
niques and drugs. Again, no bubbles must be introduced into
the venous circulation by drug injection or IV fluids; paradox-
ical R-L shunt can easily occur with elevated PVR or Valsalva-
type maneuvers. Infants under age 1 year with a large VSD
often have very labile PVR, and rapid increases can occur with
hypercarbia, acidosis, or hypoxemia; these patients may expe-
rience periods where PVR is higher than SVR, leading to R-L
shunt and further hypoxemia, which can be life threatening.
Conversely, excessive decreases in PVR, which often accom-
pany high Fio2 and hyperventilation, can greatly increase
Qp/Qs, with adverse hemodynamic consequences, including
acute RV and LV dilation and dysfunction, low diastolic BP
resulting in coronary ischemia, and in some patients, cardiac
arrest. Indeed, in 127 infants and children with CHD experi-
encing cardiac arrest under anesthesia, 18% had an L-R shunt
lesion, with VSD the most common.41 Thus, even relatively
simple lesions have the potential for extreme pathophysiologic
derangements. When anesthetizing an infant with an unre-
strictive VSD, it is prudent to decrease the Fio2 to low levels
(0.21-0.3) and to avoid hyperventilation, in order to prevent
excessive increases in Qp/Qs.
VSD closure can sometimes be carried out in the CCL,
with devices similar to those used for ASD closure, if the
VSD is suitably accessible. However, this procedure may
have significant hemodynamic instability and blood loss.59
Complications, including complete A-V block, can be seen
in up to 11% of patients, with mortality in 3%.60 The vast
majority of VSDs are closed surgically in the first 2 years
of life, with CPB, and patching of the VSD with polyester
fiber (Dacron) or the patient's own pericardium using a
transatrial approach. Contemporary surgical series from
Chapter 3  Congenital Heart Disease 97
excellent centers report mortality of 0.5%, with no complete
A-V block and no VSD recurrences or reoperations.61 Many
patients older than 6 to 12 months are candidates for early
tracheal extubation and rapid ICU discharge. Infectious
endocarditis prophylaxis is not indicated for unrepaired
isolated VSD or repaired VSD after 6 months with no resid-
ual defects.38
Atrioventricular Canal
Atrioventricular canal (AVC) results from failure of the endo-
cardial cushion to form early in fetal development. This defect
is present in 3% to 5% of patients with CHD and is particu-
larly prevalent in trisomy 21 patients, 20% to 33% of whom
have AVC.1,43,62
The three major variants of AVC are partial, transitional or
intermediate, and complete AVC. The unifying feature of all
types is the presence of a common A-V junction, with either
a single A-V valve, or if separated, both tricuspid and mitral
valves at the same level in the heart, rather than complete
septation, with tricuspid annulus inferior and mitral annu-
lus superior. Partial AVC consists of an ostium primum ASD
and a cleft in the anterior leaflet of the mitral valve. There is
no VSD component in this lesion. Transitional AVC consists
of the ostium primum ASD, common A-V valve, and a small
inlet VSD component that may be covered by A-V valve tissue.
There is some degree of A-V valve regurgitation in this lesion.
Complete AVC is characterized by the primum ASD, com-
mon A-V valve, and a large inlet VSD. Complete A-V canal is
further subdivided according to the arrangement of the ante-
rior bridging leaflet of the common A-V valve and the posi-
tion of its chordal attachments. In Rastelli type A the bridging
leaflet is mostly contained on the LV side, and the chordae are
attached to the crest of the ventricular septum63,64 (Fig. 3-12).
In Rastelli type B the bridging leaflet is more on the RV side,
and the papillary muscle of the leaflet is attached to the right
side of the ventricular septum. Type B is rare. Rastelli type C
is the most common, and the superior bridging leaflet is unat-
tached to the ventricular septum. Other variants of complete
AVC include RV or LV dominant, with discrepant ventricu-
lar size; tetralogy of Fallot with complete AVC; and complete
AVC with LV outflow tract obstruction.
The L-R shunt in AVC may occur at the atrial or ventricu-
lar levels as well as through a ventriculoatrial shunt second-
ary to A-V valve regurgitation, which is normally an LV-to-RA
shunt. The magnitude of the shunting depends on the total
sizes of the defects, the relative pressures in the left and right
cardiac chambers, and the ventricular compliance. As with a
large VSD, complete AVC shunting also depends on the relative
PVR and SVR. The magnitude of the L-R shunt ranges from
less than 2:1 in partial AVC to 3:1 to 4:1 or greater in complete
AVC in some young infants. Patients with unrepaired complete
AVC have elevated PAP and can develop elevated PVR, which
over time can become fixed, resulting in reversal of shunt and
cyanosis (Eisenmenger's syndrome). Patients with trisomy 21
are especially susceptible, developing elevated PVR sooner
 98 ANESTHESIA AND UNCOMMON DISEASES

MV

RA

R. atrium L. atrium
A
A TV
L
L

MV

TV R. ventricle L. ventricle
RV
A B
FIGURE 3-12  Atrioventricular septal defect. A, Common form of complete atrioventricular septal defect (Rastelli type A), originally
classified according to division of anterior bridging leaflet (A) and attachment to septum. Current interpretation has only the left-sided
portion of anterior leaflet as anterior bridging leaflet, and the right-sided portion is “true” anterior tricuspid leaflet. P, Posterior bridging
leaflet; L, two lateral leaflets corresponding to posterior mitral valve (MV) and tricuspid valve (TV) portions of leaflets; RA, right atrium;
RV, right ventricle. B, Schematic four-chamber view of complete atrioventricular septal defect, showing common valve and atrial and
ventricular communications. (A redrawn from Porter CJ, et al: Atrioventricular septal defects. In Emmanouilides GC, Riemenschneider TA,
Allen HD, Gutgesell HP, editors: Moss and Adams heart disease in infants, children, and adolescents: including the fetus and young adult,
Baltimore, 1995, Williams & Wilkins; B from Castaneda AR, et al, editors: Atrioventricular canal defect. In Cardiac surgery of the neonate
and infant, Philadelphia, 1994, Saunders.)

than patients with normal chromosomes, and thus must be
repaired in the first year of life. Before the 1980s, surgery
was often not offered to trisomy 21 patients, and a significant
number of these patients who had developed Eisenmenger's
syndrome presented for noncardiac anesthetic procedures.
The vast majority of these patients have since died, and it is
now unusual to encounter a patient with unrepaired complete
AVC. Other considerations after AVC repair include residual
mitral (much more common) or tricuspid insufficiency. The
BOX 3-7   n  ATRIOVENTRICULAR CANAL (AVC)
Three major types of AVC are partial, intermediate (transitional), and
complete.
Complete AVC is highly associated with trisomy 21.
Pulmonary vascular disease occurs in the first 2 years of life in
trisomy 21 patients with unrepaired complete AVC.
­sternal border.
technical difficulties of repairing malformed A-V valves result
in many patients with this residual defect (Box 3-7).
Physical examination findings vary according to the size of
the L-R shunt, from almost asymptomatic with partial AVC
to severe CHF in complete AVC in an infant with a large L-R
shunt. Patients are acyanotic with Spo2 of 95% to 100%. They
are often tachypneic and tachycardic, with poor feeding and
growth, and have frequent respiratory infections from pul-
monary congestion. Patients with CHF are diaphoretic, with
hepatomegaly and jugular venous distention. Patients with
trisomy 21 have the physical characteristics associated with
condition. The cardiac examination usually reveals an active
precordium with the apex displaced to the left. A fixed, split
S2 is similar to that heard in ASD. A systolic murmur is heard
at the left upper sternal border, ranging from grade II-IV/VI,
depending on the degree of flow across the ASD and VSD,
turbulence, and A-V valve regurgitation. Patients with Qp/Qs
greater than 3:1 have a diastolic murmur at the left lower

The ECG findings in AVC are distinctive; the PR inter-
val is prolonged in about 90% of patients, and the QRS axis
is deviated superiorly and to the right, the “northwest axis.”
This results from the deficiency of the endocardial cushion.
The QRS interval is also prolonged in the majority of patients.
Chest radiography reveals cardiomegaly and increased pul-
monary vascular markings in proportion to the degree of
L-R shunt. Patients with complete AVC presenting late, after
6 months of life, may have smaller hearts and normal pulmo-
nary vascular markings on radiography, indicating elevated
PVR that has limited the degree of shunting. Diagnosis of
AVC is by 2D and color Doppler echocardiography, which
is sufficient to define ventricular anatomy, magnitude of the
A-V valve regurgitation, any other associated defects, and
the magnitude and direction of shunting (see Fig.  3-4, B).
The relative pressures in the ventricles can also be defined. In
recent years, three-dimensional echocardiography has further
defined A-V valve morphology. MRI and CT are not indicated
unless there are other complicating anatomic features. Cardiac
catheterization is reserved to study pulmonary vascular resis-
tance and reactivity in those patients presenting for late repair,
whose PVR may be so elevated as to preclude complete septa-
tion of the heart.
The anesthetic considerations for unrepaired AVC are sim-
ilar to those noted earlier for ASD and VSD. Partial or transi-
tional AVC patients normally have small L-R shunts and will
tolerate any common anesthetic technique. Again, air bubbles
must be assiduously avoided in these patients. Infants with
complete AVC are approached similar to those with a large
VSD; excessive Fio2 or hyperventilation producing low Paco2
for prolonged periods will result in a greatly increased Qp/Qs
and hemodynamic compromise. The trisomy 21 infant, after
age 6 months with unrepaired complete AVC, presents a sig-
nificant challenge because of elevated and reactive PVR; peri-
ods of hypoxemia or hypercarbia may rapidly elevate PVR and
lead to increased R-L shunting and cyanosis. These patients
should be approached with caution and plans made to treat a
pulmonary hypertensive crisis, (such as having inhaled nitric
oxide [iNO] available). According to AHA infective endocar-
ditis guidelines, an acyanotic patient with unrepaired AVC
does not require prophylaxis. Prophylaxis is indicated in the
first 6 months after repair or in patients with residual defects
(e.g., significant A-V valve regurgitation).38
Repair of AVC is always surgical using CPB; timing depends
on the magnitude of L-R shunt, A-V valve regurgitation, and
symptomatology. Partial or transitional AVC patients with
minimal mitral regurgitation often have repair at 2 to 5 years
of age. Infants with complete AVC are repaired before age
6 months, to prevent the sequelae of long-standing elevated
PVR, particularly in trisomy 21 patients. A one-patch or two-
patch technique is used to close the ASD and VSD, attach the
common A-V valve to the patch and/or the ventricular sep-
tum, and repair the clefts in the A-V valves.65 Complete AVC
patients are at risk for pulmonary hypertensive crisis immedi-
ately after repair and thus are not extubated early in the post-
operative period; precautions to prevent this complication are
Chapter 3  Congenital Heart Disease 99
taken.66 In the modern era of very early repair, severe pulmonary
hypertensive crises are much less common. Even after repair,
many AVC patients have residual A-V valve regurgitation, which
is more important if the mitral valve is involved; this is an
important factor when evaluating patients with repaired AVC
for later anesthesia.
Double-Outlet Right Ventricle
Double-outlet right ventricle (DORV) refers to a heteroge-
neous spectrum of lesions characterized by a VSD, with both
the aorta and the pulmonary artery arising either completely
or partially from the right ventricle. DORV is present in 1%
to 1.5% of patients with CHD. The most common variant is
the subaortic-type defect, where the VSD is located beneath
the aortic valve. This arrangement is present in about half
of patients with DORV, and when pulmonary or subpulmo-
nary stenosis is present, it is known as tetralogy of Fallot–type
DORV.43,67 DORV with a subpulmonary VSD represents about
30% of these patients; if the aorta is positioned to the right
of and parallel to the PA, this is known as Taussig-Bing–type
DORV, and the physiology is similar to transposition of the
great arteries. DORV with noncommitted VSD is present in
12% to 17% of patients; the VSD is remote from the great ves-
sels, either in the inlet or the muscular septum, and may be
associated with AVC defects. The DORV with doubly com-
mitted VSD represents 5% to 10% of patients; the VSD sits
below both aortic and pulmonic valves, with varying degrees
of override.
The pathophysiology of DORV is complex and depends
on size and position of the VSD, presence of pulmonic steno-
sis, streaming of blood through the VSD to one or the other
great vessel, PVR/SVR ratio, and relative RV/LV compli-
ance. Without pulmonary or subpulmonary stenosis, DORV
patients often have similar pathophysiology to the patient with
a large VSD; Qp/Qs can be 2:1 or greater, and the patient can
develop RV dilation, which can lead to CHF. Elevated PVR
can develop over time. With obstruction to pulmonary blood
flow, the shunting can vary from left to right with a Qp/Qs of
just over 1:1, to significant obstruction to pulmonary blood
flow and cyanosis, with pathophysiology very similar to tetral-
ogy of Fallot. With transposition-type physiology, the patient
will have cyanosis because most of the RV blood is directed to
the aorta (Box 3-8).
The physical findings in DORV also depend on the degree
of L-R or R-L shunting, which in turn is influenced by the
degree of pulmonary stenosis. Presentation ranges from
BOX 3-8   n  DOUBLE-OUTLET RIGHT VENTRICLE (DORV)
Pathophysiology in the DORV patient depends on degree of right
ventricular outflow tract (RVOT) obstruction.
Cyanosis and “tetralogy of Fallot” are associated with significant
RVOT obstruction.
The acyanotic patient with VSD has no RVOT obstruction.
 100 ANESTHESIA AND UNCOMMON DISEASES
acyanotic and relatively asymptomatic patients with Spo2 of
95% to 100%, to those in CHF from very large L-R shunts,
to those with significant cyanosis (Spo2 70%-90%) from R-L
shunting. It is important to categorize the DORV patient
with (1) primarily left-to-right shunt, (2) primarily right-to-
left shunting from pulmonary stenosis, or (3) cyanosis from
transposition-type physiology and lack of mixing of systemic
and pulmonary blood flows. Murmurs are normally grade
II-IV/VI, along the left sternal border, and may be from flow
across the VSD or turbulence caused by pulmonary stenosis.
A diastolic flow murmur is heard in patients with large Qp/
Qs (>3:1).
The ECG shows no characteristic findings; sinus rhythm
is the norm, and right-axis deviation is common. Chest radi-
ography is variable and depends on degree of L-R shunting.
Cardiomegaly and increased pulmonary vascular markings
predominate in large L-R shunts. An essentially normal chest
radiograph may be seen with balanced circulation. In R-L shunt
patients, a normal or small heart with a paucity of pulmonary
vascular markings is observed. Echocardiography is the main-
stay of anatomic and physiologic diagnosis, to determine size
and position of the VSD and its relationship to the great ves-
sels, degree of pulmonary stenosis, and presence of associated
anomalies. CT and MRI are not usually indicated. Cardiac
catheterization is also not usually performed; the details of
the exact cardiac anatomy and surgical approach are normally
determined by the surgeon in the OR, with direct intracardiac
examination after CPB and aortic cross-clamping are initiated.
Repair of DORV is undertaken when the patient is symp-
tomatic and can vary from complete repair with complex
VSD patch/tunnel, to palliation with systemic-to-pulmonary
arterial shunting in the neonatal period, to an arterial switch
operation.68 CPB is typically used, and because of the complex
intracardiac repair, residual defects such as subaortic or sub-
pulmonary obstruction are seen. Approach to anesthesia for
noncardiac surgery in the DORV patient considers basic anat-
omy and pathophysiology, previous repair, and any residual
defects. Patients with a large L-R shunt are treated similar to
those with a large VSD, as previously noted. Endocarditis pro-
phylaxis is indicated if the patient is cyanotic or has residual
defects, both of which are common in DORV.
Truncus Arteriosus
Truncus arteriosus is an uncommon defect, representing
about 1% of all cases of CHD. Truncus arteriosus is defined
by the presence of a single great artery arising from the base
of the heart that provides all aortic and pulmonary blood flow.
A large, subarterial VSD is present. Truncus arteriosus results
from failure of septation of the ventricular outlets into the aorta
and pulmonary artery, caused by failure of the sixth aortic arch
to develop. A genetic cause is strongly suspected because up to
one third of these patients have microdeletions in the chromo-
some 22q11 region, with associated DiGeorge or velocardio-
facial syndromes. This syndrome is variable, but components
include absent or hypoplastic thymus and parathyroid glands
from abnormal development of the third and fourth pharyn-
geal pouches, resulting in T-cell deficiency and hypocalce-
mia. Other components include a high, arched palate, varying
degrees of micrognathia, and neurodevelopmental delay.43,69
The most common classification system is that of Collett
and Edwards. Type I truncus accounts for about 70% of cases,
characterized by a short, main PA arising from the truncal
artery and dividing into right and left PAs. Type II accounts
for almost 30% of truncus arteriosus patients, characterized
by no main PA but separated branch PAs arising directly from
the truncal artery immediately adjacent to each other. Type
III truncus is rare (~1%), characterized by widely separated
branch PAs arising from the lateral aspect of the truncal artery.
Other findings include an abnormal truncal valve, comprising
two to six leaflets, with either truncal stenosis or regurgita-
tion. Also, the aortic arch itself is hypoplastic or interrupted in
5% to 10% of truncus arteriosus patients. “Type IV” is actually
tetralogy of Fallot with pulmonary atresia, with pulmonary
blood flow supplied entirely by aortopulmonary collaterals
from the descending thoracic aorta, and so is no longer classi-
fied as truncus arteriosus70 (Fig. 3-13).
The pathophysiology of truncus arteriosus is unique and
results from the aortic, pulmonary, and coronary circulations
arising from a single artery. Because of this parallel circulation
and presence of a large VSD, there is some degree of mixing of
systemic and pulmonary circulations, producing a mild degree
of cyanosis, with Spo2 normally 85% to 95%. Left-to-right
shunting predominates, with PVR lower than SVR, and with the
normal fall in PVR in early postnatal life, the lungs are progres-
sively overcirculated, resulting in extremely large Qp/Qs (≥3:1-
4:1). CHF thus often ensues. The unique anatomy of truncus
also means that increasing pulmonary blood flow will steal
flow from the arterial side, including the coronary arteries. This
results in low diastolic BP, and myocardial ischemia is possible,
with ST-segment changes, myocardial dysfunction, and cardiac
arrest from ventricular fibrillation due to ischemia. In addi-
tion, the steal of systemic flow can lead to ischemia of the gut
and kidneys, leading to necrotizing enterocolitis and renal dys-
function and failure in the neonatal period. Unrepaired patients
who survive the neonatal period develop increased PVR in the
first few months of life and may have a temporary reduction in
CHF symptoms as the L-R shunt decreases. Eventually, reversal
of shunt from fixed, elevated PVR can ensue, causing cyanosis.
This severe pathophysiologic derangement and unsatisfactory
result from palliative neonatal procedures (e.g., PA banding)
led to complete repair of truncus arteriosus, one of the first such
lesions in neonates so approached71 (Box 3-9).
BOX 3-9   n  TRUNCUS ARTERIOSUS
Major types of truncus arteriosus (I, II, III) depend on degree of
pulmonary artery branching.
Common arterial trunk leaves systemic, pulmonary, and coronary
circulations in parallel.
Lowering PVR with excessive Fio2 and hyperventilation creates
systemic/coronary steal and myocardial ischemia.
 Chapter 3  Congenital Heart Disease 101

A B

C D
FIGURE 3-13  Classification of truncus arteriosus. A, Type I with a short main pulmonary artery segment arising from the leftward,
posterior aspect of ascending aorta. B, Type II with separate origins of right and left pulmonary arteries arising close to each other
on posterior aspect of ascending aorta. Note the left-sided aortic arch in A and B. C, Type III with separate origins of right and left
pulmonary arteries arising far apart from posterolateral aspect of ascending aorta. D, Type IV, more appropriately described as
pulmonary atresia and ventricular septal defect; separate origins of right and left pulmonary arteries arise from descending aorta.
Note the right-sided aortic arch in C and D. (Redrawn from Grifka RG: Pediatr Clin North Am 46:405-425, 1999.)

Physical examination of the patient with truncus arterio-
sus normally reveals an acyanotic or mildly cyanotic infant
with Spo2 of 85% to 95%. The magnitude of L-R shunt is usu-
ally large, and tachypnea, tachycardia, pulmonary congestion,
hepatomegaly, and diaphoresis with poor feeding and growth
are common. Peripheral pulses are bounding because of the
increased pulse pressure from diastolic runoff into the PAs.
The precordium is active, with apex displaced to left. The
heart sounds may be abnormal with a split S2, always a systolic
murmur, and grade II-IV/VI at the left sternal border from
both VSD flow and increased flow across the truncal valve.
Significant stenosis of the truncal valve is accompanied by
grade IV/VI murmur. A diastolic murmur may be heard at the
left upper sternal border with truncal valve regurgitation, or at
the left lower sternal border with increased diastolic flow from
large Qp/Qs.
 102 ANESTHESIA AND UNCOMMON DISEASES
The ECG normally reveals sinus rhythm and signs of both
LV and RV hypertrophy; ST-segment abnormalities may be
present. The chest radiograph is often remarkable for extreme
cardiomegaly and increased pulmonary vascular markings.
As PVR increases, these findings are less extreme over time.
Echocardiography is the mainstay of diagnosis and will define the
truncal valve anatomy, stenosis, and regurgitation, as well as PA
anatomy and size of the VSD. Echocardiography is also important
to determine the degree of biventricular dilation and dysfunction.
Other modalities, such as MRI, CT, or cardiac catheterization, are
rarely indicated in the initial planning of truncus arteriosus repair.
Repair of truncus arteriosus is almost always in the neonatal
period, with CPB; the VSD is closed, and an RV-to-PA conduit
is placed after the PAs are separated from the truncal artery. The
truncal valve may require repair. Importantly, even after repair,
truncus patients often have residual aortic stenosis or regurgita-
tion, and all patients will outgrow their RV-PA conduit and thus
will return for repeat surgery. The anesthesiologist must thor-
oughly evaluate their anatomy and residual defects when these
patients present for noncardiac surgical anesthesia.
The approach to anesthetic delivery in the unrepaired trun-
cus patient requires detailed attention to the pathophysiologic
derangements. In general, any agents can be used, but further
myocardial depression from anesthetics and increase in Qp/
Qs leading to coronary steal and further myocardial dysfunc-
tion must be avoided at all costs. This means that Fio2 must be
reduced and hyperventilation avoided in the young infant with
reduced PVR. PEEP of 5 to 10 cm H2O is also effective at shunting
blood flow away from the lungs. Maintaining adequate diastolic
BP, with vasoconstrictive agents if needed, is another important
goal. Strict avoidance of intravenous injection of air is critical, as
the bubbles can directly enter the systemic and coronary arteries.
Invasive monitoring in the form of arterial and CVP catheters
are indicated for major noncardiac surgery in unrepaired trun-
cus arteriosus patients. Endocarditis prophylaxis is indicated in
most of these patients because they have a cardiac indication.
Anomalous Pulmonary Venous Return
Anomalous pulmonary venous return refers to conditions where
some or all of the pulmonary veins have their blood return
to the right atrium, either directly or through the SVC or an
abnormal, connecting venous structure. The two classifications
are total anomalous pulmonary venous return (TAPVR), and
partial anomalous pulmonary venous return (PAPVR). TAPVR
is an uncommon lesion, accounting for about 1.5% to 2.5% of
CHD cases. PAPVR is often asymptomatic and is present in
about 0.5% of the population in autopsy studies; however, only
a fraction of these patients present for surgical treatment.43,72
Total APVR has four main subtypes. The supracardiac type
is seen is in 45% to 55% of TAPVR patients; the pulmonary
venous confluence connects to a vertical vein that in turn con-
nects to the innominate vein, thus draining all pulmonary
venous blood into the SVC and right atrium71 (Fig. 3-14). The
infracardiac type of TAPVR (13%-25%) consists of a pulmo-
nary venous confluence connected to a draining vein that
courses inferiorly, through the esophageal hiatus and below
the diaphragm, and usually connects to the portal venous sys-
tem; thus the blood flows through the liver to the hepatic vein
and IVC. The cardiac type of TAPVR (25%-30%) consists of
the pulmonary venous confluence draining into the coronary
sinus or directly to the right atrium. Mixed types of TAPVR
are rare and account for less than 5% of cases.
Partial APVR consists of one or two pulmonary veins drain-
ing into the SVC or right atrium in 75% of cases. In almost all
patients, this lesion is associated with a sinus venosus ASD. In
most of the remaining patients, the right pulmonary veins con-
nect to the IVC; it is rare to have anomalous left pulmonary
vein connections to the left innominate vein or coronary sinus.
The pathophysiology of PAPVR is usually mild, with Qp/Qs of
less than 2:1, because some of the pulmonary venous blood returns
to the right atrium, creating a left-to-right shunt. There also can
be shunting across the ASD itself; but because of the low pres-
sures in the atria and the relatively low pressure gradient between
them, this shunting is limited. This explains why so many PAPVR
patients are asymptomatic for many years; this pathophysiology is
similar to that of a small to moderate-sized secundum ASD, where
symptoms of dyspnea on exertion only occur during the second or
third decades of life or later. PAPVR rarely is associated with ana-
tomic obstruction to pulmonary venous flow.
Total APVR pathophysiology depends mostly on the degree
of obstruction to pulmonary venous flow. Infracardiac TAPVR
is more likely to be obstructed, with the tortuous course of pul-
monary venous return though the liver a setup for this problem;
indeed, almost all these patients have significant obstruc-
tion. Patients with supracardiac TAPVR are less likely to be
obstructed; if the vertical vein passes directly between the left
PA and left main bronchus, a “bronchopulmonary vise” is cre-
ated, leading to obstruction. Cardiac TAPVR with connection
to the coronary sinus is least likely to be obstructed. Obstruction
leads to severe pulmonary venous congestion and decreased
pulmonary blood flow. The result is severe cyanosis and respi-
ratory distress from interstitial and pulmonary alveolar edema.
In addition, further obstruction is encountered if the patient
has only a small PFO or ASD; a large interatrial communica-
tion at least allows egress of blood out of the right atrium and
may lessen the degree of functional obstruction. Infants with
TAPVR who are not obstructed, and have adequate atrial septal
defects may escape diagnosis in the neonatal period because of
only mild symptoms. Later, as PVR decreases and pulmonary
blood flow increases, the L-R shunt increases, and they will
experience mild cyanosis from the R-L shunt at the atrial level.
These patients will appear similar to infants with CHF from a
large VSD, with the exception of the cyanosis (Box 3-10).
BOX 3-10   n ANOMALOUS PULMONARY VENOUS RETURN
Major types of anomalous pulmonary venous return are partial
(PAPVR) and total (TAPVR).
PAPVR patients usually have mild symptoms of a small, left-to-right shunt.
TAPVR symptomatology depends on degree of obstruction to
pulmonary venous return.
Infradiaphragmatic TAPVR patients are prone to severe pulmonary
venous obstruction, hypoxia, and respiratory failure.
 Chapter 3  Congenital Heart Disease 103

A B

C D
FIGURE 3-14  Classification of total anomalous pulmonary venous return. A, Type I; four pulmonary veins drain into vertical vein that
enters innominate vein. B, Type II; pulmonary veins drain into coronary sinus that enters right atrium. C, Type III; pulmonary veins join to
form a descending vein that courses through diaphragm and drains into portal venous system. D, Type IV, mixed pulmonary venous return;
two right pulmonary veins and left lower pulmonary vein drain to coronary sinus while left upper pulmonary vein drains into a vertical vein.
Note that in all four types there is an atrial septal defect. (Modified from Grifka RG: Pediatr Clin North Am 46:405-425, 1999.)

The physical examination of a patient with PAPVR usu-
ally reveals a near-normal-appearing acyanotic patient,
with SpO2 of 95% to 100%. Findings depend on the degree
of L-R shunt, but with Qp/Qs typically less than 2:1, tachy-
pnea and tachycardia are minimal. Cardiac examination is
almost normal, except for the fixed, split S2, which is often
present, and a soft, I-II/VI systolic murmur at the left sternal
border. Chest radiography usually reveals mild cardiomegaly
and mild increase in pulmonary vascular markings. Some
PAPVR patients have scimitar syndrome, which is PAPVR
to the IVC, pulmonary sequestration, and hypoplasia of the
right lung. The chest radiograph reveals a curved shadow in
the shape of a scimitar, the descending anomalous right pul-
monary veins or vertical vein.
The ECG is usually normal but may show atrial arrhythmia
later in life if RA enlargement is significant. Echocardiography
usually makes the diagnosis, although CT, MRI, and cardiac
catheterization may be needed if unusual pulmonary venous
 104 ANESTHESIA AND UNCOMMON DISEASES
anatomy is suspected. TAPVR patients with obstructed pul-
monary venous return usually are severely ill, with severe
cyanosis and respiratory distress, and require emergency
tracheal intubation and ventilation as well as inotropic sup-
port. Chest radiography reveals a small heart resulting from
lack of pulmonary venous return to the left side of the heart.
The severe pulmonary venous congestion has a ground-glass
appearance. Indeed, these patients are sometimes mistaken
for infants with severe persistent fetal circulation and are
placed on extracorporeal membrane oxygenation (ECMO)
before a diagnosis is made.73
Older patients with supracardiac TAPVR that is not
obstructed have a “figure of 8” or “snowman” configuration in
which the engorged vertical vein on the left and the engorged
innominate vein and SVC on the top and right form a globular
shadow in the upper mediastinum. Urgent echocardiography
is mandatory when the diagnosis of TAPVR is suspected; in
severely ill patients this is sufficient to make the diagnosis of
infracardiac or supracardiac TAPVR and to rule out associ-
ated cardiac anomalies. Echocardiography will reveal the site
of obstruction, size of an atrial communication, and often a
severely underfilled left ventricle, compressed by an overfilled,
hypertensive right ventricle that is limiting both filling and out-
put. In less ill patients, echocardiography is usually sufficient
in straightforward TAPVR; in some cases (mixed TAPVR),
however, it cannot provide precise images, and CT angiogra-
phy, MRI, or cardiac catheterization is needed. During repair,
the surgeon will also directly examine the pulmonary venous
return to detect unsuspected variations.
Repair of PAPVR can be undertaken when the child is 2 to
4 years of age using standard CPB techniques; these patients
usually have a straightforward intraoperative course and can
be extubated in the OR. Partial APVR often presents late, so
teenagers and adults are frequently put forward for this sur-
gery. The sinus venosus ASD is repaired concomitantly using
CPB, and often the ASD patch can be placed so that the anom-
alous pulmonary vein orifices are on the left side of the patch.
If the pulmonary veins connect to the SVC, the Warden pro-
cedure may be needed; the SVC is translocated to the RA
appendage, and an intracardiac baffle is placed, leading to a
lower incidence of pulmonary venous obstruction.74
Repair of TAPVR is often a surgical emergency in a criti-
cally ill neonate; these patients require institution of CPB as
rapidly as possible to prevent cardiac arrest or severe hypox-
emic end-organ damage, including neurologic injury. Repair
is accomplished on CPB, usually with DHCA, and involves
dividing and ligating the abnormally draining vein, anas-
tomosing the pulmonary venous confluence to the back of
the left atrium, and closing atrial communications.75 These
patients often have severe PH immediately after surgery and
usually require iNO. Some TAPVR patients have recurrence of
pulmonary vein obstruction, caused by either scarring at the
anastomotic site or progressive pulmonary vein sclerosis from
long-standing in utero obstruction. Even after repair, there-
fore, any residual obstruction must be monitored during eval-
uation for a noncardiac anesthetic procedure.
The anesthetic approach in patients with PAPVR can
include any of the usual agents and techniques, because most
patients have mild pathophysiology. For TAPVR patients with
severe obstruction, attention is directed to supporting respira-
tion and circulation and institution of CPB as quickly as pos-
sible. Although the anesthesiologist may want to use high Fio2
and even iNO preoperatively to increase pulmonary blood
flow in the patient with severe PH, these maneuvers are often
counterproductive because the increased pulmonary flow is
met with a fixed anatomic obstruction, which may worsen
ventilation and oxygenation. Older patients with unre-
paired, unobstructed TAPVR have symptomatology similar to
patients with a large VSD; excessive Fio2 and hyperventilation
may make ventilation more difficult because of increased pul-
monary blood flow; these parameters are adjusted to achieve
the same baseline Spo2 and hemodynamic state that existed
before the anesthetic. Endocarditis prophylaxis is indicated in
unrepaired patients and those with residual defects.
Left-Sided Obstructive Lesions
COARCTATION OF THE AORTA
Coarctation of the aorta refers to a discrete narrowing, usually
near the insertion of the ductus arteriosus. Coarctation is one
of the most common congenital lesions, found in 8% to 11% of
patients with CHD.1 Turner syndrome has a strong association
with coarctation of the aorta. Coarctation may be an isolated
lesion, which is the case for older infants and children present-
ing with this disorder, or may have associated lesions, such as
aortic or subaortic stenosis and VSD, which is often true for
neonates presenting with coarctation.
Severity ranges from mild narrowing presenting later in life
to severe obstruction and near-interruption presenting in the
first days to weeks of life. With more severe cases of obstruc-
tion, blood flow beyond the coarctation depends on a patent
ductus arteriosus. In addition, ductal tissue is often present in
the wall of the aorta itself; thus constriction of the PDA results
in severe obstruction, lack of flow to the lower body, and
severe increase in afterload, leading to cardiovascular collapse
in the neonate.76 In this case, PGE1 is started emergently to
reopen the PDA, and resuscitation with inotropic support and
mechanical ventilation are also instituted. Because end-organ
injury (e.g., renal/hepatic failure, intestinal ischemia) often
occurs in these situations, the patient is stabilized, end-organ
function is allowed to recover, and repair is done semielec-
tively several days later.77 Infants with less severe obstruction
often have signs of CHF as the PDA closes, with cardiomegaly
and pulmonary interstitial edema, accompanied by tachypnea,
diaphoresis, and poor feeding.
Older patients are often relatively asymptomatic, and the
coarctation is discovered during routine physical examina-
tion when the patient is hypertensive in the upper extremities,
particularly in the right arm. Weakened and delayed femoral
pulses and a systolic BP gradient of 20 mm Hg or more are
hallmarks of this disease. If present, a murmur is soft, grade
I-II/VI systolic at the upper left sternal border, radiating to

the axilla and back; this is often not appreciated early in life.
Older patients also often develop collateral arterial circula-
tion, from the right and left subclavian arteries, thyrocervi-
cal trunk, and intercostal and thoracic arteries above the area
of coarctation45 (Fig.  3-15). This allows better circulation to
the lower extremities and minimizes symptomatology during
childhood. Continuous murmurs best heard at the back may
be present from these collaterals. Occasionally, adults present
with unrepaired coarctation; of necessity they have extensive
collateralization, and they have been hypertensive for decades.
These patients are prone to early hypertensive cardiovascular
disease, including coronary artery disease (CAD) and cerebro-
vascular accident (CVA, stroke), often in their 30s and 40s.
Diagnosis of coarctation is initially made by transtho-
racic echocardiography; the suprasternal notch views will
delineate the aortic arch, ductus arteriosus, and descend-
ing thoracic aorta well. Echocardiography can show whether
the ductus arteriosus is patent, as well as direction of flow in
the PDA, exact location and degree of obstruction, and pres-
ence of diastolic runoff, which is a sign of severe obstruc-
tion. In addition, the position of the subclavian arteries and,
importantly, the presence of associated intracardiac lesions
are also delineated. ECG findings may demonstrate left-
axis deviation as seen in LV hypertrophy but otherwise is
Coarctation Axillary artery
Ligamentum
arteriosum
Intercostal
Ascending arteries
aorta
Pulmonary
artery Descending Internal
aorta
thoracic
artery
FIGURE 3-15  Coarctation of the aorta. Coarctation causes
severe obstruction of blood flow in the descending thoracic aorta.
The descending aorta and its branches are perfused by collateral
channels from the axillary and internal thoracic arteries through
the intercostal arteries (arrows). (Modified from Brickner ME, Hillis
LD, Lange RA: N Engl J Med 342:256-263, 2000.)
Chapter 3  Congenital Heart Disease 105
nonspecific. Chest radiography may demonstrate cardio-
megaly and interstitial edema in infants with heart failure.
Later changes include normal or enlarged cardiac silhou-
ette and signs of collateralization (e.g., rib notching) or
pre- and post-stenotic dilation of the aorta (e.g., “figure  3”
sign). Particularly in older children, the presence of collat-
eral arterial circulation is important in planning the surgical
approach, so most patients require MRI or CT angiography
before repair (see Figs. 3-6 and 3-7). Because the risk of para-
plegia from aortic cross-clamping is higher without adequate
collateralization, these patients may require special tech-
niques, such as partial left-sided bypass.
Repair of isolated coarctation of the aorta is undertaken
as soon as the diagnosis is made, urgently in the neonate with
ductus-dependent circulation and electively in less ill infants.
Delaying surgery is thought to increase risk of chronic end-
organ dysfunction from hypertension, including the left ven-
tricle. Monitoring of arterial BP is done by arterial catheter
in the right arm; left-arm or lower-extremity arterial moni-
toring will not yield accurate information. Also, 5% to 10%
of these patients have an aberrant right subclavian artery
originating distal to the coarctation; during cross-clamping,
perfusion to the brain must be monitored by pulse oximeter
on the ear, temporal artery pulse or arterial line, or NIRS.
Repair is normally performed through a left thoracotomy,
after dissection and isolation of the aorta, the coarctation,
PDA or ligamentum arteriosum, subclavian arteries, and
intercostal and collateral arteries in the field. After cross-
clamping above and below the coarctation, the coarctation
segment and any ductal tissue are excised, and the aorta is
repaired using one of several methods. Most often the direct
or extended end-to-end anastomosis is used, with excellent
long-term results and low recurrence rate (Fig. 3-16). Other
techniques include the subclavian flap angioplasty, which
uses the proximal subclavian artery to reconstruct the nar-
rowed segment. Because some studies report a higher recur-
rence rate with this approach, many centers no longer use
this technique. Patients with subclavian flap angioplasty will
have diminished pulses, lower BP, and possibly poor growth
of the left arm (Box 3-11).
During thoracotomy, CPB typically is not used, and the
period of aortic cross-clamping is 20 to 30 minutes. Cross-
clamping often is well tolerated because patients with severe
obstruction have minimal change in afterload. Patients
with less severe obstruction have adequate LV function to
BOX 3-11   n  COARCTATION OF THE AORTA
Coarctation is normally an isolated narrowing in the juxtaductal region.
Symptoms vary from cardiovascular collapse in a PDA-dependent
neonate to late presentation with hypertension in the upper
extremities.
Early surgery with extended end-to-end anastomosis is the preferred
approach to coarctation.
Recurrent coarctation is often treated with dilation and stenting.
Blood pressure monitoring in the right upper extremity is important.
 106 ANESTHESIA AND UNCOMMON DISEASES

Incision into
narrowed arch

Coarcted
segment Ligated
arterial
duct

A B C
FIGURE 3-16  Technique of extended end-to-end repair of coarctation of aorta. A, Left thoracotomy approach is used, a cross-clamp
is applied proximal to coarctation to include left subclavian and left carotid arteries; a distal clamp is also used. B, Ductus arteriosus is
ligated and coarctation segment excised. C, Extended anastomosis is created to produce a widely patent transverse and distal thoracic
aorta. (Modified from Hoschtitzky JA, Anderson RH, Elliott MJ: Aortic coarctation and interrupted aortic arch. In Anderson RH, et al, editors:
Paediatric cardiology, ed 3, Philadelphia, 2010, Elsevier/Churchill Livingstone.)

tolerate the temporary increase in afterload and may be
hypertensive during clamping. The risk of paraplegia from
inadequate collateralization and clamping above the artery
of Adamkiewicz (major arterial supply to spinal cord, nor-
mally at T9 but variable) is very low with this approach (1 in
1000). Nevertheless, body temperature is usually cooled to
34 ° C (93.3 ° F), and BP measured in the right radial artery is
maintained at high-normal ranges to promote flow through
collaterals. Generally, patients with hypertension during
cross-clamping should not be treated with IV vasodilators,
to avoid hypotension; adjusting volatile anesthetic concen-
trations is often effective. Anticipated cross-clamp periods
longer than 30 minutes are usually approached with partial
left-sided heart bypass to provide flow to the descending
aorta. SLV techniques are normally not necessary in small
infants. Many anesthesiologists avoid thoracic epidural anal-
gesia for coarctation repair because of the paraplegia issue;
epidural anesthesia will complicate the workup and manage-
ment of this significant problem. Hypertension is common
after coarctation repair and requires effective control with IV
vasodilators and/or beta-adrenergic blocking agents in the
early postoperative period.78
Recurrent coarctation in an older child is often approached
in the interventional CCL; balloon dilation and stenting is
an effective treatment. Other approaches for severe lesions
include median sternotomy with complete anatomic recon-
struction by CPB.79 Noncardiac surgery in the patient with
coarctation of the aorta must be preceded by evaluation of the
patient's anatomy and pathophysiology. Unrepaired patients
with cardiac failure may require invasive monitoring and ino-
tropic support for major surgery. Repaired patients may have
recurrent coarctation or hypertension that may affect anes-
thetic management.
INTERRUPTED AORTIC ARCH
Complete interruption of the aortic arch (IAA) can be viewed
as the most severe end of the spectrum of coarctation of the
aorta. IAA is a relatively uncommon lesion, accounting for
approximately 1% of patients with CHD. The most common
classification divides IAA into type A, interruption at the aor-
tic isthmus just distal to the left subclavian artery (25%-40%
of cases); type B, interruption between the left subclavian
and left carotid artery (50%-75%); or type C, proximal inter-
ruption between the innominate and left carotid artery (5%)
(Fig.  3-17). The majority of patients with type B interrup-
tion have DiGeorge syndrome, associated with chromosome
22q11.2 deletions, and velocardiofacial syndrome, hypocal-
cemia, and absent thymus with T-cell immune deficiency.76,78
Severe hypoplasia of the proximal transverse aortic arch is a
variant of IAA and is approached in the same manner. Patients
with IAA present in early infancy because a PDA needs to per-
fuse the lower body. Because of the complete interruption,
closure of the PDA is associated with shock and cardiovascu-
lar collapse, with resuscitation as for the neonate with severe
coarctation performed as previously noted. IAA is rarely an
isolated lesion; almost all neonates will have a VSD and some
form of aortic valve obstruction, most often subvalvar stenosis.
Repair of IAA usually occurs in the neonatal period and
is most often done with CPB, both for complete anatomic
reconstruction of the aortic arch and to repair the associated
intracardiac defects. Periods of DHCA or regional cerebral
perfusion are often used.80 Because IAA patients normally
have two ventricles, recovery from surgery is usually uncom-
plicated. Noncardiac surgery after repair must account for
the presence of residual lesions (e.g., recurrent aortic arch
obstruction) or DiGeorge syndrome, potentially with difficult
tracheal intubation.
 Chapter 3  Congenital Heart Disease 107

Interruption at the isthmus Interruption between the left subclavian Interruption between the brachiocephalic
Type A and carotid arteries and left carotid arteries
Type B Type C
FIGURE 3-17  Classification of interrupted aortic arch. The descending aorta is supplied by the patent ductus arteriosus. (Modified
from Hoschtitzky JA, Anderson RH, Elliott MJ: Aortic coarctation and interrupted aortic arch. In Anderson RH, et al, editors: Paediatric
cardiology, ed 3, Philadelphia, 2010, Elsevier/Churchill Livingstone.)

AORTIC STENOSIS
Congenital anomalies of the left ventricular outflow tract account
for approximately 6% to 7% of patients with CHD. Congenital
valvar aortic stenosis (AS) accounts for the majority, about 75%
of patients with LVOT defects. Subvalvar AS represents about
Membranous
25%. Supravalvar stenosis is uncommon but as noted later, is a Muscular or subaortic
very significant lesion for the anesthesiologist because most of tunnel-type stenosis
subaortic
these patients have Williams’ syndrome81 (Fig. 3-18). stenosis
Isolated bicuspid aortic valves are often not diagnosed
during childhood, and the true incidence of AS is unknown;
this may well be the most common CHD lesion of all, neces-
A B
sitating treatment at any stage of life, but particularly in older
adults.78,82 Presentation of these lesions ranges from shock and
cardiovascular collapse in the neonate with severe AS whose
PDA has closed, to the asymptomatic patient with a murmur.
Intermediate presentations may include chest pain and syncope
with exertion in older patients with severe AS. Most patients
Supravalvar
have a harsh systolic murmur at the left upper sternal border, Valvar stenosis
usually grade III-IV/VI. The murmur may radiate to the carotid aortic
stenosis
arteries. Left ventricular hypertrophy and enlargement may dis-
place the ventricular apex downward and to the left.
The ECG often reveals left-axis deviation and LV hypertro-
phy. Chest radiography in the neonate usually reveals cardio-
megaly and interstitial pulmonary edema; in the older patient,
increased LV size may be apparent. Echocardiography is C D
the mainstay of diagnosis of all forms of AS; morphology of the FIGURE 3-18  Types of congenital aortic stenosis. A, Fibro­
valve and degree of subvalvar, valvar, or supravalvar stenosis muscular or tunnel type of subaortic stenosis with obstruction to left
ventricular emptying by muscular overgrowth of the entire outflow
are assessed using calculations of peak and mean Doppler gra-
tract. B, Membranous subaortic stenosis; a membrane is present
dients; area of aortic valve opening is also calculated. The pres-
1 to 2 cm below the aortic valve orifice obstructing ventricular outflow.
ence of a PDA, direction of flow in the PDA, and direction of C, Thickened, domed, fused leaflets of congenital valvar stenosis.
flow in the proximal aorta can also be delineated. Degree of LV D, “Hourglass” narrowing of the supravalvar aorta producing
hypertrophy and ventricular dysfunction can also be assessed. supravalvar stenosis. (Redrawn from Rosen DA, Rosen KR: Anomalies
Other diagnostic modalities are rarely necessary; catheteriza- of the aortic arch and valve. In Lake CL, editor: Pediatric cardiac
tion is usually reserved for intervention on the aortic valve itself. anesthesia, Stamford, Conn, 1998, Appleton & Lange.)
 108 ANESTHESIA AND UNCOMMON DISEASES
Critical AS in the neonate is most often treated urgently
in the CCL with balloon valvuloplasty. These patients are
often critically ill; resuscitation drugs and equipment must be
immediately available in case of cardiac arrest caused by ven-
tricular fibrillation from coronary ischemia, as a result of inter-
rupted aortic flow during balloon inflation. Surgical backup
for emergency ECMO initiation may be planned. After bal-
loon dilation relieves all or most of the obstruction, some aor-
tic insufficiency may result; this is usually well tolerated until
the infant recovers and grows, then has aortic valve repair or
replacement. Other approaches include surgery to resect sub-
valvar fibrous or muscle tissue, repair or replacement of a ste-
notic valve, or patch repair of supravalvar AS. All these repairs
must be done with CPB (Box 3-12).
Hemodynamic goals during anesthesia for AS patients
serve to (1) minimize resistance to flow across the AS,
(2) optimize stroke volume across the stenotic area, and
(3) optimize LV oxygen demand/supply ratio in the often-
hypertrophied ventricle. Whichever anesthetic regimen is
used, decreases in SVR (BP) must be minimized because
this will increase turbulence of flow and thus resistance
across the stenotic area. This results in less systemic cardiac
output. In addition, if the coronary arteries are involved,
as in Williams syndrome, critical myocardial ischemia
may result. Even if the coronary arteries are not directly
involved, BP lowering will compromise coronary perfusion
pressure. Therefore, maintaining normal or high-normal
BP is an important goal. In addition, tachycardia is poorly
tolerated because diastolic filling time and systolic ejec-
tion time across the obstruction are reduced, resulting in
lower stroke volume and systemic CO. Also, myocardial
O2 demand will be significantly increased, resulting in risk
for subendocardial ischemia and ventricular dysfunction.
Excessive increases in contractility will also increase the
functional gradient across the stenosis and increase myo-
cardial O2 demand. Patients poorly tolerate hypovolemia
from prolonged fasting, unreplaced blood, or third-space
fluid losses because LV filling must be maintained to opti-
mize stroke volume across the obstruction.
The pathophysiology of left-sided obstruction was
recently studied in 127 cardiac arrests under anesthesia in
pediatric patients with cardiac disease.41 Left-sided obstruc-
tive lesions accounted for 16% of the total; but 45% of these
patients could not be resuscitated and died, making patients
with these obstructive lesions extremely high-risk for anes-
thetic procedures.
BOX 3-12   n  AORTIC STENOSIS
Aortic stenosis may be subvalvar, valvar, or supravalvar.
Hemodynamic goals are to maintain afterload, normal to slow heart
rate, and preload and to avoid increases in contractility.
Williams syndrome patients often have coronary artery involvement
out of proportion to aortic stenosis.
After aortic stenosis repair, patients are often hypertensive.
Supravalvar AS associated with Williams syndrome
deserves special consideration.83 Williams syndrome is
a defect in the elastin gene on chromosome 7, resulting
in abnormal connective tissue, particularly affecting the
ascending aorta, which narrows just above the sinotubu-
lar junction, and often affecting the orifices of the coronary
arteries by partially obstructing them with a hood of abnor-
mal tissue. The supravalvar gradient itself may not be severe,
but the coronary circulation is tenuous, and any BP lowering
will significantly affect coronary perfusion, which may result
in coronary ischemia, ventricular fibrillation, and death with
anesthesia. Case reports and series detail Williams syn-
drome patients in cardiac arrest during anesthesia for non-
cardiac surgery.84,85 A cardiologist's consultation and recent
echocardiographic results are particularly important before
noncardiac surgery in these patients. Patients with signifi-
cant supravalvar AS and coronary artery involvement should
probably have cardiac surgery first, before elective surgery or
anesthesia. In addition, the coronary arteries may not be well
imaged on echocardiography, and CT angiography is often
performed.
Intraoperative course, postoperative care, and provisions
for backup assistance must be planned carefully in case of
major instability or resuscitation. Adherence to hemodynamic
goals (avoiding decreases in SVR, tachycardia, and hypovo-
lemia) is crucial to achieving the best anesthetic outcomes.
Williams syndrome patients with significant supravalvar AS
and coronary disease also often have mild to moderate supra-
valvar pulmonic and branch PA stenosis, which usually dimin-
ishes over time with patient growth.
MITRAL STENOSIS
Congenital mitral stenosis as an isolated lesion is rare,
accounting for 0.2% to 0.4% of patients with congenital heart
disease.86 Mitral stenosis can result from malformation of the
valve leaflets, a supravalvar mitral ring, or abnormal papillary
muscles. In addition, mitral stenosis can result after repair
of a left-sided A-V valve, as in complete atrioventricular
canal. Rheumatic heart disease can also cause mitral stenosis.
The presentation in isolated mitral stenosis usually involves
symptoms of pulmonary congestion and frequent respira-
tory infections, even wheezing, resulting from LA hyperten-
sion causing pulmonary venous hypertension and interstitial
edema. Infants have tachypnea, diaphoresis, poor feeding,
and failure to thrive. PH may ensue in long-standing mitral
stenosis.
Cardiac auscultation usually reveals a loud, low-pitched
mid-diastolic murmur at the apex. Chest radiography often
shows increased interstitial pulmonary vascular markings and
increased LA size, with normal LV shadow. The ECG reveals
LA enlargement, and patients with long-standing MS may
have atrial fibrillation. Echocardiography is the most impor-
tant diagnostic tool, revealing important anatomic informa-
tion and calculating a peak and mean gradient across the
valve with Doppler interrogation. In addition, the degree of
PH can be assessed. Three-dimensional echocardiography

is increasingly used for precise definition of the anatomic
defect to plan surgical approaches. Cardiac catheterization is
reserved for PH patients to assess risk of surgery.
Mitral stenosis is repaired surgically if the patient cannot
be managed medically to achieve near-normal respiratory sta-
tus and growth. Surgery usually involves repair of the valve in
infants and children; valve replacement is avoided as much as
possible in a growing child who would be obligated to future
surgery. Also, anticoagulation management in active young
children is often problematic. Occasionally, mitral stenosis can
be addressed in the CCL with balloon valvuloplasty.
Anesthetic hemodynamic goals are similar to those for left-
sided obstructive lesions noted earlier. Normal to slow heart
rate will allow for increased diastolic filling time to improve
stroke volume. Adequate intravascular volume status will
achieve the same effect. Patients with PH must be approached
with care; inadequate anesthesia, hypercarbia, or hypoxemia may
cause a sudden increase in PVR, restricting LV filling and severely
compromising systemic CO. On the other hand, excessively low-
ering PVR with high Fio2, hyperventilation, or NO, may result in
a significant increase in pulmonary blood flow without relief of
the anatomic obstruction at the mitral valve, resulting in wors-
ening ventilatory mechanics from increased interstitial edema.
Therefore, these patients should be approached carefully with an
anesthetic plan designed to achieve these goals (Box 3-13).
COR TRIATRIATUM
Cor triatriatum is an abnormal membrane, or division, present
in the left atrium above the mitral valve, resulting in varying
degrees of obstruction to flow into the left ventricle. It is a rare
lesion, accounting for only 0.1% of CHD defects87 (see Fig. 3-4, C).
The pathophysiology is essentially identical to that of mitral
stenosis, and only echocardiography often differentiates the
two conditions. Surgical repair is undertaken when the diag-
nosis is made. Milder forms of cor triatriatum may be unde-
tected for months and even years in patients whose only real
symptoms are recurrent respiratory infections and wheezing.
SHONE'S COMPLEX
Also known as Shone's syndrome or anomaly, Shone's complex
consists of multiple levels of left-sided obstruction coexisting
in the patient. Typically, at least three levels of obstruction
must be present for the diagnosis,78 usually including mitral
stenosis with a supravalvar mitral ring and parachute mitral
valve, subaortic stenosis with a fibromuscular membrane or
tunnel, and coarctation of the aorta. Additional lesions include
bicuspid aortic valve with aortic stenosis and a VSD. Severe
BOX 3-13   n  MITRAL STENOSIS
Isolated mitral stenosis is unusual in patients with CHD.
Left atrial hypertension may lead to pulmonary interstitial edema and
pulmonary hypertension.
Hemodynamic goals are to maintain afterload, normal to slow heat
rate, and normal preload.
Chapter 3  Congenital Heart Disease 109
forms of Shone's complex form a continuum on the mild side
of hypoplastic left heart syndrome (see later). Symptomatology
depends on the severity of obstruction and the level of the
most significant obstruction. Neonates with severe coarcta-
tion with Shone's complex often present similar to those with
isolated coarctation when the PDA closes. Mitral stenosis as
the most significant level of obstruction is similar to isolated
mitral stenosis discussed earlier.
The general approach in less severe obstruction is to man-
age the patient medically until large enough for surgery to
address all levels of obstruction. In some patients the coarc-
tation of the aorta is addressed in the neonatal period using
left thoracotomy without bypass; this approach may merely
shift the level of worst obstruction proximally to the subaortic
area. Pulmonary hypertension often complicates the perioper-
ative and hospital course of these patients. Careful individual
evaluation, with echocardiography, cardiac catheterization to
define the worst levels of obstruction, and medical manage-
ment, including diuretics to minimize pulmonary edema, are
necessary in these patients. Even after repair, the small size of
the left ventricle in many of these patients leads to ongoing LA
hypertension and low cardiac output.
HYPERTROPHIC CARDIOMYOPATHY
Hypertrophic cardiomyopathy (HCM) is defined as an
increase in left ventricular muscle mass, in the absence of a
condition that would produce abnormal loading of the left
side of the heart, such as valvar aortic stenosis, hypertension,
or coarctation of the aorta. The incidence of HCM is estimated
at 0.3 to 0.5 per 100,000 children and 1 in 500 adults.88 Familial
or genetic causes include glycogen or lysosomal storage dis-
eases, actin and myosin abnormalities, carnitine deficiency,
and mitochondrial cytopathies. Nonfamilial etiology includes
obesity, infants of diabetic mothers, HCM in trained athletes,
and amyloid disease. Regardless of the cause, the pathophysi-
ology is similar, and diastolic dysfunction is a major feature.
Ventricular compliance is reduced, resulting in abnormal dia-
stolic filling, in turn contributing to the reduced stroke vol-
ume. In addition, LV end-diastolic pressure is elevated, which
may eventually result in LA hypertension, pulmonary inter-
stitial edema, dyspnea, and exercise intolerance. LV systolic
function is usually preserved early in the course of HCM and
may even be hyperdynamic because of the increased muscle
mass. LV outflow tract obstruction occurs in many patients
because the thickened interventricular septum interacts with
the mitral valve apparatus to narrow the subaortic region dur-
ing systole. The thickened LV mass predisposes HCM patients
to coronary ischemia and arrhythmias, which are often ven-
tricular in origin and represent a significant risk for sudden
death. The fibrosis from this ischemia and often-disordered
arrangement of myocardial cells apparently give rise to this
risk of ventricular tachycardia and fibrillation (Box 3-14).
Patients with HCM often receive the diagnosis secondary
to their underlying syndrome or metabolic disease, or a fam-
ily history of HCM with sudden death. Dyspnea, chest pain,
 110 ANESTHESIA AND UNCOMMON DISEASES
BOX 3-14   n HYPERTROPHIC CARDIOMYOPATHY
(HCM)
Left ventricular outflow tract (LVOT) obstruction occurs from
hypertrophied ventricular septum and systolic anterior motion of
the mitral valve.
Hemodynamic goals in HCM patients are to limit contractility, avoid
increases in heart rate and decreases in afterload, and maintain
preload.
Short-acting β-blockers are important for perioperative care of HCM
patients.
and syncope are ominous symptoms indicating severe LVOT
obstruction or arrhythmia and must be investigated urgently.
An ejection systolic murmur, grade II-IV/VI, at the left ster-
nal border is usually present. The ECG may reveal a number
of abnormalities, including T-wave inversions, pathologic
Q waves, and LA and LV enlargement. ST-segment changes
may occur with myocardial ischemia. Atrial or ventricular
arrhythmias may be seen. Echocardiography is crucial for the
diagnosis and can quantitate the degree of LV hypertrophy;
LVOT obstruction is assessed by midsystolic closure of the
aortic valve. Systolic anterior motion of the mitral valve and
mitral regurgitation can also be assessed. Global LV function
and response to exertion can also be assessed. Exercise test-
ing is often performed in these patients to assess response to
increased O2 demand. Cardiac MRI can assess degree of ven-
tricular hypertrophy and assess systolic and diastolic function.
LVOT gradients of 30 to 50 mm Hg or greater are considered
significant and usually are associated with symptoms. Medical
management involves treating any underlying genetic condi-
tions and reducing dynamic LVOT obstruction by decreasing
the force of contraction and the heart rate, with β-blockers
as first-line therapy; calcium channel blockers may also be
used. Arrhythmias are often treated with amiodarone and
life-threatening ventricular arrhythmias with an implantable
cardioverter-defibrillator (ICD). Septal myomectomy is often
done in patients with severe symptoms, although this should
not be considered permanent treatment. In severe cases of
unmanageable symptoms or frank cardiac failure, the patient
is referred for heart transplantation.
Anesthesia for patients with HCM should be approached
carefully, and in general the hemodynamic goals are the same
as for LVOT obstruction. Maintaining high-normal SVR, low-
normal HR, adequate ventricular filling, and normal sinus
rhythm are all important goals. Controlling dynamic LVOT
obstruction with short-acting β-blocker infusions (e.g., esmo-
lol) is also important. Provisions for resuscitation and defibril-
lation should be readily available.
Right-Sided Obstructive Lesions
Right-sided obstructive lesions include several different con-
genital heart defects. These defects can affect any right-sided
heart structure, including the tricuspid valve, subpulmonic
area, pulmonic valve, pulmonary artery, and pulmonary
branch arteries.89 Some lesions present in the neonatal period
with cyanosis or CHF. Other lesions are asymptomatic and
may present in an adolescent or adult as fatigue.
Patients who have interatrial or interventricular communica-
tions and a right-sided obstructive lesion will shunt right to left,
maintaining cardiac output at the expense of cyanosis. Neonates
with critical pulmonary stenosis or atresia require a PDA for pul-
monary blood flow. These patients will need PGE1 therapy until
a stable source of pulmonary blood flow can be created.
EBSTEIN'S ANOMALY
Ebstein's anomaly is the most common congenital malforma-
tion of the tricuspid valve. It occurs in 1 in 20,000 live births.
Ebstein's anomaly is characterized by a downward displace-
ment of the septal and posterior leaflet attachments at the
junction of the inlet and trabecular portions of the right ven-
tricle. There is an “atrialized” RV portion between the tricus-
pid annulus and the attachment of the posterior and septal
leaflets, as well as a “malformed right ventricle”90 (Fig. 3-19).
Ebstein's anomaly has a spectrum of severity, and presentation
may occur in the neonatal period, during infancy, or in child-
hood, or it may not occur until adulthood.
Almost all patients with Ebstein's anomaly will have either an
atrial septal defect or a patent foramen ovale. The dysplastic tri-
cuspid valve leaflets may allow minimal blood flow into the tra-
beculated RV portion. In this case, there is shunting across the
ASD or PFO, and the patient is cyanotic. The atrialized RV por-
tion may have aberrant conduction, and an abnormal interven-
tricular septum may affect LV geometry and function. Tricuspid
insufficiency causes RA enlargement, and pulmonary stenosis
and atresia may result from poor antegrade flow in utero.
After birth, the neonate with Ebstein's anomaly may be
cyanotic as a result of right-to-left shunting through an ASD.
As PVR falls, forward flow and the degree of cyanosis can
RA
LA
Mitral valve
Annulus
"Atrialized"
right ventricle
Left
Tricuspid valve ventricle
leaflets
Functional right
ventricle
FIGURE 3-19  Ebstein's anomaly. Anatomy of anomaly of tricuspid
valve; RA, right atrium; LA, left atrium. Red arrowheads indicate the
normal position of the TV annulus. (Modified from Spitaels SEC:
Cardiol Clin 20:431-439, 2002.)

improve. The chronic obstruction can also lead to massive
dilation of the right atrium, CHF, and malignant dysrhythmias.
Surgical therapy can produce a two-ventricle, “one and
a half ”–ventricle, or single-ventricle repair or palliation,
depending on the degree of tricuspid valve dysplasia. A two-
ventricle repair involves tricuspid valve repair or replacement,
plication of the atrialized RV portion, and possible closure of
the interatrial communication. A one-and-a-half–ventricle
palliation is performed for patients who have a right ventri-
cle that is capable of some contribution to pulmonary blood
flow and involves creation of a superior cavopulmonary anas-
tomosis. Blood from the lower half of the body continues to
return to the right atrium and is pumped into the pulmo-
nary artery by the right ventricle. A single-ventricle palliation
is performed on patients who have no antegrade pulmonary
blood flow and are ductal dependent. The single-ventricle pal-
liation involves exclusion of the right ventricle from the circu-
lation and creation of a systemic-to-pulmonary arterial shunt.
Superior and total cavopulmonary anastomosis may be per-
formed later (Box 3-15).
Intraoperatively and postoperatively, patients with Ebstein's
anomaly are at high risk for supraventricular and ventricular
dysrhythmias. Pharmacologic agents and temporary pacing
wires should be available. In addition, milrinone, dobuta-
mine, and NO may help to improve RV function in the post-
bypass period. The poorly functioning right ventricle may also
require substantial filling pressures.
TETRALOGY OF FALLOT
Tetralogy of Fallot (TOF) is the most common cause of cyanotic
heart disease, present in 9% to 14% of patients with congestive
heart disease.1,91 The four components are a large unrestrictive
VSD, right ventricular outflow tract (RVOT) obstruction, over-
riding aorta, and RV hypertrophy. A right aortic arch is pres-
ent in 25% of patients with TOF92 (Fig. 3-20). Coronary artery
anomalies are present in 5% to 12% of patients and can com-
plicate surgical repair. For example, the left coronary artery
can originate from the right coronary artery and run across
the RVOT, close to the location of the transannular incision.
The RVOT obstruction in TOF is often multilevel. A dynamic
component results from infundibular hypertrophy and spasm,
often enhanced by sympathetic stimulation. The fixed compo-
nent of RVOT obstruction can be subvalvar, valvar, supraval-
var, or at the level of the branch pulmonary arteries.
BOX 3-15   n  EBSTEIN'S ANOMALY
Ebstein's anomaly is a tricuspid valve defect with distal displacement
of the valve and atrialization of the right ventricle.
Tricuspid regurgitation symptoms in the neonate range from mild to
severe.
Cyanosis is common in the neonate because of R-L shunting at the
atrial level.
Supraventricular tachycardia is very common in patients with
Ebstein's anomaly.
Chapter 3  Congenital Heart Disease 111
Infundibular and
valvar pulmonic
stenosis
VSD with
overriding
aortic valve
Right ventricular
hypertrophy
FIGURE 3-20  Tetralogy of Fallot. Interior of right ventricle shows
characteristic defects: pulmonic stenosis, ventricular septal defect
(VSD), overriding aorta, and right ventricular hypertrophy. (Modified
from Stayer SA, Andropoulos DB, Russell IA: Anesthesiol Clin North
Am 21:663, 2003.)
There is a broad spectrum of clinical presentation of TOF.
At one end is the “pink tetralogy” patient with a large VSD and
minimal RVOT obstruction. Blood shunts left to right through
the VSD; the patient is not cyanotic but often has some degree
of heart failure from pulmonary overcirculation. At the other
end of the spectrum is the patient with pulmonary atresia or
near–pulmonary atresia who is cyanotic, has PDA-dependent
pulmonary circulation, and requires intervention in the neo-
natal period to establish a stable source of pulmonary blood
flow. In the middle of the TOF presentation spectrum is the
“classic tetralogy.” This patient is normally well saturated at
rest but can become cyanotic with crying, agitation, pain, or
fear from infundibular spasm and subsequent R-L shunting
through the VSD. The other factor in determining the amount
of R-L shunting and cyanosis is the difference between SVR
and PVR or RV afterload. If the SVR is lower, blood will pref-
erentially shunt from right to left, producing cyanosis and
hypoxemia (Box 3-16).
BOX 3-16   n  TETRALOGY OF FALLOT (TOF)
TOF is a common cyanotic lesion.
The four components of TOF are VSD, RVOT obstruction, RV
hypertrophy, and right aortic arch (in 25%).
Cyanosis ranges from none, “pink tet” with minimal RVOT
obstruction, to severe with pulmonary atresia.
“Tet spell” is hypercyanosis from increased RVOT obstruction,
tachycardia, and hypovolemia causing increased right-to-left shunting.
Treatment of TOF involves increasing Fio2 (1), deepening anesthetic,
volume infusions, and IV phenylephrine.
 112 ANESTHESIA AND UNCOMMON DISEASES
Surgical repair consists of closure of the VSD, resection of
RV muscle bundles, and relief of any other levels of RVOT
obstruction. The approach to the RVOT and pulmonic valve
is through transatrial and transpulmonary incisions. If the
size of the RVOT and MPA are small, a transannular incision
and patch are performed. A transannular patch usually leaves
the patient with pulmonary insufficiency. In patients who
are extremely cyanotic or small, the creation of a systemic-
to-pulmonary arterial shunt is advocated in the neonatal
period to provide a stable source of pulmonary blood flow93
(Fig 3-21). The patient grows, and a full repair is undertaken
at 6 to 9 months of age. Some centers advocate a neonatal com-
plete repair of TOF; the advantages are the need for only one
surgery and no increased morbidity or mortality. The disad-
vantage is that more patients undergo repair with a transan-
nular patch or RV-to-PA conduit, which may lead to more
interventions later in life. These neonates are also often quite
ill in the perioperative period secondary to RV dysfunction.
Coronary artery anomalies are common in patients with
tetralogy of Fallot. Most often the left anterior descend-
ing artery arises from the right coronary artery and crosses
the RVOT. This anomalous coronary artery can be damaged
Shunt Ligated ductus
Atretic MPA
AAo
FIGURE 3-21  Modified Blalock-Taussig shunt. Note the atretic
main pulmonary artery (MPA) and the ligated ductus arteriosus.
GoreTex tube graft (Shunt) is sewn side-to-side between the
innominate artery and right pulmonary artery. Size of the tube
graft (3.5 mm, 4 mm, or 5 mm) is chosen at surgery depending
on patient size and caliber of pulmonary artery. Some surgeons
perform the shunt through a median sternotomy, and others
choose a lateral thoracotomy; cardiopulmonary bypass is usually
not required. AAo, Ascending aorta. (Modified from Waldman JD,
Wernly JA: Pediatric Clin North Am 46:388, 1999.)
intraoperatively and can influence the type of incision made.
In fact, it may preclude transannular patching, and place-
ment of an RV-PA conduit may be required. Also, the cyanotic
neonate with TOF may be palliated with balloon dilation of
the RVOT in the CCL to create a stable source of pulmonary
blood flow until the full repair is performed.
Perioperatively, the patient with TOF may develop a “tet
spell” characterized by cyanosis and hypoxemia. These often
occur during anesthetic induction and invasive catheter place-
ment, as well as in the prebypass period. At times, SVR may be
low because of hypovolemia and the effects of anesthetic agents.
In addition, tet spells may also occur during periods when the
patient may be lightly anesthetized. Sympathetic stimulation
may increase infundibular spasm and increase the R-L shunt
through the VSD. Treatment is to increase Fio2 (1), adminis-
ter additional anesthetics to decrease sympathetic stimulation,
augment intravascular volume, and administer systemic vaso-
constrictors such as phenylephrine. β-Adrenergic blockade
with short-acting agents such as esmolol may also be effective.
Induction in an unrepaired patient with TOF can be
accomplished intramuscularly, intravenously, or by inhala-
tion. Intramuscular induction with ketamine (5 mg/kg) pro-
duces unconsciousness without decreasing SVR or increasing
PVR. Intravenous induction with midazolam and fentanyl can
also be used safely, but decreases in SVR should be treated
promptly. Inhalation induction with sevoflurane is also
acceptable. The myocardial depressant effects of the potent
inhalational agents serve to decrease infundibular spasm and
R-L shunting. However, the anesthesiologist must take care to
avoid drastic decreases in SVR.
After repair, RV function may be impaired because of a ven-
triculotomy, and an inotrope may be required. On the other
hand, after the obstruction is relieved, the right ventricle may
be hyperdynamic and may not require inotropic support. It is
important to note that the use of inotropic agents in a patient
with repaired TOF and residual dynamic RVOT obstruction can
be problematic. Hemodynamically significant junctional ectopic
tachycardia (JET) is also common postoperatively in the patient
with TOF. JET can be treated with sedation, cooling, minimizing
catecholamine administration, correcting electrolytes, adminis-
tering magnesium, overdrive pacing, and IV amiodarone. If the
patient is extremely unstable, ECMO support may be indicated.
Patients with TOF who have been repaired generally do
well. However, they do require cardiology follow-up to moni-
tor pulmonary insufficiency and its effect on the right ven-
tricle. Placement of a valve either percutaneously in the CCL
or in the OR may be required. When an RV-PA conduit is
placed, the patient can outgrow the conduit, or the conduit
can become calcified. In either case the right ventricle can
hypertrophy in response to the increased pressure burden, and
RV-PA conduit replacement may be necessary.
PULMONARY STENOSIS
Pulmonary stenosis (PS) can occur at the subvalvar, valvar, or
supravalvar level and is quite common at 8% to 10% of all con-
genital heart defects. Depending on the severity of obstruction,
 Chapter 3  Congenital Heart Disease 113

the patient may be asymptomatic or may present with signs

and symptoms of RV failure and cyanosis from R-L shunting
through an ASD.94 Subvalvar PS can result from muscle bun-
dles in the RVOT, similar to those in TOF, or can present as
a ridge that divides the right ventricle into two chambers. In Patent
these two cases, surgical repair is necessary. arterial duct
Valvar PS can be mild, moderate, severe, or critical. When a
neonate presents with severe or critical PS and worsening RV
function, intervention is necessary. PGE1 may be initiated to
maintain ductal patency and provide a source of pulmonary
blood flow. Inotropes may also be needed. The patient can be
treated surgically or percutaneously. A balloon pulmonary val-
vuloplasty can be performed in the CCL. This procedure can
create some pulmonary insufficiency, but it also creates a source
Defect in
of pulmonary blood flow, and the ductus can be allowed to close. oval fossa
A surgical valvotomy can be performed in the OR. Subvalvar
RVOT obstruction can be noted after the relief of valvar PS. In
most patients, this hypertrophy is caused by the RV pressure load Pulmonary
from the PS and will regress after the PS is relieved. Inotropic atresia
agents may worsen this type of dynamic RVOT obstruction.
Supravalvar PS can be seen in patients with Williams syn-
drome and in patients after the arterial switch operation. This
type of PS can be treated in the CCL with stenting or in the OR
with patch augmentation of the pulmonary artery.
From an anesthetic standpoint, it is important to know Hypoplastic
right ventricle
the extent of RV dysfunction. However, in all cases except
dynamic subvalvar PS, little can be done to improve the RVOT FIGURE 3-22  Basic arrangement of pulmonary atresia with
intact ventricular septum. The right ventricular cavity is severely
obstruction. Therefore, an effort should be made to preserve
hypoplastic. Defect in oval fossa refers to the atrial septal defect
RV function by avoiding myocardial depressants and with
required in this lesion. (Modified from Daubeney PE: Hypoplasia
careful infusion of inotropes. of the right ventricle. In Anderson RH, et al, editors: Paediatric
cardiology, ed 3, Philadelphia, 2010, Elsevier/Churchill Livingstone.)
PULMONARY ATRESIA WITH INTACT VENTRICULAR SEPTUM
Pulmonary atresia with an intact ventricular septum (PA/IVS) relieve RVOT obstruction, a transannular patch and systemic-­
is a relatively uncommon congenital heart defect. It requires pulmonary arterial shunt, a systemic-pulmonary shunt, or trans-
intervention in the neonatal period, and without interven- plantation. After the initial surgery, it can be determined whether
tion, results in death in 85% of patients by age 6 months. the patient is suitable for BiV repair, one-and-a-half–ventricle
PA/IVS consists of pulmonary atresia; a small, hypertensive repair, or single-ventricle palliation.
right ventricle; a varying degree of tricuspid regurgitation; and Patients with PA/IVS are also being seen increasingly in
coronary artery abnormalities. After birth, these patients have the cardiac catheterization suite, where a similar management
ductal-dependent pulmonary blood flow, and PGE1 must be decision is made, between stenting of the ductus arteriosus or
started to maintain ductal patency95 (Fig. 3-22). stenting of the RVOT, or both. Stenting of the RVOT is per-
Sinusoids often form between the hypertensive right ventri- formed to allow RV growth and possible future BiV or one-
cle and the coronary arteries. When RV pressure is suprasys- and-a-half–ventricle repair. As with the surgical management,
temic, the myocardium is partially supplied by these sinusoids the opening of the RVOT and a reduction in RV pressures
containing deoxygenated systemic venous blood. A decrease should be avoided in patients with RVDCC.
in RV pressure can be problematic because flow may reverse,
and coronary steal may occur. In some cases the sinusoids
BOX 3-17   n PULMONARY ATRESIA WITH INTACT
supply the entire myocardium with deoxygenated blood, and VENTRICULAR SEPTUM (PA/IVS)
there are no coronary arteries arising from the aorta. The pres-
ence of RV-dependent coronary circulation (RVDCC) impacts Pathophysiology and treatment of this complex lesion depend on RV size.
treatment options for these patients (Box 3-17). Small right ventricle often leads to coronary sinusoids and
RV-dependent coronary circulation (RVDCC).
Options for repair or palliation depend on the degree of tri- In RVDCC, coronary ischemia is common; these patients receive
cuspid regurgitation, RV size, and presence of RVDCC. In the single-ventricle palliation or transplantation.
optimal situation, after some initial palliation with adequate RV PA/IVS patients with larger right ventricle usually receive RV
size, a biventricular (BiV) repair would be possible. Initial sur- decompression, and one-and-a-half–ventricle or two-ventricle repair.
gical options include the placement of a transannular patch to
 114 ANESTHESIA AND UNCOMMON DISEASES
Perioperatively, it is important to recognize that patients with
RVDCC can develop myocardial ischemia at any time. Goals
for avoidance of myocardial ischemia in these patients include
the maintenance of preload and high-normal PVR in a patient
with sinusoids who has undergone RVOT augmentation. After
placement of a modified Blalock-Taussig shunt, as in any patient,
SVR/PVR balance must be managed to avoid excessive pulmo-
nary blood flow and systemic hypoperfusion. If BiV repair is
done, inotropic support may be necessary for a marginally sized
right ventricle with varying amounts of tricuspid regurgitation.
PULMONARY ATRESIA WITH VENTRICULAR SEPTAL DEFECT
AND MAJOR AORTOPULMONARY COLLATERALS
Pulmonary atresia with a ventricular septal defect and major
aortopulmonary collateral arteries (MAPCAs) is a lesion with
considerable anatomic variability. Many experts consider this
lesion to be the extreme form of tetralogy of Fallot because the
intracardiac anatomy is almost always identical to this lesion.96
The pulmonary arteries (PAs) are not in continuity with the
RVOT. The PAs may be normal or near-normal size and sup-
plied through the ductus arteriosus. The PAs may be small, and
some pulmonary blood flow arises from aortopulmonary col-
laterals, or the PAs may be nonexistent, and all pulmonary blood
flow originates from these collateral vessels. Echocardiography,
diagnostic cardiac catheterization, CT angiography, and car-
diac MRI can all be used to delineate the anatomy (Fig. 3-23).
The clinical presentation can vary as well. The pulmonary
blood flow through the MAPCAs can be excessive, producing
Aorta
Pulmonary
trunk
Right
ventricle
FIGURE 3-23  Pulmonary atresia with ventricular septal defect. Variants of obstruction within, or absence of, the pulmonary arterial
pathways: left, imperforate pulmonary valve (arrow); middle, muscular obstruction; right, solitary arterial trunk. (Modified from Baker EJ,
Anderson RH: Tetralogy of Fallot with pulmonary atresia. In Anderson RH, et al, editors: Paediatric cardiology, ed 3, Philadelphia, 2010,
Elsevier/Churchill Livingstone.)
high So2, CHF, and possible PVR changes caused by overcir-
culation and high-pressure flow into the PAs. In contrast, the
MAPCAs may be stenotic at the aortic origin, or pulmonary
blood flow may be PDA dependent, producing cyanosis and
protecting the pulmonary vasculature (Figs.  3-24 and 3-25).
The goal of surgery is to construct adequately sized PAs from
the MAPCAs, a PA unifocalization (creation of a single source
of blood flow to each lung), to close the VSD and to con-
struct an RV-PA conduit. This may require several surgeries.
The unifocalization can be performed in one stage through a
sternotomy using CPB. After the unifocalization is complete,
the pulmonary vasculature is examined and a decision made
either to close the VSD and place an RV-PA conduit or to place
a systemic-pulmonary arterial shunt and allow the PAs to
grow. Two-stage (or more) unifocalizations are usually carried
out via thoracotomy without bypass. SLV can facilitate surgical
exposure during these procedures. After the unifocalizations,
the adequacy of the PAs for BiV repair is assessed (Box 3-18).
BOX 3-18   n PULMONARY ATRESIA WITH
VENTRICULAR SEPTAL DEFECT
Pulmonary atresia with VSD in patients with normal-sized pulmonary
arteries is approached the same as for tetralogy of Fallot.
Pulmonary atresia and VSD with hypoplastic PAs develop major
aortopulmonary collateral arteries.
Treatment strategy is to unifocalize all pulmonary blood flow to each
lung, then provide RV-PA conduit, and close VSD if possible.
No valvar No pulmonary
tissue trunk
Blind-ending
outflow tract

Aorta
Aorta
Two major problems encountered after VSD closure and
the placement of an RV-PA conduit are lung reperfusion
injury and RV dysfunction. The unifocalization and construc-
tion of a stable source of pulmonary blood flow may overper-
fuse the vasculature of lung segments that were previously
hypoperfused. Lung reperfusion injury can manifest as high
peak pressures, blood and pulmonary edema in the airways,
hypoxemia, and hypercarbia. Treatment includes suctioning,
high PEEP, and bronchodilators.
After the placement of the RV-PA conduit, the right ven-
tricle is ejecting to the pulmonary circulation for the first
time, and the unifocalized PAs are abnormal. The right ven-
tricle may not be able tolerate the greatly increased afterload.
In this case, selective PA dilators (e.g., iNO) and sildenafil may
be indicated. In addition, inotropes with pulmonary vasodilat-
ing qualities (e.g., milrinone) may be used.
Chapter 3  Congenital Heart Disease 115
FIGURE 3-24  Example of multifocal blood supply.
Both collateral arteries and pulmonary arteries
contribute to pulmonary blood supply in pulmonary
atresia with ventricular septal defect. Four collateral
arteries are illustrated, shown in red arising from
the descending aorta. Right upper artery directly
supplies the right upper lobe exclusively. Right lower
artery feeds the middle and lower lobes of right lung
through anastomosis with intrapericardial arterial
tree, shown in blue, at hilar level (central arrow). Left-
sided collateral arteries are shown feeding left lung
(arrows) through anastomoses at segmental level.
(Modified from Baker EJ, Anderson RH: Tetralogy of
Fallot with pulmonary atresia. In Anderson RH et al,
editors: Paediatric cardiology, ed 3, Philadelphia,
2010, Elsevier/Churchill Livingstone.)
FIGURE 3-25  Absence of all intrapericardial
pulmonary arteries. Pulmonary parenchyma
receives its arterial supply exclusively through
systemic-to-pulmonary collateral arteries (arrows).
(Modified from Baker EJ, Anderson RH: Tetralogy of
Fallot with pulmonary atresia. In Anderson RH et al,
editors: Paediatric cardiology, ed 3, Philadelphia,
2010, Elsevier/Churchill Livingstone.)
DEXTROTRANSPOSITION OF THE GREAT ARTERIES
Dextrotransposition (D-transposition) of the great arteries
(D-TGA) represents about 10% of all congenital heart defects.
In D-TGA the aorta arises from the morphologic right ven-
tricle, and the pulmonary artery arises from the left ventricle1
(Fig. 3-26). The three categories of D-TGA are TGA with intact
ventricular septum (50%-75% of patients), TGA with ventricu-
lar septal defect (15%-25%), and TGA with VSD and left ven-
tricular outflow tract obstruction (5% of D-TGA patients).97,98
Transposition physiology leads to a parallel circulation where
systemic venous blood returns to the right atrium, fills the right
ventricle, and is ejected into the aorta without passing through
the lungs. The pulmonary venous blood returns to the left
atrium, fills the left ventricle, and is ejected into the PA without
this highly oxygenated blood reaching the systemic circulation
(see Fig. 3-4, D). Therefore, profound arterial desaturation can
 116 ANESTHESIA AND UNCOMMON DISEASES

atrial dysrhythmias, sinus node dysfunction, baffle leaks and

obstruction, and dysfunction of the right (systemic) ventricle
(Box 3-19).
In 1975, Jatene performed the first arterial switch opera-
Patent ductus tion (ASO), the procedure currently performed today. The
Aorta arteriosus ASO involves translocation of the great arteries and coro-
Pulmonary nary arteries. This operation not only separates the systemic
artery
Atrial
and pulmonary circulations, but also makes the left ventri-
septal cle into the systemic ventricle (Fig. 3-27). Potential problems
defect after the ASO include a failing left ventricle, myocardial isch-
or
patent
emia from problems after the coronary artery transfer, and
foramen Left pulmonary hypertension. Supravalvar pulmonary stenosis
ovale atrium

BOX 3-19   n D-TRANSPOSITION OF THE GREAT

Right ARTERIES (D-TGA)
atrium
In D-TGA the aorta arises from the right ventricle and the pulmonary
Left artery from the left ventricle, resulting in parallel circulation with
Ventricular ventricle “transposition physiology.”
septal Oxygenation depends on mixing at the atrial level (most important),
defect Right PDA, or ventricular level.
ventricle Balloon atrial septostomy is often necessary in the neonatal period.
Definitive treatment of D-TGA is the arterial switch operation.

FIGURE 3-26  Transposition of the great arteries. Basic

anatomy and sites of mixing between the systemic and pulmonary
circulations. (Redrawn from Rouine-Rapp K: Anesthesia for
transposition of the great vessels. In Andropoulos DB, et al, editors:
Anesthesia for congenital heart disease, ed 2, Oxford, UK, 2010, Coronary arteries
Wiley-Blackwell.) in neoaorta

result from lack of oxygenated blood flow to the systemic cir- Translocated
culation. There must be mixing of blood at the atrial (best and pulmonary
most efficient mixing), PDA, or ventricular level for survival, arteries
so that some better-oxygenated blood passes to the right ven-
tricle and is ejected from the aorta. Patients with large VSD often
have adequate mixing and arterial saturation without further
intervention. PGE1 can be initiated to maintain ductal patency
and promote mixing. If there is still insufficient mixing, a bal-
loon atrial septostomy is performed in the CCL or at the bed-
side using echocardiographic guidance. Noncardiac surgery in
a cyanotic neonate with unrepaired D-TGA is rarely performed;
achieving adequate mixing and arterial saturation is the first pri-
ority. Corrective cardiac surgery is normally performed in the
first week of life.
Before the early 1980s, physiologic repair of TGA was
achieved with an atrial switch operation. Both the Senning
and the Mustard procedures created a baffle that rerouted Repaired initial
origins of
systemic venous blood to the left ventricle and then to the coronary arteries
PA and directed pulmonary venous blood to the right ven- FIGURE 3-27  Arterial switch operation. Typical postoperative
tricle and aorta. The right ventricle remained the systemic appearance as seen by surgeon after completion of procedure.
ventricle, the great vessels still arose from the “wrong” ven- (Modified from Salih C, Brizard C, Penny DJ, Anderson RH:
tricle, but the pulmonary and systemic circulations were sepa- Transposition. In Anderson RH et al, editors: Paediatric cardiology,
rated. Long-term complications with the atrial switch include ed 3, Philadelphia, 2010, Elsevier/Churchill Livingstone.)

may also be seen. The ASO is ideally performed within the
first month of life after PVR has decreased, but before the
left ventricle becomes deconditioned due to pumping into a
lower-resistance bed. In cases of delayed diagnosis, a PA band
can be placed as a first operation to retrain the left ventri-
cle, and the ASO can be performed later. Ideally, the ASO is
the prototypic complex corrective neonatal cardiac surgery,
in which an infant with a previously fatal lesion undergoes
corrective surgery once in the neonatal period. With excel-
lent results, mortality is now close to zero with this lesion,
and most patients are completely anatomically and physio-
logically corrected. They must all undergo routine follow-up,
but many need no cardiac medications and have normal lives
with unrestricted activities.
CONGENITALLY CORRECTED TRANSPOSITION OF THE
GREAT ARTERIES
Congenitally corrected transposition of the great arteries (cc-
TGA) is an uncommon congenital heart defect (<1% of all
CHD) with both ventriculoarterial (V-A) discordance and
atrioventricular (A-V) discordance. The right atrium receives
systemic venous blood from the SVC and IVC and empties
into the left ventricle. The left ventricle ejects into the pul-
monary artery. Pulmonary venous blood empties into the
left atrium, which empties into the right ventricle. The right
ventricle ejects into the aorta99 (Fig. 3-28). As a result of the
Aorta
Pulmonary
artery
Left
atrium Aortic
valve
Right Tricuspid
atrium valve
Pulmonary
valve
Right
Tricuspid ventricle
valve Left
ventricle
FIGURE 3-28  Congenitally corrected transposition of the great
arteries. Note in cardiac anatomy that the right ventricle dilates
and hypertrophies as the heart ages. Even with this compensation,
right ventricular wall is significantly thinner than left ventricular
wall and is not built to support systemic pressure. (Redrawn from
Arendt KW et al: Anesth Analg 107:1973-1977, 2008.)
Chapter 3  Congenital Heart Disease 117
double discordance (A-V and V-A), deoxygenated blood is
pumped into the pulmonary circulation, and oxygenated
blood is pumped systemically. In other words, physiologically,
cc-TGA leads to correct blood flow patterns and systemic oxy-
genation; however the ventricles are inverted. Other cardiac
anomalies are frequently associated with cc-TGA, including
VSD, pulmonary stenosis, pulmonary atresia, and Ebstein-like
malformation of the tricuspid valve.100 Only 1% of patients do
not have associated anomalies. Conduction abnormalities are
also very common because of abnormal position of the A-V
node. Complete heart block occurs spontaneously at a rate of
approximately 2% per year.101
The presentation of cc-TGA is usually related to the asso-
ciated cardiac anomaly. For example, patients with a signif-
icant VSD or tricuspid valve disease may present in CHF.
Patients with significant pulmonic stenosis or pulmonary
atresia may present with significant cyanosis and require
surgery to create a source of stable pulmonary blood flow,
a modified Blalock-Taussig shunt. These associated anoma-
lies must be addressed either with medical therapy or surgi-
cal intervention. However, the major long-term issue is the
presence of a morphologic right ventricle in the systemic
position. The “classic” repair involves closing the VSD and
relieving the pulmonic stenosis if present; this leaves the
right ventricle in the systemic position. After classic repair,
complications include worsening of tricuspid regurgita-
tion and worsening function of the systemic right ventri-
cle. The double-switch operation involves both an atrial and
an arterial switch. It places the left ventricle in the systemic
position and reroutes systemic venous return to the right
ventricle and pulmonary venous blood to the left ventricle102
(Fig. 3-29). Patients who have had their left ventricle pump
against the PVR chronically may require a staged procedure.
First, a PA band is placed to encourage LV retraining so that
the LV does not fail when placed in the systemic position.
After the retraining period, the double-switch operation is
undertaken.103
For patients with unrepaired cc-TGA or with classic repair,
it is important to monitor the function of the systemic (right)
ventricle for signs of dysfunction. The right ventricle may be
destined for failure because the orientation of fibers in the
myocardium is different from that of a morphologic left ven-
tricle. In addition, the systemic right ventricle becomes hyper-
trophied because of its increased workload, and it is supplied
from the right coronary artery. Myocardial O2 demand is
greater than myocardial O2 supply. Systemic ventricular fail-
ure is a major cause of morbidity and mortality in this popula-
tion (Box 3-20).
Tricuspid valve (systemic A-V valve) regurgitation is also
followed carefully in patients with unrepaired cc-TGA or clas-
sic repair. The valve is usually abnormal from the beginning,
and over time it becomes more regurgitant. In addition, as the
systemic ventricle begins to fail, it dilates and stretches the
annulus, creating more insufficiency. It is recommended that
systemic A-V valve replacement be performed before the ejec-
tion fraction is less than 45%.101
 118 ANESTHESIA AND UNCOMMON DISEASES
Superior
caval vein
Aorta
Pulmonary
trunk Pulmonary
veins
Morphologically
right
ventricle
Morphologically
left
ventricle
Inferior
caval vein
FIGURE 3-29  Double-switch operation. For congenitally
corrected transposition of the great arteries. Atrial blood flow has
been rerouted to the correct ventricles (atrial switch), and arterial
switch has been performed, resulting in physiologic correction
of blood flow. (Modified from Brawn WJ, Jones TJ, Anderson RH,
Barron DJ: Congenitally corrected transposition. In Anderson RH,
et al, editors: Paediatric cardiology, ed 3, Philadelphia, 2010,
Elsevier/Churchill Livingstone.)
BOX 3-20   n CONGENITALLY CORRECTED
TRANSPOSITION OF THE GREAT
ARTERIES
Ventricles are inverted; aorta arises from right ventricle, and
pulmonary artery from left ventricle.
Right atrium leads to left ventricle, and left atrium to right ventricle.
Other anomalies often associated with cc-TGA include VSD and
pulmonic stenosis.
Complete atrioventricular block is common in cc-TGA.
“Classic” repair leaves right ventricle in the systemic position.
Right ventricle usually fails over time.
“Double switch” operation results in physiologic correction.
When patients with cc-TGA require anesthetic care, it is
important to recognize if the defect is unrepaired or whether
nonanatomic classic repair or double–switch operation has been
performed. If the right ventricle is in the systemic position (unre-
paired or classic repair), it is important to evaluate the systemic
A-V valve and RV function. An exercise stress test may provide
important information about functional status. If the patient has
had a double switch, ventricular function and atrial baffle patency
should be evaluated. An ECG and Holter monitor are useful to
evaluate for tachydysrhythmias and the presence of heart block.
An anesthetic plan should be selected after consideration
of systemic ventricular function, systemic A-V valve regur-
gitation, presence of other intracardiac pathology, and the
potential for tachydysrhythmias and heart block. Extremes of
afterload should be avoided because increased afterload can
stress an already-failing systemic ventricle, and decreased
afterload can lead to R-L shunting and cyanosis in a patient
with unrepaired cc-TGA with VSD and pulmonic stenosis. In
addition, the clinician should take care when administering
medications that can cause bradycardia (e.g., β-blockers, dex-
medetomidine) in patients with a tendency toward complete
heart block. Pacing capability should be available should heart
block present.
Single Ventricle
Patients with a single functional ventricle make up approxi-
mately 10% to 12% of patients with CHD.1 All these lesions are
classified as “complex cyanotic congenital heart disease,” and
the anatomy is highly variable. Single-ventricle (SV) patients
may possess a single right ventricle, as in hypoplastic left heart
syndrome, or a single left ventricle, as in tricuspid atresia. In
addition, ventricular morphology is indeterminate in some
patients; others may have a rudimentary second ventricle, but
because of its size, it cannot function as a ventricular pumping
chamber, and thus the term single functional ventricle is used.
Still others have complex intracardiac anomalies such as atrio-
ventricular canal with “crisscross” A-V valves, which preclude
septation of the heart, even though technically, two ventricles
are present. The exact anatomy is important to understand;
in general, a single functional left ventricle will function bet-
ter than a single functional right ventricle, because the latter
is designed to pump only against pulmonary artery pressures
and resistance.
The goals of SV surgical palliation (there are no complete
repairs) are to separate the systemic and pulmonary circula-
tions so that the ventricle is pumping only the systemic blood
flow, and the pulmonary circulation is connected to the sys-
temic circulation through a passive flow chamber, the total
cavopulmonary connection.104 This process unloads the sin-
gle ventricle so that it is handling its normal volume, reliev-
ing cyanosis. For most SV patients, this involves three-stage
palliation: a repair in the neonatal period to provide unob-
structed systemic or pulmonary blood flow; a bidirectional
superior cavopulmonary connection (bidirectional Glenn
anastomosis), now performed at age 3 to 6 months; and finally
a Fontan completion, the total cavopulmonary anastomosis,
usually performed at age 2 to 4 years. In the modern era the
Fontan completion is often extracardiac, with an 18-mm to
20-mm polytetrafluoroethylene (PTFE) graft from the IVC
to the right PA. Other alternatives include the lateral-tunnel
Fontan, with a tube created inside the atrium to carry the IVC
blood to the right PA (Fig. 3-30). In either case, blood flows
without a ventricular chamber from the venae cavae into the
lungs and depends on an adequate transpulmonary pressure
gradient. Often a fenestration is created in the Fontan circuit

Superior
vena cava
Aorta
Right
pulmonary
artery
Right
atrium
Lateral
tunnel
Systemic
ventricle
Inferior vena
cava
FIGURE 3-30  Total cavopulmonary anastomosis. Left, Lateral-tunnel Fontan completion. Right, Extracardiac Fontan completion.
A fenestration can be placed with either of these configurations.
to allow for a pressure popoff, to relieve signs of elevated right-
sided heart pressures. This consists of a 3-mm to 5-mm cir-
cular communication, allowing right-to-left shunting and
increasing systemic blood flow, at the expense of some arterial
desaturation (Box 3-21).
HYPOPLASTIC LEFT HEART SYNDROME
Hypoplastic left heart syndrome (HLHS) is the most common
single-ventricle lesion, affecting 4% to 8% of patients with
congenital heart disease.1 As with other CHD lesions, there
is a range of anatomic variation, from aortic and mitral atre-
sia with essentially no left ventricle, through aortic and mitral
stenosis, with a small left ventricle that is inadequate to han-
dle systemic blood flow.105,106 The ascending aorta is hypoplas-
tic, and antegrade flow across the aortic valve is minimal or
nonexistent. Flow to the proximal aorta and coronary arteries
BOX 3-21   n  SINGLE-VENTRICLE LESIONS
Single-ventricle (SV) anatomy is variable and includes single left or
single right ventricle, indeterminate ventricle, or nonseptatable
two-ventricle lesion.
Most SV patients require neonatal surgery: aortic reconstruction,
systemic-pulmonary shunt, or PA band.
All SV patients undergo superior cavopulmonary connection at age 3
to 6 months.
All patients undergo Fontan operation (total cavopulmonary
anastomosis) at 2 to 4 years.
Chapter 3  Congenital Heart Disease 119
Superior
vena cava Aorta
Right
pulmonary
artery
Extracardiac
conduit Systemic
ventricle
Inferior
vena cava
depends on retrograde flow through a large PDA; the diam-
eter of the descending aorta distal to the PDA is normal107
(Figs. 3-31 and 3-32).
Closure of the PDA results in death of the patient. This
lesion is 100% fatal in the first months of life if untreated.
Prenatal diagnosis is now made in more than 50% of HLHS
patients; delivery is planned in a referral center as soon
as possible, and PGE1 is started immediately after birth to
maintain ductal patency. The first palliations for HLHS
were performed in the late 1970s and early 1980s, and now
HLHS palliations are among the most common neona-
tal complex CHD surgeries. The Norwood stage I pallia-
tion is normally done in the first week of life and consists
of reconstruction of a neoaorta, using the patient's native
aorta/aortic valve and coronary arteries, the pulmonary
valve, and a patch made from cryopreserved aortic or pul-
monary homograft tissue. The pulmonic valve is used to
fashion a neoaortic valve, so another source of pulmonary
blood flow must be provided, either a right-sided modified
Blalock-Taussig shunt from the right innominate-subcla-
vian junction to the right PA, or a RV-to-PA conduit, the
Sano modification (Fig. 3-33).
In addition, an atrial septectomy is performed to allow
unobstructed egress of blood from the left atrium to the right
atrium. Early transplant-free survival may be better with the
RV-to-PA conduit version, although these advantages are
minimal after 12 months of age.108 At age 3 to 6 months, a
bidirectional cavopulmonary anastomosis is performed, and
the Blalock-Taussig shunt or RV-PA conduit is taken down.
 120 ANESTHESIA AND UNCOMMON DISEASES

The Fontan completion is done at age 2 to 4 years. All these

surgeries are complex; the stage I palliation necessitates either
DHCA or regional antegrade cerebral perfusion, and the
Hypoplastic Glenn and Fontan stages are normally done with CPB.
ascending
aorta Alternative management strategies developed over the last
decade include the hybrid palliation. This repair is done with-
Ductus out CPB and consists of a median sternotomy and placement
of bilateral PA bands by the surgeon to limit pulmonary blood
flow. The interventional cardiologist then places a stent in the
LA PA PDA to maintain long-term patency without PGE1, and a bal-
loon atrial septostomy, with or without an atrial stent, is per-
LA formed (Fig. 3-34). The physiology is thus similar to the stage
I Norwood palliation. With the hybrid approach, a compre-
hensive stage II surgery is done at age 3 to 6 months, which
Hypoplastic includes the complete aortic reconstruction; a bidirectional
left
ventricle
cavopulmonary anastomosis is done at that time, with Fontan
RA
completion again at 2 to 4 years.109
RV
Pathophysiology is complex, and in the neonate with unre-
paired HLHS, the systemic and pulmonary circulations are in
parallel, connected by a large PDA (Fig.  3-35). PVR is rela-
tively high in the first 24 to 48 hours of life but then declines
rapidly, and because blood will flow predominantly toward
FIGURE 3-31  Native anatomy in hypoplastic left heart the path of least resistance, steal of blood flow away from the
syndrome. Note the hypoplastic left ventricle, aortic valve atresia, systemic circulation and toward the pulmonary circuit occurs
and diminutive ascending aorta. Systemic blood flow is propelled during the first week and may be progressive. This results in
by the right ventricle (RV) through pulmonary artery (PA) and ductus
inadequate flow to the systemic circulation, including coro-
arteriosus. Pulmonary venous return enters right side of heart
nary arteries and the rest of the body, resulting in low cardiac
through a foramen ovale or an atrial septal defect. LA, Left atrium;
RA, right atrium. (Modified from Nicolson SC, Steven JM, Jobes
output, progressive lactic acidosis, myocardial ischemia, and
DR: Hypoplastic left heart syndrome. In Lake CL, editor: Pediatric eventually death. During this stage, high levels of Fio2, coupled
cardiac anesthesia, Stamford, Conn, 1998, Appleton & Lange.) with hyperventilation resulting in low Paco2, will significantly

Thread-like Pulmonary trunk

aorta

Head and neck

arteries fed
through duct

Ascending
*
aorta

Dominant right ventricle

Coronary arteries
A B
FIGURE 3-32  Aortic atresia. A, Intraoperative photograph after sternotomy in patient with aortic atresia. Note the diminutive ascending
aorta (2 mm) versus pulmonary trunk. B, Angiographic image from different patient with aortic atresia. Note the filling of arteries to head
and neck through patent ductus arteriosus, with continuation of retrograde flow to fill the diminutive ascending aorta (*) and the coronary
arteries. (Modified from Wernovsky G, Dominguez TE, Gruber PJ, Anderson RH: Hypoplasia of the left heart. In Anderson RH, et al, editors:
Paediatric cardiology, ed 3, Philadelphia, 2010, Elsevier/Churchill Livingstone.)

Neoaorta
Modified
Blalock-Taussig
shunt Pulmonary
artery
Neoaorta
Pulmonary
Right artery
ventricle-pulmonary
artery shunt
FIGURE 3-33  Variations in shunt type for hypoplastic left
heart syndrome. Top, Classic right modified Blalock-Taussig shunt.
Bottom, Sano modification provides pulmonary blood flow through
right ventricle to pulmonary artery conduit. (From Ohye RG, et al.
N Engl J Med 362:1980-1992, 2010.)
lower PVR and result in a vicious cycle of systemic and cor-
onary steal; pulmonary overcirculation leads to ventricular
volume overload, which is not tolerated by the single right
ventricle. Limiting pulmonary blood flow by lowering Fio2
to 0.21, reducing minute ventilation to allow Paco2 in the 45
to 55–mm Hg range, and applying PEEP of 5 cm or more to
the lungs all serve to shunt blood away from the pulmonary
circulation and help to balance the Qp/Qs ratio toward 1:1.
Interestingly, after the stage I palliation, the pathophysiologic
Chapter 3  Congenital Heart Disease 121
PDA stent
Pulmonary
artery band
Pulmonary
artery band
Atrial
septal
stent
FIGURE 3-34  Hybrid palliative strategy for left-sided
hypoplasia. The stent in the PDA (patent ductus arteriosus)
provides unobstructed flow to the distal aorta, and the bands
placed on the right and left pulmonary arteries restrict the flow of
blood to the lungs. A catheter-based atrial septectomy is augmented
by implantation of a stent across the atrial septum, ensuring
adequate egress of pulmonary venous blood to the right atrium.
(Modified from Wernovsky G, Dominguez TE, Gruber PJ, Anderson RH:
Hypoplasia of the left heart. In Anderson RH, et al, editors: Paediatric
cardiology, ed 3, Philadelphia, 2010, Elsevier/Churchill Livingstone.)
considerations are similar to those in the preoperative period.
However, because the large PDA has been replaced by a
smaller shunt of 3 to 5 mm in diameter to provide pulmonary
blood flow, the swings in Qp/Qs are not as variable (Box 3-22).
After the stage I palliation (or hybrid approach), the goals of
anesthetic and critical care management are to achieve a Qp/Qs
as close to 1:1 as possible, with a combination of e­ levating PVR
and lowering SVR, using Fio2 and Paco2 to ­manipulate the pul-
monary circulation, and systemic vasodilators to manipulate
the SVR. Balanced Qp/Qs is usually heralded by Spo2 of 80%
BOX 3-22   n HYPOPLASTIC LEFT HEART SYNDROME
(HLHS)
HLHS results in aortic atresia or severe stenosis; systemic, brain,
and coronary blood flow depends on PDA.
Parallel circulation results in HLHS, with Qp/Qs highly variable in the
unrepaired state.
Excessive Fio2 and hyperventilation with lower PVR increase Qp/Qs and
result in systemic and coronary steal and cardiovascular collapse.
Neonatal palliation consists of aortic reconstruction with systemic-PA
shunt, RV-PA shunt, or hybrid procedure.
HLHS patients typically present for noncardiac surgery and continue
to have unstable physiology after stage I palliation.
 122 ANESTHESIA AND UNCOMMON DISEASES

Single ventricle

Complete mixing of systemic and pulmonary venous

blood at atrial and/or ventricular levels

Vasodilators
Oxygen delivery affected by HR Contractility
Hemoglobin
Pulmonary venous
(viscosity)
obstruction Preload
FIGURE 3-35 Single-ventricle pH & PCO2
pathophysiology. Complete mixing of Vasoconstrictors
Po2
Lung volume Afterload
systemic and pulmonary venous blood
occurs in the ventricle. Optimal oxygen SVR PVR Cardiac output
delivery involves a balance between
systemic vascular resistance (SVR) and
pulmonary vascular resistance (PVR)
and maintaining good cardiac output.
AV, Atrioventricular; HR, heart rate; Pco2, Excess pulmonary Inadequate pulmonary High Low
carbon dioxide partial pressure; Po2, blood flow blood flow cardiac output cardiac output
oxygen tension. ( PVR SVR) ( PVR SVR)

• Oxygen • Oxygen • High mixed venous • Low mixed venous

saturation  85% saturation  75% oxygen content oxygen content
• Decreased lung • Cyanosis • Oxygen • Oxygen
compliance saturation  80% saturation  80%
• Myocardial
• Hepatomegaly hypoxemia may • Good perfusion • Poor perfusion
produce low without
• Ventricular dilation • Lactic acidemia
cardiac output hepatomegaly,
• AV valve ventricular
regurgitation may dilation, or lactic
produce low acidemia
cardiac output

to 85% on low Fio2 and good systemic perfusion and normal BP
and HR for age. In addition, the single right ventricle often has
abnormal systolic and diastolic function and may have tricus-
pid regurgitation, so inotropic and lusitropic support is often
necessary. Maintaining hematocrit at 40% to 50% is important
to maximize O2 delivery. This circulation is very tenuous, and
despite early survival of 90% or better in many centers after
the Norwood stage I palliation, death may occur before stage
II in 10% to 15% of patients. This is thought to occur because
even minor perturbations in ventricular volume, O2 consump-
tion, or O2 saturation, as seen with upper respiratory infection
or gastroenteritis, may produce coronary ischemia or altera-
tions in Qp/Qs not tolerated by the patient. Cardiac arrest at
home or in the hospital may occur. In the HLHS patient the
period between stages I and II is often a critically unstable time.
Anesthesia for noncardiac surgery, such as feeding gastrostomy
tube, must be undertaken carefully with this pathophysiology.
Invasive monitoring and postoperative ICU admission is often
indicated. This stage is by far the most unstable, and any elec-
tive surgery is best postponed until after stage II repair.
Superior Cavopulmonary Anastomosis
After the second stage, or superior cavopulmonary anas-
tomosis, the SVC is connected to the PA and the shunt or
RV-PA conduit is taken down. This is the only source of pul-
monary blood flow in HLHS (Fig.  3-36). The volume load
on the ventricle is significantly reduced, systolic and diastolic
ventricular function improves, and the Qp/Qs ratio is below
1:1 and much less variable. SpO2 is in the 75% to 85% range,
and the physiology changes significantly in that the blood flow
is now a cardio-cerebro-pulmonary circulation. This occurs
because the cerebral blood flow is the main determinant of
SVC blood flow, which in turn is the main influence on pul-
monary blood flow. The large brain of the young infant rela-
tive to the rest of the body means that reducing the cerebral
blood flow with hyperventilation to lower Paco2 will signifi-
cantly decrease pulmonary blood flow and thus oxygenation.
The goal is to increase cerebral blood flow by allowing a Paco2
of 40 to 45 mm Hg, thus improving pulmonary blood flow and
oxygenation.110,111 (Box 3-23).
BOX 3-23   n PHYSIOLOGY AFTER BIDIRECTIONAL
CAVOPULMONARY ANASTOMOSIS (BCPA)
The SVC is connected to the right PA, resulting in a cerebral-
pulmonary-cardiac circulation.
Hyperventilation will decrease cerebral blood flow and SVC and PA
flow and will lead to arterial desaturation.
BCPA circulation is relatively stable, and elective noncardiac surgery
is often performed between the BCPA and Fontan stages in single-
ventricle patients.
 Chapter 3  Congenital Heart Disease 123

tolerated. The Fontan circulation may include the presence of

a fenestration between the Fontan circuit and the atrium; the
Reconstructed patient's baseline SpO2 with a fenestration is often 85% to 94%
outflow from but without a fenestration should be 95% or higher (Box 3-24).
right ventricle to
aortic pathways
Superior
TRICUSPID ATRESIA
cardiopulmonary Tricuspid atresia is another common form of single ventricle.
shunt The tricuspid valve has not formed, and instead a platelike
obstruction occurs between the right atrium and right ven-
tricle, resulting in a very small right ventricle112,113 (Fig. 3-37).

BOX 3-24   n PHYSIOLOGY AFTER FONTAN COMPLETION

The Fontan operation completes the total cavopulmonary anastomosis.

A single systemic ventricle, with no pulmonary ventricle, is the result.
Blood flow to the lungs depends on negative intrathoracic pressure
during spontaneous respiration.
Positive-pressure ventilation significantly compromises systemic venous
return to the lungs and should be minimized in Fontan patients.
Fontan patients are intolerant of low preload, and CVP monitoring to
achieve high-normal preload is important during major noncardiac
surgery.

FIGURE 3-36  Hypoplastic left heart syndrome after second

stage of palliation. Outflow from right ventricle has been
reconstructed during neonatal surgery, and now the superior
cavopulmonary anastomosis has been performed at age 3 to a c
6 months. (Modified from Wernovsky G, Dominguez TE, Gruber PJ, A
Anderson RH: Hypoplasia of the left heart. In Anderson RH, et al, PD
editors: Paediatric cardiology, ed 3, Philadelphia, 2010, Elsevier/
Churchill Livingstone.)

Fontan Completion
Physiology after the Fontan completion (total cavopulmonary
anastomosis) again undergoes significant changes. With a total
cavopulmonary connection, there is no pulmonary ventricle, ASD
only a tube outside or inside the heart passively carrying blood VSD
into the lungs. Blood flow depends on passive flow, which is
augmented by negative intrathoracic pressure. This depen- RV
dence on negative intrathoracic pressure is made possible with
spontaneous respiration, which is why positive-pressure ven-
tilation is often not well tolerated in the Fontan circulation.
Minimizing positive pressure and allowing spontaneous res-
piration, as well as extubating the trachea as early as possible
after any anesthetic, are important principles in the anesthetic
management of the patient with a Fontan circulation. During
anesthesia with positive pressure, volume loading is usually
necessary to bring CVP to the 12 to 15–mm Hg range, to com- FIGURE 3-37  Tricuspid atresia. Heart specimen illustrating a
pensate for the increased intrathoracic pressure and promote common variant of tricuspid atresia type IIc: d-transposition of
the great arteries associated with coarctation of the aorta (c),
blood flow into the lungs. Hypovolemia is not well tolerated
hypoplasia of the aortic arch (a), patent ductus arteriosus (PDA),
during major surgery in the Fontan patient. Other important
small ventricular septal defect (VSD), and hypoplasia of the right
considerations in the Fontan circulation are ventricular dys- ventricle (RV). Note the adequate atrial septal defect (ASD).
function or A-V valve regurgitation. Either defect will elevate (From Rosenthal A, Dick M: Tricuspid atresia In Emmanouilides GC,
the ventricular end-diastolic or atrial pressure, which decreases Riemenschneider TA, Allen HD, Gutgesell HP, editors: Moss and
the transpulmonary pressure gradient and thus pulmonary Adams heart disease in infants, children, and adolescents: including
blood flow and systemic CO. Arrhythmias are often poorly the fetus and young adult, Baltimore, 1995, Williams & Wilkins.)
 124 ANESTHESIA AND UNCOMMON DISEASES
Flow through the right ventricle to the pulmonary artery
depends on the presence of a large atrial communication for
RA-to-LA flow, then a VSD for LV-to-RV flow, which allows
PA blood flow. Surgical intervention in the neonatal period
depends on the amount of obstruction to pulmonary blood flow.
Tricuspid atresia is often accompanied by pulmonary atresia, in
which case a PDA is necessary before surgery, which involves
a systemic-to-pulmonary arterial shunt. Significant pulmonary
stenosis is treated similarly. Some patients have mild to moder-
ate pulmonary stenosis, resulting in a well-balanced circulation
and adequate SpO2 of 80% to 90%, and require no intervention
in the neonatal period. Those patients with no obstruction to
pulmonary blood flow have high SpO2 (>90%). These patients
develop pulmonary overcirculation and may develop steal from
the systemic circulation as PVR decreases over the first several
weeks of life, which may require PA banding in the first month.
Later management for the bidirectional cavopulmonary con-
nection and Fontan operation is similar to that for HLHS. The
major difference with tricuspid atresia is that the systemic left
ventricle is much more tolerant of the volume load before and
after stage II palliation; patients with tricuspid atresia are much
less tenuous than those with HLHS.
Other variants of functional SV patients include those
with unbalanced complete A-V canal. In these lesions, either
the right or the left ventricle is too small to allow septation of
the heart. Neonatal management depends on the degree of
pulmonary blood flow, as for tricuspid atresia. The cavopul-
monary connection and Fontan operations are performed at
the same time.
Coronary Artery Anomalies
Coronary artery anomalies that can complicate anesthetic care
include anomalous origin from aorta (AAOCA), anomalous
left coronary artery (LCA) arising from the pulmonary artery
(ALCAPA), and anomalous right coronary artery (RCA) aris-
ing from the pulmonary artery (ARCAPA).114
In AAOCA, the most common variants include the anom-
alous origin of the RCA from the left aortic sinus and the
anomalous origin of the LCA or its branches from the right
aortic sinus. These anomalies can present with angina, exer-
tional angina, CHF, syncope, and sudden death. Anomalous
coronary arteries arising from the aorta that course in between
the aorta and pulmonary artery are most frequently associ-
ated with death. This is thought to result from compression of
the coronary artery between the two great vessels, with result-
ing ischemia. The compression is usually during exercise.
However, the AAOCA that does not take this course can also
be associated with symptoms. These lesions include acute-
angle takeoff of a single coronary trunk with a valvelike ridge,
concomitant atherosclerosis, and intramural and oblique
coronary origins.114 Surgical repair is often accomplished by
unroofing the intramural segment of the anomalous coronary
and creating a neo-ostium in the correct sinus of Valsalva.115
Anesthetic considerations include maintenance of adequate
coronary perfusion pressure for the abnormal coronary
circulation and avoidance of sympathetic stimulation, disten-
tion of the great vessels, increased PAP, and increased CO.116
Anomalous origin of the LCA from the PA is a rare con-
genital heart defect that occurs in 1 per 300,000 live births.
ALCAPA is most often diagnosed in infancy, and the mortal-
ity of untreated ALCAPA is greater than 85% in the first year
of life. ALCAPA is one of the most common causes of myo-
cardial ischemia and infarction in children. The anomalous
coronary artery arises from the PA. As PAP decreases after
birth, collaterals form from the RCA to the LCA. Coronary
steal can occur from runoff from the LCA into the PA, creat-
ing ischemia.117 Collateral coronary circulation develops from
the RCA system to provide oxygenated blood to the myocar-
dium in LCA territory118 (Fig 3-38).
Infants with ALCAPA frequently present with global myo-
cardial dysfunction and symptoms of ischemia, including
tachypnea, diaphoresis, and fussiness with feeding. A smaller
percentage of patients with ALCAPA present in adolescence
or adulthood with ventricular dysrhythmias, shortness of
breath or angina on exertion, murmur or symptoms of mitral
insufficiency due to papillary muscle infarction, and sudden
death. The ECG may reveal ST-segment or T-wave changes
and Q waves indicative of infarction. The diagnosis is pri-
marily made by echocardiogram with a coronary artery aris-
ing from the pulmonary trunk with retrograde flow into the
PA. The RCA may be dilated as it supplies the LCA system
through collaterals (Box 3-25).
Right coronary
artery from
Left coronary aorta
artery from Collateral
pulmonary flow
trunk
FIGURE 3-38  Anomalous left coronary artery from pulmonary
artery. Arrangement when left coronary artery takes anomalous
origin from pulmonary trunk. Arrows show direction of collateral
circulation from branches of the right coronary artery to those
of the left coronary artery. Dotted lines indicate enlarged
collateral connections. (Modified from Friedman AH, Silverman
NH: Congenital anomalies of the coronary arteries. In Anderson
RH, et al, editors: Paediatric cardiology, ed 3, Philadelphia, 2010,
Elsevier/Churchill Livingstone.)

BOX 3-25   n ANOMALOUS LEFT CORONARY ARTERY
FROM THE PULMONARY ARTERY
ALCAPA results in myocardial ischemia and infarction in infants as
PVR declines and coronary flow to the LV reverses.
Dilated cardiomyopathy ensues; ALCAPA must be ruled out in infants
with DCM.
With unrepaired ALCAPA, maintaining elevated PVR with low Fio2
and hypercapnia are important to elevate PA pressure, raise left
coronary pressure, and minimize steal into the PA.
Anomalous origin of the RCA from the PA is less common
than ALCAPA and is generally less symptomatic. Because the
RCA mainly supplies the right ventricle, and because coronary
blood flow to the right ventricle occurs during both systole and
diastole and RV pressures are lower in comparison to LV pressures,
ARCAPA does not cause myocardial ischemia to the same degree
as ALCAPA. The delicate balance between myocardial O2 supply
and demand, however, can be upset perioperatively by overzealous
fluid administration or an increase in myocardial work.
Both ALCAPA and ARCAPA should be considered periop-
eratively when myocardial ischemia is encountered, especially
in children or adolescents.119 When high Fio2 is administered
and Paco2 in the blood is decreased because of increased min-
ute ventilation, PAP falls. This decrease in PAP increases the
runoff of blood through the collateral system from the coro-
nary artery with aortic origin, resulting in ischemia. Increased
myocardial O2 demand from tachycardia or increased volume
load can further exacerbate the problem. The ECG can show
signs of ischemia, and pulmonary edema and low CO from
acute LV dysfunction can also occur.
Treatment of ALCAPA and ARCAPA is indicated to pre-
vent global myocardial dysfunction in symptomatic individu-
als. However, even when asymptomatic PA origin of a coronary
artery is encountered, treatment is often recommended. Both
asymptomatic ALCAPA patients and ARCAPA patients are at
increased risk of sudden death, as well as becoming symptom-
atic over time.120 Surgical treatment may include ligation of the
anomalous coronary, allowing the whole myocardium to be sup-
plied through the normal coronary and collateral flow. More
often, the anomalous coronary is transferred from the PA to the
aorta. When this is not possible due to the position of the origin
of the coronary from the pulmonary artery, a transpulmonary
tunnel can be constructed to create an aortocoronary fistula, the
Takeuchi repair. The ligation of the anomalous coronary creates
a one-coronary system. Mortality rates range from 20% to 50%
after ligation of an ALCAPA, with a 25% incidence of late sudden
death. For this reason, coronary artery transfer and Takeuchi
repair are preferred. In patients with unrecoverable ventricular
dysfunction, cardiac transplantation may be an option.114
Anesthesia for repair of an anomalous coronary artery with
PA origin should focus on the prevention of myocardial isch-
emia before CPB. Care should be taken during induction and the
prebypass period to avoid myocardial depressants and to main-
tain systemic BP and coronary perfusion pressure to the normal
coronary artery. In addition, increased afterload and tachycardia,
Chapter 3  Congenital Heart Disease 125
increased myocardial O2 demand, and decreased myocardial
O2 supply should be avoided. Maintenance of normal PAP by
avoiding pulmonary vasodilators such as hypocapnia and high
Fio2 minimizes coronary steal from the normal coronary artery
through collateral flow. It is important to recognize that LV func-
tion may be even worse after the heart is reperfused. Typically,
significant inotropic support is required, and ECMO support
or ventricular assist device placement may be necessary while
ventricular function improves.121 Even after repair and recov-
ery, patients with coronary artery anomalies may have ongo-
ing ventricular dysfunction from myocardial scarring caused by
infarction before repair. Careful evaluation is necessary in these
patients before subsequent anesthetic procedures.
Regurgitant Valvar Lesions
Regurgitant valvar lesions are seen in many children with
congenital and acquired cardiac disease and include aor-
­
tic insufficiency, mitral regurgitation, pulmonary regurgi-
tation, and tricuspid regurgitation. Some of these lesions
are c­ongenital, but many are the residual results of surger-
ies or catheter interventions to correct valvular stenosis, are
acquired after ventricular dilation secondary to some other
underlying condition, or result from infectious endocarditis
or rheumatic heart disease. Echocardiography is the mainstay
of anatomic diagnosis, but cardiac MRI is increasingly used to
follow patients over time and to calculate accurate regurgitant
fractions to assist with timing of surgery.
In general, regurgitant lesions on the right side are tolerated
much better than those of the left side of the heart. Pulmonary
and tricuspid regurgitation normally result in few symptoms
unless severe. Increased RV impulses from the increased
chamber volume and a soft diastolic murmur at the left or
right sternal border are common findings. Over time, the right
ventricle and right atrium dilate, and symptoms of right-sided
heart failure can ensue, although this often requires years to
manifest. Arrhythmias, often atrial but sometimes ventricu-
lar, can also result from the dilated cardiac chambers. Surgical
repair or replacement of the pulmonic valve to restore normal
function halts the progression of ventricular dilation and over
time results in remodeling toward normal RV configuration.
Tricuspid valve repair is often pursued in infants and children;
even if there is a small degree of residual insufficiency, this
is well tolerated. Most patients with tricuspid or pulmonary
regurgitation tolerate general anesthesia for noncardiac proce-
dures without difficulty. Anesthetic goals are to promote for-
ward flow through the right side of the heart by maintaining
sinus rhythm and normal to high HR to minimize the diastolic
runoff time, maintain normal volume status, and avoid condi-
tions leading to pulmonary hypertension.
Aortic insufficiency (AI) may be fairly well tolerated if mild
to moderate, and if the patient's physiology has had time to
compensate for the increased volume load on the left ventri-
cle. A very active precordium with displaced LV apex is usu-
ally observed, and the patient's peripheral pulses are bounding
from the widened pulse pressure caused by low diastolic
 126 ANESTHESIA AND UNCOMMON DISEASES

pressure due to the diastolic runoff. The left ventricle will Vascular Rings
dilate, with minimal hypertrophy if there is no accompanying
Vascular rings comprise many different anatomic variations,
­aortic stenosis. The LV end-diastolic volume increases, with-
most all of which result from the abnormal regression of the
out much increase in LV pressure, or LA pressure, until late in
developing aortic arch. The double aortic arch represents
the course of the disease. Severe AI is often not well tolerated
about 60% of vascular rings and results from persistence of the
because the continuous diastolic runoff steals significant flow
embryonic fourth arch.117 The right aortic arch with aberrant
from the coronary and systemic circulation. This can result in
left subclavian artery is the next most common arrangement.
acute decompensation and ventricular fibrillation and may be
Symptoms usually include respiratory distress, stridor, or feed-
seen in cases of rapidly progressive aortic valve endocarditis.
ing difficulties caused by compression of the trachea, bronchi,
Resuscitation, mechanical support, and emergency surgery to
or esophagus from the aberrant structure. Diagnosis is often
replace the aortic valve are lifesaving.
delayed because of the common nature of these symptoms in
Mitral regurgitation results in LA hypertension and may
infants. In the modern era, CT angiography or MRI is the diag-
result in pulmonary venous hypertension and congestion,
nostic study of choice122 (Fig.  3-40). Surgery usually involves
leading to pulmonary interstitial edema and respiratory
a left thoracotomy to ligate and divide the smaller aortic arch
symptoms86 (Fig.  3-39). Anesthetic goals in both aortic and
in the case of double arch or the ligamentum arteriosum in
mitral regurgitation are similar: afterload reduction to pro-
the case of right arch with aberrant left subclavian artery. The
mote greater forward ejection of the stroke volume; sinus
encircling ring is divided in both cases. Recovery is usually
rhythm that is normal or high-normal to avoid prolongation
uneventful, although symptoms may not resolve immediately
of diastolic regurgitant time; and maintaining normal ven-
if tracheobronchomalacia accompanies the vascular ring.
tricular filling. In the case of severe acute AI with very low
diastolic BP and myocardial ischemia, elevation of coronary
perfusion pressure with vasoconstricting agents is important
OTHER CARDIAC DISEASE
(Box 3-26).
Pulmonary Hypertension
Pulmonary hypertension (PH) is a component of many con-
BOX 3-26   n  REGURGITANT VALVAR LESIONS
genital heart diseases and pediatric cardiac syndromes. The
Aortic, mitral, pulmonic, or tricuspid insufficiency (or regurgitation) definition of PH is mean pulmonary artery pressure (PAP) of
may be seen in isolation or as a component of more complex 25 mm Hg at rest or 30 mm Hg during exercise. A widely used
lesions. and practical clinical definition in CHD is a systolic PAP that
Severe aortic insufficiency is the most problematic because of low
is more than 50% of the systemic systolic pressure. Further
diastolic pressure causing coronary insufficiency.
Mitral regurgitation can cause pulmonary hypertension if severe. complicating this definition are SV patients with cavopulmo-
Pulmonary and tricuspid insufficiency are usually relatively well nary connections, in whom the absolute PAP may not be ele-
tolerated unless severe or long-standing. vated, but PVR may be elevated enough to impair pulmonary
Hemodynamic goals for regurgitant lesions are to reduce afterload, blood flow. This important distinction between PVR and PAP
maintain preload, and achieve high-normal heart rates to minimize
is evident when examining the equation calculating PVR:
diastolic time.
PVR = PAP − LAP/Qs

FIGURE 3-39 Mitral
regurgitation. Cross-sectional
LA
image (left) and color Doppler
display (right) in patient
with dysplastic mitral valvar
regurgitation. There is poor
coaptation of the leaflets
(arrow), with a large central
jet of regurgitation. LA, Left
atrium; LV, left ventricle.  (From
Smallhorn JF, Anderson RH:
Anomalies of the morphologically
mitral valve. In Anderson
RH, et al, editors: Paediatric
cardiology, ed 3, Philadelphia,
2010, Elsevier/Churchill
Livingstone.) LV
 Chapter 3  Congenital Heart Disease 127

RCCA RSA
LCCA
Trachea
Right
aortic
LSA arch Right Left
aortic aortic
arch arch

LPA
Esophagus
Left
aortic
arch

A B

Left
Right aortic
aortic arch
arch LPA

FIGURE 3-40  Complete double arch. A and B, Computed tomograms are seen from behind and above and from below. The double
arch encircles the trachea and esophagus, with the right arch dominant. LPA, Left pulmonary artery. C, Reformatted image in coronal plane
shows narrowing of trachea from compression by dominant right aortic arch. Trachea is slightly bent to the left. LSA, Left subclavian artery;
LCCA, left common carotid artery; RCCA, right common carotid artery; RPA, right pulmonary artery; RSA, right subclavian artery.  (Modified
from Yoo S, Bradley TJ: Vascular rings, pulmonary arterial sling, and related conditions. In Anderson RH, et al, editors: Paediatric cardiology, ed
3, Philadelphia, 2010, Elsevier/Churchill Livingstone.)

where blood flow through the lungs, or Qp, is exquisitely sen-
sitive to the transpulmonary pressure gradient, or PAP–left
atrial pressure (LAP). This is because the single functional
ventricle often has impaired systolic and diastolic function,
A-V valve regurgitation, and volume overload.
In pediatric and congenital cardiac and pulmonary dis-
eases, PH and anesthetic considerations and goals can be cat-
egorized into the following eight major categories, in order of
severity of pathophysiology:
1. Congenital heart disease with two ventricles and large
left-to-right shunt.123 These patients by definition develop
PH because of equal pressures in the left and right ven-
tricles, although PAP is elevated. If the patient is a young
infant, sudden decreases in PVR with high Fio2 and hyper-
ventilation are more of a threat than sudden PH crisis with
suprasystemic PAP and right-to-left shunting. The goals of
the anesthetic, as previously noted for L-R shunts, are to
balance the PVR and SVR, and use oxygen judiciously to
prevent a large increase in L-R shunt. As time passes, PH
becomes more severe and reactive, and these patients are
at risk for a PH crisis, which may be life threatening. These
crises are usually caused by inadequate anesthetic level or
an airway problem leading to hypercarbia or hypoxemia.
2. Lung hypoplasia with decreased surface area and num-
ber of small airways. This leads to elevated mean PAP
from structural deficiency of small pulmonary arterioles.
This condition is most often seen with bronchopulmonary
dysplasia (BPD), seen in former premature infants with sig-
nificant lung injury from respiratory distress syndrome of
the premature infant, with lung damage from immaturity,
lack of surfactant, infection, inflammation, and oxygen
 128 ANESTHESIA AND UNCOMMON DISEASES
and ventilator toxicity. Another condition associated with
PH from lung hypoplasia is congenital diaphragmatic her-
nia (CDH).124 These infants and young children tend not
to have overreactive pulmonary vasculature and usually
have no intracardiac shunting. Anesthetic goals include
adequate oxygenation with higher levels of Fio2 and mild
hyperventilation to achieve pulmonary vasodilation.
3. Congenital heart disease with a single functional ven-
tricle. As noted, even mild elevations in PAP and PVR
can significantly impede pulmonary blood flow and oxy-
genation.125 These patients should have judicious oxygen-
ation and careful afterload reduction. If the patient has
undergone a cavopulmonary connection, hyperventilation
is counterproductive, particularly after the bidirectional
Glenn anastomosis. This will decrease cerebral blood flow,
and because the brain is connected to the PA through the
SVC, this will decrease pulmonary blood flow and thus
oxygenation. The SV patient with elevated PVR and PAP
should be managed with high Fio2 and pulmonary vasodi-
lators (e.g., iNO).
4. Pulmonary hypertension of the newborn.126 This is
restricted to the immediate neonatal period, when
­significantly elevated PVR and PAP does not decrease
after birth. The transitional circulation (persistent fetal
circulation) remains, with high RV and PA pressures,
leading to R-L shunting at the PFP and PDA levels,
causing severe cyanosis and respiratory distress. These
patients need hyperoxygenation and hyperventilation,
treatment of metabolic acidosis, inotropic support, and
inhaled NO; if all these measures fail, ECMO should be
instituted.
5. Pulmonary hypertension secondary to left ventricu-
lar dysfunction. Patients with primary myocardial dys-
function, such as dilated cardiomyopathy, or other cause
of LV dysfunction (e.g., coronary artery anomaly) can
develop secondary PH from elevated LV end-diastolic
pressure, causing LA, pulmonary venous, and PA hyper-
tension. In addition, biventricular dysfunction with RV
disease is often present, meaning that the elevation in
PAP and PVR will significantly inhibit pulmonary blood
flow. Anesthetic goals include judicious management of
intravascular volume status to reduce preload as low as
possible, inotropic support and afterload reduction for
both left and right ventricles, and adequate oxygenation
and mild hyperventilation to reduce PVR. Pulmonary
vasodilators (e.g., iNO) are often effective.
6. Idiopathic pulmonary hypertension. These patients are
actually a minority of patients in the pediatric age group.
If PAP is elevated above systemic arterial pressure, these
patients pose a high anesthetic risk for cardiac arrest and
death. Many of these patients will have a PFO or a cre-
ated ASD to allow R-L shunting as a pressure popoff dur-
ing periods of PH above baseline, so CO is preserved at
the cost of increasing arterial desaturation. Preoperative
treatment with an effective long-term pulmonary vasodila-
tor regimen will significantly reduce the risk of anesthetic
complications. Anesthetic goals include hyperoxygenation
and hyperventilation, maintaining SVR, understanding the
degree of PA reactivity in the patient, and having iNO and
resuscitation medications available.
7. Pulmonary venous obstruction. There is a mechanical
obstruction to pulmonary blood flow; TAPVR, recurrent
pulmonary vein obstruction, and cor triatriatum are the
most common examples. Before correction, hyperventila-
tion, hyperoxygenation, and pulmonary vasodilators (e.g.,
iNO) will only worsen pulmonary interstitial and alveolar
edema and ventilatory mechanics. The primary anesthetic
goal is to support ventilation without increasing pul-
monary blood flow further by judiciously choosing Fio2
and ventilation strategies. Repairing the obstruction will
remove the mechanical cause, but often these patients have
long-standing, reactive PH.
8. Eisenmenger's syndrome. As previously noted, long-
standing L-R shunting in CHD patients can lead to long-
term increased flow and shear stress in the pulmonary
arterioles. This leads to proliferation of smooth muscle and
of intima in these small arterioles, which in turn can lead
to intravascular thrombosis and permanent occlusion127,128
(Fig.  3-41). The PH is fixed and irreversible, and PAP is
higher than systemic pressures for a significant portion of
the cardiac cycle, leading to reversal of the shunt to right to
left, causing progressive cyanosis.129 In the modern era these
patients are encountered less often, and long-term pul-
monary vasodilator therapy, such as phosphodiesterase-5
inhibitors, endothelin antagonists, and prostacyclins, have
improved both symptomatology and longevity in these
patients. Anesthetic goals include determining the neces-
sity of the anesthesia and discussing risk/benefit with the
patient and family. Hyperoxygenation, hyperventilation,
maintaining SVR, and having iNO and resuscitation medi-
cations available are all important considerations.
Other causes of PH seen in smaller groups of patients
include sickle cell disease and severe obstructive sleep
apnea (OSA).130
During preanesthetic evaluation, the degree of PH should
be determined by the anesthesiologist. A useful functional
scheme grades the degree of resting PH as mild if the PAP is
50% to 75% of systemic pressure, moderate if it is 75% to 100%
systemic, and severe if the PAP is suprasystemic. In addition, it
is important to understand the reactivity of the PH to O2 and
iNO and other pulmonary vasodilators.131 The patient's symp-
tomatology is important, with exercise intolerance the classic
symptom of PH. The 6-minute walk distance is the conven-
tional measure of the functional degree of PH. Finally, it is
important to understand the patient's medication regimens,
particularly with regard to pulmonary vasodilator therapy.132
The pathophysiology of a PH crisis begins with elevated
baseline PAP and an inciting stimulus, such as sudden cat-
echolamine release from inadequate anesthesia or analge-
sia. Hypoxemia, metabolic acidosis, and hypercarbia are also
important stimuli, because they also lead to catecholamine
 Chapter 3  Congenital Heart Disease 129

Pulmonary
artery

Endothelial
cells
Vessel
lumen Endothelin Nitric oxide Prostacyclin
pathway pathway pathway

Pre-proendothelin Proendothelin Arachidonic Prostaglandin I2

acid
L-arginine L-citrulline Smooth
muscle
Endothelin Endothelin-1 Prostacyclin cells
receptor A (prostaglandin I2)
Nitric oxide
Endothelin
receptor B
cAMP
– –
– + –
cGMP
Endothelin Prostacyclin
receptor Phosphodiesterase derivatives
antagonists type 5 Exogenous
nitric oxide Vasodilation
Vasoconstriction –
and
and antiproliferation
proliferation Phosphodiesterase
type 5 inhibitor

Vasodilation and antiproliferation

FIGURE 3-41  Pathophysiology of pulmonary hypertension leading to Eisenmenger's syndrome. Diagram shows three major
pathways involved in abnormal proliferation and contraction of the smooth muscle cells of the pulmonary artery corresponding to
important therapeutic targets in pulmonary hypertension. These help determine which of four classes of drugs will be used: endothelin
receptor antagonists, nitric oxide, phosphodiesterase type 5 inhibitors, or prostacyclin derivatives. At top of figure, a transverse section
of a small pulmonary artery (<500 μm in diameter) from a patient with severe pulmonary arterial hypertension shows intimal proliferation
and marked medial hypertrophy. Dysfunctional pulmonary artery endothelial cells (blue) have decreased production of prostacyclin and
endogenous nitric oxide, with an increased production of endothelin-1, a condition promoting vasoconstriction and proliferation of smooth
muscle cells in pulmonary arteries (red). Current or emerging therapies interfere with specific targets in pulmonary artery smooth muscle
cells. Prostacyclin derivatives and nitric oxide also have antiplatelet effects. Plus signs denote an increase in intracellular concentration;
minus signs indicate blockage of a receptor, inhibition of an enzyme, or a decrease in intracellular concentration. cAMP, Cyclic adenosine
monophosphate; cGMP, cyclic guanosine monophosphate.  (Modified from Humbert M, Sitbon O, Simonneau G: N Engl J Med 351:1425-
1436, 2004.)

release and have direct pulmonary vasoconstrictive effects.
A rapid increase in PAP and PVR occurs, leading to acute
RV failure and R-L shunting through any intracardiac or
extracardiac communications. This leads to further hypox-
emia, with an acute decrease in pulmonary blood flow and
reduced blood return to the left ventricle. Coronary ischemia
ensues, leading to acute decrease in LV function. This con-
dition further exacerbates the hypoxemia, hypercarbia, and
acidosis and creates a vicious cycle that can lead to cardiac
arrest and death (Fig. 3-42). Important clinical signs include
arterial desaturation, hypotension, bradycardia, and difficulty
with ventilation. If echocardiography is available, acute RV
dysfunction is evident with right-to-left displacement of the
interventricular septum caused by RV hypertension.
Treatment of a PH crisis includes the simultaneous insti-
tution of hyperoxygenation and hyperventilation, increasing
the depth of anesthesia (synthetic opioids such as fentanyl
are effective);133 intravascular volume infusion to support
RV ouput, inotropic support for both ventricles, support-
ing SVR, and finally a selective pulmonary vasodilator
 130 ANESTHESIA AND UNCOMMON DISEASES
Baseline PH:
mPAP >25 mm Hg
or > 50% systemic
FIGURE 3-42  Pathophysiology of pulmonary
hypertensive crisis. Patient with baseline
pulmonary hypertension (PH) experiences a
stimulus that rapidly increases pulmonary artery
pressure (PAP) and pulmonary vascular resistance
(PVR), leading to a vicious cycle of right-sided heart
failure, right-to-left shunting, further hypoxemia,
hypotension, and low cardiac output (CO). If not
interrupted, this crisis can lead to cardiac arrest.
mPAP, Mean PAP.
(iNO is first choice).134,135 If cardiac arrest ensues, standard
cardiopulmonary resuscitation (CPR) is instituted. Because of
the high incidence of inability to restore a perfusing rhythm,
ECMO may be needed (Box 3-27).
Essentially any anesthetic regimen may be used in patients
with PH, because most will maintain or lower PAP and PVR.
The halogenated anesthetics are mild pulmonary vasodilators,
but with PPV. Qp/Qs is largely unchanged in infants and chil-
dren with L-R shunts.6 Fentanyl and midazolam also have no
effect on Qp/Qs. Propofol will reduce SVR without changing
PVR; therefore L-R shunt decreases in these patients.11 In the
absence of hypoxemia or hypercarbia, ketamine has little effect
on PVR and L-R shunting.19 Etomidate also does not produce
significant change in Qp/Qs or pulmonary hemodynamics in
patients with L-R shunts.136 Dexmedetomidine decreases PAP
and Qp/Qs pressure ratio in children after cardiac surgery,
thus potentially increasing Qp/Qs in patients with unrepaired
L-R shunts.137
BOX 3-27   n  PULMONARY HYPERTENSION (PH)
Systemic or suprasystemic PH confers high anesthetic risk.
Preanesthetic treatment with pulmonary vasodilators significantly
reduces risk.
Avoidance of light anesthesia, hypoxemia, and hypercarbia is the
cornerstone in prevention of PH crises.
Pulmonary hypertensive crisis is heralded by hypoxemia, hypotension,
and bradycardia with possible cardiac arrest and death.
Hyperoxia, hyperventilation, fentanyl analgesia, volume infusion,
inotropic support, and inhaled nitric oxide are instituted
simultaneously during a PH crisis.
Hypoxia,
hypercarbia,
acidosis,
sympathetic Rapid increase
stimulation PAP and PVR
Cardiac arrest
and death
Myocardial ischemia,
low CO, increased Right-heart failure,
airway resistance R-to-L shunting,
further hypoxia
Patients with PH are at much greater risk for adverse events
with anesthesia. Studies of noncardiac anesthetics and cardiac
catheterization anesthetics indicate that cardiac arrest is 40 to
211 times more likely and death 49 to 358 times more likely in
children with PH, versus children without PH.138–140 Therefore,
careful evaluation and planning, with immediately available
backup expertise and treatment modalities (e.g., iNO, ICU
care) must be available to these patients.141
Dilated Cardiomyopathy and Myocarditis
A number of entities, both congenital and acquired, produce
a dilated, poorly functioning left (and often right) ventricle in
children, posing a significant challenge for the anesthesiolo-
gist. These may be chronic familial conditions, such as sar-
comeric protein mutations, cytoskeletal gene mutations, or
mitochondrial myopathies.88 Additional acute causes include
viral myocarditis and Kawasaki's disease. Chronic acquired
causes include anthracycline cardiotoxicity. Still other idio-
pathic causes include LV noncompaction. Common patho-
physiologies include a dilated, poorly functioning left ventricle
with low ejection fraction, at times less than 10% (Fig. 3-43).
The LV end-diastolic volume is massively increased, which is
necessary to maintain a stroke volume compatible with mini-
mal CO and greatly depressed EF (5%-25%). Mitral regurgita-
tion is a common feature from dilation of the mitral annulus,
and LA hypertension (with interstitial edema) and PH are
common sequelae. Tachycardia is often present as a compen-
satory mechanism, and atrial and ventricular arrhythmias are
often observed because of the abnormal myocardium and
dilated chamber sizes. The dilated cardiac chambers and slow

FIGURE 3-43 Cardiomyopathy. Four-chamber echocardiogram of
11-month-old infant with dilated cardiomyopathy secondary to left
ventricular noncompaction. Note the severely dilated left ventricle;
ejection fraction is 19%.
flow of blood predispose these patients to thromboembolic
complications.
Diagnosis of dilated cardiomyopathy (DCM) or myocardi-
tis is primarily by echocardiography; cardiac enzymes such as
troponin levels are also important. Chest radiography reveals
dilated cardiac silhouette and varying degrees of increased
pulmonary vascular markings. Medical management includes
treating all possible underlying causes, diuretic therapy to
reduce pulmonary congestion, ACE inhibitors and angioten-
sin receptor blockers to minimize effects of activation of renin-
angiotensin-aldosterone system, and β-blockers to counteract
the effects of excess sympathetic activity. Anticoagulation
and antiarrhythmic therapies are often used. In severe cases
unresponsive to medical therapy, ventricular assist devices are
used, occasionally as a bridge to myocardial recovery, but most
often as a bridge to cardiac transplantation, which is the ther-
apy for end-stage disease (Box 3-28).
Anesthetic considerations for DCM patients are complex
and involve a thorough understanding of the patient's current
status with the latest echocardiographic data. These patients
are exquisitely sensitive to cardiac preload, prolonged fast-
ing, and hypovolemia. Agents that rapidly reduce preload,
such as large doses of propofol, should be avoided. Normal
sinus rhythm should be maintained if possible, and afterload
should be kept normal or low. Ventricular function should be
preserved by avoiding large doses of volatile anesthetics and
Chapter 3  Congenital Heart Disease 131
BOX 3-28   n DILATED CARDIOMYOPATHY (DCM) AND
MYOCARDITIS
Patients with DCM have greatly increased LVEDV with reduced EF
(5%-25%).
Stroke volume is exquisitely sensitive to preload; coronary perfusion
is very sensitive to adequate afterload.
Mitral regurgitation, LA hypertension, and PH often result.
Positive-pressure ventilation (PPV) often improves LV function by
lowering wall tension.
Anesthetic regimens must avoid myocardial depression and
decreases in preload and afterload.
initiating inotropic support early if lower-than-baseline CO
is anticipated. PH should be approached with care to prevent
sudden PVR increases. Drugs and devices to treat arrhyth-
mia should be readily at hand. In the severely affected patient,
surgical backup to provide ECMO support should be consid-
ered. In a recent series of 34 general anesthetics for noncardiac
surgery in 26 patients with DCM, 61% experienced hypoten-
sion requiring inotropic support, two patients had significant
arrhythmia, two needed ECMO within 30 days of the proce-
dure, and one died.142 In a registry of 127 patients with car-
diac disease in cardiac arrest during anesthesia, DCM patients
accounted for 13% of arrests; however, 50% of these patients
could not be resuscitated, making DCM the single worst lesion
for successful resuscitation in this series.41
Pericardial Effusion and Tamponade
Pericardial effusion can result from bleeding postopera-
tively, infection, inflammatory conditions, thrombus, CHF,
trauma, malignancy, postpericardiotomy syndrome, and
many other causes.117 Cardiac tamponade occurs when
enough blood, fluid, or clot fills the pericardial space,
increasing the intrapericardial pressure sufficiently to affect
CO. Clinical symptoms consist of Beck's triad, which con-
sists of hypotension, elevated systemic venous pressure, and
a quiet heart on auscultation. Diastolic LA and RA as well
as LV and RV pressures equalize. Patients have dyspnea,
tachycardia, distended neck veins, narrow pulse pressure,
and pulsus paradoxus (significant variation in BP/stroke
volume with respiration resulting from increased RV filling
on inspiration that shifts intraventricular septum to left and
restricts LV filling and stroke volume).
Echocardiography is used to diagnose tamponade, and
the degree of variation in ventricular filling with respiration
is used to assess physiologic severity. Emergency drainage of
the fluid or thrombus is undertaken. If the patient is already
ventilated, volume infusion and inotropic support, along with
minimizing excessive PPV, is the strategy of choice. In the
unintubated patient, PPV, along with the reduction in pre-
load and afterload often seen with anesthesia induction drugs,
is poorly tolerated and may cause cardiac arrest. Therefore,
when possible, IV sedation with the patient in semi-Fowler
position, local anesthesia, and initial needle drainage of a large
 132 ANESTHESIA AND UNCOMMON DISEASES
BOX 3-29   n PERICARDIAL EFFUSION AND
TAMPONADE
Increases in intrapericardial pressure cause equalization of diastolic
pressures in all four cardiac chambers, resulting in tamponade
physiology.
Distended neck veins, pulsus paradoxus, tachycardia, and low
cardiac output result.
Induction of anesthesia with PPV can further compromise ventricular
filling and result in cardiovascular collapse.
Sedation, local anesthesia, and needle pericardiocentesis should be
performed first, if possible.
effusion is the preferred approach. When the initial fluid is
drained and tamponade physiology improves, induction of
anesthesia and tracheal intubation are safer if still needed. If
induction and positive pressure are needed before drainage of
any fluid, the surgeon or cardiologist must be able to drain
the fluid immediately after induction, with resuscitation drugs
and equipment readily at hand (Box 3-29).
PACEMAKERS AND DEFIBRILLATORS
Many patients with congenital heart disease have abnormali-
ties of cardiac rhythm from birth or early infancy as a result of
their condition, or these develop over time because of long-
standing pathophysiology. Many patients require epicar-
dial or transvenous pacemakers and defibrillators and often
present for noncardiac procedures. These arrhythmias may
range from complete A-V block that is congenital, A-V block
acquired as a result of surgical trauma to the A-V node or bun-
dle of His, sick sinus syndrome, and atrial fibrillation, to risk
for sudden death from ventricular tachycardia from a familial
cardiomyopathy, acquired myocardial disease, or posttrans-
plant cardiomyopathy.
When evaluating these patients for elective surgery, it is
crucial to understand three basic aspects of the patient's pace-
maker/implantable cardioverter-defibrillator (P/ICD) by ask-
ing the following questions:
1. Why was the device placed?
2. What are its basic parameters (chambers sensed/paced/
defibrillated/rate response and parameters; last pacer check
and functioning)?
3. What is the patient's underlying cardiac rhythm?
Consulting the patient's electrophysiologist whenever
possible is an important step in preoperative evaluation.143
The manufacturer of the device will have a representative
available to contact if this is not possible. The pacemaker/
defibrillators will often need to be reprogrammed preopera-
tively to the asynchronous mode with antitachycardia thera-
pies disabled because electrocautery used during surgery is
sensed as electrical activity and interferes with the function-
ing of the pacemaker, or it is sensed as an arrhythmia, result-
ing in undesired defibrillation. During surgery, the current
from the electrocautery should not pass through either the
pacemaker generator or the lead wires. Intraoperatively, it is
BOX 3-30   n PACEMAKERS AND DEFIBRILLATORS IN
SURGICAL CHD PATIENTS
Consultation with the patient's cardiologist or the manufacturer's
expert is necessary before elective anesthesia.
Understand the reasons for placement of the P/ICD, its current
functioning, and the patient's underlying cardiac rhythm.
Reprogramming pacemakers to asynchronous mode and disabling
antitachycardia therapies are necessary for most surgeries using
electrocautery.
Backup pacemaker and defibrillating capability is necessary in these
patients.
Always monitor beat-to-beat perfusion with pulse oximeter, palpation
of pulses, and arterial catheter.
Magnet mode for emergencies usually converts the P/ICD to
asynchronous mode.
Interrogate and return the device to baseline functioning after the
procedure.
critically important to monitor actual perfusion, with well-
functioning pulse oximeter, arterial line, or palpable pulses,
because electrical pacemaker spikes on an ECG monitor do
not guarantee cardiac output. Resuscitation drugs and exter-
nal defibrillator pads, as well as external pacemaker capabil-
ity, should be available. In the patient with nonexistent or
very slow underlying ventricular escape rhythm, it may be
necessary preoperatively to place a transvenous pacemaker
as a backup support device.
After surgery, the pacemaker/defibrillator is interrogated
for proper function and returned to its baseline pacing and
antitachycardia functioning. In the case of emergent surgery
when the device cannot be properly interrogated and con-
verted to asynchronous mode, perfusion must be carefully
monitored. Electrocautery should be used sparingly and in
short bursts and stopped if interfering with pacemaker func-
tion. A magnet may be placed over the pacemaker generator;
this normally converts it to asynchronous mode at a rate of
60 or 70 beats per minute and disables antitachycardia thera-
pies. However, newer devices do not always respond in this
manner. The company representative or patient's cardiologist
should be contacted emergently for advice, while not delay-
ing emergency surgery. Of note, the presence of an implanted
pacemaker or defibrillator is essentially an absolute contrain-
dication to MRI examination (Box 3-30).
THE POST–CARDIAC TRANSPLANT PATIENT
Patients with end-stage cardiomyopathy or congenital heart
disease often undergo cardiac transplantation. This therapy
is a last resort, and the number of transplants in children
reported to the International Society for Heart and Lung
Transplantation has been stable over the past 20 years at 400
to 450 per year. Survival of pediatric transplant recipients has
improved in the past two decades, now approximately 75%
at 5 years, 60% at 10 years, and 50% at 20 years.144 However,
far from being a cure, most of these patients do experience
posttransplant morbidity that can affect later anesthetic
care, with hypertension in about 75% of 10-year survivors,

REFERENCES
BOX 3-31   n THE POST–CARDIAC TRANSPLANT
PATIENT
The transplanted heart remains mostly denervated for sympathetic/
parasympathetic efferent impulses and afferent pain impulses.
Direct-acting sympathetic agents are required to increase heart rate.
Bradycardia is often an ominous sign and must be rapidly assessed
and treated.
Chronic rejection results in coronary artery vasculopathy, which can
result in myocardial ischemia and infarction without angina.
Decreased ventricular function, complete A-V block, and sick sinus
syndrome are late manifestations in the post–cardiac transplant
patient.
renal dysfunction in 17%, and coronary artery vasculopathy
(CAV) in 16%. CAV results from chronic rejection, causing
intimal buildup and gradual obstruction of coronary arter-
ies. This problem is difficult for the anesthesiologist because
patients may be having coronary ischemia; because the heart
is denervated, however, they do not experience angina.
Myocardial dysfunction, arrhythmias, and sudden death may
occur in these patients. When approaching the patient for
a noncardiac anesthetic, it is important to understand time
since transplant, date of last cardiac catheterization/biopsy,
and coronary evaluation, and the presence of antiarrhyth-
mic therapy or defibrillator. In addition, these hearts remain
denervated for parasympathetic and sympathetic nerves and
thus will respond only to direct acting β-adrenergic agents if
a faster HR is desired. Heart rate tends to be on the higher
side and varies little.
Significant bradycardia in a transplant patient is an omi-
nous sign of myocardial ischemia and must be rapidly investi-
gated and treated. Patients with known CAV must be treated
similar to an adult patient with acquired CAD, maximizing
myocardial O2 supply/demand ratio, maintaining adequate
preload and afterload, and avoiding tachycardia. The patient
undergoing emergency surgery whose CAV status is not
known should be approached as if CAV is present. The cardiac
transplant patient with acute rejection is usually quite ill and
requires inotropic and occasionally mechanical cardiac sup-
port until the myocardium recovers (Box 3-31).
CONCLUSION
Congenital heart disease presents a significant challenge for
the anesthesiologist. The increasing number of surviving chil-
dren and adults, along with the greater complexity of disease
in survivors, requires that every anesthesiologist have a work-
ing knowledge of the major categories of CHD. Children with
CHD have been consistently shown to have higher anesthetic
risk, with the rate of cardiac arrest and death being tens to
hundreds of times higher than patients without cardiac dis-
ease.40–42,139 Thorough evaluation of patient status, consulta-
tion from cardiology colleagues, and planning appropriate
intraoperative and postoperative care with the surgeon will
maximize the chances for optimizing outcomes in this com-
plicated group of patients.
Chapter 3  Congenital Heart Disease 133
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tion under anaesthesia in children with pulmonary hypertension, Br J
Anaesth 98:657–661, 2007.
139. Bhananker SM, Ramamoorthy C, Geiduschek JM, et  al: Anesthesia-
related cardiac arrest in children: update from the Pediatric Perioperative
Cardiac Arrest Registry, Anesth Analg 105:344–350, 2007.
140. Carmosino MJ, Friesen RH, Doran A, et al: Perioperative complications
in children with pulmonary hypertension undergoing noncardiac sur-
gery or cardiac catheterization, Anesth Analg 104:521–527, 2007.
141. Shukla AC, Almodovar MC: Anesthesia considerations for children
with pulmonary hypertension, Pediatr Crit Care Med 11(2 Suppl):70–73,
2010.
142. Kipps AK, Ramamoorthy C, Rosenthal DN, et  al: Children with car-
diomyopathy: complications after noncardiac procedures with general
anesthesia, Paediatr Anaesth 17:775–781, 2007.
143. American Society of Anesthesiologists: Practice advisory for the peri-
operative management of patients with cardiac implantable electronic
devices: pacemakers and implantable cardioverter-defibrillators. An
updated report by the American Society of Anesthesiologists Task Force
on Perioperative Management of Patients with Cardiac Implantable
Electronic Devices, Anesthesiology 114:247–261, 2011.
144. Williams GD, Ramamoorthy C, Anshuman S: Anesthesia for cardiac and
pulmonary transplantation. In Andropoulos DB, Stayer SA, Russell IA,
et al, editors: Anesthesia for congenital heart disease, ed 2, Oxford, UK,
2010, Wiley-Blackwell, pp 493–518.
 C H A P T E R
4
Respiratory Diseases
CARON M. HONG, MD, MSc  n
RAFAEL CARTAGENA, MD  n
ANTHONY N. PASSANNANTE, MD  n
PETER ROCK, MD, MBA, FCCM  n

KEY POINTS
Diseases of the Pulmonary Circulation
Pulmonary Arteriovenous Fistulas n Pulmonary arteriovenous fistulas have congenital and
Wegener's Granulomatosis hereditary etiology, and patients are at risk for life-threatening
Lymphomatoid Granulomatosis rupture requiring surgery.
Churg-Strauss Syndrome n Wegener's granulomatosis can affect any organ system,
Primary Pulmonary Hypertension although renal and pulmonary involvement is most com-
Obstructive Disease mon; men ages 40 to 50 are at increased risk.
Cystic Fibrosis n Lymphomatoid granulomatosis affects cardiopulmonary,
Infiltrative and Interstitial Diseases neurologic, and myeloproliferative systems; may result
Bronchiolitis Obliterans Organizing Pneumonia from opportunistic infection, and frequently progresses
Idiopathic Pulmonary Hemosiderosis to lymphoma; men age 50 to 60 are at increased risk.
Chronic Eosinophilic Pneumonia Spontaneous remission occurs in some cases; mortality is
Goodpasture's Syndrome 60% to 90% at 5 years.
Pulmonary Alveolar Proteinosis n Churg-Strauss syndrome is usually associated with long-
Sarcoidosis standing asthma, with men and women affected equally,
Systemic Lupus Erythematosus and can affect any organ system; major cause of death is
Idiopathic Pulmonary Fibrosis cardiac related.
Acute Respiratory Distress Syndrome
n Primary pulmonary hypertension is a diagnosis of exclu-
Pulmonary Histiocytosis X
sion; women are affected twice as likely as men; right-to-
Lymphangioleiomyomatosis
left shunt may occur in 30%, secondary to patent foramen
Arthritic Diseases Creating Upper Airway and
Respiratory Problems
ovale; hypoxia with resultant heart failure is typical cause
Ankylosing Spondylitis
of death.
Kyphosis and Scoliosis n Cystic fibrosis is an autosomal recessive disease, eventually
Drug-Induced Lung Injury fatal, with increased risk for airway obstruction, fluctuating
Bleomycin Toxicity pulmonary function, and chronic hypoxia; risk for sponta-
Infectious Diseases neous pneumothorax is 20%.
Influenza A (H1N1) n Bronchiolitis obliterans organizing pneumonia is a pulmo-
Severe Acute Respiratory Syndrome nary obstructive disease that may be reversible and usually
Echinococcal Disease of Lung resolves spontaneously.
Conclusion n Idiopathic pulmonary hemosiderosis is associated with
autoimmune disorders; patients have recurrent hemorrhage,

137
 138 ANESTHESIA AND UNCOMMON DISEASES
­ ulmonary fibrosis, restrictive lung disease, and pulmonary
p n Severe acute respiratory syndrome (SARS) is highly infec-
hypertension, with some cases of spontaneous remission.
n Chronic eosinophilic pneumonia may be preceded by
adult-onset asthma; women are at increased risk; prognosis
is good.
n Goodpasture's syndrome is a genetic autoimmune disorder
involving the pulmonary and renal systems.
n Pulmonary alveolar proteinosis, a lipoprotein-rich accu-
mulation in alveoli, has three forms: congenital, decreased
alveolar macrophage activity, and idiopathic; some cases of
spontaneous remission occur.
n Sarcoidosis may affect any organ system; African American,
northern European, and females are at greater risk; many
patients are asymptomatic.
n Systemic lupus erythematosus may affect any organ system;
women of childbearing age are at increased risk.
n Idiopathic pulmonary fibrosis is a rare interstitial lung dis-
ease, with smokers at increased risk for pulmonary malig-
nancy; survival is usually 2 to 3 years from diagnosis; no
effective treatment exists, with lung transplant the only
therapeutic option.
n Acute respiratory distress syndrome (ARDS) is associated
with underlying critical illness or injury, developing acutely
in 1 to 2 days; mortality is 25% to 35%.
n Pulmonary histiocytosis X is an interstitial lung disease
associated with cigarette smoking and an unpredictable
course; some spontaneous remission occurs.
n Lymphangioleiomyomatosis involves progressive dete-
rioration of lung function, associated with tuberous
sclerosis and exacerbated by pregnancy, with women
at increased risk; possible spontaneous pneumothorax
and chylothorax; death usually results from respiratory
failure.
n Ankylosing spondylitis is a genetic inflammatory process
resulting in fusion of axial skeleton and spinal deformities,
with men at increased risk; radiologic bamboo spine, sacral to
­cervical progression, and restrictive lung disease with high reli-
ance on diaphragm; extraskeletal manifestations may occur.
n Kyphosis (exaggerated anterior flexion) and scoliosis (lat-
eral rotational deformity) are spinal/rib cage deformities
with idiopathic, congenital, or neuromuscular etiology;
corrective surgery done if Cobb thoracic angle >50% lum-
bar angle >40%.
n Bleomycin is an antineoplastic antibiotic used in combina-
tion chemotherapy, with no myelosuppressive effect; toxic-
ity can cause life-threatening pulmonary fibrosis.
n Influenza A is highly infectious, presenting with flulike
symptoms and possible progression to ARDS; human-
to-human exposure is through droplets or contaminated
surfaces, with high risk for infants, children, pregnancy,
chronically ill, or renal replacement therapy patients.
No prophylactic treatment exists; treat patients with
high index of suspicion without definitive testing; rRT-
PCR and viral cultures are sensitive for pandemic H1N1
strain.
tious, transmitted by coronavirus with human-to-human
exposure via droplets or surfaces, and may progress to
ARDS.
n Echinococcal disease of lung is from canine tapeworm,
transmitted by eggs from feces; rupture of cyst may result in
anaphylactic reaction or spread of disease to other organs;
children are at increased risk. No transthoracic needle aspi-
ration is done; surgery is only option.
A thorough knowledge of pulmonary anatomy and physiol-
ogy is essential to the practicing anesthesiologist, who should
be familiar with common clinical conditions such as chronic
obstructive lung disease (COPD) and asthma. This chapter
presents a comprehensive review of less common pulmonary
conditions, organized anatomically (pulmonary vasculature,
airways, pulmonary interstitium), and conditions extrinsic
to the lungs that affect pulmonary function, such as severe
arthritic disorders. Drug-induced lung injury is also discussed,
followed by rare infectious pulmonary diseases, including
influenza A (H1N1), severe acute respiratory syndrome, and
echinococcal disease of the lung.
Many of these conditions are severe, and some are diffi-
cult to diagnose. Patients with pulmonary disease may present
with varied symptoms, including productive or nonproductive
cough, fever, shortness of breath, chest pain, and decreased exer-
cise tolerance. In most circumstances, patients who have these
conditions will already be under the care of an internist or pul-
monary specialist. The patient evaluation necessary to arrive at
an accurate diagnosis often is comprehensive, including detailed
history and physical examination; chest radiograph; pulmonary
function tests (PFTs), including ­spirometry, diffusing ­capacity,
and lung volume determination; and p ­ erhaps arterial blood
gas (ABG) analysis. For some ­conditions, bronchoscopy and
biopsy may be performed, and others require echocardiography
or ­cardiac catheterization for diagnostic certainty. For urgent or
emergent surgery, the gravity of the clinical situation often pre-
cludes additional diagnostic assessment. For elective surgery,
preoperative evaluation should include a review of these diag-
nostic studies and a determination as to whether the patient's
clinical condition has changed substantially. If a diagnosis has
already been established, there is no evidence to suggest that
additional pulmonary testing will improve pulmonary outcomes
after surgery. Spirometry and lung volume determination are the
“gold standards” for the presence or absence of pulmonary dis-
ease, but are poor predictors of patients who will develop a pul-
monary complication after surgery.1 If a diagnosis has not been
established in a patient who has symptoms consistent with one
of these respiratory diseases, pulmonary consultation should be
obtained preoperatively as the patient's pulmonary disorder may
be more urgent than an elective surgical procedure.
Unfortunately, pulmonary complications are common after
many surgical procedures, particularly those involving the
upper abdomen or thorax, possibly more likely than c­ ardiac

complications.2–5 Pre-existing lung disease, smoking, con-
gestive heart failure, American Society of Anesthesiologists
(ASA) classification, obesity, obstructive sleep apnea, anes-
thetic time in excess of 180 minutes, and advanced age are also
risk factors for pulmonary complications.4–9 There is no stan-
dard definition of exactly what constitutes a pulmonary com-
plication, but the most important complications are those that
cause significant morbidity (e.g., postoperative pneumonia)
and postoperative respiratory failure. Because all the disorders
discussed in this chapter constitute pre-existing lung disease,
patients with these disorders who come to the operating room
are at increased risk of postoperative pulmonary complica-
tions. Effective preoperative and intraoperative treatments are
discussed with the individual diseases. In the postoperative
period, aggressive treatment with mechanical measures such as
incentive spirometry can reduce pulmonary complications.10,11
Other intraoperative interventions, such as laparoscopic sur-
gery, nasogastric tube decompression, and shorter-acting neu-
romuscular blockade, may also be beneficial.12,13
DISEASES OF THE PULMONARY
CIRCULATION
Pulmonary Arteriovenous Fistulas
Pulmonary arteriovenous (AV) fistulas are abnormal commu-
nications between the arterial and venous pulmonary circula-
tion that result in shunting of blood from right to left without
traversing the pulmonary capillary network. This shunt results
in a decreased fraction of the pulmonary circulation partici-
pating in gas exchange, mixing of oxygenated and deoxygen-
ated blood, and a consequent reduction in arterial oxygen
tension (Pao2). Many patients with pulmonary AV fistulas are
asymptomatic, but some may have associated signs and pos-
sible symptoms consistent with chronic hypoxemia (Box 4-1).
Known causes of pulmonary AV fistula formation include
congenital malformations (Box  4-2). Patients with heredi-
tary hemorrhagic telangiectasia (Osler-Weber-Rendu syn-
drome), an autosomal dominant syndrome most often seen in
BOX 4-1   n PULMONARY ARTERIOVENOUS FISTULA:
SIGNS AND SYMPTOMS
Shortness of breath
Dyspnea with exertion
Bloody sputum
Cyanosis
Clubbing
Chest pain
Palpitations
Bruit
Low arterial oxygen saturation
Polycythemia
Anemia
Abnormal vasculature or nodules on chest radiograph
Chapter 4  Respiratory Diseases 139
BOX 4-2   n PULMONARY ARTERIOVENOUS FISTULAS:
ETIOLOGY
Congenital
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
Chest trauma
Cavopulmonary shunting*
Hepatic cirrhosis
Pulmonary hypertension
*First stage of a Fontan repair for single ventricle physiology, generally
performed at 4 to 6 months of age. A cavopulmonary shunt is constructed
and directs superior vena caval blood flow to the confluent pulmonary
arteries.
middle-aged women but sometimes diagnosed in early child-
hood, are more likely to have multiple fistulas and more severe
symptoms.14
Patients with pulmonary AV fistula are at risk for rup-
ture, resulting in potentially life-threatening hemothorax
and hemoptysis. Thrombus formation within the fistula
may also occur, with potential embolization of clot to the
brain, resulting in stroke or seizures. Embolization of other
organ systems is also possible. If the thrombus becomes
infected, septic emboli and potential abscess formation
may result.
Surgical intervention in the management of pulmonary
AV fistulas becomes necessary when the patient develops
more pronounced cardiac symptoms, significant respiratory
symptoms, room-air desaturation, or complications such as
emboli with central nervous system (CNS) manifestations.
Surgical preoperative evaluation requires chest computed
tomographic angiography (CTA) or pulmonary arteriogra-
phy to localize the lesion. Pulmonary lobectomy, segmentec-
tomy, or wedge resection using thoracotomy or video-assisted
­thoracoscopic surgery (VATS) are the most common proce-
dures. Embolization procedures are becoming the preferred
treatment for the majority of patients because embolization
is less invasive, is easily repeated, and may be an adjuvant to
decrease bleeding and other complications during definitive
surgical resection.15,16
Anesthetic evaluation focuses on the degree of shunt and
hypoxemia, using ABG analysis. Review of the pulmonary
angiogram will reveal the size of the lesion and whether mul-
tiple fistulas are present. A significant fistula in the nonop-
erative lung may compromise arterial oxygenation if one-lung
ventilation is required for surgical exposure. Efforts to mini-
mize flow through a pulmonary AV fistula involve avoiding
both increased pulmonary vascular resistance (PVR) and ele-
vated levels of positive end-expiratory pressure (PEEP), both
of which will increase flow through the low-resistance fistula.
Intraoperative management frequently requires one-lung
ventilation to optimize surgical exposure. A double-lumen
endotracheal tube (ETT) provides the added benefit of iso-
lating the nonoperative lung and airways from any bleeding,
 140 ANESTHESIA AND UNCOMMON DISEASES
which may occur during a potentially bloody resection. The
risk of significant bleeding is decreased if the lesion has been
embolized before resection. Large-bore intravenous (IV)
access is recommended in the event significant hemorrhage
occurs. An arterial catheter is also indicated to monitor oxy-
genation and guide resuscitative efforts. As mentioned, an
important anesthetic goal is to minimize flow through the
pulmonary AV fistula. AV fistulas do not have capillary beds
and have lower resistance to blood flow than normal pulmo-
nary vasculature. It is important to avoid a general increase
in PVR because this will increase flow through the AV fis-
tula. Similarly, minimizing the use of PEEP will minimize
increases in PVR and help minimize blood flow through
the fistula. Because of the risk of paradoxical emboli pass-
ing through the fistula, extra caution must be taken to avoid
injection of any air or particulate material into the venous
system, because such debris may bypass the pulmonary cap-
illary bed and gain access to systemic arteries, where end-
organ embolization can occur (Box 4-3).
Preoperative evaluation should include assessment of neu-
rologic function to rule out prior embolic stroke. Postoperative
evaluation should include a neurologic check as well, to look
for perioperative CNS embolization.
BOX 4-3   n ANESTHESIA CONCERNS FOR PATIENTS
WITH PULMONARY DISEASE
Pulmonary Arteriovenous Fistula
Assess for degree of shunt and hypoxemia.
Avoid increases in pulmonary vascular resistance.
Avoid elevated positive end-expiratory pressures.
Extra care is needed to prevent unintentional intravenous air injection
or any condition that would result in a venous air embolism.
Wegener's Granulomatosis
Assess for specific organ system involvement (renal and pulmonary
insufficiency).
Avoid nasal manipulation (nasal intubation).
Assess for risk of difficult airway (subglottic/tracheal stenosis).
Lymphomatoid Granulomatosis
Assess extent of organ system involvement (obstructive or restrictive
lung disease, cardiomyopathy, neuropathy, myelosuppression).
Possible adrenal suppression from long-term steroid treatment.
Churg-Strauss Syndrome
Assess level of organ system involvement (PFTs, chest radiograph,
ECG, echocardiogram).
Minimize airway manipulation secondary to airway hyperreactivity.
May need stress-dose perioperative steroids.
Primary Pulmonary Hypertension
Consider increased perioperative morbidity and mortality.
Complete cardiopulmonary workup is needed for all procedures (ECG,
echocardiography, chest radiograph, ABGs).
Spinal anesthesia is not recommended.
Maintain cardiac output and systemic vascular resistance.
Minimize increases in pulmonary vascular resistance.
Consider invasive monitoring intraoperatively.
Restrict nitrous oxide or ketamine use.
ABGs, Arterial blood gases; ECG, electrocardiogram; PFTs, pulmonary
function tests.
Wegener's Granulomatosis
Wegener's granulomatosis (WG) is a rare disorder charac-
terized by necrotizing giant cell granulomatosis of the upper
respiratory tract and lung, widespread necrotizing vasculitis,
and focal glomerulonephritis. WG may also affect the cardio-
vascular, neurologic, and gastrointestinal systems.17 Although
the etiology of WG is unknown, an autoimmune disorder is
suspected. A typical patient is in the fourth or fifth decade, and
men are twice as likely to have WG as women. Antineutrophil
cytoplasmic autoantibody (ANCA) is a serologic marker
that can help confirm the diagnosis.18 Staphylococcus aureus
has been implicated as an exacerbating cofactor.18 Symptoms
associated with WG are vague, and diagnosis can be elusive
(Box 4-4). Biopsy of a lesion is necessary to make the diagnosis.
If the disease progresses, significant respiratory and renal
compromise can occur, as well as hearing and vision loss
(Box 4-5). Cardiac involvement is uncommon, although peri-
carditis, coronary arteritis, valvular involvement, and left ven-
tricular hypertrophy have been reported. Current therapy for
WG is often based on disease severity but usually includes
cyclophosphamide, corticosteroids, methotrexate, or azathio-
prine and yields very good results, with long-term remission
occurring in the majority of patients. Recent studies have dem-
onstrated possible advantages of antistaphylococcal antibiotics
and T-cell inhibitors (leflunomide).18 Preoperative assessment
is directed toward evaluating potential complications of WG,
most often renal and pulmonary insufficiency. Blood urea
BOX 4-4   n WEGENER'S GRANULOMATOSIS: COMMON
SIGNS AND SYMPTOMS
Hematuria
Shortness of breath
Wheezing
Hemoptysis
Bloody sputum
Cough
Chest pain or pleuritis
Sinusitis
Ulcers or lesions around nose
Weight loss
Weakness
Fever
Joint pain
BOX 4-5   n WEGENER'S GRANULOMATOSIS:
COMPLICATIONS
Chronic renal insufficiency or renal failure
Hearing loss
Subglottic/tracheal stenosis
Pulmonary insufficiency
Functional nasal deformities
Ocular abnormalities
Vision loss
Ulcerative keratitis
Orbital pseudotumor

nitrogen (BUN) and creatinine levels will p ­ rovide adequate
insight into the patient's renal function. A pulmonary flow-
volume loop may be indicated if the patient is suspected of
having tracheal stenosis and, by providing information about
the dynamic changes in tracheal caliber, can supplement static
radiographic images. WG may cause either obstructive or
restrictive lung disease; the latter can be severe. Spirometry
and other PFTs such as formal lung volume measurements can
help determine the severity of such disease. Bronchoscopy and
neck/chest CT may be necessary to evaluate subglottic stenosis
and suggest which EET size can be placed safely.
Several aspects of WG may complicate management of the
patient's airway. A significant amount of granulation tissue is
likely to be present in and around the nose and nasopharynx.
Insertion of a nasotracheal tube or nasal airway may be impos-
sible, or traumatic with hemorrhage, and is best avoided.
Additionally, lesions on the epiglottis or oropharynx may
inhibit direct laryngoscopy, despite a normal airway exami-
nation. Once the vocal cords have been visualized, the ETT
may be difficult to place because of subglottic stenosis and
may require multiple l­ aryngoscopies. If the patient is receiving
corticosteroids at the time of surgery, stress dosing should be
considered (see Box 4-3).
In view of these concerns, it is best to proceed with a con-
servative plan for managing the airway in WG patients, with
immediate availability of difficult airway equipment, mul-
tiple sizes of ETTs, a videolaryngoscope or fiberoptic bron-
choscope, and the means to obtain a surgical airway, as a last
resort. If the patient has significant tracheal or bronchial ste-
nosis, care should be taken to prevent air trapping and auto-
PEEP by allowing sufficient time for exhalation if the tracheal
lesion is below the ETT. (See also Chapter 1.)
Lymphomatoid Granulomatosis
Lymphomatoid granulomatosis (LYG), also known as angiocentric
lymphoma, is a rare lymphoproliferative disease that is angiode-
structive and frequently progresses to lymphoma. LYG mimics
WG clinically and radiographically, although recent advances have
identified LYG as a malignant B-cell lymphoma associated with
immunosuppression and Epstein-Barr virus (EBV). Diagnosis
requires histologic evaluation of a biopsy specimen. LYG was
recently categorized as a lymphoma, although if diagnosed early
(grade I angiocentric immunoproliferative lesions), it is consid-
ered benign, although premalignant.19 Typically, it presents in the
fifth or sixth decade of life, affecting men twice as often as women.
The etiology of LYG is unknown, although its incidence in pop-
ulations with immune dysfunction, such as human immunode-
ficiency virus (HIV) patients and organ transplant recipients, is
significantly increased compared with the general population.
Speculation that LYG resulted from an opportunistic infection has
been confirmed through laboratory investigation.
The disease process primarily involves the lungs, although
the skin, kidneys, and CNS can also be affected. Signs and
symptoms of LYG include an increased risk of pneumo-
nia (Box 4-6). Unlike WG, glomerulonephritis is not part of
Chapter 4  Respiratory Diseases 141
BOX 4-6   n LYMPHOMATOID GRANULOMATOSIS:
CLINICAL MANIFESTATIONS
Hemoptysis
Cough
Dyspnea
Chest pain
Pneumothorax
Pleural effusions
Atelectasis
Fever and weight loss
Hepatomegaly
Erythema
Mononeuritis multiplex
Peripheral sensory neuropathy
this clinical p
­ icture. LYG is frequently fatal, with 60% to 90%
mortality at 5 years, although a small number of patients may
undergo spontaneous recovery and complete remission. The
cause of death is usually related to extensive destruction of the
lungs and resulting respiratory failure.20,21
Corticosteroids and cyclophosphamide are the treat-
ment of choice, resulting in relief of symptoms such as fever,
cough, chest pain, weight loss, and sinusitis. If not diagnosed
in the premalignant phase, and if the disease has progressed
to lymphoma, c­hemotherapy is necessary. The combina-
tion of cyclophosphamide, doxorubicin (hydroxydaunomy-
cin), vincristine (Oncovin), and prednisone (CHOP) is often
used. Radiation therapy may be indicated for localized dis-
ease. More recently, immunomodulation with interferon
alfa-2b and autologous stem cell transplantation have played
a role in treatment.20,21
In preparation for anesthesia, evaluation of the patient's
pulmonary function is the primary concern with LYG. Chest
radiography may reveal bilateral nodules, ­cavitations, ­pleural
effusions, or pneumothorax. In the presence of advanced
disease, ABG analysis and spirometry help define the extent
of the patient's respiratory c­ompromise and parenchymal
destruction. A thorough ­preoperative n ­ eurologic evaluation
is advised because of the high i­ncidence of peripheral neu-
ropathy. Toxicities related to any chemotherapeutic agents the
patient may have received should also be considered. Toxicity
related to the CHOP protocol includes peripheral neuropathy,
cardiomyopathy, and myelosuppression.
ANESTHETIC MANAGEMENT
When planning an anesthetic for a patient with LYG, the pres-
ence of or potential for peripheral neuropathy may deter the
anesthesiologist from using regional techniques, because of
concern that subsequent neurologic dysfunction will be attrib-
uted to the regional anesthesia. However, the choice of anes-
thetic must be based on a consideration of risks and benefits,
and there is no evidence that regional anesthesia worsens LYG.
Respiratory compromise increases the risk of hypoxia under
general anesthesia, or if the patient hypoventilates secondary
to sedating agents used for premedication or for monitored
anesthesia care.
 142 ANESTHESIA AND UNCOMMON DISEASES
If general anesthesia is chosen, the potential for postopera-
tive intubation and respiratory support should be addressed
with the patient. The need for postoperative mechanical ven-
tilation is more likely in patients who have advanced disease
with extensive destruction of lung tissue, pleural effusions, or
pneumothorax. There is no clear answer to which anesthetic
technique is superior, and the approach should be tailored to
the individual patient's comorbidities and the surgical proce-
dure. Long-term corticosteroid therapy in this population may
result in adrenal suppression, and stress doses of corticoste-
roids should be considered (see Box 4-3).
Churg-Strauss Syndrome
Churg-Strauss syndrome (CSS), also known as allergic granu-
lomatosis, is a rare systemic vasculitis that may affect multiple
organ systems, particularly the lungs. Diagnosis requires the
presence of at least four of six criteria: bronchospasm, eosin-
ophil count greater than 10%, neuropathy (poly or mono),
nonfixed pulmonary infiltrates, paranasal sinus abnormali-
ties, and extravascular eosinophils22 (Box  4-7). Patients fre-
quently present in the fifth or sixth decade and may have a
long-standing history of asthma. Both genders are affected
equally. Cardiac involvement occurs later in the course and
is the major cause of death. CNS manifestations such as cere-
bral infarcts, subarachnoid hemorrhage, and optic neuritis
are common.
Corticosteroids generally result in dramatic improvement
or resolution of CSS symptoms. Cytotoxic therapy should be
initiated based on the severity of disease. Patients resistant
to corticosteroids may respond to interferon-α treatment.23
Elective surgery should be postponed if management of bron-
chospasm has not been optimized. Involvement of other organ
systems may necessitate neurologic and renal evaluations.
Cardiac evaluation may require testing such as echocardiogra-
phy to assess myocardial function if the patient has congestive
heart failure (CHF) or endocarditis.
BOX 4-7   n CHURG-STRAUSS SYNDROME: CLINICAL
MANIFESTATIONS
Sinusitis
Nasal polyps
Pulmonary infiltrates
Diffuse interstitial lung disease (rare)
Hemoptysis
Pleural effusions
Cutaneous nodules and rashes
Hypertension
Glomerulonephritis
Coronary vasculitis
Endocarditis
Congestive heart failure
Peripheral neuropathy
Mononeuritis multiplex
Cerebral infarct
Subarachnoid hemorrhage
Optic neuritis
Preoperative assessment should include a chest radiograph
and PFTs. Chest radiography may reveal multiple small pulmo-
nary nodules or diffuse interstitial disease. Pleural effusions are
noted in up to 30% of CSS patients. Spirometry typically demon-
strates an obstructive pattern, although restrictive disease may
also occur. A decrease in diffusion capacity may be observed
from a loss of alveolar capillary surface area. Intraoperative
management should include universal asthmatic principles
to minimize airway reactivity. If possible, avoidance of air-
way instrumentation and positive-pressure ventilation (PPV)
is desirable. A prolonged expiratory phase may be needed in
patients with more advanced obstructive disease if PPV is used,
and preoperative spirometry will provide guidance in this area.
Nonselective beta-adrenergic blockers should be avoided, if
possible, because of the risk of bronchospasm and exacerba-
tion of CHF. If needed for control of ischemic heart disease,
selective β1-adrenergic agents, preferably short acting, should
be used. Perioperative corticosteroids should be considered
because of the risk of adrenal suppression from long-term cor-
ticosteroid therapy (see Box 4-3).
Primary Pulmonary Hypertension
Primary pulmonary hypertension (PPH) is an idiopathic dis-
ease and is a diagnosis of exclusion. The prevalence of PPH
is thought to be approximately 1:1 million, with women
being twice as likely as men to present with the disease. Some
cases appear to be genetically linked.24 Overall, PPH is more
severe and aggressive than secondary pulmonary hyperten-
sion. Vascular remodeling, an alteration in pulmonary vascu-
lar tone, and a loss of cross-sectional pulmonary arterial area
are responsible for the increase in PVR seen in this disease.
Dyspnea is the most common presenting symptom, and syn-
cope is a particularly poor prognostic sign (Box 4-8). Right-
to-left shunting may occur in the 30% of patients with a patent
foramen ovale (PFO). Death typically results from hypoxia,
a further increase in pulmonary artery pressure (PAP), and
eventually right ventricular (RV) failure.25
Historically, treatment for PPH relied on oxygen and cal-
cium channel blockers in an effort to decrease PVR (Table 4-1).
In addition, warfarin (Coumadin) is used to reduce the risk of
thromboembolism resulting from the enhanced platelet activ-
ity seen in PPH. Pulmonary embolism or primary pulmonary
vascular thrombosis is poorly tolerated in this patient popula-
tion. Diuretics and digoxin are also employed when RV failure
ensues. More recently, prostaglandins (PGI2, PGE1; alprostadil)
BOX 4-8   n PRIMARY PULMONARY HYPERTENSION:
SIGNS/SYMPTOMS
Dyspnea
Fatigue
Syncope or presyncope
Angina
Peripheral edema and other signs of right-sided heart failure
Cyanosis
 Chapter 4  Respiratory Diseases 143

TABLE 4-1  n  Current Therapies for Primary Pulmonary Hypertension

Therapy Advantages Disadvantages

Nitric oxide (NO) Pulmonary circulation with selective Possible formation of toxic byproducts; prolonged
vasodilation; increased Pao2 bleeding times; expensive

Prostaglandins (epoprostenol, Potent vasodilation; inhibits platelet Not selective for pulmonary circulation; systemic
treprostinil, iloprost) aggregation and smooth muscle cell hypotension; headaches; expensive; requires
proliferation continuous infusion or inhalation

Phosphodiesterase-5 inhibitors Possible synergy with NO therapy inhibitors —

(dipyridamole, sildenafil)

Endothelin receptor antagonist FDA approval Limited data available

(Bosentan)

Calcium channel blockers High efficacy; inexpensive Less effective in severe cases; negative inotropic
effects can worsen right ventricular failure

Oxygen Directly reduces pulmonary vascular None

resistance in cases of hypoxia

Warfarin (Coumadin) Improved long-term survival; decreases Increased bleeding risk

risk of intrapulmonary thrombosis

Magnesium Vasodilation through blockage of Ca2+ Risk of magnesium toxicity: weakness, sedation,
channels; enhance NO synthase activity; ECG changes
releases prostaglandin I

ECG, Electrocardiographic; Pao2, arterial oxygen tension (partial pressure).

and nitric oxide (NO), alone or in combination, have been

TABLE 4-2  n Preoperative Studies to Assess Pulmonary
used to induce pulmonary vasodilation, with minimal sys- Hypertension
temic effects.24,26 Currently, prostacyclins must be delivered by
continuous IV infusion because of their short half-life. NO is Study Possible Significant Findings
delivered by inhalation and requires a tank and delivery system.
Arterial blood gas Level of hypoxemia and acidosis; assess
Phosphodiesterase-5 inhibitors such as sildenafil and dipyri- analysis relative value of supplemental oxygen.
damole potentiate the NO-induced pulmonary vasodilation
and can be used separately or in combination.24 Unfortunately, Chest radiography Enlarged pulmonary arterial root;
enlarged right side of heart
cost and unwieldy delivery systems have limited the use of
these therapies to the short term or the most severe cases. New Electrocardiography Dysrhythmias; signs of right-sided
approaches to delivering PGI2 are under development, includ- heart strain
ing the inhaled, subcutaneous, and oral routes. A newer agent, Echocardiography Assess right ventricular function and
bosentan, an oral endothelin receptor antagonist thought to hypertrophy, valvular dysfunction and
inhibit smooth muscle vasoconstriction and proliferation, is right atrial enlargement, and patency
now approved by the U.S. Food and Drug Administration (FDA) of foramen ovale; estimate pulmonary
artery pressure.
to treat PPH.24,27 Adjunctive therapy with bosentan has demon-
strated promise when combined with prostacyclin therapy.26,27
Preoperative studies focus on the severity of PPH, degree e­ stimated by Doppler techniques. A more accurate but much
of hypoxia, and resulting effects on the heart (Table 4-2). ABG more invasive method of measuring pulmonary pressures,
analysis elucidates the level of hypoxia and acidemia, both of gauging response to therapies, and detecting a PFO is right-
which exacerbate pulmonary hypertension. A chest radiograph sided heart catheterization. This procedure should be con-
may reveal enlarged main pulmonary arteries or an enlarged sidered only if other studies have not provided an adequate
heart caused by RV hypertrophy or right atrial dilation. An assessment of disease severity and is not typically needed for
electrocardiogram (ECG) may also reveal changes consistent preanesthetic evaluation. The patient treated with digoxin
with pulmonary hypertension (e.g., right atrial enlargement), should have serum potassium and digoxin levels measured.
as well as the presence of abnormal cardiac rhythm (e.g., atrial
fibrillation). Sinus rhythm is essential to adequate RV filling. ANESTHETIC MANAGEMENT
Preoperative echocardiography is helpful in determining the The increased perioperative morbidity and mortality of this
extent of RV hypertrophy and function, right atrial enlarge- disease must be considered when preparing to deliver an anes-
ment, pulmonic or tricuspid valve dysfunction, and patency thetic to the PPH patient, and not assume the risk of peri-
of the foramen ovale. Pulmonary systolic pressures may be operative complications is low with a “minor” procedure
 144 ANESTHESIA AND UNCOMMON DISEASES

(see Box 4-3). Regional anesthetic techniques do not preclude conditions. It results in a significant reduction in life expec-
the need for possible invasive monitoring and vasoactive ther- tancy and quality of life. The responsible gene is found on the
apy. Each patient's needs should be considered individually. long arm of chromosome 7 and codes for a protein known as
All medications being used to treat the patient's PPH and cystic fibrosis transmembrane (conductance) regulator (CFTR),
resulting right-sided heart failure should be continued in the which functions as a chloride channel. This defect decreases
perioperative period. Warfarin should be discontinued and the water content of various secretions throughout the body,
replaced with a heparin infusion preoperatively. The risk of a resulting in increased viscosity. Diagnosis is based on sweat
thromboembolic event and a possible right-to-left shunt jus- chloride measurements, genetic testing for the CFTR gene, and
tify a preoperative hospital admission to administer heparin. clinical symptoms.28 CF is a universally fatal disease, although
Sedation must be carefully titrated; oversedation may lead to advances in therapy have resulted in significant gains in qual-
hypoxia, whereas not adequately addressing a patient's anxiety ity of life and longevity. A wide variety of clinical manifesta-
may also increase PVR. tions are seen in CF patients (Table 4-3).
Intraoperative management of PPH patients should Pulmonary manifestations result from the inability to
emphasize maintenance of cardiac output and systemic blood clear thickened and inspissated mucus from the airways. This
pressure (BP) while minimizing further increases in PAP causes airway obstruction and impaired defense against bacte-
and the risk of RV failure. Invasive monitors, used selec- rial infection, which results in the majority of deaths related to
tively, including an arterial catheter, PAC, and transesopha- CF. Recurrent bacterial infections result in dilation of the con-
geal echocardiography (TEE), allow for sampling of arterial ducting airways, leading to bronchiectasis.29 Although CF is a
blood, pharmacologic manipulation of PAP and cardiac out- chronic progressive disease, the extent of current pulmonary
put, and detection of RV failure, while maintaining adequate infection fluctuates, creating significant daily variability in a
ventricular preload. patient's pulmonary function. Eventually, as the disease pro-
Many different anesthetic techniques have been used suc- gresses, there is destruction of parenchyma and conduction
cessfully in patients with PPH; regional, epidural, and gen- airways. Loss of pulmonary arterial vascular cross-sectional
eral approaches with controlled ventilation are all reasonable area results in pulmonary hypertension. Chronic hypoxemia
options. Spinal anesthesia may result in a significant reduc- also develops.
tion in systemic vascular resistance (SVR) and may precipi-
tate a drop in preload with no change in pulmonary vascular
pressures. This may result in inadequate coronary flow
to perfuse the right side of the heart, with consequent RV TABLE 4-3  n  Cystic Fibrosis: Clinical Manifestations
ischemia and failure. Drugs typically used in the provision
Sign/Symptom Cause
of anesthesia are safe in patients with PPH. An exception
is nitrous oxide (N2O), which has been implicated in rais- Nasal sinusitis, polyps Abnormal mucus production and
ing PVR in several studies. Another exception is ketamine, secretion; chronic infection
which has sympathomimetic properties and may cause unin- Chronic bronchitis Hypersecretion of viscid mucus;
tended PVR increase. impaired host defenses
If PVR does increase, every effort must be made to avoid
Obstructive pulmonary Chronic pulmonary infections and
RV ischemia and possible RV failure. Helpful maneuvers disease airway plugging from excessive
include hyperventilation and maximizing Pao2 to decrease mucus secretion
PVR. Inhaled drugs such as NO (20-40 ppm), and prostacy-
Pneumothorax Rupture of subpleural blebs
clin (inhaled/IV) can selectively decrease PAP with minimal
through visceral pleura
decreases in systemic BP. Milrinone and amrinone are excel-
lent choices to decrease PVR and increase cardiac contrac- Failure to thrive Chronic infection; malabsorption
tility, although SVR will also be decreased. Dobutamine will Recurrent pancreatitis Obstruction of pancreatic ducts
increase contractility and may decrease PVR. To increase with viscous exocrine secretions
systolic BP and avoid RV ischemia, norepinephrine may
Gastroesophageal reflux Unknown
have a slight advantage over phenylephrine.27 Maintenance disease
of adequate intravascular volume and RV preload is also
important. Maldigestion Biochemically abnormal intestinal
mucins impair absorption of
specific nutrients; abnormal bile
secretion and absorption
OBSTRUCTIVE DISEASE
Fat-soluble vitamin Abnormal bile secretion and
Cystic Fibrosis deficiencies absorption

Cystic fibrosis (CF) is an autosomal recessive genetic disease Obstructive azoospermia Atretic or absent vas deferens
that affects chloride channels. With an incidence of 1 per 2000
Salt-loss syndromes Inability to create hypotonic sweat
to 4500 Caucasians, CF is one of the more common inherited

Patients with more advanced CF may develop spontaneous
pneumothorax. The etiology of pneumothorax is unknown
but presumably involves rupture of subpleural blebs through
the visceral pleura. This becomes more likely in advanced
disease. Over a lifetime, the incidence of pneumothorax may
be as high as 20% in adult CF patients. Application of PPV
can increase the risk of spontaneous pneumothorax. In the
event of pneumothorax, surgical pleurodesis is the treat-
ment of choice for CF patients who have a low anesthetic
risk; higher-risk patients frequently receive talc pleurode-
sis as a safer, yet less effective, alternative.30 Ventilation/­
perfusion inequality results in hypoxemia. The chronic
hypoxia seen in this population causes an increase in PVR
and pulmonary hypertension. Loss of pulmonary arterial
vascular cross-sectional area also causes increased PVR
and pulmonary hypertension, which is exacerbated by
chronic hypoxemia. The severity of pulmonary hyperten-
sion correlates with the severity of CF. Chronic pulmonary
vasoconstriction (from hypoxia) results in a musculariza-
tion of the pulmonary arterial vascular tree, which results
in cor pulmonale, although the initial enlargement of the
right v­ entricle is considered a beneficial adaptation to the
increased resistance to pulmonary blood flow. The only
medical therapy effective in treating pulmonary hyperten-
sion and improving RV performance in this population is
supplemental oxygen.31 Although lung transplantation has
been successful with a 2-year survival of greater than 50%,
about 40% of patients do not survive awaiting the trans-
plant due to organ shortage.28
The primary gastrointestinal manifestation of CF is mal-
absorption and steatorrhea caused by pancreatic dysfunction
from obstruction of pancreatic ducts with viscous exocrine
secretions, usually requiring pancreatic enzyme replacements
as well as multivitamins. Malnutrition and deficiencies of fat-
soluble vitamins such as vitamin K can increase the patient's
risk of bleeding if this issue is not addressed. Glucose intoler-
ance resulting from pancreatic dysfunction (impaired endo-
crine function) is also common and may require insulin
therapy. CF patients also have an increased incidence of gas-
troesophageal reflux disease (GERD).32
Preparation for anesthesia should focus on evaluation
of the CF patient's pulmonary status. Significant variation
in symptoms and disease severity from increased respira-
tory secretions or infection can be seen in a patient from
one day to the next. Surgery should be postponed, if pos-
sible, unless the patient is at a baseline level of health.
Preoperative testing should include a recent chest radio-
graph to diagnose pneumothorax, pneumonic processes,
or bullous disease. In one series of patients with CF, 16%
had an asymptomatic pneumothorax. Thus, chest radiog-
raphy is essential in these patients.30 Coagulation studies
such as prothrombin time and partial thromboplastin time
can provide information regarding coagulopathy result-
ing from vitamin K deficiency or general malnutrition.
Sedating premedications should be given only if absolutely
necessary, because of the risk of exacerbating pre-existing
Chapter 4  Respiratory Diseases 145
respiratory compromise, and only then under close obser-
vation with administration of supplemental oxygen to
­minimize the risk of desaturation. All CF patients should
be questioned regarding symptoms consistent with GERD.
If present, appropriate premedications and aspiration
precautions such as a rapid-sequence induction should be
considered, although CF patients may desaturate rapidly
when apneic.
ANESTHETIC MANAGEMENT
Choice of anesthetic technique will be primarily determined by
the scheduled procedure, although regional techniques offer
some advantages. Avoidance of airway instrumentation will
decrease the risk of bronchospasm and aspiration. Avoiding
PPV will decrease the incidence of perioperative pneumotho-
rax formation. If a long-acting or continuous regional tech-
nique is chosen, postoperative opioid requirements will be
less. The risk of postoperative respiratory insufficiency may be
less with regional anesthetic techniques, although this has not
been rigorously studied.
The plan for general anesthesia should take into account
the increased risk of aspiration (from GERD) and bron-
chospasm. The likelihood of chronic sinusitis and the pres-
ence of paranasal sinus polyps are reasons to avoid nasal
instrumentation, if possible. A rapid-sequence induction
proceeded by nonparticulate antacids and H2 antagonists
may help minimize the likelihood and consequences of
pulmonary aspiration of gastric contents. However, use of
rapid-sequence induction may result in uncontrolled sys-
temic and pulmonary hemodynamics, and its use must
balance airway risks with the risk of cardiovascular insta-
bility. PPV is usually preferable to spontaneous ventilation
in advanced cases of CF, because of the risk of respiratory
fatigue and marginal tidal volumes. CF is an obstructive
process, and prolonged expiratory times may be neces-
sary, as well as humidification of inspired gases and min-
imization of peak airway pressures to reduce the risk of
barotrauma and pneumothorax. Low respiratory rates and
smaller-than-usual tidal volumes may be required. Nitrous
oxide should be used with caution because of the increased
risk of pneumothorax formation with PPV, as well as the
likely presence of multiple blebs. Meticulous attention
to pulmonary toilet and suctioning of secretions is also
­advisable (Box 4-9).
BOX 4-9   n ANESTHESIA CONCERNS WITH CYSTIC
FIBROSIS PATIENTS
Assess cardiopulmonary function.
Aspiration precautions should be considered secondary to
association with gastroesophageal reflux disease.
Avoid airway instrumentation if possible.
Avoid positive-pressure ventilation if possible.
Consider regional techniques when applicable and appropriate.
Avoid nasal instrumentation.
May need to prolong expiratory times.
 146 ANESTHESIA AND UNCOMMON DISEASES
INFILTRATIVE AND INTERSTITIAL DISEASES
Bronchiolitis Obliterans Organizing Pneumonia
Bronchiolitis obliterans organizing pneumonia (BOOP) is an
inflammatory lung disease of unknown etiology. It has been
associated with bone marrow transplantation, although there
is a very low incidence of BOOP in this population;33 it has not
been conclusively determined to be more than an incidental
finding. BOOP results from the formation of granulation tis-
sue, which obstructs the lumen of small airways and extends
into the alveoli. The formation of the granulation tissue is
associated with connective tissue proliferation, fibrinous exu-
dates, and inflammation of alveolar and airway walls. These
changes yield a clinical picture that presents as a flulike illness
with cough and dyspnea. BOOP shares many characteristics
of idiopathic pulmonary fibrosis, with the most significant
difference being the reversibility of the fibrinous changes in
BOOP as a result of the preservation of lung architecture.33
Corticosteroids are often used, although some cases resolve
spontaneously. Typically, therapy lasts for 1 year, with resolu-
tion of symptoms by the end of the third month of treatment.
Symptoms may recur, particularly if the course of corticoste-
roids is not completed. Other agents such as erythromycin and
cyclophosphamide have been used, although their efficacy is
not well established. Patients who received cyclophosphamide
are at risk of leukopenia and, more rarely, thrombocytopenia
or anemia.
Radiologic evaluation is consistent with an organizing
pneumonia with patchy consolidation in a diffuse peripheral
distribution. Effusions are a rare finding. Spirometry typically
demonstrates a restrictive pattern, although it is possible to
find an obstructive component. Decreased diffusion capacity
and an increased alveolar-arterial oxygen gradient are com-
mon. Definitive diagnosis requires lung biopsy, typically per-
formed thoracoscopically. BOOP occurs in 25% to 50% of
long-term survivors of lung transplants, and 10% of all lung
transplant recipients, indicating a poor prognosis.34 It is a
manifestation of chronic rejection treated, usually unsuccess-
fully, with steroids and immunosuppressive agents.34
Because of the high success rate in treating cases of BOOP
unrelated to lung transplant, and because dramatic improve-
ment is typically seen after a few weeks of therapy with pred-
nisone, patients are unlikely to present for surgery with
respiratory compromise. These factors also suggest that it
may be prudent to defer all but the most emergent surgery
in patients just beginning treatment for BOOP. A review of
recent radiographs and spirometry, along with a history and
physical examination, typically provide enough information
as to whether the patient's pulmonary function has been opti-
mized for elective procedures.
In the event surgery is emergent and cannot be postponed,
the primary anesthetic issues relate to ventilator management.
As in other restrictive lung diseases, high peak pressures may
occur with PPV unless appropriate reductions in tidal volume
are made. Rapid arterial hypoxemia can occur with apnea
because of a decreased functional residual capacity (FRC). The
use of low levels of PEEP will improve FRC and assist in main-
taining Pao2. Continuation of PEEP or continuous positive
airway pressure (CPAP) in the postoperative period may be
necessary to maintain functional residual capacity (Box 4-10).
Idiopathic Pulmonary Hemosiderosis
Idiopathic pulmonary hemosiderosis (IPH) is a rare d ­ isorder
of unknown etiology characterized by diffuse alveolar hem-
orrhage. A diagnosis of exclusion, IPH is primarily seen in
infants and children. There is an association with cow's milk
hypersensitivity, celiac disease, autoimmune hemolytic ane-
­
mia, and several other autoimmune disorders, such as lupus,
­periarteritis nodosa, and WG (see previous WG section), which
suggests an immunologic basis for IPH, but no firm relationship
has been established. Clinically, IPH is similar to the immune-
mediated alveolar hemorrhage seen in syndromes such as
Goodpasture's syndrome (see Goodpasture's syndrome s­ ection)
and WG, although extrapulmonary involvement is not present
as it is in these disorders. Hemoptysis, anemia, and pulmonary
infiltrates on chest radiograph are the common presenting signs
and symptoms. The clinical course of IPH is variable, with some
reports of spontaneous remission. Other patients will die sud-
denly of severe alveolar hemorrhage or more gradually from
respiratory insufficiency within 3 years of initial presentation.
As a result of recurrent hemorrhage, pulmonary fibrosis with
restrictive lung disease and eventually pulmonary hypertension
and cor pulmonale will ensue (Table 4-4).
Corticosteroids are the cornerstone of therapy for IPH.
Although the long-term efficacy of corticosteroid therapy for
IPH is unclear, it is still the best option currently available.
Long-term, if not lifelong, therapy is usually required, and
complications arising from corticosteroid therapy are a con-
cern, which leads physicians to minimize doses. This increases
the risk of recurrence. Treatments with plasmapheresis, aza-
thioprine, and cyclophosphamide have been attempted with
some success, but these therapies are generally reserved
for patients refractory to corticosteroid therapy. Definitive
therapy is offered by double-lung transplantation, although
there is a case report of recurrence of IPH 40 months after
transplantation.35
Evaluation of ongoing alveolar hemorrhage and quanti-
fication of the extent of any fibrotic changes is essential for
a complete preoperative assessment. The presence of dys-
pnea or hemoptysis provides a starting point. Gas exchange
is impaired by ongoing alveolar hemorrhage, and there is an
increased need for transfusion in the perioperative period
because of the acute and chronic loss of red blood cells. It is
prudent to postpone elective surgery until active alveolar
hemorrhage resolves. Evaluating recent chest radiographs for
bilateral alveolar infiltrates or new or changing infiltrates will
help identify ongoing alveolar hemorrhage. These infiltrates
usually resolve 1 to 2 weeks after the bleeding has stopped.
“Honeycombing” may be observed if pulmonary fibrosis has

BOX 4-10   n  ANESTHESIA CONCERNS FOR PATIENTS WITH INFILTRATIVE AND INTERSTITIAL DISEASE
Bronchiolitis Obliterans Organizing Pneumonia
Assess pulmonary function.
Tailor anesthetic plan for each patient.
Idiopathic Pulmonary Hemosiderosis
Assess pulmonary function.
Evaluate for coagulopathy.
Plan for possible bronchoscopy and pulmonary toilet (use large ETT
when possible).
May require stress-dose steroids.
Avoid high airway pressures and tidal volumes.
Chronic Eosinophilic Pneumonia
Assess pulmonary function.
Delay surgery until steroid therapy implemented.
May need intraoperative bronchodilators.
Utilize PEEP cautiously and at low levels, if needed at all; minimize
intrathoracic pressures to decrease shunt.
Goodpasture's Syndrome
Assess cardiopulmonary and renal function (BUN/creatinine,
urinalysis, ABGs, ECG, echocardiography, spirometry).
Maintain oxygenation but limit supplemental O2 to lowest level
consistent with arterial saturation >90%.
Consider invasive monitors.
Arterial catheter used for all but the mildest disease; consider TEE or
PAC if assessment of volume status or adequacy of cardiac output
unclear.
Pulmonary Alveolar Proteinosis
Assess pulmonary function (level of dyspnea, baseline O2 saturation,
time since last BPL, ABGs, chest radiograph).
Double-lumen ETT required for BPL.
Invasive monitoring (PAC, TEE) may facilitate intraoperative management
for higher-risk procedures.
Sarcoidosis
Assess all organ system involvement (PFTs, ECG, echocardiography,
BUN/creatinine).
Evaluate airway to rule out lesions by indirect laryngoscopy or CT.
Possible postoperative ventilatory support.
Consider invasive monitors.
May require perioperative stress-dose steroids.
BPL, bronchopulmonary lavage; BUN, blood urea nitrogen; CT, computed tomography; ETT, Endotracheal tube; LFTs, liver function tests; PAC, pulmonary artery
catheter; PEEP, positive end-expiratory pressure; TEE, transesophageal echocardiography.
developed. Preoperative spirometry is recommended, because
a restrictive pattern develops over the course of the disease. If
active bleeding is present, the diffusion capacity will be artifi-
cially elevated because of absorption by intra-alveolar hemo-
globin. Anemia frequently develops from ongoing alveolar
hemorrhage, and measuring the amount of serum hemoglo-
bin is essential.
If intubation of the trachea is part of the anesthetic plan, the
largest possible ETT should be placed to facilitate bronchos-
copy, if needed, and adequate pulmonary toilet. As with other
restrictive processes, higher airway pressures will occur unless
either a decreased tidal volume is selected or the inspiratory
phase of ventilation is lengthened. The risk of ­pneumothorax is
Chapter 4  Respiratory Diseases 147
Systemic Lupus Erythematosus
Assess all organ system involvement (chest radiograph, PFTs, ABGs,
BUN/creatinine, LFTs).
Invasive monitors may be indicated if cardiac or pulmonary involvement
and for type of surgery (arterial catheters).
Minimize airway manipulation secondary to risk of inflammation and
potential laryngeal involvement.
Refrain from nitrous oxide use secondary to bone marrow suppression.
Ensure thorough evaluation of medications:
Echocardiography may be indicated for cardiac function with high-
dose cyclophosphamide or hydroxychloroquine.
LFTs should be evaluated for hepatotoxicity (azathioprine, methotrexate).
May require stress-dose steroids.
May require increased doses of neuromuscular blockers if taking
azathioprine.
Cyclophosphamide may prolong effects of succinylcholine.
Idiopathic Pulmonary Fibrosis
Assess cardiopulmonary function, (PFTs/spirometry, ECG,
echocardiography).
Evaluate for pulmonary hypertension/cor pulmonale.
Aspiration precautions should be considered secondary to association
with gastroesophageal reflux disease.
Acute Respiratory Distress Syndrome
Assess cardiopulmonary function.
Lung protective ventilation: low tidal volumes (~6 mL/kg predicted body
weight); PEEP to maintain arterial saturation >90%; <30 cm H2O
plateau pressures.
Utilize permissive hypercapnia as needed.
Consider invasive monitors (arterial/central venous catheters, TEE).
Provide supportive care, with carefully guided fluid resuscitation.
Ensure postoperative ventilatory support.
Pulmonary Histiocytosis X
Assess cardiopulmonary function.
Tailor anesthetic management to progression of disease.
Give special attention to possible pathologic fractures.
Lymphangioleiomyomatosis
Assess cardiopulmonary function.
May need enteral/parenteral nutrition perioperatively.
Consider postoperative ventilation support.
increased. Corticosteroids or other therapies for IPH should be
continued throughout the perioperative period (see Box 4-10).
Chronic Eosinophilic Pneumonia
Chronic eosinophilic pneumonia (CEP) is a rare disorder
of unknown etiology characterized by subacute respiratory
symptoms caused by infiltration of the alveoli and intersti-
tium by an eosinophil-rich inflammatory process. For the
­diagnosis to be made, the pneumonia must have no identi-
fiable cause (e.g., infection, sarcoidosis). CEP is more likely
to occur in women and is frequently preceded by adult-onset
asthma. Common presenting symptoms include constitutional
 148 ANESTHESIA AND UNCOMMON DISEASES
TABLE 4-4  n Sequelae of Idiopathic Pulmonary
Hemosiderosis
Sequela Etiology
Recurrent hemoptysis Active alveolar bleeding; very young
children may not be able to
expectorate heme.
Anemia Chronic iron deficiency anemia
related to sequestration of
hemosiderin within alveolar
macrophages
Pulmonary fibrosis Scar tissue and clot formation at
the sites of alveolar hemorrhage
Restrictive lung disease Pulmonary fibrosis
Pulmonary hypertension Obstruction of pulmonary blood flow
in interstitial fibrosis
Cor pulmonale Pulmonary fibrosis and
hypertension
c­ omplaints such as night sweats, weight loss, fever, and cough.
Progression to dyspnea may occur if not treated. Chest radio-
graphs may show dense peripheral infiltrates, described as a
“photographic negative of pulmonary edema.”36 Spirometry in
a symptomatic, untreated patient typically reveals a restrictive
pattern. Diffusion capacity is reduced. If bronchospasm is also
present, the picture may be mixed with a reversible obstruc-
tive component.
Corticosteroids are effective treatment for CEP patients,
with symptoms often improving in 1 to 3 days and radio-
graphic resolution over several months. Unfortunately, recur-
rence is common once corticosteroid therapy is discontinued,
and thus treatment may be needed for life. CEP patients with
concurrent asthma seem to have a lower recurrence rate, pos-
sibly because inhalation corticosteroids are used as part of
the management of their asthma.37 The prognosis for CEP is
excellent because of the effectiveness of corticosteroid therapy.
If possible, surgery should be delayed until CEP patients have
received corticosteroids and experienced resolution of symp-
toms, typically 7 to 14 days.
In the event of emergency surgery, the pathophysiologic
alterations seen in CEP are similar to those of other pneu-
monias. Fever may result in reduced intravascular volume
and increased metabolic rate. Fluid resuscitation to restore
euvolemia before induction will decrease the risk of hemody-
namic instability. The increased metabolic rate and increased
shunt fraction caused by perfusion of inflamed alveoli (which
have impaired gas exchange) will increase the speed of desatu-
ration on induction if apnea develops. Adequate preoxygen-
ation and expeditious securing of the airway are therefore
essential. Intraoperative ventilator management must be
­individualized, attempting to minimize airway pressures while
delivering adequate volumes. If an obstructive component is
present, bronchodilator ­therapy may be helpful, and expira-
tory times may need to be prolonged. PEEP should be used
with caution because it may divert blood flow from ventilated
alveoli and increase the shunt fraction. Adrenal suppression
may exist because many CEP patients are receiving long-
term corticosteroid therapy, and perioperative corticosteroids
should be considered (see Box 4-10).
Goodpasture's Syndrome
Goodpasture's syndrome (GS) is an autoimmune disorder
that affects the lungs and the kidneys. It is caused by circulat-
ing anti–glomerular basement membrane (anti-GBM) anti-
bodies that bind to the vascular basement membrane in the
lung and kidneys, resulting in an autoimmune reaction. The
end result is rapidly progressive glomerulonephritis that is
frequently accompanied by vasculitis and pulmonary hem-
orrhage. The incidence is approximately 1 per 100,000 pop-
ulation, with both genders being affected equally. Genetic
factors are thought to increase the likelihood of developing
GS, although environmental factors such as smoking, infec-
tion, inhalation injury, volume overload, and exposure to
high oxygen (O2) concentrations increase the risk of pulmo-
nary hemorrhage.38,39 The genetic component of GS is poorly
defined. However, there is increased occurrence (88%) of
HLA-DR2 in patients with anti-GBM disease compared with
controls (30%). There is also an increased incidence of disease
in twins, siblings, and cousins of those with GS. Inheritance
of certain allelic variants of immunoglobulin heavy chain also
increases susceptibility to anti-GBM disease.39 Onset of the
disease is dramatic, with sudden hemoptysis, dyspnea, and
renal failure (Box 4-11). New-onset hypertension may also be
part of the presentation. Renal biopsy is necessary to make
the diagnosis and distinguish GS from collagen vascular dis-
eases such as WG.
Because of the sudden onset and severity of the ­disease, i­ nitial
treatment frequently requires hemodialysis and mechanical ven-
tilation. If the GS patient survives the acute phase, high-dose
corticosteroids and cyclophosphamide induce immunosuppres-
sion, and plasmapheresis is used to clear anti-GBM antibodies
and complement. Therapy ­usually lasts 3 to 6 months, with reso-
lution of symptoms ­occurring within the first 2 months. End-
stage renal disease is a ­common complication of GS, and renal
transplantation may be n ­ ecessary. Early diagnosis and treatment
has a strong c­ orrelation with better outcomes.
BOX 4-11   n SYMPTOMS AND SIGNS SEEN IN
GOODPASTURE'S SYNDROME
Dyspnea
Fatigue and weakness
Hematuria
Oliguria
Hemoptysis
Anemia
Hypertension
Azotemia
Proteinuria

If possible, surgery should be delayed until medical manage-
ment is underway and pulmonary involvement has resolved.
In all likelihood, some renal insufficiency, if not failure, will
still be present. Preoperative evaluation should include BUN/
creatinine determinations and urinalysis to assess renal func-
tion. The patient's symptoms and medical condition at sur-
gery will dictate the extent of pulmonary evaluation. This may
include a chest radiograph, ABG analysis, spirometry, and dif-
fusing capacity to quantify the extent and significance of pul-
monary hemorrhage.40 If pulmonary involvement is ongoing,
hypoxemia and a restrictive defect on spirometry are com-
mon. A chest radiograph in a typical patient shows diffuse
bilateral alveolar infiltrates from the pulmonary hemorrhage.
Microcytic anemia from ongoing hemorrhage is also typical.
Oxygenation is the primary challenge of the anesthetic
management of patients who have active GS. With ongoing
alveolar hemorrhage, patients not only will have impaired gas
exchange at the alveolar level, but also will most likely be ane-
mic. These will contribute to decreased O2 delivery to the tis-
sues. Exposure of the lungs to an increased O2 tension and
high airway pressures may exacerbate alveolar hemorrhage.
These stresses, along with overaggressive fluid resuscitation,
should be avoided in all patients with GS to minimize the risk
of further anti-GBM–mediated lung injury. An intra-arterial
catheter is indicated when caring for patients with more than
mild disease. For major procedures in patients with signifi-
cant pulmonary impairment, placement of a PAC or TEE may
be helpful in guiding resuscitation and hemodynamic man-
agement. When selecting anesthetic agents and other medica-
tions, renal function must be considered, and any potentially
nephrotoxic drugs should be avoided. Dosing of medications
that rely on renal excretion should be altered based on the
patient's creatinine clearance (see Box 4-10).
Pulmonary Alveolar Proteinosis
Pulmonary alveolar proteinosis (PAP) is a rare disorder char-
acterized by accumulation of a lipoprotein-rich substance in
the alveoli. There appear to be three distinct forms of PAP.
Congenital PAP presents in infancy and is caused by muta-
tions in the genes coding for surfactant proteins; a defect in
surfactant-associated protein B (SP-B) results in accumula-
tion of surfactant-like material in alveoli.41 The secondary
form of PAP involves decreased alveolar macrophage activ-
ity, either functional impairment or decreased number, which
results in decreased clearance of surfactant products and may
be related to immunosuppression, myeloid disorders, hemato-
logic malignancies, infection, and inhalation of noxious fumes
or toxic mineral dusts. Idiopathic PAP does not fit into either
of the two previous categories and accounts for 90% of cases.42
Idiopathic PAP may also be caused by reduced clearance of
surfactant. The proteinaceous material found in the lungs of
patients with PAP is surfactant.
Patients typically present with gradual onset of cough
and worsening dyspnea with exertion. Chest pain, fever,
and hemoptysis may also be present. Patients may also have
Chapter 4  Respiratory Diseases 149
c­lubbing, cyanosis, and rales. Definitive diagnosis of PAP
requires transbronchial or open-lung biopsy. The clini-
cal course of PAP is variable. Some patients have spontane-
ous improvement or remission; others experience persistent
but stable symptoms. The other possible clinical course is
steady progression of the disease with worsening hypoxia and
increased risk of infection.
Chest radiographs typically have bilateral perihilar infil-
trates extending into the periphery in a “butterfly” or “bat
wing” distribution suggestive of pulmonary edema.43 The
appearance of the chest radiograph may be out of proportion
to the severity of the patient's symptoms. High-resolution CT
findings tend to correlate more closely with the clinical pic-
ture. Spirometry frequently reveals a mild restrictive pattern.
A severe reduction in diffusing capacity is also observed. ABG
analysis demonstrates hypoxemia and an increased alveolar-
arterial gradient from interpulmonary shunting.44
Therapy for congenital PAP is supportive; lung trans-
plantation is the only definitive therapy currently available.
Secondary PAP will typically resolve with treatment of the
underlying disorder. Whole-lung lavage, also known as bron-
chopulmonary lavage (BPL), has been used in the treatment of
acquired PAP for 40 years and is still the current standard of
care. More recent reports detail lobar lavage through fiberop-
tic bronchoscopes in PAP treatment.44 This latter approach is
time-consuming and uncomfortable for the patient and may
be most useful in patients who cannot tolerate whole-lung
lavage or the required general anesthetic.
A patient with moderate to severe disability caused by
PAP should be evaluated for the need to have BPL before any
­elective surgical procedure. Caring for patients receiving BPL
is significantly easier if the contralateral lung has been recently
lavaged, because this will dramatically improve ­oxygenation
during one-lung ventilation, which is required to perform
the procedure. Preoperative testing should be directed by
the patient's level of dyspnea, baseline O2 saturation, and
time since the last BPL was performed. In patients with more
severe symptoms, preoperative ABG analysis or measurement
of room-air, resting, arterial saturation analysis is indicated.
Chest radiography is unlikely to be useful in evaluating the
extent of disease (see Box 4-10).
BRONCHOPULMONARY LAVAGE
A general anesthetic and placement of a double-lumen ETT
are required for BPL. A rapid decrease in O2 saturation on
induction is common, making excellent preoxygenation and
expeditious placement of the double-lumen ETT essential.
An intra-arterial catheter is useful in monitoring the patient's
oxygenation and hemodynamic response to the procedure.
Confirmation of correct positioning of the ETT by fiberoptic
visualization is essential. Testing for leaks that would allow
contamination of the ventilated lung by spillage of lavage
fluid is critical. The nonventilated lung is then lavaged repeat-
edly with saline while the ipsilateral chest wall is mechani-
cally percussed. The procedure is repeated until the drained
saline is almost clear, indicating removal of the majority of
 150 ANESTHESIA AND UNCOMMON DISEASES
the ­lipoproteinaceous material. The BPL fluid should be
warmed to decrease the risk of hypothermia and the volume
of the drainage and presence of bubbles closely monitored, to
ensure isolation of the contralateral lung. Oxygenation may
improve during the instillation of fluid as alveolar pressure
increases. This results in decreased perfusion to the lavaged
lung (which is not being ventilated) and thus improves over-
all ventilation/perfusion matching. Hypoxia is most likely to
occur during the drainage phases of the procedure, when an
increase in intrapulmonary shunting occurs because of the
dramatic drop in alveolar pressure. Significant hemodynamic
changes can also occur during the infusion of saline into the
lung. Hypotension and an increase in central venous pressure
or pulmonary capillary wedge pressure may be seen. TEE
suggests these changes are caused by impaired venous return
to the left side of the heart.45 Presumably, saline infusion
compresses alveolar capillaries, increasing PVR and result-
ing in increased central venous pressure, while also causing
decreased left-sided heart output because of decreased blood
flow to the left ventricle. In some patients the contralateral
lung can be lavaged during the same anesthesia, although
several days may pass between treatments. BPL may result
in improvement lasting 12 to 18 months before it is again
required.
Sarcoidosis
Sarcoidosis is a chronic granulomatous disease of unknown
­etiology that can involve almost any organ system. The diag-
nosis is usually made in the first half of adult life, with an
occurrence in the United States of 20 to 50 per 100,000 popula­
tion, with a higher incidence in African-Americans, p ­ eople
of Northern European descent, and females. The annual
­mortality rate of a patient with sarcoid is low but is increased
by symptomatic cardiac46 or neurologic47 involvement. The
initial presentation of sarcoid will vary depending on the
organ systems affected. Sarcoidosis commonly involves the
skin, eyes, lungs, heart, and CNS. Frequently, abnormal chest
radiographs in asymptomatic individuals raise suspicion. The
lesions responsible for sarcoidosis are noncaseating granulo-
mas, which may spontaneously resolve or proceed to fibrosis.
The vast majority of sarcoid patients have pulmonary
involvement. Many are asymptomatic, whereas others will
have nonspecific complaints such as chest pain, dyspnea, and
nonproductive cough. Radiographic abnormalities progress
from bilateral hilar adenopathy to diffuse pulmonary infil-
tration, and in severe cases, pulmonary fibrosis. PFTs fre-
quently demonstrate restrictive disease with decreased lung
volumes and diffusion capacity. In some cases an obstructive
pattern may also be present because of airway narrowing. In
more advanced cases, ABG analysis reveals hypoxemia and
an increased alveolar-arterial gradient. A significant num-
ber of sarcoid patients have cardiac symptoms resulting from
myocardial granulomas or the effects of respiratory system
disease on the heart. Possible findings include conduction
abnormalities (complete heart block, bundle branch block, or
first-degree AV block), ventricular arrhythmias, CHF, peri-
carditis, supraventricular tachycardia, ventricular aneurysms,
and sudden death.46
Neurologic findings in sarcoid patients are uncommon,
although all the nervous system is at risk. Possible manifesta-
tions of neurologic involvement include seizures, progressive
dementia, diabetes insipidus, hydrocephalus, and acute mono-
neuropathy. Facial nerve neuropathy is the most common of
the neurologic lesions and usually has a benign course.47
The airways are involved in approximately 5% of patients
with sarcoidosis.48 Symptoms may include dyspnea, dyspha-
gia, throat pain, hoarseness, a weak voice, or stridor. Most
lesions are supraglottic and involve the epiglottis, aryepi-
glottic folds, and arytenoids.49 These lesions may result in
airway compromise and, rarely, the need for tracheostomy.
Vocal cord paralysis has also been reported, from recurrent
laryngeal neuropathy caused by sarcoid mediastinal lymph-
adenopathy.50 Encountering a pregnant patient with a his-
tory of sarcoid is not unusual, because sarcoid occurs with an
increased frequency in women of childbearing age. In general,
however, pregnancy tends to improve sarcoid-related symp-
toms, presumably because of increased cortisol levels during
pregnancy.51
Corticosteroids are often required to treat sarcoid and,
regardless of the lack of correlative data, remain the stan-
dard of care. Systemic corticosteroids appear to improve or
shorten the length of most symptoms related to sarcoidosis.
The relapsing, remitting nature of the disease makes it dif-
ficult to verify the efficacy of this treatment. Data are lim-
ited correlating oral steroids and improved lung function.52,53
Remission occurs within 3 years from diagnosis for more than
half of patients with sarcoidosis.54 As is often the case, early
diagnosis and treatment appear to improve the likelihood of
successful treatment. Radiation therapy and immunosuppres-
sants such as cyclophosphamide and azathioprine may also be
used. Anti-inflammatory agents, such as anti–tumor necrosis
factor (anti-TNF) therapy (adalimumab) currently are in clin-
ical trials.54
Serial chest radiographs, PFTs, and serum angiotensin-
converting enzyme (ACE) levels can be used to follow the
progress of a patient. Serum ACE appears to be synthesized
within sarcoid granulomas. High levels are associated with
more severe pulmonary infiltration, and lower levels are seen
with disease inactivity. Trends within a given patient are more
important than the absolute level of ACE. Cardiac rhythm
abnormalities can result from sarcoid heart disease and may
necessitate placement of a pacemaker or implantable cardiac
defibrillator, as well as other treatment for arrhythmias, car-
diomyopathy, and heart failure.
Preparation for anesthesia in a patient with a history of
sarcoidosis should focus on the airway and pulmonary func-
tion, as well as on evaluation of other organ systems known to
have been affected in the individual patient. A review of recent
chest radiographs along with PFTs is recommended. A history
of significant dyspnea warrants an ABG analysis. Screening
for airway involvement can be accomplished by inquiring
 Chapter 4  Respiratory Diseases 151

about dysphagia, hoarseness, or throat pain. If suspected, an Pericarditis, small pericardial effusions, valvular abnormalities,
evaluation by indirect or direct laryngoscopy and, if necessary, and endocarditis represent the majority of the cardiac mani-
head and neck CT will provide the necessary anatomic data. festations. CHF may occur, although usually not the result of
Swelling of supraglottic structures may increase the difficulty cardiomyopathy.55
of intubation and increase the risk of postoperative respiratory Treatment is typically directed at specific symptoms,
compromise. Delaying surgery to allow for adequate cortico- including nonsteroidal anti-inflammatory drugs (NSAIDs)
steroid therapy may be appropriate. Other preoperative test- for arthritic pain, glucocorticoids for anemia and thrombo-
ing is guided by the patient's history and may include ECG cytopenia, anticonvulsants for seizures, anticoagulants for
and echocardiogram if cardiac involvement or advanced pul- thrombosis, and dialysis for end-stage renal disease. Other
monary fibrosis is present. All ongoing cardiac therapy should treatments may include plasmapheresis, azathioprine, and
be continued perioperatively. Because of the sporadic nature cyclophosphamide.
of neurologic symptoms, a thorough neurologic examination Pulmonary manifestations of SLE are the direct result of
is advisable during preoperative evaluation to help differenti- autoantibody reactions in the lung vasculature, lung paren-
ate between existing deficits and those resulting from anes- chyma, and pleura (Table  4-5).56–59 Laryngeal complications
thetic interventions, surgery, or positioning for surgery. Renal in SLE have an incidence of 0.3% to 30% and range from
involvement also occurs, making review of recent electrolyte mild inflammation to vocal cord paralysis, subglottic ste-
and renal function data advisable. nosis, and acute obstruction from edema.56 Therefore, thor-
Intraoperative management of an asymptomatic patient ough airway evaluation and history is crucial preoperatively.
should be uneventful and require little change in the anesthetic Histopathologic findings include alveolar wall damage, inflam-
plan when compared with a healthy individual undergoing the matory cell infiltration, hemorrhage, and hyaline membranes.
same procedure. The patient with significant restrictive lung Some manifestations are thought to occur primarily in SLE
disease will require altered ventilator management and pos- patients with antiphospholipid antibodies, the presence of
sible postoperative ventilatory support. An intra-arterial cath- which is known as antiphospholipid syndrome (APS); 50% of
eter facilitates oxygenation and ventilation management and APS cases occur in patients with SLE, although only a minority
allows close observation and early detection of any hemody- of SLE patients have APS.57 The primary defect in APS is recur-
namic instability. In caring for patients with significant pul- rent arterial and venous thrombosis.58 However, APS is also
monary fibrosis, placement of a PAC or use of TEE may help associated with pulmonary hypertension and diffuse ­alveolar
guide resuscitation and hemodynamic management. Sarcoid
patients with an implantable cardiac defibrillator may need
to have these devices inactivated because of interference from TABLE 4-5  n Systemic Lupus Erythematosus (SLE):
electrocautery units, although modern units are less suscep- Pulmonary Manifestations
tible. In patients with deactivated devices, defibrillator pads Finding Comment
should be placed during the period of inactivation to allow for
external pacing and defibrillation, if needed. Airway manage- PRIMARY MANIFESTATIONS
ment will be dictated by the preoperative evaluation; awake Lupus pneumonitis Mimics acute infectious pneumonia
fiberoptic intubation or elective tracheostomy is occasionally
Diffuse alveolar Rare; may be associated with APS
necessary. Continuation of corticosteroid therapy with con-
hemorrhage
sideration of stress dosing is encouraged.
Lupus pleuritis Pleurisy and pleural effusion are
common in SLE
Systemic Lupus Erythematosus
Interstitial pneumonia Includes lymphocytic and BOOP
Systemic lupus erythematosus (SLE) is a connective tissue dis- variants
ease resulting from autoantibodies directed at cellular nuclei Pulmonary hypertension Resembles PPH; associated with APS
antigens found in multiple organ systems. The cause of SLE
is unknown. SLE can occur in anyone but most often affects Bronchiolitis Rare and unexplained
women of childbearing age. Its incidence is estimated at 40 per Chronic interstitial lung Resembles idiopathic pulmonary
100,000 population in North America. disease fibrosis
Arthritis is the most common clinical manifestation of SLE.
SECONDARY MANIFESTATIONS
Other common signs and symptoms include cutaneous lesions
such as butterfly malar erythema, Raynaud's phenomenon, Pulmonary embolism Caused by recurrent thrombosis
oral ulcers, and recurrent noninfectious pharyngitis. Anemia, associated with APS
thrombocytopenia, leukopenia, and an increased incidence Respiratory muscle Subsegmental atelectasis; elevated
of thrombus formation are possible hematologic sequelae. dysfunction diaphragm; “shrinking lung”
Renal involvement, in the form of glomerulonephritis, has a syndrome
highly variable course. Neurologic findings with SLE include APS, Antiphospholipid syndrome; BOOP, bronchiolitis obliterans organizing
cognitive dysfunction, migraine-like headaches, and seizures. pneumonia; PPH, primary pulmonary hypertension.
 152 ANESTHESIA AND UNCOMMON DISEASES
hemorrhage, ­particularly dire manifestations that predict a
higher mortality.59 The majority of these patients respond to
immunosuppressive therapy and rarely require emergency air-
way intervention.56
Preoperative testing should be directed toward the
affected organ systems. Many SLE patients have mild dis-
ease and require little deviation from the routine periop-
erative evaluation and care required for a given procedure.
A review of serum BUN/creatinine levels is reasonable to
rule out any occult renal involvement. Pulmonary evalu-
ation may include chest radiography, ABG analysis, and
PFTs if current symptoms and history suggest pleuropulmo-
nary involvement. A restrictive pattern is frequently seen on
PFTs, although patients with bronchiolitis will have obstruc-
tion as well. The diffusing capacity is reduced when inter-
stitial disease is present. Diffusing capacity is normal when
corrected for diminished lung volumes if respiratory muscle
dysfunction is the sole cause of underlying restrictive lung
disease.60 Patients with significant pulmonary involvement
may require postoperative ventilation. Ventilator manage-
ment should be tailored to their specific disease process:
diaphragmatic weakness or interstitial fibrosis. During the
perioperative period, patients with APS are at increased risk
of thrombosis, and appropriate precautions must be taken.
Perioperative corticosteroids may be required for patients
with adrenal insufficiency because of chronic corticosteroid
administration (see Box 4-10).
Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF), also referred to as “cryp-
togenic fibrosing alveolitis,” is an interstitial lung disease of
uncertain etiology. IPF is a progressive illness with a median
survival of 3 to 4 years. This rare condition has a prevalence
of about 5 per 100,000 population and is more common in
current or former smokers. A typical patient is a middle-aged
man. Diagnosis is based on the histologic pattern of usual
interstitial pneumonia and exclusion of other causes of this
histologic pattern. Extrapulmonary involvement does not
occur. The presentation is insidious and typically involves
dyspnea and a nonproductive cough. Physical examination
frequently reveals fine crackles at the lung bases, expanding
upward as the disease progresses. Clubbing, cyanosis, periph-
eral edema, and cor pulmonale are later findings. There must
be a restrictive pattern on spirometry and radiologic changes
on chest radiography or high-resolution CT consistent with
the diagnosis.61
Patients with IPF also have an increased incidence of pul-
monary malignancy. Unfortunately, it is unclear if resection
of these lesions adds to life expectancy in this population.62
No effective treatment is currently available, although cortico-
steroid and cytotoxic agents are frequently used. Many novel
therapies attempt to block fibrogenic pathways and may be of
benefit (Table  4-6).63 Lung transplantation is the only thera-
peutic option available for IPF patients. Although thought to
be effective, there is still only a 49% survival rate 5 years after
TABLE 4-6  n Idiopathic Pulmonary Fibrosis:
Experimental Therapies
Therapy Action
Interferon-γ 1b Inhibition of fibroblast proliferation and
collagen synthesis
Pirfenidone Inhibits synthesis of collagen and tumor
necrosis factor alpha
Acetylcysteine Stimulates glutathione synthesis
Data from Selman M, Thannickal VJ, Pardo DA, et al: Idiopathic pulmonary
fibrosis: pathogenesis and therapeutic approaches, Drugs 64:405-430, 2004.
transplantation.64 The median survival time is 2 to 3 years
from time of diagnosis.65
Patients with IPF presenting for surgery typically are
tachypneic and cyanotic and appear to be in poor health.
Preoperative evaluation should include a review of recent spi-
rometry and other PFTs. A decrease in lung volumes with a
reduction in diffusion capacity is expected. Ventilation/per-
fusion inequality and impaired diffusion result in hypox-
emia. In patients with advanced disease, echocardiography
may reveal pulmonary hypertension and cor pulmonale. IPF
patients seem to have a very high incidence of GERD.66 It is
appropriate to consider premedication to reduce gastric vol-
ume and acidity, as well as an anesthetic technique to min-
imize the risk of pulmonary aspiration of gastric contents.
An aspiration event in such a patient could easily be fatal.
Placement of an intra-arterial catheter is advised for all but
the most vigorous of these patients undergoing minor surgery
(see Box 4-10).
Patients with IPF are most likely to present to the operating
room (OR) for lung biopsy to establish the diagnosis, for lung
transplant in a curative effort, or for resection of a pulmonary
neoplasm. These procedures usually require one-lung ventila-
tion, a challenge in patients with advanced disease. Placement
of a double-lumen ETT will provide the added ability to pro-
vide passive oxygenation to the nonventilated lung in an effort
to minimize hypoxemia. Patients with advanced disease may
require postoperative care in an intensive care unit (ICU) and
possible mechanical ventilation.
Acute Respiratory Distress Syndrome
Acute respiratory distress syndrome (ARDS) is a severe form
of acute lung injury resulting from an underlying illness
or lung injury. ARDS may occur in as many as 10 to 20 per
100,000 individuals.67 Several disorders are implicated as risk
factors for developing ARDS, through direct lung injury or
a systemic inflammatory response (Table  4-7). The underly-
ing lesion is injury to the alveolar-capillary membrane and
increased membrane permeability. Proteinaceous edema
fluid accumulates in the alveoli, resulting in impaired oxy-
genation and poorly compliant (stiff) lungs. ARDS develops
acutely over 1 to 2 days. If a patient is alert and spontaneously
 Chapter 4  Respiratory Diseases 153

be inserted. For procedures involving major fluid shifts,

TABLE 4-7  n Acute Respiratory Distress Syndrome:
Associated Clinical Disorders
placement of a PAC or use of TEE may be helpful in guid-
ing resuscitation and avoiding overzealous fluid administra-
Direct Lung Injury Indirect Lung Injury tion, which might adversely impact the patient's respiratory
status. However, ARDS patients in an ICU do not have bet-
Aspiration of gastric contents Sepsis
ter outcomes when managed with a PAC as opposed to a cen-
Inhalation of toxic fumes Major trauma tral venous catheter.73 Neutral fluid balance can also benefit
Near-drowning Reperfusion injury
patients with ARDS, although appropriate fluid resuscitation
and maintenance of vital organ perfusion usually preclude
Pulmonary contusions Massive transfusions such an intraoperative fluid management strategy. Colloids
Diffuse pulmonary infection Drug overdose such as albumin and hetastarch offer no advantage over crys-
talloid solutions because impaired alveolar-capillary mem-
Data from Hudson LD, Steinberg KP: Acute respiratory distress syndrome:
clinical features, management and outcome. In Fishman AP, et al, editors:
branes allow both classes of fluid to reach the extravascular
Fishman's pulmonary diseases and disorders, New York, 1998, McGraw-Hill, space (see Box 4-10).
p 2550.

Pulmonary Histiocytosis X
ventilating, anxiety and dyspnea will be the earliest signs. As
inflammatory changes occur, tachypnea and increased work of Pulmonary histiocytosis X (PHX), also called “pulmonary
breathing will be noted. Langerhans cell granulomatosis,” is an uncommon interstitial
Mechanical ventilation is required to maintain oxygen- lung disease associated with cigarette smoking. Related disor-
ation. Chest radiographs typically reveal diffuse bilateral alve- ders are Hand-Schüller-Christian and Letterer-Siwe diseases.
olar infiltrates similar to the findings of pulmonary edema. The primary defect appears to be the pathologic accumulation
There is no laboratory test to diagnose ARDS. As a clinical of Langerhans cells around bronchioles and the pulmonary
diagnosis, criteria for diagnosing ARDS are acute onset of vasculature, leading to the formation of granulomas and fibro-
respiratory distress requiring intubation and mechanical ven- sis. Most PHX patients present in early adulthood and have
tilation; a Pao2/Fio2 ratio of less than 200, a chest radiograph a history of cigarette smoking, with men and women equally
with bilateral infiltrates suggestive of pulmonary edema, and affected.
no evidence of CHF or, if measured, a pulmonary artery Presenting symptoms are nonspecific and include nonpro-
wedge pressure less than 18 mm Hg.68 Although it has declined ductive cough, dyspnea, fatigue, fever, and weight loss (Table 4-8).
over the past 10 years, ARDS still has a high mortality rate of Reticulonodular infiltrates, upper-lobe and middle-lobe cysts,
25% to 35%. Patients who do survive generally return to a pul- and stellate nodules with sparing of the costophrenic angle on
monary function near their baseline. Any remaining defect is chest radiography highly suggest PHX; bronchoalveolar lavage
likely restrictive or involving decreased diffusion capacity, and (BAL) or biopsy confirms the diagnosis. Results of spirometry
more disabling sequelae are possible.69 may yield an obstructive, restrictive, mixed, or normal pattern.
Intraoperative management of ARDS is an extension of the A decrease in diffusion capacity appears to be the most consis-
patient's ICU care. Many patients have a severe underlying tent finding. Physical limitation in PHX patients is frequently out
injury or illness, which also requires significant perioperative of proportion to spirometry results, and ­pulmonary hypertension
attention. The approach to ventilator management plays a sig-
nificant role in ARDS mortality. Instituting low–tidal volume
ventilation of 6 mL/kg (predicted body weight) and main- TABLE 4-8  n  Pulmonary Histiocytosis X: Associated or
taining plateau pressures of less than 30 cm H2O were found Causal Comorbidities
to reduce mortality by almost 20%.70,71 This approach may
Condition Issues
result in hypercapnia and respiratory acidosis, which can be
monitored and treated with sodium bicarbonate. Permissive Spontaneous pneumothorax May be recurrent
hypercapnia is usually well tolerated and may reduce mortal-
Hemoptysis secondary to Rare
ity from lung injury.72 There is no clear evidence to support aspergillosis
that pressure-cycled ventilation is superior to volume-cycled
ventilation. Primary lung tumors Causative relationship is
unclear.
Administration of PEEP is necessary and results in recruit-
ment of alveoli and better ventilation/perfusion matching. Secondary pulmonary Common, may result in cor
No set level of PEEP has been shown to be superior.71 Other hypertension pulmonale
maneuvers, such as sigh breathing and periodic rotation of Central diabetes insipidus Occurs with central nervous
the patient to the prone position, may result in improved oxy- system involvement
genation but are not associated with improved outcomes.
Cystic bone lesions Cause bone pain and
Invasive monitors will frequently be in place when the patient pathologic fractures
arrives in the OR; if not, an intra-arterial c­atheter should
 154 ANESTHESIA AND UNCOMMON DISEASES
may play a significant role in contributing to diminished exercise
capacity. In advanced disease, pulmonary artery pressures in the
range of 60 mm Hg are not unusual.74
The course of PHX is unpredictable. Improvement or com-
plete remission may occur spontaneously or as the result of
smoking cessation. A minority of patients progress to pulmo-
nary fibrosis. Age at presentation (>26 years), forced expiratory
volume in 1 second/forced viral capacity (FEV1/FVC) ratio less
than 0.66, and right ventricular/total lung capacity (RV/TLC)
ratio greater than 0.33 are cited as predictors of advanced dis-
ease and increased mortality.75 Corticosteroids and chemo-
therapeutic agents are used in attempts to treat PHX, but the
disease is frequently refractory to treatment. Lung transplan-
tation has been performed with success, although PHX has
recurred in the transplanted lungs of patients who had extra-
pulmonary involvement and had resumed smoking.76
Patients who are in remission or have only mild symptoms
do not require special preoperative evaluation or intraoper-
ative management beyond that warranted by the scheduled
procedure. In patients with more advanced disease, a review
of PFT results and ABG analysis and evaluation of pulmonary
pressures by echocardiography or direct measurement are
recommended. Based on these results, intraoperative man-
agement should be tailored to avoid increases in pulmonary
artery pressure. Placement of a PAC may be necessary to help
achieve this goal. The risk of pneumothorax in this population
warrants an effort to minimize peak airway pressures. If dia-
betes insipidus is present, treatment with desmopressin should
be continued perioperatively. The potential for pathologic
fractures from cystic bone lesions requires special attention to
patient positioning and padding. As in all patients with pul-
monary disability preoperatively, the potential for postopera-
tive ventilatory support should be factored into the anesthetic
plan and discussed in advance with the patient (see Box 4-10).
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis (LAM) is a rare, progressive inter-
stitial lung disease of unknown origin that frequently leads to
deteriorating lung function and death secondary to respiratory
failure. LAM occurs in women of reproductive age and is exac-
erbated by pregnancy. It also occurs in male and female patients
with tuberous sclerosis. The condition results from the prolif-
eration of interstitial smooth muscle and formation of cysts,
which obliterate and obstruct the airways. Complaints of dys-
pnea are the typical presenting symptom. Individuals with LAM
develop hyperinflated lungs with an increased total lung capac-
ity. They also develop an obstructive pattern on spirometry.
Spontaneous pneumothorax caused by cyst rupture is common.
Obstruction and eventual rupture of the thoracic duct, resulting
in chylothorax, is another manifestation of LAM. Hemoptysis
occurs infrequently. Chest radiographs are normal appearing
early in the disease but resemble those of end-stage emphy-
sema in advanced disease. Reticulonodular opacities may also
be seen. An obstructive or occasionally a mixed pattern is pres-
ent on spirometry, along with a significant decrease in diffusion
capacity. Exercise capacity will be severely decreased because of
ventilation/perfusion inequality and increased work of breath-
ing.77 ABG analysis typically reveals a decrease in Po2 and Pco2,
although pH is normal.78
Estrogen is thought to play a role in the development of
LAM because of its almost exclusive occurrence in women of
childbearing age, its exacerbation by pregnancy, and pres-
ence of estrogen receptors on biopsy tissue. Recently, rapamy-
cin (sirolimus) has been suggested as a therapeutic option
for LAM. The results are not consistent, and some studies
show significant reduction in size of angiomyolipomas and
improvement of lung function.79 Corticosteroids are ineffec-
tive. Modalities to block the molecular effects of estrogen (e.g.,
doxycycline) have been somewhat more successful. These
approaches include oophorectomy, progesterone, and tamoxi-
fen. Lung transplantation is offered to patients with advanced
disease, although this is frequently complicated by disease-
associated problems such as pleural adhesions, postopera-
tive chylothorax, pneumothorax, and recurrent LAM.79 Lung
transplant may be considered as an option for end-stage pul-
monary LAM. Survival after lung transplant is 79% at 1 year
and 73% at 3 years.80
Preoperative evaluation should include a review of
recent PFTs and chest radiographs, as well as ABG analy-
sis in advanced cases. Elective surgery should be postponed
until after significant chylothorax, if present, can be drained
and chest tubes inserted to resolve existing pneumothoraces.
Recurrent leakage of lymph results in an impaired immune
response and nutritional wasting, which increase the patient's
risk of perioperative complications and should be addressed
before surgery by enteral or parenteral nutritional support.
For patients with advanced disease, ventilator management
should be similar to that for a patient with severe emphysema,
including prolonged expiratory time and avoidance of high
inspiratory pressure. Postoperative ventilatory support may
be required if the patient has severe underlying disease and is
undergoing major or extensive surgery. Placement of an intra-
arterial catheter is helpful in obtaining serial ABGs to guide
ventilator management (see Box 4-10).
ARTHRITIC DISEASES CREATING UPPER
AIRWAY AND RESPIRATORY PROBLEMS
Ankylosing Spondylitis
Ankylosing spondylitis (AkS) is a chronic inflammatory pro-
cess of unknown etiology that primarily deforms the axial
skeleton, resulting in fusion. The disease is predominantly
diagnosed in young adults, with men more likely to be affected
than women. Prevalence in the United States is about 1 in 1000
individuals. AkS apparently has a genetic component, because
most affected individuals are HLA-B27 positive.
As a result of chronic inflammatory changes at the ligamen-
tous insertions onto bone, the vertebrae begin to grow into
each other, forming outgrowths known as syndesmophytes.
These changes result in the appearance of a “bamboo spine”

in radiologic evaluation and decreased mobility of the spine.
This process generally begins in the sacral and lumbar regions,
with cervical involvement occurring much later in the disease
course. Extraskeletal manifestations of AkS may occur, par-
ticularly peripheral joint manifestations; although generally
uncommon, these include aortic insufficiency, cardiac con-
duction abnormalities, iritis, upper-lobe fibrobullous disease,
and pleural effusions. Risk of aspergilloma and hemoptysis is
high if fibrobullous disease develops.81
Involvement of the sternocostal, costovertebral, and tho-
racic spine results in decreased mobility of the thoracic cage
and a restrictive ventilatory pattern. Although common in
AkS patients, decreased exercise tolerance is thought to be
caused by deconditioning as opposed to a primary pulmonary
defect.82 The limitation in thoracic cage movement is almost
totally compensated for by increased diaphragmatic excur-
sion.83 As the disease progresses, exercise tolerance also is
decreased because of the restrictive lung process.
Historically, treatment for AkS was symptom based and
relied on NSAIDs and physical therapy to reduce back pain
and stiffness. Using NSAIDs for long-term therapy poses an
increased risk of peptic ulcers and gastritis in this population.
For this reason, cyclo-oxygenase (COX-2) inhibitors have been
increasingly used as an alternative. The controversy regarding
the cardiovascular safety of COX-2 inhibitors indicates careful
consideration of the risks and benefits. Sulfasalazine, meth-
otrexate, and corticosteroids are used in severe cases. Most
recently, more than a third of AkS patients were in remission
after 5 years of continuous TNF inhibitors therapy.84,85
ANESTHESIA MANAGEMENT
A patient with advanced AkS presents a significant challenge
to the anesthesiologist, frequently needing orthopedic proce-
dures on the hips and knees (Box 4-12). Preoperative e­ valuation
should include radiographs of the lower and ­cervical spine to
BOX 4-12   n ANESTHESIA CONCERNS FOR PATIENTS
WITH ARTHRITIC DISEASE
Ankylosing Spondylitis
Assess cardiopulmonary function.
Review radiographic imaging to determine the significance of cervical
spine disease before airway management and positioning that
necessitate movement of the neck.
Use cautious manipulation of the neck because of instability and
mobility limitations.
These patients should be regarded as having a “difficult airway.”
Neuroaxial anesthesia is very challenging.
Give special attention to positioning.
Kyphosis and Scoliosis
Assess cardiopulmonary and neurologic function.
May have significant blood loss during surgery to correct either
condition.
May have one-lung ventilation.
Deliberate hypotension may be requested intraoperatively.
Take special care with positioning.
Consider intraoperative neurophysiologic monitoring (SSEP, MEP).
Chapter 4  Respiratory Diseases 155
assess the extent of fusion. Caution should be exercised when
instrumenting the airway because of i­nvolvement of the cervical
spine. Decreased range of motion and poor mouth opening can
make direct laryngoscopy difficult, and excess force applied to
the neck can result in cervical fracture. Atlantoaxial subluxation
is also present in a subset of these patients.86 If advanced disease
is present, an alternative and conservative approach to airway
management (including an awake intubation) is strongly recom-
mended, preferably one that maintains spontaneous ventilation.
Adjuncts such as a laryngeal mask airway (LMA), videolaryn-
goscope, and fiberoptic bronchoscope should be readily avail-
able. Neuraxial anesthesia is very challenging in AkS patients.
The ossification of spinal ligaments significantly narrows or even
closes the intervertebral space and prevents optimal positioning.
Alternatives reported as successful include a lateral approach to
spinal placement87 and placement of caudal catheters.88
Intraoperative management must include special attention
to positioning because of the inflexibility of the AkS patient's
spine. Diaphragmatic function should be optimized dur-
ing spontaneous ventilation because of a restrictive thoracic
cage. This can be accomplished by avoiding the Trendelenburg
position and using large-diameter ETTs when possible.
Interscalene blocks can result in short-term ipsilateral dia-
phragmatic paralysis and should be avoided. Higher peak
pressures may occur with PPV and are expected. Adequate
ventilation during laparoscopic surgery may not be possible,
and hypercarbia may develop; if not excessive, it can be toler-
ated until the end of the procedure. Strictest extubation cri-
teria should be observed in patients with AkS, because their
heavy reliance on diaphragmatic function increases their risk
of postoperative respiratory insufficiency, and emergent rein-
tubation carries a significant risk of morbidity and failure.
Kyphosis and Scoliosis
Scoliosis is a lateral and rotational deformity of the spine that also
results in deformity of the rib cage. Kyphosis is an exaggerated
anterior flexion of the spine resulting in a rounded or hump-
backed appearance. These disorders are frequently seen together
and are referred to as kyphoscoliosis. The vast majority of cases
can be classified as idiopathic, congenital, or neuromuscular.
The idiopathic form is the most common and is more likely to
occur in women than men. Corrective surgery is performed for
scoliosis when spinal angulation, also known as the Cobb angle,
exceeds 50% in the thoracic or 40% in the lumbar spine.89
Preoperative assessment should focus on any cardiovas-
cular, respiratory, or neurologic impairment related to the
deformity. Restrictive lung disease is common, the result of
a narrowed chest cavity. Although patient history will pro-
vide significant insight into the level of disability, PFTs and
ABG analysis are crucial in evaluating the extent of restric-
tion and hypoxemia. This information will guide deci-
sions regarding postoperative ventilatory support. PFTs are
likely to demonstrate a reduced vital capacity and total lung
capacity, as well as a normal residual volume. Hypoxemia
results from v­entilation/perfusion inequality. Patients may
 156 ANESTHESIA AND UNCOMMON DISEASES
also h­ ypoventilate. Cor pulmonale resulting from chronic
hypoxemia and pulmonary hypertension may be present in
advanced cases. These concerns make electrocardiography,
echocardiography, and, in some situations, an exercise stress
test reasonable components of preoperative testing. A his-
tory and physical examination is sufficient to evaluate the
patient's neurologic status. It is important to document any
pre-­existing neurologic deficits so as to differentiate between
baseline deficits and those resulting from surgery. This is also
helpful in minimizing further injury secondary to position-
ing or airway management.
Corrective spinal surgery is the procedure most likely to
bring these patients to the OR. The many variations include
anterior, posterior, and combined approaches, as well as lum-
bar and thoracic level repairs. A combined anterior/posterior
approach under a single anesthetic has a higher rate of major
complications than a staged procedure and is best avoided if
possible.90 Many elements of the anesthetic plan, such as posi-
tioning and the need for one-lung ventilation, will be dictated
by the specific procedure.
ANESTHESIA MANAGEMENT
Despite differences in the types of spinal surgery, several con-
cerns apply to all. These procedures frequently involve signifi-
cant blood loss, possible one-lung ventilation, and the need
for deliberate hypotension. The patients have underlying pul-
monary restrictive disease. All of these factors make arterial
line placement and ABG analysis critical to effective periop-
erative management. The presence of restrictive lung disease
combined with prone or lateral positioning can make oxygen-
ation and ventilation with acceptable peak airway pressures
challenging. The use of an anesthesia machine or ventilator
capable of pressure control ventilation may be helpful. Based
on the level of preoperative disability, the need for postopera-
tive ventilation should be discussed with the patient and fam-
ily. Of note, adequate oxygenation during one-lung ventilation
for anterior thoracic approaches may be difficult. Placement
of a double-lumen ETT instead of a bronchial blocker offers
the advantage of delivering passive oxygenation to the non-
ventilated lung. However, such tubes have the disadvantage of
needing to switch to a single-lumen ETT at the end of the pro-
cedure if postoperative ventilation is required. Improvement
in the patient's pulmonary function does not occur immedi-
ately after surgery, and any improvement may take months to
several years, depending on the procedure.91
Large-bore venous access, central or otherwise, is needed to
ensure rapid replacement of intraoperative blood loss. Central
venous pressure monitoring is of limited usefulness in these pro-
cedures because of the effects of positioning on the values obtained
and possible pulmonary hypertension or cor pulmonale, which
reduces the value of central venous pressure monitoring in deter-
mining the adequacy of intravascular volume. TEE is a reasonable
choice to monitor intravascular volume status and cardiac con-
tractility, if available and if the patient's position allows.
Spinal cord monitoring such as somatosensory evoked poten-
tials (SSEPs) and, to a lesser extent, motor evoked potentials
(MEPs) are frequently used to detect direct trauma or vascular
compromise to the spinal cord. Data obtained by TEE and venous
oxygen saturation (SvO2) monitoring suggest that spinal cord
ischemia that results from distraction of the spine is the result of
both direct compression of the spinal cord as well as decreased
cardiac output and decreased BP caused by compression of vena
cava or the heart.92 Intraoperative neurologic monitoring has
become the standard of care for procedures involving signif-
icant distraction of the spine. Patient temperature, pH, and
adequate BP must all be maintained within narrow limits to
maximize the effectiveness of SSEP monitoring. Controversy
surrounds the preferred anesthetic agents with SSEP moni-
toring. The literature is frequently contradictory, and institu-
tional preferences vary greatly, although propofol infusions
and nitrous oxide are popular. The most important factor does
appear to be administration of a stable anesthetic, with mini-
mal bolus dosing and close communication with the clinician
monitoring the evoked potentials (see Box 4-12).
DRUG-INDUCED LUNG INJURY
Bleomycin Toxicity
Bleomycin is an antineoplastic antibiotic used in combination
chemotherapy for a number of malignancies, including Hodgkin's
lymphoma, Wilms’ tumor, and testicular cancer. Although effec-
tive in treating bacterial and fungal infections, bleomycin is not
used for these purposes because of its cytotoxicity. The appeal of
bleomycin in combination chemotherapy protocols is its lack of a
myelosuppressive effect. This avoids adding to the bone marrow
toxicity common to other antineoplastic agents.
Unfortunately, bleomycin carries the risk of inducing pul-
monary toxicity, which can result in pulmonary fibrosis and
can be life threatening. Total dose received relates to the
extent of pulmonary toxicity in animals, but this is less clear
in humans. There is no consensus on a cumulative dose that
increases risk, although more than 300,000 IU is the suggested
threshold.93 Intravascular administration may be a risk fac-
tor compared with intramuscular dosing.94 Chest irradiation
in conjunction with bleomycin therapy appears to increase
the risk of bleomycin-induced pulmonary fibrosis, as does
advanced age, a history of smoking, and treatment with other
chemotherapeutic agents that have pulmonary toxicities, such
as busulfan, carmustine, semustine, and lomustine. Impaired
renal function increases the risk of toxicity by reducing the
elimination of bleomycin from the body.
Pulmonary toxicity caused by bleomycin results in a simi-
lar pulmonary fibrosis as seen in IPF. Patients usually present
with a nonproductive cough accompanied by dyspnea. Chest
radiographs initially reveal bibasilar infiltrates, but as the pro-
cess continues, the radiograph will take on a “honeycomb
lung” appearance. PFTs will have a restrictive pattern in symp-
tomatic patients but are of little predictive value in asymptom-
atic patients who have been exposed to bleomycin.
Evaluation of the bleomycin patient for anesthesia focuses
on pulmonary function, symptoms (e.g., dry cough, dyspnea,
decreased exercise tolerance), and risk factors (e.g., large
cumulative dose, chest radiation, smoking). If the patient

denies symptoms, chest radiographs, PFTs, and ABG analysis
are not likely to be useful. Symptomatic patients require testing
to quantify their disability, plan appropriate perioperative care,
and determine the need for postoperative ventilatory support.
ANESTHESIA MANAGEMENT
A landmark study has guided the anesthetic management of
bleomycin patients for 35 years. Goldiner et  al.95 implicated
­hyperoxia and fluid overload as increasing the risk of periop-
erative pulmonary morbidity and mortality in patients who
received bleomycin. Although subsequent studies have ques-
tioned these guidelines, there is no reason to believe that pro-
viding a higher fraction of inspired oxygen (Fio2) than that
needed to maintain adequate oxygenation is of any benefit
to these patients. The one exception to this is during preoxy-
genation, which is relatively brief, before induction of general
anesthesia.94 When adequate oxygenation does require an Fio2
greater than 30%, use of PEEP may facilitate oxygen action
without necessitating higher levels of Fio2. Fluid therapy
should be conservative, with the goal of maintaining adequate
intravascular volume and avoiding excess fluid administra-
tion. There is no evidence to support the use of colloid instead
of crystalloid in bleomycin patients. When significant blood
loss or significant fluid shifts are expected in surgery, intra-
arterial and central venous catheters may be helpful. There is
no clear answer as to how long after completion of therapy
with bleomycin a patient continues to be at risk for pulmonary
fibrosis, although minimizing Fio2 for 1 to 2 years would seem
prudent (Box 4-13).
In patients with documented pulmonary bleomycin tox-
icity, higher-than-normal peak pressures are expected with
PPV, although this may be necessary for adequate oxygenation
and ventilation. Strict extubation criteria should be observed
because these patients are at increased risk of postoperative
pulmonary complications; sedating medications decrease
respiratory effort and should be minimized postoperatively. If
the surgery permits, the use of regional techniques with min-
imal sedation and opioids may be helpful. Good postopera-
tive pulmonary toilet, including deep breathing and coughing,
must be encouraged to reduce the risk of postoperative pul-
monary complications.
INFECTIOUS DISEASES
Influenza A
Although outbreaks of influenza are common, the strain and
severity vary significantly. Influenza pandemics occur every
few decades and are devastating. More than 40 million people
BOX 4-13   n ANESTHESIA CONCERNS FOR PATIENTS
WITH BLEOMYCIN TOXICITY
Assess cardiopulmonary function.
Use conservative fluid resuscitation.
Minimize fraction of inspired oxygen (Fio2).
Ensure aggressive postoperative pulmonary care.
Chapter 4  Respiratory Diseases 157
died during the pandemic in Spain in 1918, and 1 million died
in Hong Kong in 1968.96 Both were the result of an influenza
A strain variant (H1N1). Influenza viruses undergo continual
antigenic drift, aiding in their ability to resist the host's immu-
nity. This contributes to the continued pandemics of viruses,
particularly influenza A strains. Most recently, the H1N1
strain led to catastrophic mortality, particularly in the infant
and young population. First identified in Mexico in 2009,
H1N1 quickly spread worldwide. This variant is composed of
swine, bird, and human strains of influenza A. The rates of
transmission are higher than for the seasonal influenza. The
main route of transmission is human-to-human exposure
through large respiratory droplets or contaminated surfaces.
Patients present with a combination of flulike symptoms,
including fever, cough, shortness of breath, fatigue, diarrhea, and
vomiting. Associated comorbidities include asthma, obesity, and
diabetes mellitus. Infants and children are at increased risk, as
are patients with chronic health conditions, those receiving renal
replacement therapy, and pregnant women. Concomitant com-
plications include myocarditis, encephalitis, ARDS, refractory
hypoxemia, and secondary bacterial infections (e.g., sepsis).
A few diagnostic tests are available for influenza A, but
treatment should not be delayed awaiting results. Patients with
a high index of suspicion should be treated without a confir-
matory test. A provisional diagnosis can be established within
30 minutes to 1 hour by the rapid influenza diagnostic test
(RIDT). However, both RIDT and direct immunofluorescent
assay (DFA) are unable to differentiate between pandemic and
seasonal influenza variants and have lower sensitivity than real-
time reverse-transcriptase polymerase chain reaction (rRT-
PCR) and viral culture. Confirmation of pandemic virus can
be determined only by rRT-PCR or viral culture (Table 4-9).
Prophylactic treatment is of no benefit and increases the
risk of resistance to antiviral medication such as neuraminidase
inhibitors (e.g., oseltamivir phosphate). Early treatment in high-
risk patients with antiviral medication within 48 hours of onset of
symptoms may reduce morbidity and mortality. Older patients
are less susceptible to the recent pandemic strain, but if infected
and they develop disease, the clinical manifestations are more
severe. Vaccination is one of the most effective methods to reduce
morbidity and mortality associated with influenza. Specific vacci-
nations do not provide protection against other influenza viruses.
The vaccine is effective 14 days after vaccination.
Most deaths result from rapidly progressive respiratory fail-
ure, ARDS, and refractory shock. These patients deteriorate 3
to 5 days after onset of symptoms. They present with resistant
hypoxia and frequently require respiratory rescue therapies
such as neuromuscular blockade, inhaled NO, prone posi-
tioning, and high-frequency oscillatory ventilation (HFOV).
Extracorporeal membrane oxygenation (ECMO) may be
beneficial in patients with severe infection, but it is unclear
whether it decreases mortality.
ANESTHESIA MANAGEMENT
The anesthesiologist is at high risk of exposure to influenza
virus (Box 4-14). Therefore, full contact precautions are indi-
cated, including disposable fluid-resistant gowns, goggles, face
 158 ANESTHESIA AND UNCOMMON DISEASES

TABLE 4-9  n  Diagnostic Testing for Influenza A

Diagnostic Test Typical Processing Time Sensitivity for H1N1 2009 Method

Rapid influenza diagnostic test 0.5-1 hour 10%-70% Antigen detection

(RIDT)

Direct immunofluorescent assay (DFA) 2-4 hours 47%-93% Antigen detection

rRT-PCR* 48-96 hours 86%-100% RNA detection

Viral culture† 2-10 days ---- Virus isolation

Data from Fartoukh M, Humbert M, Capron F, et al: Severe pulmonary hypertension in histiocytosis X, Am J Respir Crit Care Med 161:216-223, 2000.
*Real-time reverse-transcriptase polymerase chain reaction.
†Differentiate among other influenza A viruses.

Southeast Asia, SARS had made its way to North America dur-
BOX 4-14   n ANESTHESIA CONCERNS FOR PATIENTS ing 2003, with hundreds of cases in Ontario, Canada. More than
WITH INFECTIOUS DISEASE 8000 reported cases of SARS worldwide resulted in over 700
Influenza A (H1N1) deaths. Whether, when, or where another outbreak may occur is
Assess cardiopulmonary function. unknown, but familiarity with the syndrome and how to contain
May have ARDS presentation. the spread are the responsibility of all health care professionals.
Severe cases may require postoperative ventilatory support. Otherwise healthy individuals can be infected by contact
Restrict steroid use.
Anesthesiologist is at high risk of exposure.
or droplet spread, which may be person to person or indi-
Use full contact precautions. rectly through contact with contaminated surfaces, because
Take special care to avoid contamination of equipment and surfaces. the coronavirus can live in the environment for 24 to 48
Provide supportive management. hours. The virus enters the body through mucosal surfaces
Severe Acute Respiratory Syndrome in the respiratory tract and eyes. The incubation period is 2
Assess cardiopulmonary function. to 7 days. Presenting symptoms are vague and include high
Anesthesiologist is at high risk of exposure. fever, dry cough, malaise, myalgia, and shortness of breath,
Use full contact precautions.
which typically progresses to pneumonia and in severe
Take special care to avoid contamination of equipment and surfaces.
Ensure supportive management. cases to v­ entilator-dependent respiratory distress syndrome.
Diagnosis is based on clinical and epidemiologic data, because
Echinococcal Disease of Lung
Assess pulmonary function.
no laboratory test reliably detects infection early in the clinical
Large cysts may cause respiratory compromise. course.98 Treatment of infected patients is primarily support-
May have one-lung ventilation. ive and similar to that of any other atypical pneumonia. None
Provide supportive management. of the currently available antiviral drugs has been shown to be
effective against SARS-CoV.

shields, gloves, and handwashing. Personal protection systems
may be advisable for personnel caring for such patients (see
SARS). Treatment and perioperative management of those
with clinically severe disease is mainly supportive and simi-
lar to that of patients with ARDS who require ventilatory
management. Intraoperative invasive monitors, such as arte-
rial and central catheters, may be useful for cardiopulmonary
management. Corticosteroids should be restricted to patients
with adrenal suppression because these drugs have been asso-
ciated with increased mortality in H1N1-infected patients,
increasing viral shedding time and the risk of coinfection.97
Severe Acute Respiratory Syndrome
Severe acute respiratory syndrome (SARS) is a highly infectious
disease transmitted by a coronavirus (SARS-CoV). It results
in atypical pneumonia, which may progress to respiratory
distress syndrome. First recognized in 2002 with cases in
ANESTHESIA MANAGEMENT
The anesthesiologist's contact with SARS patients occurs pri-
marily during airway management for patients in respiratory
distress (see Box  4-14). The anesthesiologist will be close to
the patient's upper airway and thus at high risk of exposure to
the virus. Full contact precautions are recommended, includ-
ing disposable fluid-resistant gowns, goggles, face shields,
double gloving, handwashing, and N95 (or equivalent) fit-
tested masks.99 Standard surgical face masks and gowns are
inadequate. Removal and disposal of equipment so as not to
contaminate the wearer or others is as important as using the
proper protection. Some institutions have taken the added pre-
caution of using a personal protection system (PPS) for per-
sonnel involved in high-risk procedures with SARS patients.
These PPS units consist of belt-mounted, powered air puri-
fiers with high-efficiency particulate air (HEPA) filters and a
lightweight headpiece. Use of this equipment requires training
as well as adequate donning time. The noise generated by the
system makes communication and a­ uscultation of breath and

cardiac sounds difficult.99,100 Attention must also be directed to
avoiding contamination of anesthesia workstations and equip-
ment. This includes placing HEPA filters on the inspiratory
and expiratory limbs of ventilators and anesthesia machines.
Providers must be mindful of everything they touch or that
comes into contact with the patient and ensure appropriate
cleaning or disposal of these materials. Maintaining separate
clean and dirty work areas may be helpful in this regard.100
Echinococcal Disease of Lung
Echinococcal disease or hydatid disease occurs when a human
is infected with Echinococcus granulosus, a canine tapeworm.
The eggs of the worm are passed in the feces of infested dogs.
Humans acquire the infection by unintentionally ingesting
the eggs. Larvae then migrate to the liver, with some eventu-
ally arriving in the lungs and other tissues. The parasites then
mature to form hydatid cysts. The lung forms a protective gran-
ulomatous layer around the cyst, which over time becomes
fibrotic. It is estimated that hydatid cysts grow 1 to 2 cm a year.101
As a result of the fecal-oral transmission, echinococcal lung dis-
ease is more common in children than adults. Overall it is rare
in North America but common in other parts of the world.
These cysts are frequently asymptomatic, and pulmonary
cysts are often detected on routine chest radiographs. The most
likely symptoms are cough, dyspnea, and chest pain. Rupture
of a cyst can occur spontaneously or on surgical manipula-
tion. This may result in an anaphylactic reaction or spread the
disease to other organs. For this reason, transthoracic needle
aspiration should never be attempted. Chest radiographs will
reveal a cystic lesion, which may be rather large, accompanied
by an area of pneumonitis or atelectasis. There is no effective
medical treatment for hydatid cyst of the lung, and surgical
removal is the preferred therapeutic option.
Patients with small, asymptomatic cysts require no preop-
erative evaluation beyond the routine. Larger cysts may result
in respiratory compromise, typically presenting as dyspnea.
Spirometry may reveal decreased volumes because of the
space-occupying lesion. Respiratory acidosis and hypoxemia
may also be present. In advanced disease, the patient may not
tolerate surgery or anesthesia. In these rare circumstances,
removal of the cyst has been performed under thoracic epi-
dural anesthesia with success.102
ANESTHESIA MANAGEMENT
For patients considered reasonable candidates for general
anesthesia, one-lung ventilation may be requested to optimize
surgical exposure for resection of the cyst. Isolation of the con-
tralateral lung field has the added benefit of decreasing the risk
of contamination should the cyst rupture during surgery. The
patient with only unilateral disease should have little difficulty
tolerating one-lung ventilation, because the unaffected side is
primarily responsible for gas exchange if the cyst is clinically
significant. An arterial catheter is appropriate when one-lung
ventilation is planned. Close communication between surgeon
and anesthesiologist during drainage and delivery of the cyst
Chapter 4  Respiratory Diseases 159
is essential to avoid spillage. In the event of contamination,
anaphylaxis may occur, and the anesthesiologist should be
prepared by having large-bore IV access, as well as immediate
availability of epinephrine, diphenhydramine, and corticoste-
roids (see Box 4-14).
CONCLUSION
Clinical interactions with patients who have uncommon
pulmonary conditions may range from a simple excisional
biopsy for asymptomatic pulmonary sarcoid, to a hip replace-
ment in ankylosing spondylitis, to a double-lung transplant
for end-stage cystic fibrosis. The spectrum of procedures
therefore extends from the routine to the extraordinarily
complicated. Successful management of patients with respi-
ratory disorders is often challenging in both the conceptual
and technical realms. An understanding of the pathophysi-
ology and treatment of the uncommon pulmonary disorder
will allow the anesthesiologist to anticipate likely clinical
problems and tailor anesthetic management to minimize the
chance of intraoperative and postoperative complications.
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 C H A P T E R
5
Liver Diseases
ANAHAT DHILLON, MD  n
RANDOLPH H. STEADMAN, MD  n

KEY POINTS
Normal Hepatic Anatomy
Hepatic Function in Health n The liver receives a dual afferent blood supply; the portal
Carbohydrate Metabolism vein provides 75% and the hepatic artery 25% of hepatic
Lipid Metabolism and Transport inflow. With differences in oxygen content, each source
Protein Synthesis contributes about 50% of the liver's oxygen supply.
Detoxification and Transformation n Hepatocytes make up 80% of the liver. Nonparenchymal
Bilirubin Metabolism cells include Kupffer cells, members of the monocyte-
The Injured Liver phagocyte system that play a key role in immunity. Stellate
Cellular Responses cells undergo transformation to fibroblasts and produce
Laboratory Manifestations of Hepatobiliary Dysfunction collagen in response to injury, fundamental to fibrosis and
Etiology of Liver Dysfunction cirrhosis.
Viral Hepatitis n Hepatic dysfunction affects most organ systems because of
Hydatid Cyst Disease the liver's extensive metabolic, detoxification, and digestive
Nonalcoholic Steatohepatitis functions; alterations cause encephalopathy, coagulopathy,
Genetic Causes of Liver Disease and muscle wasting.
Drug-Associated and Other Toxic Liver Disease n Liver injury leads to fibrosis and portal hypertension,
Ischemic Liver Injury which is responsible for ascites, gastrointestinal bleed-
Liver Function in the Geriatric Patient
ing, and renal dysfunction, the characteristic manifesta-
Biliary Cirrhosis
tions of cirrhosis.
Pregnancy-Associated Liver Disease
n The major causes of liver disease include noncholestatic
Systemic Effects of Liver Disease
cirrhosis, cholestatic cirrhosis, acute hepatic necrosis, bili-
Cardiovascular Effects
ary atresia, metabolic diseases, malignant neoplasms, and
Portal Hypertension and Ascites
drug-induced injury. Noncholestatic cirrhosis includes
Renal Effects
hepatitis; hepatitis C is the most common diagnosis in U.S.
Pulmonary Effects
Hepatic Encephalopathy
liver transplant recipients.
Assessment of Perioperative Risk n Nonalcoholic steatohepatitis is increasing in incidence
Anesthetic Management in the United States, possibly secondary to the obesity
Abnormal Laboratory Values in Asymptomatic Patients epidemic.
Acute Hepatitis n Alagille's syndrome is the most common form of familial
Cirrhosis intrahepatic cholestasis; 90% of patients have associated
Acute Liver Failure congenital heart disease, most often pulmonic stenosis.
Transjugular Intrahepatic Portosystemic Shunt n Alpha-1-antitrypsin deficiency, the most common meta-
Biliary Tract Procedures bolic disorder of the liver, is associated with decreasing
Hepatic Resection FEV1 and exacerbated by smoking.
Liver Transplantation n Hemochromatosis first affects the liver, then the pancreas
Postoperative Liver Dysfunction with diabetes mellitus, the skin with bronze pigmentation,
Conclusion and iron deposition in the heart with restrictive cardiomy-
opathy and arrhythmias.
162
 Chapter 5  Liver Diseases 163

n Mucopolysaccharidoses affect enzymes in glycosaminogly-
can metabolism. Each presents differently, but all may be
associated with difficult intubation from immobility and
macroglossia.
n Postoperative jaundice can result from increased production
of bilirubin, hepatocellular injury, and cholestasis. Causes
include hemolysis of transfused red blood cells, reabsorp-
tion of hematomas, liver hypoperfusion, and drug-induced
injury.
n Further key points are noted throughout the chapter.
The liver is a complex organ system with myriad functions that
is susceptible to dysfunction as a result of disease p
­ rocesses and
physiologic abnormalities. A dysfunctional liver can affect the
function of almost every organ system in the body. Anesthesia
and surgery can stress the reserve of the liver, resulting in
worsening function even without overt evidence of cause.
These factors can make the preoperative, intraoperative, and
postoperative care of patients with liver disease challenging.
An understanding of normal hepatic structure and function,
the acute and chronic responses of the liver to v­ arious types of
injury, and the behavior of the healthy or diseased liver dur-
ing perioperative events helps structure an approach to anes-
thetic management issues. Representative disease ­processes
are examined for unique aspects of ­perioperative evaluation
and care for patients with specific liver diseases.
NORMAL HEPATIC ANATOMY
depends on the normal variations in splanchnic blood flow, as
regulated by the arterioles and capillary flow of the splanch-
nic bed. Hepatic artery blood flow demonstrates autoregula-
tory changes in response to blood pressure, as well as to portal
blood flow and sinusoidal oxygen levels.
The liver comprises two lobes of unequal size, the right and
left lobes, as divided by the falciform ligament. These lobes can
be further subdivided into the eight segments of Couinaud
(Fig.  5-1), based on separate vascular and biliary branches.
Vascular outflow through the hepatic veins crosses between
segments. Segments may be surgically resected to excise patho-
logic lesions or living-directed donation for transplantation.
Microscopically, the classic concept of the hepatic histologic
structure is that of the hepatic lobule (Figs. 5-2 and 5-3). This
model is that of a polygon, typically a hexagon, with branches
of the portal triad (hepatic artery, portal vein, and bile duct)
at the vertices. A central vein, technically a venule, marks the
central axis of the lobule. Mixed arterial and portal blood flows
from the vessels at each vertex, through the sinusoids, to the
common central vein. The sinusoids are formed by one-cell-
thick plates of hepatocytes and lined with endothelial cells.
These sinusoids differ from normal capillaries because of the
Extended left hepatectomy
(left trisegmentectomy)
Extended right hepatectomy
(right trisegmentectomy)

Certain aspects of hepatic anatomy and physiology with

Right hepatectomy Left hepatectomy
implications for perioperative care of the patient with liver
disease include (1) the dual blood supply of systemic blood Right Right Left Left
via the hepatic artery and portal venous blood from the posterior anterior medial lateral
splanchnic circulation; (2) histologic arrangement of hepato- section section section section
cytes, including the unique hepatic sinusoids and the result- Hepatic vein Middle hepatic vein
ing blood-hepatocyte interface; and (3) isolation of biliary Left hepatic vein
and blood compartments with regulation of enterohepatic
circulation.1,2 VII II
VIII
The liver is the largest parenchymal organ in the human I IVa
body, representing approximately 2% of total body weight in
the adult. Blood flow to the liver is normally 100 mL/100 g of
tissue per minute, or 25% to 30% of the resting cardiac out- III
put. The metabolic functions of the liver are facilitated by the IVb
interposition of the liver between the splanchnic and systemic V
VI
venous systems. Approximately 75% of the blood supply to Umbilical vein
the liver is delivered by the portal vein. This blood is partially (remnant)
deoxygenated as a result of oxygen extraction by the splanch- Gallbladder Cystic Inferior vena cava
duct Hepatic artery
nic organs. After coursing through capillary beds of the
Bile duct Portal vein
­stomach, pancreas, spleen, and intestines, portal venous blood Hepatic duct
contains high concentrations of nutrients, as well as secreted FIGURE 5-1  Liver segments. Schematic depiction of Couinaud
and ingested exogenous substances. Under normal circum- segmental liver anatomy and the normal portal venous structures.
stances, this portal blood provides 35% to 50% of the oxygen Bracketed text shows hepatic segments resected during partial
delivered to the liver. The well-oxygenated blood of the hepatic hepatectomies. (Modified from Curley SA, Barnett CC, Abdalia EK:
artery delivers the remaining 50% to 65% of ­oxygen, despite Surgical resection for hepatocellular carcinomas, Up-to-date.
being only 25% of the liver's blood supply. Portal venous flow www.uptodate.com; accessed 1/15/12.)
 164 ANESTHESIA AND UNCOMMON DISEASES

Bile duct mixture of portal venous and arterial blood. They also lack a
Portal vein Central vein Sinusoids basement membrane, and their endothelium has fenestrations
Hepatic artery typically ranging in size from 50 to 200 nm. These ­fenestrations
and the low sinusoidal pressure allow a multitude of solutes,
including macromolecules, to enter the perisinusoidal space
of Disse. Here, molecules are in direct contact with the micro-
villi of the hepatocyte's basolateral membrane. The hepatocyte
also has specialized canalicular membrane portions with dis-
tinct microvilli. In combination with the adjacent hepatocyte,
this specialized area forms the wall of the bile canaliculi, its iso-
lation completed by tight intercellular junctions. Intracellular
actin and myosin filaments along the canalicular channel are
presumed to promote drainage of bile into the canals of Hering
and subsequently into the interlobar bile ducts.
Concentric zones radiating from the portal triad out to the
draining venule, numbered 1 to 3, reflect decreasing oxygen
content in the sinusoidal blood and decreasing concentrations
of nutrients arriving from the gut. These zones correlate with
Hepatic
artery
differential enzyme concentrations, metabolic activities, and
Bile duct Portal vein degree of cellular damage caused by a variety of agents and
situations (Fig. 5-4).
FIGURE 5-2  Hepatic lobule seen as three-dimensional
Although hepatocytes make up about 80% of the liver, a host
polyhedral unit. Terminal portal triads (hepatic artery, portal vein,
and bile duct) are at each corner and give off branches along the of other cells are found in the liver. Two important nonparen-
sides of the lobule. Hepatocytes are in single-cell sheets with chymal cells are Kupffer and stellate cells. Kupffer cells are mem-
sinusoids on either end, aligned radially toward a central hepatic bers of the monocyte-phagocyte system (macrophage derived)
venule. (Modified from Ross MH, Reith EJ, Romrell LJ: The liver. In and typically reside on the luminal aspect of sinusoidal endo-
A text and atlas, Baltimore, 1989, Williams & Wilkins. www.lww.com; thelial cells. Their phagocytic and inflammatory responses are
accessed 2/27/11.) important in sepsis, eliminating bacteria and clearing inflam-
matory mediators. Thus, patients with liver disease tend to be
prone to infectious complications. Stellate cells (Ito cells) are
found in the space of Disse and, in health, store lipids and vita-
min A. In the fibrogenic response to injury, however, the stel-
late cells undergo transformation to f­ibroblasts and produce
Bile Bile collagen, which leads to loss of fenestrations and creation of a
ductule canaliculus pseudo–basement membrane. This is believed to be a funda-
mental step in the development of hepatic fibrosis and cirrhosis.

KEY POINTS
n The liver is the largest parenchymal organ.
n Blood flow is normally 25% to 30% of cardiac output.
n Portal vein is responsible for 75% of blood flow and 35% to

50% of oxygen delivery.

n Hepatic artery is responsible for 25% of blood flow and 50%

Portal Hepatic Kupffer cell Sinusoids Central vein to 65% of O2 delivery.

vein artery n Hepatocytes are arranged in zones leading away from

­portal triad; each zone shows varying degrees of O2 con-

Terminal
branches
tent, enzyme concentrations, metabolic activity, and cellular
damage.
FIGURE 5-3  Portal triad in cross section. Blood enters
n Through the liver, carbohydrate and lipid metabolism
sinusoids (blue with black arrows) and egresses through central
vein (blue). Sinusoids contain Kupffer cells (purple). Hepatocytes ­provides an energy source for the body.
n The liver produces proteins in plasma (except for immuno-
(pinkish tan) produce bile and secrete it into bile canaliculi
(green with black arrows), which drain into bile ductule of portal globulins), detoxifies and transforms endogenous and exog-
triad. (Modified from The Internet Encyclopedia of Science. http:// enous substances, metabolizes heme, and provides immune
daviddarling.info/encyclopedia/L/liver.html; accessed 2/27/11.) function of Kupffer cells.
 Chapter 5  Liver Diseases 165

Nodal Nodal
point point

Central Terminal
vein hepatic venule

Portal
tract
Nodal Nodal 1 2 3
point point

Portal tract

FIGURE 5-4  Liver architecture. At left is classic hepatic lobule, with central vein as its center and portal tracts at three corners. In
middle is portal unit, with portal tract at its center, and central veins and nodal points at its periphery. At right is liver acinus, center of
which is terminal afferent vessel (in portal tract) and periphery of which is drained by terminal hepatic venule, or central vein. Zones 1,
2, and 3 extending from portal tract to terminal hepatic venule are shown. (Modified from Misdraji M: Embryology, anatomy, histology, and
developmental anomalies of liver. In Feldman M, Friedman L, Brandt LL, editors: Sleisenger & Fordtran's gastrointestinal and liver disease,
ed 9, Philadelphia, 2010, Saunders-Elsevier, p 1201.)

HEPATIC FUNCTION IN HEALTH
Carbohydrate Metabolism
The liver provides for the body's varying energy requirements
under the modulation of neural and endocrine regulators.
Complex interacting systems of energy storage and utiliza-
tion are required to compensate for asynchronous periods of
nutritional ingestion and energy demand. Figure 5-5 presents
a simplified diagram of carbohydrate and lipid metabolism in
the hepatocyte.
Many cells of the body are glucose dependent (e.g., eryth-
rocytes, renal medullary and retinal cells) or glucose prefer-
ential (e.g., brain cells). Maintenance of blood glucose levels
depends on nutritional circumstances. Glucose is eventually
released from stored glycogen through glycogenolysis, as pro-
moted by epinephrine and glucagon. The liver and the skel-
etal muscle contain the vast majority of the body's glycogen.
Glycogen stores in the adult liver during fasting are capable
of providing adequate glucose levels for 24 to 48 hours, repre-
senting 250 to 500 mg of glucose. During fasting the brain will
transition from glucose dependency to ketone metabolism
and thus sustain itself while greatly decreasing the body's daily
glucose utilization. Gluconeogenesis is the creation of glucose
from lactate, pyruvate, and amino acids, the products of anaer-
obic and catabolic metabolism, as stimulated by the depletion
of glycogen stores.
The liver can rapidly switch from glycogen breakdown to
glycogen formation, depending on the current nutritional
state and energy requirements. Disruption of carbohydrate
homeostasis can be a manifestation of liver dysfunction.
Acute liver injury (e.g., viral hepatitis) is often associated
with mild hypoglycemia despite normal or depressed insu-
lin levels. Hypoglycemia can be pronounced in the alcoholic
patient despite apparently minimal hepatic decompensation;
ethanol cannot be used in gluconeogenesis, and its metabo-
lism can c­ ritically reduce the availability of pyruvate. In ful-
minant hepatic failure of any cause, hypoglycemia can be life
threatening.
Glucose intolerance, conversely, is often observed in chronic
liver disease. Although insulin levels may actually be elevated
because of decreased hepatic clearance, peripheral receptors
are decreased in number. Additionally, receptor-binding char-
acteristics and activity may be altered. Hepatocytes may also
be isolated from the usual concentrated levels of portal pan-
creatic insulin release because of portosystemic shunting.
Lipid Metabolism and Transport
Fatty acids provide the most efficient energy source for both
intrahepatic and extrahepatic storage and utilization. The
liver's central role in lipid metabolism, beyond utilization,
involves regulated conversion of excess carbohydrates to fatty
acids, esterification of free fatty acids to form triglycerides for
transport and storage, and synthesis of transport proteins.
In normal circumstances, the liver takes up a relatively fixed
amount of free (nonesterified) fatty acids regardless of dietary
intake. This provides the major energy source for hepato-
cytes. The nutritional state determines the subsequent balance
between synthesis and esterification of fatty acids in the fed
state versus oxidation in the fasting state (Fig. 5-6).
 166 ANESTHESIA AND UNCOMMON DISEASES

Blood

Glucose
Fructose
Hepatocyte Pho Glut 2
Glycogen sp
Glucose

ho
Glu-6-Pase GK Regulatory protein

ryla
Glucogen Glucose-6-P 

se
cycle 
UDPG Pentose phosphate pathway Fru-1-K

 Fructose 6-P
Glucose-1-P 6-Fru Kinase/Pase Fructose-1-P
6 PF-1-K
Fruc-1,6-P2ase  
Fructose-2,6-P2
Fructose-1,6-P2
Triglycerides

Dihydroxyacetone phosphate D-glyceraldehyde 3-phosphate

Acetyl CoA Fatty Acyl-CoA -glycerol

Glycerol
Peroxisomal H2O2
 oxidation  Fatty acid
O2 synthase
Fatty Acyl-CoA PEP
Fatty acids Malonyl-CoA
PEPCK OAA
Fatty acid Fatty Acyl PYR PK Acetyl CoA
carnitine
Acyl-CoA PYRDH carboxylase
Carnitine
synthase
 T Mitochondrion Acetyl CoA
TI
Fatty Acyl-CoA CP Fatty Acyl
Carnitine carnitine PYR
I
TI  ATP citrate lyase
CP Fatty Acyl-CoA Acetyl CoA
FAD Acetyl CoA

FADH2  oxidation Tricarboxylic

OAA Citrate Citrate
acid cycle

CO2  energy

FIGURE 5-5  Hepatic carbohydrate and lipid metabolism. Gluconeogenic pathways are identified by dashed lines. 6-Fru Kinase/Pase,
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase; 6 PF-1-K, 6-phosphofructo-1-kinase; ATP, adenosine triphosphate; CoA, coenzyme
A; CPT, carnitine palmitoyltransferase; FAD, flavine adenine dinucleotide; FADH2, reduced flavine adenine dinucleotide; Fru-1-K, hepatic
fructokinase; Fruc-1,6-P2ase, fructose-1,6-biphosphatase; 1-P, 1-phosphate; 1,6-P2, 1,6-diphosphate; 2,6-P2, 2,6-diphosphate; 6-P, 6-phosphate;
GK, glucokinase; Glu-6-Pase, glucose-6-phosphatase; Glut 2, glucose transporter 2; OAA, oxaloacetate; PEP, phosphoenol pyruvate; CK,
carboxykinase; PK, pyruvate kinase; PYR, pyruvate; PYRDH, pyruvate dehydrogenase; T, carnitine:acylcarnitine transferase; UDPG, uridine
diphosphate glucose. (Modified from Roy-Chowdury N, Roy-Chowdury J: Liver physiology and metabolism. In Feldman M, Friedman L, Brandt LL,
editors: Sleisenger & Fordtran's gastrointestinal and liver disease, ed 9, Philadelphia, 2010, Saunders-Elsevier, p 1217.)

Hepatic steatosis (“fatty liver”) refers to abnormal accu-

mulation of predominantly triglycerides with fatty acids in
hepatocytes. Previously defined in terms of weight percentage
(>5%) or number of hepatocytes affected (>30% in a ­lobule),
the diagnosis is now also grossly correlated to findings of
noninvasive imaging. Conditions associated with steatosis
­ transport (e.g., albumin, transferrin, lipoprotein, haptoglo-
include obesity, alcohol ingestion, pregnancy, nonalcoholic
steatohepatitis, and certain drug toxicities, as discussed later.
Cholesterol is not a direct energy source but serves as a
structural unit of membranes and is a precursor for steroid
production. Most cholesterol is synthesized in the liver and,
in combination with dietary cholesterol, is either secreted in
the bile, incorporated into lipoproteins for plasma transport,
or converted to bile acids.
Protein Synthesis
With the exception of immunoglobulins, the liver produces
the vast majority of proteins found in plasma, including pro-
teins of coagulation, plasma-binding proteins involved in
bin), and acute-phase reactants. These proteins share many
common synthetic pathways but have distinguishing charac-
teristics of substrate, modulation, and kinetics that explain the
clinically variable response to injury and disease. For exam-
ple, the clotting factors dependent on vitamin K for post-
translational modification can be affected by K's nutritional
intake or absorption, whereas inflammatory mediators stim-
ulate acute-phase reactants. Serum albumin levels reflect not
 Chapter 5  Liver Diseases 167

Dietary cholesterol
and triglyceride
Intestine Chylomicrons

FA
storage FA energy

Nascent
Feces Remnants
HDL

Bile
FFA acids Scavenger
receptor
Hepatic HDL
Triglyceride Cholesterol LDL Cholesterol
lipase binding LCAT
ACAT site
Cholesteryl
VLDL ester
Liver LDL
receptor
FFA
Macrophage

Hormone- VLDL IDL HDL3

sensitive Triglyceride
lipase LCAT

Lipoprotein CETP HDL2

Triglyceride
lipase

Cholesteryl
Adipose tissue ester
FIGURE 5-6  Lipoprotein metabolism. FA, Fatty acid; FFA, free fatty acid; LDL, low-density lipoproteins; VLDL, very-low-density lipoproteins;
IDL, intermediate-density lipoprotein; HDL, high-density lipoproteins; CETP, cholesteryl ester transfer protein; ACAT, acylcholesterol
acyltransferase; LCAT, lecithin-cholesterol acyltransferase. (Modified from Roy-Chowdury N, Roy-Chowdury J: Liver physiology and
metabolism. In Feldman M, Friedman L, Brandt LL, editors: Sleisenger & Fordtran's gastrointestinal and liver disease, ed 9, Philadelphia,
2010, Saunders-Elsevier, p 1217.)

only production from available amino acids but also volume
of distribution, abnormal losses (e.g., ascites, pleural effu-
sion, proteinuria), and regulators responding to parameters
such as serum oncotic pressure. Another protein monitored
in patients with liver disease is alpha fetoprotein (AFP). Its role
is primarily in neonatal life, with most of it being replaced by
the first year. Hepatocellular proliferation in adulthood will
result in an increase in AFP levels. High levels are seen in acute
hepatitis and liver failure and are a marker for hepatocellular
carcinoma. Altered protein levels, which actually reflect liver
disease, will develop after variable periods, depending on the
synthetic rates and plasma half-life of the particular proteins.
Thus, although it is generally true that serum protein levels
will be decreased with liver dysfunction, the specific l­ aboratory
abnormality and time frame (hours or days for coagulation
factors vs. weeks for albumin) are important d ­ iagnostic clues
in liver disease.
Detoxification and Transformation
The liver is the major site in which both xenobiotics (foreign
chemicals) and endogenous substances undergo detoxification
and transformation. These changes usually generate less active
and more hydrophilic compounds. In notable exceptions,
transformation actually renders substances toxic, as discussed
later. The pathways involved are categorized into three phases.
Phase 1 metabolism alters the molecule by reactions, usually
involving the cytochrome P450 enzyme system (CYP450),
such as oxidation, reduction, and hydrolysis. Phase 2 metabo-
lism conjugates the parent molecule or its metabolite with a
polar molecule (e.g., acetate, amino acid, sulfate, glutathione)
and thus further enhances water solubility. Phase 3 elimina-
tion is an energy-dependent excretion. A particular molecule
may undergo any or all of these processes. Changes in the
pathway(s) utilized may occur as dictated by substrate concen-
trations, enzyme induction, disease, and nutritional status.
Bilirubin Metabolism
Bilirubin is a tetrapyrrole produced from the breakdown of
heme at the rate of about 250 mg/day in the normal adult.
About two-thirds comes from hemoglobin of senescent eryth-
rocytes processed by the reticuloendothelial system, and the
remainder mostly from nonhemoglobin hemoproteins (e.g.,
CYP450 enzymes). The turnover of myoglobin is slow enough
that its substantial hemoprotein content does not contrib-
ute significantly to bilirubin production. Heme is first con-
verted to biliverdin by heme oxygenase and then to bilirubin
 168 ANESTHESIA AND UNCOMMON DISEASES
by biliverdin reductase. This unconjugated bilirubin, which is
water insoluble and neurotoxic at high levels, is bound to albu-
min and transported to the hepatocyte, where it is conjugated
with glucuronic acid to form bilirubin monoglucuronide and
diglucuronide. After secretion into canaliculi, bilirubin is
incorporated into bile and remains unchanged through the
gallbladder and most of the small intestine. In the terminal
ileum and colon, hydrolysis by bacterial enzymes produces
urobilinogen, which is reabsorbed, and re-excreted predomi-
nantly in bile, with a small fraction filtered by the kidney into
the urine.
THE INJURED LIVER
Cellular Responses
The liver can sustain injury from a variety of processes, both
primary to the organ (e.g., viral hepatitis) and secondary (e.g.,
right-sided heart failure or metastatic cancer). Regardless of
the cause, general categories of cellular consequences are typi-
cally observed.
Hepatitis is simply liver injury associated with the incur-
sion of inflammatory cells. Depending on the type of hepatitis,
hepatocyte injury may stimulate the inflammatory response
(e.g., toxic injury) or may be secondary to it. Degeneration is
defined in terms of microscopic findings. Foamy degeneration
occurs with ineffective biliary excretion, whereas ballooning
degeneration is found in toxic and immunologically m ­ ediated
injury. Steatosis specifically represents accumulation of fat
droplets in the cell. Multiple small accumulations are seen in
microvesicular steatosis (e.g., acute fatty liver of pregnancy),
whereas macrovesicular steatosis is defined as a large nucleus-
displacing droplet (e.g., obese and diabetic patients).
Necrosis can occur after a variety of injuries. Necrosis
results in poorly stained cells with lysed nuclei, frequently
exhibiting zonal distributions. Centrilobular necrosis is a com-
mon pattern in which the most severe damage immediately
surrounds the central vein. This is characteristic of toxins and
ischemic injury, the latter presumably reflecting the decreas-
ing oxygen content of the sinusoidal blood as it flows to the
terminal venule, whereas the toxic pattern may reflect not only
relative hypoxia but also regions of high metabolic a­ ctivity
and biotransformation. Periportal necrosis, conversely, is
exceedingly unusual but may be found in pre-eclamptic
patients for unknown reasons. With most injuries, a variety
of necrotic and inflammatory patterns are seen. Focal necro-
sis denotes scattered necrosis within lobules, whereas more
severe ­bridging necrosis spans adjacent lobules. Apoptosis is the
energy-­dependent deconstruction of cells with an attenuated
inflammatory response and salvage of cell components that
can be reused. The conditions and regulators that ­influence
apoptosis in the liver are being elucidated.3,4 Whether the bal-
ance between necrosis and apoptosis can be predicted or even
manipulated clinically remains to be seen.
Regeneration and fibrosis represent two different outcomes
in the liver's attempt to replace injured liver units. The liver,
since the Greek myth of Prometheus, has a reputation for its
unparalleled ability to regenerate. When its connective tissue
framework is left intact, the liver can actually re-form itself
from less than half of its original size, as demonstrated in
living-directed liver donors. Similarly, the liver that has under-
gone extensive necrosis may subsequently recover essentially
normal structure, except for minor abnormalities of bile duct-
ules and parenchymal arrangement. Stimulating factors thus
far identified in the human include epidermal, transforming,
and hepatocyte growth factors.
Fibrosis is a much different consequence of injury response.
It is generally irreversible and will compromise function.
Fibrosis results from the deposition of collagen within the
space of Disse, around portal tracts, or around the central
vein by transformed stellate cells. Previously healthy hepato-
cytes are eventually replaced with connective tissue. Cirrhosis
is the term applied to nodules of regenerating hepatocytes
within such scar tissue, reflecting the impact of disruption of
the normal connective framework before or during regenera-
tion. This architectural disruption results in increased resis-
tance to hepatic blood flow, with eventual portal hypertension
and decreased functional mass with impaired metabolic and
excretory function. Box 5-1 outlines causes of hepatic fibro-
sis and cirrhosis, which represent the consequences of a wide
range of diseases. In the Western world, about 90% of cirrho-
sis of known etiology is related to alcoholic liver disease, viral
hepatitis, or biliary disease. Approximately 10% of cases are of
unknown etiology and are termed cryptogenic cirrhosis.
Laboratory Manifestations of Hepatobiliary
Dysfunction
Most common tests have limitations of sensitivity and
­specificity and assess narrow aspects of hepatic function. The
­concept of a panel of tests that represent a measure of hepatic
reserve or “liver function tests” is flawed. However, different
patterns of abnormalities do often correlate with the under-
lying pathology and allow further targeted investigation.
Table  5-1 summarizes common tests used to evaluate liver
disease. These tests can be broadly divided into two catego-
ries, those that reflect liver injury and those that reflect liver
function. The markers of direct injury include released hepatic
enzymes. Synthetic function can be reflected in protein levels
and clotting times, whereas dye clearance and drug transfor-
mation can be used to investigate blood flow and metabolic
capacity.
TESTS THAT REFLECT HEPATIC CLEARANCE
Ammonia
The liver normally clears ammonia from the blood and
­converts it to urea for renal excretion. With severe liver dys-
function or portosystemic shunting, ammonia levels may be
elevated. Although typically used in the evaluation of possible
hepatic encephalopathy, ammonia levels correlate poorly with
the severity of clinical presentation.
 Chapter 5  Liver Diseases 169

BOX 5-1   n CAUSES OF HEPATIC FIBROSIS AND CIRRHOSIS

Medications and Toxins Chronic hepatitis (B, C, and D) Tyrosinosis

Alcohol Cytomegalovirus Wilson's disease
α-Methyldopa Echinococcosis Wolman's disease
Amiodarone Schistosomiasis
Arsenic Syphilis (tertiary and congenital)
Other Causes
Autoimmune chronic hepatitis
Carbon tetrachloride
Chlordecone
Metabolic and Genetic Disorders Biliary obstruction (chronic)
α1-Antitrypsin deficiency Budd-Chiari syndrome
Isoniazid
Alagille's syndrome Cystic fibrosis
Methotrexate
Biliary atresia Idiopathic portal hypertension
Methylene diamine
Fanconi's syndrome Jejunoileal bypass
Nitrofurantoin
Fructose intolerance Nonalcoholic steatohepatitis
Oral contraceptives
Galactosemia Primary biliary cirrhosis
Pyrrolizidine alkaloids
Gaucher's disease Primary sclerosing cholangitis
Sulfa antibiotics
Glycogen storage disease Right-sided heart failure and tricuspid
Vitamin A
Hemochromatosis regurgitation (chronic)
Infections Hereditary tyrosinemia Sarcoidosis
Brucellosis Ornithine transcarbamylase
Capillariasis Porphyrias

TABLE 5-1  n  Characteristic Biomarkers in Liver Disease

HEPATOCELLULAR NECROSIS BILIARY OBSTRUCTION

Etiologies and Lab Results Toxin or Ischemia Viral Alcohol Complete* Partial Chronic Infiltration

Transaminases 50-100× 5-50× NL to 5× NL to 5× 1-3×

(aminotransferases) 2-5×

Alkaline phosphatase (ALP) 1-3× 1-3× 1-10× 2-20× 2-20× NL to 20×

Bilirubin 1-5× 1-30× 1-30× 1-30× 1-5× NL to 5×

Prothrombin time (PT) Prolonged; minimal or no improvement with Often prolonged; may improve Normal
vitamin K with parenteral vitamin K

Albumin Decreased in chronic disease Often normal; may be Usually normal

decreased

Illustrative disorders Shock liver, Hepatitis Pancreatic Hilar tumor, Sarcoid, metastatic
acetaminophen A or B cancer sclerosing carcinoma
toxicity cholangitis

Modified from Daven TJ, Sxharschmidt B: Biochemical liver tests. In Feldman M, Friedman LS, Sleisenger MH, editors: Sleisenger & Fordtran's gastrointestinal and liver
disease, ed 7, Philadelphia, 2002, Saunders, p 1231.
*Acute onset of complete biliary obstruction may result in massive elevations in transaminases that are transient and in the range of 20 to 50 times normal.
×, Times elevation from normal, NL, normal.

Bilirubin TESTS THAT REFLECT SYNTHETIC FUNCTION

As discussed with normal metabolism, bilirubin is a product
of heme breakdown. It exists in conjugated (water soluble) and
unconjugated (lipid soluble) forms, which are reported impre-
cisely as the direct and indirect fractions, respectively. Serum bil-
irubin is usually less than 1 mg/dL and primarily unconjugated.
Elevated serum levels occur in most significant liver diseases;
degree of elevation correlates with prognosis in primary bili-
ary cirrhosis, alcoholic hepatitis, and fulminant liver failure. The
appearance of conjugated bilirubin in the blood is thought to be
caused by reflux from the hepatocyte, but this does not discrimi-
nate between obstructive and parenchymal causes. Other causes
of elevated bilirubin include Gilbert's syndrome, increased pro-
duction (e.g., hemolysis, i­neffective erythropoiesis, hematoma
resorption), and inherited d ­ isorders of bilirubin transport.
Albumin
Albumin is synthesized only in the liver, typically at a rate of 100
to 200 mg/kg/day in the adult, and under normal ­circumstances
the plasma half-life is 3 weeks. Abnormalities are poorly specific
for liver disease, however, because many factors affect its produc-
tion and turnover. For example, nutritional state, plasma osmotic
pressure, and thyroid levels all affect the rate of albumin produc-
tion. The increased albumin losses seen in nephrotic syndrome,
burns, and protein-wasting enteropathies also affect the balance
between production and loss of albumin. Hypoalbuminemia can
be helpful in assessing chronic liver disease when nonhepatic
causes are excluded. Its prolonged half-life means that measured
changes are slow to develop and slow to revert to normal in rela-
tion to the onset and resolution of the causative process.
 170 ANESTHESIA AND UNCOMMON DISEASES

Prothrombin Time elevated in many forms of liver disease, presumably as a result

Prothrombin time (PT) determinations depend on serum of leakage from damaged cells. Substantial hepatic necrosis as
concentrations of fibrinogen, prothrombin, and factors V, VII, found in chemical and ischemic injury appears to be partic-
and IX, all of which are products of the liver. Furthermore, the ularly associated with elevation of these enzymes. Advanced
half-life of these factors is short enough (<24 hours) that the cirrhosis can exist without significant elevations if active cell
PT changes rapidly. Given their short half life, factor V and VII injury is absent or minimal at the time of evaluation.
levels can also be followed in evaluating liver f­ unction in ful- The relative increase in AST compared with ALT can be use-
minant liver failure. An abnormal PT can result from reduced ful in supporting a diagnosis of alcohol injury (AST/ALT >2)
factor synthesis (e.g., vitamin K deficiency, liver ­ failure, versus most other acute liver injuries (AST/ALT ≤1), although
­warfarin therapy) or increased factor loss (e.g., disseminated cirrhosis is also associated with AST/ALT ratio greater than 1.
intravascular coagulation). Absolute levels can be diagnostic when extreme and helpful
Vitamin K deserves special mention in the context of the when moderately elevated (see Table 5-1).
PT. Prothrombin and factors VII, IX, and X undergo post-
Lactate Dehydrogenase
translational carboxylation of glutamic acid residues that
Because of its presence in tissues throughout the body, lactate
is necessary for activity and requires vitamin K as a cofac-
dehydrogenase (LDH) usually offers little diagnostic discrimi-
tor. Deficiency of vitamin K or antagonism of this process by
nation beyond that of the transaminases. However, LDH does
­warfarin (Coumadin) alters the PT. Additionally, in the jaun-
demonstrate a short-lived but exceptionally high elevation in
diced patient, a favorable response to parenteral vitamin K
ischemic injury, as well as a moderate but sustained increase
implies that intake or absorption of vitamin K is abnormal,
in some malignancies.
versus a nonresponse, which implies that parenchymal disease
is at least partly the basis for the abnormality (see Table 5-1).
KEY POINTS
SERUM ENZYME TESTS
n No single test is specific for hepatic reserve.
Alkaline Phosphatase
n Hepatic clearance may be tested with ammonia and biliru-
Hepatic alkaline phosphatase (ALP) is concentrated in the
bin levels.
canalicular hepatocyte membrane and bile duct epithelial
n Bilirubin can be elevated secondary to hemolysis, hema-
cells, and increased production and release appear to cause the
toma resorption, and disorders of biliary transport.
elevated ALP levels seen in cholestasis. However, ALP exists in
n Synthetic function can be tested with albumin and pro-
normal tissues throughout the body as well as in extrahepatic
thrombin time.
neoplasms. Elevated levels are not specific for biliary disease
n Albumin is made only in the liver, but many factors affect
because states of increased metabolic activity are associated
production and turnover.
with increased ALP activity in the affected tissue. Therefore,
n Abnormal PT can result from reduced factor synthesis or
young adults with rapid bone growth and gravid patients with
increased factor loss.
placental production routinely have elevated ALP levels. ALP
n Serum enzymes may reflect hepatocyte or injury, but none
levels as high as three times normal occur in many liver dis-
is isolated to the liver; GGTP is more specific for the liver
eases. More pronounced increases suggest infiltrative pro-
than ALP.
cesses or biliary obstruction, which can be intrahepatic (e.g.,
tumor) or extrahepatic. Even if the entire biliary tree is not
obstructed, ALP can be greatly elevated.
ETIOLOGY OF LIVER DYSFUNCTION
Gamma-Glutamyl Transpeptidase
Liver dysfunction has been categorized in a variety of ways.
γ-Glutamyl transpeptidase (GGTP) has a tissue distribution
Clinical presentation (e.g., jaundice), etiology (e.g., viral
similar to alkaline phosphatase except that it has low concen-
­hepatitis), circumstances (e.g., postoperative liver dysfunc-
trations in bone. Thus, GGTP may be helpful in discriminat-
tion), time frame, and severity (e.g., subfulminant liver failure)
ing the source of ALP elevations. However, GGTP can also be
are common descriptors, but none offers a complete descrip-
quite sensitive to the ingestion of alcohol and drugs, including
tion. For example, acute liver failure may have an infectious
several anticonvulsants.
or toxic etiology, whereas viral hepatitis may result in abrupt,
Transaminases (Aminotranferases) severe liver dysfunction or may proceed along a chronic, sub-
Aspartate transaminase (AST, formerly known as SGOT [serum clinical course.
glutamic-oxaloacetic transaminase]; also called aspartate ami-
notransferase) and alanine transaminase (ALT, formerly SGPT
[serum glutamic-pyruvic transaminase]; also alanine amino-
Viral Hepatitis
transferase) are participants in gluconeogenesis. Both enzymes Although a vast number of viruses can produce hepatitis
are plentiful in the cytosol of the hepatocyte, and an AST iso- (Table  5-2), only five viruses produce liver disease as their
zyme is present in the mitochondria as well. AST is also found primary clinical manifestation.5 Each of the five hepatitis
­
in a variety of tissues, including heart, brain, and skeletal viruses has been designated with a letter (e.g., hepatitis A, hep-
muscle; ALT is more specific to the liver. These enzymes are atitis B) according to their clinical manifestations (Table 5-3).
 Chapter 5  Liver Diseases 171

fecal-oral route after ingestion of contaminated food or drink.

TABLE 5-2  n  Uncommon Causes of Viral Hepatitis
The virus is absorbed through the small bowel and trans-
Virus Vaccine Available ported by the portal blood flow to the liver.7 HAV replicates in
the liver and is then shed into the blood or, more frequently,
Epstein-Barr virus (EBV) No through the bile and into the stool. Viral shedding begins as
Cytomegalovirus (CMV) No early as the second week of infection and consequently may
occur before the patient experiences any clinical signs or symp-
Human herpesvirus type 1 (HHV-1) In development
toms of hepatitis. Viral shedding may continue until 2 weeks
Human herpesvirus type 2 (HHV-2) In development after the onset of jaundice. Although the virus is shed into the
Coxsackievirus type B No
stool in high titers, viral titers in the blood remain low dur-
ing the short (1-2 weeks) viremic phase.8 As such, transmis-
Echoviruses No sion of HAV by blood transfusion is extremely rare, although
Adenovirus Yes, for certain subtypes;, transmission from a single donor has been reported.9,10 The
limited to military use virus has also been transmitted to hemophiliac patients with
­contaminated factor VIII concentrates.11
Yellow fever virus Yes
After an incubation of 15 to 50 days, patients may experi-
Varicella-zoster virus Yes ence the acute onset of systemic complaints, ­including fever,
Measles Yes malaise, nausea, vomiting, and abdominal pain. Patients may
also note the appearance of dark urine and jaundice. Mild
hepatic enlargement and tenderness is noted in approxi-
mately 85% of patients, with splenomegaly in up to 15%.12
It is important to remember that although each virus infects Coagulopathy, encephalopathy, and renal failure are rare in
the liver, the hepatitis viruses have different biochemical, patients with acute HAV infection.12,13 The infection is nor-
biologic, and clinical characteristics. Indeed, the viruses do mally a self-limited illness, with complete recovery usually
not form a phylogenetic family and are not actually related. in less than 2 months; however, serious complications can
Although infection with each virus can be associated with occur.14 Underlying liver disease is associated with increased
significant morbidity and mortality, infection with any virus risk of fulminant hepatic failure with HAV superinfection.15,16
may result in an anicteric illness and may not be diagnosed as Chronic hepatitis does not occur, but an atypical, relapsing
hepatitis.6 course has been described in both children and adults.17
Diagnosis of HAV infection is usually confirmed by sero-
HEPATITIS A logic testing. Anti-HAV immunoglobulin M (IgM) is detect-
The hepatitis A virus (HAV) is a 27 to 32–nm, nonenveloped able in the serum approximately 3 weeks after exposure.
virus (Picornaviridae) with a 7.5-kilobase genome of single- Early diagnosis is also possible with the detection of HAV
stranded (ss) RNA. HAV is almost always transmitted by the in stool using electron microscopy or the detection of viral

TABLE 5-3  n  Characteristics of Human Hepatitis Viruses A (HAV) to E (HEV)

Hepatitis A B C D E

Virus family Picornaviridae Hepadnaviridae Flaviviridae Viroid Caliciviridae

Genome ssRNA Partially dsDNA SsRNA ssRNA ssRNA

Transmission:
 Fecal-oral Yes No No No Yes
 Sexual No Yes Rare Rare No

Blood/percutaneous Rare Yes Yes Yes No

Incubation period 15-50 days 4-26 wk 2-26 wk 3-7 wk 15-60 days

Immunity IgG anti-HAV IgG HBsAB Unknown IgG HBsAb IgG anti-HEV

Chronic hepatitis No Yes Yes Yes No

Fulminant failure <1% <1% Rare 2%-10% 1% (30% in pregnancy)

Cirrhosis No Yes Yes Yes No

Modified from Ryder SD, Beckingham IJ: BMJ 322:151-153, 2001; and Berenguer M, Wright T: Viral hepatitis. In Feldman M, Friedman L, Sleisenger M, editors:
Sleisenger & Fordtran's gastrointestinal and liver diseases, ed 7, Philadelphia, 2002, Saunders.
Ss, Single-stranded; ds, double-stranded; Ig, immunoglobulin.
 172 ANESTHESIA AND UNCOMMON DISEASES
RNA; however, both methods are impractical. Although 75%
of adult patients with HAV have clinical manifestations, up
to 70% of infections in children younger than 6 years are
asymptomatic.18 Their bowel hygiene and capacity to act as
asymptomatic carriers make children the principal reservoir
for the virus.
Hepatitis A infections occur throughout the world but are
more common in developing countries with poor sanitation.
In the United States, the incidence of HAV infection is 9 to
10 per 100,000 population, with an overall seroprevalence of
30%. Two highly effective vaccines18 available in the United
States since 1996 are recommended for children19 and adults18
with chronic liver disease. Anesthesiologists and all health
care providers should consider immunization. In the event of
possible transmission of HAV to a health care provider, a sin-
gle dose of 0.02 mL/kg immune globulin is highly effective in
preventing infection if given within 14 days of exposure.18
HEPATITIS B
The hepatitis B virus (HBV) is a 42-nm, enveloped virus
(Hepadnaviridae) with 3.2-kb genome of partially double-
stranded (ds) DNA. Worldwide, more than 400 million people
have chronic HBV infection.20,21 Unlike HAV, HBV is primar-
ily transmitted by blood, blood products, and sexual con-
tact. Perinatal infection can occur, with evidence of infection
occurring across mucous membranes through semen, saliva,
and breast milk.22 Intravenous (IV) drug use remains a major
mode of HBV transmission,23 and outbreaks among IV drug
abusers are frequently reported.24 Nosocomial transmission
has occurred through use of multidose vials of local anesthet-
ics.25 Acupuncture has been linked to occasional outbreaks of
HBV infection.26 Fortunately, transfusion-related HBV infec-
tion is rare because HBV screening of donated blood has been
routine for almost two decades.21 Nevertheless, an estimated
1:50,000 to 1:63,000 transfused units transmits HBV.27
In the United States, Canada, Europe, and Australia, sexual
transmission is the most important mode of HBV infection.28,29
Both heterosexual and homosexual activities can transmit
HBV, but heterosexual activity accounts for the majority of
HBV infections. Prostitutes, their clients, and individuals with
many sexual partners are at an increased risk of HBV infec-
tion. The risk of heterosexual transmission is greater when the
infected person is female than when male.5 In endemic regions
such as China and sub-Saharan Africa, most HBV infections
occur neonatally or in early childhood,21 and sexual transmis-
sion is less important.
After parenteral exposure, an asymptomatic incuba-
tion period ranges from 4 to 26 weeks (average, 6-8). During
this period, infected hepatocytes synthesize and secrete
large quantities of noninfective hepatitis B surface antigen
(HBsAg). Consequently, HBsAg is detectable before the onset
of signs and symptoms of hepatitis. Hepatitis B DNA (HBV-
DNA) is detectable in the serum by polymerase chain reaction
(PCR) shortly after HBsAg and indicates active viral replica-
tion. HBeAg, another important indicator of active viral rep-
lication, is also detectable at this time. Continued expression
of HBeAg is an important biochemical predictor of progres-
sion to chronic hepatitis. IgM antibodies to hepatitis core
antigen (HBc), a viral protein not detected in the serum, can
be detected in the serum shortly before the onset of acute ill-
ness. IgM anti-HBc is gradually replaced by IgG anti-HBc over
several months. IgG anti-HBs does not appear until after the
resolution of jaundice and clinical symptoms and after the dis-
appearance of HBsAg. During this “core window” after the
disappearance of HBsAg and before the appearance of anti-
HBs, IgM anti-HBc (and IgM anti-HBe) are the only labora-
tory markers of HBV infection.
Of the approximately 325,000 new HBV infections in the
United States each year, approximately 60% of patients will
develop subclinical disease without jaundice and completely
recover. About 25% of infected patients develop acute hepati-
tis, characterized by fever, nausea, vomiting, anorexia, abdom-
inal pain, and jaundice. Almost all patients who develop acute
hepatitis recover completely, although about 1% of patients
develop fulminant hepatic failure, which can be fatal with-
out liver transplantation. From 5% to 10% of patients become
“healthy carriers” of HBV disease. These individuals do not
normally manifest signs or symptoms of hepatitis but are
able to transmit the disease to others. Less than 5% of HBV-
infected patients will develop a persistent infection, character-
ized by mild but persistent elevation of serum transaminases
for months to years. Most patients with persistent infection
ultimately recover; however, 20% to 30% will develop chronic
hepatitis and cirrhosis. Patients who develop chronic hepati-
tis may have a defective immune response.30-32 HBV c­ irrhosis
is a significant risk factor for hepatocellular carcinoma, and
approximately 10% of patients with HBV cirrhosis will develop
hepatocellular carcinoma.
Unlike HAV, HBV infection tends to be more severe in
younger patients. In neonates and children younger than 1 year,
risk of an infection becoming chronic is 90%. For ­children age
1 to 5 years, risk of chronic infection is 30%. For children older
than 5 years, risk of chronic infection approaches that of
adults.21,33 Transplacental passage of HBeAg from an infected
mother to the fetus is thought to induce immune tolerance in
the neonate.34
Highly effective HBV vaccines have been available for
more than 20 years. In 1991 the U.S. Centers for Disease
Control and Prevention (CDC) recommended universal
childhood vaccination against HBV in the United States.
Broad-based vaccination initiatives have been effective in
reducing the incidence of HBV infection in Alaska35 and
reducing the incidence of hepatocellular carcinoma in
Taiwan.36 Before HBV vaccination was widespread, the inci-
dence of anti-HBs among anesthesiologists was greater than
fourfold higher that of the general population.37 As such, the
practice of anesthesiology is an independent risk factor for
the development of HBV infection.38,39 All anesthesiologists
should be vaccinated against HBV.
In the event of possible transmission of HBV to a non-
immunized individual (e.g., accidental needlestick), passive
immunization with hepatitis B immune globulin (HBIG) is

available. Current recommendations are to administer HBIG
in a dose of 0.05 to 0.07 mL/kg immediately after exposure. A
second dose 30 days after exposure may further reduce the risk
of HBV infection. If HBIG is not given within 7 days of infec-
tion, antiviral treatment should be considered.
Most antiviral therapy in HBV is directed toward the treat-
ment of chronically infected patients.40 Therapy with inter-
feron alfa has proved effective in the elimination of HBeAg
in patients with chronic infection.41,42 Therapy normally con-
sists of a 16-week course of 5 mU daily or 10 mU three times
weekly. Lamivudine, a nucleoside analog, is available orally
for HBV therapy.43 Long-term lamivudine therapy reduces
fibrosis and necrosis in patients with chronic HBV infec-
tion.44 Despite these impressive results, however, lamivudine-
resistant mutants have emerged.45 Adefovir dipivoxil, another
nucleoside analog, is also effective against HBV.46 Adefovir
seems to have efficacy against lamivudine-resistant mutants.47
HEPATITIS D (DELTA AGENT)
Hepatitis D virus (HDV) is a 35-nm viroid with a 1.7-kb
genome of ssRNA. The viroid is enveloped with HBsAg and
requires coinfection with hepatitis B virus for HDV infection
and replication. Delta agent was first noted in 1977,48 and its
unique structure was described in 1986.49 As with HBV, HDV
is transmitted parenterally. IV drug abuse remains the most
common mode of transmission in North America, Europe,
and Australia.50-52 Sexual transmission of HDV can occur,53
but may be less efficient than for HBV. Perinatal infection of
HDV is rare.
Hepatitis D infection can occur in two settings.54 In acute
coinfection, HDV occurs at the same time as acute HBV infec-
tion, usually when a patient has been exposed to blood or
serum from a patient harboring both infections. Superinfection
can occur when a patient with a persistent HBV infection or
chronic hepatitis becomes infected with HDV. Coinfection
with HBV and HDV results in a more severe course of acute
hepatitis and increased risk (3%-4%) of fulminant hepatic fail-
ure. Nevertheless, approximately 90% of coinfected patients
have complete recovery and develop immunity. Secondary to
defective immunity, patients with chronic HBV infection pro-
vide the ideal host for HDV superinfection. About 10% of
patients superinfected with HDV develop fulminant hepatic
failure that rapidly progresses. Most of the remaining 90%
develop an accelerated cirrhotic picture.55 A small percentage
of patients will recover and develop immunity.
The diagnosis of HDV infection is normally made by the
detection of IgM anti-HDV. IgM anti-HDV is not normally
detectable in patient serum until the onset of acute hepatitis
and jaundice. It is possible to detect HDV antigen in patient
serum before the onset of hepatitis during the late incubation
period; however, HDVAg is present only transiently, and thus
testing may be unreliable. HDV-RNA is the earliest marker of
infection and can be detected by PCR, but this is rarely used to
establish HDV infection.
There is no specific treatment for HDV infection. Because
HDV infection is only possible in the case of HBV infection,
Chapter 5  Liver Diseases 173
and vaccination reliably prevents HBV infection, vaccina-
tion against HBV remains the best method to prevent HDV
infection.
KEY POINTS
n Hepatitis A virus is transmitted by the fecal-oral route,
with rare progression to liver failure. Superinfection with
underlying liver disease can result in hepatic failure, and
­vaccination is recommended.
n Hepatitis B virus is transmitted by body fluids; 60% of
patients have subclinical disease, and 1% with acute HBV
infection develop fulminant liver failure.
n About 1% of HBV patients develop chronic hepatitis and
cirrhosis, with 10% risk of hepatocellular carcinoma.
n Superinfection of HBV-infected patients with hepatitis D
increases the risk of fulminant hepatic failure.
n Hepatitis C is transmitted by body fluids; 80% of patients
develop chronic hepatitis, 25% with cirrhosis.
HEPATITIS C
The hepatitis C virus (HCV) is a 55-nm enveloped virus
(Flaviviridae) with 9.4-kb genome of ssRNA. Worldwide,
more than 170 million people have chronic HCV infection.56
HCV was not identified until 1989.57 As with HBV, HCV is
primarily transmitted by blood, blood products, and sexual
contact. The two main risk factors for HCV infection are IV
drug use and blood transfusion before 1990.58,59 Indeed, HCV
has been identified as the etiologic agent in more than 85% of
all cases of posttransfusion “non-A, non-B” hepatitis before
1991.5 Since routine screening for anti-HCV and blood donor
risk factor assessment by most blood donor centers in 1991,
transfusion-related infection of HCV is a rare event.58,59 An
estimated 1 in 103,000 transfused units transmits HCV.27
Consequently, IV drug use has emerged as the principal
risk factor for HCV infection in North America, Europe, and
Australia.60 Perinatal transmission is rare and occurs exclu-
sively from mothers who are HCV-RNA positive at delivery.61,62
Perinatal transmission may be more common if coinfection
with human immunodeficiency virus (HIV) exists.63 It is
unclear whether cesarean birth increases or decreases the risk
of perinatal transmission.61,64-66 Breastfeeding appears to pose
little risk to the infant.67,68 As noted earlier, sexual transmis-
sion of HCV is possible; however, transmission is significantly
less efficient than for HBV. Nevertheless, prostitutes and their
clients, men who have sex with men (MSM), and individuals
with multiple sexual partners are at increased risk for HCV
infection. Some suggest that coinfection with HIV69 or her-
pes simplex virus type 2 (HSV-2)58 may increase the likelihood
of HCV infection. Although the virus is present in saliva of
chronically infected persons,70 transmission through casual
contact seems an unusual means of transmission.71 Patient-to-
patient transmission has occurred during colonoscopy,72 and
patients have been infected during surgery.73 In one hospital,
an anesthesia assistant became infected from a patient and
subsequently spread the infection to five other patients.74
 174 ANESTHESIA AND UNCOMMON DISEASES
In contrast to HBV, HCV has a high rate of progression to
chronic disease and eventual cirrhosis. After infection, HCV
has a long incubation period that ranges from 2 to 26 weeks
(average, 7-8 weeks).56 Of the approximately 175,000 persons
infected in the United States each year, 75% will develop sub-
clinical disease. The remaining 25% develop a symptomatic
disease characterized by fever, nausea, vomiting, abdominal
pain, anorexia, and jaundice. Approximately 1% of patients
with symptomatic disease develop fulminant hepatic fail-
ure that rapidly progresses to death without transplantation.
Almost 80% of all patients infected with HCV develop chronic
hepatitis, characterized by mild, episodic elevations in trans-
aminases and occasional jaundice.56 More than 25% of patients
with chronic hepatitis develop cirrhosis. HCV cirrhosis is a
significant risk factor for hepatocellular carcinoma, with an
estimated risk of 1% to 4% per year.56,75
The detection of antibodies against HCV is both sensi-
tive and specific for HCV infection. Newer, third-generation
enzyme immunoassays (EIAs) can detect antibodies within 4
to 10 weeks of infection.75 Unlike HBV, PCR to detect HCV-
RNA is often used in clinical practice to determine viral load,
a significant predictor of antiviral therapy efficacy.76 Detection
of HCV-RNA is the most sensitive and specific test of HCV
infection.77 Significant controversy surrounds the use of liver
biopsy in HCV-infected patients.78–81
Various treatment regimens are available for HCV infec-
tion. Standard interferon three times weekly for 24 to 48 weeks
(approved in 1990) is successful in treating HCV infection.75
Interferon alfa (2a or 2b), 3 MU three times weekly for 24
to 48 weeks, has shown response rates as high as 40%76 and
seems to be more effective than standard interferon. Pegylated
interferons have been used to treat HCV since the late 1990s,
with superior results compared with interferon alfa.82 When
pegylated interferons are combined with ribavirin, studies
have shown response rates as high as 88% in certain patient
groups.83,84
No vaccine is available for HCV infection. Therefore, avoid-
ing exposure is the best prevention. For anesthesiologists and
other health care professionals, adherence to universal pre-
cautions is critical. Prophylaxis after an accidental exposure is
not currently recommended. There are no randomized, con-
trolled trials examining the efficacy of therapy in acute HCV
infection; however, one study showed that after treatment with
interferon alfa-2b for 24 weeks, 43 of 44 patients did not have
detectable HCV-RNA.85
HEPATITIS E
The hepatitis E virus (HEV) is a 32-nm, nonenveloped virus
(Caliciviridae) with 7.5-kb genome of ssRNA. HEV was dis-
covered in 1983 and is part of the alpha supergroup of viruses.
HEV is responsible for the majority of cases of what was pre-
viously called “enterically transmitted non-A, non-B hepa-
titis” (ET-NANBH).86 As with HAV, HEV is almost always
transmitted via the fecal-oral route through the ingestion
of contaminated food or drink. During epidemics, the most
common mode of transmission is the ingestion of water with
fecal contamination.87 Compared with HAV, there is a low
rate of person-to-person transmission of household contacts.
Nosocomial infection has been reported.88 After ingestion,
HEV is absorbed through the small bowel and transported by
the portal blood flow to the liver. After an incubation period of
15 to 60 days (average, 35-42) a preicteric phase characterized
by fever and malaise is reported by 95% to 100% of patients.
An icteric phase characterized by abdominal pain, nausea,
vomiting, anorexia, and jaundice follows shortly thereafter.
Symptoms normally resolve in less than 6 weeks, although ful-
minant hepatic failure is a rare but reported complication. A
characteristic feature of HEV is the high incidence of progres-
sion to fulminant hepatic failure in pregnant women. If con-
tracted in the third trimester, HEV mortality may exceed 20%.
The diagnosis of HEV is normally made by exclu-
sion after travel to an endemic area (South and Central
America; Southeast Asia, including China, India, and Africa).
Nevertheless, assays to detect both IgM anti-HEV and IgG
anti-HEV are commercially available. PCR can be used to
detect HEV-RNA; however, this is usually done for research
purposes.
Currently, no vaccine is available for HEV infection. The
administration of immune globulin from endemic areas has
not decreased infection rates during epidemics.89 Health care
providers should use universal precautions when dealing with
patients with suspected HEV infection. Pregnant women
should avoid any type of exposure to HEV.
HEPATITIS G
Hepatitis G virus (HGV) was first described in the serum of
a patient with “non-A, non-B, non-C” hepatitis.90 HGV and
so-called GB viruses have been described.91 HGV and GB are
detectable in a substantial number of blood donors92 and have a
genomic sequence similar to HCV. However, HGV/GB does not
appear to cause liver disease.93 Indeed, the initial patient was later
found to have HCV infection. Interestingly, patients coinfected
with HIV and HGV/GB seem to have prolonged survival.94
Hydatid Cyst Disease
Hydatid cyst disease is caused by an infection of the animal
tapeworm Echinococcus. As with all tapeworms, Echinococcus
lives in the small bowel of hosts. Definitive hosts include car-
nivorous animals such as dogs, wolves, and other canines.
Tapeworm-infected canines pass eggs in their feces, which
contaminate the environment. Sheep, cattle, and humans
become intermediate hosts when they ingest the eggs by eating
contaminated foodstuffs. Infected domestic dogs remain the
most important vector for transmission of hydatid disease.95,96
Once the eggs are ingested, gastric acid and digestive pancre-
atic enzymes dissolve the egg's external shell. The larvae then
penetrate the bowel wall, enter the portal circulation, and are
carried to the liver. Approximately 70% of the larvae remain in
the liver, with 20% infecting the lungs, although other organs
can be infected, including the brain,97 spinal cord,98,99 kidney,100
and heart.101

In the liver, Echinococcus infection results in virtually no
symptoms until the cysts become very large. Although pain is
the most common complaint, a large cyst may cause obstruc-
tive jaundice, cholangitis, pancreatitis, or portal hyperten-
sion.95,96 Blunt trauma may cause cyst rupture.102 Diagnosis is
normally made by serologic testing after abdominal imaging
reveals hepatic cysts. An eosinophilia may also be present.
The treatment of large hydatid cysts is surgical, and the
anesthesiologist is likely to encounter patients scheduled for
cyst drainage. The surgical approach may be attempted by
laparoscopy,103 laparotomy, or thoracotomy if a subdiaphrag-
matic cyst is present. There are multiple case reports of an
anaphylactic reaction to hydatid fluid during surgical exci-
sion.104-106 Preoperative steroids and antihistamines107 should
be considered.
Nonalcoholic Steatohepatitis
Although the incidence of chronic viral or alcoholic hepa-
titis has not increased significantly in the past few years,
the overall number of patients with liver dysfunction has
increased secondary to the well-recognized obesity epidemic.
Nonalcoholic steatohepatitis (NASH) is becomingly increas-
ingly recognized as the most common cause of liver disease
in the United States.108 Few of these patients progress to cir-
rhosis but often have moderate degrees of dysfunction. The
diagnosis of NASH is based on a liver biopsy showing steato-
sis that is often indistinguishable from alcoholic liver disease
(Fig.  5-7), evidence of negligible alcohol consumption, and
absence of HBV or HCV infection.109,110 The etiology of NASH
is unknown, but it is often associated with obesity, type 2 dia-
betes, and hyperlipidemia.111
Patients may present with fatigue, malaise, and right
upper quadrant discomfort with elevated enzyme levels. Most
patients have only increased enzymes, but a few will progress
to cirrhosis. To date, no good predictors of disease progres-
sion exist, but presence of inflammation on biopsy, diabetes,
and high AST may be associated factors.112,113 NASH has a bet-
ter overall prognosis than alcoholic liver disease, with fewer
patients progressing to transplantation and improved 10-year
survival. However, NASH is associated with hepatocellular
carcinoma.114 There is no proven therapy, although weight
loss may result in improved enzyme levels and histologic find-
ings.115 Modification of risk factors for hyperlipidemia and
diabetes is also recommended.
Genetic Causes of Liver Disease
ALAGILLE'S SYNDROME (ARTERIOHEPATIC DYSPLASIA)
Alagille's syndrome (AGS) is a rare inherited disorder char-
acterized by the progressive loss of the intralobular bile ducts
and narrowing of extrahepatic bile ducts.108 It is the most com-
mon form of familial intrahepatic cholestasis, and more than
90% of patients experience chronic cholestasis.116,117 AGS has
an autosomal dominant pattern of inheritance, and more than
90% of patients have a mutation in the jagged 1 (JAG1) gene
Chapter 5  Liver Diseases 175
FIGURE 5-7  Photomicrograph shows histology of
nonalcoholic steatohepatitis in 62-year-old woman. Mallory
hyaline bodies (pink filamentous structures, black arrowhead) are
cytoplasmic inclusions in hepatocytes consisting of abnormal
keratin, hyaline, and other proteins. They are usually found in
hepatocytes that are ballooned (black arrow) and are morphologic
hallmarks of alcoholic and nonalcoholic steatohepatitis. Mallory
bodies are not cause but rather consequence of cellular injury.
Usually, hepatocytes with Mallory bodies do not contain large
fat vacuoles, although microvesicular fat may be seen. In this
frame, other hepatocytes are present, containing macrovesicular
fat globules (white arrow), which occupy almost all cytoplasm,
displacing nucleus (white arrowhead) to periphery. (Hematoxylin-
eosin stain, ×400.) (From Lall C, et al: Nonalcoholic fatty liver
disease, AJR Am J Roentgenol 190:993-1002, 2008.)
on the short arm of chromosome 20; others have a mutation
in NOTCH-2.117,118 AGS has an incidence of approximately
1:100,000 live births. Most patients present with jaundice, clay-
colored stools, and other symptoms of mild cholestasis during
the neonatal period. Patients might also present with rapidly
progressive, fulminant hepatic failure. AGS is slowly progres-
sive, and treatment is generally supportive. Approximately
15% of patients will require transplantation.119 A Kasai pro-
cedure is generally not considered beneficial and thus is not
recommended, especially because the risk during liver trans-
plantation may increase with previous Kasai surgery.120
Although the primary manifestation is cholestasis, AGS is of
particular interest to anesthesiologists because of the high mor-
bidity of its associated conditions. More than 90% of patients
with AGS have congenital heart disease. Approximately 67%
of patients have uncomplicated peripheral pulmonic steno-
sis; however, the remaining 33% have more serious defects,
including tetralogy of Fallot (16%), patent ductus arteriosus
(5%), ventricular septal defect (4%), and atrial septal defect
(4%). The presence of significant cardiovascular disease is
associated with increased perioperative mortality during liver
transplantation.119 As many as 85% of patients have “butterfly
vertebrae” resulting from clefting abnormalities.111,116 Patients
are described as having a characteristic facies, and as many
as 90% of patients have ophthalmologic abnormalities, usually
 176 ANESTHESIA AND UNCOMMON DISEASES
anterior chamber defects.108,121 The facial features are defined
by a broad nasal bridge, triangular facies, and deep-set eyes,
but are not specific to Alagille's syndrome.122 Patients have a
characteristically short stature, and resistance to growth hor-
mone has been described.123
A meticulous preoperative evaluation of patients with arte-
riohepatic dysplasia is critical for perioperative planning and
optimal care. Severity and type of dysfunction can be highly
variable, so associated conditions are evaluated, with partic-
ular attention to each patient's cardiac,124 hepatic, renal, and
orthopedic disease.125 In some patients, vitamin K deficiency
results from malabsorption. If blood loss is possible, preop-
erative clotting studies may be indicated. Malnutrition can be
a major concern, and proactive treatment with high-energy
supplements and fat-soluble vitamins is recommended. Severe
postoperative cholestasis has been reported in patients with
Alagille's syndrome.126
ALPHA1-ANTITRYPSIN DEFICIENCY
Deficiency of α1-antitrypsin is the most common metabolic
disease affecting the liver. The disease is most common among
white Europeans, in whom the incidence may be as high as 1 in
1500 persons.127 The disease is somewhat less common among
North American and Australian whites, about 1 in 2000 per-
sons. The incidence among African, Asian, and Hispanic indi-
viduals is low. The precise geographic distribution depends on
the specific genotype.
A potent serine protease inhibitor, α1-antitrypsin is synthe-
sized in the liver and secreted into the blood. As it circulates,
it binds to and promotes the degradation of serine proteases
produced throughout the body. One of the most important
proteases inhibited by α1-antitrypsin is elastase. Indeed, α1-
antitrypsin is responsible for more than 90% of all the serum
antielastase activity and is principally involved in the degrada-
tion of alveolar elastase. Once bound to its protease target, the
α1-antitrypsin/protease complex binds to a receptor on hepa-
tocytes and is removed from the circulation.128
The α1-antitrypsin gene has been localized to chromo-
some 14 and is part of the serine protease inhibitor (SERPIN)
supergene. This gene cluster also encodes for corticosteroid-
binding globulin, C1 inhibitor, and antithrombin III.127 At
least 17 different mutant alleles of α1-antitrypsin have been
described; however, two mutations account for the major-
ity of disease. Individuals homozygous for the more com-
mon S mutation (Glu264Val) have a 40% decrease in serum
α1-antitrypsin concentration.129 The S mutation is more
common among Southern Europeans, with peak inci-
dences recorded in the Iberian peninsula.127 Individuals
homozygous for the more serious Z mutation (Glu342Lys)
have an 85% decrease in serum α1-antitrypsin concentra-
tion.129 Unlike the S mutation, the Z mutation is more com-
mon among Northern and Western Europeans, with peak
incidences in northern France, the United Kingdom, and
Scandanavia.127 In general, the S mutation only produces
clinically significant disease when combined with the Z
mutation (SZ genotype).
The low serum protein concentrations observed in individ-
uals with α1-antitrypsin deficiency do not occur secondary to
defective protein synthesis, but rather to ineffective processing
and secretion.130,131 These ineffective processes leave the hepa-
tocyte with large quantities of defective protein that accumu-
late in the cell. Defective processing is particularly severe in
the Z mutation, where processing errors lead to the formation
of long polymers of Z–α1-antitrypsin.130 In both mutations,
the excess of defective α1-antitrypsin is visible under light
microscopy as large cytoplasmic inclusions. Stores of excessive
defective protein ultimately can interfere with normal hepatic
function.132
The abnormal accumulation of defective protein leads to
hepatocyte death and eventual cirrhosis. In general, the sever-
ity of hepatic disease is closely associated with the amount of
accumulated protein. Liver disease does not occur in patients
with unusual mutations of α1-antitrypsin that do not result
in the accumulation of defective protein in the hepatocyte.
Clinical presentation and age at onset vary significantly among
patients with α1-antitrypsin deficiency, even among individu-
als with the same genotype. The variation in age at onset of
liver disease may result from variations in the rate of synthe-
sis between individuals.133 Indeed, the appearance of jaun-
dice in infants with ZZ α1-antitrypsin deficiency may reflect
a chronic infection resulting in increased synthesis of defec-
tive protein.134 Regardless, the appearance of jaundice dur-
ing the neonatal period is a poor prognostic sign. Although
α1-antitrypsin deficiency has other manifestations, it is well
accepted that liver disease most influences survival. The
other primary clinical manifestations occur secondary to the
absence of normal protease inhibition, which is most appar-
ent in the lung; patients with α1-antitrypsin deficiency have
early onset of panlobular emphysema. All individuals experi-
ence an age-related decline in the forced expiratory volume in
1 second (FEV1) after age 30; however, this decline is acceler-
ated by α1-antitrypsin deficiency. This acceleration is further
exacerbated by tobacco smoke, which can double the rate of
decline.135
The diagnosis is made by the measurement of serum α1-
antitrypsin concentration. The genotype is confirmed by
protein electrophoresis. There is no specific therapy for α1-
antitrypsin deficiency, and liver transplantation may be
required.
CYSTIC FIBROSIS
Cystic fibrosis (CF) is the most common lethal inherited dis-
ease among white populations, with an incidence of approx-
imately 1 in 3300 persons in the United States. CF was one
of the first genetic diseases to be characterized. The gene for
CF, the cystic fibrosis transmembrane conductance regula-
tor (CFTR), resides on chromosome 7. Presence of the gene
results in defective cellular chloride conductance. Although
the principal manifestation of CF is pulmonary with associ-
ated viscid secretions, atelectasis, emphysema, and chronic
infections with Pseudomonas aeruginosa, hepatic abnormali-
ties may complicate 20% of cases. Portal hypertension and

eventual hepatic cirrhosis may complicate up to 10% of all CF
cases and represent the second most common cause of death
after respiratory failure. As the median age of CF patients
increases secondary to a reduction in mortality, the concern is
increased incidence of liver disease.
Although pathologic elevation of liver enzymes is fre-
quently observed in infants, most patients with CF do not
progress to cirrhosis.136 Nevertheless, certain genotypes are
clearly associated with liver dysfunction and an increased inci-
dence of cirrhosis.137 There is also an increased incidence of
liver disease in patients with certain major histocompatibil-
ity complex (MHC) genotypes,138 male gender, coexisting liver
disease, and poor nutrition (especially fatty acid deficiency).
Major liver disease is rarely noted in the absence of pancreatic
insufficiency. When hepatic disease advances to cirrhosis, it
normally presents during the first decade of life. Portal hyper-
tension is usually manifested by splenomegaly, hypersplenism
with thrombocytopenia, and ascites.139 Bleeding of esophageal
varices is also noted in some patients.
Transjugular intrahepatic portosystemic shunt (TIPS)
has been used with success in children and adolescents with
refractory esophageal bleeding.140,141 In severe cases, liver
transplantation has been performed.142,143 The anesthesiolo-
gist should be aware that the metabolism of certain drugs144
may be increased in CF secondary to increased hepatic drug
clearance.145
GALACTOSEMIA
Galactosemia is an inherited deficiency of the enzyme
galactose-1-phosphate uridyltransferase, which catalyzes
­ orders comprise a family of 10 different diseases. Each disease
the conversion of galactose-1-phosphate to UDP-galactose;
deficiency leads to the abnormal accumulation of galactose-
1-phosphate in cells. The enzyme is normally present in liver
and erythrocytes. Galactosemia is a rare disorder, approxi-
mately 1 in 60,000 live births. Galactose-1-phosphate is directly
toxic to cells, and accumulation is most notable in the kid-
ney, liver, and brain. Breast milk contains lactose, a disaccha-
ride consisting of glucose and galactose. As newborn infants
receive up to 20% of their caloric intake in the form of lac-
tose, infants with galactosemia rapidly accumulate galactose-
1-phosphate. Routine newborn screening normally makes the
diagnosis of galactosemia. If the diagnosis is not made, the
accumulation of galactose-1-phosphate can ultimately lead to
cataracts, severe mental retardation, and cirrhosis.
Treatment involves the avoidance of lactose in the diet;
however, patients treated appropriately still develop long-
term complications, including cognitive impairment, cata-
racts, speech abnormalities, and primary ovarian failure.146,147
Infants born with galactosemia have an increased incidence
of Escherichia coli neonatal sepsis that normally precedes the
diagnosis of galactosemia.148 Without treatment, the disease is
generally fatal, although case reports of adult patients present-
ing with decompensated cirrhosis exist.149 Galactokinase defi-
ciency, another inherited disorder of galactose metabolism, is
less common than galactosemia and generally has a milder
course.150
Chapter 5  Liver Diseases 177
Galactosemia may present the anesthesiologist with several
unique challenges. Newly diagnosed newborns who have been
treated for a short time may have elevated clotting times and
may be prone to bleeding. Some patients may have hemoly-
sis, and preoperative evaluation of hemoglobin may be valu-
able in any jaundiced patient. Also, albuminuria may cause an
osmotic diuresis, and thus urine volume may be a poor indica-
tor of intravascular volume.
KEY POINTS
n Infants with galactosemia may have elevated clotting times,
hemolysis, and albuminuria.
n Glycogen storage disorders types I, II, and IV are associated
with severe hepatic disease; type III with muscular disease;
and type IV with cardiomyopathy.
n Careful glucose monitoring is mandatory in patients with
type I or III glycogen storage disease.
GLYCOGEN STORAGE DISEASES
Glycogen is the principal storage form for glucose in the human
body. It is composed of long chains of glucose joined together
by α-1,4 linkages. The chains intermittently branch to form
long, treelike strands of stored glucose. Glycogen stands as a
ready reserve for glucose in times of metabolic need. Glycogen
metabolism principally occurs in skeletal muscle and liver.
Skeletal muscle glycogen provides exercising muscles with a
ready source of fuel while hepatic glycogen serves to main-
tain plasma glucose during fasting. The glycogen storage dis-
is characterized by a glycogen metabolism enzyme deficiency.
Only glycogen storage disorder types I, III, and IV are associ-
ated with severe hepatic disease (Table 5-4).
The perioperative management of any patient with a
glycogen storage disorder requires meticulous care and plan-
ning. Obviously, the blood glucose level should be carefully
­monitored in any patient with a type I or III glycogen stor-
age disorder. Nothing by mouth (NPO) guidelines should
be ­followed, and patients may require preadmission for IV
­administration of glucose-containing fluids. Case reports of
successful anesthetic management of patients with a type I
glycogen storage disease have been reported.151-153 Patient-
controlled sedation with propofol during spinal anesthesia has
also been successfully employed.154 Patients with a type III gly-
cogen storage disease may pose a special challenge to anesthe-
siologists secondary to muscle disease.155 Liver transplantation
has been used to treat type I, III, and IV glycogen storage dis-
eases,156 but cardiomyopathy may persist in type IV secondary
to cardiac amylopectin deposition.157
HEREDITARY FRUCTOSE INTOLERANCE
Hereditary fructose intolerance (HFI) is an inherited defi-
ciency of the enzyme fructose-1,6-bisphosphate aldolase
(aldolase B). Aldolase B catalyzes the conversion of fructose-
1,6-bisphosphate to two triose phosphates, dihydroxyace-
tone phosphate and glyceraldehyde-3-phosphate. Deficiency
 178 ANESTHESIA AND UNCOMMON DISEASES

TABLE 5-4  n  Glycogen Storage Diseases

Enzyme Main Clinical

Disease Deficiency Features Liver Disease Treatment Notes

Type Ia (von Glucose-6- Profound Hepatomegaly (normal Portal diversion Type Ib (10% of
Gierke's phosphatase hypoglycemia spleen) shunting type I disease)
disease) Growth failure Hepatic adenomas (by Glucose also associated
Metabolic acidosis second decade of life) supplements with neutropenia
Hyperlipidemia Occasional hepatocellular (cornstarch, and neutrophil
Renal failure (by carcinoma nocturnal glucose dysfunction
second decade infusion)
of life) Liver transplantation
Diagnosis in infancy

Type IIIa Liver and Profound Hepatomegaly (normal High-protein, low- Type IIb (15% of
(Cori- muscle hypoglycemia spleen) carbohydrate diet type III) has
Forbe's debranching Growth failure Hepatic adenomas (less Glucose normal muscle
disease) enzyme Progressive muscle common than type I) supplementation debranching
weakness with Rare hepatocellular (cornstarch, enzyme and
activity carcinoma nocturnal glucose no muscular
Muscle atrophy infusion) rarely symptoms
More tolerant to necessary Generally improves
fasting than type I with age
Diagnosis in infancy

Type IV Branching Failure to thrive Hepatosplenomegaly Death without liver Rare

(Andersen's enzyme Abdominal distention Progressive transplantation
disease) Miscellaneous macronodular cirrhosis
gastrointestinal Hepatic failure
complaints
Cardiomyopathy
Hypoglycemia rare
Diagnosis in infancy

leads to the abnormal accumulation of fructose-1-phosphate
and initiates severe symptoms when patients are exposed to
fructose. The enzyme is normally present in liver, kidney,
and small bowel. HFI is a rare disorder, with an incidence of
approximately 1 in 23,000 live births.
When patients consume fructose or sucrose (a disaccharide
consisting of glucose and fructose), the acute presentation of
abdominal pain, malaise, hypoglycemia, nausea, and vomiting
is often noted. Continued ingestion of fructose yields jaundice,
hepatomegaly, and renal dysfunction.158 Persistent fructose
consumption results in fulminant hepatic failure. Treatment
consists of the avoidance of fructose and sucrose in the diet.
Unlike galactosemia, patients are normally without symptoms
if fructose is avoided, and intellectual development is unim-
paired. Some investigators believe that HFI is underdiag-
nosed, and formal testing yields the diagnosis among patients
with unexplained, chronic abdominal pain.159 Secondary to
an almost-complete absence of dietary sucrose, patients with
HFI have excellent dentition.160 Oral medications containing
sucrose or fructose are avoided in patients with HFI.
HEREDITARY HEMOCHROMATOSIS
Hereditary hemochromatosis is an autosomal recessive dis-
ease characterized by an inappropriately high degree of iron
absorption. In the past, it had been theorized that the disor-
der occurred due to alcohol abuse and was merely a secondary
nutritional disorder; however, the gene was later found to
reside on the short arm of chromosome 6, closely linked to the
genes encoding for human leukocyte antigen (HLA).161,162 It
was not until 1996 that the gene responsible for hemochroma-
tosis (HFE) was discovered, allowing for formal genetic test-
ing and diagnosis.163 A variety of conditions, both acquired
and idiopathic, can be characterized by excessive total body
iron (Box 5-2). In many cases, these diseases mimic hereditary
hemochromatosis and may be superficially indistinguishable
in their clinical manifestations. Nevertheless, it is universally
accepted that hereditary hemochromatosis refers specifically
to increased iron absorption secondary to HFE-related genetic
mutations.
As specific HFE mutations are identified and investigated,
it has become increasingly clear that hereditary hemochroma-
tosis represents a spectrum of clinical disease. Indeed, some
homozygotes may manifest disease without a substantial
increase in iron stores,164 whereas others do not manifest clini-
cal symptoms in any appreciable way. In addition, although
HFE is equally distributed between the genders, clinical dis-
ease is two to eight times more common in men than women.
Patients with hereditary hemochromatosis can be classified
into four groups: (1) genetic predisposition without abnor-
malities, (2) iron overload without symptoms, (3) iron over-
load with early symptoms, and (4) iron overload with end
organ damage.165 Other factors, genetic and environmental,166

BOX 5-2   n  IRON OVERLOAD CONDITIONS
Primary Iron Overload
Hereditary hemochromatosis (HFE)
Non-HFE related
Juvenile hemochromatosis
Transferrin receptor-2 mutations
Ferroportin-1 mutation
African iron overload
Secondary Iron Overload
Red blood cell transfusions
Iron-loading anemias
Thalassemia major
Sideroblastic anemia
Chronic hemolytic anemia
Aplastic anemia
Pyruvate kinase deficiency
Long-term dialysis
Chronic liver disease
Hepatitis B
Hepatitis C
Alcoholic liver disease
Nonalcoholic steatohepatitis
Portocaval shunting
Modified from Harrison SA, Bacon BR: J Hepatol 38:S14-S23, 2003.
certainly influence the development of clinical disease. The
early observation of the link among hereditary hemochroma-
tosis, cirrhosis, and alcohol abuse may be explained by alcohol
further increasing iron absorption.167
The normal adult has a total body iron content of 3 to 5 g.
Most iron is recycled through the phagocytosis of senescent
erythrocytes, and only 1 to 2 mg of iron is normally lost each
day.168 Losses may be greater among menstruating women
and in the case of acute or chronic blood loss. Consequently,
dietary iron absorption is tightly regulated, with the amount
absorbed paralleling the body's needs. In hereditary hemo-
chromatosis, regulatory processes fail.169,170 This results in an
abnormal increase in dietary iron absorption with iron depo-
sition in the skin, heart, pancreas, joints, and liver. Hereditary
hemochromatosis is surprisingly common. In some white
European populations, 10% to 12% of people are heterozy-
gous carriers of the disease.170 The incidence of homozygous
hereditary hemochromatosis ranges between 1:100 and 1:400
in whites of European descent.171,172
The primary presentation of symptomatic hereditary
hemochromatosis is becoming rare. Most patients are asymp-
tomatic and report for evaluation and genetic testing after
a family member develops the disease. Nevertheless, most
symptomatic patients present in the fifth or sixth decade of
life. The liver is the first organ to be affected in hemochro-
matosis, and hepatomegaly is noted in almost 100% patients.
The most common presenting symptoms include generalized
weakness, malaise, arthralgias, abdominal pain, and impo-
tence (in men).173 Physical examination may reveal hepa-
tomegaly and, in advanced cases, signs and symptoms of
cirrhosis, including ascites and jaundice. Diabetes mellitus,
Chapter 5  Liver Diseases 179
secondary to pancreatic iron deposition, may also occur,
although it is rare in the absence of cirrhosis. Iron deposition
in skin may give patients a bronze coloration; hemochroma-
tosis has been referred to as “bronze diabetes.” Iron deposi-
tion in the heart can lead to fibrotic changes and most often
to a restrictive cardiomyopathy. An increase in fatal and non-
fatal arrhythmias is also noted. An arthropathy, especially of
the hands, is noted in about 50% of patients but does not usu-
ally present before age 50.
As iron accumulates in the liver, significant hepatocyte
damage occurs. The fundamental disease mechanism results
from direct iron toxicity and the consequent increase in
iron-generated free-radical production.174-177 The increased
oxidative stress results in lipid peroxidation,176,177 mitochon-
drial injury,165 and impaired calcium homeostasis.174,175 This
results in an inflammatory response, fibrin deposition, and
ultimately cirrhosis. Further oxidative stress may result in
DNA damage and an increased risk of hepatocellular carci-
noma.175 Hepatocellular carcinoma is the most common cause
of death in patients with hereditary hemochromatosis, and
the risk is 200 times greater than in the general population.178
Complications arising from cirrhosis and congestive heart
failure are other common causes of death.
Once the diagnosis of hereditary hemochromatosis is made,
treatment with phlebotomy and reduction in alcohol and
dietary iron intake should be initiated. The goal of therapy is
to make the patient non–iron deficient or nonanemic.165 Thus,
careful monitoring of hemoglobin, iron levels, ferritin, and
transferrin saturation should guide therapy. Although phle-
botomy and careful monitoring of dietary intake effectively
reduce iron stores, therapy does not reverse cirrhosis or totally
eliminate the risk of hepatocellular carcinoma. This is espe-
cially true among patients diagnosed at an advanced age. As
such, early diagnosis and treatment, ideally before the onset of
symptoms, is critical. Liver transplantation may represent the
only treatment in patients with advanced disease or with hepa-
tocellular carcinoma; however, many studies reveal decreased
survival in transplant patients with hereditary hemochroma-
tosis compared with other indications.179
HEREDITARY TYROSINEMIA TYPE 1
There are four known deficiencies in the catabolism of tyro-
sine: alkaptonuria and tyrosinemia types 1, 2, and 3. Only
hereditary tyrosinemia type 1 (HT-1) is associated with
liver disease. HT-1 is an inherited deficiency of the enzyme
fumarylacetoacetate hydrolase (FAH). The enzyme catalyzes
the final step in phenylalanine and tyrosine catabolism, the
conversion of fumarylacetoacetate to acetoacetate and fuma-
rate. FAH deficiency leads to the abnormal accumulation of
“upstream” tyrosine metabolites fumarylacetoacetate (FAA)
and maleylacetoacetate (MAA). Both FAA and MAA are con-
verted to two toxic products, succinyl acetoacetate (SAA) and
succinylacetone (SA). SAA and SA interfere with DNA ligase
activity,180 reduce blood and liver stores of glutathione,181 and
interfere with heme metabolism. These effects combine to
decrease the body's ability to deal with oxidative stress and
 180 ANESTHESIA AND UNCOMMON DISEASES
directly result in mutagenic damage and chromosomal break-
age.182 Initially, liver biopsy reveals steatohepatitis; however,
this advances to fibrosis and cirrhosis.
Although a rare disorder affecting approximately 1 in
100,000 births, the incidence of HT-1 may be higher in north-
ern Europe (1:8000) and in Quebec, Canada (1:1846).183,184
Essentially, two forms exist, acute and chronic. In acute HT-1,
patients present with symptoms of severe hepatic dysfunction
during the first 6 months of life. Liver biopsy reveals steato-
hepatitis that advances to fibrosis and micronodular cirrho-
sis with bile duct proliferation. In general, the acute form is
rapidly fatal within the first year of life without hepatic trans-
plantation. The chronic form of HT-1 presents more slowly,
with patients rarely seeking medical care before age 1 year. The
progress of hepatic dysfunction tends to occur more slowly,
and patients develop other symptoms, including nephropa-
thy, rickets, and serious neurologic problems.185 Secondary to
continued DNA damage, a substantial risk of hepatocellular
carcinoma exists. Liver biopsy reveals less cholestasis than the
acute form; however, macronodular and micronodular cirrho-
sis are eventually noted.
Liver transplantation is normally indicated within the
first decade of life in patients with chronic HT-1; how-
ever, advances in treatment are promising.186,187 Patients may
develop hypertrophic cardiomyopathy. Anemia, thrombocy-
tosis, and prolonged clotting times may be observed. No spe-
cific information addresses anesthetic care in patients with
HT-1, although preoperative assessment of cardiac, hepatic,
metabolic, and hematologic function should be considered.
LYSOSOMAL STORAGE DISEASES
Lysosomal storage diseases are a heterogenous group of dis-
eases resulting from different defects in lysosomal function.
Each disease normally reflects a lysosomal enzyme deficiency
and a consequent inability to metabolize various biomole-
cules. Most diseases follow an autosomal recessive pattern of
inheritance. Of the more than 30 well-classified diseases, only
a small number result in hepatic impairment.
Mucopolysaccharidoses
Each mucopolysaccharidosis (MPS) results from the defi-
ciency of an enzyme responsible for glycosaminoglycan
(GAG) metabolism. GAGs are complex, long-chain carbohy-
drates that are normally linked to proteins to form proteogly-
cans. Proteoglycans are common constituents of connective
tissue.
Mucopolysaccharidosis type I (MPS-I) results from the
deficiency of α-l-iduronidase. At least three phenotypes exist.
MPS-IH (Hurler's disease) has an acute course characterized by
hepatosplenomegaly, mental retardation, and death normally
occurring in the first decade. MPS-IS (Scheie's disease) has a
less severe course characterized by hepatosplenomegaly after
age 5 years and normal life span without mental retardation.
MPS-IH/S (combined Hurler/Scheie) follows an intermediate
course. In all these MPS-I diseases, hepatosplenomegaly can
be massive, with profound skeletal dysplasia.188 Myocardial,
coronary, and valvular heart disease are common.188 Corneal
“clouding” is an expected complication, and patients may pres-
ent for corneal transplant. Patients frequently require surgical
intervention for orthopedic abnormalities. A stiff neck, large
tongue, and tonsillar hypertrophy may make intubation diffi-
cult.189,190 Copious airway secretions may be treated with anti-
cholinergics. Fiberoptic intubation through a laryngeal mask
airway (LMA) may represent a useful technique, especially in
children.191 Patients should be considered at risk for airway
obstruction and postobstructive pulmonary edema.192 Failure
of epidural anesthesia has been reported and may be related to
the accumulation of glycosaminoglycans (GAGs) in the epi-
dural space.193 Perioperative antibiotics may be indicated in
patients with valvular disease.
Mucopolysaccharidosis type II (MPS-II, Hunter's disease)
results from the deficiency of iduronate sulfatase and has an
X-linked recessive pattern of inheritance. Both a severe infan-
tile and a mild juvenile form of the disease exist. In addi-
tion to massive hepatosplenomegaly, GAGs accumulate in
the head and neck, and patients have a short neck and large
tongue. Unlike MPS-I, corneal disease is rare. Nevertheless,
endotracheal intubation can be difficult,189,190 and acute airway
obstruction has been reported.194 Failure of the LMA to secure
the airway in a patient with MPS II has been reported.195
Again, however, fiberoptic LMA intubation may be useful in
children,191 and sleep apnea and pulmonary edema have been
reported.192
Mucopolysaccharidosis type VII (MPS-VII, Sly's syn-
drome) results from the deficiency of β-glucuronidase and
has an autosomal recessive pattern of inheritance. At least
four phenotypes exist.196 The neonatal form of MPS-VII pres-
ents as hydrops fetalis and is uniformly fatal.197 An infantile
form presents as hepatosplenomegaly, jaundice, and inguinal
and umbilical hernias. It is rapidly progressive and has a poor
prognosis. A second infantile form also presents as hepato-
splenomegaly, but seems to have a milder course.198 The adult
form of MPS-VII presents in adolescence and is not normally
complicated by hepatic involvement. Patients may have car-
diac involvement with mitral and aortic insufficiency. Acute
aortic dissection has been reported. Because of the accumu-
lation of GAGs in the head and neck, patients with Sly's syn-
drome may also be difficult to intubate, although this has not
been specifically reported with MPS-VII. Intraoperative com-
plete heart block has been observed.199 Patients with aortic
or mitral insufficiency may require perioperative antibiotic
prophylaxis.
LIPID STORAGE DISORDERS
Each of the lipid storage disorders results from the deficiency
of an enzyme responsible for lipid metabolism. The lipid stor-
age disorders include Fabry's disease, Gaucher's disease, and
Niemann-Pick disease; only the latter two have hepatic mani-
festations and are discussed here.
Gaucher's disease (GD) results from the deficiency of
acid β-glucosidase and has an autosomal recessive pattern
of inheritance. GD is the most common lysosomal storage

disease. Three phenotypes have been described: adult, infan-
tile, and juvenile.200,201 Adult Gaucher's disease (GD type 1)
represents 99% of cases and has a variable onset. It is charac-
terized by thrombocytopenia,202 anemia, and hepatospleno-
megaly. Bone pain is a common complaint, and pathologic
fractures can occur. Although hepatosplenomegaly may be
the most prominent feature, most morbidity results from
bone pain. Intelligence is normal, and neurologic symptoms
are rare. The availability of placental and now recombinant
glucocerebrosidase has improved morbidity in many patients
and can result in decreased liver volume.202,203 Blood coagula-
tion abnormalities have also improved.204 Adult GD has a car-
rier rate of approximately 1:18 among Ashkenazi Jews and an
annual incidence of approximately 1:1000 live births in the
United States.190
The accumulation of glycosphingolipids in the head and
neck may make endotracheal intubation difficult, and patients
may require a smaller-than-predicted endotracheal tube.
Patients should be considered at risk for upper airway obstruc-
tion.205,206 A small mouth may make LMA insertion difficult.205
Preoperative evaluation should include a baseline hemoglo-
bin and platelet count, because patients are at risk for anemia
and thrombocytopenia. Spinal anesthesia has been used with
success.207
Infantile Gaucher's disease (GD type 2) is characterized by
hepatosplenomegaly and severe developmental delay. Stridor
and laryngospasm are frequent complications. The disease
progresses rapidly, and death occurs before age 2. Juvenile
Gaucher's disease (GD type 3) is characterized by ataxia, hep-
atosplenomegaly, and mental retardation. The typical onset
occurs during childhood, and patients normally die before age
15. Juvenile GD has a peak incidence in the Swedish Norrbotten
population, with an incidence of 1 in 50,000 persons.
Gastroesophageal reflux and chronic aspiration can compli-
cate both type 2 and type 3 GD. As in type 1 GD, the airway
management of patients with types 2 and 3 may be difficult,
and patients are at risk for postoperative respiratory compro-
mise.208 Regional anesthesia has been used with success and
should be considered.
Niemann-Pick disease (NPD) results from the deficiency
of sphingomyelinase and has an autosomal recessive pattern
of inheritance. At least six phenotypes of NPD have been
described, but three types (A, B, and C) make up the majority
of cases.209 Infantile neuropathic NPD (NPD type A) normally
presents before 6 months of age and is characterized by hepa-
tosplenomegaly, lymphadenopathy, seizures, and mental retar-
dation. A progressive loss of intellectual capacity and motor
function results from increased deposition of sphingomy-
elin in the central nervous system (CNS). Non-neuronopathic
NPD (NPD type B) has a variable age of presentation and a
more heterogenous expression. Nevertheless, most patients
are diagnosed in childhood with hepatosplenomegaly. Unlike
type A, patients with type B NPD are neurologically intact,
and systemic deposition of sphingomyelin is more promi-
nent. Hepatic cirrhosis may develop, and portal hypertension
and ascites can complicate the disease. Many type B patients
Chapter 5  Liver Diseases 181
develop pulmonary disease characterized by severe diffusion
limitations. Such patients may have low Pao2 and develop cor
pulmonale and right ventricular failure in the second decade of
life. Patients with type C NPD have a deficiency in cholesterol
transport that leads to a disease that is phenotypically similar
to types A and B NPD.210 Patients with type C disease present
with prolonged neonatal jaundice. Hepatosplenomegaly is less
severe than in types A and B, and patients normally undergo
slowly progressive neurodegeneration.
Airway management may be more difficult in patients with
NPD.211 Pulmonary disease may complicate perioperative care,
especially in individuals with type B disease. Liver transplan-
tation has successfully reduced some of the clinical manifesta-
tions in patients with type A and B NPD. However, morbidity
and mortality of liver transplantation may be extremely high
secondary to pulmonary and neurologic disease.212,213
OTHER LYSOSOMAL STORAGE DISEASES
Mannosidosis results from the deficiency of α-mannosidase.214
An infantile form of the disease is characterized by progres-
sive mental retardation and hepatosplenomegaly. Cataracts
and corneal clouding may also be observed. An adult form has
a delayed onset and allows for longer survival. A small mouth
and a large tongue may make intubation difficult. Death nor-
mally occurs before age 5. An autosomal recessive pattern of
inheritance is noted in this rare disease.
Wolman's disease results from the deficiency of acid lipase
and is characterized by the deposition of cholesterol esters
throughout the body.215 Hepatosplenomegaly and eventual
cirrhosis are among the more prominent manifestations; how-
ever, pulmonary disease with a high alveolar diffusion gradi-
ent may be severe. Adrenal calcification is a unique f­eature.
Neonatal survival is impossible without total parenteral nutri-
tion, and death occurs within the first year of life. Bone marrow
transplantation has been used successfully to treat Wolman's
disease.216 No specific information is available on anesthesia in
patients with Wolman's disease.
PORPHYRIA
The porphyrias make up a family of inherited diseases result-
ing from deficiencies in one or more of the enzymes required
for heme synthesis. The enzymatic deficit results in the accu-
mulation of “upstream” metabolites and consequent symp-
toms (Fig. 5-8). More than 75% of heme synthesis occurs in
the bone marrow, and thus porphyrias are associated with
variable hepatic disease. Traditionally, porphyrias are gener-
ally divided into erythropoietic or hepatic types, depending
on whether the excess production of metabolic intermediates
takes place in the liver or in the bone marrow. Porphyrias can
be further divided into those with neurovisceral symptoms
(acute porphyrias) and those characterized by photosensitivity
and cutaneous symptoms (cutaneous porphyrias). Table  5-5
summarizes the characteristics of the various porphyrias.217
Acute intermittent porphyria (AIP) is the most common
type of porphyria, with a prevalence of about 1:10,000 to
1:20,000 people. Secondary to the disease's ability to cause
 182 ANESTHESIA AND UNCOMMON DISEASES

Cytosol Mitochondria
XLSA

ALA synthase Succinyl CoA

ALA 
Glycine
ADP ALA dehydratase

HEME
PBG

AIP PBG deaminase

Ferrochelatase EPP

HMB
Protoporphyrin IX
CEP Urogen III
cosynthase

Protogen oxidase VP
Urogen I Urogen III

Urogen
decarboxylase Coprogen oxidase
PCT
HEP
Protogen IX
Coprogen I Coprogen III

HCP

FIGURE 5-8  Heme synthesis and enzymatic defects in porphyrias. Defects begin with formation of δ-aminolevulinic acid (ALA) from
succinyl coenzyme A (CoA) and glycine. The enzymatic defect in each porphyria is shown by a red broken line. In patients, the substrate
for the defective enzyme accumulates and is excreted into urine or stool. XLSA, X-linked sideroblastic anemia; ADP, ALA dehydratase
porphyria; PBG, porphobilinogen; AIP, acute intermittent porphyria; HMB, hydroxymethylbilane; CEP, congenital erythropoietic porphyria;
Uro'gen, uroporphyrinogen; Copro'gen, coproporphyrinogen; Proto'gen, protoporphyrinogen; PCT, porphyria cutanea tarda; HEP,
hepatoerythropoietic porphyria; HCP, hereditary coproporphyria; VP, variegate porphyria; EPP, erythropoietic protoporphyria. (Anderson K:
Porphyrias: an overview. Up-to-date. www.uptodate.com; accessed 2/27/11.)

neuronal damage, the incidence of AIP among patients with
psychiatric disorders may be as high as 1:500.218,219 AIP may
be considered the prototype for all acute porphyrias, because
the presentation of all acute porphyrias is similar, with spe-
cific diagnosis requiring laboratory analysis. In AIP, patients
have a deficiency of porphobilinogen (PBG) deaminase activ-
ity. Because a complete deficiency would be incompatible with
life, most patients have approximately 50% of normal PBG
deaminase activity. The deficiency results in an increase in
cellular δ-aminolevulinic acid (ALA). Most patients are gen-
erally asymptomatic until some event stimulates the produc-
tion of ALA. The deficiency of PBG deaminase activity results
in relative ALA overproduction and consequent symptoms.
Precipitating factors that lead to an acute exacerbation include
(1) stimulation of ALA synthetase production in the liver;
(2) endocrine factors, including the female reproductive cycle;
(3) fasting, especially in combination with alcohol intake;
(4) induction of hepatic CYP450 that leads to ALA synthe-
tase production through a reduction in inhibitory heme; and
(5) emotional stress, including surgery and chronic illness.217
Clinical onset occurs most often after puberty and is more
common in women, likely secondary to the effects of hor-
mones and corticosteroids on the liver.
An acute attack is normally heralded by the presence of
colicky abdominal pain, nausea, and vomiting, followed by
the appearance of dark urine.220 Patients with AIP may also
complain of diarrhea or constipation. Classically, neurologic
symptoms follow the onset of visceral complaints and may
be highly variable. Patients may experience seizures, periph-
eral neuropathy, and cranial nerve deficits. They may become
psychotic. Hyponatremia may be observed secondary to the
syndrome of inappropriate secretion of antidiuretic hormone
(SIADH).
The cornerstone of treatment in AIP, as all acute porphyr-
ias, includes the recognition and avoidance of precipitating
factors. Once precipitating factors have been eliminated,
glucose therapy (400 g/day) and/or heme arginate (3 mg/kg/
day for 3 days) may be instituted.217 Glucose and heme argin-
ate work to decrease ALA synthetase activity and reduce the
urinary excretion of ALA and shorten the length of an acute
attack.
In the patient with a history of acute porphyria, optimal peri-
operative care includes careful planning and communication
among surgeons, anesthesiologists, and internists. Presurgical
admission for IV hydration with glucose-containing fluids is
an important step in the patient with a history of acute attacks.


TABLE 5-5  n  Classification of the Human Porphyrias

MAJOR BIOCHEMICAL FINDINGS*

Site/Clinical Enzyme
Disease Features Affected Inheritance Urine Plasma RBCs Feces

ADP HepaticΔ/Acute ALAD Autosomal recessive ALA, copro III ALA, copro III Zinc proto and low —
ALAD activity

AIP Hepatic/Acute PBGD Autosomal dominant ALA, PBG, copro — Low PBGD activity —

HCP Hepatic/Acute and CPO Autosomal dominant ALA, PBG, copro III — — Copro III
cutaneous

VP Hepatic/Acute and PPO Autosomal dominant ALA, PBG, copro III Fluorescence — Copro III and proto
cutaneous peak at 626 nm

PCT Hepatic/Cutaneous UROD Autosomal dominant¸ Uro and hepta-CP Uro and hepta-CP — Isocopro

HEP HepaticΔ/Cutaneous UROD Autosomal recessive Uro and hepta-CP Uro and hepta-CP Zinc proto and low Isocopro
UROD activity

CEP Erythropoietic/ UROS Autosomal recessive Uro I and copro I Uro I and copro I Uro I and copro I Copro I
Cutaneous

EPP classic Erythro/Cutaneous FECH Autosomal dominant — Proto Free proto Proto

EPP variant Erythro/Cutaneous ALAS-2 X-linked recessive — Proto Free and zinc proto Proto

Modified from Anderson K: Porphyrias: an overview. Up-to-date. February 2011.

* Increases of importance for diagnosis in most cases.
Δ, These hepatic porphyrias also have erythropoietic features, including increases in erythrocyte zinc protoporphyrin.
¸, UROD inhibition in PCT is mostly acquired, but an inherited deficiency of the enzyme predisposes in familial (type 2) disease.
ADP, δ-Aminolevulinic acid dehydratase porphyria; RBCs, red blood cells, erythrocytes; ALAD, aminolevulinic acid dehydratase; Copro, coproporphyrin; Proto, protoporphyrin; AIP, acute intermittent porphyria; PBGD,
porphobilinogen deaminase; HCP, hereditary coproporphyria; CPO, coproporphyrinogen oxidase; VP, variegate porphyria; PPO, protoporphyrinogen oxidase; PCT, porphyria cutanea tarda; UROD, uroporphyrinogen
decarboxylase; Uro and hepta-CP, uroporphyrin and heptacarboxyl porphyrin; Isocopro, isocoproporphyrin HEP, hepatoerythropoietic porphyria; CEP, congenital erythropoietic porphyria; Erythro, erythropoietic; UROS,
uroporphyrinogen III synthase; EPP, erythropoietic protoporphyria; FECH, ferrochelatase; ALAS-2, δ-aminolevulate synthase, erythroid-specific form.
Chapter 5  Liver Diseases
183
 184 ANESTHESIA AND UNCOMMON DISEASES

n Anesthetic management of porphyria patients includes

TABLE 5-6  n  Porphyria and Safety of Anesthetics
avoiding precipitating drugs, early IV hydration and glucose
Generally administration, and avoidance of hypothermia.
Considered Generally n Acute exacerbation may be treated with glucose and heme
Safe Unclear Considered Unsafe arginate.
INTRAVENOUS AGENTS
WILSON'S DISEASE (HEPATOLENTICULAR DEGENERATION)
Midazolam Ketamine Barbiturates Wilson's disease (WD) is an autosomal recessive disease that
Lorazepam Diazepam Etomidate results in the abnormal accumulation of copper in the liver,
Propofol
kidney, and CNS. One of the oldest diseases to be recognized
INHALED AGENTS as familial, WD was first described by Kinnear Wilson in 1912
Nitrous oxide Isoflurane Enflurane
as a progressive disease characterized by hepatic cirrhosis and
Desflurane Halothane softening of the lenticular nucleus.231 Over the past century,
WD has changed from a universally fatal familial disease to a
ANALGESICS
treatable disease with multiple therapeutic options. WD is pres-
Fentanyl Alfentanil ent in all populations and has an incidence of approximately
Morphine Sufentanil 1 in 30,000 persons. The gene responsible has been located in
MUSCLE RELAXANTS chromosome 13. The disease is more common among Jewish
eastern Europeans and certain Asian populations.232
Succinylcholine Atracurium Copper is an essential metal required for the normal func-
Vecuronium Pancuronium
tion of a variety of enzymes, including lysyl oxidase, super-
LOCAL ANESTHETICS oxide dismutase, tyrosinase, and monoamine oxidase.233,234
Bupivacaine Lidocaine
Copper metabolism is a complex process.235 Briefly, copper is
Procaine absorbed from the small intestine and bound to albumin. More
than 90% of copper-bound albumin is taken up by the liver.234
VARIOUS
In the liver, copper binds to apoceruloplasmin to form cerulo-
Atenolol Glucocorticoids plasmin. It is noteworthy that the incorporation of copper into
Atropine Hydralazine apoceruloplasmin is an ATP-dependent process. Saturated
Droperidol with six molecules of copper, ceruloplasmin is released into
Labetalol
Neostigmine
the blood. Ceruloplasmin is also an acute-phase reactant, with
increased levels found in various inflammatory conditions.
Modified from Jensen NF, Fiddler DS, Striepe V: Anesth Analg 80:591-599, Throughout the body, copper is taken up by cells and deliv-
1995; and Stevens JJ, Kneeshaw JD: Anesth Analg 82:416-418, 1996.
ered to its target enzymes after binding to various thiol-rich
metallochaperones.236 The only physiologic means of copper
A large carbohydrate load may suppress the synthesis of ALA excretion is through the bile. In WD, patients lose the ability
synthetase and may be beneficial.221 The selection of appropri- to mobilize copper for biliary excretion.237 This defect leads to
ate anesthetics and analgesics is important, because many drugs increased serum levels of copper. High levels of copper induce
frequently used in anesthesia have the capacity to induce ALA metallochaperone production. Because metallochaperones are
synthetase and CYP450.222,223 Table 5-6 summarizes the safety of able to sequester copper in a nontoxic form, patients normally
various drugs frequently used in anesthesia. Many otherwise- remain asymptomatic until copper supply overwhelms the
asymptomatic patients with AIP (or any acute porphyria) may absorptive power of metallochaperones. Ceruloplasmin levels
present for anesthesia with a misdiagnosed “surgical” abdomen. are low in patients with WD, as in patients with liver cirrhosis
Patients should be kept warm because cold-induced stress may of any cause.238
precipitate an acute crisis. Regional anesthesia has been used The presentation of hepatolenticular degeneration varies
with success.224 Liver transplantation has been used success- widely. In general, patients present with symptoms of liver dis-
fully to cure AIP.225 Attempts to treat other porphyrias with liver ease before the onset of neurologic symptoms.239 Normally,
transplantation have met with mixed success.226-230 WD presents in children and young adults with nonspecific
symptoms, including nausea, vomiting, and abdominal pain.
Patients may give a history of mild, intermittent jaundice,
KEY POINTS
and some patients may present with hepatomegaly or hepato-
n Porphyrias are divided into acute and cutaneous forms. splenomegaly. WD may also present as fulminant hepatic fail-
n Acute intermittent porphyria is most common (1:10,000 to ure240,241 or as an incidental, asymptomatic elevation of serum
1:20,000). transaminases. WD can imitate a variety of liver diseases,
n Porphyria exacerbation can be precipitated by stimulation including autoimmune hepatitis. WD should be considered in
of ALA synthetase, endocrine factors (female reproductive the differential diagnosis of established liver disease, even in
cycle), fasting, induction of CYP450, and emotional stress. the preschool-aged child.242
 Chapter 5  Liver Diseases 185

Most patients present with the neurologic manifesta-

Drug-Associated and Other Toxic Liver Disease
tions of WD in adulthood. Pseudosclerosis is noted, and Drug induced liver injury is a common problem, with an
patients present with parkinsonian features or rigid dys- annual incidence of approximately 1 in 10,000 to 100,000
tonia. The classically described lenticular degeneration of p
­ opulation.252 Up to 10% of all adverse drug reactions are liver
WD tends to present in childhood and is more often asso- injury, and drug-induced hepatic injury is the most common
ciated with dystonia. Children are often described as hav- cause of acute liver failure in the United States.253,254 The liver
ing a “sardonic smile.” The clinical hallmark of WD is the receives high concentrations of ingested compounds by portal
presence of a Kayser-Fleischer ring, a yellow-brown ring blood flow from the splanchnic bed. Hepatocytes in turn take
around the cornea. The Kayser-Fleischer ring is caused up such compounds and subject them to metabolic processes
by copper deposition in Descemet's membrane. The ring with detoxification and biotransformation.
is best demonstrated under slit-lamp examination; how- Drug-induced liver injury can be classified according to
ever, the ring may be plainly visible. The Kayser-Fleischer clinical presentation and laboratory findings, the mechanism
ring is present in more than 98% of patients with neuro- of toxicity, or the histologic findings.255 An exhaustive list of
logic manifestations of WD and more than 80% of patients naturally occurring substances, manufactured chemicals, and
with WD.243 Approximately 30% of patients with WD will pharmacologic agents has been implicated in liver disease,
have psychiatric symptoms. The most common symptoms with pharmaceuticals being the most common. Table 5-7 pro-
include depression and irritability; however, patients may vides examples of the types of damage caused by represen-
present with frank catatonia.243,244 tative agents and is by no means a complete listing. Clinical
The diagnosis of hepatolenticular degeneration requires manifestations range from minor asymptomatic biochemi-
a high index of suspicion, because the presentation is simi- cal changes to cholestatic signs and symptoms to massive
lar to many causes of cirrhosis. Indeed, WD may underlie liver necrosis, depending not only on the agent but also on
coexisting liver disease. In general, the diagnosis should the patient's pre-exposure condition, concurrent disease, and
be considered in any patient younger than 40 with the extent of exposure. Clinical presentation is not limited to acute
signs and symptoms of hepatic dysfunction, especially in
cirrhotic patients with unexplained CNS dysfunction. As
noted earlier, the presence of a Kayser-Fleischer ring and a TABLE 5-7  n  Types of Toxic Hepatic Injury
low serum ceruloplasmin level virtually seals the diagno-
Hepatocellular Damage Representative Agents
sis. In patients with normal ceruloplasmin levels, high uri-
nary copper and high copper on liver biopsy may support Microvesicular fatty change Tetracycline, salicylates, yellow
the diagnosis. phosphorus, ethanol
d-Penicillamine is considered the “gold standard” in the Macrovesicular fatty change Ethanol, methotrexate,
medical treatment of WD, capable of reversing the hepatic, amiodarone
neurologic, and psychiatric manifestations. Penicillamine
Centrilobular necrosis Bromobenzene, carbon
therapy is not likely to be effective in patients with fulmi- tetrachloride, acetaminophen,
nant failure, dystonia, or severe lenticular degeneration. halothane, rifampin
Adverse reactions to penicillamine include rashes, lymph-
Diffuse or massive necrosis Halothane, isoniazid,
adenopathy, and a lupuslike syndrome. Life-threatening acetaminophen, methyldopa,
thrombocytopenia245 or leukopenia246 is uncommon. trinitrotoluene, Amanita
Because penicillamine has an antipyridoxine effect, pyri- phalloides (mushroom) toxin
doxine should be supplemented. Trientine may be effective
Hepatitis, acute and chronic Methyldopa, isoniazid,
in penicillamine-sensitive patients.247,248 Zinc, which may nitrofurantoin, phenytoin,
induce more metallochaperone production, is also effec- oxyphenisatin
tive.249 Liver transplantation may be required in cases of
Fibrosis-cirrhosis Ethanol, methotrexate,
fulminant liver failure and will reverse the hepatic manifes- amiodarone, most drugs
tations of WD.249,250 Improvement of neurologic symptoms that cause chronic hepatitis
has been inconsistently reported.249,251
Granuloma formation Sulfonamides, methyldopa,
Anesthesia in patients with Wilson's disease should
quinidine, phenylbutazone,
include a careful preoperative assessment with regard to the hydralazine, allopurinol
multiple organ systems that can be affected. A preopera-
tive platelet count should be obtained in any patient taking Cholestasis (with or without Chlorpromazine, anabolic
hepatocellular injury) steroids, erythromycin
d-penicillamine. Because metoclopramide may exacerbate estolate, oral arsenicals
a patient's extrapyramidal symptoms, it should be avoided. contraceptives, organic
Droperidol, promethazine, and prochlorperazine should arsenicals
also be avoided in patients with hepatolenticular degenera-
Data from Crawford JM: The liver and biliary tract. In Cotran RS, Kumar V,
tion because these agents may aggravate pre-existing move- Collins T, editors: Robbins pathologic basis of disease, ed 6, Philadelphia, 1999,
ment disorders. Saunders, p 869.
 186 ANESTHESIA AND UNCOMMON DISEASES
hepatitis; some drugs will cause a chronic histologic inflam-
matory change with a syndrome resembling autoimmune
hepatitis. Still others can cause endothelial damage leading
to vascular complications such as sinusoidal obstruction syn-
drome or Budd-Chiari malformation. Toxic injury can thus be
included in virtually every differential diagnosis in the patient
with liver disease. The diagnosis of drug-induced liver injury
can be difficult given the variability in presentation and time
course of the disease. Key factors that suggest the diagnosis
include exposure preceded the onset of liver injury, no under-
lying liver disease, injury improving when drug is discontin-
ued, and injury recurring more rapidly and with increased
severity after repeated exposure.256
Several distinctions are important in considering toxic
liver disease. One issue concerns the type of toxicity of a
substance. Although certain chemicals enter the body in
toxic form, injury in most cases results from metabolites
that, ironically, are the result of hepatic transformation.
Another categorization of toxins is based on the consistency
with which they cause disease. Intrinsic hepatotoxins con-
sistently produce damage in a dose-dependent manner in
otherwise healthy patients, most often with a short latency.
Amanita mushrooms and trichlorethane are examples of
intrinsic hepatotoxins. Idiosyncratic hepatotoxin exposure,
in contrast, produces liver disease infrequently with variable
severity and after a variable latent period. The idiosyncratic
pattern can obviously be extremely challenging diagnosti-
cally. Some idiosyncratic hepatotoxins produce mild symp-
toms or asymptomatic biochemical changes with routine
exposure (e.g., isoniazid, halothane) but can cause severe
liver disease in susceptible individuals and in certain cir-
cumstances. Also, under certain conditions, even intrinsic
hepatotoxins can produce variable injury in exposures oth-
erwise considered safe (e.g., acetaminophen in patient with
alcoholic hepatic injury).
Many drugs will cause an increase in ALT up to three
times the upper limit of normal, which is considered sub-
clinical.257 Most of these abnormalities are benign and resolve
with discontinuation of the medication. Acute injury is the
most common, but the pattern may be hepatocellular (cyto-
toxic) damage (resembling hepatitis), cholestatic (resembling
extrahepatic obstructive jaundice), mixed, or steatotic (resem-
bling Reye's syndrome).258 Acetaminophen and antibiotics,
in particular amoxicillin-clavulanate, are the most frequently
implicated medications for acute injury.259 Chronic injury can
primarily be categorized as chronic hepatitis and steatosis. A
subtype of chronic hepatitis is similar to type I autoimmune
hepatitis, with a female preponderance, serologic markers, and
histologic features.260 Steatotic injury can be difficult to differ-
entiate from nonalcoholic steatohepatitis; both types of injury
can progress to fibrosis and cirrhosis. Chronic liver disease
can also result from vascular obstructive lesions, chronic cho-
lestasis, and related tumors.
The treatment for drug-induced liver injury is initially
withdrawal of the drug. N-acetylcysteine is recommended for
acetaminophen toxicity and l-carnitine for valproic acid.261
INHALATIONAL ANESTHETICS
Hepatic injury associated with the administration of inhala-
tional anesthetic agents is especially important to the anesthe-
siologist. Halothane was introduced into practice in 1956 and
was rarely associated with hepatic necrosis. It is now accepted
that halothane actually produces at least two types of hepato-
toxicity. Up to 20% of adult patients who receive a halothane
anesthetic exhibit slight increases in transaminases and vari-
able clinical complaints of fever, nausea, and malaise. From
1:7000 to 1:35,000 patients, depending on risk factors, will
have fulminant hepatic necrosis termed halothane hepati-
tis. Transaminases and bilirubin levels are elevated, and the
patient is jaundiced and often encephalopathic. The classic
histologic examination reveals hepatitis with centrilobular
necrosis; zonal, bridging, and panlobular forms of necrosis
have been described. Risk factors include age (rare in child-
hood), gender (twice as common in women), repeated expo-
sure within 3 months (up to 15-fold increase), and perhaps a
history consistent with the milder postoperative hepatotoxic
symptoms listed earlier. Mortality has been reported at 10%
to 50%, although recovery is typically complete in survivors.
Halothane hepatitis is a model for idiosyncratic hepato-
toxicity, and thus its mechanisms have been extensively inves-
tigated. A variety of observations, including increased risk
from re-exposure and the often-reported fever, rash, arthral-
gias, and eosinophilia, led to research supporting the theory
of an immunologic basis for halothane hepatitis. Cytochrome
P450 2E1 (CYP2E1) metabolizes halothane to trifluoroacetyl
chloride. This reactive molecule was initially investigated as
a direct hepatotoxin. The current immunogenic theory, how-
ever, focuses on its acetylation of endoplasmic reticulum pro-
teins. These trifluoroacetylated (TFA) proteins in turn are
thought to serve as neoantigens that elicit an antibody response
to both the altered proteins and the native hepatocyte proteins
in susceptible patients. Corroborating evidence includes the
detection of TFA proteins in patients with a history of halo-
thane exposure, as well as antibodies to the TFA hapten (and
carrier protein components) in patients with actual halothane
hepatitis. Further support can be found in reports of cross-
sensitization to methoxyflurane and perhaps enflurane by
prior halothane exposure. Further, although as much as 20%
of absorbed halothane may be metabolized, newer agents
undergo significantly less biodegradation (approximate val-
ues: enflurane 2%-3%, sevoflurane 1%-2%, isoflurane 0.2%,
and desflurane 0.02%) and are believed to be rarely or never
the cause of hepatitis.
Ischemic Liver Injury
The manifestations of ischemic injury to the liver have been
labeled as hepatic infarction, shock liver, centrilobular necro-
sis, and most commonly, the inaccurate term “ischemic hep-
atitis” (inflammatory changes are minimal). As might be
expected, hypotension and hypoxemia are the usual precip-
itating factors and result from processes ranging from obvi-
ous cardiac dysfunction, intraoperative events, and trauma to

less apparent causes. Diagnosis depends on identification of
an offending episode and typical biochemical response. LDH
usually is greatly increased both in terms of absolute values
and relative to transaminase elevations. Biopsy is not typi-
cally required but, when performed, demonstrates widespread
necrosis of the central lobule with minimal inflammation.
Severity ranges from subclinical biochemical changes to ful-
minant failure. Treatment is supportive with correction of the
instigating process.
Liver Function in the Geriatric Patient
The liver exhibits functional and structural changes with
aging. Decreased liver weight with fibrosis and proportion-
ally decreased blood flow has been described. Functionally,
reduced regenerative capacity, altered response to endocrine
stimulation, and altered drug metabolism are relevant to the
perioperative physician.262 Overall function, however, is rela-
tively resilient to these changes. Data are conflicting on the
impact of age on risk in the geriatric patient undergoing anes-
thesia. For example, one series in the 1980s of portosystemic
procedures showed better mortality in patients age 55 and
younger,263 although differences in disease severity and comor-
bidities were either pronounced or not described. General
survival of cirrhotic patients with bleeding varices in differ-
ent eras have correlated with Child-Pugh classification but not
age.20,264 There is little evidence that age is an important peri-
operative risk factor compared with actual hepatic function.
Biliary Cirrhosis
Biliary cirrhosis is simply cirrhosis caused by biliary obstruc-
tion of any type, regardless of location in the biliary tree.
Primary biliary disease is defined as immunogenic disease of
the intrahepatic bile ducts. Secondary biliary cirrhosis occurs
with prolonged obstruction from mechanical causes, scleros-
ing cholangitis, and diseases that promote cholestasis, such as
biliary atresia and cystic fibrosis.
PRIMARY BILIARY CIRRHOSIS
Primary biliary cirrhosis (PBC) is an autoimmune disease
usually occurring with other autoimmune diseases (e.g., rheu-
matoid arthritis, CREST syndrome, pernicious anemia, sicca
complex). In the modern era, PBC is often diagnosed before
actual cirrhotic changes, and thus primary biliary “cirrhosis”
has become something of a misnomer. PBC follows a progres-
sion through four stages. It is first characterized by periductu-
lar inflammation and interlobular duct injury with granuloma
formation, then reactive ductular proliferation with cholesta-
sis. Decreasing inflammation follows, but with development
of septal fibrosis and architectural disruption with worsening
cholestasis. Finally, cirrhosis occurs with obliteration of nor-
mal bile ducts, continued inflammation, and cholestasis.
Primary biliary cirrhosis has a 10:1 predilection for women,
usually of middle age. Although found in populations world-
wide, PBC is more prevalent and increasing in incidence in
Chapter 5  Liver Diseases 187
Western countries. ALP elevation, fatigue, and pruritus are
typical but nonspecific early findings. Diagnosis is based on
antimitochondrial antibodies with confirmatory liver biopsy.
A variety of autoantibodies may be present, especially rheu-
matoid factor, anti–smooth muscle, and thyroid specific; these
may occur without obvious coexisting disease. Advanced dis-
ease leads to portal hypertension and cirrhosis.
Liver failure typically occurs 5 to 10 years after diagnosis of
PBC. Prognostic models appear to be more accurate than in
many types of progressive liver disease and are helpful in con-
sidering the appropriate time for consideration of liver trans-
plantation. Immunosuppressive drugs have had limited success
in controlling the progression of PBC. Ursodeoxycholic acid
(UDCA), a hydrophilic bile acid, has been shown to increase
survival time without transplantation in PBC patients.265 A
multicenter trial, however, did not find this benefit; patients
were allowed to continue UDCA or switch from placebo to
UDCA on completion of the trial and did not experience sig-
nificant improvement of transplant-free survival.266 UDCA
currently remains a standard treatment for PBC, but further
evaluation through large-scale studies is anticipated.267
SECONDARY BILIARY CIRRHOSIS
Prolonged biliary obstruction, whether intrahepatic or extra-
hepatic (also known as extrinsic or mechanical obstruction),
can lead to cirrhosis regardless of etiology. Many diseases
can cause secondary biliary cirrhosis. Primary sclerosing chol-
angitis is the most common cause of secondary intrahepatic
cholestasis but is still less common than PBC. In infancy and
early childhood, cholestatic syndromes associated with atre-
sia of intrahepatic and extrahepatic ducts often demonstrate
rapid progression to fibrosis. Even when relief of obstruction
is possible, this progression is not reliably halted. Adults more
often have extrahepatic cholestasis, such as chronic pancreati-
tis with stricture, pancreatic cancer, and choledocholithiasis.
Presentation and diagnosis depend on the instigating
process, but jaundice and pruritus are often present. ALP is
typically highly elevated both absolutely (>4 times normal)
and relative to other liver panel abnormalities. Treatment
involves diagnosis and treatment of the cause of cholestasis.
Extrahepatic obstruction is often successfully relieved by sur-
gical or endoscopic procedures. Intrahepatic obstruction is
more problematic, with limited curative options.
Biliary atresia, for example, is an idiopathic fibroprolif-
erative disease that affects the extrahepatic biliary tree. The
cause of biliary atresia is unknown, but viral, toxic, genetic,
and immune etiologies have been proposed. Splenomegaly,
jaundice, acholic stool, dark urine, and hyperbilirubinemia all
suggest the disease. These symptoms should prompt imme-
diate evaluation for biliary atresia because the success of sur-
gical intervention improves at a younger age.268,269 The Kasai
procedure (hepatoportoenterostomy), in which a hilar core is
opened to allow the cut bile ducts to drain unobstructed, can
delay cirrhosis until age 3 to 4 years. Biliary atresia, however,
remains the most common reason for liver transplantation
in younger children, with 60% to 80% of patients requiring
 188 ANESTHESIA AND UNCOMMON DISEASES
a transplant. Of note for the anesthesiologist, 70% of infants
have no other anomalies, and 10% to 15% have biliary atre-
sia splenic malformation, which may include situs inver-
sus, asplenia or polysplenia, and cardiac anomalies. These
patients tend to have a poorer outcome. The remaining 10%
to 15% of patients have associated congenital malformations,
including renal abnormalities, choledochal cysts, and cardiac
defects.270,271
Pregnancy-Associated Liver Disease
Most biochemical tests remain within the normal ranges of
the general population during pregnancy. Exceptions include
alkaline phosphatase and albumin. ALP production by the
placenta causes elevations in early pregnancy, eventually
reaching levels that are three to four times normal nongravid
values. Although albumin production is thought to be normal
in pregnancy, increased blood volumes result in serum albu-
min decreases of about 1 g/dL.
INTRAHEPATIC CHOLESTASIS OF PREGNANCY
Intrahepatic cholestasis of pregnancy (IHCP) occurs fre-
quently in pregnancy, with great variation between popula-
tions. Its cause is unknown, but associated factors include a
personal or family history of IHCP and history of cholestasis
with oral contraceptives. Onset is usually in the third trimes-
ter, typically with symptoms of pruritus, nausea, and in some
cases, abdominal pain. Jaundice occurs in about one fourth
of patients, typically weeks after the onset of pruritus. ALP is
usually elevated beyond the normal increases of pregnancy,
and transaminases are usually normal but may occasionally be
slightly elevated. In rare cases when liver biopsy is performed,
histologic findings are usually limited to cholestasis without
inflammatory or necrotic changes.
Intrahepatic cholestasis usually has minimal maternal
impact; resolution of symptoms and laboratory abnormali-
ties is typically complete within 1 month of delivery. The inci-
dence of premature delivery and perhaps perinatal mortality
is increased. Treatment includes observation of mother and
fetus; UDCA, which decreases pruritus and may slow IHCP
progression; and prophylactic vitamin K to compensate for
cholestatic malabsorption.
PRE-ECLAMPSIA AND ECLAMPSIA
Pre-eclampsia occurs in up to 10% of pregnancies in general.
Pre-eclampsia is the triad of hypertension (>140/90 mm Hg),
proteinuria (>300 mg/24 hr), and edema, usually occurring in
the late second or the third trimester, that cannot be attributed
to other causes. Eclampsia occurs when seizures are superim-
posed on pre-eclampsia, which occurs in about 0.3% of pre-
eclamptic patients. The pathophysiology of pre-eclampsia
remains undefined, although often-overlapping proposed
mechanisms include endothelial cell injury, abnormal spi-
ral artery development with compromised placental perfu-
sion, thromboxane imbalance with prostacyclin, intravascular
volume contraction, and abnormal renal function. Recent
attention has focused on disruption of endothelial produc-
tion of nitric oxide (NO), prostacyclin, and tissue plasmino-
gen activator (TPA). This approach emphasizes the change in
vascular tone as well as coagulation changes.
Serum transaminases ranging from several times normal
to as high as 100 times normal are found in almost 25% of
pre-eclamptic patients and 90% of women with eclampsia.
Symptoms include epigastric or right upper quadrant dis-
comfort. Complications believed to be associated with pre-
eclampsia and eclampsia include hepatic rupture or infarction,
fulminant hepatic failure, and subcapsular hematoma. Biopsy
has demonstrated periportal fibrin deposition and areas of
necrosis. Treatment is delivery, after which rapid normaliza-
tion of laboratory values is typical. This decision is relatively
straightforward when the fetus has an adequate maturity pro-
file to ensure viability, but is problematic earlier in pregnancy.
Delay in delivery entails risk of progression of pre-eclampsia
but is thought to improve outcome in the fetus.
HELLP SYNDROME
The syndrome of hemolysis, elevated liver enzymes, and low
platelets occurs in late pregnancy and usually with at least
some of the signs of pre-eclampsia. Moderate transaminase
elevations and thrombocytopenia are defining conditions of
HELLP. Microangiopathic hemolysis is thought to be related
to fibrin deposition; it produces schistocytes and fragment
cells on peripheral smear, elevated serum LDH, and decreased
hemoglobin. Biopsy, although rarely required, reveals peri-
portal or focal necrosis and sinusoidal fibrin deposition with
hemorrhage. Maternal complications of HELLP include sei-
zures (eclampsia), placental abruption, and disseminated
intravascular coagulation (DIC). Fetal complications include
prematurity, intrauterine growth retardation, and increased
perinatal mortality (as high as 30% in some earlier series).
Treatment, as with pre-eclampsia, is delivery. Liver trans-
aminases typically normalize within 1 week, whereas platelet
counts continue to decline for 24 to 48 hours postpartum and
eventually normalize in 2 weeks.
HEPATIC INFARCTION OR RUPTURE
Hepatic rupture is thought to occur in about 1 in 200,000
pregnancies, most often in association with pre-eclampsia
or eclampsia, less often with acute fatty liver of pregnancy
or HELLP syndrome, and rarely without associated hepatic
disease. Clinically, infarction or rupture presents as acute
abdominal pain and distention, vomiting, and shock in the
third trimester or immediately postpartum. Elevated trans-
aminases, anemia, and DIC are common, but the diagnosis
can be confirmed with magnetic resonance imaging (MRI)
or computed tomography (CT) when time allows. Bedside
ultrasound may be invaluable as a time-saving diagnostic tool.
Survival requires early diagnosis and rapid treatment. Surgical
intervention has included packing of the liver, resection of the
involved segment or lobe (usually right), and even transplan-
tation. Radiographically guided embolization has also been
described in cases limited to a single lobe.

ACUTE FATTY LIVER OF PREGNANCY
Acute fatty liver of pregnancy (AFLP) occurs in the third tri-
mester and is of variable severity but can be fatal. It occurs in
about 1 in 15,000 pregnancies and is more likely to occur in
pre-eclamptic patients. Clinical presentation reflects the sever-
ity of the disease and ranges from nausea, abdominal pain, and
general malaise to progressive liver failure with jaundice, coag-
ulopathy, encephalopathy, and uremia. Expected laboratory
abnormalities include elevated transaminases, prolonged clot-
ting times, hypoglycemia, and uremia. Liver biopsy will dem-
onstrate centrilobular microvesicular fatty deposition with
either absent or minimal inflammation and necrosis. Essential
hepatic architecture is preserved, and eventual regression
to normal hepatic tissue is found in survivors. Treatment is
delivery, the delay of which must include a thoughtful assess-
ment of fetal viability balanced against the possibility of rapid
deterioration. Liver transplantation has been described as a
treatment for AFLP, but timely delivery appears to result in
complete reversibility of the disease in most cases.
KEY POINTS
n Alkaline phosphatase can be elevated 3 to 4 times nor-
mal values in normal pregnancy, and albumin levels may
decrease by 1 g/dL.
n Pre-eclampsia is hypertension, proteinuria, and edema in
the late second or third trimester; 0.3% of patients develop
seizures. Delivery is definitive treatment.
n The HELLP syndrome is complicated by seizures, placental
abruption, and DIC; delivery is definitive treatment.
n Of gravid patients, 1% to 3% will have liver test abnormali-
ties sometime during pregnancy. Patients with pre-existing
liver disease may experience deterioration during preg-
nancy, and pregnant patients can develop coincident liver
disease.
SYSTEMIC EFFECTS OF LIVER DISEASE
The diseased liver's pervasive impact on the function of other
organ systems might be predicted by its myriad roles in health.
This discussion briefly outlines systemic abnormalities associ-
ated with hepatic dysfunction that are of particular concern to
the anesthesiologist in the perioperative period.
Cardiovascular Effects
The impact of chronic liver disease on the cardiovascular sys-
tem is extremely complex and variable from patient to patient
and under different circumstances within the same patient.
The cardiovascular profile of the cirrhotic patient is classi-
cally described as a hyperdynamic state with greatly increased
cardiac output low systemic vascular resistance, and mod-
estly reduced arterial blood pressure. These effects worsen
with progression of disease, possibly related to increased pro-
duction of NO and splanchnic vasodilation. Despite this sus-
tained increase in cardiac output, functional exercise capacity
Chapter 5  Liver Diseases 189
of the cirrhotic patient is decreased. Available data show that
cirrhotic patients undergoing exercise testing respond with
lower-than-normal peak heart rates, lack of increased left ven-
tricular ejection fraction, abnormally increased end-diastolic
volumes with subnormal maximal cardiac output, and auto-
nomic reflex abnormalities.272 Ability to compensate for the
vasodilation is exhausted, with systemic blood pressure often
maintained by vasoconstriction in the renal and hepatic beds.
These patients are affected by anesthetic choices and surgery;
those with end-stage cirrhosis are often unable to tolerate the
stress of surgery.
Absolute intravascular volume is usually increased in cir-
rhotic patients, but coexisting renal disease, the impact of syn-
thetic failure through decreased oncotic pressure, treatment
of ascites with paracentesis or diuretics, and other factors may
dramatically affect intravascular volume. Even with increased
intravascular volume, the actual clinical behavior of the
patient is often that of relative hypovolemia. General vasodila-
tion, widespread arteriovenous shunting, and depressed car-
diac response are presumably major factors. Decompensation
with abrupt decreases in volume may be related to attenuated
sympathetic effects on the heart and the systemic vasculature.
Furthermore, although the healthy liver can displace a portion
of its blood volume into the central circulation with sympa-
thetic simulation, this compensatory mechanism is impaired
or absent in the setting of cirrhosis.273,274
Cirrhotic cardiomyopathy has increasingly been recognized
as an important entity separate from alcoholic cardiomyop-
athy.273 Cirrhotic cardiomyopathy is characterized by systolic
and diastolic dysfunction as well as electromechanical abnor-
malities. As the incidence of NASH increases, it is important
to note that these patients are at increased risk for athero-
sclerotic disease, independent of obesity, as well as increased
mortality.275-278 Therefore, it may be advisable to have a lower
threshold for preoperative cardiac testing in cirrhotic patients.
An electrocardiogram (ECG) that shows an increased QT
interval may indicate severe liver disease, increased brain
natriuretic peptide, and decreased survival.279 Dobutamine
echocardiography may be a better stress test in advanced cir-
rhosis because patients may not be able to vasodilate further
with dipyridamole.
Portal Hypertension and Ascites
The appreciation of esophageal variceal bleeding from cir-
rhotic obstruction of portal blood flow and the actual term
“portal hypertension” are more than 100 years old. The conse-
quences of portal hypertension, such as ascites, variceal hem-
orrhage, and encephalopathy, still cause significant morbidity
and mortality in patients with advanced liver disease.
In Western societies, portal hypertension is most often
associated with cirrhosis. Portal hypertension can actually be
found in a variety of situations, however, and its causes have
been categorized by mechanism and location. This way of con-
sidering portal hypertension incorporates both the forward
and backward models of portal hypertension that have been
 190 ANESTHESIA AND UNCOMMON DISEASES
variously favored in the past. Elevated pressure can result pri-
marily from increased flow, increased resistance to flow, or
both. If increased resistance is present, it may be prehepatic,
intrahepatic (presinusoidal, sinusoidal, or postsinusoidal), or
posthepatic. Box 5-3 and Figure 5-9 demonstrate this categori-
zation schema with several examples. The relative resistance of
portosystemic collateral pathways, while not causal, will affect
the degree of portal hypertension.
Pressure within the portal vein is usually less than 10 mm
Hg, although variability is introduced by the influence of
intra-abdominal pressure on the absolute venous pressure.
The hepatic venous pressure gradient (HPG) can be used to
control for this variability and attempt to localize the cause of
increased portal venous pressure. HPG is the gradient between
hepatic venous pressure and the wedged hepatic venous pres-
sure. The latter, in a manner analogous to pulmonary artery
occlusion pressure, estimates the intrasinusoidal pressures of
the liver. Shortcomings of this measurement include variable
sinusoidal communications arising from different pathologic
processes, causing variability in pressures, and measurement
from the efferent vessel, causing occlusion artifact. When
available, HPG can be used to localize etiology (e.g., HPG
would be normal if the cause of portal hypertension were pre-
hepatic) and monitor therapeutic interventions (e.g., sequen-
tial HPG can be used to verify improvement after β-blockade).
Portal hypertension is typically defined as an absolute pressure
greater than 10 mm Hg or an HPG of greater than 5 mm Hg.
The HPG at which portosystemic collaterals begin to develop
appears to be 10 to 12 mm Hg in alcoholic cirrhosis.280 These
are most often gastroesophageal varices.
BOX 5-3   n CATEGORIZATION AND EXAMPLES
OF PORTAL HYPERTENSION ETIOLOGIES
Increased Flow Predominates
Arterial-portal fistula
Splenic hemangiomatosis
Increased Resistance Predominates
Prehepatic
Portal vein thrombosis
Splenic vein thrombosis
Intrahepatic
Presinusoidal
Schistosomiasis
Azathioprine
Sinusoidal
Cirrhosis
Alcoholic hepatitis
Methotrexate
Postsinusoidal
Budd-Chiari syndrome
Posthepatic
Caval web
Cardiogenic
Right-sided heart failure
Tricuspid regurgitation
Variceal bleeding is believed to be possible with an HPG of
greater than 12 to 15 mm Hg, although the degree of elevation
above this threshold is poorly related to bleeding risk. HPG of
greater than 10 mm Hg is a strong predictor of clinical decom-
pensation.281 Variceal bleeding is associated with 6-week mor-
tality of 15% to 20%, depending on the degree of underlying
cirrhosis.282-284
Whether by the development of varices or intentional por-
tosystemic shunt procedures, significant portal blood flow
can bypass the liver to the systemic venous circulation. This
circumvention of hepatocyte processing has been implicated
in the prolonged and exaggerated effects of medications with
high hepatic extraction, persistence of endogenous vaso-
dilating substances usually cleared by the liver, and hepatic
encephalopathy.
Ascites is often present in the setting of severe cirrhosis
and portal hypertension. As described previously, the nor-
mal sinusoid is lined with fenestrated endothelium and has no
basement membrane. The normal sinusoidal pressure is low
enough as to be almost balanced by oncotic pressure. With
increasing sinusoidal pressure, however, protein and fluid
move into the interstitium, with increased volume and increas-
ing protein content of hepatic interstitial fluid and lymph. This
flow eventually exceeds lymphatic return and accumulates in
the abdomen as ascites. Interestingly, as the sinusoids develop
a pseudo–basement membrane (so-called capillarization), less
protein transudes through the now partially obstructed fenes-
trations. As a result, the protein content of the ascitic fluid can
decrease with advancing disease.
The long-standing treatment of ascites includes diuretic
therapy and paracentesis in conjunction with sodium restric-
tion. IV infusion of albumin with paracentesis has decreased
the rapidity of ascites reaccumulation in some patients, per-
haps because of the sinusoidal changes. The treatment of
­ascites results in intravascular depletion. During laparotomy,
the loss of large volumes of ascites can result in the activa-
tion of the renin-angiotensin-aldosterone system through an
acute increase in splanchnic vasodilation resulting in circula-
tory dysfunction. This hemodynamic effect can be mitigated
by the preemptive administration of albumin at 8 g/L of ascites
removed.273,285 Preoperative paracentesis with appropriate vol-
ume replacement may also reduce hemodynamic effects.
Refractory ascites may be treated with TIPS without an
increase in mortality compared to paracentesis. However,
there is a significant increase in encephalopathy, particularly
in patients with a history of encephalopathy, older patients,
and those with renal insufficiency.286,287 TIPS may also play a
role in patients that have severe portal hypertension that is a
contraindication to surgery.288,289
Renal Effects
Renal function is usually reduced in advanced liver disease.
Processes such as infection or immune-mediated disease may
primarily affect both the liver and kidneys. However, in cir-
rhosis and sometimes in acute liver failure, renal function can
 Chapter 5  Liver Diseases 191

Cirrhosis

Resistance to Hepatic dysfunction

Backward theory intrahepatic blood flow

Vasodilators Hypoalbuminemia
Portal Portal systemic Nitric oxide, glucagon,
hypertension shunt prostacyclin, activation of K
channels, cytokines,
endotoxemia, adenosine

Forward theory Peripheral and splanchnic PVBF Plasma

vasodilatation HABF oncotic
Splanchnic AV shunting THBF pressure
GI bleeding
Liver and
intestinal Effective blood volume
lymph flow
Ascites and
edema
Volume receptor stimulation
Ascites and
edema
Neural factors Humoral factors Intrarenal factors
Sympathetic Renin Endothelin
nervous activity Aldosterone Urinary kallikrein
Role of Angiotensin II or PGs
hepatorenal ADH Thromboxane
reflex Refractory to ANF Leukotrienes
PAF
Adenosine

Tubular sodium retention and reduced renal blood flow

FIGURE 5-9  Pathways for cirrhosis-induced portal hypertension: forward and backward theories. Cirrhosis and portal
hypertension induce circulatory changes that decrease effective blood volume. This activates volume receptors and stimulates
neurohumoral and intrarenal reflexes, which decreases renal blood flow and increases renal retention of sodium. K+, Potassium ion; GI,
gastrointestinal; AV, arteriovenous; PVBF, portal venous blood flow; HABF, hepatic arterial blood flow; THBF, total hepatic blood flow; ADH,
antidiuretic hormone; ANF, atrial natriuretic factor; PGs, prostaglandins; PAF, platelet-activating factor. (Modified from Mushlin PS, Gelman S:
Anesthesia and the liver. In Barash PG, Cullen BF, Stoelting RK, editors: Clinical anesthesia, ed 4, Philadelphia, 2001, Lippincott Williams &
Wilkins, p 1088.)

deteriorate as a consequence of liver dysfunction. This phe-
nomenon is termed hepatorenal syndrome (HRS). Prerenal
failure and acute tubular necrosis can also occur in the setting
of severe liver disease. These conditions are discussed with
emphasis on their differentiation from hepatorenal syndrome.
Hepatorenal syndrome is the type of renal failure specifi-
cally associated with advanced liver disease. It usually occurs
in patients with ascites. As previously discussed, advanced liver
disease often produces a cardiovascular profile of high car-
diac output with low peripheral resistance and a relative, if not
absolute, hypovolemia. This can predictably result in renal dys-
function of hypoperfusion (“prerenal”) etiology. However, in
HRS, the decrease in renal cortical flow appears exaggerated.
Cortical blood flow can actually be significantly decreased,
even with normal glomerular filtration rates. Such patients,
with an increased resistive index by Doppler studies, are at
high risk to progress to renal insufficiency.290 The proposed
sites and mechanisms of renal vasoconstriction occurring in
a patient with generalized vasodilation are active topics of dis-
cussion. Suggested mediators include prostaglandins, NO, cat-
echolamines, and endothelins.291,292 HRS is typically designated
as type I or type II. Type I occurs acutely over days in patients
with marginal hepatic function and is associated with instigat-
ing factors such as gastrointestinal bleeding, infection, or hypo-
volemia in about half of cases. Type II HRS is slowly progressive
and occurs in patients with better-preserved and more stable
hepatic function who often have refractory ascites. Diagnostic
criteria for HRS are (1) advanced liver disease with portal
hypertension, (2) elevated serum creatinine or decreased cre-
atinine clearance, (3) absence of other etiology, (4) lack of
response to volume expansion, and (5) absence of proteinuria,
obstructive uropathy, or parenchymal renal disease.293 Despite
criteria, accurate diagnosis can be problematic.294
Although the kidney in HRS remains unchanged histologi-
cally and function may return to normal after liver transplanta-
tion,295 spontaneous recovery is rare, and there is currently no
 192 ANESTHESIA AND UNCOMMON DISEASES

other definitive treatment. The goals of pharmacologic treat- effusions are initially transudative and more often occur on the
ment are as a bridge to transplant. Treatment with arterial vaso- right side. Effusion can occasionally occur in isolation but is
constrictors and volume expansion are the more promising most often associated with ascites. In the latter case, transdia-
approach. The mechanism of this treatment appears to be related phragmatic communications between the peritoneal and pleu-
to vasoconstriction of the splanchnic circulation and reversal of ral cavities are thought to allow movement of fluid into the
the decreased effective circulating volume. This is theorized to chest. The impact on lung mechanics includes decreased lung
improve effective blood volume and perhaps suppress renin- volumes and pulmonary compliance, as well as elevated pleu-
angiotensin and sympathetic activity to more normal ranges. ral pressures (abnormalities also caused by massive ascites).
Interestingly, simple volume expansion is not particularly effec- Moderate hypoxemia, thought to be an effect predominantly
tive,296 but colloid infusion may improve the response to V1 vaso- of intrapulmonary shunt, is common, but improvement after
pressin agonists.297 Increasing experience suggests promising evacuation of the effusion is unpredictable.305 Without resolu-
results with the combination of a vasopressin agonist and albu- tion of the hepatic process, repeated thoracenteses and perhaps
min;297-302 however, concerns exist about increased incidence of portosystemic shunting may be required.
ischemic complications. The combination of midodrine, octreo- Some diseases that affect the liver will also primarily affect
tide, and albumin is also a promising treatment strategy.303,304 the lung, including cystic fibrosis, α1-antitrypsin deficiency,
The diagnosis of prerenal failure should be considered because sarcoidosis, and primary biliary cirrhosis. Several reports also
it may well be reversible if treated promptly. The question of describe patients undergoing sclerosis of esophageal varices
whether prerenal failure can progress to HRS in some patients who develop a range of pulmonary deterioration. These prob-
is unanswered. Acute tubular necrosis (ATN), when it occurs, is lems range from worsening hypoxemia and decreased vital
often precipitated by a combination of sustained hypoperfusion capacity to full-blown adult respiratory distress syndrome
and nephrotoxic agents such as nonsteroidal anti-inflammatory (ARDS). The etiology of these problems may have been embo-
drugs (NSAIDs), contrast dye, and aminoglycoside antibiotics. lization of sclerosants.306
Elevated bilirubin, which itself has been postulated to be nephro- Two syndromes that are sometimes confused but have
toxic, is associated with an increased incidence of ATN. very different findings and implications are hepatopulmonary
Characteristics helpful in distinguishing prerenal failure and syndrome and portopulmonary hypertension (Table  5-8).
HRS are limited. HRS sometimes demonstrates tubular dam-
age with proteinuria and, in fact, may progress to ATN. Urine
sodium will be low in both processes, whereas urinary creatinine TABLE 5-8  n Distinguishing Hepatopulmonary Syndrome
and Portopulmonary Syndrome
will be high compared with levels in the plasma. Proteinuria,
high urine sodium, and low urine creatinine are typical of ATN. Hepatopulmonary Portopulmonary
Volume challenge of the patient with renal dysfunction is a logi- Syndrome Hypertension
cal approach to diagnose and begin treatment of prerenal failure. Defining Liver dysfunction Lack of general
characteristics Intrapulmonary agreement
vascular dilations Commonly cited
KEY POINTS (IPVDs) criteria:
Abnormal alveolar- Portal
n Cirrhotic patients have depressed response to sympathetic
arterial oxygen hypertension
stimulation, abnormalities with autonomic reflex, diastolic gradient (>15 mm Resting mPAP
dysfunction, and possible systolic dysfunction. Hg with room air) >25 mm Hg
n Relative intravascular depletion may be exacerbated by Other PAOP <15 mm
paracentesis for ascites and diuretic therapy. cardiopulmonary Hg
causes excluded Other causes
n Hepatorenal syndrome may be treated with albumin,
excluded
octreotide, midodrine, and albumin.
n Hepatopulmonary syndrome is characterized by room-air Common Platypnea Orthopnea
Pao2 less than 60 mm Hg partially corrected with oxygen, symptoms Orthodeoxia Dyspnea on
Arterial desaturation exertion
with evidence of intrapulmonary shunting; HRS is an indi- Fatigue
cation for transplantation.
n Portopulmonary syndrome is characterized by elevated PAP Common Clubbing Hypoxemia with
signs and Decreased DLco exertion
and PVR and may be treated with sildenafil and IV epopros-
diagnostics CE-Echo positive* Elevated PAP
tenol. Severe pulmonary hypertension is a contraindication
to transplantation. Management Oxygen Vasodilator trial
supplementation
Liver transplantation
Pulmonary Effects
mPAP, Mean pulmonary artery pressure; PAOP, pulmonary artery occlusion
The diseased liver impacts lung function in a variety of ways. pressure; DLco, carbon monoxide diffusing capacity.
*Contrast-enhanced echocardiography: positive when contrast appears in left
Almost 10% of patients with cirrhosis, for example, will develop side of heart within three to six cardiac cycles of appearance in right side of
pleural effusion. Classically termed “hepatic hydrothorax,” such heart and in the absence of another cause.

Hepatopulmonary syndrome (HPS) is defined by the presence
of liver disease, an increase alveolar-arterial gradient on room
air, and evidence of intrapulmonary vascular dilations.307,308 A
room-air Pao2 less than 60 mm Hg is highly suggestive of HPS.
A contrast-enhanced echocardiogram will detect intrapulmo-
nary shunting. Peripheral pulmonary vasculature (precapillary
and capillary) has characteristic vascular dilations, thought to
increase the distance between red blood cells and the alveoli,
which impairs oxygenation. This effect is exaggerated in the
sitting position with increased basilar blood flow, accounting
for the symptoms of platypnea (worsened shortness of breath
in upright position) and orthodeoxia. Supplemental oxygen
will typically improve saturation. To date, multiple medical
therapies have been attempted for HRS without benefit. Liver
transplantation is usually effective, although improvement
may be seen only after several months.309,310
Portopulmonary hypertension (POPH) is a distinctly dif-
ferent process that appears histologically similar to primary
pulmonary hypertension with medial hypertrophy. POPH
is defined by the presence of pulmonary arterial hyperten-
sion (mean PAP >25 mm Hg) in the setting of portal hyper-
tension. Because patients with liver disease generally have
high cardiac output, peripheral vascular resistance of greater
than 240 dynes/sec/cm-5 is often used.311 POPH is thought to
be secondary to an imbalance of vasomediators resulting in
vasoconstriction, endothelial damage causing remodeling,
and microthrombosis.312 Patients with symptoms of pulmo-
nary hypertension (e.g., dyspnea) should be evaluated with a
screening test of echocardiography. Pulmonary artery pres-
sures (PAPs) may respond to vasodilators such as IV or inhaled
epoprostenol or inhaled NO.313 The mortality of liver trans-
plantation in patients with POPH and mean PAP greater than
40 mm Hg is considered prohibitively high, although there
are scattered case reports of survivors.314 Aggressive preop-
erative therapy315 of POPH may be associated with improved
outcome. Other prostanoids, endothelin receptor antagonists,
and phosphodiesterase-5 inhibitors have all been associated
with positive results.316
Hepatic Encephalopathy
Hepatic encephalopathy can be associated with acute or
chronic liver disease and can itself be slowly progressive
or can deteriorate rapidly. It is a neuropsychiatric disorder
that should be a diagnosis of exclusion. Differential diagno-
ses include intracranial processes (e.g., hemorrhage, tumor,
abscess), hypoxemia, neurologic infection, sepsis, and meta-
bolic encephalopathy. Primary neuropsychiatric disorders can
have similar presentations.
Clinical observation and limited animal models have led
to the generally accepted concept that hepatic encephalopa-
thy is caused by the failure of the liver to clear neurotoxins
or their precursors arising from the gut. Box  5-4 lists sev-
eral substances considered in the development of hepatic
encephalopathy, which help explain current treatments.
Ammonia is generally believed to play a central role in hepatic
Chapter 5  Liver Diseases 193
BOX 5-4   n THEORIZED PATHOGENIC SUBSTANCES IN
HEPATIC ENCEPHALOPATHY
Ammonia
γ-Aminobutyric acid (GABA)
True neurotransmitters
False neurotransmitters (aromatic amino acid excess)
Serotonin
Manganese
Endogenous opioids
encephalopathy. Ammonia is produced by colonic bacterial
activity and small-bowel deamination of glutamine, absorbed
into the portal circulation, and in health, removed by the liver.
Hepatic dysfunction, especially in association with portosys-
temic shunting, allows increased systemic ammonia concen-
trations. Glutamine synthetase inhibition can blunt cerebral
edema and intracranial hypertension in animals with portoca-
val shunting and ammonia infusions.317 This observation has
supported the concept that CNS metabolism of ammonia with
resultant increases of glutamine leads to an osmotic gradient
capable of causing cerebral edema. Ammonia is also capable
of altering the blood-brain barrier and influencing glutamate-
associated neurotransmission.
Despite these interesting findings, however, blood ammo-
nia levels have not consistently correlated with the severity of
hepatic encephalopathy. Lactulose, however, is still a main-
stay of treatment for hepatic encephalopathy. The therapeutic
mechanisms of lactulose are purportedly both acidification of
the gut and catharsis resulting in decreased ammonia absorp-
tion. Ammonia load can be further decreased with poorly
absorbed antibiotics that decrease bacterial activity, decreased
protein ingestion, and control of gastrointestinal bleeding.
γ-Aminobutyric acid (GABA) has received attention because
in animal models of hepatic encephalopathy, both expression
of GABA receptors and blood-brain GABA movement were
increased. The “false neurotransmitter” or amino acid imbal-
ance theory is based on the increased proportion of aromatic
versus branched-chain amino acids often found in patients
with hepatic encephalopathy. Increased aromatic amino acids
are proposed to be the precursors for false neurotransmitters,
such as octopamine, tyramine, and phenethylamine.
Clinically, branched-chain amino acid supplementation has
been reported to improve hepatic encephalopathy.318 Poorly
absorbed antibiotics such as neomycin and rifaximin have
also shown to be of benefit.319 The severity of hepatic encepha-
lopathy is assessed on the basis of cognitive function, behav-
ior, motor function, and level of consciousness. As shown in
Figure 5-10, a stage of 1 through 4 can be assigned according
to these changes.
ASSESSMENT OF PERIOPERATIVE RISK
Up to 10% of patients with advanced liver disease require a sur-
gical procedure in the final 2 years of life.320 Estimation of peri-
operative risk in the patient with liver disease is problematic.
 194 ANESTHESIA AND UNCOMMON DISEASES

STAGES OF HEPATIC ENCEPHALOPATHY

0 1 2 3 4
Normal

Hypersomnia, insomnia, or inversion of sleep pattern

Slow responses
Lethargy
Minimal disorientation
Somnolence
State of consciousness Confusion
Semi-stupor
Stupor
Coma

Subtly impaired computations

Shortened attention span
Loss of time
Grossly impaired
Loss of place
Intellectual function Inability to compute

Loss of self
No intellect

Exaggeration of normal behavior

Euphoria or depression
Garrulousness
Irritability
Decreased inhibitions
Overt change in personality computations
Anxiety or apathy
Inappropriate behavior
Personality-behavior Bizarre behavior
Paranoia or anger
Rage

No personality-
behavior

Metabolic tremor
Muscular incoordination
Asterixis
Impaired handwriting

Slurred speech
Ataxia
Hypoactive and hyperactive reflexes
Nystagmus
Neuromuscular abnormalities Babinski clonus
Rigidity
Dilated pupils
Opisthotonos
Coma

FIGURE 5-10  Progression of hepatic encephalopathy. Diagram depicts grades of hepatic encephalopathy and clinical features
associated with advancing stages. (Modified from Ferenci P : Clinical manifestations and diagnosis of hepatic encephalopathy. Up-to-date.
www.uptodate.com; accessed 2/27/11.)
 Chapter 5  Liver Diseases 195

TABLE 5-9  n Approach to Patient with Liver Disease Steatohepatitis. Fatty liver itself does not contraindicate
for Elective Surgery elective surgery, whether of alcoholic or nonalcoholic (NASH)
etiology. It is important to verify that acute alcoholic injury
Disease Approach to Surgery
is not also present and further emphasize to the patient the
Acute hepatitis Postpone surgery until normalization of importance of alcohol abstinence in avoiding direct paren-
biochemical profiles. chymal damage and worsening of perioperative liver abnor-
Chronic hepatitis Proceed with surgery if clinical course malities. Patients with severe steatohepatitis tend to show
and laboratory parameters have increased morbidity and mortality in major hepatobiliary sur-
been stable; unspecified increased gery,328 although other associated factors are surgical time and
perioperative risk.
body mass index. NASH is the presumed etiology of increased
Obstructive jaundice Proceed with surgery, with attention to cirrhosis in morbidly obese patients. Among patients under-
fluid resuscitation. Endoscopic or going gastric bariatric surgery, a voluntary multi-institutional
percutaneous preoperative biliary survey329 reported an incidence of previously undiagnosed
drainage is controversial.
cirrhosis of almost 6% and mortality of 4%, with all deaths
Cirrhosis: occurring postoperatively. More recent data from a single
Child's classes A Optimize and proceed with surgery. institution's 48 consecutive bariatric patients found 33% to
and B (See text for special concern in cases
have NASH and a further 12% to have advanced fibrosis.330
requiring cardiopulmonary bypass.)
Coagulation: Goal of prothrombin Mortality was not reported, but NASH and fibrosis were both
time within 2 seconds of normal. associated with diabetes mellitus but not body mass index in
Parenteral vitamin K; if ineffective, this obese population.
fresh-frozen plasma or cryoprecipitate.
Ascites: If conservative management Cirrhosis. Cirrhosis is the liver abnormality for which most
(fluid restriction/diuretics) is perioperative data exist and for which a generally accepted clas-
ineffective, use paracentesis. sification has been developed and verified. Specifically, the
Encephalopathy: Evaluate and
Child-Turcotte and Child-Turcotte-Pugh (CTP) classifications
treat triggering processes (e.g.,
gastrointestinal bleeding, uremia, of cirrhosis have been shown to correlate well with perioperative
medications); consider lactulose. mortality rates (Table 5-10). Data from the 1980s331 and 1990s332
show remarkably similar mortalities of approximately 10% for
Child's class C Postpone surgery while improving
Child's classification, or cancel surgery
Child's class A, 30% for Child's B, and 80% for Child's C disease
for nonsurgical management in patients undergoing open abdominal procedures. Recent
experience indicates that laparoscopic cholecystectomy333-335 is
Modified from Rizvon MK, Chou CL: Surgery in the patient with liver disease,
Med Clin North Am 87:211-227, 2003.
better tolerated in Child's A and B cirrhotic patients, even con-
sidering higher conversion to open procedures than controls.
Endoscopic intervention is often chosen for Child's C patients.
Available data are often either outdated, retrospective, non- The distinction between Child's A and Child's B dis-
specific to etiology, or of limited subject size. While acknowl- ease may be important in patients undergoing cardiopulmo-
edging these shortcomings, generally accepted guidelines are nary bypass. Two very small series indicate that Child's A
summarized in Table 5-9 and Figure 5-11 and expanded here. patients will experience a marginal increase in complications,
but reported a 50% to 80%336,337 mortality in their Child's B
Acute Hepatitis. High mortality rates from older studies are
patients.
often quoted for patients with acute hepatitis undergoing elec-
The subjective nature of measurement of ascites and
tive surgery. Patients were predominantly undergoing explor-
encephalopathy in the CTP has led to increasing investigation
atory laparotomy for possible surgically correctable jaundice
on the model for end-stage liver disease (MELD) (Table 5-11).
in an era before the availability of accurate noninvasive diag-
The MELD is used for organ transplant allocation but is an
nostic techniques. These studies showed mortality of approx-
effective predictor of mortality in patients with cirrhosis.338
imately 10%321,322 for viral hepatitis and almost 55%323,324 for
The other major concern with the Child scoring system is the
alcoholic hepatitis. Acute hepatitis has thus been considered a
lack of inclusion of renal status. Renal dysfunction is associ-
contraindication to elective surgery, although these outcomes
ated with perioperative complications and thus should be con-
have not been retested in the setting of modern anesthetics
sidered in decision making. A cutoff MELD score of 14 has
and techniques.
been proposed, with better positive and negative predictive
Chronic Hepatitis. The patient's clinical and biochemical values than with CTP.339 Others have used a MELD of 8 as a
status should be used to assess perioperative risk. In the symp- cutoff. There is still no consensus as to which of the two scor-
tomatic patient with synthetic or excretory abnormalities, data ing systems should be used. The benefit of the CTP is the ease
from different eras indicate increased perioperative risk.325,326 of use and the length of experience. Not surprisingly, emer-
Conversely, well-compensated, asymptomatic chronic hepati- gency surgery and intra-abdominal surgery carry a signifi-
tis appears to add minimal perioperative risk.327 cantly higher risk of perioperative morbidity and mortality.340
 196 ANESTHESIA AND UNCOMMON DISEASES

Suspect liver disease from

history/physical

Blood tests: Bilirubin, INR,

Imaging:
creatnine, albumin, Endoscopy
CT/MRI/US
ALT/AST/ALP

No evidence
of cirrhosis or Cirrhosis and/or portal
portal hypertension hypertension: Assess
(PHTN) or acute severity with MELD
hepatitis/acute score/Child’s score.
liver failure Imaging/EGD for PHTN

MELD10, MELD10-15, MELD15,

Proceed with Child’s A, Child’s B,/ Child’s C,
surgery No PHTN PHTN PHTN

Prefer for outpatient Proceed Low-Risk High-Risk Emergency: Consider

GI/hepatology with Surgery: Surgery: Proceed with evaluation for
assessment surgery Proceed Consider caution and liver
with caution evaluation for inform patient transplantation
and close liver of risk. and
perioperative transplantation. alternatives
monitoring Defer surgery to surgery.
until clinical
situation changes.

FIGURE 5-11  Algorithm for preoperative assessment of patients with suspected liver disease. MELD, Model for end-stage liver
disease; see text.

TABLE 5-10  n  Child-Turcotte-Pugh Classification of Cirrhosis*

Factor and Score 1 2 3

Serum bilirubin (mg/dL) <2 2-3 >3

Serum albumin (g/dL) <3.5 3-3.5 >3

Ascites None Easily controlled Poorly controlled

PT prolongation (seconds) 0-4 4-6 >6

(INR) (<1.7) (1.7-2.3) (<2.3)

*The Child-Turcotte-Pugh score is calculated by adding the scores of the five factors (possible scores therefore range from 5 to 15).
Child's Class is A (5 or 6), B (7, 8, or 9), or C (10 and greater).
PT, Prothrombin time; INR, international normalized ratio.

ANESTHETIC MANAGEMENT
TABLE 5-11  n Model for End-Stage Liver Disease
(MELD) Score* Concern for liver function may arise in a variety of clinical
scenarios. An asymptomatic patient presenting for any elec-
Score Surgical Risk
tive procedure may have previously undetected laboratory
<10 Low risk abnormalities. The patient with obvious jaundice or asci-
10-15 Intermediate risk
tes, on the other hand, may present for related diagnostic
or therapeutic interventions. Patients with advanced or life-
>15 High risk threatening hepatic dysfunction may require interventions
*MELD score = (9.6 × loge[creatinine]) + (3.8 × loge[bilirubin]) + (11.2 × such as biliary decompression, partial hepatic resection, and
loge[INR]) + 6.4 liver transplantation; alternatively, these patients may require

unrelated emergency procedures such as appendectomy, frac-
ture repair, or cesarean delivery, with significant risk posed by
their hepatic process.
The dilemmas faced by clinicians in these situations are
cited in earlier sections. Laboratory value profiles are helpful,
but not specific, in diagnosing disease processes. Perioperative
data for specific diseases are limited and often reflect a vari-
ety of diagnostic criteria, anesthetic management techniques,
and eras. Additionally, assessment of hepatic reserve is prob-
lematic. Although extraction tests have been used to assess
hepatic function (particularly in transplant candidates),341,342
and newer nuclear imaging techniques show promise for risk
stratification in the future,343,344 neither is well correlated with
surgical risk or universally available.
Anesthetic management is discussed from two perspec-
tives: management issues ranging from asymptomatic lab-
oratory abnormalities to fulminant failure and anesthetic
considerations for procedures directly involving the liver.
Supporting data, when available, are cited. Management rec-
ommendations are otherwise based on common practice,
available reports, and the authors’ opinions.
Abnormal Laboratory Values in Asymptomatic
Patients
Previous series have reported the incidence of elevated trans-
aminases in asymptomatic patients without prior diagnostic
abnormality to range from less than 1% to greater than 10%.
In the 1970s, an often-quoted study345 found that 11 of 7620
patients (0.14%) scheduled for elective surgery had unexpected
significant elevations of liver function studies. Of particular
interest, three patients developed jaundice even though their
surgical procedures were canceled. A large series of asymp-
tomatic patients undergoing nondirected screening indicates
that the prevalence of asymptomatic elevation in liver values
may be much higher three decades later. Approximately 15% of
2294 patients had transaminase levels greater than normal, and
almost 4% had levels greater than twice normal.346 A high prev-
alence of NASH was considered a likely cause for the findings.
Other likely and important diagnoses are listed in Box 5-5.
Approximately one third of asymptomatic patients with-
out risk factors will have normal values on repeated laboratory
BOX 5-5  n DIFFERENTIAL DIAGNOSIS IN ASYMPTOMATIC
PATIENTS WITH LIVER DYSFUNCTION*
False positive (especially likely in asymptomatic patients without risk
factors)
Early and/or subclinical hepatitis
Nonalcoholic steatohepatitis
Drug or toxic effect
Ischemic injury
Infiltrative process
Biliary disease
*Elevated levels or abnormal findings on liver function studies.
Chapter 5  Liver Diseases 197
evaluation. Conversely, acute hepatitis is still considered a
contraindication to elective surgery. The cautious and often-­
recommended path is to postpone elective surgery until
further evaluation and signs and symptoms allow either deter-
mination of etiology or resolution of the undefined process.
Others advocate a tiered response;347 for example, if transami-
nases were elevated less than two times normal, risk factors
for acute hepatitis would be reassessed. If the absence of risk
factors was confirmed, this algorithm would then proceed to
elective surgery. Regardless of the approach chosen, careful
reassessment of the patient's history is indicated (Box  5-6).
The divided opinion of experts reflects the unanswered
dilemma for the clinician, which is to determine when acute
hepatitis has been adequately excluded to justify the delivery
of an anesthetic for elective surgery.
Acute Hepatitis
Patients with acute hepatitis should not be subjected to an
anesthetic for an elective procedure. Some patients will require
urgent surgery (1) without time for a definitive diagnosis or
resolution of asymptomatic laboratory abnormalities or (2)
with known acute hepatitis. It seems prudent to manage the
former group with the same principles that would be applied
for known acute hepatitis; thus these situations are discussed
together. (Acute hepatic failure is an entirely different entity
that is discussed separately.)
It is generally accepted (with supporting data but without
absolute proof) that decreased hepatic blood flow is an impor-
tant cause of perioperative hepatic dysfunction in patients
with acute hepatitis, and that efforts should therefore be made
to maintain total blood flow to the liver. Peripheral procedures
will have less impact than abdominal procedures, but proce-
dure location is usually mandated by circumstance. In ani-
mal models and humans, it appears that halothane decreases
total hepatic blood flow by decreasing both portal venous
and hepatic arterial blood flow348,349 and should be avoided.
Isoflurane is the best studied alternative and appears to preserve
hepatic blood flow much better than halothane. Total intra-
venous anesthesia (TIVA) may prove to be another reason-
able alternative in these patients. Positive-pressure ventilation
BOX 5-6   n LABORATORY ABNORMALITIES IN
ASYMPTOMATIC PATIENTS WITH
HEPATITIS: DIAGNOSTIC STRATEGY
1. Reassess risk factors for acute hepatitis.
n Viral hepatitis exposures
n Toxic exposures
n Alcohol history
n Medication history
2. Repeat liver panel laboratory studies (LFTs).
n Order viral hepatitis laboratory studies, especially with even
marginal indication from history.
3. Consider hepatology consultation.
n Worsening LFTs and/or positive viral serology
n Transaminases that remain more than twice normal
 198 ANESTHESIA AND UNCOMMON DISEASES
BOX 5-7   n ACUTE HEPATITIS FOR URGENT SURGERY:
INTRAOPERATIVE MANAGEMENT
1. Preserve hepatic blood flow.
n Avoid halothane (isoflurane is best-studied alternative and
better preserves flow).
n Consider regional anesthesia if procedure and coagulation
allow.
n Maintain normocapnia.
n Avoid positive end-expiratory pressure (PEEP) if possible.
n Provide generous volume maintenance.
2. Avoid medications with situational potential hepatotoxicity
whenever possible.
n Halothane
n Acetaminophen, particularly in alcoholic patient
n Sulfonamides, tetracycline, and penicillins
n Amiodarone
3. Perform postoperative surveillance clinically and biochemically for
progression of hepatic dysfunction.
n Consider postoperative intensive care admission for 24 to 48
hours.
4. Suspect infectious etiology.
n Provider exposures are treated as high risk for viral hepatitis.
(PPV) and positive end-expiratory pressure (PEEP) would
be expected to decrease liver flow,350 but spontaneous venti-
lation with an elevated carbon dioxide and splanchnic sym-
pathetic stimulation could also be detrimental. Drugs with
known or suspected hepatotoxicity should be avoided, if pos-
sible (Box 5-7); examples are also provided in the prior discus-
sion of hepatotoxins.
Cirrhosis
As previously described, cirrhosis is a sequela of many differ-
ent types of liver injury and represents a histologic diagno-
sis rather than a single disease process. The key elements of
disruption of normal architecture by scarring with nodules of
regenerating parenchyma are common to all causes, but some
causes have typical associated findings (Box 5-8). These and
several less common causes are detailed in previous sections,
and Box 5-1 provides a more complete list.
BOX 5-8   n  COMMON CAUSES OF CIRRHOSIS
Alcohol
Viral hepatitis: hepatitis B, C, and D (delta)
Nonalcoholic steatohepatitis
Metabolic
Wilson's disease
Hemochromatosis
α1-Antitrypsin deficiency
Diabetes mellitus
Galactosemia
Autoimmune
Drug or toxin other than alcohol
Primary biliary cirrhosis
Cholestasis (prolonged)
Cystic fibrosis
BOX 5-9   n COMORBIDITIES AND COMPLICATIONS OF
CIRRHOSIS
Portal hypertension
Ascites
Variceal bleeding
Hypoalbuminemia
Coagulopathy
Renal dysfunction (hepatorenal syndrome as extreme presentation)
Central nervous system effects (hepatic encephalopathy as extreme
presentation)
Hepatopulmonary syndrome
Pleural effusion(s)
Portopulmonary hypertension
Glucose intolerance
Circulatory changes: high cardiac output and low systemic vascular
resistance
Ironically, the cirrhotic patient often suffers more from
extrahepatic manifestations of the disease than from loss of
hepatic parenchyma. Such issues as coagulopathy and altered
drug metabolism are important considerations, but the anes-
thesiologist must be cognizant of a wide range of comorbidi-
ties and complications that occur with cirrhosis (Box 5-9).
Portal hypertension has already been discussed in terms of
its role in the development of significant varices and ascites.
The patient's history should be reviewed for portosystemic
shunts, such as a surgical splenorenal shunt or the now more
common TIPS procedure. Ascites is important preoperatively
for many reasons. Its presence may have led to treatment with
spironolactone, paracentesis, or in resistant cases, even the
placement of a peritoneal-systemic shunt. All these treatment
modalities may result in blood volume and electrolyte abnor-
malities, which should be assessed preoperatively. Enthusiastic
paracentesis can also cause or exacerbate hypoalbuminemia.
All patients with cirrhosis and portal hypertension should
be considered at risk for esophageal varices. These dilated veins
communicating blood from the hypertensive portal system to
lower-pressure systemic veins can be the source of massive
bleeding. Esophageal varices may be treated with endoscopic
sclerotherapy. Blind instrumentation of the esophagus should
be undertaken with caution.
Abnormal PT and hypoalbuminemia reflect decreased syn-
thetic reserve. If time permits, the response to vitamin K can be
determined; otherwise, fresh-frozen plasma (FFP) is often used
to bring the PT within acceptable range. Hypofibrinogenemia
or dysfibrinogenemia from altered synthesis and fibrinolysis
may also be responsible for coagulopathy and may be treated
with cryoprecipitate. Thrombocytopenia, thought to be
caused by both splenic sequestration and decreased peripheral
survival, should be addressed as required by the procedure
in question. Qualitative abnormalities of platelet function,
including abnormal activation, may also exist but are difficult
to assess.
Review of the patient's history must recognize the multi-
systemic impact of cirrhosis. If time allows, correctable abnor-
malities of coagulation, metabolic status, and intravascular

status should be addressed preoperatively. Child's classifica-
tion and MELD scoring should be evaluated for stratification
of perioperative risk (see Tables 5-10 and 5-11). It is important
to remember that most patients with significant cirrhosis have
at least some degree of cognitive dysfunction and memory
lapse; verification of history and signs of early encephalopa-
thy should be sought from objective observers. Box 5-10 lists
other important considerations.
The course of cirrhosis can be stable for long periods, but
this belies the minimal systemic reserve that is often present.
Perturbations that would be minor and well tolerated in the
healthy patient may precipitate decompensation in the cir-
rhotic patient. Dietary indiscretions, infection, minor trauma,
and medication interruptions may not be tolerated. Also, pro-
cedures considered minor in most patients may be major chal-
lenges to the cirrhotic patient, especially in the case of high
Child's classification or significant preoperative deterioration.
Cirrhotic patients should be managed perioperatively with
many of the same considerations as the patient with acute
hepatitis (see previous section), except that elevated intra-
cranial pressure or severe hypoglycemia is not as high a con-
cern. Box  5-11 includes common additional cardiovascular,
coagulation, and metabolic abnormalities that must also be
addressed. Correction of PT to within 2 seconds of normal
is generally recommended for invasive procedures. Portal
hypertension and ascites may be present. Changes in pharma-
cokinetics and pharmacodynamics should be expected but are
often unpredictable. Drugs with high hepatic extraction are
especially affected by portosystemic shunting of blood. Highly
protein-bound medications are affected by hypoalbuminemia,
and the pharmacodynamic effects of drugs such as vasopres-
sors (decreased) and sedatives (increased) may be altered.
Acute Liver Failure
Acute liver failure or fulminant hepatic failure can occur
rarely with any number of insults to the liver that result
in the loss of sufficient hepatic parenchyma to precipitate
acute decompensation. Diagnosis of the syndrome requires
acute hepatocellular failure (without prior significant liver
disease) and encephalopathy. The time interval between
onset of illness and progression to encephalopathy may be
BOX 5-10   n ANESTHETIC CONSIDERATIONS IN
CIRRHOTIC PATIENTS
Etiology of cirrhosis
Complications of cirrhosis, particularly related to Child's
classification
History of disease progression
History of therapeutic interventions
Current medications
Deterioration of status associated with current illness
Seek reliable confirmation: suspect patient's cognitive function and
memory.
Chapter 5  Liver Diseases 199
BOX 5-11  n ANESTHETIC PREPARATION AND
MANAGEMENT OF PATIENTS WITH CIRRHOSIS
1. Consider same issues as in acute hepatitis (see Boxes 5-8, 5-9,
and 5-10):
2. Preserve hepatic blood flow.
n Avoid halothane (isoflurane is best studied alternative and
better preserves flow).
n Consider regional anesthesia if procedure and coagulation allows.
n Maintain normocapnia.
n Avoid high PEEP if possible.
n Provide generous volume maintenance.
3. Avoid medications with situational potential hepatotoxicity when
possible.
n Halothane
n Acetaminophen, particularly in the alcoholic patient
n Sulfonamides, tetracycline, and penicillins
n Amiodarone
4. Anticipate presence or development of abnormalities.
Coagulation
n Attempt to correct prothrombin time to within 2 seconds of normal.
n Consider cryoprecipitate if fresh-frozen plasma ineffective or
fibrinogen abnormality.
n Correct thrombocytopenia appropriately for procedure.
n Anticipate higher-than-normal blood loss for procedure.
Hemodynamics
n Anticipate relative hypovolemia, worsened by treatment of ascites.
n Assess for presence of high cardiac output and low peripheral
resistance.
n Suspect portal hypertension and variceal bleeding, even without
history.
n Anticipate depressed response to ionotropes and vasopressors.
n Consider invasive monitoring.
Pharmacokinetics and Pharmacodynamics
n Altered volume of distribution may occur.
n Decreased serum albumin and increased gamma globulins are
seen.
▪n Intravascular volume is unpredictable, especially with ascites
treatment.
n Portosystemic shunted blood bypasses liver.
n Drugs highly extracted by liver are especially affected.
n Increased sensitivity to sedative medications may be present.
correlated with both etiology and prognosis. Ischemic hep-
atitis and many toxic injuries progress to encephalopathy
in days, whereas viral hepatitis and cryptogenic failure are
more typically associated with 1 month between onset and
the development of encephalopathy. Also, the presence of
jaundice for more than 1 week before encephalopathy may
indicate a poor prognosis. These observations have led to
the use of various nomenclatures for acute hepatic failure
(Box 5-12).
Worldwide, the most common causes of acute liver fail-
ure are drugs, particularly acetaminophen, and viral hepati-
tis. Box  5-13 lists the more common causes in approximate
order of likelihood for centers in the United Kingdom and
United States. The differential diagnosis of acute liver failure
is limited. Sepsis may be associated with cholestasis, DIC, and
encephalopathy without actual hepatocellular destruction.
Decompensation of chronic liver disease can also be confused
 200 ANESTHESIA AND UNCOMMON DISEASES
BOX 5-12   n NOMENCLATURE FOR ACUTE LIVER
FAILURE
Original Definition of Acute Hepatic Failure or Fulminant Hepatic
Failure
Hepatocellular failure (jaundice or coagulopathy)
No prior diagnosis of significant liver disease
Encephalopathy within 8 weeks of onset
Nomenclature Refinements Based on Syndrome Development
Subfulminant hepatic failure
Encephalopathy develops between 2 weeks and 3 months after
jaundice.
Fulminant hepatic failure
Encephalopathy develops within 2 weeks of jaundice.
Hyperacute liver failure
Encephalopathy develops within 1 week of jaundice.
Acute liver failure
Encephalopathy develops between 1 and 4 weeks of jaundice.
Subacute liver failure
Encephalopathy develops between 5 and 12 weeks after jaundice.
BOX 5-13   n ETIOLOGY OF ACUTE LIVER FAILURE
Common
Acetaminophen toxicity
Hepatitis B
Cryptogenic
Hepatitis A (most common worldwide cause)
Toxicity other than acetaminophen
Uncommon
Wilson's disease
Vascular disease
Pregnancy associated
Ischemia
Reye's syndrome
Infections other than hepatitis A and B
with acute liver failure, particularly when a reliable patient his-
tory is not available.
Acute liver failure is a medical emergency. Etiology-
specific therapy should be implemented when present.
N-Acetylcysteine, for example, is used to treat acetamino-
phen toxicity, whereas emergency delivery is indicated for fail-
ure associated with fatty liver of pregnancy. A major dilemma
occurs for the intensivist managing acute liver failure. With
appropriate supportive care, some patients can survive with
recovery of hepatic function, especially patients with acet-
aminophen toxicity and hepatitis A. Other patients are unlikely
to survive without liver transplantation. Much effort has been
expended in devising,351 verifying,352-354 and refining355 meth-
ods to separate these two patient groups. The patient who may
be a candidate for transplantation should be transported to
an experienced transplant center without delay. This allows
implementation of the dual processes of constant reassess-
ment of prognosis for recovery and transplant candidacy.
BOX 5-14   n COMORBIDITIES AND COMPLICATIONS
SEEN WITH ACUTE LIVER FAILURE
Encephalopathy
Cerebral edema with elevated intracranial pressure
Consider other causes (hypoxemia, electrolyte abnormality,
hypoglycemia.
Hemorrhage
Gastrointestinal: typically gastric ulceration and not variceal origin
Coagulopathy
Respiratory failure
Adult respiratory distress syndrome
Pneumonia and/or aspiration in encephalopathic patient
Renal failure
Hypovolemia
Acute tubular necrosis
Hepatorenal syndrome
Hypoglycemia
Hypotension
Relative hypovolemia
Generalized vasodilation
Sepsis
Anesthesia should not be administered to patients with
acute liver failure, except for potentially lifesaving emergency
procedures. Management issues encompass not only the
issues previously discussed for acute hepatitis, but also atten-
tion to often-severe neurologic, hemodynamic, and metabolic
derangements. Box 5-14 outlines relevant systemic effects of
acute liver failure.
Direct measurement of intracranial pressure (ICP) can be
invaluable for advanced encephalopathy. However, placement
of a monitoring device does have substantial risk of bleed-
ing and infection in these patients, and clinical indicators of
damaging ICP increase under anesthesia may be both delayed
and insensitive. If direct monitoring is not available, patients
should be presumed to have elevated ICP with poor intracra-
nial elastance. Maintenance of adequate cerebral perfusion
pressure may be problematic because of relative hypovolemia
and generalized vasodilation.
Hemorrhage should be anticipated in acute liver failure.
Severe coagulopathy often requires extensive transfusion.
Gastrointestinal bleeding tends to be related to stress ulcer-
ations, rather than the variceal bleeding found in chronic liver
disease. Hypoglycemia can be profound because of decreased
intake and loss of hepatic release. ARDS occurs frequently in
acute liver failure and can present a dilemma in attempting
to avoid hypercapnia for ICP concerns while avoiding ventila-
tory pressure and volume lung injury in ARDS. Renal failure
has been attributed to prerenal mechanisms, hepatorenal syn-
drome, and ATN. Regardless of etiology, patients with acute
liver failure frequently require hemofiltration or hemodialy-
sis, and nephrotoxic medications should be avoided whenever
possible.
Invasive hemodynamic monitoring must be considered to
incur a higher-than-normal risk in the patient with acute liver
failure. Considering the interplay of systemic abnormalities
just outlined, however, management of these patients typically

requires invasive monitoring. Finally, it is unlikely that coagu-
lation abnormalities can be fully corrected. The possibility of
large-volume transfusion requirements should be anticipated,
with adequate venous access, fluid-warming devices, person-
nel, and blood bank support. Box 5-15 summarizes anesthetic
management issues.
Transjugular Intrahepatic Portosystemic Shunt
The TIPS procedure, in use since 1989, is sometimes referred to
as “transjugular intrahepatic portosystemic stent shunt” in ear-
lier literature. This terminology emphasized the importance of
stenting open hepatic tissue, to avoid the loss of patency expe-
rienced with the original technique of ballooning without stent
placement. With the refinement of this procedure, patients were
provided with portosystemic shunting to relieve portal hyper-
tension without undergoing major surgery. Box 5-16 lists char-
acteristics of patients presenting for TIPS. The essentials of
TIPS involve placing a catheter into the hepatic vein through
the right jugular approach, passage of a specialized needle and
then guidewire into a major tributary of the portal vein, and
passage of an angioplasty balloon and metallic stent over this
wire to create and maintain a tract through the hepatic tissue.
Mortality is increased in patients undergoing emergency
TIPS. Early mortality may approach 80% in patients with risk
factors.356 In one small series, patients with Child-Pugh class C
disease not only failed to have resolution of ascites but also had
higher mortality than patients randomized to repeated para-
centesis.357 In a larger series of 60 patients, mortality without
liver transplant was similar in TIPS and paracentesis groups
at 1 and 2 years, although multivariate analysis demonstrated
association of TIPS with survival not requiring listing for liver
transplantation.358
Complications that can lead to significant morbidity include
puncture of the liver capsule or injury to a hepatic artery with
extensive bleeding. Increased central venous pressure has been
BOX 5-15   n ANESTHETIC MANAGEMENT AND PREPARATION OF PATIENTS WITH ACUTE LIVER FAILURE
1. Preserve hepatic blood flow.
n Avoid halothane (isoflurane is best studied alternative and better
preserves flow).
n Consider regional anesthesia if procedure and coagulation allow.
n Maintain normocapnia.
n Avoid high positive end-expiratory pressure (PEEP) if possible.
n Provide generous volume maintenance.
2. Avoid medications with situational potential hepatotoxicity whenever
possible (halothane, amiodarone, acetaminophen).
3. Suspect infectious etiology.
n Treat provider exposures as high risk for viral hepatitis.
4. Anticipate elevated intracranial pressure (ICP) with compromised
cerebral perfusion pressure.
n Assess with direct ICP monitoring if available.
n Elevate the patient's head.
n Consider osmotic diuresis.
n Consider barbiturates.
n Consider hypertonic saline.
n Avoid systemic hypotension.
Chapter 5  Liver Diseases 201
observed after shunting, and the cirrhotic patient with poor
cardiac function may decompensate; myocardial infarction
has been reported. Encephalopathy is a risk of any portosys-
temic shunting procedure. Modern TIPS procedures maintain
a patency rate of greater than 90% per year. When necessary,
revision or repeat TIPS has become commonplace in active
centers.
Anesthetic considerations for patients undergoing TIPS
are, in essence, those of managing the patient with cirrhosis
complicated by ascites and portal hypertension, except for
the rare patient who presents with presinusoidal or venous
causes of portal hypertension. Although some centers per-
form TIPS with the patient under sedation, most cases are
performed using general anesthesia. Sedated patients report
significant pain during intrahepatic dilation and stent
deployment. The unpredictable response of patients with
advanced cirrhosis to sedative and narcotic medications
should also be considered in choosing between sedation and
general anesthesia.
BOX 5-16  n PATIENTS REQUIRING TRANSJUGULAR
INTRAHEPATIC PORTOSYSTEMIC SHUNT (TIPS)
Diagnoses
Portal hypertension, most frequently from cirrhosis, with:
Bleeding varices and/or
Ascites failing medical management
Comorbidities of Cirrhosis
Bleeding varices
Emergency procedure associated with increased mortality
Ascites
Recent paracentesis and/or diuretic therapy may cause
hypovolemia
Cardiovascular
Typically high cardiac output and low peripheral vascular resistance
Depressed response to inotropes and vasopressors
n Preserve cerebral perfusion pressure.
5. Consider electroencephalography (EEG) to detect seizure activity
perioperatively.
6. Anticipate hypoglycemia, sometimes profound, with added
perioperative stress.
7. Prepare for adult respiratory distress syndrome.
n Consider PEEP (in conflict with ICP concerns and hepatic
perfusion).
n Consider decreased tidal volumes with permissive hypercapnia
(balance with ICP concerns).
8. Anticipate hypotension.
n Relative hypovolemia
n Hemorrhage
n Extensive vasodilation
9. Prepare for massive transfusion requirements.
n Alert blood bank.
n Secure adequate venous access.
10. Utilize invasive hemodynamic monitoring.
 202 ANESTHESIA AND UNCOMMON DISEASES
Biliary Tract Procedures
Biliary tract procedures include cholecystectomy, choledochal
cyst excision, and biliary tumor resection. General character-
istics of patients undergoing procedures of the biliary tract
are listed in Box 5-17. Although open cholecystectomy is still
­performed in select patients with anticipated technical diffi-
culties or coexisting disease (e.g., advanced cirrhosis, bleeding
diathesis), most institutions now prefer laparoscopic chole-
cystectomy. Indications for cholecystectomy are cholelithiasis,
choledocholithiasis, and cholecystitis. Patients in this group
are often otherwise healthy, although cirrhotic patients often
require cholecystectomy and may present the challenges of
coagulopathy and portal hypertension. Patients with severe
cardiopulmonary disease may poorly tolerate the pneumo-
peritoneum required for laparoscopic surgery; conversely,
pulmonary function after laparoscopy is superior to that of
open, high abdominal surgery.
The extrahepatic biliary tree infrequently may be the site of
primary tumors or cystic dilation (choledochal cysts) that may
present as symptoms of cholangitis, pancreatitis, or cholecystitis.
Surgical excision is required and, depending on location, may be
technically challenging and result in extensive blood loss.
Endoscopic retrograde cholangiopancreatography (ERCP)
has become a cornerstone in the assessment and often the
management of patients with suspected biliary obstruction.
It is typically implemented after suspicious ultrasound, CT,
or MRI. Institutional variation in the anesthetic management
of patients undergoing ERCP ranges from sedation to general
anesthesia. Trends include the increased use of sedation or
general anesthesia in referral centers undertaking more com-
plex procedures and the cooperative development by involved
professional societies of national management guidelines.359
BOX 5-17   n PATIENTS REQUIRING BILIARY TRACT
PROCEDURES
Diagnoses
Cholecystectomy
Cholelithiasis
Cholecystitis
Choledocholithiasis
Biliary duct tumor
Choledochal cyst
Comorbidities/complications*
Respiratory embarrassment from abdominal pain
Obstructive jaundice
Coagulopathy from vitamin K malabsorption with chronic biliary
obstruction
Cholelithiasis associated with:
Female gender
Obesity
Cystic fibrosis
Crohn's disease
Sickle cell anemia
*Associated with biliary tract disease.
Anesthetic preparation should focus on any coexisting dis-
eases and complications, with medical optimization as time
allows (Box  5-18). Even healthy patients with biliary disease
will often be profoundly hypovolemic and may be actively
experiencing nausea and vomiting. Narcotics should be titrated
with the awareness that their stimulation of the sphincter of
Oddi may precipitate worsened pain in the conscious patient
preoperatively and technical failure of cholangiography intra-
operatively. Atropine, glycopyrrolate, naloxone, and glucagon
have all been reported to reverse this narcotic-induced spasm.
Transfusion and special monitoring are typically not required.
Hepatic Resection
A wide range of patients undergo hepatic resection. Living-
directed donors are healthy individuals whose excised lobes
will be transplanted into another patient. Most other patients
have benign or malignant primary hepatic tumors or meta-
static tumors to the liver. This large group may have a variety
of associated disease processes such as cirrhosis and any num-
ber of unrelated diseases. More rarely, patients near extremis
may require resection for problems such as trauma or preg-
nancy-associated rupture with uncontrolled bleeding.
Technologic applications such as intraoperative sonog-
raphy, ultrasonic suction aspiration, harmonic scalpels, and
the argon laser coagulator have become a routine part of
liver resections in many centers. Hepatic cryotherapy, orig-
inally as an open procedure360 and now under radiologic
guidance, has been used for lesions otherwise unresectable
because of underlying liver disease or anatomic position.
BOX 5-18  n ANESTHETIC CONSIDERATIONS IN PATIENTS
UNDERGOING BILIARY TRACT SURGERY
1. Check for elevated prothrombin time (PT).
n Vitamin K may correct if time allows; otherwise, use fresh-frozen
plasma.
2. Pay attention to volume status when vomiting, decreased oral
intake, or fever is present.
3. Consider rapid-sequence induction or awake intubation in patients
with nausea and vomiting.
4. Perioperative opioids may cause spasm of sphincter of Oddi.
5. Blood loss typically is minimal unless complex biliary repair or
coagulopathy.
Open Procedures
Pain can significantly affect respiratory status and can be difficult to
manage.
Consider epidural analgesia or intercostal nerve blocks.
Laparoscopic Procedures
Pneumoperitoneum associated with:
Increased incidence of pneumothorax and pneumomediastinum
Subcutaneous emphysema
Decreased venous return
Increased peak inspiratory pressures
Hypercapnia from insufflated CO2 and decreased pulmonary
compliance

BOX 5-19  n ANESTHETIC MANAGEMENT AND
PREPARATION FOR PATIENTS
UNDERGOING HEPATIC RESECTION
1. Define volume management strategy (restrictive volume vs.
euvolemia).
2. Consider risk and benefits of epidural catheter placement.
3. Consider invasive hemodynamic monitoring.
4. Secure adequate intravenous access for massive transfusion.
5. Alert blood bank of potential for extensive transfusion
requirements.
6. Consider use of cell salvage and rapid infusion device.
7. Anticipate possibility of postoperative hepatic insufficiency.
n Hypoglycemia
n Coagulopathy
8. Anticipate postoperative complications such as atelectasis,
effusion, pneumonia, and renal insufficiency.
Overall morbidity and mortality of patients undergoing
tumor resection or destruction have improved remarkably
in recent experience.
The anesthetic management of patients undergoing liver
resection does have two areas of controversy (Box 5-19). The
first involves fluid management. Traditionally, the patient is
kept relatively euvolemic or even slightly hypervolemic dur-
ing dissection; as in any procedure with the risk of sudden
blood loss, the patient can be more rapidly resuscitated if
hemorrhage occurs. The other approach is to minimize flu-
ids throughout dissection in order to achieve a low central
venous pressure (CVP). Some surgeons augment this by
intermittent occlusion of vascular inflow. Because CVP is a
critical determinant in hepatic venous pressures, the lower
the CVP, the lower is the bleeding from cut hepatic surfaces.
Many centers have adopted this approach.361-365 Importantly,
after resection and confirmation of hemostasis, fluid resusci-
tation is undertaken. Proponents of this approach believe that
the presumed increased risks of organ hypoperfusion, possi-
ble hemorrhage in a hypovolemic patient, and even air embo-
lism are outweighed by the improved surgical conditions and
decreased blood loss and transfusion requirements reported.
Postoperative analgesia is the second area of controversy
in the anesthetic management of patients undergoing liver
resection.366-368 Many centers routinely place epidural cath-
eters for pain management; others do not. Although postop-
erative pain is significant in this upper abdominal chevron
incision, many anesthesiologists are concerned that the
postoperative fluctuations of coagulation seen in any major
abdominal procedure will be dangerously accentuated with
the resection of large amounts of hepatic tissue. Data are lim-
ited to guide the clinician in weighing the risk of epidural
catheter placement in a patient who may become coagulo-
pathic against the presumed benefits of epidural analge-
sia.369-371 The possibility of massive blood loss always exists
in these procedures. The blood bank should be alerted and
appropriate venous access attained. Cell salvage may be used
if cancer and infection are not present.
Chapter 5  Liver Diseases 203
Liver Transplantation
ORTHOTOPIC LIVER TRANSPLANT
Liver transplantation has made a remarkable transition from
a procedure of desperate last resort to a commonly recom-
mended therapy (Table 5-12). In the United States, data indi-
cate 80% to 90% 1-year survival across all groups and 70%
to 80% 5-year survival. With improved survival, recurrences
of infection (first hepatitis B, now hepatitis C) as well as the
morbidities of long-term immunosuppression have become
management issues. Indeed, transplantation can be viewed as
exchanging an otherwise untreatable disease (e.g., cirrhosis or
acute liver failure) with the treatable disease of immunosup-
pression. Box 5-20 lists the most common diagnoses of U.S.
liver transplant candidates for adult and pediatric patients.
Box 5-21 provides important anesthetic considerations in liver
transplant cases.
THE PREVIOUSLY TRANSPLANTED PATIENT
The remarkable improvement in patients surviving liver trans-
plantation and the number of transplantations performed
means that more patients will present for surgery who have
had a liver transplant. Many of these patients seek all health
care at their transplant center. For practical and economic rea-
sons or medical urgency, however, many patients likely will
seek care elsewhere. Faced with this situation, the anesthesi-
ologist should evaluate the function of the transplanted liver
through history, examination, and routine liver panel stud-
ies as described for patients in general. Within a few months
of transplantation, serum bilirubin and transaminase levels
should return toward or to normal range. AST changes in par-
ticular are monitored as indications of graft rejection. ALP
and GGTP are more likely to remain elevated after liver trans-
plant and must be considered in their trends rather than abso-
lute values.
Conservative management of the patient with the trans-
planted liver applies the principles discussed for the patient
with acute hepatitis. However, minimal data exist to indicate
that the transplanted liver is at particularly increased risk for
perioperative dysfunction. Immunosuppressive protocols
should be maintained and their pharmacologic interactions
with perioperative medications considered.
Postoperative Liver Dysfunction
Every anesthesiologist should be prepared to provide at least
initial consultation and care for the postoperative patient
with liver dysfunction. The specter of hepatic necrosis from
halothane exposure still looms large in the minds and liter-
ature of many colleagues in other specialties. As discussed
previously, halothane is rarely a cause of severe hepatic
injury, and newer volatile agents have never been convinc-
ingly implicated. The anesthesiologist can help to ensure
that the more likely, although perhaps less dramatic, causes
of postoperative dysfunction are considered based on their
relative probability.
 204 ANESTHESIA AND UNCOMMON DISEASES

TABLE 5-12  n  Anesthetic Management Issues for Patients Undergoing Liver Transplantation

Management Issues Comments

CENTRAL NERVOUS SYSTEM MONITORING

Intracranial pressure (ICP) monitoring Used most often in fulminant hepatic failure
There is a risk of hemorrhage

LABORATORY MONITORING

Hemoglobin, ABGs Frequent monitoring assists in resuscitation

Calcium, potassium Abnormalities in both are common and can result in cardiac disturbances

Coagulation tests PT, PTT, fibrinogen, and platelet count

Thromboelastography Some centers routinely use to identify fibrinolysis early

POTENTIAL FOR MASSIVE TRANSFUSION

Venous access Large-bore central access and large peripheral access are routine

Blood bank protocols 10 to 20 units of RBCs and fresh-frozen plasma should be ready at start of case, and more
should always be available
Cryoprecipitate and platelets may be needed

HEMODYNAMIC MONITORING

Blood pressure monitoring Arterial lines in radial or femoral site are recommended

Pulmonary artery catheter Continuous cardiac output and mixed venous saturation catheters allow rapid assessment
of oxygen delivery and utilization
Pulmonary artery pressures allow for diagnosis of pulmonary hypertension and acute
intraoperative changes

Transesophageal echocardiography Useful in assessment of cardiac function, especially during reperfusion as well as for
tamponade
Risk of bleeding in patients with varices must be considered

ABGs, Arterial blood gases; PT, prothrombin time; PTT, partial thromboplastin time; RBCs, red blood cells (erythrocytes).

The reported incidence of hepatic abnormalities after anes-

thesia depends on pre-existing state of health, population, pro-
BOX 5-20  n MOST COMMON DIAGNOSES IN U.S.
PATIENTS REQUIRING LIVER cedure, era, and the defining criteria for dysfunction. Studies
TRANSPLANTATION report that 25% to 75% of postoperative patients develop
abnormal laboratory values, but a much smaller percentage
Adult
progress to clinically significant disease or jaundice. Box 5-22
Cirrhosis from hepatitis C
Cirrhosis from alcohol lists causes of postoperative jaundice. Three general categories
Cryptogenic cirrhosis of postoperative abnormalities are increased bilirubin produc-
Primary biliary cirrhosis tion, hepatocellular injury, and cholestatic disorders.
Autoimmune cirrhosis Bilirubin overproduction can cause jaundice in the pre-
Cirrhosis from hepatitis B
viously healthy patient when bilirubin production exceeds
Acute liver failure
Primary sclerosing cholangitis hepatic processing capacity. About 250 mg of bilirubin
is usually conjugated daily, but the healthy liver can con-
Pediatric
Biliary atresia (extrahepatic)
jugate up to three times that amount. Several periopera-
Autoimmune cirrhosis tive situations can exceed this production. About 10% of
Acute liver failure transfused red blood cells (RBCs), if older than 2 weeks, are
Obstructive biliary disease destroyed within 1 day of administration. Similarly, RBCs
Cystic fibrosis
within hematomas are rapidly hemolyzed during resorp-
Cirrhosis
Neonatal hepatitis
tion. The placement of stents (e.g., as discussed with early
Congenital hepatic fibrosis TIPSS series) and mechanical valves can result in frag-
Inborn errors of metabolism mentation or so-called mechanical hemolysis. Laboratory
values usually show a pattern of mildly elevated AST and

BOX 5-21   n  ANESTHETIC CONSIDERATIONS IN PATIENTS UNDERGOING LIVER TRANSPLANTATION
Coagulation*
Decreased or abnormal factor synthesis
Fibrinolysis
Disseminated intravascular coagulation
Thrombocytopenia
Metabolic Abnormalities†
Hypoglycemia in acute hepatic failure; glucose intolerance in cirrhosis
Respiratory alkalosis common with hypoxemia-driven tachypnea
Metabolic acidosis from peripheral shunting, causing tissue
hypoperfusion
Metabolic alkalosis from volume contraction of paracentesis; diuresis,
or vomiting
Cardiovascular
High cardiac output with low peripheral resistance is typical.
Peripheral arteriovenous shunting causes paradoxical tissue ischemia.
Increased endogenous vasodilators are usually metabolized by liver.
Formation of true arteriovenous fistulas occurs.
Cardiomyopathy may occur with such disorders as alcoholism and
Wilson's disease.
Cardiac reserve must be adequate to tolerate rigorous challenges of
transplantation.
*Almost universally abnormal; severity and direct causes are variable.
†
Arise from variety of causes; overall picture is unpredictable.
BOX 5-22   n  CLASSIFICATION AND EXAMPLES OF POSTOPERATIVE JAUNDICE
Pre-Existing Limitation of Capacity for Bilirubin Metabolism
Chronic liver disease
Gilbert's disease
Unappreciated Pre-Existing Disease with Natural or Accelerated
Progression
Viral hepatitis
Cirrhosis
Autoimmune hepatitis
Hepatocellular Injury
Ischemic hepatitis
Viral hepatitis
Drug hepatotoxicity
Increased Bilirubin Load
Breakdown of hemoglobin from transfused erythrocytes
Resorption of large hematomas
LDH, reduced haptoglobin, unconjugated hyperbilirubine-
mia, and reticulocytosis. The peripheral smear may reveal
schistocytes. Unrecognized pre-existing diseases can result
in a relative or absolute overproduction of bilirubin. The
amount of hemoglobin that can be conjugated decreases
in Gilbert's disease. Glucose-6-phosphate dehydrogenase
(G6PD) deficiency, sickle cell disease, and the thalassemias
can result in increased hemolysis with what would usually
Chapter 5  Liver Diseases 205
Pericardial effusion may require preoperative or early intraoperative
drainage.
Portopulmonary hypertension confers exceptionally high perioperative risk.
Respiratory
Hypoxemia is common.
Ascites and pleural effusions occur with respiratory compromise.
Intrapulmonary shunting results from endogenous vasodilators.
Hepatopulmonary syndrome is associated with intrapulmonary vascular
dilations.
Adult respiratory distress syndrome may be present, particularly in acute
failure.
Neurologic
Encephalopathy is common, with variable severity.
Encephalopathy of acute liver failure is often associated with critical ICP
elevation.
Direct ICP measurement is invaluable for intraoperative management.
Renal
Dysfunction is common; severity ranges from mild to hepatorenal
syndrome.
Osmotic diuretics and dopamine are often used, but without proven
efficacy.
Preoperative or intraoperative dialysis may be considered in anuric
patients.
Hemolysis
Mechanical (e.g., stents, cell-salvage processing)
Pre-existing disease (e.g., G6PD deficiency)
Transfusion reaction
Intrahepatic Cholestasis
Benign postoperative cholestasis
Medication associated
Extrahepatic Biliary Obstruction
Postoperative pancreatitis
Biliary stricture
Cholecystitis
Calculous
Acalculous
be insignificant stress. Table 5-13 compares laboratory pat-
terns that may be seen in postoperative liver dysfunction.
Hepatocellular necrosis can account for postoperative jaun-
dice and transaminase abnormalities. Ischemic liver injury
typically manifests 1 to 10 days after the insult. Hypoperfusion
from hypotension, cardiopulmonary bypass, and mechanical
interruption of flow as well as hypoxemia have been associated
with this type of injury. Venous congestion from right-sided
 206 ANESTHESIA AND UNCOMMON DISEASES
TABLE 5-13  n  Biochemical Patterns of Postoperative Liver Dysfunction
Dysfunction AST and ALT ALP
Bilirubin AST (↑) Other
overproduction ALT NL medications
Ischemic injury ↑ 5×-100× (↑) 2×
Viral infection ↑ >10× (↑)
Anesthetic associated; ↑ to ↑↑ — —
severe
Benign postoperative (↑) ↑ 3×
cholestasis
Extrahepatic ↑ ↑
cholestasis
AST, Aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; unconj, unconjugated; PT, prothrombin time.
NL, Normal; (↑), mild or no increase; ↑, increased; ↑↑, marked increase; ×, times normal; —, not applicable or unavailable.
heart failure may exacerbate the damage. As previously dis-
cussed, liver blood flow is decreased with most anesthetics. In
the case of unrecognized chronic disease, small decreases in
blood pressure and cardiac output may not allow the hepatic
arterial flow to compensate for decreased portal venous flow
to the liver. Transaminase levels are greatly elevated, as is
LDH, as previously described in patterns of hepatic injury. If
liver biopsy is performed, centrilobular or panlobular necro-
sis is found. The injury can progress to acute liver failure.
Treatment is supportive with maintenance of perfusion and
oxygen delivery.
Viral hepatitis is an unusual but important cause of post-
operative jaundice. Some percentage of patients will have an
acute infection with a time course that conspires to manifest
perioperatively, or a chronic infection that results in hepatic
deterioration postoperatively. Transfusion-borne disease is
less likely than preoperative infection in the current era. The
disease can present anytime in the first 2 postoperative weeks
with typical laboratory findings; previously discussed sero-
logic studies and RNA analysis are indicated.
Anesthetic-associated injury is discussed earlier with hep-
atotoxins. The newer inhalational anesthetics are rarely, if
ever, associated with hepatic injury of consequence, because
of decreased biotransformation and improved hepatic per-
fusion compared with halothane. Other drugs that should
be considered in postoperative liver dysfunction are tetracy-
cline, isoniazid, phenytoin, penicillin, acetaminophen, and
sulfonamides.
Benign postoperative cholestasis occurs with or without
jaundice. It tends to occur in critically ill patients. Its causes
are believed to be multifactorial, having significant over-
lap with issues such as increased bilirubin load and hypo-
perfusion. Treatment is supportive, and mortality is related
to processes other than cholestasis. Major infection can also
cause intrahepatic cholestasis. In fact, some authors consider
this simply to be another cause of benign postoperative cho-
lestasis, whereas others distinguish the two. Regardless of
LDH Bilirubin Others
↑ ↑Unconj ↑Reticulocytes
↑Schistocytes
↑↑ (↑) 2-3× —
(↑) ↑ Serologies and RNA
analysis
↑ Leukocytosis,
eosinophilia
— ↑ 3× PT (↑)
— ↑ —
nomenclature, infection should be considered in the differen-
tial diagnosis of postoperative cholestasis.
Extrahepatic cholestasis is a rare cause of postoperative
jaundice but should be considered. Causes include cholecys-
titis (with or without cholelithiasis), postoperative pancreati-
tis, and complications of surgery that disrupt the biliary tract.
AST/ALT, ALP, and total bilirubin are typically mildly to mod-
erately elevated. Total parenteral nutrition (TPN) has been
associated with both acalculous cholecystitis and cholelithia-
sis, as well as steatohepatitis and even micronodular cirrhosis
with long-term administration.
A general approach to the patient with postoperative liver
dysfunction is to review the history for any overlooked evidence
of pre-existing liver disease. A biochemical liver profile, com-
plete blood cell count, and clotting times should be assessed.
Elevations of unconjugated bilirubin can arise from break-
down of transfused RBCs, hemolysis from mechanical devices
or pre-existing disease, hematoma resorption, or Gilbert's syn-
drome. Haptoglobin, reticulocyte count, and LDH can be used
to help confirm the etiology. In the case of conjugated hyper-
bilirubinemia, further discriminating laboratory testing should
be pursued. Greatly increased transaminases and LDH with-
out evidence of obstruction are consistent with ischemic injury,
drug-associated injury, or active viral infection. Abdominal
sonography can be used to evaluate obstruction. Sepsis, TPN,
medication effects, and acalculous cholecystitis can also cause
cholestasis and conjugated hyperbilirubinemia.
CONCLUSION
The vital roles of the liver, even in health, are of a complexity
and number beyond current understanding. Patients with liver
disease, or those without liver disease undergoing procedures
affecting the liver, can present great challenges to the anesthe-
siologist. With the current epidemic of patients deteriorating
from chronic hepatitis C and the limited number of organs
available for transplantation, anesthesiologists can expect

to care for an increasing number of patients with significant
hepatic dysfunction. Innovations in therapy require the appli-
cation of basic management principles and critical review.
ACKNOWLEDGMENT
The authors would like to acknowledge the significant contri-
butions of Keith Littlewood, MD, and Edward C. Nemergut,
MD, the authors of a previous version of this chapter.
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 C H
Obesity and Nutrition Disorders
Obesity
Pathophysiology
Comorbidities
Respiratory Effects
Cardiovascular Effects
Gastrointestinal and Metabolic Effects
Airway Considerations
Pharmacologic Issues
Nutrition Disorders
Conclusion
KEY POINTS
n Obesity is a common disease. The number of overweight,
obese, and morbidly obese persons has increased alarm-
ingly in the last three decades.
n Body mass index (BMI) is only one measure of obesity;
some patients with high BMI are in good health.
n Distribution of fat is a better predictor of health risk than
weight alone; gynecoid (gluteofemoral) fat distribution
predicts better risk than android (abdominal) distribution.
Fat tissue is an active endocrine organ.
n Hypertension, diabetes, cardiac disease, dyslipidemia,
arthritis, and back pain are common problems in obese
patients, who are also at increased risk for depression and
cancer, as well as social discrimination.
n Obese women may have more menstrual irregularities,
subfertility, stress incontinence, and hirsutism.
n Obstructive sleep apnea (OSA) is a common problem
among obese persons, with many negative anesthetic impli-
cations and insufficient screening of surgical patients.
n Ventilation is more difficult in obese patients; OSA,
BMI, and large neck circumference also can make intu-
bation challenging. A consistent approach with head
elevation and preoxygenation can increase apnea time
significantly.
A P T E R
6
IAN YUAN, MEng, MD  n
ASHISH C. SINHA, MBBS, MD, PhD, DABA  n
n Drug dosing in the obese patient must consider total,
lean, and ideal body weight, along with lipophilic drug
characteristics.
n Nutrition disorders can significantly impact surgical out-
comes, especially postoperative infections.
OBESITY
Obesity is a common disease, at least in most of the developed
world; parts of the developing world, such as China and Egypt,
also have increasing overweight and obesity rates. With one
third of the U.S. adult population and one sixth of U.S. children
classified as obese,1 obesity is now the second most common
cause of preventable deaths in the United States, second only to
smoking.2,3 In the 1970s, 15% of the U.S. population was clas-
sified as obese; this has steadily increased to 33% and for the
first time has now leveled off in the past few years. Clinically,
minority populations have a much higher incidence of obesity.
Alarmingly, the incidence of childhood obesity has tripled
since 1980 and had reached 17% in 2008, with no signs of
abating. Long-term health and social consequences for these
children are substantial. They have a significantly greater
­
chance of developing associated medical problems, such
as diabetes, hypertension, and heart disease, and at a much
younger age. As they grow into obese teenagers and young
adults, they are the same children who are much more likely
to suffer from depression and social isolation.
In economic terms, the estimated medical cost of obesity in the
United States is a staggering $147 billion.4 Globally, the incidence
of obesity has more than doubled since 1980, with more than 1
in 10 adults now classified as obese; o­ besity is now the fifth lead-
ing risk of death. According to the World Health Organization,
“Once considered a high-income c­ ountry ­problem, overweight
and obesity are now on the rise in l­ow- and middle-income
countries, particularly in urban settings. Overweight and obesity
are linked to more deaths ­worldwide than underweight.” Perhaps
for the first time in human h ­ istory, there are more o­ verweight
than underweight people in the world.
215
 216 ANESTHESIA AND UNCOMMON DISEASES
Pathophysiology
Obesity is a function of a person's weight being dispropor-
tionately greater than their height. There are different ways of
classifying a person as overweight or obese and even morbidly
obese. For example, a person who is 100 pounds above their
ideal body weight is considered morbidly obese. A patient with
a body mass index (BMI) of 30 kg/m2 or more is classified as
being obese. BMI is calculated by using the person's weight
in kilograms (kg) divided by the person's height in meters
squared (m2). Table 6-1 lists other weight classifications based
on BMI.
Although one of many methods for estimating body
fat, BMI does not correlate well with the distribution of fat
(android or “apple” vs. gynecoid or “pear”). BMI also does not
take into account the amount of pre-existing muscle mass often
seen in some athletes or even weightlifters. Other methods
used to estimate body fat and distribution include measure-
ments of skin fold, waist circumference, waist-to-hip cir-
cumference ratios, or radiographic studies such as computed
tomography (CT), ultrasound, and magnetic resonance imag-
ing (MRI). For adult patients with a BMI of 25 to 34.9 kg/m2,
waist circumference should be used in addition to BMI to
identify risk factors, with higher risks associated with males
with a waist size greater than 40 inches and females with a
waist size more than 35 inches.
Many factors contribute to overweight and obesity. On a
basic level, an energy imbalance between the caloric intake and
caloric expenditure—in which caloric intake exceeds ­calories
consumed in basal metabolic demand, work, or ­exercise—
leads to overweight and ultimately obesity. As excess calories
are stored in the body as fat, obesity can result from over-
consumption of food, insufficient physical activity, or other
f­ actors (Table 6-2). A 2% differential in this balance can lead
to a 5-pound (2.2-kg) increase in weight every year.
Comorbidities
Obesity is associated with an increased incidence of s­everal
diseases. Higher morbidity caused by overweight and o ­ besity
has been observed for hypertension, type 2 diabetes, coronary
TABLE 6-1  n  Body Mass Index (BMI) and Weight Status
BMI Weight Status
<18.5 Underweight
18.5-24.9 Normal
25.0-29.9 Overweight
30.0-39.9 Obese
40.0-49.9 Morbidly obese
50.0-69.9 Super morbidly obese
>70.0 Ultra-obese
TABLE 6-2  n  Etiologies of Obesity
Etiologic Category Examples
Familial/genetics Bardet-Biedl syndrome
Prader-Willi syndrome
Diseases Hypothyroidism
Cushing's disease
Polycystic ovary syndrome
Depression
Eating disorders
Medications Antidepressants
Steroids
Societal factors Poor access to healthy foods
Larger food portions
heart disease, cerebrovascular accident (stroke), gallbladder
disease, osteoarthritis, sleep apnea and respiratory ­problems,
and endometrial, breast, prostate, and colon cancer. Obesity
is also associated with complications of pregnancy, men-
strual irregularities, hirsutism, stress incontinence, and
­psychological disorders such as depression.
Fat distribution also plays an important role in the type of
associated disease. Visceral fat, typically seen in males with an
android (truncal) fat distribution, represent a risk factor for
the development of cardiovascular disease and type 2 diabe-
tes. Visceral adipose tissue mass frequently correlates with the
development of insulin resistance. This is not the case with
total or subcutaneous adipose tissue mass.5,6 It is now known
that the adipocytes of visceral fat tissue are more lipolytically
active than subcutaneous adipocytes and contribute more to
the plasma free fatty acid (FFA) level. Subcutaneous adipose
tissue (SAT) is divided into superficial subcutaneous adipose
tissue (sSAT) and deep subcutaneous adipose tissue (dSAT) by
the layer of fascia superficialis. Deep SAT is strongly linked to
insulin resistance, particularly in obese males.7 Interestingly,
subcutaneous leg and hip adipose tissue have a protective role
against diabetes and cardiovascular disease.
Obesity affects many organ systems (Table  6-3). During
the perioperative period, the anesthesiologist is primarily con-
cerned with cardiovascular, respiratory, and g­astrointestinal
diseases.
OBESITY-HYPOVENTILATION SYNDROME
Between 10% and 20% of OSA patients eventually develop
obesity-hypoventilation syndrome (OHS), also known as
­pickwickian syndrome. OHS is defined as a combination of
obesity (BMI ≥30 kg/m2) and chronic hypercapnia (Paco2
≥45 mm Hg) accompanied by sleep-disordered breathing.
Patients ­
typically present with daytime hypersomnolence
as well. Patients with severe OHS may develop polycythe-
mia, ­pulmonary hypertension, and right-sided heart ­failure.
Obstructive sleep apnea causes hypoventilation, leading
to hypoxia and ­ hypercapnia, with metabolic alkalosis to
 Chapter 6  Obesity and Nutrition Disorders 217

arterial hypoxemia. General anesthesia further decreases the

TABLE 6-3  n  Comorbidities in Obese Patients
FRC in an obese patient (~50%) compared with a nonobese
Disease Category Select Comorbidities patient (~20%), leading to a decrease tolerance of apnea.
Preoxygenation with anesthesia induction helps prolong the
Cardiovascular Obesity cardiomyopathy apnea period, although arterial hypoxia is still quite com-
Hypertension
Ischemic heart disease
mon during direct laryngoscopy. The addition of continuous
Hyperlipidemia positive airway pressure (CPAP) helps improves FRC at the
Sudden cardiac death expense of cardiac output and oxygen (O2) delivery.
The extra weight around the chest wall also causes decreased
Respiratory Obstructive sleep apnea (OSA)
Obesity hypoventilation syndrome (OHS) lung compliance, resulting in rapid, shallow breathing pat-
Restrictive lung disease terns in obese patients. This increases the work of breathing,
causing increased O2 consumption and increased carbon diox-
Endocrine Diabetes
Cushing's disease
ide production. Therefore, obese patients have increased CO2
Hypothyroidism production and increased O2 consumption partly because of
Polycystic ovary syndrome (PCOS) increased effort to mobilize and increased energy requirement
Infertility for breathing in trying to move the chest wall, causing up to a
Gastrointestinal Gastroesophageal reflux disease (GERD) 70% increase in the energy expenditure for breathing.
Fatty liver
Gallstones
Cardiovascular Effects
Genitourinary Menstrual abnormalities
Female urinary incontinence The risk of comorbidities rises with increasing BMI. Even
Renal calculi though exertional dyspnea and lower-extremity edema are
common and nonspecific, even electrocardiography and phys-
Malignancy Breast, prostate, colorectal, cervical,
renal, and endometrial cancer ical examination can underestimate the degree of cardiac dys-
function in the obese patient group.9,10 The increased length of
Musculoskeletal Osteoarthritis of weight-bearing joints assisted ventilation, longer hospital stay, and increased risk of
Back pain
renal dysfunction are more often seen than increased mortal-
ity, at least in cardiac surgery patients.11
Adipose tissue is highly vascular, with each kilogram of fat
containing 3000 m of blood vessels. This causes cardiac out-
compensate for respiratory acidosis. Initially the acid-base put to increase 0.1 L/min for each kilogram of excess weight
disturbance is limited to nocturnal periods, with a return to related to adipose tissue. The result is that 50% to 60% of obese
homeostasis during the day. Over time, however, the central patients also have hypertension from hypervolemia caused by
respiratory centers become desensitized to hypercapnia, and excess extracellular fluid volume and increased cardiac out-
nocturnal episodes of apnea occur. Gradually, an increased put. Systemic hypertension could eventually lead to concen-
reliance on hypoxic drive for ventilation develops (see Airway tric left ventricular hypertrophy (LVH), ultimately leading to
Considerations). congestive heart failure (CHF).12,13 The right side of the heart
Patients with OHS are more sensitive to the respiratory is frequently affected because of CHF from the left ventricle or
depressive effects of opioids and hypnotics.8 Because of the pulmonary hypertension from chronic arterial hypoxemia or
added complexity of arterial hypoxia, hypercapnia, pulmonary increased pulmonary blood volume.
hypertension, and right-sided heart failure, invasive monitor- Obese patients often have poor exercise tolerance. Because
ing should be considered in obese patients along with baseline of LVH and a stiffened left ventricle during exercise, cardiac
arterial blood gas (ABG) levels as a reference point for further output can only be increased by increasing heart rate, without
management. a corresponding increase in stroke volume or ejection fraction.
In addition to these cardiac issues, obesity (especially
­central obesity) is also an independent risk factor for the
Respiratory Effects
development of ischemic heart disease. Acid-base and elec-
Obese patients have an increased amount of chest wall a­ dipose trolyte disturbances, volume overload, and coronary heart
tissue, causing a mass effect on the thoracic cage and ­abdomen. ­disease also put obese patients at higher risk for arrhythmias,11
This extra weight impedes the normal diaphragmatic especially atrial fibrillation.
motion, especially in a supine position, resulting in splint- In evaluating risk of perioperative morbidity and mortal-
ing of the d ­ iaphragm. This causes a decrease in f­unctional ity, the anesthesiologist focuses on age, gender, cardiac and
residual c­apacity (FRC), expiratory reserve volume (ERV), respiratory fitness, electrolyte imbalances, and heart fail-
and total lung capacity (TLC). The FRC may decrease to ure as predictors. The American Heart Association (AHA)
the point that small-airway closure occurs with resulting provides recommendations for evaluation of obese surgical
ventilation/­perfusion mismatch, right-to-left shunting, and patients.11
 218 ANESTHESIA AND UNCOMMON DISEASES
Gastrointestinal and Metabolic Effects
GASTROESOPHAGEAL REFLUX DISEASE
Contrary to popular belief, obese patients without symptoms
of gastroesophageal reflux disease (GERD) have a resistance
gradient between the stomach and gastroesophageal junction
similar to that in the nonobese population, in both the supine
and the upright position.14 Although obese patients have 75%
greater gastric volume than nonobese persons, a faster gas-
tric emptying time compensates for most of this extra volume.
This implies that the risk of aspiration at anesthesia induction
is probably overestimated by most clinicians.
DIABETES MELLITUS
Obesity is an important independent risk factor for type 2
­diabetes mellitus. All obese patients should have a random
glucose test preoperatively and if indicated, a glucose toler-
ance test. The stress response of surgery may trigger hypergly-
cemia and necessitate exogenous insulin in the perioperative
period. Preoperative blood glucose levels are obtained, with
hourly follow-ups operatively as well as in the i­mmediate
p­ ostoperative period.
METABOLIC SYNDROME
Metabolic syndrome, sometimes referred to as “­ insulin resistance
syndrome” or syndrome X, seems to result from the maladapta-
tion to overnutrition of genes selected to survive undernutrition.15
Medicine traditionally viewed the relationship between insulin
and glucose as confined to diabetes. In fact, the hyperinsulinemia
of insulin resistance is associated with a range of apparently
unconnected d ­ isturbances that include hyperglycemia, hypercho-
lesterolemia, ­hypertriglyceridemia, hypertension, hyperviscosity
(increased ­hematocrit), hypercoagulability and hyperuricemia.15
Each of these ­disturbances poses a cardiovascular risk to the
patient, but in concert, they are deadly to the macrovascu-
lar system. Although Reaven16 first elucidated the relationship
between insulin resistance and metabolic disturbance in 1988,
Himsworth had observed almost five decades earlier that some
diabetic patients required increasing amounts of insulin and
appeared to become i­ncreasingly insensitive or “resistant.”
Weight gain and insulin resistance are the primary causes of
metabolic syndrome. Fat distribution also seems to be involved
in cardiovascular risk differences in patients. Upper abdomi-
nal fat (around the digestive organs), usually in the male, and
gluteofemoral (subcutaneous) in the female patient explain
some of the disparate risk. Fat, the largest endocrine organ in
the body, produces many inflammatory mediators, including
­adiponectin, which appears to play a significant role in insulin
resistance. Adiponectin has an inverse relationship with obesity,
with levels decreasing with increasing obesity, and negatively
with glucose, insulin, triglycerides, and increasing BMI.17,18
THROMBOEMBOLIC EVENTS
The risk of deep vein thrombosis (DVT) in obese patients
undergoing nonmalignant abdominal surgery is approximately
twice that of nonobese patients, with a similarly increased risk
of pulmonary embolus or embolism (PE). Stein et al.19 showed
that in the nonsurgical population, the relative risk of DVT and
PE was 2.5 and 2.21, respectively, comparing obese patients
with nonobese patients. Obese females under age 40 were noted
to be the highest-risk group for DVT and PE. The use of sub-
cutaneous heparin and pneumatic devices has helped decrease
incidence and thereby improve outcomes in these patients.
Airway Considerations
The pharynx is a collapsible tube that is controlled by more than
20 pairs of pharyngeal muscles. The pharyngeal airway size is
determined by the structural properties of the airway and neu-
ral regulation of the pharyngeal dilating muscles. Anatomically,
the pharyngeal airway is formed by the space surrounded by
soft tissue such as the tongue and soft palate. The soft tissue is
itself enclosed in a rigid craniofacial bony structure that limits
its outward expansion. Therefore, an increase in soft tissue sur-
rounding the airway or a decrease in the rigid bony structures
surrounding the soft tissue would reduce the amount of space
for the airway. The pharynx further narrows or closes when
the neural control mechanism is diminished during sleep or
­general anesthesia, leading to obstruction of the airway.20
OBSTRUCTIVE SLEEP APNEA
Cessation of airflow of more than 10 seconds, characterized by
frequent episodes of apnea or hypopnea during sleep, defines
obstructive sleep apnea. OSA is seen in 38% of obese men and
28% of obese women; odds ratio (OR) is 6.7 in heavy smokers.
In the general population, 11.4% of males and 4.7% of females
have moderately severe OSA. This number increases with age,
with OR increasing 1.8 with each decade of life.
Clinical diagnosis of OSA is made when the frequency of
apnea or hypopnea per hour of sleep (apnea-hypopnea index
[AHI]) is >5/hr in adults. Severity of OSA is determined by
the AHI: mild (6-15/hr), moderate (16-30/hr), and severe
OSA (AHI >30/hr). OSA is now recognized as an independent
risk factor for the development of hypertension, cardiovascu-
lar morbidity and mortality, and sudden death.21
Obesity is a common feature of OSA patients.20 Alternately,
not all obese patients have OSA, and not all patients with OSA
are obese.22,23 Obesity has two distinct mechanisms affecting
pharyngeal airway collapsibility. First, obesity increases soft
tissue mass surrounding the pharynx, leading to a smaller
upper airway. This is especially true for patients with a large
neck circumference, which represents regional obesity near the
pharyngeal airway, and thus has a stronger correlation to OSA
severity than BMI. Second, obesity, particularly central obe-
sity, decreases lung volume through an increase in visceral fat
volume. The decrease in lung volume causes pharyngeal wall
collapsibility from “decreased longitudinal tracheal traction.”
Recent studies show that waist circumference may be an even
better predictor for OSA than neck circumference or BMI.24,25
Perioperative airway management starts with the preop-
erative interview. There is a high prevalence (>24%) of undi-
agnosed OSA in the surgical patients, and appropriately, it is

even higher in the obese surgical patient. All obese patients
undergoing surgery should therefore be suspected of having
OSA preoperatively. During the airway evaluation, a modified
Mallampati class 3 or 4, or excessive submandibular soft tissue,
also indicates anatomic imbalance, which may suggest OSA.
With OSA as a primary risk factor, Langeron et al.26 reported
five independent risk factors for potential difficult mask venti-
lation (age >55; BMI >26 kg/m2; ­snoring; beard; lack of teeth).
The relationship among OSA, obesity, and difficult tracheal
intubation is more controversial. Siyam and Benhamou27
showed a higher incidence of difficult intubations in OSA
versus non-OSA patients (21.9% vs. 2.6%), whereas Neligan
et al.28 showed that in morbidly obese patients, there was no
relationship between the presence and severity of OSA, BMI,
or neck circumference and difficulty of intubation or laryngos-
copy grade. Chung et al.29,30 cited the STOP-BANG question-
naire as an ideal screening tool for OSA: snoring, tiredness,
observed apnea, high blood pressure, high BMI, advanced
age, large neck circumference, and male gender (Box 6-1).
During anesthesia induction, the obese OSA patient should
be placed on a “ramped position,” with elevation of torso and
head combined with the semiupright position (Fig. 6-1). This
position increases lung volume, decreases pharyngeal closing
pressure by improving the pharyngeal anatomic disparity, and
improves the alignment of the oral, laryngeal, and pharyngeal
axes when combined with placing the patient in a “sniffing”
position. Preoxygenation with 100% O2 by a ­tight-fitting mask
using CPAP can increase apnea t­olerance time and oxygen-
ation (see Fig. 6-1). At our institution, this consistent approach
has resulted in no incidences of “could not intubate, could not
ventilate” scenarios over the last 2000+ morbidly obese cases.
Airway maneuvers such as mandible advancement, neck
extension, and mouth opening (triple airway maneuver), in
addition to use of an oral airway, often aid in oxygenation and
prevention of airway obstruction. About 10% of obese patients
are difficult to ventilate, and about 1% are difficult to intubate.
There are multiple reasonable approaches to the airway in the
BOX 6-1   n STOP-BANG QUESTIONNAIRE TO SCREEN
FOR OBSTRUCTIVE SLEEP APNEA (OSA)
1. Snoring: Do you snore loudly (louder than talking or loud enough
to be heard through closed doors)?
2. Tired: Do you often feel tired, fatigued, or sleepy during the daytime?
3. Observed: Has anyone observed that you stopped breathing during
your sleep?
4. Blood pressure: Do you have, or are you being treated for, high
blood pressure?
5. Body mass index: BMI greater than 35 kg/m2?
6. Age: Older than 50?
7. Neck circumference: Greater than 40 inches?
8. Gender: Are you male?
High risk of OSA: “Yes” to three or more items.
Low risk of OSA: “Yes” to less than three items.
Modified from Chung F, et al: Anesthesiology 108:812-821, 2008.
Chapter 6  Obesity and Nutrition Disorders 219
FIGURE 6-1  Obese patient (BMI, 91 kg/m2) placed in ramped
position, with tightly secured mask on pressure-support settings.
The mask is duplicating the patient's home CPAP settings to
increase apnea time after induction.
obese and morbidly obese patient. Direct laryngoscopy with
a class 1 airway combined with a ramped position has a high
degree of success. Intubating laryngeal mask airway (LMA),
awake fiberoptic intubation, and video laryngoscopy also have
high success rates.
Importantly, the clinician should not become fixated on
intubating or on just one approach to the airway. The anesthe-
siologist should be prepared to stop, re-evaluate, and change
equipment, position of head, or person intubating. Use of
short-acting neuromuscular blockade (­succinylcholine or
rocuronium with Sugamadex availability) allows the patient
to return to spontaneous respiration. Clearly the American
Society of Anesthesiologists (ASA) “difficult airway a­ lgorithm”
still applies for obese patients in case of difficulties with mask
ventilation or intubation. Awake intubation should be consid-
ered when any element of the triple airway maneuver is dis-
turbed in obese patients with severe OSA. Kheterpal et  al.31
showed that limited mandible advancement is an independent
risk factor for impossible mask ventilation. During an awake
intubation, upper airway anesthesia by local a­ nesthetic could
blunt the reflexive increase of pharyngeal dilator muscles as a
response to pharyngeal narrowing or obstruction. Preservation
of the neural compensatory mechanism is important, and thus
deep sedation should be avoided.
AIRWAY MAINTENANCE
Ventilator settings can be challenging, potentially with
increasing CO2, decreasing oxygen saturation (SaO2), and
­intolerable peak pressures in the airway. The starting settings
may be ­positive end-expiratory pressure (PEEP) of 8 to 10 cm
H2O, tidal volume of 10 to 12 mL/kg of ideal body weight,
and respiratory rate of 12 to 14/min. These values may need
to be adjusted, along with inspiratory/expiratory (I:E) ratio,
until ­satisfactory peak pressures, SaO2 and end-tidal CO2 are
achieved. An easy way to re-establish saturation after induc-
tion, or at any time during anesthesis, is a recruitment maneu-
ver (e.g., applying CPAP), 30 cm H2O for 30 seconds, or even
40 cm H2O for 40 seconds. A high index of suspicion for
 220 ANESTHESIA AND UNCOMMON DISEASES

suboptimal tube position, which can be checked using a fiber-
optic scope, can be critical. Volatile agents are usually chosen
based on solubility; desflurane was shown to be better than
isoflurane, propofol,32,33 or sevoflurane,33 but these data are
now questionable.34
Pharmacologic Issues
The physiologic changes associated with obesity alter the
pharmacokinetic and pharmacodynamic properties of many
drugs. Obese patients have an increased amount of both fat
and lean body weight compared with nonobese patients of
similar age, height, and gender. These changes affect the
­volume of ­distribution of some drugs (Table 6-4).35,36
In addition, increases in cardiac output and total blood
­volume and changes in regional blood flow can also affect
peak plasma concentration, clearance, and elimination
­half-life of many anesthetic agents. With increasing obesity,
the less vascular fat mass starts accounting for an increasing
amount of total body weight (TBW). Therefore, drug dosing
based on TBW may result in overdose of an obese patient.
To ­compensate for some of the obesity-related physiologic

TABLE 6-4  n  Dosing for Common Anesthetics

Drug Dosing Scalar* Altered Pharmacokinetics

HYPNOTICS

Thiopental Induction: LBW Increased central volume of distribution and clearances; induction dose adjusted
Maintenance: TBW to LBW results in same peak plasma concentration as dose adjusted to
cardiac output

Propofol Induction: LBW During induction, similar time of loss of consciousness exists between obese
Maintenance: TBW subjects given LBW dose and nonobese subjects given TBW dose. Propofol has
high affinity for excess fat, so systemic clearance and volume of distribution at
steady state correlate better to TBW

Midazolam, diazepam Induction: TBW Central volume of distribution increases along with body weight; prolonged
Maintenance: TBW duration of action because larger initial doses are needed

OPIOIDS

Fentanyl/Sufentanil Induction: TBW Increased volume of distribution and elimination half-life as related to obesity
Maintenance: IBW

Alfentanil Induction: LBW Prolonged elimination

Maintenance: LBW

Remifentanil Induction: LBW Infusion based on LBW in obese patients resulted in similar plasma concentration
Maintenance: LBW as TBW for nonobese patients

Morphine No information available

NEUROMUSCULAR BLOCKING AGENTS

Succinylcholine Induction: TBW Doses based on 1 mg/kg of TBW resulted in better intubating conditions
compared with dosing based on IBW or LBW

Atracurium/ Induction: TBW Absolute clearance, volume of distribution, and elimination half-life unchanged
Cisatracurium Maintenance: TBW because of organ-independent Hoffman elimination

Vecuronium Induction: IBW Doses based on TBW may result in prolonged duration of action from increased
Maintenance: IBW volume of distribution and impaired hepatic clearance

Rocuronium Induction: IBW

Maintenance: IBW

Pancuronium Induction: IBW Low lipid solubility; shorter-acting neuromuscular blockers are preferred for obese
Maintenance: IBW patients

LOCAL ANESTHETICS

Lidocaine Intravenous: TBW Increased epidural fat content and epidural venous engorgement
Epidural: 75% TBW

Data from Ogunnaike BO, et al: Anesth Analg 95:1793-1805, 2002; and Ingrande J, Lemmens HJ: Br J Anaesth 105(suppl 1):i16-i23, 2010.
*LBW, Lean body weight; TBW, total body weight; IBW, ideal body weight.

changes, ­dosing ­scalars other than TBW are frequently used,
including lean body weight (LBW), ideal body weight (IBW),
and adjusted body weight (ABW).
LEAN BODY WEIGHT
Lean body weight is the difference between TBW and fat mass.
In obese patients, LBW increases, although at a slower rate
of increase compared with TBW. LBW represents the highly
­vascular portion of the body and is significantly correlated to
­cardiac output (CO), which is an important determinant in the
early distribution kinetics of drugs. LBW is often c­ alculated
using the following formula37:
LBW(men) = (1.10 × Weight[kg]) − 128(Weight 2/
(100 × Height[m])2 )
LBW(women) = (1.07 × Weight[kg]) − 148(Weight 2/
(100 × Height[m])2 )
IDEAL BODY WEIGHT:
Ideal body weight is the optimal weight associated with maxi-
mum life expectancy for a given height. Before the use of BMI
to quantify obesity, TBW above 20% of IBW was defined as
being obese. However, the use of IBW indicates that all patients
of the same height should receive the same dose; it also fails to
account for changes in body composition associated with obe-
sity. More specifically, in morbidly obese patients, underdos-
ing may occur because the calculated IBW is less than LBW.
Common formulas to calculate IBW follow:
IBW(men) = 50 + 2.3(Height[inches] − 60)
IBW(women) = 45.5 + 2.3(Height[inches] − 60)
PHARMACOLOGY FOR INHALATION AGENTS:
Isoflurane is more lipophilic than either sevoflurane or des-
flurane and is therefore infrequently used in obese patients.
However, studies have shown that administering 0.6 mini-
mum alveolar concentration (MAC) of isoflurane for proce-
dures lasting 2 to 4 hours results in similar recovery times in
both obese and nonobese patients.38
Sevoflurane and desflurane have been advocated for use in
obese patients because these are the least lipophilic and least
soluble volatile anesthetics.32,33 This theoretically limits their
distribution into adipose tissue, although in practice the effect
of BMI on desflurane uptake is not significant. Emergence and
recovery are faster with desflurane or sevoflurane than with
isoflurane, in both obese and nonobese patients. However,
studies comparing emergence time using desflurane versus
sevoflurane in obese patients have yielded conflicting results
thus far. A judiciously managed volatile anesthetic, whether
sevoflurane or desflurane, should be able to provide similar
results in terms of wake-up times and recovery.34
Nitrous oxide (N2O) is probably best avoided because of the
need to keep a high fraction of inspired oxygen concentration
(FiO2), N2O's ability to distend bowel, as well as the small but
significant increase in the incidence of postoperative nausea
and vomiting attributed to its use.39–42
Chapter 6  Obesity and Nutrition Disorders 221
EMERGENCE FROM ANESTHESIA
A semiupright or lateral position is recommended for obese
OSA patients at the end of surgery for better oxygenation and
pharyngeal airway maintenance. Residual inhalation anesthet-
ics and paralysis are capable of depressing peripheral chemo-
sensitivity, leading to decreased hypoxic ventilatory response
and increased arousal threshold. After extubation, pharyngeal
obstruction should be recognized immediately and relieved
with nasal or oral airways and assisted ventilation with pos-
itive-pressure ventilation by face mask. Pharyngeal swelling
caused by laryngoscopy and excessive fluid perioperatively
can worsen the obstruction present preoperatively.
In the immediate postoperative period, a sitting or lateral
position is recommended rather than a supine position. In
OSA patients with pharyngeal obstruction, CPAP with O2 is
also frequently necessary. Postoperatively, even in transit from
the operation room to the recovery room, the addition of an
open CPAP system (e.g., Boussignac mask) helps decrease the
period for atelectasis and improves ­oxygenation status in the
ultra-obese patient. It is ­preferable to place this group of patients
in the same hospital location because of multiple advantages.
Minimal monitoring, including SaO2, sometimes with end-tidal
CO2, along with periodic nursing checks to judge somnolence,
can prevent disasters from becoming tragedies. The ­nursing
care is ­consistent, and providers are familiar and comfortable
with this patient ­subset and their unique needs and ­challenges.
Additionally, the psychosocial impact of their large size among
­caregivers is diminished when ultra-obese patients are cared for
­consistently at the same location. (Minimal monitoring, includ-
ing SaO2, sometimes with end-tidal CO2, along with frequent
nursing checks to judge somnolence, can prevent near-disasters
from becoming tragedies.)
NUTRITION DISORDERS
In 1974, Butterworth43,44 labeled nutrition disorders of
hospita­lized patients as “the skeleton in the hospital closet.”
Preoperative nutritional assessment can help predict risk of
postoperative surgical complications.45 Generally, this applies
to postoperative complications, especially wound infections,
but also impacts mortality. Interestingly, other studies have
established that patients presenting for surgery may have
a 44% rate of malnourishment, and up to 75% in patients
admitted to the intensive care unit.46 In patients presenting
for ­elective ­spinal surgery, rate of serious infections correlated
closely with nutritional status.47
Anesthetic management in developed countries can some-
times be impacted by the presentation of victims of abuse and
neglect who may have severe protein-energy malnutrition
(PEM; also protein-calorie malnutrition). This p ­ roblem is more
common in developing countries. The obese malnourished
patient is the familiar encounter for anesthesia providers in the
developed countries. Table 6-5 lists disorders of fat-soluble and
water-soluble vitamins as well as protein-energy deficiencies
(kwashiorkor, marasmus) with anesthetic considerations.48–58
 222 ANESTHESIA AND UNCOMMON DISEASES

TABLE 6-5  n  Nutritional Disorders and their Anesthetic Implications

Nutrients Clinical Signs/Symptoms Perioperative Issues

FAT-SOLUBLE VITAMINS

Vitamin A Deficiency: Night blindness, xerophthalmia, decreased

immune function
Toxicity: Nausea, irritability, anorexia, vomiting, blurry Occurs rarely; main concern is liver disease in severe
vision, headaches, hair loss, muscle/abdominal pain, cases
drowsiness, altered mental status
In chronic cases, liver disease (hepatomegaly, portal
hypertension from venous sclerosis, congestion),
pseudotumor cerebri

Vitamin D48 Deficiency: Rickets in children, osteomalacia in Muscle weakness can occur in ICU patients
adults
Toxicity: Hypercalcemia, hypertension, vomiting, Occurs rarely; primary concern would be problems
dehydration, constipation, muscle weakness caused by hypercalcemia and hypertension

Vitamin E49 Deficiency: Neuromuscular problems such as

spinocerebellar ataxia, myopathies, and dysarthrias;
anemia, impaired immune response
Toxicity: Vitamin E acts as an anticoagulant and Occurs rarely; all these factors combine to increase
potentiates antiplatelet effects of medications such as incidence of bleeding problems
aspirin; also decreases activity of vitamin K

Vitamin K50 Deficiency: Ecchymosis, petechiae, hematomas, Goal is to correct coagulation defect before surgery
oozing of blood at surgical or puncture sites, Typically, vitamin K–dependent coagulation factor
stomach pain deficiency can be restored with transfusion of fresh-
frozen plasma (FFP; 10-15 mL/kg IV). Alternatively,
prothrombin complex concentrate (25-50 IU/kg) can
be administered at higher cost*
Toxicity: None known

WATER SOLUBLE VITAMINS

Vitamin C Deficiency: Scurvy with increased mucous membrane Uncommon in current Western diet; vitamin C is
bleeding involved in wound healing but has minimal effect on
anesthetic care
Toxicity: None; water soluble, and excesses are not
absorbed

Vitamin B1 Deficiency: Beriberi, characterized by peripheral
(thiamine)51 neuropathy, mental confusion, muscular atrophy,
edema, tachycardia, cardiomegaly, and congestive
heart failure (CHF)
Wernicke's encephalopathy, linked to alcohol
abuse, characterized by confusion, nystagmus,
ophthalmoplegia, anisocoria, ataxia, coma, and death
if untreated
Korsakoff's syndrome, characterized by inability to
form new memories, confabulations, and
hallucinations
Toxicity: Tachycardia, hypotension, arrhythmias,
convulsions, anaphylaxis
Most often found in chronic alcohol abuse patients
In nonemergent patients, it is advisable to delay
surgery and stabilize patient with alcohol intoxication,
withdrawal, or treat with “banana bag” of thiamine,
folic acid, multivitamin, and magnesium
Cardiac issues (e.g., CHF) are also a concern; again,
surgery should be delayed in nonurgent patients to
treat CHF issues
Extremely uncommon

Vitamin B2 Deficiency: Angular cheilitis, photophobia, scrotal

(riboflavin) dermatitis (oral-ocular-genital syndrome), iron
deficiency anemia
Toxicity: No evidence of toxicity with excessive intake

Vitamin B3 Deficiency: Pellagra, characterized by the “four Ds”:

(niacin) dementia, dermatitis, diarrhea, and death
Toxicity: Skin flushing from histamine release, itching,
rashes, hepatic toxicity

TABLE 6-5  n  Nutritional Disorders and their Anesthetic Implications—Cont'd
Nutrients Clinical Signs/Symptoms
Vitamin B6 52,53
Deficiency: Microcytic anemia, electroencephalographic
abnormalities, dermatitis with cheilosis (scaling on
lips, cracks at corners of mouth) and “glossaries”
(tongue lesions), depression and confusion, weakened
immune function
Toxicity: Numbness and pain in extremities; severe
cases lead to progressive sensory neuropathy
characterized by ataxia (loss of control of bodily
movements)
Vitamin B12 Deficiency: Megaloblastic anemia, fatigue, weakness,
(cobalamin)54–56 constipation, loss of appetite, weight loss;
Neurologic changes such as numbness and tingling in
hands and feet can also occur, in addition to ataxia,
depression, confusion, dementia, poor memory, and
soreness of mouth or tongue
Toxicity: No adverse effects identified
PROTEIN-ENERGY DEFICIENCY
Marasmus57 Severe deficiency of almost all nutrients, especially
protein and carbohydrates
Kwashiorkor58 Acute childhood form of protein-energy malnutrition
characterized by edema, anorexia, ulcerating
dermatomes, and enlarged liver with fatty infiltrates
Distinguished from kwashiorkor by having enough caloric
intake but insufficient protein intake
*FFP has short half-life of 4 to 6 hours, and oral vitamin K (1 mg) must be administered concurrently. Intravenous vitamin K is available but carries a higher risk of
anaphylaxis. Large doses of vitamin K should be avoided because of postoperative warfarin (Coumadin) resistance.
CONCLUSION
Obesity presents a complex anesthetic challenge. The degree of
obesity, comorbidities, and management issues are variable and
interrelated. Associated medical and interventional concerns
must always be considered, despite a negative patient history.
Alternately, not all patients have coexisting disease (e.g., hyperten-
sion, difficult airway). The anesthesiologist needs to be especially
vigilant with the obese surgical patient, as well as patients with
nutrition deficiencies and risk of ­postoperative complications.
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 C H A P T E R
7
Renal Diseases
MAURIZIO CEREDA, MD  n
PATRICK NELIGAN, MA, MD, FCAI  n
MICHAEL G.S. SHASHATY, MD, MSCE  n
JIRI HORAK, MD  n

n Patients with pre-existing chronic kidney disease are at

Specific Renal Diseases increased risk for acute perioperative deterioration; even
Glomerular Disease
mild perioperative changes in renal function can have sig-
Tubulointerstitial Disease
nificant outcome implications.
Disorders of Tubular Function
n Perioperative management of patients with (or at risk for)
Renal Cystic Disease
kidney injury relies on hemodynamic management and
Renal Involvement in Systemic Disease
reducing adverse effects; no specific renal protection strat-
Vascular Disease of Kidney
egy has yet improved outcomes.
Renal Failure
Chronic Kidney Disease
Acute Kidney Injury
Perioperative Renal Dysfunction
The kidneys are highly vascular and metabolic organs that
Renal Replacement Therapy
ultrafilter the blood, excrete byproducts of metabolism, and
Renal Transplantation
control water and electrolyte balance. Injuries to the kidneys
Intraoperative Considerations for the Patient with Kidney
may involve the vasculature or the renal tissue (or both) and
Disease may be primary diseases of the kidneys or part of a multisys-
Hemodynamic Management tem disease complex, such as vasculitis, Wegener's granuloma-
Pharmacologic Choices tosis, or systemic lupus erythematosus (see also renal-related
Anesthetic Effects on Renal Function discussion in other chapters).
The three major anatomic demarcations in the kidney
are the cortex, the medulla, and the renal pelvis. The cortex
receives most of the blood flow and is mainly concerned with
reabsorbing filtered material. The medulla is a highly met-
KEY POINTS
abolically active area that serves to concentrate the urine.
n The presence of chronic or acute kidney disease has sig- The pelvis collects urine for excretion. Injury to any of these
nificant negative effects on surgical outcomes. Knowledge ­anatomic sites may precipitate acute kidney injury (AKI;
of key pathophysiologic aspects of glomerular and tubu- acute renal failure), which, if persistent, may result in end-
lar disorders is a key component to optimal perioperative stage renal disease.
management of renal patients. This chapter highlights specific renal diseases, including
n Coexisting renal disease greatly affects management of other glomerular disease (e.g., nephritic syndrome) and tubuloin-
systems. Kidney disorders can result from systemic illness and terstitial disorders (e.g., nephritis), as well as renal effects of
invariably compromise other organ systems; renal patients ­systemic disease and vascular involvement of the kidney. Renal
are at especially high risk for cardiovascular complications. replacement therapy and renal transplantation are addressed,
n Simplified criteria for acute kidney injury emphasize along with perioperative management of the kidney transplant
changes in serum creatinine and urine output and reliably patient and general intraoperative and specific anesthetic con-
predict patient outcomes. siderations for renal patients.

225
 226 ANESTHESIA AND UNCOMMON DISEASES
SPECIFIC RENAL DISEASES
Depending on the structures involved, renal diseases are
either glomerular or tubular in origin. In glomerular diseases
the glomerular structures are damaged, and deposits of anti-
gen, antibodies, and complement can be detected by micros-
copy. These patients typically present with various degrees of
hematuria, proteinuria, and salt and water retention. In tubu-
lar diseases the tubular cell structure or the peritubular inter-
stitium is damaged more than the glomerulus, characterized
by abnormal handling of fluid and electrolytes.
Glomerular Disease
GLOMERULONEPHRITIS
Glomerulonephritis accounts for approximately 7% of patients
diagnosed with end-stage renal disease (ESRD) in the United
States, and its importance relative to diabetes and hyperten-
sion has decreased since the 1980s.1 Glomerulonephritides are
characterized by intraglomerular inflammation and cellular
proliferation associated with hematuria with secondary renal
impairment over days to weeks. Hematuria in patients with
glomerulonephritis is characterized by the presence of dys-
morphic red blood cells (RBCs)2 or RBC casts in the urine,
findings that differentiate hematuria of glomerular origin
from extraglomerular bleeding. Glomerulonephritis may be
a primary process, with disease almost entirely restricted to
the kidneys (e.g., poststreptococcal glomerulonephritis), or a
secondary process occurring in association with more diffuse
inflammation (e.g., systemic lupus erythematosus). Patients
with glomerulonephritis generally present with one of five
clinical syndromes: asymptomatic hematuria, acute glomeru-
lonephritis, rapidly progressive glomerulonephritis, nephrotic
syndrome, or chronic glomerulonephritis.
Asymptomatic hematuria refers to macroscopically or
microscopically detected blood in the urine of patients who
have normal glomerular filtration rate (GFR) and no evi-
dence of a systemic disease known to affect the kidneys.
Immunoglobulin A (IgA) nephropathy (mesangioprolifera-
tive glomerulonephritis) is a common cause of asymptomatic
hematuria often associated with simultaneous respiratory or
gastrointestinal (GI) tract infection. IgA nephropathy occurs
in all age groups, with a peak incidence in the second and
third decades.3,4 Despite a mild clinical presentation with
benign hematuria, ESRD ultimately develops in 20% to 40% of
patients within 5 to 25 years after diagnosis.5 There is no cure
for IgA nephropathy. In patients with proteinuria but minimal
renal insufficiency, angiotensin-converting enzyme (ACE)
inhibitors appear effective in preventing progressive renal
functional loss.6 Patients at high risk of ESRD have received
glucocorticoids with or without adjunctive cytotoxic agents,
although efficacy remains unclear.
The renal lesion of Henoch-Schönlein purpura (HSP) is
almost identical to that of the more severe variants of IgA
nephropathy. However, as a small-vessel vasculitis, HSP also
presents with a purpuric rash largely affecting the lower limbs,
arthritis or arthralgia, and abdominal pain with or without
rectal bleeding. The disease is most common in those younger
than 20 years. Renal involvement can also occur in adults, who
are thought to have a worse prognosis. Although the classic
renal presentation is hematuria and mild proteinuria, 28% of
patients in a multicenter study had nephrotic-range protein-
uria at renal biopsy.7
Acute glomerulonephritis is a syndrome characterized by
the abrupt onset of macroscopic hematuria, oliguria, and acute
renal failure (ARF/AKI). It manifests with a sudden decrease
in the GFR and with fluid retention, resulting in generalized
edema and hypertension. Urinary protein excretion varies
widely in this syndrome, but the rate is generally less than 3 g
of protein per day. Edema probably results from renal sodium
retention caused by the sudden decrease in the GFR.
Poststreptococcal glomerulonephritis (PSGN) is the best
known example of acute glomerulonephritis, occurring 1 to
12 weeks after streptococcal pharyngitis. It is representative of
a larger group of postinfectious glomerulonephritides, such
as that associated with endocarditis, in which acute glomeru-
lar injury results from immune events triggered by bacterial,
viral, or protozoal infection. Glomerular injury results from
an inflammatory response to glomerular deposits of IgG and
C3. It remains unclear whether these deposits arise from cir-
culating immune complexes or complexes formed in situ, or
both.8 PSGN is an acute, reversible disease, presenting initially
with gross hematuria, sharp increase in creatinine, and edema.
Spontaneous resolution, seen in the vast majority of patients,
is generally rapid; diuresis usually ensues within 1 to 2 weeks,
and serum creatinine concentration returns to baseline within
4 weeks. PSGN predominantly affects children age 2 to 10 years,
but almost 10% of patients are older then 40.9,10 Although most
patients eventually have a complete recovery, some develop
hypertension, recurrent or persistent proteinuria, and chronic
renal insufficiency.10 The long-term prognosis of patients
with PSGN has been controversial. The reported incidence of
chronic renal insufficiency can be as high as 20%.9,10
Rapidly progressive glomerulonephritis (RPGN) is an
uncommon clinical syndrome characterized by signs of glo-
merulonephritis (hematuria, proteinuria, and RBC casts) and
a rapid decline in renal function that can lead to ESRD within
days to weeks. It accounts for only 2% to 4% of all the glomeru-
lonephritides. Although causes are heterogeneous, the patho-
logic hallmark of this syndrome is the presence of extensive
cellular crescents surrounding most glomeruli. Crescents result
from the proliferation of parietal epithelial cells and mononu-
clear phagocytes within Bowman's capsule.11 RPGN is divided
into three types: anti–glomerular basement membrane (anti-
GBM), immune complex, and pauci-immune, distinguished
pathologically according to the presence and character of glo-
merular immune deposits.12 Anti-GBM antibody disease is
characterized by linear deposition of immunoglobulin along
the glomerular basement membrane. Such deposition is the
result of circulating antibodies to type IV collagen.13 This type
of RPGN has two peaks of onset age: in the third decade, with
a male preponderance, and in the sixth and seventh decades,

affecting both genders equally.14 Associated pulmonary capil-
laritis (Goodpasture's syndrome), seen in approximately one
half of cases, is more common in young men, whereas isolated
damage to the kidneys is more common in older patients.12
Lung hemorrhage is the most common cause of death dur-
ing early disease and should be suspected with hemoptysis or
alveolar opacities on chest radiography with coincident hemo-
globin decrease.
Immune complex crescentic glomerulonephritis has a variety
of causes, including PSGN, HSP, membranoproliferative glo-
merulonephritis, and lupus nephritis. The immune complex
form of RPGN accounts for one third to one half of cases in
children and young adults, but is much less common in patients
older than 60.12 Pauci-immune RPGN, accounting for more
than 50% of cases, is characterized pathologically by minimal
glomerular immunoglobulin deposition.12 Serologically, how-
ever, these diseases are linked in about 90% of cases by the find-
ing of antineutrophil cytoplasmic antibodies. This category is
represented by microscopic polyangiitis, granulomatosis with
polyangiitis (GPA, also called Wegener's granulomatosis), and
idiopathic crescentic glomerulonephritis. Microscopic polyangi-
itis is associated with cutaneous (purpura), neurologic (mono-
neuritis multiplex), or gastrointestinal vasculitis together with
renal failure. Pulmonary symptoms, caused by nongranulo-
matous arteriolar vasculitis and capillaritis, are present in only
50% of patients. By contrast, GPA is dominated by sinopulmo-
nary manifestations, including sinusitis, airway lesions, and
nodular or cavitating lung lesions.
Unless complicated by systemic disease, RPGN typically
has an insidious onset, with nonspecific symptoms such as
malaise and lethargy. Urinalysis invariably demonstrates
hematuria, usually dysmorphic RBCs, and moderate protein-
uria; nephrotic-range proteinuria occurs in less than 30% of
patients.15 RPGN should be treated aggressively. A delay in the
diagnosis and initiation of therapy increases the risk of ESRD,
and the likelihood of renal recovery is poor without therapy.16
Glucocorticoids and cyclophosphamide are the traditional
therapeutic agents, although recent study has shown rituximab
may be at least as effective as cyclophosphamide.17 Plasma
exchange is typically used to remove circulating pathogenic
autoantibodies in patients with anti-GBM antibody disease.18
Chronic glomerulonephritis is a syndrome manifest by
progressive renal insufficiency in patients with glomerular
inflammation, hematuria, and often, hypertension. The dis-
ease may be idiopathic or associated with one of several sys-
temic diseases, including hepatitis B or C, cryoglobulinemia,
and systemic lupus erythematosus (SLE).19 The kidney is the
organ most often affected by SLE, and lupus nephritis is one
of the most serious manifestations of this autoimmune dis-
ease. The clinical spectrum of lupus nephritis ranges from
mild urinary abnormalities to AKI and chronic kidney disease
(CKD; chronic renal failure). This affects patients in the 20s
and 30s, with black women especially predisposed. Patients
complain of lethargy, arthralgia or arthritis, rashes, and symp-
toms of pleurisy and pericarditis in the months before pre-
sentation.20 Clinically significant nephritis develops most
Chapter 7  Renal Diseases 227
frequently within 3 years after diagnosis and rarely develops
after 5 years.21 Asymptomatic hematuria or nonnephrotic pro-
teinuria may be the only clues to renal involvement and should
prompt further tests for other evidence of glomerular disease.
Although tubulointerstitial nephritis can be a prominent com-
ponent of lupus nephritis, immune complex glomerulone-
phritis is the primary histopathologic finding.
NEPHROTIC SYNDROME
Nephrotic syndrome presents as “heavy” proteinuria (protein
excretion >3 g/day), hypoalbuminemia, edema, and varying
degrees of hyperlipidemia and lipiduria. The most common
histologic lesions associated with primary nephrotic syn-
drome are focal segmental glomerulosclerosis, membranous
glomerulopathy, minimal change disease, and membranopro-
liferative glomerulonephritis (MPGN).22 Diabetes is the most
common cause of nephrosis (Box  7-1). Among the nondia-
betic glomerulopathies, minimal change disease accounts for
the majority of the cases of nephrosis in children, whereas
membranous glomerulopathy causes most of the adult cases.23
MPGN is a histologic finding with several etiologies and may
present with nephrotic syndrome or as an acute or chronic
glomerulonephritis (see earlier). Idiopathic MPGN generally
affects persons between ages 5 and 30 years and has a slight
female predominance. With the recognition of a causal rela-
tion between hepatitis C virus (HCV) infection and MPGN,
diagnoses of idiopathic MPGN are now uncommon.24 Patients
with HCV-associated MPGN present 10 to 15 years after
infection in middle age and have subclinical liver disease
with mild biochemical abnormalities. HCV is also a common
cause of cryoglobulinemia. This systemic disorder has a range
of renal manifestations, including nephrotic syndrome, and
is characterized by malaise, anemia, peripheral neuropathy,
polyarthralgia, and a purpuric rash, together with lower limb
ulceration and Raynaud's disease.
Depending on the causative disease, nephrotic syndrome
may be reversible or may eventually result in renal fail-
ure, whereas other patients may respond to treatment of an
underlying systemic disease or to corticosteroid and immu-
nosuppressant therapy. ACE inhibitors are often used in both
hypertensive and nonhypertensive patients because these
agents are known to limit urinary protein loss.
BOX 7-1   n DIFFERENTIAL DIAGNOSIS OF NEPHROTIC
SYNDROME
Primary
Minimal change disease
Membranous glomerulopathy
Focal segmental glomerulosclerosis
Membranoproliferative glomerulonephritis
Secondary
Diabetes
Human immunodeficiency virus
Hepatitis B and hepatitis C
 228 ANESTHESIA AND UNCOMMON DISEASES
Fluid management can be particularly difficult in patients
with nephrotic syndrome, and assessment of volume status
may require invasive monitoring. Low plasma oncotic pres-
sure causes diffuse interstitial edema because of fluid leakage
from the intravascular space and may result in low intravas-
cular volume,25 particularly in patients undergoing aggressive
diuretic treatment. In cases of reduced GFR and less severe
hypoalbuminemia (e.g., >2 g/dL), however, volume overload
caused by enhanced sodium and water reabsorption at the
tubular level may be the primary driver of edema.26 In these
patients, diuretic therapy may be necessary. However, patients
with nephrotic syndrome tend to respond poorly to diuret-
ics, perhaps because protein binding of drug is decreased
in plasma, resulting in increased volume of distribution.27
Therefore, higher and more frequent diuretic doses, or the
combined use of loop and thiazide diuretics, may be needed.
limited data suggest that coadministration of intravenous (IV)
albumin and loop diuretics may improve diuresis compared
with diuretics alone.28
The pharmacokinetics of other drugs with high protein
binding, including most anesthetic drugs, are also affected by
the low proteinemia of nephrotic syndrome, and doses should
be reduced accordingly.26
Patients with nephrotic syndrome have a particularly high
frequency of cardiovascular disease and should undergo a
thorough cardiac evaluation before higher-risk surgeries. In
fact, altered apolipoprotein metabolism causes hyperlipid-
emia, whereas loss of anticoagulant plasma proteins leads to
a hypercoagulable state. One study of nephrotic syndrome
patients estimated a 1%/yr risk of venous thromboembolic
events and a 1.5%/yr risk of arterial thromboembolic events,
with the greatest risk concentrated in the first 6 months after
diagnosis (~5% and ~3%, respectively).29 These patients
require diligent prophylactic anticoagulation with heparin and
compressive devices in the perioperative period (Box 7-2).
Tubulointerstitial Disease
NEPHRITIS
Acute interstitial nephritis is characterized by a peritubular
inflammation causing renal insufficiency, sterile pyuria, and
leukocyte casts (Table 7-1). Hematuria and proteinuria are also
observed but are of lower degree than in glomerular diseases.
Altered sodium reabsorption and reduced urine-concentrating
ability are more frequently seen than edema and hypertension.23
Systemic manifestations such as rash, fever, and peripheral
BOX 7-2   n ANESTHETIC CONSIDERATIONS IN
PATIENTS WITH NEPHROTIC SYNDROME
Establish cardiac risk stratification.
Measure albumin concentration.
Assess volume status, and consider invasive monitoring.
Reduce doses of drugs with high protein binding.
Provide venous thromboembolism prophylaxis.
TABLE 7-1  n  Signs of Nephritis
Type Signs
Acute interstitial nephritis Sterile pyuria
Leukocyte casts
Eosinophiluria
Eosinophilia
Chronic tubulointerstitial Polyuria
nephropathy Acidosis
Hyperkalemia
Pyelonephritis Pyuria, bacteriuria
Signs of infection
Flank pain
eosinophilia are often observed. Acute interstitial nephritis
is caused by drugs, particularly antibiotics and nonsteroidal
anti-inflammatory drugs (NSAIDs), but can also be caused by
infectious and autoimmune diseases. Discontinuation of the
inciting agent usually results in renal recovery, but corticoste-
roids may be necessary in some patients.
Pyelonephritis is an acute interstitial inflammation caused
by a bacterial infection. Fever and signs of acute infection
are usually observed, although the inflammatory response
can be blunted in elderly and immunosuppressed patients.
Pyelonephritis can be a cause of septic shock, particularly in
hospitalized patients.
NEPHROPATHY
Chronic tubulointerstitial nephropathy is a slowly evolving
interstitial inflammation and is a relatively common cause
of chronic kidney disease (renal failure). Patients usually
have pyuria, mild proteinuria, and minimal or no hematuria.
Tubular dysfunction characterizes this disease, with hyperka-
lemia, nongap metabolic acidosis, and polyuria. Chronic tubu-
lointerstitial nephropathy can be caused by chronic ingestion
of NSAIDs and acetaminophen,30 as well as by other drugs
(e.g., cyclosporine, tacrolimus), toxins, autoimmune disease,
and neoplastic disorders.
Disorders of Tubular Function
Bartter's syndrome (juxtaglomerular cell hyperplasia) is char-
acterized by sodium (Na+), chloride (Cl−), and potassium (K+)
ion wasting. It is caused by a rare autosomal recessive genetic
defect of the Na+, K+, 2Cl− transporter in the thick ascending
limb of the loop of Henle.31 The two forms of Bartter's syn-
drome are neonatal, characterized by polyhydramnios, and
classic, with onset at age 2 to 3 years and characterized by
polyuria, failure to thrive, and vomiting. Patients present with
findings similar to loop diuretic effects, with hypokalemia,
hypochloremic metabolic alkalosis, and increased urinary
Na, K, and Cl concentrations. Patients are not hypertensive,
although renin, angiotensin, and aldosterone levels are ele-
vated; renal prostaglandin production is typically increased.
Patients with Bartter's syndrome are treated acutely with saline

infusion and potassium supplementation. The s­yndrome
responds to chronic inhibition of prostaglandin synthesis,
probably because cortical blood flow is reduced.23
Gitelman's syndrome is an autosomal recessive disorder of
the Na+, Cl− transporter in the distal convoluted tubule that
mimics the effect of thiazide diuretic use. It has similar fea-
tures to Bartter's syndrome, but Gitelman's has a later onset
and is characterized by hypocalciuria and hypomagnesemia.31
Liddle's syndrome is an autosomal dominant disorder charac-
terized by constant activation of the epithelial sodium channel in
the collecting tubule despite low aldosterone l­evels, resulting
in excess sodium reuptake and potassium wasting. Patients pres-
ent in their teenage years with s­ ymptoms similar to those caused
by mineralocorticoid excess, including hypertension, poly-
uria, failure to thrive, and hypokalemia. Treatment includes salt
restriction, potassium supplementation, and lifelong adminis-
tration of triamterene or amiloride.23
Pseudohypoaldosteronism type I (PHA-I) is an autosomal
dominant resistance to the action of aldosterone, character-
ized by renal sodium loss and decreased sodium concentra-
tions in sweat and saliva. The levels of aldosterone and its
metabolites are typically increased, distinguishing it from true
hypoaldosteronism. The onset of PHA-I is in early life, with
failure to thrive, vomiting, and hyponatremia. Respiratory
tract infections are common and resemble cystic fibrosis.
Treatment mainly consists of sodium supplementation and is
particularly important during periods of stress, such as illness
or surgery.
Fanconi's syndrome is a global dysfunction of the proxi-
mal tubules, resulting in urinary loss of amino acids, glu-
cose, bicarbonate, Na, K, and phosphate. The main clinical
manifestations are growth retardation, rickets, hyperchlore-
mic type II renal tubular acidosis, polyuria, dehydration, and
symptomatic hypokalemia. Fanconi's syndrome has multiple
causes leading to dysfunction of different tubular channels.
Etiology may be genetic (cystinosis, Wilson's disease, galac-
tosemia, glycogenosis) or acquired (heavy-metal poisoning,
tetracycline, chemotherapeutics). Treatment involves sodium
and fluid replacement, correction of acidosis and hypoka-
lemia, vitamin D and phosphate supplementation, and cor-
rection of the underlying causes when possible. Cystinosis
usually evolves to ESRD within 10 years of diagnosis. The
early use of cysteamine decreases lysosomal cystine and
delays the evolution of renal failure, avoiding renal transplant
in some patients.32
Renal tubular acidosis (RTA) represents a group of differ-
ing renal tubular defects that share abnormalities of Na and Cl
handling. Normal renal function, and indeed control of acid-
base balance, requires the kidney to excrete a net load of Cl−
over Na+ because dietary intake of these ions is similar. In RTA
the nephron excretes insufficient Cl−, reducing the strong ion
difference and resulting in nongap metabolic acidosis.33
Proximal renal tubular acidosis (type II) is a problem of
Na and Cl handling in the proximal tubule, leading to hypo-
kalemic nongap metabolic acidosis. The most common cause
is urinary excretion of light chains associated with multiple
Chapter 7  Renal Diseases 229
myeloma (occult or overt), but it can also be caused by car-
bonic anhydrase inhibitors or occur as part of Fanconi's syn-
drome.34 Proximal RTA is defined by the inability to acidify
the urine below a pH of 5.5. In some cases there is excess uri-
nary elimination of sodium and its companion anion bicar-
bonate because of mutations in the gene SLC4A4, encoding
the Na+/HCO3− cotransporter NBC-1,35 resulting in limited
ability to excrete chloride. The diagnosis of RTA-II can be
confirmed by urine alkalinization to more than 7.5 after an
IV sodium bicarbonate load.23 Treatment is by Na adminis-
tration as sodium acetate or sodium bicarbonate. In adults,
if mild, acidosis may not require treatment because it is nat-
urally self-limiting; as the plasma bicarbonate concentration
falls, the mid- and distal nephron can reabsorb enough of
the reduced filtered bicarbonate load to maintain acid-base
balance.34
Hypokalemic distal renal tubular acidosis (type I) is caused
by an abnormality of chloride excretion in the distal tubule.
There is a parallel reduction in the excretion of NH4. In its
autosomal dominant form, distal RTA is associated with muta-
tions in the gene encoding the Cl−/HCO3− exchanger AE1 or
band 3 protein.36 In adults, it is most often seen in association
with autoimmune diseases, classically Sjögren's syndrome.
Patients with RTA-I have severe metabolic acidosis with
serum bicarbonate levels close to 10 mmol/L and are unable to
acidify urine to less than a pH of 5.5. Several mechanisms for
hypokalemia have been postulated,36 but the underlying cause
has not been established.37 Patients frequently present with
kidney stones caused by hypercalciuria, which is caused by
increased calcium mobilization from bone buffers. Compared
with proximal RTA, patients with distal RTA require a much
lower dose of alkali replacement because treatment does not
result in a substantial bicarbonate diuresis.34
Hyperkalemic distal renal tubular acidosis (type IV) is
caused by impaired excretion of both Cl− and K+ in the dis-
tal tubule, leading to nongap acidosis and hyperkalemia. The
underlying cause is either aldosterone deficiency or tubular
resistance to aldosterone. The former occurs in chronic renal
insufficiency, especially diabetic nephropathy, from inade-
quate renin secretion. Other notable causes of RTA-IV include
primary adrenal insufficiency, congenital adrenal hyperplasia,
and several medications (e.g., NSAIDs, cyclosporine, trime-
thoprim, potassium-sparing diuretics).The acidosis is usually
mild, with serum bicarbonate concentrations above 17 meq/L.
Urine pH is usually lower than 5.5, unlike RTA types I and II.34
Patients with RTA-IV need treatment when the hyperkalemia
is significant. Use of fludrocortisone, thiazides, and sodium
bicarbonate can be considered.23
Renal Cystic Disease
Renal cysts can be observed in a significant percentage of the
population and are usually asymptomatic. Polycystic kidney is
a severe inherited disease that can be transmitted in an auto-
somal recessive or dominant manner. The recessive form has
an incidence of 1 in 20,000 live births and usually results in
 230 ANESTHESIA AND UNCOMMON DISEASES
perinatal death from extreme renal enlargement causing pul-
monary compression and hypoplasia. The dominant form
occurs in 1 of 800 live births and results in significant disease
by adult age. The pathogenesis involves alteration in the syn-
thesis of the tubuloepithelial membrane receptor polycistin.38
At age of presentation, the kidneys are massively enlarged, and
patients complain of flank pain, hypertension, hematuria, and
recurrent pyelonephritis. This disease leads to ESRD in 50% of
cases.23 About 10% of patients also have cerebral arterial aneu-
rysms, and cysts may form in other organs as well. Therapy
includes management of hypertension, prevention of kid-
ney infections, and renal transplantation. Some patients may
require nephrectomy because of recurrent severe pyelonephri-
tis or discomfort from the megakidney.
Renal Involvement in Systemic Disease
HYPERTENSION AND DIABETES
Long-standing, poorly controlled hypertension frequently
causes renal dysfunction and accounts for about 20% of ESRD
cases.39 African American ethnicity is a particular risk factor
for this complication. Hypertension initially causes functional
alterations in the renal circulation, with rightward displace-
ment of the autoregulatory curve (Fig.  7-1), followed by
­permanent histologic changes at the arteriolar level.40 When
autoregulation is completely lost, both systemic hypoten-
sion and hypertension may result in worsening renal func-
tion. High glomerular intravascular pressures cause increased
­capillary permeability and proteinuria,41 whereas low blood
pressure (BP) results in renal cell ischemia.
High
Chronic
hypertension
with chronic
Intraglomerular pressure
renal disease
Normal
Chronic
hypertension
with normal
renal function
Low
80 120 160
Mean arterial pressure (mm Hg)
FIGURE 7-1  Relationship between intraglomerular pressure
and mean arterial pressure. This typically follows a sigmoid
curve, because autoregulation of afferent and efferent vessel
tone maintains constant glomerular blood flow despite significant
changes in blood pressure. In hypertensive patients, this
relationship shifts to the right but is maintained. When renal
disease superimposes, the curve becomes more linear, and
changes in blood pressure directly affect glomerular blood pressure
and flow. (Data from Palmer BF: N Engl J Med 347:1256-1261,
2002.)
Accelerated hypertension is a particular condition in which
an extremely elevated BP causes significant acute kidney
injury characterized by marked proteinuria. The goal in the
management of these patients is to obtain an acute reduction
in mean arterial pressure of approximately 25%, followed by
further reductions over weeks. In patients who present with
accelerated hypertension, excessively rapid correction of BP
can lead to renal ischemic injury.
Diabetes mellitus is the most important cause of ESRD.
Although type 1 diabetes is more frequently associated with
renal involvement, the prevalence of patients with type 2 dia-
betes and renal disease has increased, probably because of
their longer survival. Diabetic nephropathy is characterized by
proteinuria, the extent of which predicts the onset and the out-
come of renal insufficiency.42 Proteinuria not only is a marker
of renal disease but also contributes to causing further renal
damage.43 In fact, in animal models, excessive tubular reab-
sorption of protein may cause interstitial inflammation, scar-
ring, and fibrosis.41
Poorly controlled BP, hyperglycemia, and hypercholes-
terolemia are risk factors for the development of diabetic
nephropathy44 and therefore must be controlled to prevent or
limit diabetic kidney disease. Improved glycemic control has
been shown to reduce the incidence of diabetic nephropathy.45
Strict BP control has beneficial effects on the kidney in dia-
betic patients,46 and its benefit is probably higher for those
patients with significant proteinuria.47
Although the BP goal can be reached with any agent, ACE
inhibitors are more effective in slowing nephropathy than
other classes of antihypertensive drugs, both in diabetic and in
nondiabetic patients.48 This effect of ACE inhibitors is prob-
ably related to their ability to reduce or prevent proteinuria.49
Similar renoprotective effects are seen with angiotensin recep-
tor blockers.50 The use of ACE inhibitors in patients with com-
promised renal function is often associated with a moderate
increase in serum creatinine and potassium levels. This effect
should be seen as a normal response to decreased BP and a
marker of drug effectiveness rather than a sign of deteriora-
tion of renal function and an indication to discontinue ACE
inhibitor therapy.40 Calcium channel blockers also have bene-
ficial effects on renal function, although they do not appear to
be as renoprotective as ACE inhibitors in African Americans
with hypertensive nephropathy.51 Additional measures pro-
posed to slow the progression of chronic diabetic and non-
diabetic nephropathy are dietary protein intake restriction,
smoking cessation, and lipid-lowering medications.
SICKLE CELL DISEASE
Sickle cell disease is the cause of a significant nephropathy
with hematuria, papillary necrosis from occlusion of vasa
recta, AKI from renal hypoperfusion or rhabdomyolysis, and
CKD from glomerulosclerosis. Proteinuria is detected in a
high percentage of patients. An inability to concentrate urine
is the hallmark of sickle cell nephropathy, resulting from loss
of the countercurrent exchange mechanism caused by loss of
perfusion to the vasa recta. The intraoperative management of
 Chapter 7  Renal Diseases 231

patients with sickle cell nephropathy should follow the general 600
recommendations on sickle cell management, with additional Light lines show
actual counts

Number of patients (in thousands)

care to avoid renal hypoperfusion.52 500
Dialysis: 2020, 533,800;
2006, 354,754
400
Vascular Disease of Kidney
Chronic atherosclerotic stenosis of the renal arteries is a 300
relatively common condition in the older population with
extrarenal atherosclerosis on angiographic studies.53 Renal 200
artery stenosis can cause progressive ischemic nephropa-
thy and, when bilateral, results in significant renal dysfunc- 100 Transplant: 2020, 250,813;
tion. However, this condition is often underdiagnosed, mainly 2006, 151,502
because specific chemical markers of renal ischemic disease
0
are lacking. Most often, the diagnosis is made by radiologic 80 84 88 92 96 00 04 08 12 16 20
investigations such as duplex ultrasonography, angiography, Year
computed tomography (CT), or magnetic resonance imaging FIGURE 7-2  Projected growth of prevalent dialysis and
(MRI) angiography. Although renal artery atherosclerosis is transplant populations. Light lines show actual counts up to
often associated with systemic hypertension, correction of the 2006. (Data from Collins AJ: Clin J Am Soc Nephrol 4:S5–S11, 2009.)
stenosis does not always result in BP normalization, because
hypertension is more likely to be essential in the majority of
cases.54 Thrombosis of the renal artery may complicate pre- Glomerular filtration rate
existing stenosis or may be caused by hypercoagulability, 80 60-79 30-59 30
trauma, or aortic dissection; and it can precipitate AKI/ARF. 100
Fibromuscular dysplasia of the renal artery, a noninflamma-
tory nonatherosclerotic stenotic condition, occurs mainly in 80
young women and still has no known causes. Unlike athero-
% of population

sclerotic stenosis, this condition rarely causes renal failure, 60

and hypertension in these patients is most likely of renovas-
cular etiology.55
Medical management of renal artery stenosis centers on
control of hypertension, with ACE inhibitors the drugs of
choice, although inhibition of angiotensin-mediated effer-
ent tone may precipitate renal failure in patients with bilat-
eral renal artery stenosis and should be carefully monitored in
these patients, especially if used with a diuretic. Surgical cor-
rection of renal artery stenosis is aggravated by a significant
rate of complications, particularly in patients with coexisting
aortic disease, and is probably not indicated in patients with
advanced nephropathy.54 The use of percutaneous angioplasty
and stenting has emerged as an attractive alternative to the
surgical corrective approach.56
RENAL FAILURE
The terms acute renal failure (ARF) and chronic renal failure
(CRF) are classified here as, respectively, chronic kidney dis-
ease and acute kidney injury.
Chronic Kidney Disease
Chronic kidney disease has become increasingly frequent in
the western world39; the population of patients with ESRD
requiring dialysis has tripled over the past 19 years1 and is pro-
jected to increase to more than 500,000 by 202057 (Fig. 7-2).
These patients' prevalent mortality has been steadily declining
but is still approximately 200 deaths per 1000 patient-years.1,57
40
20
0
20-29 30-39 40-49 50-59 60-69 70-79 80 Total
Age by decade
FIGURE 7-3  Distribution of glomerular filtration rate.
Expressed as mL/min/1.73 m2 body surface area (BSA) by age
for nondiabetic subjects. (Data from Clase CM, Garg AX: BMJ
329:912–915, 2004.)
The prevalence is higher in advanced ages and in certain eth-
nic groups (e.g., African American, Native American).1 Recent
studies have detected an extremely high rate of mild to mod-
erate renal dysfunction in the U.S. population, particularly in
elderly persons (Fig. 7-3).58 These patients are at risk for pro-
gression to CKD if further kidney damage is superimposed.
A significant number of patients with CKD undergo sur-
gery for reasons that may or may not be related to kidney
disease; therefore, understanding the pathophysiology and
the clinical management of these patients is crucial for the
anesthesiologist. In fact, CKD significantly complicates peri-
operative management and impacts surgical outcomes. In
patients with CKD necessitating dialysis, mortality rates of
4% after general surgery and of 10% after cardiac surgery have
been reported, with morbidity rates approaching 50%.59 This
increased rate of complications probably results from the low
 232 ANESTHESIA AND UNCOMMON DISEASES
renal reserve of patients with CKD and their reduced ability
to respond to the stress, fluid load, and tissue trauma caused
by surgery. However, morbidity increases with the organ dys-
function and coexisting disease often found in these patients.
Pathophysiology. Many different renal and extrarenal
pathologic conditions result in the loss of glomerular function
as their “final common pathway.” Renal dysfunction is pro-
gressive and usually divided in stages according to the GFR60
(Table 7-2). Proteinuria is also used as an index of the severity
of kidney disease and can be used to predict renal survival.61
The loss of GFR can be accelerated by events such as intercur-
rent diseases, nephrotoxins, and surgery. Eventually, ESRD is
reached when the GFR decreases below a critical point and the
kidney is unable to maintain homeostasis unless renal replace-
ment therapy is initiated.
When renal tissue is lost, surviving nephrons undergo adap-
tive changes, with tubular hypertrophy, afferent vessel vasodi-
lation, and increased glomerular blood flow.41 By increasing
tubular excretion or reabsorption of water and solutes, these
changes allow the remaining nephrons to compensate for lost
tissue and to maintain near-normal handling of the glomeru-
lar ultrafiltrate. On the other side, these same changes seem
to accelerate the progression of kidney disease. Glomerular
capillary hypertension from afferent vasodilation causes glo-
merulosclerosis, increased endothelial permeability, and pro-
teinuria, which probably promotes further renal damage;43,61
excessive tubular reabsorption of urinary protein may cause
peritubular inflammation, scarring, and fibrosis.41
A progressive inability to maintain tight control of
body fluid composition follows the exhaustion of renal
TABLE 7-2  n  Stages of Renal Dysfunction
Stage Description Creatinine Clearance*
1 Normal or increased GFR— >90
people at increased risk or with
early renal damage
2 Early renal insufficiency 60-89†
3 Moderate renal failure (chronic 30-59
renal failure)
4 Severe renal failure (pre–end-stage 15-29
renal disease)
5 End-stage renal disease (ESRD, <15
uremia)
Modified from National Kidney Foundation (K/DOQI) and Parmar MS: BMJ 325:85–90, 2002.
*Approximate glomerular filtration rate (∼GFR); mL/min/1.73 m2.
†
May be normal for age.
compensatory mechanisms. Patients with low GFR are prone
to sodium accumulation and hypervolemia because they may
not be able to excrete the equivalent of their sodium intake.
When the regulation of urine osmolality and free-water excre-
tion is impaired, changes in water intake may cause sodium
concentration abnormalities. Inability to excrete potassium
by the distal tubule results in K+ accumulation. Patients with
CKD usually tolerate significant hyperkalemia, partly from
increased intestinal excretion. However, acute processes such
as acidosis, surgery, and tissue necrosis can trigger rapid
increases in serum potassium and cause life-threatening
arrhythmias. Decreased phosphate excretion causes accu-
mulation of this electrolyte and its precipitation in tissues,
together with calcium. Hypocalcemia is also caused by defi-
cient renal production of vitamin D and by lower intestinal
absorption of calcium, and it results in secondary hyperpara-
thyroidism, bone resorption, and renal osteodystrophy.
Patients with CKD develop a metabolic acidosis that is ini-
tially associated with hyperchloremia and normal anion gap.
When renal failure becomes severe, inability to excrete titrat-
able acids causes an increased anion gap.
The uremic syndrome characterizes renal decompensa-
tion and is caused by accumulation of catabolic byproducts.
Although the severity of uremia is usually quantified from
blood urea nitrogen (BUN) levels, uremic syndrome is caused
by accumulation of different substances and several hormonal
and metabolic defects. Central nervous system (CNS) mani-
festations may range from personality changes to coma and
seizures, with onset related more to the rapidity of the onset
of azotemia than to its absolute level. Peripheral and auto-
nomic neuropathies are relatively common and cause sensory
Metabolic Consequences
Concentration of parathyroid hormone starts to rise
(GFR ~ 60-80)
Decrease in calcium absorption (GFR <50)
Lipoprotein activity falls
Malnutrition
Onset of left ventricular hypertrophy
Onset of anemia (erythropoietin deficiency)
Triglyceride concentrations start to rise
Hyperphosphatemia
Metabolic acidosis
Tendency to hyperkalemia
Azotemia develops
 Chapter 7  Renal Diseases 233

loss, gastroparesis, and sympathetic dysregulation. Uremia

TABLE 7-3  n  Signs of Uremic Emergency
causes gastric mucosal irritation and gastric ulcers in a sig-
nificant fraction of patients who have uncompensated CKD. Emergency Signs
Uremic patients have a bleeding diathesis even when coagu-
Fluid overload Hypertension, pulmonary edema,
lation times are normal. This bleeding tendency is caused peripheral edema
by a platelet dysfunction resulting from inadequate release
of von Willebrand factor and factor VIII by the endothelial Electrolyte Hyperkalemia, hyponatremia,
imbalance hypocalcemia
cells.23 Renal failure may also cause a predisposition to throm-
bosis from hyperfibrinogenemia, antiphospholipid antibod- Acid-base Increased anion gap, hyperchloremia,
ies, hyperhomocysteinemia, and anticoagulatory protein C abnormalities low plasma CO2, hyperventilation
deficiency. Patients with CKD typically have significant ane- Encephalopathy Seizures, coma, decreased airway
mia, mainly caused by deficient production of erythropoietin, reflexes, obtundation
although GI bleeding and iron deficiency may contribute.
Systemic Congestive heart failure, cardiac
Multiple cardiovascular derangements are associated with hypoperfusion tamponade
CKD. Hypertension usually results from fluid overload but
also neuroendocrine imbalance. Patients with CKD often Bleeding diathesis Normal platelet count and coagulation
times, increased bleeding times
have significant left ventricular (LV) hypertrophy and enlarge-
ment, associated with systolic and diastolic dysfunction, and
are prone to heart failure.62 Anemia significantly contributes
to the adverse effects of CKD on the cardiovascular system, by BOX 7-3   n  CAUSES OF CHRONIC KIDNEY DISEASE*
increasing cardiac output and myocardial oxygen demand and
by causing LV hypertrophy and enlargement.23 Uremic peri- n Dehydration

n Infection
carditis occurs infrequently in dialysis patients but should be
n Uncontrolled hypertension
considered because its presence can be complicated by peri- n Renal disease exacerbation
cardial hemorrhage and tamponade. n Heart failure

n Nephrotoxins

Clinical Presentation. Patients with CKD often present n Urinary obstruction

with a history of a known kidney disease that has been medi-
cally managed along its evolution and that has relatively con-
trolled manifestations. Therefore, many patients with CKD
present in a compensated state and with relatively mild symp-
toms. Vague malaise or nocturia may be the only complaints.
However, some patients may present with the signs and symp-
toms of acute renal decompensation and uremic emergency
(Table  7-3), a condition that should be rapidly addressed by
a nephrologist and that often requires emergent initiation of
hemodialysis.23 This is more likely in patients with rapidly
progressing or unrecognized renal disease. In other patients,
an acute event or illness may overcome the residual renal
reserve or cause further kidney damage, precipitating acute
kidney injury on CKD (Box 7-3).
Patients receiving chronic dialysis usually present in a rela-
tively compensated state, but they may have signs of hypovo-
lemia if fluid removal has been overzealous. When either the
dose or the timing of dialysis is inadequate (Box 7-4), some
of the clinical manifestations of uremia resurface.63 Pericardial
effusions caused by uremic pericarditis are slow to evolve and
rarely result in tamponade, but they should be suspected in the
presence of hypotension, pulsus paradoxus, and jugular vein
enlargement.
Anemia accounts for many of the symptoms and signs
observed in CKD patients, such as malaise, low exercise abil-
ity, decreased mental acuity, LV dilation, and hypertrophy.
Improvement in such symptoms has been reported if anemia
is corrected by erythropoietin administration.23 A major clin-
ical trial in patients with CKD, however, demonstrated that
n Major surgery
* As well as superimposed acute kidney injury.
BOX 7-4   n  SIGNS OF INADEQUATE DIALYSIS
Anorexia, nausea, vomiting, diarrhea
Peripheral neuropathy
Weakness, poor functional status
Decreased alertness
Ascites, pericarditis
Hypertension, fluid overload
Persistent anemia despite erythropoietin
Minimal urea reduction with dialysis
normalizing hemoglobin levels (>13 g/dL) with erythropoie-
tin versus a rescue approach (treating only when level <9 g/dL)
only modestly improved symptoms while significantly
increasing the risk of stroke.64 As such, the risks of erythro-
poietin for mild anemia in this population may outweigh the
benefits.
Patients who are not receiving dialysis are typically under-
nourished because of anorexia and hypercatabolism associated
to CKD. Additionally, some patients may be receiving a low-
protein diet as an attempt to delay the need for dialysis and to
limit the progression of renal disease.39 The protein weight loss
is often masked by the increase in body water content. Patients
who do receive dialysis should be fed an adequate amount of
 234 ANESTHESIA AND UNCOMMON DISEASES
protein, because currently available dialysis systems afford
efficient solute-clearing capabilities, and protein intake limi-
tation is unnecessary.63 The clinical manifestations of renal
osteodystrophy are usually evident only when bone and renal
disease are advanced and include bone and joint pain, lytic
lesions on radiographs, and occasionally, spontaneous bone
fractures.23 Growth retardation and bone deformities are com-
mon in children. Pruritus is common in patients with severe
kidney disease, particularly in those on dialysis, and is prob-
ably caused by calcium precipitation in the skin.
Patients receiving hemodialysis have a surgically created
access that can consist of a native arteriovenous (AV) fistula or
a synthetic graft. Some patients may present with a hemodial-
ysis catheter placed in a central or femoral vein. Dialysis access
sites are at high risk of clotting and infection and should be
inspected for patency and local irritation. Long-term dialysis
patients have a long history of peripheral and central cannula-
tion and may present a challenge for central access.
Differential Diagnosis. Any diseases that damage the kid-
ney at the glomerular or tubular level may progress to CKD.
Diabetes and hypertension are by far the most important
causes of ESRD in the United States, accounting together for
more than 60% of cases.57 Glomerular diseases and tubuloin-
terstitial diseases cause 18% and 7% of cases, respectively, fol-
lowed by cystic kidney disease (5%).39
The differential diagnosis is usually straightforward and
based on history, imaging, and laboratory analysis (Box 7-5).
Renal biopsy is indicated in patients with unexplained CKD
who do not have atrophic kidneys on ultrasound and in
patients with nondiabetic nephritic syndrome. Establishing a
differential diagnosis is important, especially when the con-
dition causing renal failure can be controlled and further
renal damage can be prevented, such as with vasculitis, drug-
induced nephropathy, autoimmune disease, renal ischemia,
and infectious diseases.
Given the high prevalence of diabetes and hypertension in
patients with CKD, it is not surprising that the most important
comorbidities associated with CKD involve the cardiovascu-
lar system (Box  7-6). Cardiac disease is the most important
cause of death in patients with ESRD.62 Congestive heart fail-
ure is present in 40% of patients receiving dialysis and is an
BOX 7-5   n DIFFERENTIAL DIAGNOSIS OF CHRONIC
KIDNEY DISEASE
Diabetes
Hypertension
Glomerulonephritis
Cystic kidney disease
Ischemic renal disease
Pyelonephritis
Analgesic nephropathy
Hereditary diseases
Autoimmune diseases
Vasculitis
BOX 7-6   n COMORBIDITIES OF CHRONIC KIDNEY
DISEASE
n Hypertension
n Diabetes
n Coronary artery disease
n Congestive heart failure
n Dyslipidemia
n Peripheral vascular disease
n Immune depression
important predictor of death. About 75% of CKD patients
have LV hypertrophy and diastolic dysfunction at initiation
of dialysis.62 LV dysfunction improves with dialysis, correc-
tion of anemia, and renal transplant.63 Coronary artery dis-
ease (CAD) is common in patients with CKD, with a reported
prevalence of 40%,65 and is an important cause of LV dysfunc-
tion and mortality. The “classic” risk factors contribute to
prevalence of CAD, but CKD itself might be an independent
risk factor; significant CAD is also observed in CKD patients
who are neither hypertensive nor diabetic.65
Hypertension is almost universal in renal failure, whether
a pre-existing causative factor or secondary manifestation of
fluid overload and endocrine dysregulation. Hyperlipidemia is
highly prevalent in CKD patients, manifesting with increases
in triglycerides (TGs) and very-low-density lipoproteins
(VLDLs) and decreased high-density lipoproteins (HDLs).23
Patients with nephrotic syndrome have a 90% prevalence of
hypercholesterolemia. Control of hyperlipidemia is important
not only to decrease CAD risk but also to reduce proteinuria
and help preserve glomerular function.
Patients with advanced kidney disease are particularly
prone to infections and delayed wound healing and may not
respond to certain immunizations, such as hepatitis B. This
is partly caused by malnutrition but also by specific deficien-
cies in humoral and cell-mediated immunity, such as impaired
phagocytosis, defective lymphocyte function, and impaired
antibody response.23 Hemodialysis does not completely cor-
rect this immunodeficiency and adds risk of infection.
PREOPERATIVE EVALUATION AND PREPARATION
The preoperative evaluation of the patient with CKD should
start with a thorough history and physical examination, focus-
ing on the comorbidities associated with kidney diseases
and the signs and symptoms of uremia, fluid overload, and
inadequate dialysis. Laboratory studies should assess electro-
lyte concentrations, acid-base status, urea and creatinine lev-
els, hematocrit, platelet count, and coagulation. Electrolytes
should not be measured immediately after dialysis because
of incomplete equilibration between plasma and intracellu-
lar fluids. Platelet dysfunction is not related to a low platelet
count and can be detected only with bleeding time, measured
as the time to cessation of hemorrhage after a standardized
skin incision.66 However, this test seems to have a limited pre-
dictive value for clinical bleeding and is used infrequently.
Patients who are receiving adequate dialysis are less likely to

have significant platelet dysfunction, and their risk of bleed-
ing should not be excessive. A chest radiograph is usually
ordered to rule out fluid overload, although probably not in
younger patients who are adequately dialyzed, have good exer-
cise ­tolerance, and are having lower-risk surgeries. An electro-
cardiogram (ECG) is obtained to screen for changes caused by
myocardial ischemia and by electrolyte abnormalities.
The cardiac risk stratification of patients with CKD is not
straightforward. In fact, the sensitivity and specificity of symp-
toms such as chest pain and reduced exercise tolerance are
decreased compared with the population without renal dis-
ease. Silent myocardial ischemia is relatively common because
of the frequency of diabetes and autonomic neuropathy,
whereas dyspnea on exertion may be caused by fluid overload.
The classic signs of congestive heart failure may be absent
in patients who have ventricular dysfunction but are receiv-
ing adequate dialysis. The cardiac evaluation of CKD patients
is further complicated by the lesser accuracy of noninvasive
evaluation in this population. In renal transplantation candi-
dates, myocardial scintigraphy and dobutamine stress echo-
cardiography had less than75% sensitivity for significant CAD
on angiography and had poor predictive power for myocardial
events.67 Therefore, in CKD patients undergoing higher-risk
surgeries, the threshold for requesting a cardiac evaluation
and for obtaining a coronary angiogram should be lower than
in the nonrenal population.65 One group proposed that renal
transplantation candidates who are asymptomatic for myocar-
dial ischemia but have diabetes or are older than 50 undergo
noninvasive cardiac evaluation, followed by coronary arteri-
ography and revascularization if indicated.68 According to this
same algorithm, patients who are symptomatic for ischemia or
heart failure should receive an invasive evaluation. Although
no evidence is available in patients undergoing nontrans-
plant surgeries, it is reasonable to follow a similar approach
for procedures with similar and higher risk. The outcomes of
revascularization in patients with CKD are worse compared
with the remaining population. Percutaneous balloon angio-
plasty has a higher rate of restenosis in renal than in nonrenal
patients, although better results have been obtained with stent
placement.69 Coronary artery bypass graft (CABG) surgery
in CKD patients carries higher perioperative morbidity and
mortality, but patients may have a lower rate of restenosis and
better long-term survival than those with angioplasty.65
In preparation for elective surgery, patients with ESRD
should receive dialysis the day before surgery. This is essen-
tial to achieve a volume status as close to normovolemic as
possible, to allow the patient to tolerate fluid loads associated
with surgery, and to obtain normal electrolyte concentrations.
On the other hand, excessive fluid removal may cause hypo-
volemia and predispose the patient to intraoperative hemody-
namic instability. The dialysis records, when available, can help
to assess the adequacy of dialysis. Urea should decrease more
than 65% during a dialysis session. Dry weight, defined as the
lowest weight tolerated in absence of hypovolemic symptoms,
is recorded to monitor the efficacy of fluid removal and ideally
should be relatively stable over time, with 3% to 4% weight gain
Chapter 7  Renal Diseases 235
between sessions.70 Dialysis should not be performed immedi-
ately before surgery because of the possibility of rapid fluid
shifts and hypokalemia. In the case of emergent surgery, it may
be possible to proceed without dialysis if a minimal weight
gain between treatments is documented; however, patients
with signs of fluid overload or with life-threatening hyperka-
lemia may need emergent dialysis before the operation if time
allows. Otherwise, patients need to be managed medically and
receive dialysis after the operation. Significant hyperkalemia,
when present, can be temporarily controlled with pharmaco-
logic means. Intraoperative use of ultrafiltration is relatively
common during on-pump cardiac surgery,71 and it also has
been reported during noncardiac surgery.72 Potassium levels
above 5.5 mEq/L are usually considered a contraindication to
elective surgery because tissue trauma and cell death can cause
potassium to increase to life-threatening levels. Hypokalemia
should not be treated unless at life-threatening levels.
Blood pressure should be optimized before elective sur-
gery. Current recommendations for long-term CKD man-
agement set a BP goal below 130/80 mm Hg.65 Hypertension
in CKD patients is usually volume dependent and responds
to adequate dialysis, but most patients also require phar-
macologic therapy.63 Perioperative beta-adrenergic blockers
should be considered for patients at increased cardiac risk.
Hypertension management is important not only for myocar-
dial protection but also because the use of certain antihyper-
tensive drugs (ACE inhibitors, angiotensin receptor blockers)
has been shown to limit the evolution of renal disease.
Control of anemia is important because anemia is an important
cause of LV hypertrophy, heart failure, and angina. Hematocrit
should be optimized before surgery. For ambulatory ESRD
patients, hemoglobin of 11 to 12 g/dL is considered optimal63;
this value is also used as a target before surgery, although
this practice is not supported by clinical evidence. The target
hemoglobin level can be achieved by increasing erythropoie-
tin administration if time allows or by transfusion for urgent
surgery. Correction of anemia also helps to improve the plate-
let dysfunction of renal failure.73 If platelet dysfunction is sus-
pected or documented, it can be treated by administration
of desmopressin or cryoprecipitate, both of which increase
the level of von Willebrand factor and improve the interac-
tion between platelets and endothelial cells.23 Their onset of
action is rapid, which renders both drugs useful intraopera-
tively. However, the prolonged use of desmopressin is limited
by induction of tachyphylaxis. Estradiol is also effective in the
treatment of platelet dysfunction, but its peak effect is delayed
for several days. Common long-term pharmacologic therapies
administered to patients with CKD are listed in Table 7-4.
Acute Kidney Injury
Acute kidney injury, formerly known as acute renal failure,
refers to rapid loss of renal function characterized by a dra-
matic reduction in GFR and inadequate solute excretion. It is
caused by hypovolemia (prerenal injury), a medley of intrinsic
injuries to the nephron (as previously discussed), and injury to
 236 ANESTHESIA AND UNCOMMON DISEASES

pelvis to the urethra. for obstruction proximal to the urinary

TABLE 7-4  n Common Medications Taken by Patients
with Chronic Kidney Disease
bladder to result in AKI, however, it must be bilateral or occur
in the patient with a single functional kidney. Abdominal com-
Comorbidity Agents partment syndrome (see later) appears to combine prerenal
Hypertension Beta-adrenergic blockers
and postrenal components. Intrinsic ARF is associated with
Calcium channel blockers renal parenchymal injury. This results from ischemic or toxic
Angiotensin-converting enzyme (ACE) injury to renal tubular epithelial cells (acute tubular necrosis)
inhibitors and from glomerular, vascular, and interstitial inflammatory
Angiotensin antagonists disease processes (Box 7-7).
Fluid overload Thiazides Confusion concerning the extent and definitions of kid-
Furosemide ney injury have been addressed and clarified by the Acute
Osteodystrophy and Calcium supplements
Dialysis Quality Initiative (ADQI; www.adqi.net) group, who
hypocalcemia Phosphate binders produced a now–universally accepted staging system for kid-
Calcitriol ney injury known as the RIFLE criteria (risk, injury, failure,
loss, end stage).75 This is based on rapid onset of renal injury,
Diabetes Insulin
Oral hypoglycemics which may be oliguric or nonoliguric; thus there are both
urine output and GFR criteria (Table 7-5). The RIFLE crite-
Anemia Erythropoietin, iron ria have been successfully used to predict patient outcomes.76
Although widely adopted by intensive care specialists, these
criteria have been subsequently superseded by two groups.
or compression of the renal effluent system (postrenal). AKI Initially the Acute Kidney Injury Network (AKIN) modified
manifests as acute reduction in urine output (oliguria) or an the RIFLE criteria to reflect a simpler staging system for AKI.77
increase in the circulating concentration of nitrogenous waste This approach has been consolidated by the Kidney Disease:
products, which ultimately lead to the syndrome of uremia. In Improving Global Outcomes (KDIGO) group. The modifica-
clinical practice, serum urea and creatinine are used as measur- tions these staging systems introduced to RIFLE were based
able markers of uremia but are not responsible for it. Oliguria on emerging data indicating that a small change in serum cre-
is defined as a urine volume less than 400 to 500 mL/24 hr. atinine influences outcome. In addition, the “L” and “E” com-
Oliguria is not necessary for the diagnosis of AKI, although it ponents were thought to be less useful for prognostication.
is often the presenting sign. Until recently, there has been no Therefore, we recommend the latest version of these criteria
consensus on an operational definition of AKI.74 (Table 7-6).
The AKI syndromes have traditionally been classified into
three major categories on the basis of their pathophysiology: ACUTE TUBULAR NECROSIS
prerenal, renal, and postrenal. Prerenal AKI is associated with Acute tubular necrosis (ATN) results in AKI from a number
a reduction in renal blood flow and glomerular perfusion, sec- of processes. Medullary ischemia results from hypoxic injury
ondary to hypotension or hypovolemia. In the initial stages to the thick limb of the loop of Henle. This leads to slough-
there is no damage to the tubules; if it is sustained, however, ing of cells (casts), which block tubular flow. The tubular pres-
ischemic injury results. Postrenal AKI is characterized by acute sure builds up, and glomerular filtration is inhibited. Ischemic
obstruction to the urinary tract, at any level from the renal ATN is common in perioperative medicine, resulting from

BOX 7-7   n CAUSES OF INTRINSIC ACUTE KIDNEY INJURY

Acute Tubular Necrosis Rhabdomyolysis Endocarditis
Ischemia
Acute Interstitial Nephritis Systemic Diseases
Hypotension
Drug Induced Systemic lupus erythematosus
Hypovolemic shock
Penicillins Multiple myeloma
Sepsis
Cephalosporins Diabetes mellitus
Cardiac arrest
Sulfonamides Amyloidosis
Cardiopulmonary bypass
Rifampin Acute glomerulonephritis
Drug-Induced Nephropathy Phenytoin Poststreptococcal glomerulonephritis
Aminoglycosides Furosemide Rapidly progressive glomerulonephritis
Radiocontrast agents Nonsteroidal anti-inflammatory drugs (NSAIDs)
Vascular Syndromes
Amphotericin
Infection Related Hemolytic uremic syndrome
Cisplatinum
Bacterial infection Thrombotic thrombocytopenic purpura
Pigment Nephropathy Viral infections Systemic vasculitis
Intravascular hemolysis Rickettsial disease Renal artery thromboembolism
Cryoglobulinemia Tuberculosis Renal vein thrombosis
 Chapter 7  Renal Diseases 237

TABLE 7-5  n  RIFLE Criteria for Acute Kidney Injury (AKI)

RIFLE GFR Criteria UO Criteria Sensitivity/Specificity

Risk Increased creat × 1.5 or UO <0.5ml/kg/hr High sensitivity

GFR decrease >25% for 6 hours

Injury Increased creat × 2 or UO <0.5 mL/kg/hr High sensitivity

GFR decrease >50% for 12 hours

Failure Increased creat × 3 or UO <0.3 mL/kg/hr High sensitivity

GFR decrease >75% or for 12 hours or
creat >4 mg/dL anuria × 12 hours

Loss Persistent AKI (or ARF) = complete loss of kidney function >4 weeks High specificity

End-stage kidney End-stage kidney disease = loss >3 months High specificity
disease

GFR, Glomerular filtration rate; creat, serum creatinine; UO, urine output; ARF, acute renal failure.

capacity and polyuria. Cellular repair takes place, and GRF

TABLE 7-6  n Staging Classification for Acute Kidney gradually returns to normal.
Injury (AKI)

CRITERIA RENAL FUNCTION TESTS

A normally functioning kidney is able to conserve salt and
Stage Serum Creatinine (SCr) Urine Output
water. A sensitive indicator of tubular function is sodium
1 Increase ≥26 μmol/L <0.5 mL/kg/hr handling because the ability of an injured tubule to reabsorb
[0.3 mg/dL] within >6 hours sodium is impaired, whereas an intact tubule can maintain
48 hours or (consecutive)
this reabsorptive capacity against hemodynamic stress. With
Increase ≥1.5 to 1.9 ×
reference/baseline SCr a prerenal insult, the urinary sodium concentration (UNa)
should be less than 20 mEq, and the calculated fractional
2 Increase ≥2 to 2.9 × <0.5 mL/kg/hr excretion of sodium (FENa) should be less than 1% [FENa =
reference SCr >12 hours
(UNa/PNa) ÷ (UCr/PCr); Cr, creatinine]. Urine osmolality is high
3 Increase ≥3 × reference <0.3 mL/kg/hr in prerenal syndrome. If the patient has tubular damage for any
SCr or >24 hours or reason, UNa will be greater than expected (>80 mEq) and urine
Increase ≥354 μmol/L Anuria for 12 hours
osmolality low.
[4 mg/dL] or
RRT initiated regardless There is minimal consensus as to what constitutes AKI/
of stage ARF. In clinical practice, urea, a breakdown product of pro-
tein that is partially reabsorbed, and creatinine, a metabolic
From Kidney Disease: Improving Global Outcomes (KDIGO) group. www.kdigo.org/.
RRT, Renal replacement therapy.
byproduct of muscle metabolism that is partially secreted, are
used as markers for renal failure. Serum urea underestimates
GFR. Serum creatinine is a better marker, assuming that
hypovolemia, hypotension, or deliberate ischemia, such as muscle turnover is constant. Thus, in a trauma victim, who
application of suprarenal cross-clamps (in cardiac and aor- may have significant muscle injury, creatinine may underes-
tic surgery). ATN also results from a variety of toxic insults, timate renal function. Serum creatinine is insensitive to even
including aminoglycoside and glycopeptide (vancomycin) substantial declines in GFR, which may be reduced by up to
antibiotics, NSAIDs, radiographic contrast, pigment (rhabdo- 50% before creatinine increases. Creatinine overestimates the
myolysis), heavy metals, and solvents. GFR, so it is difficult to assess true renal function using the
The clinical course of ATN can be divided into three serum creatinine value. Conventional wisdom holds that a
phases: initiation, maintenance, and recovery. In the initia- doubling of the serum creatinine level is indicative of renal
tion phase the kidney is injured, and progression is poten- failure. However, this may be misleading in patients with
tially preventable. When renal failure becomes established, reduced muscle turnover (critically ill or elderly patients).
GFR may decrease dramatically and manifest as oliguria, The creatinine clearance (~GFR) has been used as a method
with accumulation of nitrogenous waste products of metab- of overcoming these problems. The following method of cal-
olism and development of uremia, confusion with cognitive culation is most often used:
decline, pericarditis, and platelet dysfunction. This mainte-
Creatinine clearance (mL/min] =
(140 − Age) × Weight
nance phase lasts days to weeks. The recovery phase lasts 4
to 6 weeks and is characterized by poor renal concentrating (72 × Creatinine)
 238 ANESTHESIA AND UNCOMMON DISEASES

For female patients, multiply the result by 0.85 (age in

TABLE 7-8  n Urinalysis Findings in Patients with Acute
years; weight, kg). There are many reasons why this calcu- Kidney Injury (AKI)
lation may be inaccurate, including variations in creatinine
production from person to person and from time to time. Type of AKI Urinalysis
Furthermore, the weight as an index of muscle mass may Prerenal Benign or hyaline casts
be inaccurate in obese or edematous (particularly in critical
care) patients. A more effective method would be to com- Acute tubular necrosis Hemegranular or epithelial cell
casts
pare what is in the urine to what is in the serum as a mea-
sure of clearance. Acute interstitial WBCs, WBC casts, eosinophils,
The serum creatinine (SCr) level is usually falsely raised by nephropathy proteinuria
error inherent in measurement. The urinary creatinine (UCr) Acute glomerulonephritis RBCs, dysmorphic RBCs, RBC
level is falsely raised by tubular secretion. These errors tend to casts, proteinuria
cancel each other out, so the following equation gives a rea-
Postrenal Benign ±hematuria
sonably accurate estimate of GFR:
RBCs, Red blood cells; WBCs, white blood cells.
Creatinine clearance ( � GFR ) = UCr (mg/mL )
× Urine volume × (100 / SCr ) This is prevented with early, aggressive volume resuscitation
and control of the source of bleeding.
The differences in the way the kidneys handle urea and cre-
atinine also is of diagnostic value (Table 7-7). It is known that RHABDOMYOLYSIS
urea is reaborbed and creatinine is not reabsorbed. In dehy- Rhabdomyolysis refers to the release of large quantities of
dration (prerenal syndrome) the urea/creatinine ratio is ele- muscle cell contents as the result of traumatic or nontraumatic
vated (from factor of 10 to factor of 20). injury of skeletal muscle. a linear relationship exists between
In conclusion, if renal dysfunction is suspected, concen- the degree of trauma and the likelihood of developing pigment
trating capacity (urinary sodium [UNa] and osmolality) and nephropathy, as quantified by the serum creatine phosphoki-
GFR (creatinine clearance) should be measured. Renal failure nase (CPK) level. In addition to myoglobin, the protein pri-
index (RFI) is a consolidated figure that may be used as a sin- marily responsible for renal injury, there is a dramatic increase
gle score. It is calculated as follows: in the serum concentration of the intracellular ions phosphate,
potassium, and magnesium. The serum calcium concentra-
RFI = U Na / ( U Cr / SCr )
tion subsequently falls dramatically.
Urinary microscopy is a useful diagnostic technique for Four mechanisms are believed to contribute to the development
AKI/ARF, particularly in the early stages. The presence of dif- of AKI/ARF in myoglobinuria: hypovolemia, renal vasoconstric-
ferent cells or casts indicates the etiology of the disease process tion, heme-mediated proximal tubular cell toxicity, and intratubu-
(Table 7-8). lar cast formation. Renal perfusion rapidly decreases after muscle
cell injury as a result of massive fluid sequestration into the injured
Trauma. AKI/ARF is a frequent complication of major tissue. Circulating concentrations of the renal vasoconstrictors
trauma, often associated with severe hypovolemia and ATN. epinephrine, norepinephrine, endothelin, and angiotensin II
greatly increase. Usually, myoglobin is reabsorbed by the proximal
tubule and metabolized by releasing free iron, which is soaked up
TABLE 7-7  n  Evaluation of Oliguria by glutathione, but in rhabdomyolysis, this mechanism is over-
whelmed. Free heme proteins scavenge nitric oxide, contributing
Prerenal ATN to vasoconstriction, and generate free radicals, which are nephro-
U/P osmolality >1.4:1 1:1 toxic. In addition, in the presence of an acidic urine, myoglobin
binds with a renal excretory protein (Tamm-Horsfall) to form a
U/P creatinine >50:1 <20:1
cast that obstructs the tubules and causes ATN.
Urine Na (mEq/L) <20 >80 Although first described in trauma, rhabdomyolysis
FENa (%) <1 >3
occurs in other circumstances as well (Box 7-8). Presenting
symptoms in rhabdomyolysis usually reflect the primary dis-
RFI%* <1% >1% ease process, with superimposed symptoms of muscle injury
CCR (mL/min) 15-20 <10 or renal failure. Occasionally the patient may present with
acute limb compartment syndrome resulting from a closed
BUN/Cr >20 <10
fracture of crush injury or inappropriate surgical closure.
*Renal failure index, calculated as urinary sodium/(urinary creatinine/serum The patient complains of pain, swelling, tenderness, and
creatinine). bruising; with neurovascular impairment the pain is severe.
ATN, Acute tubular necrosis; U/P, urine/plasma ratio; Na, sodium; FENa,
fractional excretion of sodium; CCR, creatinine clearance; BUN/Cr, blood urea Urgent fasciotomy is required. Rhabdomyolysis is suspected
nitrogen/creatinine ratio. by the presence of tea-colored urine and a rising CPK level.

BOX 7-8   n  CAUSES OF RHABDOMYOLYSIS
Traumatic Causes
Crush injury
Lightning strike/electrocution
Immobilization
Extensive burns
Heat-Related Causes
Heatstroke
Overexertion (marathon running)
Malignant hyperthermia
Neuroleptic malignant syndrome
Inflammatory Causes
Polymyositis
Dermatomyositis
Sepsis
Snakebite
Toxic Causes/Associations
Alcohol
Cocaine
Amphetamine
Ecstasy (MDMA)
Lysergic acid diethylamide (LSD)
HMG-CoA reductase inhibitors
If the diagnosis cannot be separated from hemoglobinuria,
microscopic examination of urine is necessary. The patient
may develop severe hyperkalemia, hyperphosphatemia,
hyperuricemia, and lactic acidosis. Profound hypocalcemia
may develop as the result of deposition of calcium salts in
injured muscle.
Of strategies proposed to prevent AKI in patients with rhab-
domyolysis, the only approach supported by evidence is aggres-
sive volume replacement. The nature of the fluid (isotonic,
hypotonic) is less important than the absolute volume. Urinary
alkalization with sodium bicarbonate or sodium acetate is
unproved, as is the use of mannitol to promote diuresis.78,79
ABDOMINAL COMPARTMENT SYNDROME
The abdominal compartment syndrome refers to an abrupt
increase in intra-abdominal pressure leading to organ dys-
function and resulting in hypotension, respiratory compro-
mise, liver and mesenteric ischemia, and AKI/ARF. Abdominal
compartment syndrome is most often seen in trauma patients
who require massive volume resuscitation. Extravasation of
large quantities of resuscitation fluid into the bowel wall leads
to massive edema and abdominal hypertension. The syn-
drome may also occur in settings associated with mechanical
limitations of the abdominal wall, such as tight surgical clo-
sures or scarring after burn injuries, that reduce abdominal
compliance. Renal insufficiency results from decreased renal
perfusion and correlates with the severity of the increased
intra-abdominal pressure. Oliguria usually develops when
the intra-abdominal pressure exceeds 15 mm Hg; anuria usu-
ally develops at pressures greater than 30 mm Hg. The specific
cause of renal abdominal compartment syndrome is unclear.
Venous compression and obstruction undoubtedly contribute,
Chapter 7  Renal Diseases 239
along with direct cortical compression and aortic and renal
artery compression.
The diagnosis of abdominal compartment syndrome is
based on clinical suspicion and measurement of bladder
pressures, by injecting 50 mL of saline into the empty blad-
der through the Foley catheter. The tubing of the drainage bag
is cross-clamped and a 16-gauge needle inserted through the
aspiration port and connected to a pressure transducer.
Treatment consists of abdominal decompression, usu-
ally surgical. The abdominal wall is opened, and the fascia is
left open. This is covered by a wound device or the skin. Once
edema has subsided, the abdominal wound is closed, although
definitive surgery may be delayed for 1 year or more. If abdomi-
nal hypertension is suspected, the anesthesiologist must weigh
the cost and benefit of further fluid resuscitation. There is a
direct relationship between the volume of crystalloid adminis-
tered and the incidence of abdominal compartment syndrome.
In this situation, colloid resuscitation is probably preferable.80–82
PERIOPERATIVE RENAL DYSFUNCTION
Renal dysfunction is relatively common in the postoperative
period and occurs more often in certain types of surgery; aor-
tic reconstruction has a reported 25% rate.83 Postoperative
renal dysfunction manifests with a spectrum of severity, from
mild defects to renal failure requiring dialysis. When AKI/
ARF superimposes on other underlying diseases, a significant
increase in morbidity and mortality is observed,84,85 but even
a moderate renal dysfunction can worsen surgical outcomes.
In fact, survival after cardiac surgery is decreased in patients
who have moderate86 and even subtle87 renal impairment post-
operatively. Patients with mild renal dysfunction have lon-
ger postoperative hospital stays after vascular surgery.88 Thus,
perioperative renal morbidity cannot be underestimated, and
its prevention becomes especially important. Unfortunately,
none of the currently proposed risk reduction strategies is
supported by strong clinical evidence. The study of risk reduc-
tion of renal complications therefore continues.
Pathophysiology. The kidney is subject to multiple harm-
ful events in the perioperative period; renal hypoperfusion is
one of the most important factors that contribute to renal dys-
function.89 The most common causes of decreased renal blood
flow are hypovolemia, heart failure, and vascular clamping.
Renal hypoperfusion results in hypoxic damage to the outer
portion of the renal medulla, an area that is exquisitely sensi-
tive to hypoxia. In fact, this region receives a poor blood sup-
ply relative to its high oxygen consumption because of intense
solute reabsorption by the thick segment of the loop of Henle.
Alterations in ionic pumps, loss of intracellular adenosine tri-
phosphate (ATP), increased intracellular calcium, and tubular
epithelial cell swelling and sloughing are characteristic of renal
hypoxic damage. Also, hypoxic injury might render the kidney
more sensitive to subsequent ischemic events, as suggested by
the loss of renovascular autoregulation observed in animals
after renal ischemia.89
 240 ANESTHESIA AND UNCOMMON DISEASES

Nephrotoxic substances are also important contributors

TABLE 7-9  n Risk Factors and Anesthetic Management
to renal injury, and their effect is synergistically increased by for Perioperative Renal Dysfunction
concomitant renal ischemia and hypoperfusion.89 One of the
mechanisms of contrast dye nephropathy, a common cause of Factors Management
perioperative renal dysfunction, is probably the ultrafiltration PATIENT
of a high osmotic load that, by stimulating an increased tubular
solute reabsorption, may increase tubular oxygen consumption Pre-existing renal Optimize volume status and cardiac
disease output; administer IV fluids and/
and favor cell hypoxia. Anti-inflammatory drugs acutely injure Heart failure or inotropes; consider invasive
renal cells by inhibiting formation of prostaglandins, and their hemodynamic monitoring and/or
effect is enhanced when the kidney is hypoperfused. In fact, transesophageal echocardiography.
prostaglandins are generated during renal hypoperfusion to Optimize BP management before
maintain blood flow to the peritubular vessels and to decrease surgery; maintain near-basal BP
intraoperatively.
tubular reabsorption. Suppression of their formation may lead
to tubular cell ischemia. Finally, pre-existing renal disease, dia- Advanced age,
betes, hypertension, and chronic ischemia increase the suscep- hypovolemia,
sepsis, diabetes,
tibility of the kidney to superimposed ischemic or chemical
hypertension,
insults.90 This is related to lower renal functional reserve, to cholestasis
impaired renovascular autoregulation, as seen in hypertensive
patients, and to the often-permanent effects of renal insults, SURGICAL
which probably accumulate over a patient's life span. Vascular, heart, and Optimize volume status and cardiac
major abdominal output.
Risk Factors. The risk of perioperative renal dysfunc- surgery Consider mannitol for vascular
tion is significantly affected by patient-related factors such as Trauma clamping, although supporting
Transplant evidence is minimal.
advanced age,83 left ventricular dysfunction,84 and pre-existing
renal insufficiency.84 A significant part of the population has PHARMACOLOGIC
mild to moderate renal dysfunction, particularly elderly per- Antimicrobials Avoid hypovolemia.
sons58 (see Fig. 7-3) and is at increased risk for progression to NSAIDs Avoid nephrotoxic antimicrobials, or
Contrast dye optimize schedule and formulation.
renal failure if further renal damage is superimposed in the
Avoid NSAIDS in patients at risk.
perioperative period. The presence of diabetes and systemic Avoid contrast studies, or give
hypertension is associated with increased risk for postopera- N-acetylcysteine and bicarbonate;
tive renal dysfunction, although it is unclear whether this is consider ultrafiltration.
an independent risk factor or a consequence of pre-existing BP, Blood pressure; IV, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs.
renal insufficiency. Cholestasis is associated with an increased
risk of renal morbidity, probably because of increased endo-
toxemia.91 Evidence of a genetic predisposition to postoper- prolonged duration of aortic cross-clamping94 are associated
ative renal impairment has been reported. In a prospective with worsened renal function after aortic surgery. Renal injury
study of patients undergoing cardiac surgery, certain alleles after aortic clamping is related not only to parenchymal isch-
of the apolipoprotein E genotype have been associated with emia but also to inflammatory activation and ischemic reper-
higher postoperative elevation of creatinine,92 suggesting that fusion injury of the bowel. Avoidance of aortic cross-clamping
risk stratification might be accomplished by gene testing in the with endovascular repair should prevent these complications.
future. Table  7-9 lists the risk factors for perioperative renal A randomized controlled trial (RCT) comparing endovascu-
dysfunction. lar and open infrarenal aortic aneurysm repair showed a simi-
Among surgery-related factors, extensive surgery, high larly low incidence of renal complications in both study arms,
intraoperative blood loss, and transfusion requirement sig- probably from the low rate of renal complications in patients
nificantly increase the risk for renal dysfunction,83 but vas- with only infrarenal aneurysms.95 Newer devices allowing
cular and cardiac procedures are associated with the highest repair of more proximal aneurysms that would otherwise
risk of renal morbidity. In particular, the incidence of post- require suprarenal clamping have the potential of decreasing
operative renal morbidity after aortic surgery is high and has the incidence of renal complications in the future.
not decreased despite improved surgical and anesthetic man- Patients undergoing cardiac surgery are at high risk for
agement. In patients undergoing aortic thoracoabdominal renal complications, which increases further with valve
aneurysm repair, Rectenwald et  al.93 found a 28% incidence replacement.96 In a prospective cohort study in patients under-
of renal dysfunction associated with worse outcomes. Patients going cardiac surgery, Chertow et al.97 identified 10 risk factors
undergoing vascular surgery have a high incidence of preop- for renal morbidity and stratified patients into three groups
erative kidney disease83 because of their comorbidities, a fact with increasing risk (Box 7-9). This model has been validated
that partly explains the high frequency of perioperative renal in a broader population of patients and may provide a guide
morbidity in this population. Both proximal location and for the risk stratification of patients undergoing this type of

BOX 7-9   n  INDEPENDENT RISK FACTORS FOR ACUTE
KIDNEY INJURY AFTER CARDIAC SURGERY
Valvular surgery
Decreased creatinine clearance
Intra-aortic balloon pump
Prior heart surgery
New York Heart Association class IV
Peripheral vascular disease
Ejection fraction <35%
Pulmonary rales
Chronic obstructive pulmonary disease
Systolic hypertension or hypotension
Modified from Chertow GM et al: Circulation 95:878–884, 1997.
surgery.98 Renal impairment after cardiac surgery is related
to renal hypoperfusion, inflammatory activation by the
cardiopulmonary bypass, and endotoxemia resulting from
bowel ischemia. However, it is not clear whether avoid-
ance of cardiopulmonary bypass decreases the incidence
of postoperative renal failure. The finding of a significant
decrease in renal impairment with off-pump surgery99,100
has not been confirmed in all studies.101,102 A large RCT
comparing off-pump with on-pump coronary bypass did
not specifically address renal morbidity but showed com-
parable outcomes and better cost-effectiveness with off-
pump technique.103
RENAL REPLACEMENT THERAPY
Renal replacement therapy (RRT) involves the use of semi-
permeable biocompatible membranes to remove nitrogenous
waste products, ion products of metabolism, and fluid from
the body. Indications for RRT are listed in Box 7-10. The three
types of RRT are intermittent hemodialysis, peritoneal dial-
ysis, and continuous RRT. Two processes underlie RRT: dif-
fusion and convection. In diffusion, solutes move along an
electrochemical gradient from a compartment where they are
in high concentration to one where they are in lower concen-
tration (Fig.  7-4). An electrolyte solution runs countercur-
rent to blood flowing on the other side of a semipermeable
(small-pore) filter. Small molecules such as urea move along
Membrane/filter
Blood flow
Concentration
Compound in gradient
Compound in LOW
HIGH
concentration
Dialysate flow
Chapter 7  Renal Diseases 241
BOX 7-10   n INDICATIONS FOR RENAL REPLACEMENT
THERAPY
Oliguria (urine output <200 mL/12 hr)
Anuria (urine output <50 mL/12 hr)
Hyperkalemia (K+ >6.5 mEq/L)
Severe acidemia (pH <7.1)
Azotemia (urea >180 mg/dL)
Pulmonary edema
Uremic encephalopathy
Uremic pericarditis
Uremic neuropathy/myopathy
Severe dysnatremia (Na+ >160 or <115 mEq/l)
Hyperthermia
Drug overdose with dialyzable toxin
the concentration gradient into the dialysate fluid. Larger mol-
ecules are poorly removed by this process. Solute removal is
directly proportional to the dialysate flow rate. In convection,
or ultrafiltration, solute is carried across a semipermeable
membrane in response to a transmembrane pressure gradient
(solvent drag). This mimics the actual situation in the normal
human kidney (Fig.  7-5). The rate of ultrafiltration depends
on the porosity of the membrane and on the hydrostatic pres-
sure of the blood, which in turn depends on blood flow. This
is effective in removal of fluid and middle-sized molecules,
which are thought to cause uremia.
Intermittent hemodialysis is the most widely used and
effective RRT. Large amounts of fluid can be removed, and
electrolyte abnormalities can be rapidly corrected. The sys-
tem includes a double-lumen IV catheter or AV fistula, a pump
that forces blood into a filter (semipermeable membrane),
dialysate fluid (usually deionized water) that flows in and out,
and a return line to the patient. The blood flow rate is 200
to 400 mL/min, dialysate flow about 500 mL/min, filtration
rate 300 to 2000 mL/hr, and urea clearance 150 to 250 mL/
min. With this high flow and clearance rate, depending on
the extent of their catabolism, patients require only 3 to 4
hours of dialysis, two or three times a week. Dramatic fluid
and osmotic shifts between the intravascular and extravas-
cular compartments cause transient hypotension and dis-
equilibrium. Many critically ill patients cannot tolerate this.
With hemodialysis, preferential solute and water removal
Diffusion
concentration FIGURE 7-4  Schematic representation of diffusion.
 242 ANESTHESIA AND UNCOMMON DISEASES
HIGH pressure
FIGURE 7-5  Schematic representation of convection.
Solute dissolved
from blood occurs as blood courses through the dialyzer and
comes in “contact” with dialysate across a closed network
of semipermeable membranes. These membranes allow dif-
fusive movement of non–protein-bound solutes, according
to their molecular size and chemical gradients, between the
dialysate and blood. Water and sodium removal depends on
a hydrostatic transmembrane pressure gradient between the
dialysate and blood that is set up by the head of pressure of
blood moving into the dialyzer, resistance to blood return
to the patient, and negative pressure in the dialysate com-
partment created by rapid countercurrent flow of dialysate.
Anticoagulation with heparin is the standard method for pre-
venting thrombosis of the extracorporeal circuit during acute
intermittent dialysis.
Dialysis disequilibrium syndrome is a self-limited condi-
tion characterized by nausea, vomiting, headache, altered
consciousness, and rarely seizures or coma. It typically occurs
after a first dialysis in extremely uremic patients. The syn-
drome is triggered by rapid movement of water into brain cells
after development of transient plasma hypo-osmolality as sol-
utes are rapidly cleared from the bloodstream during dialysis.
The incidence of this complication has fallen in recent years
with the more gradual institution of dialysis and the precise
prescription of dialysis to include such variables as membrane
size, blood flow rate, and sodium profile.
Peritoneal dialysis has the advantage of being simple and
cost-effective. A small tube is surgically inserted into the peri-
toneal cavity. Dextrose is infused into the peritoneum and left
in situ for 4 to 6 hours. Waste products diffuse along the con-
centration gradient into the fluid, which is drained over 30 to
40 minutes. The major disadvantages of peritoneal dialysis are
poor solute clearance, poor uremic control, risk of peritoneal
infection, and mechanical obstruction of pulmonary and car-
diovascular performance.
Continuous renal replacement therapy is used in inten-
sive care units to treat hemodynamically unstable patients.
In critical illness the phenomenon of capillary leak increases
the interstitial volume and makes patients edematous. This
makes the clearance of solute difficult to calculate and indeed
to implement. Continuous techniques lead to more effective
urea and water clearance. Continuous RRT combines dialy-
sis and ultrafiltration and has been used to manage patients
with AKI/ARF, shock, sepsis, and massive fluid overload.
Membrane/filter Convection
Pressure gradient
Solvent drag
in solvent LOW pressure
RENAL TRANSPLANTATION
Renal transplantation provides better survival and quality
of life than dialysis for patients with ESRD. There is a long-
term survival advantage associated with cadaveric (“deceased
donor kidney” is preferred by the Association of Organ
Procurement Organizations) renal transplantation over dialy-
sis. This difference is most pronounced in patients with dia-
betes and glomerulonephritis as causes of ESRD.104–106 Ideally,
renal transplantation should precede the need for dialysis. The
unfavorable relationship between duration of dialysis therapy
and outcome is progressive; 4 years of dialysis therapy confers
about 70% of additional mortality and graft loss compared
with transplantation before the dialysis therapy.107,108 Renal
transplantation may lead to complete resolution of cardiovas-
cular complications, systolic dysfunction, LV hypertrophy, LV
dilation, and uremia,109 as well as other comorbidities related
to ESRD.110
The rate of cadaveric kidney donation remains at approxi-
mately 9000 per year despite persistent public education and
legislative adjustments to facilitate the organ donation process.
Thus, the wait for a cadaveric kidney can be as long as sev-
eral years. Meanwhile, the mean annual mortality of dialysis
patients waiting for a transplant is 6% to 10%.104 Fortunately,
the number of living kidney donors has increased, exceeding
the number of cadaveric donors in 2001 for the first time in
the United States.111
The introduction of cyclosporine in 1983 followed by a series
of effective new immunosuppressive agents—corticosteroids,
tacrolimus, mycophenolate, azathioprine, and sirolimus—
and protocols led to low mortality and a 1-year graft survival
close to 90% by the mid-1990s.112–114 Antilymphocyte antibod-
ies are now used in addition to immunosuppressants.115,116 In
1987 the United Network for Organ Sharing (UNOS) began
to administer the Organ Procurement and Transplantation
Network under contract with the U.S. Department of Health
and Human Services. An allocation algorithm was developed
that ranked patients according to their waiting time and pro-
vided points for varying degrees of human leukocyte anti-
gen (HLA) matching in an effort to use organs equitably. The
­algorithm for cadaveric donor kidney allocation between 1995
and October 2002 is listed in Table 7-10, together with subse-
quent changes. The algorithm requires constant re-evaluation
 Chapter 7  Renal Diseases 243

TABLE 7-10  n  UNOS Point System for Cadaver Kidney Allocation*

Category Points Assigned before Oct 2002 Changes

Time of waiting 1 point assigned to the patient waiting the longest, No change
fractions proportionately assigned to the remainder,
1 additional point for each full year waiting

Estimation of wait From time of UNOS registration after GFR <20 mL/min From time of dialysis or GFR <20 mL/min†
Time lost during inactivity No loss for inactivity‡

Antigen mismatch 7 points for 0 B and DR mismatch 2 points for 0 DR mismatch

5 points for 1 B or DR mismatch 1 point for 1 DR mismatch§
2 points for 2 B or DR mismatch

Panel-reactive antibody 4 points, if panel-reactive antibody >80% No change

Pediatric 4 points for age <11 years; 3 points for age 11 yr No change
but <18 yr

ECD kidneys Waiting time-based allocation§ No category

From Danovitch GM, Cecka JM: Am J Kidney Dis 42:882-890, 2003.

* Before October 2002, with then subsequently implemented, adopted, and proposed changes.
†
 Proposed changes.
‡
 Adopted.
§
 Subsequently implemented.
UNOS, United Network for Organ Sharing; GFR, glomerular filtration rate; B, blood; DR, donor-related; ECD, eligible cadaver donor; all donors older than 60 years, or
donors older than 50 years with a history of hypertension, renal dysfunction, or nontraumatic cause of death.

as the reality of the expanding waiting list changes with time
and new implications of previous policy decisions become
available.
ANESTHETIC CONSIDERATIONS
Because CKD patients have coexisting disease, a more exten-
sive preoperative evaluation is required. Figure  7-6 presents
one proposed management strategy for patients with ESRD
who are candidates for transplantation.
Anesthesia monitoring should be selected based on specific
cardiac comorbidities. A pulmonary artery pressure catheter
is rarely required, but it should be considered in patients with
severe CAD and LV dysfunction, moderate to severe valvular
abnormalities, or significant pulmonary artery hypertension.
Volume status can vary with the time since the last dialysis.
Intraoperative volume expansion increases renal blood flow
and is associated with improved graft function.117–121 Only
administration of mannitol combined with volume expansion
has been shown to decrease the incidence of ATN after trans-
plantation.122,123 Hydroxyethyl starch solutions should be used
with caution because of adverse effects on renal function.124
Hemostasis. Multiple hemostatic abnormalities have
been associated with ESRD.125 Abnormal platelet function
and decreased levels of both factor VIII and von Willebrand
factor are common. Preoperative dialysis improves platelet
function and is the mainstay of the prevention of uremic
bleeding, although it is not always immediately effective.
Desmopressin, 0.3 μg/kg intravenously 1 hour before sur-
gery, and cryoprecipitate, 10 units over 30 minutes (effective
in 1 hour), offer an alternative and effective treatment for
the temporary reversal of uremic bleeding in patients who
require urgent invasive procedures.126,127
Hyperkalemia. Mild to moderate hyperkalemia leading to
direct, aldosterone-independent, renal potassium secretion is
now considered to be an adaptive response.128 Stable serum
potassium levels of 5.0 to 5.5 mmol/L before surgery should
be tolerated.
INTRAOPERATIVE CONSIDERATIONS FOR
THE PATIENT WITH KIDNEY DISEASE
Hemodynamic Management
Intraoperative hemodynamic management of the renal patient
is challenging. In anuric or oliguric patients, intravenous fluid
administration should be limited to the correction of losses,
given their reduced tolerance to fluid overload. Hypotension,
hypovolemia, and renal hypoperfusion may accelerate the
progression to ESRD and should be avoided in patients with
residual renal function. However, the frequent coexistence of
systolic and diastolic left ventricular dysfunction renders these
patients prone to having low cardiac output. Also, many surgi-
cal patients present with poorly controlled hypertension while
their kidneys cannot tolerate large swings in blood pressure
due to compromised autoregulation.
Therefore, patients with kidney disease undergoing higher-
risk procedures often need invasive hemodynamic monitoring
with arterial, central venous, and pulmonary artery catheters.
There are no definite recommendations to guide the choice
of monitoring techniques. In fact, the accuracy of filling
 244 ANESTHESIA AND UNCOMMON DISEASES

Low Risk Intermediate Risk High Risk

Must satisfy all these Age >50 or diabetes May have any of these
criteria: without symptoms of criteria:
a. Age <50 CAD or CHF a. Symptomatic CAD
b. Non-diabetic b. Evidence of previous MI
c. No history or symptoms c. CHF
of CAD or CHF
d. Normal ECG
Exercise-thallium
Dobutamine echo Cardiac catheterization
Dipyridamole-thallium

Limited or Extensive
Negative Positive no CAD CAD

Poor CABG candidate

CABG
(severe diffuse disease,
markedly depressed LVSF)

Transplant

No
transplant

FIGURE 7-6  Management strategy for end-stage renal disease. In ESRD patients who are candidates for transplantation. CAD,
Coronary artery disease; CHF, congestive heart failure; ECG, electrocardiogram; echo, echocardiogram; MI, myocardial infarction; CABG,
coronary artery bypass grafting; LVSF, left ventricular systolic function. (Modified from De Lemos JA, Hillis LD: Diagnosis and management
of coronary artery disease in patients with end-stage renal disease on hemodialysis, J Am Soc Nephrol 7:2048, 1996.)

pressures to estimate patient volume status is questionable,129 cannulation should also be avoided because this procedure
and no benefit of routine intraoperative use of pulmonary is frequently complicated by thrombosis, which compromises
artery catheters has been documented.130 The choice of hemo- dialysis access.
dynamic monitoring should be based on the history and char-
acteristics of the individual patient and directed at specific Pharmacologic Choices
hemodynamic goals, such as optimization of cardiac output.
The anesthetic management of patients with AKI/CKD is
The use of intraoperative transesophageal echocardiography
complicated by the fact that the pharmacokinetics of sev-
for hemodynamic and volume status monitoring may have a
eral anesthetic drugs are significantly altered. Drugs that
role in patients with renal disease.
are lipid insoluble, are ionized, and that undergo significant
The available evidence guiding the choice of IV fluids is still
renal excretion are more heavily affected by kidney dysfunc-
sparse, but the use of balanced solutions rather than normal
tion. Although renal failure does not always increase the dura-
saline offers advantages such as avoidance of hyperchloremic
tion of a single dose of these drugs, repeat administration or
acidosis. Potassium-containing solutions are usually avoided
infusion should be at reduced dosage and the effect should be
in anuric patients with higher potassium levels, although the
monitored if possible. AKI/CKD may also affect the response
potassium intake associated with administration of moderate
to more liposoluble drugs that are not mainly excreted by the
amounts of these fluids is minimal. It is still unclear whether the
kidney. In fact, some drugs are biotransformed by the liver to
use of colloids benefits renal patients. Renal toxicity of dextran
active metabolites that do undergo significant renal excretion
is known, but alterations in renal function have been reported
and, therefore, can be accumulated in patients with renal fail-
also with hetastarch, and the safety of its use in patients with
ure. Additionally, all drugs that are highly protein bound have
renal insufficiency is unclear.131 The Intensive Insulin Therapy
an increased free fraction in the presence of hypoproteinemia,
and Pentastarch Resuscitation in Severe Sepsis (VISEP) trial
such as with nephrotic syndrome. Finally, the response to hyp-
has suggested that hetastarch administration is associated with
notic drugs is often increased in uremic patients, an effect that
adverse renal outcomes.132 However, modern tetrastarches
has been ascribed to higher permeability of the hematoence-
may have lower toxic potential.133 The status of these agents is
phalic barrier. Table  7-11 lists various anesthetic choices in
currently unclear because of ongoing controversy concerning
patients with CKD/CRF.
the major investigator in many safety trials.134
Intravenous access is usually difficult in patients with
ESRD, and central venous access is often needed. The veins INDUCTION
and arteries of the nondominant upper extremity should Doses of induction agents should be decreased signifi-
be spared from vascular cannulation, because they may cantly because of increased free fraction of these drugs, par-
be needed for dialysis access in the future. Subclavian vein ticularly barbiturates. The same consideration applies to

TABLE 7-11  n  Choices of Anesthetic Agents for Renal Patients
Agent Type Preferred
Inhaled agents Isoflurane
Desflurane
Induction agents Etomidate
Ketamine
Opioids Fentanyl
Remifentanil
Alfentanil
Neuromuscular blockers Cisatracurium
Atracurium
Mivacurium
benzodiazepines used for induction or as premedicants.
Propofol is not significantly excreted by the kidney; and
although patients with ESRD have slightly increased vol-
ume of distribution for propofol, its half-life is not signifi-
cantly prolonged in these patients.135 A higher induction-dose
requirement for propofol in one study comparing patients
with ESRD and normal patients was ascribed to concomitant
anemia and hyperdynamic circulatory state.136 The choice of
anesthetic induction dose should also consider possible auto-
nomic dysfunction, hypovolemia, pericardial tamponade, and
preoperative ACE inhibitors,137 all of which can cause hypo-
tension after induction of anesthesia. A safe induction strat-
egy is a slow titration of anesthetic and sedative agents, unless
rapid-sequence induction is indicated.
Ketamine is hepatically metabolized, has a short redistribu-
tion half-life, is well tolerated hemodynamically, and is indi-
cated in patients at risk for hypotension. However, the active
metabolites norketamine and dehydronorketamine are renally
excreted and have the theoretic potential for accumulation
after prolonged use.138 Etomidate can be used in hemodynami-
cally unstable patients, given the good hemodynamic profile
of this drug. The use of prolonged infusions of etomidate is
contraindicated because of adrenal suppression and possible
accumulation of the solvent propylene glycol in renal patients.
MUSCLE RELAXANTS
Rapid-sequence induction is often indicated in patients with
kidney disease because of the high incidence of gastropare-
sis. Succinylcholine is not contraindicated as long as there is
no pre-existing hyperkalemia. In fact, succinylcholine causes
a transient increase in serum potassium levels, although
this effect in renal patients is similar to that in normal sub-
jects.139 The use of succinylcholine in the absence of significant
adverse effects has also been reported in moderately hyper-
kalemic patients.140 Rocuronium is an acceptable alternative
to succinylcholine for rapid-sequence induction if a longer
paralysis can be accepted. Kidney disease does not affect the
response to a single dose of rocuronium. The elimination of
rocuronium is mainly biliary, although 26% renal excretion
Chapter 7  Renal Diseases 245
Use with Caution Avoided
Enflurane Methoxyflurane
Sevoflurane
Thiopental Diazepam
Propofol Lorazepam
Midazolam
Morphine Meperidine
Hydromorphone
Vecuronium Pancuronium
Succinylcholine Doxacurium
Rocuronium
has been measured in humans.141 Its duration of action is only
slightly prolonged after repeat doses.142 Indeed, the plasma
clearance of rocuronium is not affected by renal dysfunction,
although the volume of distribution is increased, resulting in
a longer half-life.
Pancuronium has an increased half-life when creatinine
clearance is lower than 50 mL/min,143 and therefore its pro-
longed or repeat administration should be avoided. Because
alternative muscle relaxants are less affected by renal dys-
function, pancuronium is usually avoided in these patients.
Vecuronium is mainly biotransformed and excreted by the liver,
with only 15% renal excretion. However, its duration of action
is prolonged in patients with ESRD because of decreased clear-
ance, increased response to blood concentrations, and accu-
mulation of the active metabolite 3-desacetyl-vecuronium.144
Although the prolonged infusion of vecuronium for muscle
relaxation in the intensive care unit should be avoided, its
intraoperative use in patients with CKD is safe, provided that
the appropriate dose adjustments and neuromuscular moni-
toring are implemented.
Doxacurium, another nondepolarizing muscle relaxant, is
mainly excreted by the kidney, and the time to recovery from
muscle relaxation is significantly increased in patients with
creatinine clearance less than 40 mL/min.145 Atracurium and
its isomer cisatracurium are the most attractive options for
patients with kidney dysfunction. In particular, cisatracurium
is more potent and leads to less histamine liberation than atra-
curium and thus has become popular. Both drugs undergo
non–organ-dependent elimination by the Hoffman reaction,
with a non–dose-dependent clearance, and with production
of laudanosine.146 Although accumulation of laudanosine
caused cerebral irritation in experimental models, there are
no reports of seizures caused by cisatracurium in humans.147
Even when the elimination of muscle relaxant is prolonged
from renal failure, the use of reversal agents is still safe because
these drugs undergo significant renal excretion (50% with neo-
stigmine), and their duration of action is prolonged by renal
dysfunction.148 In addition, reversal of muscle relaxation with
neostigmine is not delayed after a single dose of vecuronium.149
 246 ANESTHESIA AND UNCOMMON DISEASES
MAINTENANCE AND POSTOPERATIVE PERIOD
Although most IV agents used during anesthesia and postop-
eratively undergo hepatic metabolism, some undergo trans-
formation to active metabolites that are renally excreted and
may accumulate during renal failure. This effect is more sig-
nificant after prolonged use, such as in the postoperative
period. Morphine undergoes 10% conjugation to morphine-6-
glucuronide, a molecule with very high potency that rap-
idly accumulates in the cerebrospinal fluid of patients in
renal failure,150 and this may lead to significant sedation.
Morphine-6-glucuronide has significant interindividual vari-
ability, probably because of genetic polymorphism at the opi-
oid receptor,151 and has a delayed onset, probably from a slow
transfer through the hematoencephalic barrier.152 Morphine-6-
glucuronide can be cleared by hemodialysis. Similar to mor-
phine, meperidine is transformed to neurotoxic metabolites
and should be used with care or avoided. Remifentanil, fen-
tanyl, and alfentanil do not have active metabolites and are
well tolerated in patients with kidney disease.
Among the benzodiazepines, midazolam, lorazepam, and
diazepam are transformed to renally excreted metabolites and
should be used with care, particularly during postoperative
sedation. Also, current lorazepam formulations contain pro-
pylene glycol, a renally excreted toxic substance that accu-
mulates after prolonged high-dose administration in patients
with renal failure.153 The use of total intravenous anesthesia
with propofol, remifentanil, and cisatracurium has been pro-
posed for renal patients and is probably safe.154,155
Regional anesthesia is often chosen in renal patients, par-
ticularly for peripheral procedures such as creation of AV fis-
tulas, for which brachial plexus blocks are a popular choice.
Central neuraxial blockade can be used safely, provided the
anesthesiologist remembers that renal patients are prone to
hemodynamic instability and hypotension when sympathetic
blockade is superimposed to pre-existing autonomic dys-
function. The occurrence of epidural hematoma after neur-
axial block has been reported in a patient with CKD,155 and a
high index of suspicion should be maintained. However, this is
probably a rare event in patients who are adequately dialyzed.
Anesthetic Effects on Renal Function
The evidence that some inhalational anesthetic agents can
lead to altered renal function has raised the concern that renal
morbidity may be caused by these agents. Both methoxyflu-
rane and enflurane have been shown to cause impairment in
urine-concentrating ability and ADH-resistant polyuria.156–158
This effect has been ascribed to both these gases being highly
biotransformed, because the minimally metabolized isoflu-
rane and desflurane are not associated with renal effects159,160
even when they are administered for an extended time.161
Renal injury from anesthetic gases is related to liberation
of inorganic fluoride.162 Experimental studies show that flu-
oride damages the collector duct cell and crystal deposition
at the mitochondrial level, probably resulting in impairment
of Na+,K+-APTase and water resorption.163 Based on animal
dose-response curves, a critical fluoride level of 50 μM is con-
sidered toxic to the kidney.164 Sevoflurane has been associated
with liberation of fluoride near the toxic range.165,166 Alterations
in sensitive biochemical markers of altered renal function have
been observed when sevoflurane was administered to healthy
volunteers, compared with desflurane.167 However, no altera-
tions in BUN or creatinine were observed with sevoflurane in
these volunteers. Multiple clinical studies have failed to show
clinically significant renal function alterations after adminis-
tration of sevoflurane.166–169 This discrepancy between sevoflu-
rane and methoxyflurane, despite comparable serum fluoride
levels, may be explained by the faster clearance of sevoflurane,
which results in shorter exposure of renal cells to increased
fluoride. However, the finding that methoxyflurane, and not
sevoflurane, undergoes significant microsomal biotransfor-
mation in the kidney, with resulting higher intraparenchymal
fluoride concentrations, may explain why actual renal injury
does not seem related to serum fluoride concentrations.170
Sevoflurane is degraded to the vinyl ether named com-
pound A when administered at low, fresh gas flow (<1 L/min)
and particularly when baralyme absorbers of smaller size
are used. Compound A induces dose-related nephrotoxic-
ity in animal models,171 and the concern that toxic blood lev-
els are possible in humans undergoing low-flow sevoflurane
anesthesia has resulted in a warning by the U.S. Food and
Drug Administration against the use of sevoflurane at fresh
gas flows less than 2 L/min. However, there is little evidence
that sevoflurane leads to clinically significant renal alterations
compared with other inhaled anesthetic agents, as observed
by Mazze et al.172 in a retrospective analysis of 1941 patients
undergoing sevoflurane anesthesia. This can be explained
by compound A levels in humans being well below the lev-
els observed in animal studies, and human kidney is probably
less sensitive to this substance than rat kidney because of dif-
ferent biotransformation. The concern that sevoflurane might
exacerbate pre-existing renal disease has also been raised.
However, renal toxicity has not been detected when sevoflu-
rane was administered in patients with renal insufficiency
with a relatively high flow of 4 L/min.173
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161. Kong KL, Tyler JE, Willatts SM, et  al: Isoflurane sedation for patients
undergoing mechanical ventilation: metabolism to inorganic fluoride
and renal effects, Br J Anaesth 64:159–162, 1990.
162. Taves DR, Fry BW, Freeman RB, et  al: Toxicity following methoxyflu-
rane anesthesia. II. Fluoride concentrations in nephrotoxicity, JAMA 21:
91–95, 1970.
163. Cittanova ML, Lelongt B, Verpont MC, et  al: Fluoride ion toxicity
in human kidney collecting duct cells, Anesthesiology 84:428–435,
1996.
164. Cousins MJ, Mazze RI: Methoxyflurane nephrotoxicity: a study of dose
response in man, JAMA 225:1611–1616, 1973.
165. Kobayashi Y, Ochiai R, Takeda J, et al: Serum and urinary inorganic fluo-
ride concentrations after prolonged inhalation of sevoflurane in humans,
Anesth Analg 74:753–757, 1992.
166. Frink EJ Jr, Ghantous H, Malan TP, et al: Plasma inorganic fluoride with
sevoflurane anesthesia: correlation with indices of hepatic and renal
function, Anesth Analg 74:231–235, 1992.
167. Eger EI 2nd, Gong D, Koblin DD, et  al: Dose-related biochemical
markers of renal injury after sevoflurane versus desflurane anesthesia
in volunteers, Anesth Analg 85:1154–1163, 1997.
168. Smith I, Ding Y, White PF: Comparison of induction, maintenance, and
recovery characteristics of sevoflurane-N2O and propofol-sevoflurane-N2O
with propofol-isoflurane-N2O anesthesia, Anesth Analg 74:253–259, 1992.
169. Hara T, Fukusaki M, Nakamura T, et al: Renal function in patients dur-
ing and after hypotensive anesthesia with sevoflurane, J Clin Anesth
10:539–545, 1998.
170. Kharasch ED, Hankins DC, Thummel KE: Human kidney methoxyflu-
rane and sevoflurane metabolism. Intrarenal fluoride production as a
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82:689–699, 1995.
171. Gonsowski CT, Laster MJ, Eger EI 2nd, et al: Toxicity of compound A
in rats: effect of increasing duration of administration, Anesthesiology
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172. Mazze RI, Callan CM, Galvez ST, et  al: The effects of sevoflurane on
serum creatinine and blood urea nitrogen concentrations: a retrospec-
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173. Conzen PF, Nuscheler M, Melotte A, et al: Renal function and serum flu-
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 C H A P T E R
8
Neurologic Diseases

BENJAMIN K. SCOTT, MD  n

DIMITRY BARANOV, MD  n

Hereditary Peripheral Neuropathies KEY POINTS

Primary Hereditary Motor and Sensory Neuropathies, n Hereditary motor and sensory neuropathies (HMSNs) are
Including Charcot-Marie-Tooth Disease
disorders of myelination of the peripheral nervous sys-
Hereditary Sensory and Autonomic Neuropathies
tem resulting in progressive loss of motor and sensory
Neurodegenerative Disorders with Autonomic Failure
function.
Multiple System Atrophy
n In familial dysautonomia (HSAN-III), anesthesia manage-
Pure Autonomic Failure
ment is directed at prevention and prompt treatment of
Basal Ganglia and Cerebellar Disorders
dysautonomic crises.
Parkinson's Disease
n Multiple system atrophy is a new term synonymous with
Huntington's Disease (Chorea)
Shy-Drager syndrome, striatonigral degeneration, and
Sydenham's Chorea (Rheumatic Chorea)
olivopontocerebrellar atrophy.
Dystonias
n Parkinson's disease symptoms include tremor, bradykine-
Diseases of Myelin
sia, rigidity, and postural instability; medical management
Multiple Sclerosis
restores dopaminergic versus cholinergic balance.
Nitrous Oxide–Induced Subacute Combined Degeneration
n Huntington's disease is characterized by choreoathe-
Peripheral Nerve Disease and the Polyneuropathies
toid movements (butyrophenones and phenothiazines
Guillain-Barré Syndrome
may temporarily alleviate), dementia, and psychiatric
Motor Neuron Diseases
disturbances.
Amyotrophic Lateral Sclerosis
n Sydenham's chorea is an acute manifestation of rheumatic
Friedreich's Ataxia
fever.
Spinal Muscular Atrophy
n Dystonias are a broad group of movement disorders in
Neuroectodermal Disorders
which sustained involuntary muscle contractions lead to
Neurofibromatoses
abnormal postures or repetitive movements.
von Hippel–Lindau Disease
n Multiple sclerosis has an unpredictable pattern of relapse,
Tuberous Sclerosis
which may coincide with postoperative recovery.
Sturge-Weber Syndrome
n Guillain-Barré syndrome is characterized by ascending
Posterior Fossa Anomalies and Arnold-Chiari
Malformations paralysis with areflexia.
Chiari I Malformation n Neurofibromatosis is a multisystem disease requiring a
Chiari II Malformation, Myelomeningocele, and multidisciplinary surgical team for optimal outcomes.
Hydrocephalus n Multisystem von Hippel–Lindau disease is characterized by
Klippel-Feil Syndrome and Other Cervical Spine CNS lesions combined with pheochromocytoma and renal
Disorders of Childhood cell carcinoma; most patients require neurosurgical pro-
Mucopolysaccharidoses cedures or surgery for removal of pheochromocytoma or
renal cell carcinoma.

251
 252 ANESTHESIA AND UNCOMMON DISEASES
n Tuberous sclerosis is also a multisystem disease, ide-
ally requiring multidisciplinary team management; most
patients require surgical procedures or imaging studies
during childhood and typically have various degrees of
mental retardation.
n Sturge-Weber syndrome is a rare congenital (not heritable)
vascular disorder of unknown etiology marked by facial
angioma (port-wine stain) and leptomeningeal angioma.
n Chiari malformation type I patients should be evaluated
for degree of brainstem compression, cranial nerve involve-
ment, spinal cord compression, and increased intracranial
pressure.
n In patients with Klippel-Feil syndrome, main consideration
is catastrophic cervical spinal cord injury during induction
of anesthesia and positioning.
n Mucopolysaccharidoses can trigger new, potentially cata-
strophic neurologic complications; a difficult to impossible
airway is the central concern.
n Further anesthetic issues are detailed for specific neuro-
logic diseases in the boxes.
Neurologic disorders represent a unique challenge to anesthe-
siologists by affecting the same biosubstrate targeted by anes-
thetic agents to produce the state of anesthesia. The direct
consequence of neurologic disorders is often dramatically
altered pharmacodynamics of anesthetics. Anesthetic agents
are also in essence reversibly neurotoxic, and thus their use
in patients with already-compromised neurologic function
might lead to further deterioration of existing symptomatol-
ogy. Monitoring the recovery of neurologic function from the
effects of anesthesia is further complicated in patients with
neurologic deficits. Many neurologic disorders also are very
rare, with only minimal or no anesthesia experience reported
in the literature.
This combination of factors in neurologic patients demands
maximum caution and planning in the administration of anes-
thesia. The last two decades have seen rapid development in
the understanding of genetic mechanisms and the underlying
pathophysiology of many neurologic conditions, which in turn
has led to better management of these disorders. It also helped
to create newer, more precise classifications for many classes
of neurologic disorders, guided more by etiology and patho-
physiology than by pure symptomatology. However, signifi-
cant overlap still exists between different classes of neurologic
disorders, which is further complicated by cross-referencing
to older eponymic classification. This chapter groups different
disorders by the commonality of their anesthesia and periop-
erative challenges.
HEREDITARY PERIPHERAL NEUROPATHIES
Inherited disorders of peripheral nerves are a part of a much
larger group of inherited or acquired polyneuropathies that
often coexist with systemic, infectious, and metabolic diseases
(e.g., diabetes mellitus, thyroid disease, neoplastic syndromes)
or are caused by exposure to various agents (e.g., heavy met-
als, alcohol, certain medications). As such, the hereditary
neuropathies are a common and diverse group of genetically
determined neurologic diseases. They are primarily charac-
terized by a dysfunction of peripheral sensory neurons in the
presence of additional muscle weakness or autonomic system
dysfunction. However, a dysfunction of the central nervous
system (CNS) and other organ systems is more prominent in
some types of hereditary neuropathies, which is of special rel-
evance to the anesthesiologist treating these patients.
Historically, classification of the hereditary peripheral neu-
ropathies was primarily based on clinical manifestations and
eponyms were used to designate a specific combination of
clinical symptoms (e.g., Riley-Day syndrome, Charcot-Marie-
Tooth disease). However, significant phenotypic variability
led to nosologic confusion. Modern classification of heredi-
tary neuropathies is based on clinical and electrophysiologic
characteristics, modes of inheritance, and underlying genetic
mutations. The hereditary neuropathies are usually divided
into three major groups according to their main clinical mani-
festation: predominantly motor involvement, predominantly
sensory or autonomic involvement, or neither. These major
groups are further divided into types (usually based on dif-
ferences in clinical presentation, pathology, nerve conductiv-
ity studies) and subtypes (based on genetic characteristics).
Table 8-1 summarizes some of the more prevalent hereditary
types of polyneuropathy; a comprehensive description can be
found in a recent review.1
As in the previous edition of this textbook, this chapter con-
tinues to use the modern classification, with cross-­referencing
to traditional eponyms. All major medical reference databases
use this classification, and patients in clinical anesthesia prac-
tice increasingly are diagnosed according to this terminol-
ogy, which is widely accepted in the mainstream neurologic
practice.
Primary Hereditary Motor and Sensory
Neuropathies, Including Charcot-Marie-Tooth
Disease
The hereditary motor sensory neuropathies (HMSNs) repre-
sent a spectrum of disorders caused by a specific mutation in
one of several myelin genes that results in defects in myelin
structure, maintenance, and formation. The association of dif-
ferent mutations within the same gene with various clinical
phenotypes is a common finding in this group of peripheral
neuropathies. This variability suggests that these disorders rep-
resent a spectrum of related phenotypes caused by an under-
lying defect in peripheral nervous system myelination. The
HMSNs, otherwise known as Charcot-Marie-Tooth disease
(CMTD), have been classified as types 1 to 7, which are further
subdivided, thus consisting of close to 30 clinical syndromes;
the vast majority are very rare and have never been reported
in the anesthesia literature. Because of the paucity of rele-
vant anesthesia data on currently identified phenotypes, only
Charcot-Marie-Tooth types 1 and 2 (CMT-1 and CMT-2) and
 Chapter 8  Neurologic Diseases 253

TABLE 8-1  n  Hereditary Peripheral Neuropathies*

Clinical Manifestations/Underlying Electrophysiologic

HMSN/HSAN Type Pathology Inheritance Patterns Findings

HEREDITARY PRIMARY MOTOR AND SENSORY NEUROPATHIES (HMSNs)

HMSN type 1 (Charcot-Marie-Tooth Demyelinating disorder, distal weakness, Autosomal dominant Moderate to severe
disease type 1, CMT-1): five onset in 1st-2nd decade of life, slow reduction in nerve
subtypes identified progressing, “onion bulbs” conduction velocities

HMSN type 2 (Charcot-Marie-Tooth Neuroaxonal (not demyelinating) Autosomal dominant Normal to mildly reduced
disease type 2, CMT 2): eight disorder, distal weakness, slow nerve conduction
identified subtypes progressing velocities

HMSN type 3 (Dejerine-Scottas Demyelinating disorder, severe Autosomal dominant Severe reduction in nerve
or congenital hypomyelinating hypotonia in early childhood or at conduction velocities
syndrome): three identified subtypes birth, “onion bulbs”

HMSN type 4: seven identified Large group of disorders, typically Autosomal recessive Severe reduction
subtypes with early, severe presentation and or absent nerve
rapidly progressing, demyelinating, conduction velocities
sometimes prominent sensory deficit

HEREDITARY PRIMARY SENSORY AND AUTONOMIC NEUROPATHIES (HSANs)

HSAN type 1 (hereditary sensory Small axon loss, acromutilation Autosomal dominant
radicular neuropathy)

HSAN type 2 (congenital sensory Large and small axon loss Autosomal recessive
neuropathy)

HSAN type 3 (Riley-Day syndrome or Large and small axon loss, with Autosomal recessive
familial dysautonomia) dysautonomic crises, lack
lacrimation

HSAN type 4 (congenital insensitivity Congenital sensory neuropathy with Autosomal recessive
to pain with anhidrosis) anhidrosis, C-axon loss (see text)

*Inherited neuropathies other than HMSN/HSAN include hereditary neuropathy with pressure palsy, hereditary brachial plexopathy, and giant axonal neuropathy.

HMSN type 3, which together are the most common heredi-
tary peripheral neuropathies,2 are discussed here. Combined
prevalence is almost 40 per 100,000 population.
Pathophysiology and Diagnosis. HMSN type 1, or CMT-1,
is a demyelinating disorder of peripheral nerves that most
often presents in the first or early-second decade of life,
although infants can also be affected.3 Significant family his-
tory is typical. Diffuse slowing of nerve conduction veloc-
ity and gradually progressing distal muscle weakness with
early loss of coordination characterize CMT-1. It is associ-
ated with loss of reflexes, talipes (pes) cavus, and hammer
toe. Later, distal calf atrophy develops (classic “stork leg”
deformity), in combination with gradual loss of propriocep-
tion and sense of vibration. Abnormal concentric myelin for-
mations are called “onion bulbs” and are found around the
peripheral axons. These are a characteristic feature of CMT-1,
usually revealed by sural nerve biopsy. The CMT-1A
­subgroup of patients may present with proximal muscle wast-
ing and weakness. Dematteis et al.4 also observed obstructive
sleep apnea (OSA) in this subtype of patients, with a high
degree of correlation between the severity of neuropathy and
degree of obstruction. Even later changes include atrophy
of the intrinsic hand and foot muscles, footdrop, palpable
hypertrophy of the peripheral nerves, and possible scolio-
sis and kyphosis. Disease exacerbation may occur in preg-
nancy.5 Life expectancy is unaffected.
Type 2 HMSN, or CMT-2, also called axonal CMT, is a
heterogeneous disorder with normal or borderline nerve
conduction velocity. It is primarily an axonal, not a demy-
elinating, disorder, with neuropathy the result of neuro-
nal death and wallerian degeneration (no onion bulbs on
biopsy). The clinical course is similar to that of CMT-1, but
sensory symptoms predominate over motor symptoms, and
peripheral nerves are not palpable. Patients with CMT-2 C
subtype display significant vocal cord and diaphragmatic
weakness, resulting in OSA, which is of concern to the anes-
thesiologist.6 Onset is usually in the second or third decade
of life, but can be seen in early childhood, with rapid clinical
progression.
Type 3 HMSN includes two syndromes: D ­ ejerine-Sottas
syndrome and congenital hypomyelinating neuropathy (CHM).
Both are characterized by profound hypotonia, presenting in
early infancy or at birth, in the case of CHM. Dejerine-Sottas
syndrome is clinically similar to CMT-1, although its manifesta-
tions are more severe and appear in early childhood.
 254 ANESTHESIA AND UNCOMMON DISEASES
The preoperative evaluation and preparation of HMSNs
may be complicated because of similarity in clinical pre-
sentation with other genetic or acquired polyneuropathies
(Box 8-1).
No specific treatments for HMSNs are available. Symp­
tomatic supportive care consists of orthopedic corrective joint
procedures for talipes cavus and scoliosis deformities and
physical and occupational therapy. Orthopedic procedures are
usually staged, ranging from soft tissue procedures and osteot-
omy to triple arthrodesis. Multiple administrations of general
or regional anesthesia might be required.
Preoperative preparation of patients with HMSNs is dic-
tated by the extent of clinical involvement and coexisting mor-
bidities. The degree of motor neurologic involvement should
be evaluated and affected muscle groups noted. Atrophic
denervated muscles usually display significant resistance to
nondepolarizing muscle relaxants and are unreliable for mon-
itoring of neuromuscular blockade (NMB).
Patients with CMT-1 and CMT-2 C should be evaluated
for restrictive pulmonary disease related to scoliosis and dia-
phragmatic weakness and potential OSA. Respiratory insuf-
ficiency has been described in patients with CMT.7-9 Careful
planning for extubation and a possible need for postopera-
tive respiratory support may be necessary in these patients.
Patients with HMSNs may have undetected cardiac conduc-
tion abnormalities.10,11 Although this association is not strong,
all patients with an HMSN should have a preoperative ECG.
Pregnancy often leads to exacerbation of the symptoms of
CMTD and, in combination with diaphragmatic splitting, can
lead to respiratory compromise.9
BOX 8-1   n DIFFERENTIAL DIAGNOSIS OF HEREDITARY
MOTOR SENSORY NEUROPATHIES
Genetic Neuropathies
Refsum's disease
Metachromatic leukodystrophy
Familial brachial plexus neuropathy
Adrenomyeloneuropathy
Pelizaeus-Merzbacher disease
Amyloid neuropathies
Acquired Neuropathies
Metabolic Disease
Diabetes mellitus
Thyroid disease
Vitamin B12 deficiency
Infectious Disease
Neurosyphilis
Leprosy
Human immunodeficiency virus
Other Diseases
Chronic alcoholism
Heavy-metal intoxications
Vasculitis
Neoplastic syndromes
Chronic inflammatory demyelinating polyneuropathy
ANESTHETIC CONSIDERATIONS
The anesthetic experience for HMSN types 1, 2, and 3 is
limited to a number of case reports9,10,12-21 and retrospective
reviews.22,23 Despite the absence of strong evidence advocating
for or against the use of specific anesthetic agents or particular
anesthetic techniques, a number of important concerns have
been raised in the literature regarding anesthetic management
of these patients (Box 8-2).
Drugs triggering malignant hyperthermia (MH) have
been used in patients with CMTD without complication.22,23
However, in two reports of MH during general anesthesia in
CMTD patients, the authors advocate against the use of suc-
cinylcholine and volatile agents.15 Furthermore, an approach
postulating that any patient with a neuromuscular disease
should be considered to be at increased risk for MH adds to
this controversy. The review of the available literature describ-
ing anesthesia management in patients with HMSN indicates
that most authors prefer to avoid administering MH-triggering
agents in patients with HMSN types 1, 2, and 3, partly because
of medicolegal considerations.
Succinylcholine use in these patients is associated with
increased risk of malignant arrhythmias secondary to exag-
gerated hyperkalemic response.24 Although succinylcholine
has been used in CMTD without untoward effects,22,23 it seems
appropriate to avoid its use in any patient with suspected mus-
cular denervation.
Nondepolarizing muscle relaxants have been used success-
fully in patients with HMSNs without indications of prolonged
BOX 8-2   n HEREDITARY PERIPHERAL NEUROPATHIES:
ANESTHETIC ISSUES
Hereditary Motor and Sensory Neuropathies (HMSNs)
Informed consent regarding the effect of anesthetic agents on the
course of the disease is difficult to provide because of a lack of
conclusive evidence in the literature.
Thorough preoperative interview and maximal patient participation
regarding the choice of anesthetic technique are advisable,
combined with detailed documentation of these discussions.
Neuroaxial and regional anesthesia are not contraindicated, but lower
concentrations of local anesthetic and careful titration are advisable.
Patients with advanced disease have increased risk of perioperative
respiratory depression and sleep apnea.
Avoid monitoring neuromuscular blockade at the affected muscles to
avoid overdose.
Use of depolarizing muscle relaxants should be avoided when
possible in patients with HMSNs.
Hereditary Sensory and Autonomic Neuropathies: Familial
Dysautonomia (HSAN-III)
Preoperative and intraoperative maintenance of euvolemia is critical
to prevent severe hypotonic episode.
Invasive intraoperative hemodynamic monitoring is recommended, as
dictated by degree of autonomic dysfunction and type of surgery.
Prolonged postoperative ventilatory support might be needed,
especially in patients with compromised respiratory function.
Rapid-sequence induction should be considered in patients with a
history of aspiration and gastroesophageal reflux.
Tight body temperature control is important the HSAN-III patient.

duration of action.22,23,25,26 However, some authors express rea-
sonable concern that adequate monitoring of NMB could
be complicated because of altered responses on the affected
muscles, which are not always obvious during clinical assess-
ment.27 Additionally, there is at least one case report of pro-
longed neuromuscular block with vecuronium.28 Inadequate
reversal of NMB in patients with pre-existing respiratory
compromise can lead to serious complications. Some advocate
avoiding the use of nondepolarizing muscle relaxants in such
patients whenever possible.12,14,18
Neuroaxial anesthetic techniques have been success-
fully used in patients with HMSN without untoward effects,
including for vaginal delivery and cesarean section.9,17,18,20,29,30
However, some authors correctly point out that medicole-
gal concerns must be considered when designing anesthesia
plans for these patients.9,18 Despite lack of evidence that anes-
thesia affects the course of pre-existing neuromuscular dis-
ease, regional anesthesia may be erroneously blamed for any
subsequent deterioration in sensory or motor deficits. This is
especially true in pregnancy, which as noted, is associated with
exacerbation of neurologic symptoms in women with CMTD.
Additionally, the choice between general or regional/neurax-
ial anesthesia in patients with CMTD complicated by respira-
tory compromise is guided by the preservation of respiratory
function in the perioperative period. In patients with phrenic
nerve involvement, whose respiration depends on accessory
muscles, regional block involving intercostal muscles can lead
to acute respiratory failure.31 In other case reports, however,
patients with CMTD required prolonged respiratory support
after general anesthesia.32,33
Patients with CMT-1 have demonstrated increased sen-
sitivity to thiopental, correlating with the degree of motor
and sensory deficit.34 However, propofol and total intrave-
nous anesthesia (TIVA) have been successfully used in these
patients without untoward effects.13,16
Anesthetic management in the vast majority of patients
with HMSN appears to be uncomplicated and should be
directed to accommodate any coexisting systemic conditions.
However, detailed preanesthesia assessment and thorough
documentation of informed consent, with maximum patient
participation in the decision-making process on choice of
anesthesia technique, are crucial.
Hereditary Sensory and Autonomic Neuropathies
The hereditary sensory and autonomic neuropathies (HSANs)
are a diverse and constantly expanding group of disorders
affecting the development of autonomic and sensory neu-
rons. Until recently, seven such disorders have been described,
with familial dysautonomia (HSAN type III), also known as
Riley-Day syndrome, and HSAN type IV, also known as con-
genital insensitivity to pain with anhidrosis (CIPA), the most
recognized and well understood. All HSANs are manifested
by both sensory and autonomic dysfunction present at vari-
able degrees, with a unique feature for all types being absence
of a normal axon flare response after intradermal injection of
Chapter 8  Neurologic Diseases 255
histamine phosphate. The reported anesthetic experience for
HSANs is limited to anesthesia management of patients with
familial dysautonomia (HSAN-III) and CIPA (HSAN-IV).
The clinical presentation, diagnosis, and management of other
HSANs have been reviewed.35
FAMILIAL DYSAUTONOMIA (HSAN TYPE III, OR RILEY-DAY
SYNDROME)
Familial dysautonomia (FD) is a rare genetic disorder that
affects, almost exclusively, persons of Ashkenazi Jewish
extraction. It is the most prevalent and well studied of all
HSANs. Development of autonomic and sensory neurons is
impaired, resulting in reduced population of nonmyelinated
and small-diameter myelinated axons. The sympathetic neu-
rons are primarily affected, and sympathetic ganglia are small.
The parasympathetic neurons and large axons are generally
spared. FD presents at birth and progresses with age. In the
past, more than 50% of patients died before 5 years of age.
Currently, because of improvements in diagnosis and treat-
ment, newborns diagnosed with FD have a greater than 50%
chance to live past age 30.
Although FD has close to 100% penetrance, the presen-
tation of the disease at different life stages is highly variable.
Autonomic dysfunction is the most prominent feature, present-
ing the greatest impediment to normal functioning, and usu-
ally overshadows the sensory deficits. Dysautonomic crisis is
the most dramatic feature of this syndrome, characterized by
episodes of severe nausea and vomiting associated with agita-
tion, hypertension, tachycardia, excessive sweating, and sali-
vation, which are easily triggered by emotional or physical
stress, or arousal from sleep.
The clinical diagnosis of FD is usually established soon
after birth by demonstrating the presence of four main cri-
teria: absence of tears with emotional crying, absence of
lingual fungiform papillae, hypotonic or absent patellar
reflexes, and absence of axon flare to intradermal injection
of histamine in children of Ashkenazi Jewish descent. Many
other systems are affected at various stages in life, and the
myriad of clinical manifestations of FD can be divided into
two main groups: sensory dysfunction and autonomic dys-
function (Box 8-3). Differential diagnosis typically does not
present a problem, considering availability of genetic testing
and the fact that this disease is restricted to Ashkenazi Jews.
However, many other conditions have some similar symp-
toms of autonomic and sensory dysfunction. All HSANs,
cranial nerve and nuclear dysplasias, cri du chat (cat's cry)
syndrome, and Möbius syndrome can have some of the fea-
tures found in FD. Many eye conditions have similar ocular
manifestations with those of FD.
Treatment of FD patients is symptomatic. Diazepam is the
most effective treatment for dysautonomic crisis with vomit-
ing. It also normalizes blood pressure and heart rate in these
patients. Increased salt and fluid intake is used to treat dehy-
dration and hyponatremia and associated postural hypoten-
sion. Fludrocortisone and midodrine are also used for this
purpose. Surgical procedures performed on these patients
 256 ANESTHESIA AND UNCOMMON DISEASES
BOX 8-3   n FAMILIAL DYSAUTONOMIAS: SENSORY AND AUTONOMIC DYSFUNCTION
Sensory System
Decreased pain sensation, often with hypersensitivity of palms, sole,
neck, and genital areas; decreased temperature sensation.
Visceral sensation is intact.
Sense of vibration and proprioception is affected in older individuals;
ataxia.
Hypotonia in younger children; often disappears with age; decreased
tendon reflexes.
Prone to self-injury; unrecognized fractures; scoliosis and joint
deformities.
Autonomic System
Gastrointestinal System
Impaired oropharyngeal coordination and impaired swallowing, resulting
in dysphagia and frequent aspirations in newborns and infants.
Abnormal esophageal motility; decreased lower esophageal sphincter
pressure and esophageal reflux.
Gastrointestinal dysmotility, complicated by cyclic vomiting (part of
dysautonomic crisis).
Respiratory System
Recurrent pneumonias result from aspirations.
Insensitivity to hypoxia and hypercapnia (no ventilatory response).
Low tolerance for hypoxia; profound hypotension and bradycardia in
response to hypoxia.
Cardiovascular System
Rapid, severe orthostatic hypotension without compensatory
tachycardia.
Episodes of severe hypertension and tachycardia as part of
dysautonomic crisis.
Syncopal episodes produced by various stimuli (e.g., full bladder, large
bowel movement).
include gastrostomy in the majority of patients before age
5 years, to provide fluid and alimentation in patients with
dysphagia; fundoplication for treatment of gastroesophageal
reflux (GER) and associated pneumonia; and spinal fusions
for severe scoliosis.
ANESTHETIC CONSIDERATIONS
Anesthesia for surgical procedures had been associated with
great risks in patients with FD.36-38 Recent progress in the
understanding of existing risks and improved preoperative
preparation resulted in significantly improved perioperative
outcomes.39-42 Good working knowledge of FD manifesta-
tions and a systematic approach to preoperative assessment
are essential for successful anesthetic management of these
patients (see Box 8-2).
The respiratory system should be evaluated for signs of
chronic or acute infections from repeated aspirations. Chest
radiography is warranted in all patients. In patients with
restrictive pulmonary disease caused by chronic pneumonias
and scoliosis, arterial blood gas (ABG) analysis is included.
Severe intraoperative hypotonia is a well-recognized risk
of general anesthesia.36-38 Cardiac output depends on preload
because of a lack of compensatory sympathetic response to
hypotonia. Correction of existing dehydration and hypona-
tremia is essential for intraoperative hemodynamic stability in
Postural hypotension.
Postural hypertension can develop in older patients.
Dysautonomic Crisis
Episodes of severe nausea and vomiting associated with agitation,
hypertension, tachycardia, and excessive sweating/salivation.
Easily triggered by emotional or physical stress and arousal from sleep.
Other Manifestations
Renal System
Dehydration azotemia.
Progressive loss of renal function with age.
Central Nervous System/Developmental
Emotional lability, probably related to catecholamine imbalance.
Prolonged breath holding with crying, decerebrate posturing, syncope,
cyanosis; may be misinterpreted as seizures.
Normal intelligence.
Delayed development.
Ocular Manifestations
Absence of overflow tears with emotional crying in all patients.
Corneal insensitivity; abrasions and spontaneous injuries; ulcers.
Optic neuropathy increases with age.
Laboratory Findings
Elevated blood urea nitrogen (BUN).
Hyponatremia associated with excessive sweating.
Catecholamine imbalance: elevated dopa/DHPG ratio.
Dopa, 3,4-Dihydroxyphenylalanine; DHPG, 3,4-Dihydroxyphenylglycol.
these patients. Intravenous (IV) prehydration with crystalloids
is often recommended to achieve euvolemic status preopera-
tively.42,43 Patients are evaluated for the presence and severity of
GER; antacids need to be administered preoperatively to affected
patients. Renal function is assessed to rule out significant renal
failure, which can affect the choice of muscle relaxants. Patients
with FD are prone to anticipation anxiety that can trigger dysau-
tonomic crisis. Preoperative medication with benzodiazepines is
recommended. Preoperative medication with opioids is contra-
indicated because of possible increased sensitivity to the agents.
Intraoperative management of FD patients is directed
toward better cardiovascular stability, prevention of pulmo-
nary aspiration, prevention of postoperative respiratory com-
promise, and adequate postoperative pain control. Invasive
hemodynamic monitoring (intra-arterial line and central
venous catheters) has been advocated in the past but was
not used in one reported series without untoward effects.39,42
It appears reasonable to use invasive monitoring in patients
with postural hypotension and for extensive surgery with
large fluid shifts. Immediate preinduction administration of
fluid bolus can reduce blood pressure (BP) variation. BP insta-
bility intraoperatively is treated by additional fluid boluses
and direct-acting vasopressors, if the patient is unresponsive
to administration of fluids. Any episodes of desaturation are
promptly addressed by increased oxygen concentration to

avoid profound hypotension and bradycardia from lack of
hypoxic compensatory responses.
Rapid-sequence induction with cricoid pressure should
be considered in patients with GER and a history of repeated
aspirations.
Careful planning for extubation, postoperative ventilatory
support, and weaning from the respirator in the intensive care
unit (ICU) should be part of the routine postoperative man-
agement for these patients. In the past, FD patients frequently
required prolonged ventilation in the ICU setting after general
anesthesia. Reports indicate that with alternative techniques,
such as epidural39 or local anesthesia, or deep propofol seda-
tion with spontaneous ventilation,42 these patients can recover
from anesthesia quickly without need for postoperative respi-
ratory support.
Although patients with FD have decreased perception of
pain and temperature, their visceral perception is intact, and
they need sufficient levels of anesthesia and postoperative
pain control. Postoperative pain should be promptly treated
to avoid dysautonomic crisis. Nonsteroidal anti-inflammatory
drugs (NSAIDs) or paracetamol will suffice in many cases.
Opioids should be used cautiously to avoid respiratory depres-
sion. Regional techniques can be useful.39
There have been no reports of adverse or prolonged
responses of FD patients to any specific anesthetic agents or
muscle relaxants. For appropriate surgical procedures, regional
anesthesia is well tolerated.39 Use of deep propofol sedation for
endoscopic outpatient procedures has been reported, with excel-
lent results.42 Body temperature needs to be carefully monitored
because of impaired temperature control in these patients. The
eyes should be lubricated and protected at all times.
Familial dysautonomia is a serious anesthetic challenge that
can be hazardous in these patients without proper preopera-
tive preparations and intraoperative management. However,
current approaches have resulted in significantly reduced
mortality and morbidity in FD patients.
CONGENITAL INSENSITIVITY TO PAIN WITH ANHIDROSIS
Pathophysiology and Diagnosis. Congenital insensi-
tivity to pain with anhidrosis, or HSAN type IV, is a rare
autosomal recessive neuropathy characterized by recur-
rent episodic fever, anhidrosis (absence of sweating), pain
insensitivity, self-mutilating behavior, and mental retar-
dation.35 Death from hyperthermia has been reported in
infants with CIPA. Besides anhidrosis, it differs from FD
by complete insensitivity to superficial and deep painful
stimuli and normal lacrimation, much milder autonomic
dysfunction, with absent postural hypotension or dyspha-
gia. Self-inflicted multiple injuries are typical for these
patients. This is often accompanied by accidental trauma,
burns, wound infections, skin ulcers, joint deformities, and
osteomyelitis.
There is only limited anesthetic experience in patients
with CIPA.1,44-46 Okuda et  al.44 suggest three important
considerations in the anesthesia management of patients
Chapter 8  Neurologic Diseases 257
with CIPA: anxiety alleviation, temperature control, and
adequate pain control. Despite congenital insensitivity to
pain, general anesthesia was found to be necessary. Overall
requirements of general anesthetics necessary for maintain-
ing stable hemodynamics have been only slightly reduced.
General anesthesia was used in all patients in these reports
without any adverse reactions to the IV or inhalational anes-
thetic agents, opioids, or succinylcholine. In one report, a
patient died after intraoperative cardiac arrest without clear
cause, although the authors suspected that the high concen-
tration of halothane used (2%) could have been responsi-
ble.45 Previous recommendations against the use of atropine
(or other anticholinergic drugs) to avoid hyperpyrexia in
these patients was not supported by the results reported in
this series. Many patients received atropine without untow-
ard effects.
NEURODEGENERATIVE DISORDERS WITH
AUTONOMIC FAILURE
Autonomic failure (or dysautonomia), with its protean range
of manifestations and symptoms, is a common part of an
immensely diverse group of disorders in which some or all ele-
ments of the autonomic nervous system are affected. Autonomic
failure to varying degrees is a part of the ­presentation of many
systemic diseases (e.g., diabetes mellitus, amyloidosis), infec-
tious diseases (e.g., leprosy, human immunodeficiency virus
[HIV], rabies), immune disorders (e.g., acute dysautonomia,
Guillain-Barré syndrome), paraneoplastic disorders, hereditary
autonomic disorders (e.g., all HSANs, dopamine β-hydroxylase
deficiency), and neurodegenerative disorders. A comprehen-
sive discussion on various aspects of autonomic dysfunction
in these conditions can be found in most neurology and medi-
cal textbooks. This section discusses only the most prevalent
neurodegenerative disorders in which autonomic failure plays
a prominent role, presenting a significant anesthetic challenge.
Parkinson's disease (PD), dementia with Lewy body dis-
order (LBD), multiple system atrophy (MSA), and pure
autonomic failure disorder (PAF) are all neurodegenera-
tive disorders of unclear etiology, presenting with variable
degrees of autonomic dysfunction. Based on the differences
in the neuropathology, these disorders can be divided into
two subgroups: Lewy body syndromes (PD, LBD, and PAF)
and multiple system atrophy. All these disorders are char-
acterized by the presence of α-synuclein in the neuronal
cytoplasmic inclusions (Lewy bodies, as in Lewy body syn-
dromes) or the glial cell inclusions (GCIs, as in MSA); thus
these disorders are often called synucleinopathies. In PD,
neurodegeneration is predominant in the substantia nigra
and other brainstem nuclei and in peripheral autonomic
neurons. Motor dysfunction is more prominent than auto-
nomic failure in PD patients. Neuronal degeneration in PAF
is restricted to peripheral autonomic neurons; thus the symp-
toms of pure autonomic failure without other manifestations.
Extensive cortical involvement, in addition to degeneration
of brainstem nuclei and peripheral autonomic neurons, is
 258 ANESTHESIA AND UNCOMMON DISEASES

characteristic for LBD, which presents as severe dementia
associated with parkinsonism and autonomic failure.
In MSA, cytoplasmic inclusions are found in the glial cells
(GCIs) and not neurons (Lewy body). These inclusions are
associated with degenerative changes in the central neurons
in basal ganglia, cortex, and spinal cord, but not in periph-
eral autonomic neurons. Two phenotypes of MSA are cur-
rently identified based on the predominant clinical picture of
parkinsonism (MSA-P) or cerebellar dysfunction (MSA-C). In
the past, the patients with a predominant picture of autonomic
failure were diagnosed with Shy-Drager syndrome. Currently,
this term is rarely used, because all patients with MSA have a
significant degree of autonomic dysfunction.47
Autonomic failure in patients with Lewy body syn-
dromes and MSA typically manifests with orthostatic and
postprandial hypotension, bladder dysfunction, gastroin-
testinal (GI) motility disorders, and erectile dysfunction
(ED). Orthostatic and postprandial hypotension is often
the earliest and most disabling aspect of dysautonomia in
many patients. Other symptoms of autonomic dysfunction,
as described for familial dysautonomia, can be present. The
differential diagnosis can be difficult because of frequent
overlapping of the clinical picture between these condi-
tions, especially in the initial stages of the disease process.
Definitive diagnosis in some disorders could be established
only on postmortem histopathologic examination. However,
thorough clinical examination helps to distinguish between
PD, LBD, MSA, and PAF (Table  8-2). The subject of neu-
rodegenerative disorders with autonomic failure has been
reviewed.47,48
Anesthetic management of PD is described later. Although
LBD is the second most common cause of dementia after
Alzheimer's disease, there are no reports of anesthetic man-
agement in the literature. It appears reasonable to assume that
the principles of anesthetic management of patients with LBD
are common to those in patients with other forms of dementia.
In LBD patients with advanced dysautonomia, the same pre-
cautions should be taken as in patients with MSA.

TABLE 8-2  n Differential Diagnosis of Multisystem Atrophy, Parkinson's Disease, Pure Autonomic Failure, and Dementia
with Lewy Bodies

Characteristic Multisystem Atrophy Parkinson's Disease Pure Autonomic Failures Dementia with Lewy Bodies

Central nervous Multiple involvements Multiple involvements Unaffected Multiple involvements

system
involvement

Site of lesions Mainly preganglionic, Peripheral autonomic Mainly peripheral Cortex, brain stem,
central; degeneration postganglionic autonomic postganglionic peripheral autonomic
of interomediolateral neurons neurons; loss of postganglionic neurons
cell columns ganglionic neurons

Progression Fast; median survival, Slow Slow; up to 15 years and Slow

6-8 years after first longer
symptoms

Prognosis Poor Good Good Moderate to poor

Autonomic Early onset, severe Late onset, usually Severe, usually the only Unclear, but can be severe
dysfunction mild to moderate manifestation

Extrapyramidal Common Common Absent Common

involvement

Cerebellar Common Common Absent Common

involvement

Lewy bodies Mostly absent Primarily in substantia Present in autonomic Cortex, brainstem,
nigra neurons hippocampus

Glial cytoplasmic Present Absent Absent Absent

inclusions
(postmortem
staining)

Response to Poor Good Moderate

chronic levodopa
therapy

Dementia Uncommon Usually not severe, Uncommon Early, severe, rapidly

25%-30% of patients progressing

Modified from Marti MJ, Tolosa E, Campdelacreu J: Mov Disord 18(suppl 6):21-27, 2003; and Kaufmann H, Biaggioni I: Semin Neurol 23:351-363, 2003.

Multiple System Atrophy
In 1998, consensus committees representing the American
Autonomic Society and the American Academy of Neurology
defined multiple system atrophy as a sporadic, progres-
sive, neurodegenerative disorder of undetermined etiology,
­characterized by features in the three clinical domains of
­parkinsonism, autonomic failure, and cerebellar or pyramidal
dysfunction. In the past, the terms striatonigral degeneration,
olivopontocerebellar atrophy, and Shy-Drager syndrome were
used, depending on the predominance of clinical symptoms in
any of these three domains.
Multiple system atrophy is a fatal disease that typically pres-
ents in the fourth to sixth decade of life, with mean disease
duration of 6 years from onset of symptoms. Because of the
significant similarity of clinical presentation to other neuro-
degenerative disorders, MSA is often not diagnosed until later
stages. Parkinsonism is a predominant symptom in 80%, and
cerebellar dysfunction in 20%, of all patients. Parkinsonism is
usually not responsive to antiparkinsonian medications, which
helps to differentiate MSA from PD. The most common and
early presentation of autonomic dysfunction is urinary inconti-
nence and ED. Orthostatic hypotension is found in half of MSA
patients and is usually mild. Reduced heart rate variability and
absence of compensatory tachycardia during hypotension is
characteristic. Paradoxically, supine hypertension is present in
more than half of patients and complicates their management.
Recurrent syncope is a sign of severe orthostatic hypotension.
Severe constipation, fecal incontinence, and decreased sweat-
ing are other signs of autonomic dysfunction in MSA.
Obstructive sleep apnea or central sleep apnea and sleep-
related inspiratory stridor associated with bilateral vocal cord
paresis or dysfunction have been reported in MSA patients.49
There are no currently available treatments that can mod-
ify the clinical course or address the underlying pathologic
MSA process. All the treatments are symptomatic, intended
for improving the quality of life in these patients. Orthostatic
hypotension is treated with administration of fludrocortisone
or milrinone (oral adrenergic vasoconstrictor). The presence
of significant supine hypertension limits the use of vasopres-
sors. Erythropoietin has been reported to be useful in the
treatment of patients with associated anemia and severe hypo-
tension. Tracheostomy and respiratory support is reserved for
the patients with stridor and central sleep apnea.
ANESTHETIC CONSIDERATIONS
Perioperative management of patients with MSA is a formi-
dable challenge because of potential hemodynamic instabil-
ity and respiratory compromise in the postoperative period
(Box  8-4). A few case reports in the literature indicate no
adverse effects to most of the common anesthetic agents.50-60
The management is directed at ensuring hemodynamic sta-
bility through invasive hemodynamic monitoring, adequate
preoperative hydration, and maintenance of normovolemia
with fluid replacement intraoperatively. Preoperative opti-
mization of fludrocortisone therapy is recommended. Some
Chapter 8  Neurologic Diseases 259
BOX 8-4   n NEURODEGENERATIVE DISORDERS WITH
AUTONOMIC FAILURE: ANESTHETIC ISSUES
Multiple System Atrophy (MSA)
Perioperative hemodynamic instability, related to autonomic failure
with orthostatic hypotension and sometimes severe supine
hypertension, is to be expected. Invasive hemodynamic monitoring
may be of benefit in perioperative management of patients with
severe symptoms.
Obstructive and central sleep apnea and sleep-related inspiratory
stridor may occur. The risk of postoperative airway obstruction and
apneic episodes is increased in patients with MSA.
In patients with advanced dementia and parkinsonism, anesthetic
considerations are similar to those in patients with other forms of
dementia and Parkinson's disease.
No specific anesthetic techniques or agents are contraindicated in
MSA patients.
Pure Autonomic Failure
Anesthetic considerations are similar to those in patients with MSA.
controversy surrounds the potentially unpredictable response
to vasopressor amines because of sympathetic hypersensitivity
caused by autonomic denervation.52,61 Therefore, it is recom-
mended to administer vasoactive medications very cautiously
in much smaller doses than usual. However, vasopressors have
been used without adverse effects for treatment of hypoten-
sion intraoperatively, when titrated judiciously.53,54,60
Significant intraoperative supine hypertension has been
reported, with minimal response to labetalol but profound
hypotension after hydralazine administration.62 The hypo-
tension responded only to vasopressin infusion. Short-acting
vasodilators such as sodium nitroprusside may be a better
choice for intraoperative supine hypertension. The hyperten-
sive episodes in autonomic failure are particularly responsive
to transdermal nitroglycerin.63
Neuraxial anesthesia techniques have been successfully
employed in patients with MSA, including for labor and
delivery, with a greater degree of hemodynamic stability,
also avoiding possible difficulties with extubation in these
p
­ atients.51,56,57,59,64 It is speculated that patients with autonomic
failure are less likely to respond with hypotension to sympa-
thectomy caused by neuraxial block because they are already
sympathectomized. The data in the literature support this
hypothesis.
When general anesthesia is chosen, careful planning for
extubation and postoperative monitoring of the respiration in
the ICU setting is warranted, especially in MSA patients with a
history of stridor or central or obstructive sleep apnea.
Pure Autonomic Failure
Pure autonomic failure is a sporadic, slow-progressing neuro-
degenerative disorder of the autonomic nervous system (ANS)
that typically affects individuals in the sixth decade of life. PAF
is characterized by an isolated impairment of the peripheral
and central ANS. No symptoms of parkinsonism, cerebellar
 260 ANESTHESIA AND UNCOMMON DISEASES
dysfunction, or dementia are usually present. The orthostatic
hypotension in this syndrome is typically severe and more
disabling than in other neurodegenerative disorders with
autonomic failure. Other symptoms of autonomic failure are
similar to those seen in MSA. The prognosis in PAF patients,
however, is much better.
There is only one case report in the literature of general
anesthesia without complications in a patient with PAF;65 it is
unclear whether the patient also had epidural anesthesia per-
formed. However, the authors advocate the use of epidural
anesthesia and invasive hemodynamic monitoring for greater
hemodynamic stability.
The same principles of anesthetic management used for
patients with MSA should be applied when managing PAF
patients.
BASAL GANGLIA AND CEREBELLAR
DISORDERS
Parkinson's Disease
Parkinson's disease is a chronic progressive neurodegener-
ative disease characterized by resting tremor, bradykinesia,
rigidity, and postural instability. In addition to these cardi-
nal signs, many patients with PD will experience secondary
symptoms attributable to the disease or its pharmacother-
apy. Dementia is common, especially in advanced stages, as
are fatigue and depression. Hallucinations, psychosis, anos-
mia, and autonomic instability are also well-described
nonmotor features of the disease. Diagnosis is clinical,
requiring at least two of the four cardinal signs. Prevalence
has been estimated at approximately 1% of the population
over 60.66 To date, attempts to identify risk factors have
produced contradictory results. Older age has been per-
sistently associated with increased risk of PD. Other puta-
tive risk factors include environmental exposure to heavy
metals, pesticides, and herbicides; dietary factors; and body
weight. Although most cases appear sporadic, several genes
have recently been linked to PD, particularly in those cases
manifesting before age 50.67
Pathophysiology. Coordination of movement depends on
a complex feedback loop in which the cortex sends informa-
tion to the basal ganglia and cerebellum and in turn receives
information from these structures through the thalamus.
Because of their anatomic location, these pathways are often
referred to as “extrapyramidal.” PD is characterized by neu-
ronal loss, depigmentation, and gliosis in the substantia nigra
pars compacta and pontine locus ceruleus, as well as degen-
eration of the putamen, globus pallidus, hippocampus, and
brainstem nuclei. The result of this degeneration is a relative
dopamine deficiency, particularly in the striatum and puta-
men, and unopposed cholinergic activation of inhibitory
γ–­aminobutyric acid (GABA) transmission from the striatum.
The end result of this imbalance is excessive inhibition of the
thalamus, which suppresses both the cortical motor system,
leading to bradykinesia and tremor, and the brainstem motor
areas, leading to gait and postural instability.
The precise mechanism of degeneration in PD has yet to
be elucidated. Programmed cell death, protein misfolding and
aggregation, abnormal proteosomal degradation, oxidative
stress, mitochondrial dysfunction, and immunomodulation
and inflammation have all been proposed. Although no uni-
versally accepted pathologic criteria exist for the diagnosis of
PD, one hallmark of the disease appears to be the presence of
eosinophilic, intracytoplasmic inclusions known as Lewy bod-
ies. Composed primarily of α-synuclein, in association with
ubiquitin, complement, and numerous cytoskeletal proteins,
Lewy bodies are found in the substantia nigra, locus ceruleus,
cerebral cortex, and sympathetic ganglia of PD patients, as well
as in the cardiac sympathetic plexus, dorsal vagal nucleus, and
myenteric plexus of the intestines. Importantly, Lewy bodies
are not specific for PD and are found in other neurodegenera-
tive diseases (e.g., MSA, progressive supranuclear palsy, Lewy
body dementia), in Down syndrome, in amyloidopathies (e.g.,
Alzheimer's disease), in tau-protein–associated diseases
(e.g., frontotemporal dementia), and even in a small percent-
age of normal elderly brains.68 It remains unclear whether
Lewy bodies represent a pathologic neurotoxic process, or as
recent evidence suggests, play a neuroprotective role.69
Medical Management. Pharmacologic management of PD
patients seeks to balance dopaminergic and cholinergic effects
in the striatum and thus preserve motor function and qual-
ity of life while minimizing medication-related side effects.
Current therapies attempt to achieve these goals by blocking
acetylcholine transmission, enhancing dopamine production,
or stimulating central dopamine receptors (Table  8-3).70-72
Motor symptoms generally respond better to treatment than
extramotor symptoms, but effectiveness diminishes in later
stages. Although several agents have shown possible neuro-
protective effects in human and animal studies, currently no
treatment significantly reverses or delays PD progression.
Surgical Management. Surgical treatment of PD began in
the early 20th century and was originally based on the inten-
tional lesioning of deep brain structures. Thalamotomy was
performed to ameliorate tremor and pallidotomy to con-
trol both parkinsonism and levodopa-induced dyskine-
sias. Although the introduction of stereotactic localization
improved outcomes and reduced complications from these
surgeries, the continued risk of permanent paresis, visual field
cuts, gait disturbances, dysarthria, and hypersalivation, com-
bined with the development of deep-brain stimulation tech-
niques, have led to a pronounced shift away from permanent
surgical lesioning.
Drawing on the intraoperative observation that focal
electric stimulation of the brain induced a functional but
reversible “lesion,” implantable deep-brain stimulation of
the subthalamic nucleus (STN), globus pallidus (GPi), and

TABLE 8-3  n  Pharmacologic Therapy of Parkinson's Disease
Drug Features
DOPAMINE PRECURSORS
Levodopa Converted to dopamine by dopa
decarboxylase
Combined with carbidopa (see
Sinemet)
Treats akinetic symptoms, tremor,
and rigidity
Not as effective for postural
instability
Motor fluctuations and dyskinesias
often become impediments to
therapy.
Evidence for both neurotoxic and
neuroprotective effects70
Carbidopa Decarboxylase inhibitor that does not
cross blood-brain barrier
Prevents peripheral conversion of
levodopa to dopamine
Reduces nausea, vomiting, orthostatic
hypotension
Sinemet Combination of carbidopa/levodopa
Available in 1:10 and 1:4 ratio
Controlled-release formulation also
available
DOPAMINE AGONISTS
Bromocriptine Sometimes used as levodopa-sparing
Cabergoline monotherapy in younger patients
Pramipexole Fewer “on-off” fluctuations and less
Ropinirole dyskinesia than levodopa
Apomorphine Apomorphine used as parenteral
“rescue” therapy for levodopa-
induced motor fluctuations
ANTICHOLINERGICS
Trihexylphenidyl Most useful in patients under age 70
Benztropine without significant akinesia or gait
disturbance
May be used adjunctively for persistent
tremor
Improve DA/Ach balance
Rapid withdrawal may precipitate
exacerbation of symptoms
CATECHOL O-METHYLTRANSFERASE (COMT) INHIBITORS
Tolcapone Prolong and potentiate levodopa effect
Entacapone by increasing plasma half-life
Chapter 8  Neurologic Diseases 261
Side Effects Contraindications
Nausea, somnolence, dizziness, History of psychosis
headache, confusion Narrow-angle glaucoma
Hallucinations/delusions Concurrent monoamine
Agitation oxidase inhibitor (MAOI)
Pyschosis therapy
Motor fluctuations (“wearing-off
phenomenon”)
Dyskinesias/dystonias
Homocysteine elevation (proposed)
Peripheral neuropathy if concomitant
elevated methylmalonic acid
Rebound hypertension with
withdrawal
Similar to levodopa History of psychosis
Dopaminergic dysregulation Recent myocardial infarction
syndrome (compulsive use, cyclic Severe vascular disease
mood disorder) Breastfeeding
Impulse control disorders
Dopamine withdrawal syndrome
(resembling cocaine withdrawal)
Valvular heart disease (cabergoline)
Angina and orthostasis
(apomorphine)
Acute somnolence (pramipexole)
Common and may limit use Relatively contraindicated
Memory impairment, confusion, in elderly or cognitively
hallucinations impaired patients
Peripheral antimuscarinic effects Prostatic hypertrophy
Closed-angle glaucoma
Dyskinesia Liver disease may be a relative
Hallucinations contraindication.
Confusion Liver function must be
Nausea monitored for the first
Orthostatic hypotension 6 months in all patients.
Hepatotoxicity (tolcapone)
Diarrhea
Continued
 262 ANESTHESIA AND UNCOMMON DISEASES

TABLE 8-3  n  Pharmacologic Therapy of Parkinson's Disease—Cont'd

Drug Features Side Effects Contraindications

MONOAMINE OXIDASE B (MAO-B) INHIBITORS

Selegiline Modest effect in some patients Nausea Use caution with concomitant
Rasagiline Inhibit breakdown of DA Headache SSRIs or TCAs
May be neuroprotective Diarrhea Does not precipitate
Insomnia (selegiline's amphetamine hypertension with
metabolites) concomitant tyramine
Confusion in elderly ingestion

ANTIVIRALS
Amantadine Mild antiparkinsonian activity
Mechanism unclear (likely
dopaminergic, anticholinergic, and
NMDA mediated)
Short-term monotherapy for mild
disease
May reduce levodopa-induced
dyskinesia and motor fluctuations
May reduce impulse control disorders in
patients taking dopamine agonists71
Side effects are rare in monotherapy
but include livedo reticularis,
ankle edema, hallucinations,
confusion, and nightmares.
Central nervous system side effects
are more likely when used
adjunctively.

HORMONE REPLACEMENT
Estrogen Adjunctive therapy in postmenopausal Adverse effects associated with long-
women term estrogen use
Effect may be indirect through improved
subjective well-being.
Improved “on time,” but not objective
scales of ADLs in one study72
Few data on estrogen/progesterone

DA, Dopamine; Ach, acetylcholine; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants; ADLs, activities of daily living.

ventralis intermedius (Vim) have all been successful in ame-
liorating PD symptoms. Vim stimulation appears to be most
effective for tremor-predominant cases. Evidence from ran-
domized controlled trials (RCTs) suggests that both STN and
GPi are effective for treatment of motor symptoms and bra-
dykinesia. STN stimulation appears to provide a greater dose-
sparing effect in terms of future medication use, and GPi may
provide superior control of dyskinesias as well as fewer altera-
tions of mood, cognition, and behavior.73
In addition to its reversibility, deep-brain stimulation
appears safer than lesioning, even when bilateral. The treat-
ment effect may be modulated; it causes less permanent collat-
eral damage to the surrounding brain, without ruling out the
possibility of new medical or surgical therapies as they become
available. Drawbacks include increased time and expense,
including specialized intraoperative and postoperative device
management, the infection risk of indwelling hardware,
potential magnetic resonance imaging (MRI) incompatibility,
and the need for periodic battery replacement. Anesthesia for
deep-brain stimulation is discussed later.
Future directions for surgical management include neu-
ral transplantation of dopaminergic cells, targeted infusion of
glial cell line–derived neurotrophic factor (GDNF), gene ther-
apy, and continuous duodenal levodopa infusion.
ANESTHETIC CONSIDERATIONS
Preoperative Concerns. A thorough history of the patient's
symptoms, disease severity, and medication regimen should be
obtained. The patient's prescribed medication regimen should
be optimized before scheduling surgery. Because several med-
ications used to treat PD have a relatively short half-life, doses
should be continued through the morning of surgery, and
until as close to induction of anesthesia as feasible for after-
noon or unscheduled procedures (Box 8-5).
Preoperative Evaluation. Cognitive impairment may pre-
dispose patients to postoperative delirium, and baseline men-
tal status should be assessed. Neurologic symptoms, including
tremor, muscle rigidity, and bradykinesia, should also be
assessed. Patients with PD are particularly vulnerable to respi-
ratory complications, and the preoperative evaluation should
elicit evidence of swallowing dysfunction, retained or exces-
sive oropharyngeal secretions, dyscoordination or rigidity of
accessory muscles of respiration, and recent or active respi-
ratory infection. From a cardiovascular standpoint, patients
should be evaluated for arrhythmia and hypertension, as
well as evidence of hypovolemia and orthostatic hypoten-
sion, which are common medication side effects. Autonomic
dysfunction, including abnormal micturition, salivation, GI

BOX 8-5   n BASAL GANGLIA AND CEREBELLAR
DISORDERS: ANESTHETIC ISSUES
Parkinson's Disease (PD)
Medication effects are common and include motor fluctuations
and dyskinesias, orthostatic hypotension, and antimuscarinic
symptoms.
Deep-brain stimulation is a safe, reversible treatment for patients
without cognitive impairment; implantation requires patient
cooperation with intraoperative neurologic examination. Risks
include air embolism and intracerebral hemorrhage.
Patients with PD undergoing any surgery should continue their
medication regimen until immediately before surgery and should
resume their medications as soon as possible postoperatively.
Medications with potential extrapyramidal side effects should be
avoided.
Patients with PD are particularly vulnerable to aspiration, respiratory
compromise, and postoperative delirium.
Huntington's Disease (HD)
Patients with advanced disease are at risk for aspiration and
respiratory complications.
Patients with HD may have decreased pseudocholinesterase activity.
Sydenham's Chorea (SC)
Preoperative evaluation must include ECG and evaluation for carditis
and valvular disease.
Procedural sedation may be difficult because of patient movement
and may be facilitated by the use of neuroleptics, benzodiazepines,
or propofol.
Patients with SC should receive long-term prophylaxis against
recurrent group A streptococcal pharyngitis.
Dystonias
Dystonic symptoms may complicate positioning and in severe cases,
airway management.
Dystonic symptoms are often relieved by sedation.
Dystonic patients may be managed using anticholinergic or
dopaminergic therapy, leading to possible drug-drug interactions.
There are no specific contraindications to any particular anesthetic
agent, although many have been implicated in acute dystonic
reactions.
function, and temperature regulation should be considered.
Seborrheic dermatitis of the face, ears, and skin folds is com-
mon in PD patients and should be recognized as a manifes-
tation of underlying autonomic dysfunction. Weight loss and
malnutrition are also common in patients with more advanced
disease, and GI dysmotility and esophageal reflux disease can
increase the risk of aspiration. Glucose utilization is often dis-
rupted, and preoperative serum glucose should be measured.
Intraoperative Management. As suggested, intraoperative
challenges in the management of patients with PD include
increased aspiration risk, potential for autonomic instability
and arrhythmia, and relatively high incidence of orthostatic
hypotension. Tremor and rigidity may make positioning and
cooperation difficult for patients undergoing sedation or pre-
induction vascular access or monitor placement. On the other
hand, regional anesthesia may reduce the risk of aspiration and
respiratory complications, minimize the risk of postoperative
Chapter 8  Neurologic Diseases 263
nausea and vomiting, and facilitate earlier ability to resume
enteral medications. When tremor is a serious impediment to
the safe performance of a procedure (e.g., ophthalmologic sur-
gery), diphenhydramine may be a useful adjunct for reducing
tremor in the awake or sedated patient.
In the absence of hypovolemia or cardiac dysfunction,
propofol is a good choice for induction of general anesthe-
sia because of its rapid metabolism and predictable offset.
Although case reports have linked propofol to dyskinesias,
it has also been noted to diminish tremor in the postopera-
tive period.74,75 Thiopental has been associated with dyskine-
sias in several reports.76,77 Although ketamine may increase
oral secretions and is relatively contraindicated because of its
potential to cause hypertension through an exaggerated sym-
pathetic response, it has been used without incident.78 Inhaled
anesthetics have been associated with an increase in postop-
erative rigidity.
Nondepolarizing neuromuscular blockers may mask
tremor, but patients with PD appear to have normal sensitivity
to these drugs. Hyperkalemia has been reported in one patient
with presumed denervation from chronic PD who received
succinylcholine.79 However, a subsequent case series found
no evidence of hyperkalemia in PD patients exposed to succi-
nylcholine.80 Anticholinesterase agents have been used in the
treatment of some parkinsonian symptoms and are presumed
safe to use for the reversal of NMB. Because it does not cross
the blood-brain barrier, glycopyrrolate is the preferred anti-
cholinergic, particularly in patients with cognitive deficits.
Opioid medications should be used with caution in patients
who are unlikely to tolerate respiratory depression. Fentanyl
and remifentanil may exacerbate muscle rigidity, although this
effect is amenable to treatment with neuromuscular blockers
and may be blunted by coadministration of propofol. At low
doses, morphine has been reported to decrease dyskinesias,
but at high doses it may actually precipitate them.81 NSAIDs
may be beneficial as part of an opioid-sparing strategy.
Medications that may precipitate extrapyramidal symptoms
or dystonic reactions, including phenothiazines (prometha-
zine), butyrophenones (droperidol), and metoclopramide are
contraindicated in patients with PD. Benzodiazepines may
diminish tremor, but may also exacerbate delirium and should
be avoided in patients with significant dementia. Vasodilators
should be used with caution in patients at risk for hypovole-
mia, and hypotension should be treated with volume resusci-
tation and direct-acting agents such as phenylephrine rather
than ephedrine.
Postoperative Concerns. Patients with PD should be
watched closely for postextubation respiratory failure. These
patients are at increased risk of laryngospasm, inability to han-
dle oral and respiratory secretions, and aspiration pneumonia.
Respiratory reserve is likely to be diminished, especially in
patients with preoperative muscle rigidity and dyscoordina-
tion. Intraoperative atelectasis and medication effects are likely
to impair respiratory function further. Oral secretions may be
a contraindication to noninvasive ventilation. In patients who
 264 ANESTHESIA AND UNCOMMON DISEASES
fail to meet criteria for extubation or who are reintubated for
respiratory failure, antiparksinonian medications should be
continued via gastric tube to maximize chances of successful
extubation.
ASSOCIATED PROCEDURES
Anesthesia for Deep-Brain Stimulator Placement. Deep-
brain stimulation (DBS) surgery is generally accomplished
using two separate procedures. In the first stage, a stereotactic
head frame is placed with the patient in a semi-upright posi-
tion, and leads are then placed through burr holes using ste-
reotactic guidance and patient cooperation. Several techniques
have been used to facilitate lead placement; all share the goal
of protecting the airway, providing adequate patient comfort,
and allowing patient cooperation with intraoperative neuro-
logic examination to optimize lead positioning. Monitored
anesthesia care, scalp block, IV sedation, and general anes-
thesia using an asleep-awake-asleep technique have all been
described. Maintenance of airway patency and ventilation are
particularly important, given the difficulties of airway man-
agement once the head frame is in place. In addition to their
potential for disinhibition or confusion in patients with cogni-
tive deficits, the effects of GABAergic medications on electro-
physiologic brain monitoring and their tendency to suppress
tremor and rigidity may contraindicate their use.
Intraoperative risks include an increased potential for
venous air embolism in the semi-upright position and intra-
cerebral hemorrhage (2%-4% of DBS cases).82 Maintenance
of systolic BP less than 140 mm Hg has been suggested in an
effort to reduce the risk of hemorrhage.82 Stimulator implan-
tation is usually performed 1 to 4 weeks after lead placement.
Because neuromonitoring is not required, DBS is usually per-
formed under general anesthesia and carries risks similar to
permanent pacemaker implantation.
Anesthesia for Patients with Implantable Deep-Brain
Stimulators. Anesthesia for patients with implantable deep-
brain stimulators has not been well studied. MRI compat-
ibility varies slightly by device, and the manufacturer should
be consulted before proceeding with MRI in these patients.
Electrocautery has the theoretic potential to cause generator
malfunction and inappropriate electrode activation or CNS
burns, but a recent review found no evidence of such complica-
tions.83 If possible, bipolar diathermy eliminates this concern.
Scant evidence is available to guide intraoperative device man-
agement. Turning off the device intraoperatively seems a safe
approach,84 but whether it is necessary is unclear. Postoperative
akinesia may respond to levodopa, but some recommend turn-
ing the generator back “on” before emergence from anesthesia.85
Huntington's Disease (Chorea)
Huntington's disease (HD; Huntington's chorea) is an inher-
ited progressive neurodegenerative condition whose hall-
marks include choreoathetoid movements, dementia, and
psychiatric disturbances. Although the exact mechanism has
yet to be fully elucidated, HD appears to develop from the
neurotoxicity of an abnormal variant of the protein hunting-
tin, arising from an autosomal dominant mutation involving
a trinucleotide expansion (CAG) in the Huntington gene on
chromosome 4p.86 Onset typically occurs in middle age, with
the development of chorea, which is often accompanied by
insidious progression of cognitive and personality changes.
Choreatic movements are often subtle initially, but progress
to the point of interference with normal movement. In late
stages, chorea begins to affect the diaphragm and the muscles
of the aerodigestive tracts, leading to dysphagia, dysarthria,
and involuntary phonation. Onset and severity of the dis-
ease are influenced by the number of inherited trinucleotide
repeats; because somatic instability can increase the number
of repeats each generation, inheritance is subject to anticipa-
tion, the genetic phenomenon in which subsequent genera-
tions may experience earlier onset and worsened severity of
the disease. Patients with juvenile-onset HD typically experi-
ence a rapidly progressive course. Prevalence of HD in Europe
and North America has been estimated at 5 to 8 per 100,000
population.87
Although the huntingtin protein is expressed throughout
the body, it appears that only a subset of neurons are affected
by the abnormal variant.88 The typical pathologic finding in
patients with HD is diffuse atrophy of the caudate and puta-
men. Early onset is also associated with atrophy of cerebellar
Purkinje cells.89 At the cellular level, cytoplasmic and intranu-
clear aggregates of the amino-terminus of mutant huntingtin
are characteristic; whether these aggregates are causative or
protective remains unclear. Huntingtin is necessary for nor-
mal embryonic development, and the presence of trinucleotide
expansion does not seem to affect this process. In the adult, its
role is less clear, although huntingtin is known to interact with
multiple proteins and may play a role in protein trafficking,
vesicular transport and anchoring, endocytosis, postsynaptic
signaling, or cell survival.90 Conversely, the abnormal variant
in HD may disrupt a wide variety of processes and pathways,
including protein degradation, axonal transport, and synap-
tic transmission, and may lead to excitotoxicity, cellular meta-
bolic dysfunction, and abnormal apoptosis.90
To date, management of patients with HD remains support-
ive. Physical and occupational therapy, nutrition, and psychoso-
cial counseling are important strategies for maximizing quality
of life. Chorea may respond to treatment with tetrabenazine,
which blocks dopamine transport. However, use of this agent
may worsen bradykinesia, cognition, and mood. Neuroleptic
agents may also be useful in controlling chorea as well as agi-
tation and psychosis. Depression is common in patients with
HD and may respond to tricyclic antidepressants (TCSs) or
selective serotonin reuptake inhibitors (SSRIs). Recent stud-
ies have evaluated the possible disease-modifying effects of
vitamin E, creatine, coenzyme Q10, highly unsaturated fatty
acids (HUFAs), ethyl eicosapentaenoate (fatty acid derivative),
minocycline (antiapoptotic), and riluzole (inhibitor of striatal
glutamine). None of these agents has demonstrated a robust
benefit, but trials are ongoing.91 Gene therapy, vaccination with

the huntingtin protein, DBS, and surgical delivery of fetal tis-
sue or neurotrophic factors have been proposed, and in some
cases studied in animals or small human trials.92,93
ANESTHETIC CONSIDERATIONS
Data regarding anesthetic management of HD patients are
limited. Patients with HD may have difficulty holding still
during procedures performed with sedation (see Box  8-5).
Butyrophenones and phenothiazines may alleviate chorei-
form movements, and benzodiazepines may be used to treat
acute anxiety. However, caution should be used in patients
with dementia, who are at increased risk for postoperative
delirium. In advanced stages, patients with HD are vulnerable
to dysphagia, aspiration, and respiratory complications. No
clear contraindications seem to exist to the use of the common
induction agents, neuromuscular blockers, or inhaled anes-
thetics. One case of delayed recovery from thiopental has been
reported, but others have used this drug without incident.94
Patients with HD may have decreased pseudocholinesterase
activity, but only a single case of delayed recovery from succi-
nylcholine has been reported.95,96
ASSOCIATED PROCEDURES
Although there are no procedures specifically related to the
treatment or management of HD, patients with advanced
disease may require gastric feeding tube placement. These
patients are also at high risk for falls. Orthopedic procedures,
in particular hip and femur fixation, may be required.
Sydenham's Chorea (Rheumatic Chorea)
Sydenham's chorea (SC) is an acute manifestation of rheu-
matic fever, occurring in approximately one third of cases.
Chorea is often asymmetric and occasionally unilateral, and
it is generally accompanied by muscular weakness and emo-
tional lability. Although the incidence of rheumatic fever has
declined to 2 to 14 cases per 100,000 people in Europe and
North America,97 almost 500,000 new cases occur each year,
primarily in the nonindustrialized world.98 Children ages 5 to
13 years are most likely to be affected by SC, and girls are twice
as likely to develop SC as boys.99 A familial predisposition to
both acute rheumatic fever and to SC has been suggested. Onset
of chorea is typically gradual, occurring 1 to 8 months after
the inciting group A streptococcal infection. Emotional labil-
ity may precede motor symptoms, which often progress from
subtle hand movements to irregular writhing movements of
the arms. Ballistic movements, facial grimacing, tongue fascic-
ulations, and diffuse hypotonia are also common. Psychiatric
manifestations include irritability, inappropriate laughing or
crying, and obsessive-compulsive behaviors. Symptoms, both
motor and psychiatric, generally resolve in 3 to 4 months, and
most patients recover completely. However, persistent symp-
toms have been described more than 2 years after onset,100 and
up to 20% to 30% of SC patients have relapses, particularly
those who do not receive antibiotic prophylaxis against recur-
rent streptococcal infection.101
Chapter 8  Neurologic Diseases 265
The pathogenesis of SC remains incompletely understood.
Group A streptococcal infection stimulates the formation of
antibodies against the N-acetyl-β-d-glucosamine (NABG
or GlNAc) streptococcal antigen. These antibodies appear
to cross-react with host antigens, leading to valvular injury
in rheumatic endocarditis, for example. Some of these anti-
bodies bind to lysoganglioside on the surface of neurons, ini-
tiating a calcium-mediated cell-signaling cascade.102 Others
cross-react with tubulin, suggesting a link to the pathogenesis
of other antibody-mediated motor neuropathies.103,104 At the
gross anatomic level, small studies using MRI, positron emis-
sion tomography (PET), and single-photon emission com-
puted tomography (SPECT) suggest that the basal ganglia
and s­ triatum are subject to reversible changes consistent with
hypermetabolism and hyperperfusion.105-107
Initial treatment of acute rheumatic fever involves anti-
biotic therapy to eliminate carriage of group A streptococci,
anti-inflammatory therapy (aspirin) for patients with cardi-
tis, and heart failure management for those with severe val-
vular lesions. Evidence suggests that treatment with steroids
may hasten resolution of SC.108,109 Numerous agents have been
used in the pharmacologic management of chorea symptoms,
including valproic acid, carbamazepine, haldol, benzodiaz-
epines, and pimozide. Intravenous immune globulin (IVIG)
and plasma exchange have also been used. All have shown
benefit in small studies, but no conclusive evidence supports
any of these treatments. Antibiotic prophylaxis against recur-
rent group A streptococcal pharyngitis is indicated for second-
ary prevention of recurrent episodes of rheumatic fever.110,111
ANESTHETIC CONSIDERATIONS
Preoperative evaluation of the patient with Sydenham's cho-
rea or a history of rheumatic fever should include electrocar-
diogram (ECG) and evaluation for endocarditis and valvular
disease (see Box  8-5). As with other movement disorders,
procedural sedation may be challenging, and symptomatic
treatment of chorea with neuroleptics, benzodiazepines, or
propofol may be helpful. A lack of published experience with
SC patients precludes any list of contraindications other than
those related to cardiac complications of acute rheumatic fever
and possible interactions involving the drugs used for symp-
tom management.
Dystonias
Dystonias are a broad group of movement disorders in which
sustained involuntary muscle contractions lead to abnormal
postures or repetitive movements. Classification schemes have
centered on age of onset (early vs. late), anatomic distribution,
and etiology (primary vs. secondary). Numerous genetic sub-
types have also been identified. Prevalence estimates for dys-
tonias as a group have varied widely. The most-often cited
figures for the United States come from a 30-year study of
Rochester, Minnesota, which found an incidence of 2 cases of
generalized dystonia per 1 million persons per year, and 24
cases of focal dystonia per 1 million per year.112
 266 ANESTHESIA AND UNCOMMON DISEASES
Etiology. Primary dystonias are generally characterized by
a gradual onset and progression of symptoms, and occur in
the absence of other neurologic, imaging, or laboratory abnor-
malities. Early-onset dystonias present in childhood or young
adulthood, often beginning in one leg, and become general-
ized in a majority of patients. Late-onset dystonias (occurring
in adulthood) typically present in the neck, arms, or face, and
are likely to remain focal or segmental (involving contiguous
body areas).
Cervical dystonia, also referred to as “spasmodic torticol-
lis,” is the most common primary focal dystonia.113 Dystonia
may involve rotation, lateral flexion, or anterior flexion of
the head and is painful in 50% of patients. Dystonic con-
tractions may lead to finer movements of the head that may
resemble tremor.114,115 Oromandibular and facial dystonias
involve the muscles of the jaw, tongue, and larynx and may
cause difficulty with speech and swallowing. Spasmodic
dysphonia refers to a focal dystonia of the laryngeal mus-
cles, most often involving the adductor muscles, and there-
fore causing difficulty with vocalization rather than airway
occlusion. Blepharospasm involves the periocular muscles
and may impact vision when severe enough to cause pro-
longed involuntary eye closure. Blepharospasm may also
occur in conjunction with oromandibular and facial dysto-
nias, a constellation referred to as Brueghel's or Meige's syn-
drome. Focal or segmental dystonias of the upper extremity
are also common. These are generally unilateral, are often
absent at rest, and may produce an apparent tremor in addi-
tion to abnormal posturing. Repetitive performance of spe-
cific muscular tasks may produce occupational dystonias,
such as writer's cramp or the embouchure dystonia that
has affected players of woodwind or brass instruments. An
interesting feature of many focal dystonias is the presence
of a geste antagoniste, or specific maneuver, such as a light
touch to the overlying skin, which will relieve the dystonic
contractions.
Several hereditary dystonias have been identified, and
genetic predisposition or vulnerability likely plays a role in
many cases. Mutation of the TOR1A gene, which encodes tors-
inA, an ATP-binding protein, may account for as many as half
of all cases of early-onset primary dystonia.116,117 Other heredi-
tary dystonias include dopa-responsive dystonia, an early-onset
form often associated with parkinsonian features and notable
for its responsiveness to levodopa therapy; various forms of
dystonia plus parkinsonism; several types of paroxysmal dys-
kinesia; and myoclonus dystonia, an autosomal dominant con-
dition involving myoclonic upper body jerks with dystonic
features.
Secondary dystonias occur as a result of an alternative
primary process. In these cases, dystonia is generally asso-
ciated with additional neurologic, laboratory, or imaging
abnormalities. Stroke, medication effects, and muscu-
loskeletal or CNS trauma are common causes. Atypical
presentations should also prompt further investigation.
Numerous degenerative, genetic, and metabolic disease
processes have been associated with dystonia; notable
examples include Wilson's, Huntington's, and Leigh's dis-
eases; corticobasal degeneration; and cyanide or manga-
nese toxicity.
Pathophysiology. Primary dystonias are not associated
with specific neuropathology and do not appear to involve
neuronal cell degeneration. They have also been difficult to
localize anatomically. PET and functional MRI studies have
suggested abnormal metabolic activity in the motor cortex
and supplementary motor areas, the cerebellum, and the basal
ganglia.118,119 DBS recordings have implicated abnormal func-
tion of the globus pallidus.120 Functionally, electrophysiologic
studies suggest that dystonia involves loss of normal inhibi-
tory signals, abnormal plasticity of the motor cortex, and sub-
tle abnormalities of sensory function.121 The neurochemistry
of dystonia remains poorly understood. The overlap between
dystonia and parkinsonism, as well as the acute dystonic
reactions that can accompany pharmacologic antagonism of
dopamine receptors, suggest the importance of dopaminer-
gic pathways in the neurochemistry of dystonia. The clinical
observation that anticholinergic therapy can be effective in
treating childhood dystonia suggests the importance of cho-
linergic pathways as well.
Treatment. Treatment of dystonia is symptomatic.
Appropriately, dopa-responsive dystonia can be almost com-
pletely abolished with levodopa therapy. This response is gen-
erally sustained, and required doses are often small enough to
prevent motor side-effects. Up to 15% of other dystonias will
also respond to levodopa therapy.122 Anticholinergic drugs,
including trihexyphenidyl and tetrabenazine, have also been
widely used in the treatment of dystonia, but evidence for their
efficacy is equivocal.123 Anecdotal evidence also suggests that
some patients may benefit from benzodiazepines, baclofen,
carbamazepine, zolpidem, or dopamine receptor blockers.
Injection of affected muscle groups with botulinum toxin
(BoNT-A and BoNT-B) has proved safe and effective and is
now considered a first-line therapy for patients with cervi-
cal dystonia, blepharospasm, focal upper limb dystonias, and
spasmodic dysphonia.124,125 Although sustained benefits are
possible using botulinum toxin, not all patients will respond,
and some will develop resistance to BoNT-A.126 These patients
may respond to the alternate serotype BoNT-B, but some
patients will fail treatment with either type. In patients with
medication-resistant segmental or generalized primary dys-
tonia, DBS of the globus pallidus has been effective in con-
trolling symptoms for a majority of patients.127 Long-term
follow-up data are limited. Although some evidence indicates
a benefit in focal dystonia treated with DBS, data for the treat-
ment of secondary dystonia are mixed.128
ANESTHETIC CONSIDERATIONS
Preoperative evaluation of the patient with dystonia should
focus on the severity of the dystonic movements, known trig-
gers or sensory tricks to break spasm, and potential interac-
tions with levodopa or anticholinergic therapy (see Box 8-5).
Although symptoms are often relieved with sedation, cervical

or oropharyngeal dystonias may complicate airway manage-
ment, and in severe cases, fiberoptic intubation techniques
may be indicated for patients with limited mobility of the
neck or jaw. Spasms are abolished by NMB and also appear
to be relieved by inhaled nitrous oxide (N2O) concentrations
greater than 50%.129 No anesthetic agents are contraindicated,
although there are numerous case reports of acute dystonia
during and immediately after general anesthesia using various
techniques including N2O/sevoflurane, N2O/propofol, and
propofol/fentanyl/vecuronium.130-133
DISEASES OF MYELIN
The myelin diseases are a large group of neurodegenerative
disorders associated with abnormal myelinization of either
the central or the peripheral nervous system and also referred
to as “demyelinating diseases.” This group can be subdivided
into dysmyelinating and demyelinating disorders. The dysmy-
elinating subgroup includes disorders associated with inher-
ited defective production of myelin, often manifesting at birth,
whereas demyelinating disorders are acquired later in life
and are characterized by a loss of normal myelin (Box  8-6).
Regardless of the exact cause, abnormal myelinization of the
nervous system leads to impairment of nerve conduction
and eventual loss of function in the affected nerves across the
whole spectrum of the nervous system. Although different
BOX 8-6   n  DISEASES OF MYELIN
Central Nervous System
Multiple sclerosis
Leukodystrophies
Central pontine myelinosis
Subacute combined degeneration
Tabes dorsalis
Multifocal leukoencephalitis
Devic's disease
Acute disseminated encephalomyelitis
Peripheral Nervous System
Hereditary primary motor sensory neuropathies
Acute (Guillain-Barré syndrome) or chronic inflammatory
demyelinating polyneuropathy
Demyelinating (Acquired)
Multiple sclerosis
Central pontine myelinosis
Subacute combined degeneration (vitamin B12 deficiency)
Tabes dorsalis
Acute disseminated encephalomyelitis
Progressive multifocal leukoencephalopathy
Mercury intoxication
Dysmyelinating (Congenital/Hereditary)
Hereditary primary motor sensory neuropathies
Leukodystrophies
Krabbe's disease
Alexander's disease
Pelizaeus-Merzbacher disease
Canavan's disease
Others
Chapter 8  Neurologic Diseases 267
disorders in this group may vary significantly in their presen-
tation, all tend to have a broad range of symptoms involving
many sensory, motor, and cognitive functions, which usually
progress with time, leading to various degrees of disability.
For most of the myelin disorders, no anesthesia experiences
have been reported. Therefore the focus here is on the most
common conditions in this group for which a sufficient num-
ber of reports address various aspects of perioperative care in
these patients. The same anesthetic considerations could be
extrapolated when providing anesthesia care for patients with
similar conditions.
Multiple Sclerosis
Multiple sclerosis (MS) is an acquired inflammatory autoim-
mune disorder possibly caused by an interplay of genetic and
environmental factors, although its exact etiology is unknown.
MS is characterized by widespread, initially partially revers-
ible, demyelination of axonal sheaths in the CNS and sub-
sequent development of sclerotic lesions in the brain, which
eventually results in permanent neurodegeneration. MS pres-
ents with a wide variety of signs and symptoms involving sen-
sory, motor, autonomic, and cognitive functions (Box  8-7).
MS characteristically first manifests in patients in their 20s to
40s, with a twofold to threefold higher prevalence in women.
BOX 8-7   n MULTIPLE SCLEROSIS: CLINICAL SIGNS/
SYMPTOMS*
Sensory Symptoms
Numbness, “pins and needles,” tingling in limbs
Swelling, tightness, coldness of limbs
Proprioceptive deficits
Facial sensory symptoms
Ophthalmic Symptoms
Visual loss related to optic neuritis
Diplopia
Internuclear ophthalmoplegia
Motor Symptoms
Subacute paraparesis or paraplegia, more in lower extremities
Spasticity and possible contractures
Coordination
Vertigo
Gait imbalance
Limb ataxia
Autonomic Nervous System Dysfunction
Bladder, bowel, and sexual dysfunction
Possible orthostatic hypotension
Other Symptoms/Signs
Temperature and exercise insensitivity (Uhthoff phenomenon or
heating reaction)
Pain
Fatigue
Depression
Seizures
*From most common to less common.
 268 ANESTHESIA AND UNCOMMON DISEASES

Many of these patients develop severe disability over time, and
many die from complications related to MS. The etiology, epi-
demiology, pathophysiology, clinical presentation, and treat-
ment of MS have been recently reviewed.134
None of the signs or symptoms listed in Box  8-7 is diag-
nostic of or unique to MS, which can present with neuro-
logic symptoma found in other nervous system disorders. The
combination of these symptoms and the clinical course of MS
progression eventually leads to the diagnosis. The following
subtypes of the disease progression have been identified:
n The relapsing-remitting subtype is characterized by acute
onset of new symptoms (relapses, or exacerbations) fol-
lowed by long periods of remission, during which most
symptoms tend to abate or completely reverse. Timing of
relapses is unpredictable, and often no precipitating factor
can be identified. Up to 80% of patients have this pattern as
initial presentation of MS.
n Secondary progressive MS is characterized by progression of
the clinical picture without periods of obvious remission.
Many patients with relapsing-remitting disease eventually
convert to secondary progressive MS.
n The primary progressive subtype is found in patients
whose clinical symptomatology continues to accumulate
without significant improvements in symptoms after ini-
tial onset of MS.
n The progressive-relapsing subtype is the rarest form and is
characterized by steady, progressive development of dis-
ability with superimposed acute episodes of new neurologic
symptoms.
The MS progression patterns may have a significant effect
on the decision making in the perioperative management
of these patients. Although relapses in patients with near-­
complete remission or sudden worsening of existing symp-
toms can be precipitated by perioperative events, they are not
necessarily synonymous with poor prognosis, but have a pow-
erful emotional effect on MS patients and may dramatically,
even if only temporarily, affect their quality of life.
Factors clinically established as exacerbating MS include
stressful events such as emotional and physical trauma, infec-
tions, surgery, and the peripartum period.135 Hormonal and
temperature fluctuations appear to be clinically correlated
with exacerbations as well. Even small elevations in body core
temperature above normal, as occur in the perioperative set-
ting, can block nerve conduction in previously demyelinated
nerve fibers and produce new neurologic deficits or worsen
others.136 Previously, Edmund and Fog137 documented clini-
cal deterioration with temperature elevations in 75% of MS
patients. However, it is important to emphasize that no evi-
dence indicates that exposure to these precipitating factors
affects the overall prognosis of the disease in these patients.
Treatment. Current therapies for MS are not curative but
attempt to ameliorate acute or chronic symptoms and dis-
ability and reduce the number of future exacerbations. Most
MS relapses respond to glucocorticoid therapy in the early
phases, but many patients fail to respond to corticosteroids
as their number of exacerbations increases. Patients with
optic neuritis respond to oral and IV adrenocorticotropic
hormone (ACTH) and prednisone in the acute phases and
experience fewer relapses. Other immunosuppressive agents,
such as cyclophosphamide, cytarabine, and azathioprine,
have shown intermittent success at preventing the number
and severity of relapses, but do carry side effects. Patients
with severe motor spasticity and bladder dysfunction are
treated with antispastic medications, which provide some
relief. Alternative therapies not clinically proven but tried in
severely resistant cases include plasmapheresis, hyperbaric
oxygen therapy, linoleate supplementation, and interferons.
The most recent, controversial development is related to the
“vascular hypothesis,” suggesting that MS could be caused
by the chronic cerebrospinal venous insufficiency frequently
found in these patients.138 Cerebral venous balloon angio-
plasty result in significant improvement in the course of
MS in preliminary reports. The results of these series are
inconclusive until proper blinded randomized studies can be
conducted. However, if this treatment were to gain a wider
acceptance, administering anesthesia for this procedure may
significantly increase exposure to patients with MS among
anesthesiologists.
ANESTHETIC CONSIDERATIONS
Case reports and observational studies are limited regarding
anesthesia effects and perioperative management in patients
with multiple sclerosis.135,139-150 Some of the earlier reports
implicated a possible connection between the use of general
or neuroaxial anesthesia and relapse of MS or worsening of
existing symptoms.141,143 Despite these reports providing scant
conclusive evidence to support this claim, it has been diffi-
cult to disprove this connection because of the unpredictable
nature of relapses and the potential for the temporary wors-
ening of existing neurologic deficits, even in the absence of
a new demyelinating event. This worsening can be caused by
relatively benign perioperative derangements of homeostasis,
such as hyperthermia or hyponatremia, or administration of
anesthetic agents. This usually brief deterioration is most likely
caused by an enhanced effect of these conditions on already-
impaired but clinically silent conduction delay in previously
demyelinated nerves. Current opinion in anesthesia literature
does not support the idea that administration of anesthesia
can be linked to a new demyelinating event in patients with
MS. In the absence of large, controlled prospective studies, it
is impossible to resolve this issue. Given this lack of conclusive
evidence, designing an anesthetic plan for patients with MS,
even currently asymptomatic, poses a number of unique chal-
lenges (Box 8-8).
Patients with MS presenting for surgery and anesthesia
may typically fit a number of distinct clinical scenarios, which
require different approaches to perioperative management.
In patients with the relapsing-remitting pattern in a remis-
sion presenting for elective or emergency surgery, the main

BOX 8-8   n MULTIPLE SCLEROSIS (MS): ANESTHETIC
ISSUES
Patients with MS have an unpredictable pattern of relapse that may
coincide with postoperative recovery.
Informed consent regarding the effect of anesthetic agents on
the course of the disease is difficult to provide due to lack of
conclusive evidence in the literature.
Thorough preoperative interview and maximal patient participation
regarding choice of anesthetic technique is advisable, combined
with detailed documentation of these discussions.
Neuroaxial and regional anesthesia are not contraindicated in MS
patients, but lower concentrations of local anesthetic and careful
titrations are advisable.
Epidural anesthesia may be preferable to spinal anesthesia.
Patients with MS are at increased risk of intraoperative autonomic
dysfunction.
Patients with advanced disease are at increased risk of perioperative
respiratory depression and sleep apnea.
Avoid monitoring neuromuscular blockade at the affected muscles to
avoid overdose.
Use of depolarizing muscle relaxants should be avoided when
possible in MS patients.
concern is a possible postoperative relapse, either precipitated
by perioperative events or merely coincidental. It is of particu-
lar importance to inform these often asymptomatic but fearful
patients regarding the lack of conclusive evidence connecting
the use of anesthetic agents and MS exacerbation episodes.
Thorough preoperative interview, detailed anesthesia con-
sent, and maximal engagement in the decision-making pro-
cess regarding the choice of anesthetic technique and agents
are crucial in this group of patients. Asymptomatic pregnant
patients with a history of MS pose a special challenge regarding
the use of epidural or spinal anesthesia for labor or cesarean
section. Because MS mainly affects women in their child-
bearing years, many of these women will likely need anesthe-
sia for cesarean birth or ask for analgesia for labor. A further
complication is that late pregnancy is associated with relief
of MS symptoms and reduced number of relapses. However,
the possibility of postpartum relapse increases compared with
nonpregnant patients, although pregnancy does not seem to
adversely affect the overall prognosis of the disease.
Use of neuraxial blockade in patients with MS is controver-
sial because of the potential for direct neurotoxicity exerted
by local anesthetics, especially on demyelinated nerves. Local
and regional anesthesia remains a controversial topic in MS
patients because of the potential pharmacodynamic effects
on nerve conduction. With the pathology of demyelination in
MS, one might expect that the potential for neurotoxicity with
local anesthetics administered in the epidural or intrathecal
space would be higher. However, several retrospective studies
have not demonstrated a significant increase in MS exacerba-
tions with either epidural or spinal local anesthetic administra-
tion.139,143,151-153 Although unproved, many clinicians believe that
repeated doses of local anesthetics for regional anesthesia carry
a potentially increased risk for neurotoxicity, both locally and
Chapter 8  Neurologic Diseases 269
centrally, because the blood-brain barrier may be more perme-
able as a result of chronic inflammatory changes. Therefore,
many believe that lower concentrations of local anesthetics
should be used and combined with narcotics, because there
have been no reports of significant adverse events with epidural
or intrathecal opioids. In a few anecdotal reports, regional or
neuroaxial anesthesia precipitated MS episodes in previously
undiagnosed patients, and temporary worsening of symptoms
followed neuroaxial block for labor.
The prevailing view is that administration of spinal anes-
thetic exposes the spinal cord to higher, potentially toxic con-
centrations compared with epidural anesthesia.139 Despite
these concerns and the limited evidence available, the exist-
ing literature largely supports the view that use of regional
anesthesia does not lead to true relapses of MS and should be
strongly considered in willing patients. This topic has been
recently reviewed.149
The paucity of conclusive evidence regarding the effects of
local and regional anesthesia on the course of MS, combined
with a higher probability of postpartum relapse requires very
thorough prenatal discussion of anesthetic choice, including
careful documentation of these discussions. A recent survey of
practicing anesthesiologists in the United Kingdom indicates a
majority would perform epidural or spinal anesthesia in preg-
nant MS patients, provided special consideration were given
to the relevant issues.154
In a patient with the relapsing-remitting pattern scheduled
for an elective procedure who is found to have new neurologic
deficits, it is prudent to delay surgery for neurologic consul-
tation and therapeutic intervention. In patients with progres-
sive patterns of MS, anesthetic considerations are generally
governed by the disease progression and severity, associated
degree of disability, and comorbidities. Patients with advanced
disease should be evaluated for signs of autonomic dysfunc-
tion, which would warrant the use of invasive monitoring to
guide hemodynamic support intraoperatively. Compensatory
mechanisms in response to intraoperative events, anesthetic
agents, and vasopressors may be altered in these patients.
Patients with cranial nerve involvement and history of upper
airway obstruction and compromised respiratory function
should be considered for postoperative ventilatory support in
the ICU. Intraoperative positioning of patients with spasticity
and contractures can be challenging and may require advance
planning. Increases in body temperature are known to lead to
dramatic increases in symptoms and may precipitate an onset
of new symptoms. As a result, hyperthermia must be carefully
avoided. Even mild fevers should be actively pre-empted and
aggressively treated when detected.
Anesthetic induction agents and inhaled gases have no
demonstrable adverse effects on nerve conduction and
have not been implicated in the literature as contributing
to MS progression. Drugs often administered under anes-
thesia, including anticholinergics, atropine, and glycopyr-
rolate, may also lead to increases in body temperature and
should be used with caution. The use of depolarizing muscle
 270 ANESTHESIA AND UNCOMMON DISEASES
relaxants also carries theoretic risks in MS patients, more
specifically those with profound neurologic deficits that
often cause upregulation of motor-end-plate acetylcholine
receptors and the hyperkalemic response to depolarization.
We have not found any studies that implicate nondepolariz-
ing muscle relaxants in neurologic sequelae perioperatively;
thus their use appears to be safe. Drugs used to treat MS and
associated disorders need to be taken into consideration,
especially corticosteroids and antiepileptic medications.
Nitrous Oxide–Induced Subacute Combined
Degeneration
Subacute combined degeneration (SCD) is a neurodegener-
ative demyelinating disorder of the spinal cord observed in
patients with vitamin B12 deficiency usually suffering from
pernicious anemia, various conditions leading to malnu-
trition, tropical sprue, or HIV infection. A wide range of
neurologic symptoms consistent with myelopathy, such as
progressive weakness, sensory ataxia, paresthesias, spastic-
ity, paraplegia, incontinence, dementia, and visual loss result
from progressive degeneration of the dorsal and lateral white
matter of the spinal cord and in the brain. Neurologic symp-
toms may occur in patients without megaloblastic anemia.
This condition is of particular interest to an anesthesiologist
because of the unique role that N2O can play in the develop-
ment of this condition. By oxidizing the cobalt in the cobola-
min, N2O inactivates vitamin B12 and consequently reduces
methionine synthase activity. Inadequate production of
methionine leads to failure of myelin maintenance in spinal
cord and axonal degeneration.155
Subacute combined degeneration has been reported in pre-
viously healthy recreational N2O abusers with normal blood
levels of B12.156 However, even single use of N2O for anesthesia
in asymptomatic patients with subclinical deficiency of vita-
min B12 may lead to delayed SCD development.157-160 Repetitive
and prolonged exposure to N2O in patients with B12 deficiency
increases the probability of SCD development. Additionally,
SCD tends to develop days or even weeks after uncomplicated
anesthesia with N2O, rendering it difficult to make a con-
nection between the use of N2O and the progressive neuro-
logic deterioration.161 Classic signs of developing myelopathy,
often in combination with personality changes and intellectual
impairments, after recent surgery in patients with pre-existing
disorders predisposing to vitamin B12 deficiency should assist
in arriving at correct diagnosis.
Prompt treatment with vitamin B12 and methionine supple-
mentation usually lead to rapid stabilization and often gradual
improvement and although not necessarily complete, reversal
of symptoms. In patients with known vitamin B12 deficiency
or predisposing conditions such as malnutrition, gastritis, or
gastrectomy, N2O should not be used for anesthesia. With the
availability of newer inhalational and intravenous agents char-
acterized by low context-sensitive decrement times, N2O can
be easily replaced without sacrificing the speed of emergence
from general anesthesia.
PERIPHERAL NERVE DISEASE AND THE
POLYNEUROPATHIES
Peripheral nerve disease covers a wide variety of causation
and clinical entities (Box  8-9). The peripheral nervous sys-
tem (PNS), which encompasses all neural structures out-
side the spinal cord and brainstem, includes a broad variety
of cell types, nerve fibers, anatomic variability, and function.
Likewise, the pathologic conditions capable of affecting the
PNS at multiple points also vary greatly. Signs and symptoms
of polyneuropathies can therefore include impaired motor
function, spasm and fasciculations, reflex changes, sensory
loss, pain and paresthesias, dysesthesias, ataxia, tremor, tro-
phic changes, and autonomic dysfunction. These can all have
acute or chronic onset and duration.
Guillain-Barré syndrome (GBS) is an example of a poly-
neuropathy with motor, sensory, and autonomic components.
It is also an example of demyelinating PNS disease discussed
in the preceding section. The anesthetic considerations of the
polyneuropathies in general are discussed here using GBS as
an illustrative example. However, diagnosis of a specific etiol-
ogy for a mixed polyneuropathy can be challenging. In large
studies, a sizable number of patients remain without a specific
diagnosis of causative agent. Polyneuropathies encountered by
anesthesia providers include those caused by ischemia, diabe-
tes, drugs, rheumatoid arthritis, lupus, sarcoid, Sjögren's dis-
ease, paraneoplasm, acquired metabolic syndrome, uremia,
and alcohol. Of particular interest are the polyneuropathy
of critical illness162,163 and acute quadriplegia and myopathy
attributed to prolonged NMB and corticosteroid use.164 The
inherited polyneuropathies are covered later in this chapter.
Individual neuropathies caused by trauma, radiation, reflex
sympathetic dystrophy (RSD), or inflammation of individual
peripheral nerves are not covered here.
Guillain-Barré Syndrome
Guillain-Barré syndrome, also known as acute idiopathic
polyneuritis or acute inflammatory polyneuropathy, is a cell-­
mediated immunologic response against peripheral nerves
with a number of variant forms (Table 8-4).165-169 GBS is found
worldwide, in both genders and all ages, with an incidence
of about 1.5 per 100,000 population. Pathologic examina-
tion demonstrates perivascular lymphocytic and inflamma-
tory cell infiltration, segmental demyelination, and wallerian
degeneration along entire peripheral nerves and scattered
throughout the PNS. Damage is primarily axonal and thought
to result from an immune-mediated response to myelin pro-
teins.170 In 60% to 70% of patients, GBS is preceded by a mild
GI or respiratory influenza-like illness by 1 to 3 weeks, with
Campylobacter jejuni, Epstein-Barr virus (EBV), or cytomega-
lovirus (CMV) most frequently identified.171 Other preceding
events statistically associated with GBS include surgery, other
viral illness, vaccination, and lymphomatous disease. GBS is
characterized by paresthesias, numbness, and progression to
mainly symmetric weakness. Distal extremities are affected

BOX 8-9   n  PRINCIPAL NEUROPATHIC SYNDROMES
I. Syndrome of acute motor paralysis with variable disturbance of
sensory and autonomic function
A. Guillain-Barré syndrome (GBS; acute inflammatory polyneuro­
pathy; acute autoimmune neuropathy)
B. Acute axonal form of GBS
C. Acute sensory neuro(no)pathy syndrome
D. Diphtheritic polyneuropathy
E. Porphyric polyneuropathy
F. Certain toxic polyneuropathies (thallium, triorthocresyl phosphate)
G. Rarely, paraneoplastic
H. Acute pandysautonomic neuropathy
I. Tick paralysis
J. Critical illness polyneuropathy
II. Syndrome of subacute sensorimotor paralysis
A. Symmetric polyneuropathies
1. Deficiency states: alcoholism (beriberi), pellagra, vitamin B12
deficiency, chronic gastrointestinal disease
2. Poisoning with heavy metals and solvents: arsenic, lead, mer-
cury, thallium, methyl n-butyl ketone, n-hexane, methyl bromide,
ethylene oxide, organophosphates (e.g., TOCP), acrylamide
3. Drug toxicity: isoniazid, ethionamide, hydralazine, nitrofuran-
toin and related nitrofurazones, disulfiram, carbon disulfide,
vincristine, cisplatin, paclitaxel, chloramphenicol, phenytoin,
pyridoxine, amitriptyline, dapsone, stilbamidine, trichloethyl-
ene, thalidomide, clioquinol, amiodarone, adulterated agents
such as l-tryptophan
4. Uremic polyneuropathy
5. Subacute inflammatory polyneuropathy
B. Asymmetric neuropathies (mononeuropathy multiplex)
1. Diabetes
2. Polyarteritis nodosa and other inflammatory angiopathic
neuropathies (Churg-Strauss, hypereosinophilic, rheumatoid,
lupus, Wegener's granulomatosis, isolated peripheral nervous
system vasculitis)
3. Mixed cryoglobulinemia
4. Sjögren-sicca syndrome
5. Sarcoidosis
6. Ischemic neuropathy with peripheral vascular disease
7. Lyme disease
C. Unusual sensory neuropathies
1. Wartenberg's migrant sensory neuropathy
2. Sensory perineuritis
D. Meningeal-based nerve root disease (polyradiculopathy)
1. Neoplastic infiltration
2. Granulomatous and infectious infiltration (e.g., Lyme, sarcoid)
3. Spinal diseases (e.g., osteoarthritic spondylitis)
4. Idiopathic polyradiculopathy
III. Syndrome of chronic sensorimotor polyneuropathy
A. Less chronic, acquired forms
1. Paraneoplastic: carcinoma, lymphoma, myeloma, and other
malignancies
2. Chronic inflammatory demyelinating polyneuropathy (CIDP)
3. Paraproteinemias
4. Uremia (occasionally subacute)
5. Beriberi (usually subacute)
6. Diabetes
first, followed by proximal upper extremities and cranial mus-
cles in 50% of patients. Pain and paresthesias may accompany
variable sensory loss and areflexia.
Signs and symptoms can be limited to lower extremities
or can involve progression to total muscular paralysis with
Chapter 8  Neurologic Diseases 271
7. Connective tissue diseases
8. Amyloidosis
9. Leprosy
10. Hypothyroidism
11. Benign sensory form in elderly patients
B. Syndrome of more chronic polyneuropathy, genetically deter-
mined forms
1. Inherited polyneuropathies of predominantly sensory type
a. Dominant mutilating sensory neuropathy in adults
b. Recessive mutilating sensory neuropathy of childhood
c. Congenital insensitivity to pain
d. Other inherited sensory neuropathies, including those
associated with spinocerebellar degenerations, Riley-Day
syndrome, and universal anesthesia syndrome
C. Inherited polyneuropathies of mixed sensorimotor types
1. Idiopathic group
a. Peroneal muscular atrophy (Charcot-Marie-Tooth; heredi-
tary motor and sensory neuropathy [HMSN], types I and II)
b. Hypertrophic polyneuropathy of Dejerine-Sottas, adult and
childhood forms
c. Roussy-Levy polyneuropathy
d. Polyneuropathy with optic atrophy, spastic paraplegia,
spinocerebellar degeneration, mental retardation, and
dementia
e. Hereditary liability to pressure palsy
2. Inherited polyneuropathies with a recognized metabolic
disorder
a. Refsum's disease
b. Metachromatic leukodystrophy
c. Globoid-body leukodystrophy (Krabbe's disease)
d. Adrenoleukodystrophy
e. Amyloid polyneuropathy
f. Porphyric polyneuropathy
g. Anderson-Fabry disease
h. Abetalipoproteinemia and Tangier disease
IV. Neuropathy associated with mitochondrial disease
V. Syndrome of recurrent or relapsing polyneuropathy
A. Guillain-Barré syndrome
B. Porphyria
C. Chronic inflammatory demyelinating polyneuropathy
D. Certain forms of mononeuritis multiplex
E. Beriberi or intoxications
F. Refsum's disease, Tangier disease
VI. Syndrome of mononeuropathy or plexopathy
A. Brachial plexus neuropathies
B. Brachial mononeuropathies
C. Causalgia
D. Lumbosacral plexopathies
E. Crural mononeuropathies
F. Migrant sensory neuropathy
G. Entrapment neuropathies
Data from Adams RD, Victor M, Ropper AH, editors: Principles of neurology,
New York, 1997, McGraw-Hill.
paresthesias and autonomic dysfunction (hypotension and
hypertension, sinus tachycardia or bradycardia, diaphoresis
or anhidrosis, and orthostatic hypotension). Hyponatremia,
the syndrome of inappropriate secretion of antidiuretic hor-
mone (SIADH), and diabetes insipidus can also occur. Nerve
 272 ANESTHESIA AND UNCOMMON DISEASES
TABLE 8-4  n  Guillain-Barré Syndrome and Its Variant Forms
Incidence/Occurrence Motor or Sensory
ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY
Most common in developed Both motor and sensory
countries of Europe and North
America
ACUTE MOTOR AXONAL NEUROPATHY
Mainly northern China Motor only; axonal damage
ACUTE MOTOR-SENSORY NEUROPATHY
Prolonged course Resembles pure variant
but with some sensory
MILLER-FISHER VARIANT
— No significant weakness,
but can involve cranial
nerves
conduction studies show reduced amplitude of motor evoked
potentials, slowed conduction, prolonged latency, and pro-
longed F waves. Diagnosis is made with an increased find-
ing of protein in the cerebrospinal fluid (CSF) with a normal
cell count. The differential diagnosis includes the muscu-
lar dystrophies, acute spinal cord injury, chronic inflam-
matory demyelinating polyneuropathy, transverse myelitis
or myelopathy, renal failure, polyneuropathy of critical ill-
ness, prolonged corticosteroid use, chronic NMB, and acute
hyperphosphatemia.
Supportive care is an important component of the manage-
ment of GBS. Up to one third of patients will require some
period of mechanical ventilation because of neuromuscular
respiratory insufficiency. Paroxysmal hypertension and ortho-
static hypotension are both common in patients with GBS.
Although these patients are at increased risk for arrhythmia,
sustained sinus tachycardia is common and generally does not
require treatment. Patients with significant autonomic dys-
function may also require ICU management. Patients who
become bedbound also require aggressive skin care, deep vein
thrombosis prophylaxis, pharmacologic maintenance of a
bowel regimen, and physical therapy, as well as acute psycho-
social support if needed. Acute and subacute neuropathic pain
is common and may require opioid analgesia as well as with
nonopioid adjuncts, such as gabapentin or pregabalin, carba-
mazepine, and TCAs.
Current evidence does not support the use of corticoste-
roids or interferon-beta in the management of GBS.172 On
the other hand, large multicenter RCTs have demonstrated
the superiority of plasmapheresis over supportive care alone.
The proposed mechanism of action is removal of circulating
antibodies, complement, and other immunoactive factors.
Patients treated with plasmapheresis in the first 30 days after
onset (and ideally within 7 days) had earlier return of strength,
Characteristic Signs Suspected Etiology
85%-90% of cases; peripheral Cell-mediated immune, and
nerve demyelination humoral; attacks myelin
and Schwann cells
Seasonal; higher incidence of Immune, motor axons;
respiratory failure higher association with
Campylobacter jejuni
Axonal damage of both motor —
and sensory
Ataxia, ophthalmoplegia, Often C. jejuni as well;
areflexia antibodies to cranial nerve
myelin
reduced likelihood and duration of mechanical ventilation,
and improved recovery.173,174 Multiple studies also support the
use of IVIG, which seems as effective as plasma exchange.174-177
Interestingly, no data support the use of these two therapies
in combination or in conjunction with steroids, and choice of
treatment is often guided by locally available experience and
resources.
A majority of patients will experience progression of
GBS for up to 2 weeks and begin remission at 4 weeks. Most
patients experience a complete recovery. Up to 15% have per-
sistent, mild neurologic deficits, and 5% to 10% have a pro-
tracted course with significant permanent neurologic deficits.
Mortality, generally from prolonged mechanical ventilation,
fatal arrhythmia, pulmonary embolism or other sequelae of
critical illness, is estimated at 5%.178 Up to 10% of patients
will experience relapses, generally responsive to resumption
of immunotherapy, and 2% progress to a diagnosis of chronic
inflammatory demyelinating polyneuropathy (CIDP).179
Factors associated with prolonged course and limited recov-
ery include old age, rapid onset of disability, severity of
symptoms, need for mechanical ventilation, and prodromal
diarrheal illness.180,181
ANESTHETIC CONSIDERATIONS
Anesthetic management in patients with Guillain-Barré syn-
drome is similar to that for motor neuron degeneration and
other demyelinating conditions (Box  8-10). Succinylcholine
should be avoided because of the potential for potassium
release, and clinicians should be especially aware of the poten-
tial for increased sensitivity to nondepolarizing NMB. An
arterial line may be useful for patients with autonomic dys-
function, and postoperative ventilation may be necessary
because of reduced respiratory function. Regional anesthe-
sia is controversial; a limited number of case reports claim an

BOX 8-10   n GUILLAIN-BARRÉ SYNDROME (GBS):
ANESTHETIC ISSUES
Up to one third of GBS patients will require mechanical ventilation;
almost all will have severely diminished respiratory reserve.
Autonomic instability, including episodic severe hypertension and
orthostatic hypotension, are common and may warrant invasive
monitoring.
Early plasmapheresis or intravenous immune globulin (IVIG) therapy
can improve outcomes in GBS patients.
Patients with severe disease are vulnerable to complications
of critical illness, including decubitus ulcers, venous
thromboembolism, and ventilator-associated pneumonia.
association with onset or exacerbation of GBS,182,183 although
uneventful use in obstetric patients has also been reported.184,185
Autonomic instability may also complicate regional anes-
thesia; one case report describes a cardiac arrest in a patient
with autonomic instability from GBS after low subarachnoid
block.186 At least three reports of GBS onset in the immediate
postoperative period suggest that anesthesia or surgery may
be a trigger, but supportive evidence is lacking.187-189 Although
extensive data on the use of general anesthesia for GBS patients
are not available, several case reports describe successful use
of general anesthesia with and without NMB for emergency
exploratory laparotomy, video-assisted thoracoscopy, gastros-
tomy, abdominal aortic aneurysm repair, and coronary artery
bypass grafting.190-194
MOTOR NEURON DISEASES
Motor neuron diseases are characterized by variable, progres-
sive, degenerative loss of motor neurons in the frontal cortex,
the ventral horn of the spinal cord, and the lower cranial nerve
nuclei. Clinically, this degeneration manifests as muscle weak-
ness, atrophy, and corticospinal tract signs, often without sig-
nificant cognitive or sensory impairment. Pathologic changes
include loss of anterior horn cells in the spinal cord and lower
brainstem, in which loss of large fibers precedes that of small
fibers. Astrocytes and lipofuscin replace the absent neurons.
In addition to depletion of large motor nerve fibers, there is
loss of muscarinic, cholinergic, glycinergic, and GABA recep-
tors, up to and including the motor cortex. Mutations involv-
ing superoxide dismutase have been identified in some types
of motor neuron degeneration, suggesting that free-radical
activity may contribute to disease progression.195 Box 8-11 cat-
egorizes several of the most common forms of motor neuron
disease; amyotrophic lateral sclerosis, Friedreich's ataxia, and
spinal muscular atrophy are discussed in more detail.
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a progressive neu-
rodegenerative disease involving a combination of upper
motor neuron (UMN) and lower motor neuron (LMN) signs
Chapter 8  Neurologic Diseases 273
BOX 8-11   n  DEGENERATIVE MOTOR NEURON DISEASES
Amyotrophic lateral sclerosis (ALS)
Progressive muscular atrophy
Primary lateral sclerosis
Progressive bulbar (pseudobulbar) palsy
Inherited motor neuron diseases
Autosomal recessive spinal muscle atrophy
l Type I: Werdnig-Hoffmann, acute
l Type II: Werdnig-Hoffmann, chronic
l Type III: Kugelberg-Welander
▪l Type IV: Adult onset
Familial ALS
Familial ALS with dementia or Parkinson's disease (Guam)
Other
l Arthrogryposis multiplex congenita
l Progressive juvenile bulbar palsy (Fazio-Londe)
▪l Neuroaxonal dystrophy
Associated with other degenerative disorders
Olivopontocerebellar atrophies
Peroneal muscle atrophy
Friedreich's ataxia
Guillain-Barré syndrome
Balo's disease
Acute disseminated encephalomyelitis following measles,
chickenpox, smallpox, mumps, rubella, or influenza
Acute and subacute necrotizing hemorrhagic encephalitis
Acute encephalopathic form (Hurst's disease)
Subacute necrotic myelopathy
Acute brain purpura
and symptoms. Characteristic UMN findings include lack of
coordination, hyperreflexia, and spasticity. Degeneration of
LMNs produces weakness, muscle atrophy, and fasciculations.
Asymmetric limb weakness is the most common present-
ing symptom in patients who are ultimately diagnosed with
ALS, but a minority of patients will present with bulbar symp-
toms (dysphagia or dysarthria), axial or truncal weakness, or
respiratory insufficiency. Diagnosis is based on the presence
of UMN and LMN signs in multiple segments, supported by
electrophysiologic testing and not ruled out by neuroimag-
ing or laboratory studies suggesting an alternative diagno-
sis.196,197 Although disease progression is generally relentless
and median survival after diagnosis is only 3 to 5 years, sig-
nificant individual variation is present in terms of distribution
and spread of symptoms. The most common cause of death in
ALS is neuromuscular respiratory failure, often complicated
by progressive dysphagia. Survival may be prolonged in those
patients who elect to undergo tracheostomy and gastrostomy
to facilitate long-term mechanical ventilation and total enteral
nutrition.
Several related forms of motor neuron disease, which were
previously understood as separate disease entities, are increas-
ingly thought to belong to a spectrum of motor neuron degen-
eration that includes ALS. Progressive muscular atrophy is a
condition in which LMN signs predominate. Primary lateral
sclerosis involves primarily UMN signs. Although many of
these patients will ultimately develop some LMN involvement
as well, this variant and a related form of UMN-dominant ALS
 274 ANESTHESIA AND UNCOMMON DISEASES
appear to have a more benign course. Progressive bulbar palsy
refers to UMN and LMN degeneration of the cranial nerves,
which often generalizes to other anatomic segments and is
then referred to as “bulbar-onset ALS.” Flail arm and flail leg
syndromes are ALS variants involving asymmetric progressive
LMN degeneration of the proximal arm or distal leg and are
also notable for a more gradual progression to other segments
and respiratory muscle weakness.198
Pathophysiology and Incidence. Although ALS has clas-
sically been understood as a disease confined to the motor
neurons, recognition of a subset of patients with ALS who
also develop frontotemporal dementia, autonomic insuffi-
ciency, parkinsonism, supranuclear gaze palsies, and sensory
loss has led to the term ALS-plus. It has become increasingly
clear that many patients with ALS will also have either clini-
cal or subclinical manifestations of cognitive and executive
dysfunction, autonomic dysregulation (decreased bowel
motility, hyperhidrosis, sympathetic hyperactivity), extrapy-
ramidal signs, and paresthesias or mild sensory loss. Autopsy
results suggest that the histopathologic hallmarks of ALS are
often identifiable to a lesser extent in sensory and autonomic
pathways.199-201
Incidence of ALS in Europe and North America has been
estimated at 1.5 to 2.7 per 100,000 people per year.195,202 Men
are more likely to be affected than women before age 70, at
which time the male/female ratio begins to equalize. Age is
the only established risk factor for the development of ALS,
and incidence rises with each decade, peaking at age 74.195
Epidemiologic studies demonstrate a gradual increase over
time in both the incidence and the mortality of ALS, which
may represent patterns of environmental exposure, or alter-
natively, may be a function of increased life expectancy.203–205
Approximately 10% of cases are thought to be familial; the
rest are sporadic. Cigarette smoking, heavy-metal expo-
sure, military service, agricultural labor, and other occu-
pational exposures have all been suggested as risk factors,
but none of these factors has been clearly established. Three
high-prevalence geographic clusters have been identified in
Guam, West New Guinea, and the Kii Peninsula of Japan,
but it remains unclear whether environmental exposure or
genetic vulnerability is responsible. Several gene mutations
identified in familial cases of ALS, including SOD1 (super-
oxide dismutase), ANG, TDP-43, and FUS, have also been
found in some patients with sporadic ALS, suggesting that
these may represent important susceptibility factors.206–209
The precise etiology of ALS also remains obscure. Free-
radical damage, excitotoxicity, cytoskeletal abnormalities,
viral infections, mitochondrial dysfunction, and abnormal
programmed cell death or RNA processing have all been
under suspicion.
Frontal motor neurons in the motor strip disappear in
patients with ALS, followed by retrograde degeneration of
axons in the corona radiata, internal capsule, cerebral pedun-
cles, pontine base, medullary pyramids, and corticospinal
tracts. Astrocytic gliosis replaces the lost motor neurons,
a process that may be evident on MRI as bilateral white-mat-
ter abnormalities. The spinal cord and ventral roots atro-
phy and become sclerotic. Affected muscles demonstrate
denervation atrophy and fiber-type grouping characteris-
tic of re-­enervation. At the cellular level, neurofilament and
ubiquitin-­positive inclusions are common, as are eosinophilic
aggregates called bunina bodies, which contain cystatin C, a
protease inhibitor, and appear unique to ALS.
Symptom Management and Palliation. Until recently,
treatment of ALS has been entirely supportive and focused
on symptom management. As the disease progresses, many
patients will require respiratory support, initially noninva-
sive but often leading to an eventual tracheotomy for full-
time mechanical ventilation. Recent efforts to improve
respiratory function using an implantable diaphragmatic
pacemaker have shown some promise in preliminary trials
in ALS patients.210 With progressive dysphagia, gastrostomy
for total enteral nutrition may also be elected. Dysarthria is
common in later stages of the disease, and nonverbal forms
of communication become increasingly important. Many
patients will also develop dyspnea and may benefit from
chest physiotherapy, truncal support, supplemental oxygen,
benzodiazepine therapy, and inhaled or IV opiates. Muscle
spasm may be a significant source of pain and disability for
ALS patients.
Quinine was previously considered the therapy of choice,
but concerns over its safety profile have virtually eliminated
its use for ALS. In its place, carbamazepine and phenytoin
have been suggested, and baclofen, neurontin, and tizani-
dine have been used to treat spasticity, although there is lit-
tle evidence to support the use of any of these therapies.211
Sialorrhea, generally pseudohypersalivation from neuromus-
cular weakness, is also common and may be treated with
atropine, hyoscyamine, amitriptyline, or botulinum toxin
injection of the salivary glands. Conversely, patients may
also develop thickened or retained secretions, necessitating
humidification, increased hydration, and chest physiother-
apy. Finally, many patients with advanced disease will have
outbreaks of inappropriate crying or laughter, referred to as
the “pseudobulbar affect.” Despite limited data, amitriptyline
and fluvoxamine have been used for the treatment of pseu-
dobulbar affect. Although the mechanism is unclear, there is
better evidence for the use of a combination of dextrometh­
orphan (a mild NMDA antagonist) and quinine, a cyto-
chrome P450 inhibitor that may prolong the effective plasma
levels of dextromethorphan.212
Pharmacologic Therapy. Countless pharmacologic agents
have been evaluated for their potential to delay or reverse the
progression of ALS. To date, riluzole remains the only agent
with demonstrated mortality benefit in ALS.213,214 Although
its mechanism of action in ALS is unclear, riluzole is a sodium
channel blocker, has anti-NMDA activity, and is thought to
attenuate glutamate-induced excitotoxicity. Riluzole is gen-
erally well tolerated. Metabolism is through the cytochrome

P450 enzyme 1A2 and may be affected by other inhibitors or
inducers of this pathway. Notable side effects include weak-
ness, dizziness, and GI distress. Increases in transaminases
are common and can be significant. All patients should have
liver enzymes tested frequently in the first few months of use
and periodically thereafter. A number of other glutamate
antagonists, neurotrophic factors, antioxidants, and immu-
nomodulatory and antiapoptotic agents are currently under
investigation, as are stem cell treatments and gene therapy.
ANESTHETIC CONSIDERATIONS
Preoperative evaluation should include a review of the indi-
vidual patient's symptomatology as well as any medications
used in symptom management. Patients with prominent bul-
bar symptoms or advanced disease are at increased risk of
aspiration and respiratory insufficiency. Prediction of respira-
tory failure based on the results of pulmonary testing (various
inspiratory force and vital capacity assessments) is imprecise,
but decreased measures of inspiratory force (particularly SNIF,
or maximal sniff nasal inspiratory force test) and vital capacity
less than 50% of predicted are concerns.
Succinylcholine should be avoided because of the risk of
exaggerated hyperkalemic response. Nondepolarizing neu-
romuscular blockers should be used with extreme caution
because of the potential for increased sensitivity to these
drugs. Although elective intubation of patients with signifi-
cant neuromuscular weakness is problematic, there is no abso-
lute contraindication to any anesthetic technique for patients
with ALS. In a case series of patients with ALS undergo-
ing general anesthesia for diaphragmatic stimulation, use of
short-acting analgesic and amnestic agents, in conjunction
with avoidance of NMB, facilitated postoperative extubation
and was not associated with increased 30-day mortality.215
Successful use of total IV general anesthesia without NMB
has also been described.216 Others have reported success using
local or regional techniques, including peripheral nerve block
and neuraxial anesthesia.217,218
Friedreich's Ataxia
Friedreich's ataxia is a progressive, autosomal recessive genetic
syndrome characterized by ataxia, sensory and motor neu-
ropathy, cardiomyopathy, and diabetes mellitus. The disease
has been linked to loss-of-function mutations of the frataxin
gene, generally involving inheritance of an expanded trinucle-
otide repeat (GAA), which is further subject to age-dependent
somatic expansion.219 Although its precise function is unclear,
frataxin is a mitochondrial protein overexpressed in patients
with Friedreich's ataxia, and mutant frataxin may lead to
excess mitochondrial iron storage and thus to injury from oxi-
dative stress.220 Incidence of Friedreich's ataxia in Caucasians
has been estimated at 1:50,000, and this syndrome accounts
for approximately half of all familial ataxias.221 Onset generally
occurs before age 25, and typical presentation includes vary-
ing degrees of ataxia in all four limbs, diminished or absent
lower extremity reflexes, and pyramidal signs.
Chapter 8  Neurologic Diseases 275
Anatomically, Friedreich's ataxia is characterized by degen-
eration of long ascending and descending fibers in the pos-
terior columns and spinocerebellar tracts of the spinal cord
and the sensory cells in the dorsal root ganglia. Nerve con-
duction studies are consistent with a primarily sensory axonal
neuropathy, and neuropathology demonstrates degenera-
tion of myelinated sensory nerve fibers and secondary axonal
degeneration. In addition to neuropathologic changes, a car-
diomyopathy is often present, typified by cardiomyocytic
hypertrophy, lymphocytic and eosinophilic infiltrates, and
interstitial fibrosis and fatty degeneration.
Cerebellar dysarthria, optic atrophy, and swallowing dys-
function are common in Friedreich's ataxia patients. With
degeneration of the posterior columns of the spinal cord
and dorsal roots, loss of proprioception and vibration sense
occurs early in the disease course. Autonomic involvement
may lead to bladder dysfunction. Motor neuron degeneration
also leads to distal muscle atrophy and subsequently, in young
patients, to the development of talipes (pes) cavus and kypho-
scoliosis. Many patients will be confined to a wheelchair as
the disease progresses. Hypertrophic cardiomyopathy leads
to an increased risk of lethal arrhythmia, and most patients
will develop electrocardiographic and echocardiographic
abnormalities.222 As many as one third of patients will develop
impaired glucose tolerance or diabetes mellitus.223
Treatment of Friedrich's ataxia is primarily supportive.
Antioxidant therapy has been advocated based on the theory
that it is a disease of oxidative stress. However, data support-
ing the use of vitamin E, coenzyme Q10, and the free-­radical
scavenger idebenone are limited or conflicting. Although no
clear evidence indicates that idebenone improves neurologic
function in patients with Friedreich's ataxia, the drug has
an excellent safety profile, and some data support its use in
patients with cardiomyopathy.224 Iron chelation, primarily
with the agent deferiprone, has also been studied, but the risk
of agranulocytosis and the typically normal or low serum iron
levels in patients with Friedreich's ataxia are limitations to this
approach.225 Gene therapy and targeted modulation of DNA
transcription (e.g., using histone deacetylase inhibitors) are
promising future therapies.226
ANESTHETIC CONSIDERATIONS
Friedreich's ataxia patients with bulbar symptoms are at risk
for aspiration and postoperative respiratory compromise, and
patients with severe scoliosis may have restrictive lung dis-
ease or impaired respiratory reserve. As in other motor neu-
ron diseases, succinylcholine should be avoided, and patients
may exhibit increased sensitivity to nondeploarizing neuro-
muscular blockers. There are no contraindications to any spe-
cific anesthesia technique, including regional anesthesia. An
IV technique for general anesthesia and e­ndotracheal intu-
bation using alfentanil and propofol has been used without
complication.227 Safe use of nondepolarizing NMB with care-
ful train-of-four measurement has also been described.228,229
Neuromonitoring for spine, cardiac, or vascular surgery
may be complicated, because these patients generally have
 276 ANESTHESIA AND UNCOMMON DISEASES

abnormal somatosensory evoked potentials. As noted previ- ANESTHETIC CONSIDERATIONS

ously, patients with Friedreich's ataxia are also at significantly
increased risk for cardiomyopathy and congestive heart fail-
ure, as well as lethal arrhythmia, and should be evaluated for
cardiac disease before surgery.
Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) refers to a group of degener-
ative disorders of the anterior horn cells and lower brainstem
motor nuclei, resulting in diffuse proximal muscle weakness.
SMA type I, or Werdnig-Hoffman disease, typically presents in
the neonatal period and is characterized by severe, symmetric
flaccid paralysis and generally results in death from respira-
tory failure during the first year of life. SMA type II (interme-
diate form) and type III (Kugelberg-Welander disease) present
slightly later (3 months to 2 years), have more variable degrees of
weakness, and progress more slowly.230 SMA type IV is a slowly
progressive, adult-onset variant with a more benign course.
Spinal muscle atrophy is inherited in an autosomal reces-
sive pattern, although sporadic cases account for a small
minority. Most forms are caused by mutations or deletions of
the survival motor neuron 1 (SMN-1) gene on chromosome
5q. A  clinically heterogeneous group of non-5q SMA disor-
ders have also been described, but these are rare. The vari-
ability in onset and progression of disease in all forms of SMA
is thought to depend partly on the ability of a related protein,
referred to as SMN-2, to carry out the functions of SMN-1.
SMN is believed to be involved in mRNA synthesis in motor
neurons and may inhibit apoptosis.231,232
Treatment of patients with SMA is supportive, prevent-
ing aspiration and providing supplemental nutrition, chest
physiotherapy, and respiratory support. Valproate increases
expression of SMN type II in vitro and may improve strength
in patients with SMA type III or IV.233,234 Although promising
in preclinical studies, phenylbutyrate showed no benefit in an
RCT.235 In a mouse model, gene therapy using a viral vector to
augment spinal cord SMN expression has shown promise.236
Patients with SMA are at variably increased risk for perioper-
ative respiratory compromise. Patients who are not mechan-
ically ventilated preoperatively may require or may benefit
from noninvasive positive-pressure ventilation in the postop-
erative period. Degeneration of the anterior horn cells leads to
decreased choline acetyltransferase (part of acetylcholine syn-
thesis pathway) and may produce increased sensitivity to non-
depolarizing NMB. Succinylcholine should be avoided because
of its potential to cause an exaggerated hyperkalemic response
and myotonia-like contractions. Narcotics should be titrated
carefully because of potential postoperative respiratory hypop-
nea. Neuraxial and regional anesthesia have been used success-
fully in SMA patients,237–240 but blocks affecting the accessory
muscles of respiration or the diaphragm may not be well toler-
ated. TIVA has been used successfully, as has dexmedetomidine
for semiawake fiberoptic intubation.240–242 In a retrospective
case review in pediatric patients with SMA, successful anes-
thetics included balanced general anesthesia with inhalational
agents, TIVA approaches, and regional techniques.243
NEUROECTODERMAL DISORDERS
Neuroectodermal disorders belong to a group of con-
genital malformations affecting structures of ectoder-
mal origin and are characterized by coexistent skin and
nervous system lesions. Neurofibromatosis type I (von
Recklinghausen's disease) and type II, von Hippel–Lindau
disease (VHLD), tuberous sclerosis, and Sturge-Weber
syndrome are of particular interest to anesthesiologists
because of the multiple anesthetic challenges that these
patients may present. Table 8-5 provides patterns of inher-
itance, genetic characteristics, and encoded proteins asso-
ciated with identified genetic mutations.
Neurofibromatoses, VHLD, and tuberous sclerosis are also
often called phakomatoses on the basis of the patchy oph-
thalmologic manifestations observed in these disorders.
Significant progress in understanding pathogenesis reveals that

TABLE 8-5  n  Neuroectodermal Disorders: Genetic Characteristics and Mutations

Disorder Pattern of Inheritance Genetic Mapping and Protein Product

Neurofibromatosis type I Autosomal dominant trait, familial transmission NF1 gene on chromosome 17, truncated
(von Recklinghausen's disease) in 50%, the rest are spontaneous mutations. (nonfunctional) neurofibromin

Neurofibromatosis type II Complete penetrance, variable expression NF2 tumor suppressor gene on chromosome 22,
truncated merlin; other genes may be involved

von Hippel–Lindau disease Autosomal dominant trait with variable high VHL gene on chromosome 3, VHL protein; other
penetrance genes may be involved

Tuberous sclerosis Autosomal dominant trait, one-third are familial TSC1 gene on chromosome 9 and TSC2 on
transmission, the rest are spontaneous chromosome 16, encoding for hamartin and
mutations or mosaicism. tuberin, respectively
Complete penetrance, variable expression

Sturge-Weber syndrome Not inherited Unknown

 Chapter 8  Neurologic Diseases 277

phakomatosis is characterized by loss of function of various
tumor suppressor genes, which in turn leads to the development
of benign or malignant tumors in many tissues.244 Although the
inheritance patterns and pathogenesis of Sturge-Weber syn-
drome are unknown, it is usually discussed together with phako-
matoses because of the similarity of the clinical manifestations
and the distribution of lesions observed in these disorders.245 All
these neuroectodermal disorders are chronic conditions, with
increasing pathology over the patient's lifetime.
Neurofibromatoses
Neurofibromatoses are genetic disorders of the nervous
system primarily affecting the development and growth
­ is much less prevalent in the general population (1:210,000)
of neural tissues and causing subsequent growth of neural
tumors. The  neurofibromatoses are divided into type I, or
NF1, also known by its eponym as von Recklinghausen's dis-
ease, and type II, or NF2. The former is much more common
and accounts for 90% of all neurofibromatoses. These two
types have different causes, and their clinical manifestations
and diagnostic criteria differ significantly (Table 8-6). Other
rare forms of neurofibromatosis have been reviewed.246
While evaluating a patient diagnosed with neurofibroma-
tosis for surgery and anesthesia, it is important to make a dis-
tinction between NF1 and NF2. Unlike patients with NF1,
in which associated pathology may involve all systems in the
body, relevant clinical manifestations of NF2 are largely lim-
ited to intracranial pathology.247 Importantly, although NF2
than NF1 (1:5000), most of the patients with NF2 will require

TABLE 8-6  n  Comparison of Neurofibromatosis Types 1 and 2 (NF1 vs. NF2)

NF1 NF2

Neural tissue tumors
Neurofibromas (major feature) of the skin,
peripheral nerves and along nerve roots;
plexiform neurofibromas (can become
malignant), astrocytomas (not malignant), optic
nerve gliomas
Vestibular (often called acoustic neuromas)
or other cranial nerve schwannomas (main
feature); spinal schwannomas, astrocytomas,
meningiomas, and ependymomas

Cutaneous manifestations Café au lait spots (usually the first symptom of Rare
NF1), cutaneous neurofibromas

Ocular manifestations Pigmented iris hamartomas or Lisch nodules None

Central nervous system Epilepsy, hydrocephalus, and mild mental Intracerebral calcifications
(besides tumors) retardation more frequent than in general
population

Cardiovascular involvement Essential hypertension, renovascular None

(renal artery stenosis) hypertension,
pheochromocytoma-related hypertension,
vascular neurofibromatosis, aortic and cerebral
aneurysms, obstruction of major thoracic
vessels by neurofibromas

Pulmonary involvement Fibrosing alveolitis None

Osseous involvement Many bone abnormalities, including chest None

deformities, kyphoscoliosis, sphenoid and
occipital bone dysplasia, and long-bone
deformities

Other systems Neurofibromas of gastrointestinal system, None

intestinal carcinoid tumors, association with
multiple endocrine neoplasia syndrome type III,
which includes pheochromocytoma, NF1, and
medullar thyroid carcinoma

Diagnostic criteria Cutaneous (95% of adult patients), nodular Bilateral acoustic neuromas or first-degree
(peripheral nerves) and plexiform (30%) relative with NF2 in combination with unilateral
neurofibromas, café au lait spots, Lisch nodules acoustic neuroma, meningioma, glioma, or
(95%), optic nerve glioma schwannoma

Symptoms Symptomatic picture of NF1 is immensely diverse Tinnitus and poor balance from eighth nerve
and determined by degree of involvement of tumors. Headache, facial pain, facial
various body systems. Severity of symptoms numbness, and other symptoms are related to
varies widely among patients. pressure effect of growing neural lesions.
 278 ANESTHESIA AND UNCOMMON DISEASES
surgical removal of cranial nerve schwannomas, an NF2 pri-
mary manifestation. As a result, anesthesiologists in neurosur-
gical practice frequently see these patients, whereas in general
practice the likelihood of seeing patients with NF2 is very low.
To date, most anesthetic and medical literature concerned
with management of neurofibromatosis is limited to NF1.
Here, we cover mainly the issues related to the perioperative
management of NF1 patients. The specifics of NF2 anesthetic
management are addressed when relevant.
PREOPERATIVE EVALUATION
The severity of clinical manifestations of NF1 varies greatly
between patients and usually increases over the patient's life-
time. NF1 might involve multiple organ systems, thus present-
ing a formidable challenge to an anesthesiologist. Familiarity
with the clinical manifestations of NF1 and a systematic
approach to preoperative assessment of these patients are
essential to successful anesthetic management.247
Airway Assessment. Thorough assessment of the airway
is important in NF1 patients. Neurofibromas associated with
NF1 can affect any segment of the airway. Intraoral lesions
have been reported in up to 5% of patients with NF1, involv-
ing the tongue and the laryngeal and pharyngeal structures,
leading to obstruction and dyspnea.247 Plexiform and major
subcutaneous neurofibromas are often found in the cervical
region and parapharyngeal spaces. Large lesions can cause
significant airway distortion and obstruction. Unanticipated
sudden airway obstruction after induction of general anesthe-
sia has been reported requiring emergency tracheostomy.248,249
Large neurofibromas originating in the posterior mediasti-
num, retroperitoneal space, or cervical paraspinal areas can
lead to progressive compression of the distal airway.250,251
Additionally, involvement of the recurrent laryngeal nerve
can result in unilateral vocal cord paralysis.252 Cranial nerve
involvement from the large intracranial tumors found in neu-
rofibromatosis can lead to impairment and loss of effective gag
reflex and swallowing mechanisms,247 which can leave the air-
way unprotected after extubation in these patients.
Additionally, some NF1 patients can have macrocephaly,
mandibular abnormalities, and undiagnosed cervical spine
instability, further complicating airway management. Patients
with neurofibromas involving the cervical spine should be
evaluated for cervical instability, including radiography, neck
CT, or MRI as needed.
Cardiovascular Assessment. All NF1 patients should be
screened for hypertension, which is common and caused by
renal artery stenosis, catecholamine-secreting nodular plexi-
form neurofibroma, or pheochromocytoma (found in up to
1% of patients).253 In patients with hypertension that is parox-
ysmal or resistant to routine treatment, it is essential to exclude
pheochromocytoma, which is associated with high intraopera-
tive morbidity and may lead to death if not detected preop-
eratively.247 All patients with NF1 should be questioned for
the presence of brief headaches, anxiety attacks, palpitations,
and night sweats, which are common for pheochromocytoma.
Coarctation of the abdominal or thoracic aorta is another rare
cause of hypertension in NF1. Other cardiovascular pathologic
processes associated with NF1 include vena caval obstruction
by mediastinal tumors, generalized vasculopathy caused by
vascular nodular proliferation, and potential association with
hypertrophic cardiomyopathy.247
Pulmonary Assessment. Pulmonary function should be
evaluated for the presence of restrictive lung disease, which
can be caused by kyphoscoliosis, intrapulmonary neurofi-
bromas, and progressive pulmonary fibrosis associated with
NF1.247 Patients are questioned for the presence of cough or
dyspnea. Chest radiography and ABG analysis are ordered if
pulmonary involvement is suspected, to help evaluate the need
for postoperative ventilation and ICU admission.
Central Nervous System Assessment. CNS tumors are
major manifestations of both NF1 and NF2. Therefore, all
patients must be evaluated for undiagnosed CNS tumors and
increased intracranial pressure (ICP). The clinician cannot
rely on absence of intracranial or intraspinal tumors on earlier
examinations, because new, asymptomatic tumors in different
locations can appear over time. Also, new neurologic symp-
toms should not be ascribed to the pre-existing CNS lesions,
and the possibility of new pathology should be explored.
Additionally, these patients should be assessed for the pres-
ence of epilepsy and questioned for the nature of their seizures
and type of anticonvulsant therapy. The possibility of cere-
bral aneurysms or intracranial internal carotid artery steno-
sis should be investigated if the patient is symptomatic.254 The
brainstem structures can also be affected by neurofibroma or
gliomas, which can lead to central hypoventilation, requiring
ventilation support with prolonged weaning after surgery.255
Mild mental retardation may be present in these patients, and
the degree of the patient's cooperation should be evaluated.
Other Systems. Patients with NF1 may have carcinoid
tumors, especially in the duodenum,247 and present with car-
cinoid syndrome and significant risk of perioperative morbid-
ity and mortality. Symptoms of carcinoid syndrome include
flushing, bronchoconstriction, diarrhea, and right-sided heart
lesions. Perioperative management of patients with carcinoid
syndrome has been reviewed.256 The association of NF1, carci-
noid tumor, and pheochromocytoma would make the correct
diagnosis especially difficult.257
In pregnancy, NF1 presents an increased risk of severe
hypertension, potentially rapid growth of CNS lesions, and
intracranial hypertension. Patients should be assessed for the
presence of an intraspinal tumor before deciding to employ
neuraxial anesthesia. The association of pregnancy, NF1, and
pheochromocytoma carries very high risks.247
ANESTHETIC CONSIDERATIONS
Anesthetic experience in patients with neurofibromatosis is
limited to few case reports. The anesthetic challenges in these
patients are many, and anesthetic management should be
based on the existing pathology and its severity (Box 8-12).

BOX 8-12   n NEUROECTODERMAL DISORDERS:
ANESTHETIC ISSUES
Neurofibromatosis (NF1 and NF2)
Anesthetic challenges relate to the severity of symptoms, which vary
greatly between patients, from insignificant to life threatening, but
increase with age.
Intracranial tumors are frequently present, and patients with
neurofibromatosis must be evaluated for possible intracranial
hypertension.
Airway involvement is common and takes different forms. Thorough
examination of the entire length of the airway is mandatory to
avoid unanticipated, life-threatening complications. Consider
special airway techniques.
Cardiovascular pathology is common, extremely diverse, and
progresses with age. Preoperative optimization may be required.
Thorough evaluation of hypertension is mandatory to exclude
associated pheochromocytoma.
Pulmonary, endocrine, and renal pathology is less common but can
have serious anesthetic implications and should be included in the
evaluation.
No specific anesthetic techniques or agents are contraindicated in
NF1 or NF2 patients.
von Hippel–Lindau Disease (VHLD)
Anesthetic challenges are mainly determined by the type of surgery.
Independent of type of surgery, all patients with VHLD must be
evaluated for concurrent pathology.
Presence of spinal or cerebellar lesions (hemangioblastomas) is a
relative contraindication for the use of neuroaxial anesthesia and
should be considered even in asymptomatic patients.
Tuberous Sclerosis (TS)
Patients typically display various degrees of mental retardation and
poor cooperation.
Seizure disorder is one of the main manifestations of TS. Effects
of anticonvulsant therapy on anesthetic agents, especially
neuromuscular blockers, need to be considered.
Airway management should consider high probability for intra-airway
lesions, including significant obstruction and potential for bleeding;
adequate preparations must be made.
Intrapulmonary, cardiac, and renal lesions are frequent findings
in patients with TS. Functional evaluation of these systems
preoperatively is advisable with such involvement.
No specific anesthetic techniques or agents are contraindicated in
TS patients.
Awake fiberoptic intubation is the preferred approach in
patients with airway lesions, although even elective awake
fiberoptic intubation can fail when gross anatomic distor-
tion is present.258,259 In pediatric or mentally impaired patients,
an asleep fiberoptic intubation in a spontaneously breath-
ing patient should be considered. Sevoflurane induction fol-
lowed by fiberoptic intubation in spontaneously breathing
patients has been successfully employed.260 Alternatively, dex-
medetomidine has been successfully used for awake fiberop-
tic intubation in a patient with cervical lesions compressing
the spinal cord.259 In all NF1 patients with complicated air-
way, advanced planning as outlined in the American Society
of Anesthesiologists (ASA) guidelines for the difficult air-
way management is advised.261 A difficult airway cart and
possibly equipment for emergency tracheostomy should be
immediately available, depending on the severity of airway
distortion.262
Chapter 8  Neurologic Diseases 279
The severity of the cardiovascular or cerebrovascular
pathology will dictate the extent of hemodynamic monitoring.
An intra-arterial catheter is advised in all patients with severe
hypertension and associated cerebrovascular pathology to
ensure appropriate cerebral perfusion pressure. Use of central
venous and pulmonary artery catheters should be reserved for
patients with active pheochromocytoma, carcinoid syndrome,
and cardiac lesions with advanced cardiac disease.
Neuraxial anesthesia should not be performed in patients
with increased ICP or intraspinal lesions. The presence of sig-
nificant kyphoscoliosis might also complicate conduction of
neuraxial anesthesia.263 If it is perceived that neuraxial anes-
thesia is preferable because of the high risk of general anesthe-
sia, spinal cord neurofibromas and intracranial hypertension
need to be ruled out using CT or MRI.264,265
Although there have been many reports of altered response
to nondepolarizing muscular blockers and succinylcholine, the
results of a large retrospective study indicate that the response
to various muscular blockers is unchanged in patients with
neurofibromatoses.247,266 However, NMB should be monitored,
especially in NF1 patients with renal impairment or those
receiving anticonvulsant therapy. Succinylcholine should be
avoided in the presence of neurologic deficits. There are no
contraindications to any specific anesthetic agents. Potent
inhalational agents and N2O should be used with caution in
patients with large intracranial tumors and increased ICP.
Positioning of NF1 patients may be complicated by gross
deformities of the chest, spine, or the neck. Potential cervi-
cal instability should be considered when positioning these
patients.259 The combination of chest deformities and intra-
thoracic neurofibromas can lead to severe hemodynamic com-
promise caused by the sternal compression of the heart in the
prone position.267
Careful planning for extubation is warranted in patients
with a difficult airway. Postoperative respiratory support
and slow weaning may be necessary in patients with restric-
tive lung disease of hypoventilation syndromes because of the
brainstem involvement.
von Hippel–Lindau Disease
von Hippel–Lindau disease is an autosomal dominant neo-
plastic syndrome of variable expression. VHLD is charac-
terized by the development of various benign or malignant
tumors and cystic lesions in many organ systems.268 Whereas
hemangioblastomas of the retina and the CNS are the most
typical lesions found in VHLD patients, lesions of many other
visceral organs are also frequently found (Table 8-7). The clin-
ical presentation of VHLD is highly variable and progressive.
Various tumors can affect multiple organs at the same time.
Penetrance of VHLD increases with age, reaching 90% by age
60.269 In the past, the majority of patients with VHDL died of
complications of the renal cell carcinoma and CNS hemangio-
blastoma. With improvements in the treatment and diagnosis
of VHDL, including serial screening and a multidisciplinary
approach to management of these patients, their life expec-
tancy has significantly improved.268 Over their lifetime, the
 280 ANESTHESIA AND UNCOMMON DISEASES

TABLE 8-7  n  Von Hippel–Lindau Disease: Distribution of Lesions

Lesion Frequency in Patients Mean Age at Onset Clinical Symptoms

CENTRAL NERVOUS SYSTEM (CNS)

Retinal hemangioblastoma 25%-60% 25 yr Glaucoma, vision loss, blindness

CNS Hemangioblastomas
Cerebellum 44%-72% 33 yr Headache, nausea, ataxia, motor and
Brainstem 10%-25% 32 yr sensory deficits, hearing loss; pain
Spinal cord 13%-50% 33 yr syndromes
Lumbosacral nerve roots <1% Unknown
Supratentorial <1% Unknown

Other CNS Lesions

Endolymphatic sac tumors (petrous 11% 22 yr Hearing loss, tinnitus, vertigo, facial
bone papillary adenoma) paresis

Syringomyelia 80% (in patients with CNS

lesions)

VISCERAL
Renal cell carcinoma or cysts 25%-60% 39 yr Hematuria, flank pain

Pheochromocytoma 10%-20% 30 yr Often asymptomatic, with sudden

hypertensive crisis

Pancreatic tumor or cysts 35%-70% 36 yr Abdominal pain, jaundice

Epididymal cystadenoma 25%-60% Unknown

Broad ligament cystadenoma Unknown Unknown

majority of patients with VHLD require surgical treatment
under general anesthesia for the CNS hemangioblastomas,
sometimes preceded by embolization, pheochromocytomas,
and renal cell carcinoma.
Several serious anesthetic concerns in patients with VHLD
need to be considered during preoperative evaluation. These
patients need to be evaluated for the presence of pheochromo-
cytomas, CNS lesions, and renal function impairment caused
by renal cell carcinoma.
Pheochromocytomas in VHLD can be multiple, bilateral,
and in some patients the only manifestation of the disease,
with 5% of the tumors being malignant. Although pheo-
chromocytomas are found only in 10% to 20% of VHLD
patients, the recent preoperative screening for hidden pheo-
chromocytomas is essential because of the high potential
for perioperative hypertensive crisis and potential mor-
tality associated with undiagnosed pheochromocytoma,
especially in pregnancy.270 Anesthesia for a patient with
pheochromocytoma has been reviewed271 and is also covered
in Chapter 13. Definitive diagnosis is based on demonstrat-
ing excessive production of catecholamines, by measuring
urine and blood levels of catecholamines and urinary meta-
nephrines, and supported by CT and MRI.269
Patients with VHLD should be evaluated for the pres-
ence, distribution, and size of the CNS lesions. Symptoms
of increased ICP or local mass effect can be present in these
patients (see Table  8-7). The postoperative central hypoven-
tilation syndrome and bulbar palsy with impairment of
swallowing mechanisms have been reported after removal of
brainstem hemangioblastomas.272 Postoperative respiratory
support and careful planning for extubation are warranted.
The experience of anesthetic management of patients with
VHLD is limited to a few case reports in the literature.273-283
The choice of anesthesia and monitoring in these patients is
dictated by type of surgery and extent of existing pathology
(see Box  8-12). For example, the anesthetic management for a
patient undergoing posterior fossa decompression in the sitting
position for the excision of intramedullary hemangioblastoma
differs from that for nephrectomy for renal cell carcinoma. There
is no contraindication to use of any specific anesthetic agents. The
use of an intra-arterial catheter is indicated for craniotomy and
pheochromocytoma removal. Use of a central venous or pulmo-
nary artery catheter is warranted for the removal of pheochro-
mocytoma. Neuraxial anesthesia has been successfully used for
cesarean section or delivery in patients with VHLD.273,275,279,281,282
However, risks related to use of neuraxial anesthesia in patients
with an asymptomatic spinal cord or cerebellar hemangioblas-
toma should be carefully considered.284
Tuberous Sclerosis
Tuberous sclerosis (TS) complex is inherited as an autosomal
dominant trait with a prevalence of 1 in 50,000 to 300,000 pop-
ulation. TS is a multisystem disorder primarily characterized
by cutaneous and neurologic involvement. However, cardiac,
pulmonary, and renal involvement have also been reported.244

The clinical picture of TS is determined by the organs involved
and the extent of that involvement. However, the most fre-
quent clinical presentation of TS is generalized or partial
seizures, which typically start in early childhood. The sever-
ity and onset of the seizure disorder correlate with degree of
developmental problems.189
The characteristic skin lesions are usually the first evidence
of TS, with the most common being hypopigmented macula in
different shapes (90%), adenoma sebaceum (50%), “shagreen”
patches, café au lait spots, fibromas, and angiomas. The CNS
pathology consists of subependymal nodules or giant cell astro-
cytomas (90%) and hamartomatous regions in the cortex called
tubers, which give the name to the disorder and are believed to be
the cause of seizures (80%-100%) and mental retardation (50%).
Developmental delays and behavioral problems are found in 45%
to 70% of patients with TS. Cardiac rhabdomyomas are present
in up to 50% of infants with TS and often regress with age.285
A high incidence of congenital heart disease in patients with TS
has been reported.285 Cardiac abnormalities secondary to TS can
lead to obstruction of flow, congestive heart failure, arrhythmias,
conduction delays, and pre-excitation. Renal lesions composed
of primary renal cysts and angiomyolipomas are found in half of
all patients with TS. Renal angiomyolipomas are associated with
early-onset severe hypertension and may result in renal hemor-
rhage. Pulmonary cysts and lymphangiomyomatosis have been
reported. Pleural thickening can lead to recurrent spontaneous
pneumothorax. Upper airway fibromas and papillomas involv-
ing the tongue, the palate, and sometimes the larynx or pharynx
have been reported in TS patients.
No specific treatment exists for most TS manifestations,
except standard medical anticonvulsant therapy. Based on
clinical series, many patients with TS require general anesthe-
sia for diagnostic or surgical procedures in their childhood.285
Most of these patients have surgery for intractable seizures
caused by tuberous lesions.
PREOPERATIVE EVALUATION
Preoperative evaluation of patients with TS should be directed
toward determination of the extent of neurologic, cardiovas-
cular, pulmonary/airway, and renal involvement. Data on the
nature of seizure disorder, anticonvulsant medications and their
effectiveness, degree of mental retardation, and behavioral prob-
lems should be collected. Patient cooperation is also assessed.
Increased ICP caused by intracranial lesions should be excluded.
Cardiovascular assessment includes an ECG and is per-
formed in all patients to exclude arrhythmias, conduction
defects, or pre-excitation, which are often found in patients
with rhabdomyomas. If heart involvement is suspected, echo-
cardiography and chest radiography are performed to rule out
congenital heart disease and congestive heart failure caused
by rhabdomyomas or TS pulmonary involvement. The upper
airway should be evaluated for the presence of TS nodular
tumors. A history of spontaneous pneumothorax is noted,
because it can recur and is associated with high mortality.
Chest radiography and ABG analysis are ordered if pulmo-
nary involvement is suspected, to help evaluate the need for
Chapter 8  Neurologic Diseases 281
postoperative ventilation and ICU admission. Renal function
should be assessed and associated hypertension ruled out.
ANESTHETIC CONSIDERATIONS
The experience of anesthetic management of patients with TS
is limited to a number of case reports and retrospective series
reported in the literature285-290 (see Box  8-12). No specific
anesthetic agents are contraindicated in TS, and the choice of
anesthetic is determined by the magnitude of the surgical pro-
cedure and the severity of TS. Airway management might be
complicated in patients with airway lesions, and alternatives
to direct laryngoscopy should be considered. Careful planning
for extubation in these patients is warranted and is based on
the size of the airway masses and extent of pulmonary involve-
ment. Anticonvulsant therapy should be optimized before
surgery and continued throughout the perioperative period.
Anesthetic management is tailored to prevent exacerbation of
seizures. NMB should be monitored with a nerve stimulator.
Patients receiving chronic anticonvulsive therapy may have
higher requirements for nondepolarizing muscle relaxants.291
Regional anesthesia is not contraindicated in TS patients and
has been safely employed.287
Sturge-Weber Syndrome
Sturge-Weber syndrome (SWS) is a rare congenital (not heri-
table) vascular disorder of unknown etiology.245 Its hallmark
manifestations are a facial angioma (port-wine stain) and a
leptomeningeal angioma. The facial angioma, besides present-
ing a serious aesthetic problem for the patient, can also involve
the eye structures, leading to glaucoma. In cases of increased
intraocular pressure refractory to medication, surgical inter-
vention is recommended. The leptomeningeal angioma is asso-
ciated with progressive neurologic symptoms, such as seizures
(80%), hemiparesis, mental retardation (50%-66%), behavioral
problems, visual field defects, and hydrocephalus. Seizures are
treated with anticonvulsant therapy but may be refractory in
more than 50% of patients, in whom hemispherectomy or lim-
ited surgical excision of epileptogenic tissue has been performed
successfully. Differential diagnosis of SWS is not problematic
because clinical features do not overlap with other disorders.
Prognosis for SWS patients is determined largely by the severity
of seizures and size of leptomeningeal angioma. However, the
disease is typically not fatal. There is no specific treatment for
SWS, although the cutaneous, ocular, and neurologic manifes-
tations are managed medically or surgically with mixed success.
Most of the patients with SWS requiring a surgical pro-
cedure will need it for the surgical treatment of facial or
ocular angioma or removal of intracranial leptomeningeal
angioma causing seizures that are refractory to medical ther-
apy. Preoperative evaluation of patients with SWS should be
directed toward determination of the extent of neurologic
pathology and associated symptoms. Patients should be evalu-
ated for signs of increased ICP and hydrocephalus. If the surgi-
cal procedure is not for the treatment of seizures, optimization
of anticonvulsant therapy should be considered.
 282 ANESTHESIA AND UNCOMMON DISEASES

Minimal evidence in the literature supports any particu-
lar anesthetic approach to these patients. Two case reports
describing anesthetic management of patients with SWS pro-
vide no information regarding adverse reactions to particular
anesthetic regimens.292,293 Adverse outcomes related to use of
general anesthesia are also not reported in the surgical litera-
ture on management of patients with Sturge-Weber syndrome.
POSTERIOR FOSSA ANOMALIES AND
ARNOLD-CHIARI MALFORMATIONS
The “Arnold-Chiari malformation” (Chiari malformation type II)
is the traditional eponym used in the anesthesia literature to
denote a group of congenital posterior fossa anomalies. This
group of disorders includes many other disorders besides Chiari
malformation type I (CM-I) and type II (CM-II), and the list
grows every year (Table 8-8). The semantic confusion in the litera-
ture regarding precise definition and classification of this group of
disorders can be explained by rapid progress in the neuroimaging
characterization of existing pathology and in the understanding
of brainstem and cerebellar development. However, the current
lack of understanding of etiology and pathogenesis in most of
these conditions precludes a complete classification that would
be accepted in all the different fields of medicine involved with
the management of posterior fossa disorders.294
This discussion details CM-I and CM-II, which constitute the
vast majority of all posterior fossa anomalies in the general pop-
ulation. The rest (or at least some) of these disorders and their
characteristic features are presented in Table 8-8. In the past the
term Arnold-Chiari malformation was often used as a combined
term for different types of posterior fossa abnormalities or used
interchangeably with Chiari types I and II. To avoid this seman-
tic confusion, we use the Chiari I and II malformation definition,
which is most often used in the modern literature.
Chiari I Malformation
Chiari malformation type I is anatomically defined as an
extension of the cerebellar tonsils below the foramen mag-
num. It is not associated with caudal displacement of the

TABLE 8-8  n  Posterior Fossa Anomalies, Including Chiari Malformations

Malformation Pathophysiology Clinical Features Associated Pathology

Chiari type I malformation
Cerebellar tonsils displaced
into cervical spinal canal,
small posterior fossa
Usually presents in late teens or Syringomyelia, syringobulbia,
adult years scoliosis, skeletal anomalies
Wide variety of neurologic
symptoms caused by upper
cervical canal compression

Chiari type II malformation Cerebellar vermis and Presents at birth or early infancy Myelomeningocele and
brainstem displaced into Lower brainstem and cranial other lumbosacral neural
cervical spinal canal nerve dysfunction tube closure defects,
Could be medical emergency hydrocephalus, syringomyelia

Chiari type III malformation Cerebellum displaced into large Respiratory and swallowing Corpus callosum agenesis,
(very uncommon) occipital encephalocele disorders, cranial nerve deficits, tentorium dysplasia,
dystonias (often fatal) midbrain deformities

Dandy-Walker malformation
Cystlike dilation of fourth
ventricle, enlarged posterior
fossa, hypoplasia and
anterior rotation of cerebellar
vermis
Very heterogeneous in Corpus callossum agenesis,
presentation, depending on brainstem anomalies,
associated pathology hydrocephalus
Ataxia, brainstem dysfunction,
mental retardation (varies),
hydrocephalus

Jourbet's syndrome Cerebellar vermis aplasia Motor hypotonia, ataxia, Occipital meningocele,
(extremely rare) behavioral delay scoliosis, hydrocephalus,
hepatic fibrosis

Cerebellar disruptions Cerebellar tissue loss Motor deficits, mental retardation,

(rare) often early death

Pontocerebellar Pontine hypoplasia, cerebellar Severe developmental disorders,

hypoplasias hypoplasia seizures, often early death
(rare)

Rhombencephalo-synapsis Fusion of cerebellar Variable presentation Hydrocephalus,

(extremely rare) hemispheres, vermis Mental retardation, epilepsy, ventriculomegaly
agenesis, fusion of dentate and spasticity are common.
nuclei and superior
cerebellar peduncles
 Chapter 8  Neurologic Diseases 283

TABLE 8-9  n Chiari Malformation Type 1: Associated TABLE 8-10  n Chiari Malformation Type 1: Signs and
Abnormalities Symptoms

Abnormality Features Signs/Symptoms Features

SKELETAL CAUSED BY COMPRESSION AT CRANIOCERVICAL JUNCTION

Basilar impression Decreased overall cervical spine Occipital/posterior cervical Associated with Valsalva
Atlanto-occipital fusion mobility combined with c-spine pain maneuvers
Klippel-Feil syndrome instability
Atlantoaxial assimilation Increased risk of neurologic injury Weakness Typically caused by distortion
from minor trauma Sensory deficits of medulla
Hyperreflexia
Scoliosis Common finding in patients with Babinski response
syringomyelia
Vocal cord paralysis, Typically caused by involvement
CENTRAL NERVOUS SYSTEM hoarseness, dysarthria of lower cranial nerves
Syringomyelia Usually maximal in cervical spinal cord Dysphagia, recurrent
aspirations
Sleep apnea
Sinus bradycardia, syncope
medulla or supratentorial abnormalities. The etiology of Ataxia Symptoms of the rare
CM-I is not well established. The small size of the poste- Nystagmus cerebellar syndrome
rior fossa causing the cerebellar displacement is the most
CAUSED BY SYRINGOMYELIA
likely explanation. Downward tonsillar displacement is not
Upper limb weakness with Usually starts distally at hand
associated with any actual malformations of the cerebellum atrophy and spreads proximally
or midbrain structures found in most other posterior fossa
anomalies. CM-I is associated with various skeletal and CNS Suspended sensory loss Pain and temperature
loss; touch and position
abnormalities (Table  8-9). The diagnosis of CM-I in other-
preserved
wise asymptomatic patients is made progressively more often
during the investigation of these abnormalities with neuroim- Progressive scoliosis
aging techniques.295 Lower motor neuron
The signs and symptoms of CM-I can be divided into paralysis
those caused by the compression of dural or neural struc-
ture by the displaced cerebellar tonsils and those related to
the progressive development of syringomyelia (Table  8-10).
The patients with CM-I usually become symptomatic in their differs. The patients scheduled for craniectomy already pres-
late teens. However, some may first display symptoms at a ent with some degree of neurologic involvement, which indi-
more advanced age, even in the presence of the syringomy- cates significant compression of the neural elements in the
elia.296 The differential diagnosis in CM-I with syringomyelia craniocervical junction. Most pregnant patients diagnosed
is complex because of the wide range of neurologic symp- with CM-I are either asymptomatic or have already under-
toms and signs. Many neurologic diseases of the spinal cord gone surgical correction.297
and cerebellum (e.g., MS, SMA, ALS, spinocerebellar atax- Neurologic assessment is directed toward evaluation of signs
ias, mononeuropathy multiplex, cervical disc degenerative of brainstem compression or cranial nerve involvement: vocal
disease) have a similar clinical picture. However, CNS and cord dysfunction, ventilation disorders, and swallowing control.
skeletal imaging studies resolve most of these difficulties. A It is important to determine whether any neurologic symptoms
paucity of imaging findings in the patient with a florid clini- are exacerbated with laughing, coughing, or exertion or during
cal neurologic picture might make it difficult to differenti- flexion-extension of the neck. Symptoms of increased ICP are
ate CM-I from hematomyelia, astrocytoma, or ependymoma sought. Appropriate imaging studies should be performed in
of the spinal cord; Leigh's disease; or necrotizing myelopathy. all patients with suspected CM-I. The presence of syringomy-
elia is determined even in patients without a clinical picture of
PREOPERATIVE EVALUATION myelopathy, especially in parturients, in whom neuroaxial anes-
Patients with CM-I require anesthesia that falls under two thesia is considered. The presence and location of motor deficit
categories: (1) suboccipital craniectomy with or without cervi- are noted to avoid overdosing nondepolarizing muscle relaxants
cal laminectomy for the decompression of neural structures by monitoring NMB on denervated muscles.
trapped in the foramen magnum (occasionally, decompres- Autonomic function should be evaluated in patients with
sion or shunting of coexisting syrinx is required) and (2) significant brainstem involvement. Subclinical autonomic
anesthesia for labor and delivery and cesarean section in par- dysfunction, a well-recognized condition in CM-I, can result
turients. Generally, both categories pose similar anesthetic in unstable hemodynamics, lack of compensatory responses
risk, although the preoperative neurologic status typically to hypotension, hypoxia, and hypocarbia intraoperatively.298,299
 284 ANESTHESIA AND UNCOMMON DISEASES
The absence of heart rate beat-to-beat variability and lack of
cardiac responses to postural maneuvers are good predictors
of autonomic dysfunction.
Cervical spine assessment is directed toward evaluation
of possible associated cervical spine abnormalities listed in
Table  8-8. Limited range of motion could result from cervi-
cal spine fusion combined with hypermobility between fused
segments. Therefore, lateral and anteroposterior flexion-­
extension cervical spine radiographs are recommended.
ANESTHETIC CONSIDERATIONS
General Anesthesia for Neurosurgical Procedures. A num-
ber of case reports in the literature detail anesthetic manage-
ment of these patients for suboccipital decompression.299-303
There is no evidence that any particular anesthetic agents are
contraindicated for these patients. Although in one case the
patient developed asystole after dural incision and draining of
CSF, the patient promptly responded to atropine and ephed-
rine administration without sequelae.303
During induction of anesthesia and positioning, flexion-
extension of the neck should be limited to prevent further
compression of the neural structures. Fiberoptic bron-
choscopic intubation, awake or asleep, is recommended in
patients with skeletal cervical spine abnormalities and unsta-
ble cervical spine.304 Careful planning for extubation, and
possibly postoperative respiratory support with slow wean-
ing, is indicated in patients with pronounced brainstem
compression and cranial nerve involvement because of the
increased risk of postoperative ventilatory failure299 or com-
promised upper airway reflexes.305-307 Use of invasive mon-
itoring is usually limited to the arterial line for measuring
BP and ABG analysis in the postoperative period, if needed.
Although often performed in the sitting position and associ-
ated with high risk of venous air embolism in the past, sub-
occipital decompression is routinely performed in the prone
position at present; thus there is no need for right atrial cath-
eter placement.
Anesthesia for Labor and Delivery. There are a number
of case reports308-314 and retrospective series297 on anesthetic
management in pregnant patients with posterior fossa anoma-
lies. In patients without elevated ICP or significant neurologic
symptomatology at delivery, it seems safe to employ epidural,
spinal, or general anesthesia with inhalational agents, whether
for vaginal or cesarean birth. In patients with increased ICP
and neurologic deficits associated with syringomyelia, the
risks and benefits for any form of anesthesia should be care-
fully weighed, bearing in mind that dural puncture may result
in the sudden neurologic deterioration caused by further cere-
bellar herniation.313,314 For labor, a combination of cervical and
pudendal blocks, supplemented by parenteral opioids, may
be the safest approach.297 For cesarean delivery, general endo-
tracheal anesthesia directed toward preventing ICP increase
should be considered. Other considerations for decompressive
suboccipital craniotomy discussed in the next section are also
valid in these patients.
Chiari II Malformation, Myelomeningocele,
and Hydrocephalus
Chiari malformation type II is distinct from CM-I in its pre-
sentation, anatomy, prognosis, and outcomes. One striking
feature is that CM-II is present in practically every child born
with meningomyelocele (MMC). Conversely, CM-II is diag-
nosed only in children with MMC.315 Additionally, hydro-
cephalus is found or will develop in more than 80% of children
born with MMC and CM-II and often presents as a medi-
cal emergency requiring urgent shunt placement. Therefore,
these conditions and their implications for anesthesia care are
discussed together.
Although the etiology of CM-II is not well understood,
McLone and Knepper316 propose a likely explanation. Both
open neural tube defect and incomplete spinal occlusion lead
to CSF leakage from the fetal spinal canal and ventricular
system. The lack of ventricular CSF distention precludes the
full development of the normal-size posterior fossa, which in
turn leads to the caudal displacement of the rapidly develop-
ing cerebellum into the spinal canal along with the brainstem.
Anatomically, CM-II is characterized by the caudal displace-
ment of the cerebellar vermis (not the cerebellar tonsils, as
in CM-I) below the foramen magnum. The vermis could
reach as far down as the upper thoracic spinal canal as the
child ages. Other neuroanatomic anomalies typically found
in CM-II include small, upward-rotated cerebellum; caudal
displacement of the medulla (and sometimes the pons) into
the spinal canal; small posterior fossa; multiple ventricular
anomalies; and small fourth ventricle and aqueduct. The fora-
men magnum is often enlarged. Also, hypoplasia or aplasia
of cranial nerve nuclei is often present (20%). Other associ-
ated abnormalities of MMC and CM-II include neurogenic
bladder, neurogenic bowel, multiple orthopedic deformities,
and lower extremity fractures. These latter conditions often
require repeated corrective surgical procedures under general
anesthesia.
It is important to understand that the first indication of pos-
sible CM-II in the newborn is the presence of MMC, which will
require urgent repair. However, these neonates must be eval-
uated for the signs and symptoms of CM-II. Asymptomatic
CM-II is the most common cause of death in children with
MMC younger than 2 years. Close to one third of patients with
MMC will develop symptoms of brainstem compression, and
one third of them will die315 before age 5 years. Therefore, all
symptomatic CM-II patients should be aggressively evalu-
ated for hydrocephalus and considered for CSF shunt place-
ment. Symptomatic CM-II in children younger than 2 years
typically has a different presentation than in older children
(Table 8-11).
PREOPERATIVE EVALUTION
Most children with CM-II undergo MMC repair procedure in
the first hours of their life. The principles of anesthetic manage-
ment for MMC repair can be found in most pediatric anesthesia
texts. All other procedures typically required by these patients
during their lifetime can be divided into three categories: (1)
 Chapter 8  Neurologic Diseases 285

TABLE 8-11  n  Chiari Malformation Type II: Clinical Presentation in Early and Late Childhood

Group Presentation Signs/Symptoms Implications

Younger children Increasing hydrocephalus Inspiratory stridor caused by abduction of Often emergency presentation, life
(≤2 yr) Brainstem dysfunction vocal cords with paralysis/paresis threatening
Cranial nerve dysfunction Apneic episodes, including cyanotic expiratory Shunt placement is lifesaving
(10th, 9th) apnea of central origin (although not in all infants).
Swallowing difficulties, chronic aspirations,
weak gag reflex, dysphagia, malnutrition

Older children Cervical myelopathy Weakness and spasticity of upper extremities, Slowly progressing, rarely life
Syringomyelia occipital headache, craniocervical pain, threatening
ataxia, sensory loss, scoliosis Decompressive surgery is often
performed after normal CSF
shunt function is confirmed.

CSF, Cerebrospinal fluid.

emergency decompressive surgery or CSF shunt placement in
stridorous infants, (2) elective decompressive procedure (e.g.,
cervical laminectomy), or (3) corrective surgical procedures for
associated pathology (e.g., bladder surgery, orthopedic proce-
dures) in patients without obvious symptoms of CM-II.
Emergency Procedures. These patients should be evaluated
for the signs of vocal cord dysfunction and breathing disor-
ders. Patients with these symptoms may develop respiratory
depression, such as apneic spells and vocal cord paralysis, even
if the ICP is well controlled.305,317 Patients should be monitored
postoperatively in the ICU for the signs of apnea and the com-
promised airway. Careful planning for extubation is recom-
mended. Volemic status should be evaluated in patients with
unrepaired MMC, with potentially significant loss of CSF.
Elective Procedures. The most important step in the sur-
gical and anesthetic preoperative evaluation of these patients
is to rule out nonfunctioning shunt or latent hydrocephalus.
Otherwise, the considerations are similar to those described
in patients with CM-I.
ANESTHETIC CONSIDERATIONS
Anesthetic management in the literature on CM II is limited
to two case reports and a series. There are no clear contra-
indications to any particular anesthetic agents. Positioning of
the patient may be a challenge, especially in those cases when
shunt placement is performed simultaneously with MMC
repair. Extremes of the neck flexion or extension should be
avoided to prevent further compression of neural structures
in the upper cervical canal. Inhalational mask induction, even
in the asymptomatic child, can be complicated by apneic spells
and laryngospasm.318
In the past, when suboccipital decompressive craniectomy
and duraplasty were performed, an increased risk of inadver-
tent hemorrhage from the occipital or transverse sinuses had
to be considered in these patients. This life-threatening com-
plication was associated with venous air embolism and carried
very high mortality. This surgery is rarely recommended at
present. However, invasive hemodynamic monitoring is indi-
cated for decompressive cervical laminectomy.
Succinylcholine should be avoided in patients with motor
deficits, which are typically present in these patients after
MMC repairs or as a result of cervical myelopathy. NMB
should be monitored on the limbs not affected by motor defi-
cits to avoid overdosing.
Intraoperative considerations for orthopedic, urologic, and
other corrective procedures in asymptomatic patients are sim-
ilar to those in patients with CM-I.
KLIPPEL-FEIL SYNDROME AND
OTHER CERVICAL SPINE DISORDERS
OF CHILDHOOD
Anesthetic care of patients with cervical spine disorders result-
ing from congenital or developmental alterations in childhood
represent a unique and complex challenge. Increased suscep-
tibility to cervical spine injury and subsequent neurologic def-
icit, often combined with anatomically difficult airway, are
common for this diverse group of disorders of different eti-
ology. Understanding of the anatomic and pathophysiologic
features of these disorders, thorough preoperative evaluation,
and appropriate early management are essential in preven-
tion of neurologic injury and other anesthetic complications
in these patients.319,320 Klippel-Feil syndrome is a member of
this group and is often mentioned in the anesthetic literature.
It also presents one of the most formidable anesthetic chal-
lenges. For simplicity of presentation, other disorders in this
section are discussed in conjunction with the discussion of the
preoperative evaluation and anesthetic management of this
syndrome.
Klippel-Feil syndrome is a rare congenital anomaly of the
cervical spine (1 in 42,000 births) typically characterized by
fusion of two or more cervical vertebrae. It is unclear whether
Klippel-Feil syndrome is a discrete entity with common
genetic etiology or a phenotypic presentation of a heteroge-
neous group of congenital spinal deformities.321 The classic
triad of short neck, low posterior hairline, and limitations of
cervical motion are found in less than half of patients with this
condition. Other common associated findings include con-
genital scoliosis (50% of patients), renal abnormalities (33%),
 286 ANESTHESIA AND UNCOMMON DISEASES

Sprengel's deformity (congenital elevation of scapula), hear-
ing impairment, posterior fossa dermoid cysts, and congeni-
tal heart disease (most often ventricular septal defect). Overall
decreased neck mobility is the most common physical find-
ing and is often combined with hypermobility between fused
vertebral segments, which puts these patients at high risk for
either spontaneous neurologic injury or that resulting from
minor trauma.322
Many neurologic symptoms caused by cranial nerve abnor-
malities, cervical radiculopathy, or myelopathy are typically
found in the second or third decade of life. Most neurologic
manifestations are secondary to chronic compression of the
cervical spinal cord, pons, medulla, and stretching of the cra-
nial nerves. Sudden neck movement or minor falls can cause
basilar artery insufficiency and syncope. Tetraplegia has been
reported as a result of minor trauma in these patients.322
Klippel-Feil syndrome is often classified into three types,
depending on the location of the fused cervical vertebrae. The
presentation of clinical and anatomic features of this syndrome
varies widely, ranging from mild deformity to severe disability.
Cervical spine abnormalities similar to those observed in
Klippel-Feil syndrome are frequently seen in other uncommon
disorders listed in Table 8-12.319 Cervical instability, increased
risk of severe neurologic injury from minor trauma, and diffi-
cult airway are common features in all these conditions. A full
description of these disorders and relevant anesthetic issues
are addressed in subsequent sections of this chapter or other
chapters.
PREOPERATIVE EVALUATION
Preoperative assessment in patients with cervical spine dis-
orders should primarily be directed at the evaluation of
degree of cervical instability present, pre-existing neurologic
impairment, and airway evaluation. A previous uneventful
anesthetic history is a poor predictor of difficult airway or
neurologic complications in patients with Klippel-Feil syn-
drome, because cervical fusion becomes progressively worse
with time.323 Therefore, lateral and anteroposterior flexion-
extension cervical spine radiographs are recommended.
Cervical MRI is indicated to assess the degree of neuro-
logic involvement, such as cord compression and myelopa-
thy. Other perioperative considerations should include the
following:
Congenital heart defects and cardiac conduction abnormalities.
Preoperative ECG and echocardiography are indicated.
Assessment of pulmonary function, which could be severely
compromised in patients with chest deformities and
advanced scoliosis. Consider chest radiography and pul-
monary function tests.
Renal function. Patients with Klippel-Feil syndrome should be
evaluated for kidney anomalies and renal failure.
ANESTHETIC CONSIDERATIONS
Anesthetic experience in Klippel-Feil syndrome patients is
limited to a number of case reports.304,320,324-328 The main anes-
thetic challenge in these patients is airway management and
positioning (Box  8-13). Awake fiberoptic intubation is the
preferred approach whenever possible.304,324,328 However, most
pediatric and mentally impaired (Down syndrome) patients
are not suitable candidates, and asleep fiberoptic intuba-
tion in a spontaneously breathing patient should be consid-
ered. Direct laryngoscopy is likely to be difficult because of
multiple facial, neck, and chest deformities. However, when
direct laryngoscopy is chosen, a neutral neck axis needs to be
maintained to avoid neurologic sequelae. The laryngeal mask
airway can be used to ventilate these patients, although intu-
bation via laryngeal mask may be technically difficult.30
Positioning of patients with Klippel-Feil syndrome may be
difficult because of multiple head, neck, and thoracic defor-
mities. Great care must be taken to avoid any cervical ten-
sion or sudden neck movements while positioning these
patients. It is important to understand that the risk of neu-
rologic injury in these patients is not limited to laryngoscopy
and intubation and may develop thereafter.320,324,329 Regional
anesthesia has been successfully performed in Klippel-Feil
patients326,327 and might be preferable if indicated, to avoid
potential neurologic and respiratory complications related to

TABLE 8-12  n  Cervical Spine Disorders

Disorder Cervical Spine Abnormalities Symptoms

Down syndrome Occipitocervical or atlantoaxial instability Muscle weakness, gait abnormality, neck pain

Achondroplasia Foramen magnum stenosis, lumbar spine Severe sleep apnea and sudden death in
stenosis early childhood
Cervical instability is uncommon.

Spondyloepiphyseal dysplasia Odontoid hypoplasia and/or os odontoideum Persistent hypotonia; motor developmental
with atlantoaxial instability delay

Mucopolysaccharidoses Odontoid hypoplasia with atlantoaxial Severe neurologic compromise secondary to

Morquio's syndrome instability and progressive myelopathy; upper cervical spinal cord compression;
extradural soft tissue hypertrophy sudden death

Isolated odontoid anomalies: aplasia, Progressive atlantoaxial instability Symptoms of upper cervical spinal cord injury,
hypoplasia, os odontoideum sudden death
 Chapter 8  Neurologic Diseases 287

function is contraindicated. Careful planning for extubation

BOX 8-13   n CHIARI MALFORMATION TYPE 1
AND OTHER POSTERIOR FOSSA AND
CERVICAL SPINE DISORDERS OF
CHILDHOOD: ANESTHETIC ISSUES
Significant autonomic dysfunction can be present, resulting in
potential hemodynamic instability.
Airway management and intraoperative positioning are directed at
limiting cervical flexion-extension in patients with clinical and
imaging evidence of cervical spine compression.
Patients with existing vocal cord dysfunction and compromised
ventilatory function and swallowing plan for postoperative
ventilatory support.
No specific anesthetic techniques or agents are contraindicated
in patients with Klippel-Feil syndrome or other childhood spinal
disorders.
For labor and delivery neuroaxial anesthesia can be performed safely,
but should be avoided in patients with increased intracranial
pressure and existing neurologic deficits.
airway management. It can be difficult to perform, consid-
ering the various spine deformities associated with this con-
dition. Succinylcholine should be avoided in the presence of
neurologic deficit. In patients with associated renal anoma-
lies accompanied by renal failure, the use of nondepolarizing
muscle relaxants for which excretion is dependent on renal
is warranted in patients with significantly compromised pul-
monary function and after difficult intubation. No contra-
indications exist to any specific anesthetic drugs in patients
with Klippel-Feil syndrome.
MUCOPOLYSACCHARIDOSES
Inclusion of mucopolysaccharidoses in the chapter on uncom-
mon neurologic disease is debatable for a number of reasons.
These are primarily metabolic disorders affecting many organs
and systems in the body containing connective tissue, most
prominently the skeletal system and soft tissue. However, most
of these disorders either affect the nervous system directly or
result from skeletal and joint deformities (Table 8-13). These
neurologic deficits create the potential for triggering new,
potentially catastrophic neurologic complications and often
pose a formidable anesthetic challenge in the perioperative
care for these patients.
The mucopolysaccharidoses are hereditary lysosomal stor-
age disorders caused by the deficiency of various enzymes
necessary for the metabolism of glycosaminoglycans (GAGs),
previously called mucopolysaccharides. Excess accumula-
tion of partially degraded GAGs within cells causes ­cellular

TABLE 8-13  n  Mucopolysaccharidosis (MPS): Types and Clinical Features

Usual Age
Type Common Name (Diagnosis) Clinical Features

PRIMARILY CNS DISEASE WITH LESS SKELETAL AND SOFT TISSUE DISEASE
MPS-III, Sanfilippo's syndrome 2-6 yr Aggressive behavior followed by progressive mental retardation and
subtypes A-D types A-D neurologic decline; milder physical features of MPS-I

PRIMARILY SKELETAL AND SOFT TISSUE DISEASE WITH RANGE OF CNS MANIFESTATIONS
MPS-I Hurler's syndrome 1-2 yr Severe cardiac and skeletal abnormalities, hydrocephalus, mental
retardation, severe coarse facies, hepatosplenomegaly, airway obstruction,
dystosis multiplex, often placid and loving; death by age 10 years

Hurler-Scheie 1-5 yr Intermediate severity of skeletal abnormalities, micrognathia, moderate

syndrome coarse facies, possible normal intelligence; death by 20s

Scheie's syndrome 3-15 yr Milder form with slow progression; aortic valve and joint disease, corneal
clouding, normal facies and mentation; life span of several decades

MPS-II Hunter's syndrome: 1-3 yr No corneal clouding; physical disease similar to MPS I; aggressive
severe behavior and developmental delay

Hunter's: mild 1-5 yr Normal or near-normal intelligence

MPS-VII Sly's syndrome Birth to 5 yr Variable intermediate physical presentation similar to MPS-I

SKELETAL DISEASE AND SOFT TISSUE STORAGE WITHOUT SIGNIFICANT CNS INVOLVEMENT
MPS-IV Morquio's syndrome 1 yr to Skeletal disease with ligament laxity and high incidence of odontoid
type A and type B late teens, dysplasia and atlantoaxial instability, short stature, possible corneal
depending opacities, normal intelligence
on severity

MPS type VI Maroteaux-Lamy 1-5 yr Severe skeletal disease as in MPS-I but without CNS disease, although
syndrome (mild to hydrocephalus and severe cervical spinal cord compression may occur
severe form) later in course; death in teens and 20s

CNS, Central nervous system.

 288 ANESTHESIA AND UNCOMMON DISEASES
­ ysfunction. The faulty metabolism results in serious struc-
d tracheal wall distort the airway, and difficulties with intuba-
tural and functional abnormalities in a wide variety of tissues,
particularly bone and cartilage. There are now nine muco-
polysaccharidosis (MPS) disorders, classified as types I to IX,
based on enzyme deficiency and severity of the phenotype.
With the exception of Hunter's syndrome (MPS-II), which is
an X-linked disorder, the mucopolysaccharidoses are inher-
ited in an autosomal recessive pattern. The cumulative inci-
dence is estimated at 1 in 20,000 live births. Table 8-13 outlines
the classification system and summarizes the associated clini-
cal features.
Diagnosis is made by elevated GAG concentration in
urine or demonstration of enzyme deficiency in leukocytes.
Treatment options include enzyme replacement, bone marrow
transplantation, and cord blood transplantation. These thera-
pies are symptomatic and may alter the natural progression of
the disease but do not prevent eventual decline in function.
The MPS continues to worsen as the patient grows older, and
most patients will die of pulmonary or cardiac complications.
ANESTHETIC CONSIDERATIONS
The anesthetic implications of MPS are extensive and relate
to the end-organ dysfunction and anatomic distortions expe-
rienced by this patient population (Box 8-14). Complications
with general anesthesia are common, and morbidity and mor-
tality are primarily caused by airway issues. Upper airway
abnormalities such as macroglossia, hypertrophic tonsils and
adenoids, patulous lips, micrognathia, friable tissues, copious
secretions, and restrictive temporomandibular joint move-
ment can hinder adequate ventilation. Many patients have
obstructive breathing at baseline, with sleep apnea and need
for continuous positive airway pressure. Bone marrow trans-
plant can reverse upper airway obstruction.330 Lower airway
abnormalities from deposition of GAG in the epiglottis and
BOX 8-14   n MUCOPOLYSACCHARIDOSES:
ANESTHETIC ISSUES
Difficult to impossible airway is the central concern in the anesthesia
care of mucopolysaccharidosis (MPS) patients.
Thorough preoperative airway assessment and history are crucial.
Plan for awake fiberoptic intubation in the cooperative patient.
Have equipment and skilled personnel immediately available for
emergency surgical airway.
Evaluate for cervical spine compression and cervical instability. If
present, minimize the range of flexion-extension during induction
and positioning.
Many MPS patients are uncooperative, requiring special approaches
when planning for fiberoptic intubation in spontaneously breathing
patients.
Respiratory compromise is common; plan for extended ventilatory
support in the ICU.
Valvular disease, lesions of coronary arteries, and pulmonary
hypertension are common and require cardiac evaluation. In
compromised patients, use of invasive hemodynamic monitoring is
warranted.
Neuroaxial and regional anesthesia are not contraindicated in patients
with MPS but should be avoided in those with hydrocephalus.
tion can increase with age as this process continues.331 A short
neck with a narrow, anterior larynx accompanied by possible
cervical instability or history of cervical fusion offers addi-
tional airway challenges, particularly in those with Hurler's
syndrome (MPS-I). Incidence of difficult intubation and
failed intubation is reported as 53% and 23%, respectively.332,333
Tracheotomy is also technically difficult because of a large
mandible, short neck, and retrosternal trachea, and it was
impossible even postmortem in one case report.334,335
Cardiac abnormalities also result from MPS. Mitral and
aortic valves thicken, causing insufficiency that may progress
to cardiomyopathy.336 Deposition of GAGs in arterial walls
causes systemic hypertension and coronary artery disease.
Coronary lesions are diffuse and can lead to ischemia or sud-
den death. Coronary angiography may not predict the sever-
ity of the diseases.330,337 Pulmonary hypertension secondary to
chronic hypoxemia of pulmonary disease and airway obstruc-
tion can lead to right-sided heart failure.
Pulmonary dysfunction is another frequent complica-
tion in MPS patients. Kyphoscoliosis causes a restrictive dis-
ease with recurrent pneumonia and ventilation/perfusion
mismatch, resulting in chronic hypoxemia and hypercarbia.
Patients with Morquio's syndrome (MPS-IV) are also prone to
atlantoaxial instability and odontoid dysplasia. This can lead
to central apnea from cord compression.338
Neurologic complications of MPS vary depending on the
particular classification. Developmental delay and sleep dis-
turbance are common. Vertebral subluxation can occur at any
level of the spinal column and compromise the spinal cord.
Communicating hydrocephalus frequently develops and can
cause increased ICP. Seizures are uncommon in most of these
patients.
Patients with MPS often present for surgery, usually
for ear, nose, and throat procedures and hernia repairs.
Anesthetic management should begin with a preoperative
evaluation that establishes which type of MPS is involved
and what components of the disease are present.333 Careful
review of cardiac, pulmonary, and neurologic function are
paramount, and workup may include ECG, chest radio-
graph, neck films, pulmonary function tests, and echocar-
diogram, as indicated. Preoperative flexion-extension films
to evaluate stability of the cervical spine are recommended
in those with Morquio's syndrome.339 Detailed inspection
of the airway, review of anesthesia records, and neck imag-
ing can help predict airway difficulties.333 However, the air-
way can worsen with time and disease progression. Age and
level of mental retardation are also important consider-
ations in planning an anesthetic procedure. Premedication
with benzodiazepines can be helpful in the uncooperative
patient but should be avoided in those with an airway prone
to obstruction. An antisialagogue should be administered
to decrease secretion but used cautiously in patients with
heart disease.
Because most reported anesthetic complications in the MPS
patient population involve airway or positioning difficulties,

regional anesthesia may be a safer option.340-342 Regional
technique may prove problematic if the patient cannot lie
flat because of skeletal pain or respiratory compromise or is
unable to cooperate because of mental retardation.339 If gen-
eral anesthesia is required, the airway can be secured before
induction with topicalization of the airway and awake fiberop-
tic intubation. A reverse guidewire technique is also possible
after appropriate sedation.
When inducing general anesthesia before securing the
airway, inhalation induction with spontaneous ventilation
is recommended.341,343 For those unable to cooperate with
inhalation induction, IV induction with ketamine has been
used successfully.341 Intravenous access should be estab-
lished before induction, and difficult airway equipment
should be immediately available. Nasotracheal intubation
is discouraged because of anatomically altered nasal pas-
sages and friable tissues. Recent literature has shown that
the laryngeal mask airway (LMA) can be used successfully
in this population for maintenance of adequate ventilation
during general anesthesia and for assistance with fiberoptic
intubation through the LMA.344 Limited use of the angulated
video-assisted intubation laryngoscope has also facilitated
intubation in MPS patients with cervical spine instability.345
Intraoperative considerations include careful positioning
to avoid cervical subluxation and arterial cannulation in
patients with severe pulmonary or cardiac dysfunction.338
Narcotics should be titrated carefully to avoid respiratory
depression. There are no reported abnormal responses to
muscle relaxants or anesthetic agents. Extubation should
be performed with caution in patients with the mucopoly-
saccharidoses, because they have increased incidence of
atelectasis and airway obstruction secondary to traumatic
tissue edema.
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 C H A P T E R
9
Muscle Diseases
MICHAEL K. URBAN, MD, PhD  n

Muscular Dystrophies Infective and Toxic Myopathies

Pathophysiology Human Immunodeficiency Virus
Diagnosis and Differential Necrotizing Myopathy
Anesthetic Considerations Thyrotoxic Myopathy
Myotonias
Myotonic Dystrophy
Myotonia Congenita
Myotonia Fluctuans
KEY POINTS
Metabolic Myopathies n Patients with muscular diseases have a postoperative
Glycogen Storage Myopathies ­pulmonary complication rate of 25% to 48%. Their inabil-
Myoglobinuria ity to take deep inspirations and cough predisposes them to
Glycogenosis Type I (von Gierke's Disease) atelectasis and pneumonia.
Glycogenosis Type II (Pompe's Disease) n Muscular dystrophies have variable modes of inheritance
Mitochondrial Myopathies and clinical presentation, characterized by progressive
Oxidative Phosphorylation Disorders muscle weakness and often associated with global systemic
Luft's Disease effects.
Complex I Deficiency n Both cardiac and respiratory complications are major deter-
Complex IV Deficiency minants of quality of life and life span in patients with
Coenzyme Q Deficiency Duchenne's muscular dystrophy. The leading cause of death
Anesthetic Considerations is cardiomyopathy; its severity is unrelated to that of skeletal
Disorders of Fatty Acid Metabolism muscle involvement. Therefore the potential for significant
Carnitine Deficiency ventricular dysfunction and cardiac conduction defects must
Acyl-Coenzyme A Dehydrogenase Deficiency be considered in planning anesthesia.
Carnitine Palmitoyltransferase Deficiency n Malignant hyperthermia is definitively associated only with
Disorders of Pyruvate Metabolism triggering agents in patients with central core disease and
Malignant Hyperthermia King-Denborough syndrome. However, volatile anesthetics
Muscle Channelopathies and succinylcholine may trigger rhabdomyolysis and hyper-
Hyperkalemic Periodic Paralysis metabolic responses in myopathic patients.
Hypokalemic Periodic Paralysis n Muscle dystrophies are characterized by increased intramyo-
Myasthenias plasmic calcium concentration, explaining the increased
Myasthenia Gravis sensitivity of these patients to inhalational agents and depo-
Anesthetic Considerations larizing relaxants.
Eaton-Lambert Myasthenic Syndrome n In patients with myotonias, succinylcholine can induce sus-
Inflammatory Myopathies tained muscle contractions, preventing adequate ventilation
Dermatomyositis or intubation.
Polymyositis n Patients with mitochondrial myopathies are at increased
Inclusion Body Myositis risk of developing propofol infusion syndrome.
Overlap Syndromes n Myoglobinuria is a common metabolic abnormality among

the substrate use muscle diseases. Alkalinization of urine

296

with sodium bicarbonate may prevent precipitation of
hematin in the renal tubules and reduce the risk of renal
failure.
n Patients with myasthenia gravis are at risk for postoperative
controlled ventilation and should be assessed preoperatively
using the MG severity score.
Since the writing of this chapter by J. D. Miller and
H.  Rosenbaum, the genetic defects and molecular mecha-
nisms involved in many of the muscle diseases have been
­elucidated. In some cases this has facilitated the management
of patients with muscular disorders. However, it still requires
an astute clinician to make the diagnosis of a muscle disease
and to assess the magnitude of the compromise in normal
physiologic functions. Common complaints such as fatigue,
weakness, and polymyalgias are nonspecific symptoms, with
etiology extending from neuromuscular disorders through
rheumatologic problems to psychiatric conditions. A detailed
neuromuscular physical examination and routine diagnostic
testing, including electromyography (EMG), serum electro-
lytes, thyroid function tests, and serum creatine kinase evalu-
ation, may not provide a definitive diagnosis. In fact, many
of these patients may have a final, nonspecific diagnosis of
“fibromyalgia” or chronic fatigue syndrome. However, some
will have life-threatening muscle disorders that must be recog-
nized if these patients are to be treated effectively.
Perioperative respiratory complications are a major con-
cern for patients with muscular diseases. General anesthesia
and surgery, particularly abdominal and thoracic procedures,
result in postoperative pulmonary changes, specifically a loss
of lung volumes and an increase in the alveolar-arterial gradi-
ent. This is the reason for a postoperative pulmonary compli-
cation rate of 25% to 48%. Patients with chronic respiratory
muscle weakness have a higher incidence of postoperative
respiratory complications because of the loss of respiratory
reserve. In addition, their inability to take deep inspirations
and cough makes them more susceptible to atelectasis and
pneumonia. However, a preoperative diagnosis of respira-
tory compromise may be difficult in patients with skeletal
muscle weakness, because their respiratory reserve is rarely
challenged. Preoperative pulmonary function testing of these
patients provides an assessment of the severity of the pulmo-
nary disease and potential pulmonary risk of undergoing the
planned procedure. Patients with deteriorating skeletal mus-
cle strength can also develop kyphoscoliosis with concomitant
restrictive lung disease.
If possible, administration of muscle relaxants should be
avoided, as should long-acting agents, if required. Hypomotility
of the gastrointestinal (GI) tract may lead to delayed gastric
emptying and increase the risk of pulmonary aspiration. This
would favor securing the airway using rapid-sequence induc-
tion with succinylcholine, although in some patients this has
been associated with ventricular fibrillation, rhabdomyolysis,
and malignant hyperthermia.
Because some patients with muscle disease will also have a
cardiomyopathy, the depressant effects of volatile anesthetics
Chapter 9  Muscle Diseases 297
may provoke congestive heart failure (CHF). The respiratory
depressant effects of a narcotic anesthetic, however, may require
prolonged postoperative respiratory support. In all cases, after
general anesthesia the clinician must anticipate the possibility
of postoperative ventilation and, once extubated, the need for
intensive respiratory therapy. Regional anesthesia avoids some
of the complications of general anesthesia and may provide
a vehicle for postoperative analgesia without employing nar-
cotics. However, even if regional techniques are employed to
reduce anesthetic requirements and provide postoperative pain
management, it may still be n­ ecessary to ­protect the airway and
ensure adequate oxygenation during the procedure through
the use of general endotracheal anesthesia.
These points are all common considerations when anesthe-
tizing patients with muscle disease. This chapter delineates the
characteristics of specific muscle diseases and the impact on
perioperative anesthetic planning.
MUSCULAR DYSTROPHIES
Muscular dystrophies are a group of hereditary myopathic
diseases characterized by progressive weakness. Clinical
­presentation is heterogeneous, from severe fatal childhood
forms to relatively benign adult forms. The dystrophies are
all best characterized by painless degeneration and atro-
phy of skeletal muscles without evidence of muscle dener-
vation.1 Originally these diseases were characterized on the
basis of their clinical presentation (e.g., limb-girdle myopa-
thy). The discovery of dystrophin and related molecules has
given “muscular dystrophy” a molecular biologic basis for
diagnosis, genetic mapping, and treatment.2 Dystrophin is a
large (427-kbp) rod-shaped protein representing about 5%
of ­membrane-associated cytoskeletal protein;3,4 its gene is
located on the short arm of the X chromosome. Along with
several other sarcolemmal proteins, dystrophin stabilizes the
muscle surface membrane during contraction and relaxation
(Fig. 9-1). The dystrophin-associated complex binds intracel-
lular actin to the extracellular basal lamina, which mechani-
cally stabilizes the sarcolemma during muscle contraction.
Pathophysiology
Muscular dystrophies are characterized by degeneration of the
skeletal muscle fibers and replacement with fibrous and fatty
connective tissue, without accumulation of intermediate met-
abolic substrates. There is no evidence for direct neurologic
involvement. The breakdown of the muscle fiber sarcolemma
occurs early in the disease, with an influx of calcium and the
activation of proteases, and the eventual destruction of tissue
by inflammatory elements. The absence of dystrophin results
in a loss of skeletal muscle membrane integrity and subsequent
breakdown of the sarcolemma with an influx of extracellular
calcium, activation of cellular proteases, inflammation, necro-
sis, and replacement fibrosis.
Duchenne's muscular dystrophy (DMD, also called pseu-
dohypertrophic muscular dystrophy) is the most common
 298 ANESTHESIA AND UNCOMMON DISEASES
Intracellular
Cytoskeletal
Dystrophin
Syntrophin
complex
Dystrobrevin
25kD
 50 43 35 35
Dystroglycans
Sarcospan
17q 4q 13q 5q

Sarcoglycans
Extracellular
Laminin 2
(merosin)
FIGURE 9-1  Principal extrajunctional molecules relevant to muscular dystrophy. (Redrawn from Molnar MJ, Karpati MJ: Muscular
dystrophies related to deficiency of sarcolemmal proteins. In Schapira AH, Griggs RC, editors: Muscle diseases, Boston, 1999, Butterworth-
Heinemann, p 84.)
form, seen in 1 per 3500 births. The myopathy is associ-
ated with mutations of the dystrophin gene located in the
Xp21 stripe, inherited as a sex-linked recessive trait; most
of the reported cases are male. However, well-documented
cases in females range in severity from full DMD to mild
weakness. Transmission of this disease in female offspring
of n­ ormal fathers can occur when there is early inactiva-
tion of the normal X chromosome (Lyon hypothesis). Only
one X chromosome is active in any cell, with inactivation
of the other X-chromosome occurring early in embryogen-
esis. Some heterozygotic females with DMD would then be
expected to carry the abnormal X chromosome as the only
active dystrophin gene in most cells. Female children with
Turner's syndrome (XO) would also present with DMD. It is
unclear whether heterozygotic females pose the same anes-
thetic risks as males with DMD.5 Although DNA testing can
detect multiple deletions, duplications, and point mutations
in the dystrophin gene, proximal limb muscle biopsy remains
the standard for diagnosis. Skeletal muscle biopsy early in the
disease process may demonstrate necrosis and phagocytosis
of muscle fibers, as well as areas of vigorous muscle regenera-
tion. Immunostaining reveals the complete lack of dystrophin
at the surface of the muscle fibers.
Diagnosis and Differential
Progressive and symmetric skeletal muscle weakness and wast-
ing with histologic evidence of dystrophic muscle changes are
diagnostic of DMD.6 The initial clinical presentation involves
a waddling gait, frequent falling, and difficulty climbing
stairs because of proximal muscle weakness in the pelvic gir-
dle. Also, weakness in the shoulder girdle and trunk erectors
leads to thoracolumbar scoliosis. Certain muscles, particularly
the calves, demonstrate early hypertrophy. The pelvic girdle
and proximal leg muscle weakness is responsible for Gowers’
sign, with the child climbing up the legs to stand up. However,
Emerin
actin
Calpain
Nucleus
Integrin 7
12q
Collagen VI
the child's condition usually goes undiagnosed until age 3 to
5 years. This is rapidly followed by atrophy of the other prox-
imal muscles. All muscles are ultimately involved except for
the cranial muscles and the external anal sphincter. Because
of lack of denervation, there is intact sensation, but the proxi-
mal deep tendon reflexes (DTRs) disappear in half of patients
by age 10. The earlier the onset, the more rapid is the downhill
course. Usually the child is unable to walk by age 9 to 11 years.
Joint contractures appear during this period because of the
uneven loss of agonist and antagonist muscle groups.
In the heart, loss of dystrophin affects l-type calcium chan-
nels with increased intracellular calcium. The excess calcium
activates proteases that degrade the contractile proteins, lead-
ing to inflammation and myocardial cell death and fibrosis,
producing a dilated cardiomyopathy. Cardiomyopathy is the
major cause of death in DMD patients.7 The timing and sever-
ity of the cardiomyopathy in DMD is unrelated to the sever-
ity of skeletal muscle degeneration. Although all patients with
DMD will eventually develop cardiomyopathy, symptoms may
not become apparent because of their inability to exercise.
Uncharacteristic symptoms of CHF in this population may
include sleep disturbances, loss of appetite, nausea, abdominal
pain, cough, or increased secretions. These patients will have a
resting tachycardia. Physical findings of a cardiomyopathy on
examination may include jugular venous distention, displace-
ment of the point of maximal impulse (PMI), and S3/S4 gallop.
Scarring of the posterobasal portion of the left ventricle pro-
duces tall, right precordial R waves and deep, left precordial
Q waves in the electrocardiogram (ECG). Mitral regurgitation
may also be present because of papillary muscle dysfunction.
The “gold standard” for assessing cardiac function in DMD
patients is the two-dimensional echocardiogram. However,
cardiac magnetic resonance imaging (MRI) has been shown
to be a more reliable noninvasive measure of cardiac func-
tion in DMD patients. In some cases, gadolinium contrast
has been used in conjunction with cardiac MRI to visualize
 Chapter 9  Muscle Diseases 299

fibrotic areas. Several studies have shown the benefits of ste-

TABLE 9-1  n American College of Chest Physicians
roid therapy on skeletal, respiratory, and cardiac muscle func- Consensus on Preoperative Pulmonary
tion; steroid treated DMD children maintained normal cardiac Evaluation of DMD Patients
function longer than untreated DMD children.8 In addition,
angiotensin-converting enzyme (ACE) inhibitors slow the Recommendation/
progression of cardiac dysfunction in DMD patients. Assessment Monitoring Level Evaluation
Duchenne's dystrophy produces respiratory muscle weak- Oxygenation Spo2 <95% on Requires
ness, which places these patients at increased risk for peri- room air by pulse measurement
operative pulmonary complications. Respiratory muscle oximetry of Paco2
weakness is detectable by age 10, but the diaphragm is usually
Lung volumes FVC in seated,
spared. There is a progressive decrease in total lung capacity upright position
and vital capacity. Inability to cough and clear secretions pre-   <50% of predicted Increased risk of
disposes these patients to pneumonia, which is often fatal by perioperative
about the third decade. However, about 15% of patients have respiratory
complications
a much slower disease course, which stabilizes about the time
  <30% of predicted High risk of
of puberty. These patients also have lower-than-average intel- perioperative
ligence with mild cerebral atrophy, presumably from the lack respiratory
of normal brain dystrophin; initiating perioperative incen- complications
tive spirometry may therefore prove difficult. Some clinicians Cough MEP <60 cm HOH Preoperative training
believe that exercise enhances muscle destruction; however, strength PCF <270 L/min in assisted cough
physical therapy that involves passive movement to prevent devices
contractures and resistance exercises for the lungs to increase
DMD, Duchenne's muscular dystrophy; Spo2, oxygen saturation; FVC, forced
endurance may be helpful. Because contractures represent a vital capacity; Paco2, arterial carbon dioxide tension; MEP, maximum expiratory
major disability, DMD patients often have elective procedures pressure; PCF, peak cough flow.
to relieve these contractures. Thus, perioperative complica-
tions that prolong their inactivity may actually exacerbate
their condition by preventing the important postoperative
physical therapy. normal) up to age 3 years and then decrease by about 20%
The American College of Chest Physicians 2009 consen- per year as muscle atrophies. Increased plasma levels of liver
sus statement on the respiratory management of patients with enzymes have also been noted (aminotransferases/transami-
DMD recommends preoperative assessment of oxygenation, nases, lactate dehydrogenase); however, liver damage has not
lung volumes, and cough strength9 (Table 9-1). Oxygen (O2) been described in DMD, suggesting a skeletal origin.
saturation below 95% on room air by pulse oximetry is con- Table  9-2 lists the other, less common forms of muscular
sidered a “clinically significant abnormality” and warrants dystrophy and their clinical course. Becker's muscular dystro-
further assessment, which may include arterial blood gas phy (BMD) is an allelic variant of DMD in which the mutated
(ABG) analysis. Assessment of lung volumes involves mea- dystrophin gene produces a reduced amount of a truncated
suring forced vital capacity (FVC) in the seated, upright posi- dystrophin protein. The pace of muscle destruction in BMD
tion. DMD patients with FVC less than 50% should receive is much slower than in DMD, with symptoms usually appear-
preoperative training with noninvasive positive-pressure ing in early adolescence. Most BMD patients will develop a
ventilation (NPPV) to facilitate postoperative extubation. In cardiomyopathy by age 30, which may not correlate with the
addition, because the coughing and clearing of secretions are degree of skeletal muscle destruction. BMD is usually fatal
important aspects of pulmonary toilet after surgery, preopera- from respiratory or cardiac complications between ages 30
tive measurement should include maximum expiratory pres- and 60.
sure (MEP) and peak cough flow (PCF). Using these values as Facioscapulohumeral dystrophy (FSHD) is the third most
guidelines, patients should receive preoperative training in the common muscular dystrophy, with a pattern of progressive
postoperative use of manual and mechanically assisted cough muscular weakness involving the face, scapular stabilizers,
devices. proximal arm, and fibula. Patients with FSHD usually present
In addition to the cardiac and pulmonary manifestations, with shoulder weakness and scapular winging. FSHD is also
DMD effects are systemic with the possible need for neuro- associated with retinal abnormalities and hearing loss, but the
logic, GI, nutritional, and physical therapy support. Many of cardiac muscle is usually spared.
these patients have elevated plasma muscle enzymes aldolase The limb-girdle muscular dystrophies (LGMDs) are a hetero-
and creatine kinase (CK) levels early in disease progression. geneous grouping of sarcoglycanopathies, a class of transmem-
The MB fraction of CK, normally present only in heart mus- brane proteins that associate with dystrophin in a glycoprotein
cle, cannot be used as a guide to cardiac injury because it is complex.12 Common clinical features include early involve-
also elevated as a result of the destruction of regenerating skel- ment of the proximal muscles of the legs, followed by shoul-
etal muscle in DMD.10,11 CK levels are highest (50-100 times der muscles with scapular winging. Affected individuals have
 300 ANESTHESIA AND UNCOMMON DISEASES

TABLE 9–2  n  Other Muscular Dystrophies Compared with Duchenne's (DMD)

Comorbidities and Anesthetic

Dystrophy Inheritance Clinical Course Concerns

Becker's muscular X-linked, same locus as DMD
dystrophy (BMD) Reduced amount and
abnormal dystrophin
Later onset (age 12  yr)
More benign course
Death in early 40s, most often from
pneumonia
Cardiac involvement is less frequent
and less severe, but heart failure is
common cause of death.
Pseudohypertrophy common
Reports of cardiac arrests
intraoperatively and postoperatively
(patients at risk for rhabdomyolysis)

Emery-Dreifuss X-linked Slow progression Early atrial arrhythmias progressing

muscular Early contractures in elbow, ankles, to asystole: prophylactic ventricular
dystrophy (EDMD) and neck pacemaker suggested
Significant cardiac risk with sudden Possible cardiomyopathy, ventricular
death often between ages 30 and fibrosis, and cardiomegaly
60 years Possible difficult intubation from limited
neck motion (although flexion is
more limited than extension)

Rigid spine X-linked? Slow progression Severe restrictive lung disease

syndrome Painless limitation of neck and Weak respiratory muscles
trunk motions Cardiomyopathy
Scoliosis
Difficult intubation

Facioscapulo-humeral Autosomal dominant Onset in adolescence Rare cardiac involvement

(Landouzy- inheritance Weakness of pectoral, orbicularis, Abnormal vital capacity
Dejerine) shoulder, and pelvic muscles Normal CO2 response curve
dystrophy (FSHD) (less than DMD) Frequent upper respiratory tract
Life span minimally affected infections
Postoperative respiratory
complications

Limb-girdle muscular Five subtypes predominantly
dystrophies autosomal recessive
(LGMDs) Severe childhood autosomal
recessive dystrophy gene
located on 17q12-21
Two most common subtypes:
Erb's type (early onset, shoulder
girdle primarily involved)
Leyden-Möbius (late onset, pelvic
girdle involvement)
Severity between DMD and FSHD
Variable cardiac involvement
Sinus tachycardia and right bundle
branch block most common ECG
abnormalities
Early severe diaphragmatic weakness
(hypoventilation, hypercarbia)
Heart transplant in severe childhood
autosomal recessive dystrophy

Distal myopathies Autosomal dominant Welander's myopathy: onset after Possible cardiomyopathy secondary
age 30 to interstitial fibrosis of the heart
Seen mostly in Sweden muscle in Markesberry's dystrophy
Mainly affects hands
Markesberry's: onset in fifth decade
of life,feet involved
Early adult-onset myopathy:
involvement of anterior or
posterior compartment of legs

Oculo-pharyngeal Onset after age 30 years, slow Dysphagia, dyscoordination of

muscular dystrophy progression
Weakness of pharyngeal muscles,
ptosis, limbs, extraocular
muscles (rare diplopia)
Similar symptoms to ocular
myasthenia gravis
No dysarthria, dyspnea
posterior pharynx, and esophageal
involvement cause aspiration and
inanition.
Sensitivity to muscle relaxants;
anticipate mechanical ventilation
postoperatively
Anticholinesterase agents do not
reverse weakness.
Normal sensitivity to vecuronium in
case report17
 Chapter 9  Muscle Diseases 301

TABLE 9–2  n  Other Muscular Dystrophies Compared with Duchenne's (DMD)—Cont'd

Comorbidities and Anesthetic

Dystrophy Inheritance Clinical Course Concerns

Congenital muscular Fukuyama's form, autosomal Onset at birth Seizures and mental retardation in
dystrophy recessive Proximal more than distal muscles Fukuyama's form
involved
Slow progression
Creatine kinase slightly elevated
Death by age 10 in Fukuyama's form
(seen frequently in Japan)

a characteristic stance of lordosis, abducted hips, and hyper-

extended knees. The facial and ocular musculature is usually
spared. There are usually no associated cognitive or cardiac
abnormalities. Onset of LGMD is in late childhood, with slow
progression. In contrast to most muscular dystrophies that
affect the proximal musculature, the distal myopathies affect
the forearms, hands, and lower legs.
BOX 9-1   n ANESTHETIC ISSUES IN MUSCULAR
DYSTROPHY
Potent Inhalational Anesthetics
Use is not recommended because potent inhalational anesthetics
may trigger a malignant hyperthermia–like syndrome in patients
with Duchenne's muscular dystrophy and depress myocardial
contractility.

Anesthetic Considerations
Patients with muscular dystrophies often require surgery for
muscle biopsy, the correction of scoliosis, the release of con-
tractures, and exploratory laparotomy for ileus (Box 9-1). The
surgical risk is the lowest early in the disease course, before
the patient has significant comorbidities. Thus, it is impera-
tive to determine the severity of the disease and the associ-
ated comorbidities. Among patients with muscular dystrophy,
50% to 70% demonstrate some cardiac abnormality, although
these are clinically significant in only 10% of patients and
often in the terminal phase of the disease. No correlation has
been established between the severity of the cardiac disease
and the severity of the skeletal disease. Necrosis and fibrosis
of the myocardium in DMD is typically limited to the pos-
terobasal and lateral free walls of the left ventricle, whereas
in the other muscular dystrophies the fibrosis may be more
diffusely dispersed. Dysrhythmias occur frequently, even after
minor trauma. Complex ventricular premature beats correlate
with both abnormal left ventricular function and an increased
incidence of sudden death.11 These patients probably have
impaired cardiac autonomic function with increased sympa-
thetic tone, explaining the resting tachycardia and the propen-
sity to develop arrhythmias.7
Patients undergoing surgery should have a recent echo-
cardiogram. Echocardiography will demonstrate mitral valve
prolapse in 10% to 25% of patients. It may also show pos-
terobasilar hypokinesis in a thin-walled ventricle and a slow
relaxation phase with normal contraction, characterizing the
cardiomyopathy seen in DMD. However, preoperative echo-
cardiography may not always reflect the ability of the diseased
myocardium to respond to perioperative stress.13 Heart failure
can occur during anesthesia for major surgery even with nor-
mal preoperative echocardiography and electrocardiography,
and sudden death can occur even in patients with fully com-
pensated cardiac status. Angermann et al.14 advocate the use
Hypnotics
Pentothal should be given in small increments, when used.
Propofol has been recommended as the preferred hypnotic, but
higher-than-expected doses may be required for induction.
Consider the myocardial status of the patient.24 Some patients have
significant cardiomyopathy, and reduced heart rate and decreased
contractility with an induction dose of propofol may lead to
profound hypotension and reduced end-organ perfusion.
Opioids
Use of narcotics eliminates the need for myocardial depressants
or inhalational agents; however, consider the use of short-acting
opioids and the need for postoperative ventilation.
Muscle Relaxants
Administration of nondepolarizing muscle relaxants is usually
followed by an increased response, both in maximal effect and
duration of action.23
Recovery from neuromuscular blockade in muscular dystrophy
patients has been reported to be three to six times longer than in
healthy adults. In addition, postoperative pulmonary complications
have been associated with the use of long-acting neuromuscular
blockers.
The combined effects of primary smooth muscle abnormalities,
inactivity, and general anesthesia induces gastric dilation, delayed
gastric emptying, and the risk of pulmonary aspiration.
Regional anesthesia may be a good alternative to general anesthesia
to avoid the risk of triggering agents and respiratory depression
and to allow the use of local anesthetics for postoperative
analgesia.
of stress echocardiography using angiotensin to detect latent
heart failure and identify inducible contraction abnormalities.
Atrial and atrioventricular conduction defects with bra-
dycardia are common in Emery-Dreifuss muscular dystro-
phy (EDMD), and again, the severity of heart disease does
not correlate with the degree of skeletal muscle involvement.
Several anesthesiologists have recommended preoperative
prophylactic cardiac pacing in EDMD patients undergoing
general anesthesia and having emergency pacing available
 302 ANESTHESIA AND UNCOMMON DISEASES
when any form of anesthesia is used. Regional anesthesia
has been used successfully in EDMD patients for lengthen-
ing of both Achilles tendons; in one case a temporary trans-
venous pacemaker was inserted before administration of the
anesthetic.15,16 In addition, EDMD patients may prove diffi-
cult to intubate and careful assessment with cervical radiogra-
phy should be undertaken preoperatively. A total intravenous
anesthetic (TIVA) or a nitrous/narcotic technique that omits
volatile anesthetics and depolarizing agents, to avoid malignant
­hyperthermia–­triggering agents, would seem appropriate if a
general anesthesia technique cannot be avoided.15 To date, how-
ever, malignant hyperthermia has not been described in EDMD.
Perioperative respiratory complications are a major con-
cern when anesthetizing patients with muscular dystro-
phy. As previously discussed, at the end of the first decade of
life, reductions in inspiration, expiration, vital capacity, and
total lung capacity become prominent and reflect the weak-
ness of respiratory muscles. Decreased ability to cough and
the accumulation of oral secretions predispose muscular
dystrophy patients to postoperative respiratory tract infec-
tions. Respiratory insufficiency, however, may not be appar-
ent because impaired skeletal muscle function prevents these
patients from exercising enough to exceed their limited
breathing capacity. Preoperative pulmonary function studies
are valuable in determining the postoperative course of these
patients. Patients with a vital capacity of greater than 30% of
the predicted value can usually be extubated immediately after
surgery. With progression of the disease (vital capacity less
than 30% of predicted) and the added morbidity of kyphosco-
liosis, which can contribute to a restrictive respiratory pattern,
postoperative ventilatory support will be required. Delayed
pulmonary insufficiency may occur up to 36 hours postop-
eratively, even if the patient's skeletal muscle strength appar-
ently returned to preoperative level. Sleep apnea may also
compound the respiratory problems and may contribute to
development of pulmonary hypertension. Preoperative intro-
duction to chest physiotherapy and nasal continuous positive
airway pressure (CPAP) and their use early in the postopera-
tive period have been effective in decreasing the incidence of
respiratory complications.9
Sometimes the first indication that a child has muscular
dystrophy is an unexplained cardiac arrest or myoglobinuria
with malignant hyperthermia–like findings during general
anesthesia.17 In patients with muscular dystrophies, do inha-
lational agents and succinylcholine trigger malignant hyper-
thermia?18 In 2000, Breucking et al.19 investigated 200 families
with muscular dystrophy of the Duchenne and Becker types
who had received a total of 444 anesthetics. Sudden cardiac
arrests occurred in six patients with undiagnosed disease at
the time they received a general anesthetic of an inhalational
agent and/or succinylcholine. There were also nine, less severe
incidents of fever, rhabdomyolysis, and masseter spasm.
The authors recommended the avoidance of the triggering
agents—succinylcholine and volatile anesthetics—to decrease
the risk of severe anesthetic complications. In earlier reports,
Cobham and Davis20 (1964) and Richards21 (1972) found no
temperature rise or cardiac arrest after using virtually all anes-
thetic agents available at that time in DMD patients. Richards
reported using halothane 37 times and succinylcholine
12 times, all without subsequent problems.
Nevertheless, since those publications, several case reports
have described life-threatening complications (dysrhythmias,
cardiac arrest, rhabdomyolysis) after anesthesia with muscle
relaxants and inhalational agents. The anesthetic complica-
tions often seemed to parallel the severity of the muscle dis-
ease. Succinylcholine has been involved in the majority of
lethal complications in patients with unsuspected DMD,19
leading the U.S. Food and Drug Administration in 1992 to
issue a warning with regard to the administration of succi-
nylcholine in young children and adolescents. Larach et al.22
reported that 48% of pediatric patients with cardiac arrest dur-
ing anesthesia had an unrecognized myopathy, with 67% of
these associated with succinylcholine-induced hyperkalemia.
An inherent membrane defect in DMD may render the mus-
cle more susceptible to injury induced by inhalational anes-
thetics and depolarization with succinylcholine. Patients with
DMD may have an upregulated isoform of the acetylcholine
receptor that is more sensitive to the effects of succinylcholine.
These agents probably trigger rhabdomyolysis and nonspecific
hypermetabolic responses in DMD patients rather than malig-
nant hyperthermia.18 Case reports have documented the use
of propofol, narcotics, and nondepolarizing muscle relaxants
in DMD patients without complications,23,24 but as with the
earlier series of uneventful anesthetics with triggering agents,
large series are required to document their safety. In patients
with DMD, onset of nondepolarizing neuromuscular block-
ade may be significantly delayed, which must be considered
when rapid-sequence induction is required. However, the pro-
longed recovery from neuromuscular blockade may require
postoperative ventilation.
MYOTONIAS
Myotonia is derived from the Greek word meaning “muscle
stiffness.” In these muscle diseases, alterations in the ion chan-
nels allow the muscle membrane to become easily depolarized,
resulting in repetitive discharges. The myotonias are divided
into dystrophic and nondystrophic groups. The dystrophic
patients have progressive muscle wasting and weakness (myo-
tonic dystrophy). The nondystrophic group has an alteration
in the electrical hyperexcitability of muscle fibers, leading to
prolonged relaxation after voluntary muscle contraction. In
the myotonias the pathognomonic finding is muscle stiffness,
which consists of slowed muscle relaxation after vigorous con-
traction (Thomsen, Becker). In some patients the stiffness may
resolve with repeated muscle contractions, whereas in others it
may be exacerbated. It is usually worse if a period of rest is fol-
lowed by a period of exercise, and it can be provoked by cold.
Myotonia results from an abnormality in the electrical
properties of the sarcolemma, predisposing the muscle mem-
brane to becoming easily depolarized. This results in a charac-
teristic EMG pattern of repetitive discharges (myotonic runs).

A diagnostic clinical sign of myotonia is percussion myotonia;
after being struck by a percussion hammer, the muscle contin-
ues to contract for a time and becomes transiently indented.
Myotonic Dystrophy
Myotonic dystrophy (dystrophia myotonia, DM; Steinert's dis-
ease) is extremely variable in presentation, from asymptom-
atic cases to congenital DM with respiratory insufficiency and
mental retardation25 (Table 9-3). It is an autosomal dominant
inherited neuromuscular disorder with a worldwide preva-
lence of 1 in 8000. The genetic defect is a result of the abnor-
mal expansion of the nucleotide CTG on chromosome 19,
which codes for a serine-threonine protein kinase. The rela-
tionship between the genetic defect and the clinical findings
is still unknown. However, knockout mice that completely
lack this enzyme develop normally. Expressivity of the genetic
defect must also be variable; both minimally affected and
severely affected individuals may be seen within a family.
Four types of myotonic dystrophy are described: congen-
ital (CDM), juvenile or early onset (JDM), adult onset, and
late onset. The most severe form is CDM, which presents as
hypotonia rather than myotonia. CDM has a high mortality
during the neonatal period from respiratory distress. Cranial
muscle weakness occurs at birth, which gives these infants a
characteristic tent-shaped mouth. JDM children may have
some facial weakness early in life, but major muscle weakness
is often delayed and accompanied by some mental retardation.
In adult-onset DM, symptoms appear during the second and
fourth decades of life, with progressive muscular weakness.
Muscle weakness and wasting are the most disabling features
of DM. Wasting is usually most prominent in the cranial mus-
culature and distal limb muscles. Temporalis and masseter
muscle atrophy leads to the classic appearance of the “hatchet
face.” DTRs are usually reduced or absent. Weakness of the
muscles of the vocal cord apparatus results in nasal speech and
TABLE 9-3  n  Clinical Features of Myotonic Dystrophy
System Manifestations
Neuromuscular Myotonia, weakness
Reduced deep tendon reflexes
Ocular Cataract, ptosis
Ophthalmoparesis, retinal pigmentation
Endocrine Testicular atrophy, diabetes, pituitary
dysfunction, hyperparathyroidism
Skin Frontal balding, pilomatrixoma
Cardiovascular Hypotension, syncope, palpitations, mitral
valve prolapse, sudden death
Gastrointestinal Dysphagia, pseudo-obstruction
Central nervous Mental retardation
Immune Reduced immunoglobulin levels
Chapter 9  Muscle Diseases 303
propensity for aspiration pneumonia. The distal limb muscles
first affected lead to footdrop and weak handshake.
Myotonic dystrophy is a multisystem disease and can affect
the heart (conduction system), smooth muscle (impaired
intestinal motility), eye (cataracts), brain (mental retardation),
and endocrine system (e.g., testicular atrophy, insulin resis-
tance, hypometabolism). Cardiac conduction abnormalities
are common and may cause sudden death. In one report, 57%
of DM patients had conduction defects, one third of whom had
first-degree atrioventricular block unresponsive to atropine.9
Many of these patients also have an associated cardiomyopa-
thy, and CHF can be a cause of death. Because anesthetics can
increase vagal tone or induce arrhythmias, transthoracic pac-
ing should be readily available.
The pulmonary complications of DM are the result of
chronic aspiration and central hypoventilation. Weakness of
the respiratory muscles causes alveolar hypoventilation, hyper-
capnia, and hypoxemia, resulting in increased somnolence.
In some patients an increased respiratory effort is required in
one group of respiratory muscles (diaphragm) to overcome the
myotonia in other respiratory muscles (intercostals). Smooth
muscle atrophy leading to poor gastric motility, coupled with
a diminished protective cough reflex, promotes aspiration.
Recurrent aspiration pneumonia can lead to chronic pulmo-
nary damage such as bronchiectasis and pulmonary hyperten-
sion. The hypersomnolence seen with DM is often associated
with carbon dioxide (CO2) retention and appears to be primar-
ily a central nervous system (CNS) manifestation of the disease.
A recently recognized variant of DM is proximal myotonic
myopathy (PROMM). This disorder has features in common
with DM (e.g., facial muscle weakness, frontal balding), but
the muscle weakness and stiffness is predominantly confined
to proximal rather than distal muscles and usually appears in
adolescence.
ANESTHETIC CONSIDERATIONS
Because myotonic dystrophy is a systemic disease, anesthetic
management must include consideration of the multiple man-
ifestations of the disease. All these patients must be treated as
though they have both cardiomyopathy and cardiac conduc-
tion defects. Medications that increase vagal tone or anesthetic
plans causing hypoxia may result in high cardiac conduction
blocks. Therefore, transthoracic pacing and antiarrhythmic
medications should be readily available. If possible, inhala-
tional agents should be avoided because of their myocardial
depressant and conduction system effects.26 These patients
are at risk of aspiration and should remain NPO (nothing by
mouth), and relatively rapid protection of the airway should
be achieved with an endotracheal tube.
Rather than relaxation, however, succinylcholine will pro-
duce contractures lasting for several minutes. These con-
tractures can be severe enough to prevent intubation and
ventilation and are not inhibited by nondepolarizing agents.
Other agents may also induce myotonic contractures, includ-
ing methohexital and etomidate, as well as propofol. The
reversal of neuromuscular blockade by neostigmine could
 304 ANESTHESIA AND UNCOMMON DISEASES
precipitate a myotonic response; thus it is advisable to use
shorter-acting nondepolarizing muscle relaxants or avoid
relaxation. Myotonic contractions can occur, however, even in
the presence of neuromuscular blocking agents and neuraxial
anesthesia, because direct stimulation of the muscle (surgical
stimulation) may result in contraction.
The combination of central respiratory depression and
weak respiratory musculature makes myotonic patients vul-
nerable to the respiratory depressant effects of most sedatives,
hypnotics, and narcotics. Therefore, when possible, regional
anesthesia is the preferred anesthetic, and when general anes-
thesia is required, the patient must be monitored postoper-
atively. The myotonic responses to DM can be treated with
phenytoin (4-6 mg/kg/day) or quinine (0.3-1.5 g/day).
Myotonia Congenita
Myotonia congenita, a distinct entity from the congenital
onset of DM, is characterized by two forms, one described by
Thomsen in 1876 as autosomal dominant and the other by
Becker in the 1950s as autosomal recessive inheritance. Both
forms are the result of mutations in the gene that codes for
the major chloride channel.27 The Thomsen variant is a mild
disease with generalized myotonia, usually recognized in early
childhood because of frequent falling. Cranial and upper-limb
musculature is most severely affected, sometimes resulting in
difficulty chewing. The myotonic responses occur after a rest
interval and may result in the patient falling to the ground in
a rigid state. Some patients have an athletic appearance as a
result of muscle hypertrophy. Many patients have lid lag and
blepharospasm, which involves myotonia of the lid muscula-
ture. The Becker recessive variant is similar to the dominant
form, except that the myotonia is usually more severe and
presents later in life (after age 10) and does not progress in
severity beyond the third decade. These patients are usually
handicapped in their daily activities because of leg muscle
stiffness and generalized weakness. The stiffness of myotonia
is treated with medications that reduce the increased excitabil-
ity of the cell membrane by acting at the sodium channel (local
anesthetics, antiarrhythmics).
Myotonia Fluctuans
Becker also described individuals with the dominant form of
nondystrophic myotonia in which muscle stiffness fluctuated
from day to day. These individuals do not experience muscle
weakness, but rather have a prolonged time for relaxation after
voluntary muscle contraction and external mechanical stim-
ulation. The stiffness (contractures) that occurs after heavy
exercise may last 30 minutes to 2 hours, with days or weeks
between incidents.28 Succinylcholine has triggered myotonic
crisis, with difficulty in ventilation and intubation, and thus
should be avoided in these patients.29 The duration of neuro-
muscular blocker therapy will be increased in patients with
myotonia fluctuans, but anticholinesterases should be avoided
because they may trigger a myotonic crisis.
A variant of myotonia fluctuans has been described in
which the myotonia occurs during exercise and is not relieved
by warming a cold limb. In another variant, with persistent
and sometimes severe myotonia, increased serum potassium
will aggravate the myotonia. Children with this disorder may
experience acute hypoventilation and coma after eating a meal
rich in potassium, caused by myotonia of the thoracic mus-
cles. Often these children are misdiagnosed as having a seizure
disorder. Clearly, mutations of the sodium-chloride channels
of muscle can result in several different clinical syndromes,
including the systemic form found in myotonic dystrophy.
METABOLIC MYOPATHIES
Muscle contraction requires energy in the form of adenosine
triphosphate (ATP), which is provided from the metabolism
of glycogen, glucose, and fatty acids. The metabolic pathways
of all three converge into acetyl coenzyme A (acetyl-CoA),
which is oxidized in the mitochondria through the Krebs cycle
and respiratory chain to ATP (Fig.  9-2). In metabolic myop-
athies, defects in this process are either defects of substrate
use (involving glycogenosis) or disorders of lipid metabo-
lism. Tsujino et al.30 report that patients with muscle substrate
use disease present with two major clinical presentations:
(1) acute, recurrent, reversible muscle dysfunction that man-
ifest as exercise intolerance or myalgias, or (2) fixed, often
­progressive weakness. The disorders presenting as acute revers-
ible muscle weakness can usually be differentiated into defects
in glycogen or lipid metabolism based on their presentation.
Because glycogen metabolism is important for intense aerobic
exercise, patients with defects in glycogen metabolism experi-
ence muscle cramping and weakness after strenuous exercise,
whereas patients with lipid metabolic defects often complain of
muscle cramping or weakness after prolonged moderate exer-
cise. Prolonged fasting can exacerbate these conditions and
lead to respiratory muscle fatigue and myoglobinuria.
Metabolic myopathies of infancy or early childhood usu-
ally present as multisystem disorders. The “floppy infant syn-
drome” is the simplified clinical description for children with
heterogeneous metabolic myopathies. These children are at
risk for respiratory complications, because of diminished
respiratory effort and cough reflex, and aspiration pneumonia.
These metabolic defects are also likely to result in develop-
mental CNS defects, cardiomyopathies, and cardiac conduc-
tion defects. The progressive atrophy of skeletal musculature
will lead to contractures and scoliosis, which may require sur-
gical correction.31
Glycogen Storage Myopathies
The glycogen storage disorders are the result of muscle enzy-
matic defects in glycogenolytic or glycolytic pathways lead-
ing to the accumulation of glycogen. The myopathy is not
caused by the accumulation of glycogen, however, but rather
by the block in energy production, and thus substrate use dis-
eases. The glycogen storage diseases were assigned Roman
 Chapter 9  Muscle Diseases 305

Glucose Fatty acids

Glycolysis

CPT-1 Carnitine

H Pyruvate
Long Acyl-carnitine
ADP ATP
Carnitine - acylcarnitine
TP VLCAD translocase
CPT - II
H Pyruvate ATP ADP

Outer mitochondrial membrane

Long Acyl-CoA

Inner mitochondrial membrane

PDHC Acetyl-CoA

Citrate Aconitase 3-Ketoacyl-

CoA
Isocitrate
KT HAD
Oxaloacetate TCA cycle a-Ketoglutarate -oxidation 3-Hydroxyacyl-
H Acyl-CoA LCAD CoA
Malate ETF x MCAD Hydratase
Succinyl-CoA SCAD
NADH
Fumarate Enoyl-CoA
FADH2 H Succinate
ETF red
H
H H ADP ATP
ETF
DH
I
II
III IV V
CoQ Cyt c

FIGURE 9-2  Substrate metabolism. Respiratory chain complexes encoded exclusively by nuclear DNA are solid; complexes encoded by
both nuclear and mitochondrial DNA are cross-hatched. (Redrawn from Rosenberg RN et al, editors: The molecular and genetic basis of
neurological disease, Boston, 1997, Butterworth-Heinemann, p 201.)

numerals in the order of their discovery and classified as
“muscle ­diseases of glycogenosis” by Cori (Fig.  9-3). This
­section discusses these myopathic nonlysosomal glycogenoses
in their enzymatic sequential order.31,32
DEBRANCHING ENZYME DEFICIENCY (TYPE III,
CORI-FORBES DISEASE)
This disease of childhood, with hepatomegaly and liver dys-
function, growth retardation, and fasting hypoglycemia, often
resolves spontaneously around puberty. The debranching
enzyme has two catalytic functions; a transferase attaches a glu-
cosyl unit to the acceptor chain of the phosphorylase–limit dex-
trin (PLD), and then the glucosyl unit is hydrolyzed. Infusion
of fructose, as well as a high-protein diet, will increase blood
glucose levels because gluconeogenesis is not affected. Patients
without resolution at puberty have early evidence of mus-
cle involvement, both skeletal and cardiac. However, clinical
myopathy is uncommon and usually manifests later (third and
fourth decade), after the liver symptoms have remitted. Serum
CK is increased in patients with myopathy. The myopathy pres-
ents as weakness rather than exercise intolerance, cramps, or
myoglobinuria. Wasting of the distal leg and intrinsic hand
muscles can lead to a diagnosis of motor neuron disease. The
course is slowly progressive and usually not incapacitating.
BRANCHING ENZYME DEFICIENCY (TYPE IV,
ANDERSON'S DISEASE)
The branching enzyme catalyzes the last step in glycogen bio-
synthesis by attaching short glucosyl chains to a peripheral
chain of the nascent glycogen. In the enzyme-deficient state
the abnormal unbranched glycogens precipitate and are no
longer available for glucose production. The clinical manifesta-
tions include hepatosplenomegaly, cirrhosis, hypotonia, mus-
cle wasting, and cardiomegaly. Most patients with Anderson's
disease die early. Patients who survive to maturity may also
exhibit CNS and peripheral nervous system dysfunction.
MYOPHOSPHORYLASE DEFICIENCY (TYPE V,
MCARDLE'S DISEASE)
Patients with myophosphorylase deficiency typically exhibit
exercise intolerance with myalgia, cramping, stiffness, and
weakness of the muscles exercised. The exercise intolerance
usually develops during the teenage years, but weakness is
usually not manifested until later decades. Most patients learn
to adapt to their limited exercise tolerance and only later in
life does the fixed proximal weakness impose significant limi-
tations in lifestyle. If exercise continues with cramping, myo-
globinuria may occur with subsequent renal failure. In this
disease, as well as some of the other muscle glycolygenoses,
 306 ANESTHESIA AND UNCOMMON DISEASES

(Lysosome) Epinephrine defects have not been characterized. McArdle's disease is

exercise transmitted as an autosomal recessive trait with localization
on chromosome 11.
Cyclic AMP
Acid maltase II (Ca)
Because prolonged muscle ischemia can lead to permanent
Protein kinase
muscle weakness with atrophy and myoglobinuria with renal
failure, tourniquets should be avoided. Experimentally, lim-
Phosphorylase b kinase ited muscle exercise tolerance has been extended with glucose
VIII infusions, so glucose-containing solutions should be infused
Glucose Glycogen Phosphorylase a Phosphorylase b intraoperatively. Adequate hydration and mannitol infusions
IV V-VI when urine output decreases should be employed to prevent
UDPG PLD myoglobinuria. Succinylcholine should be avoided to prevent
III muscle fasciculations and breakdown. For the same reason,
Glucose 1-P postoperative shivering should be avoided by using a warmer
I for intravenous (IV) fluids and warming blankets.

Glucose 6-P Blood glucose

MUSCLE PHOSPHOFRUCTOKINASE DEFICIENCY
(TYPE VII, TARUI'S DISEASE)
Fructose 6-P Phosphofructokinase (PFK) deficiency is similar to myophos-
ATP VII XII phorylase deficiency in its clinical presentation and diagnosis.
ADP
Fructose 1,6-P
This enzyme converts fructose-6 and fructose-1-phosphate to
Dihydroxyacetone fructose-1,6-diphosphate, with the defect thus blocking the
Phosphate metabolism of glycogen, glucose, and fructose. As with myo-
Glyceraldehyde 3-P (2) phosphorylase deficiency, prolonged ischemic exercise in PFK
may result in muscle necrosis and myoglobinuria. However,
3-P-Glyceroyl phosphate (2) renal failure is not as common in PFK as in myophosphor-
2 ADP ylase. Because the enzyme defect also affects erythrocytes,
IX
2 ATP some patients also exhibit increased hemolysis with jaun-
3-Phosphoglycerate (2)
X
dice. PFK is a tetrameric enzyme that is under the control of
three structural genes (M, L, P), but only the M gene subunit
2-Phosphoglycerate (2) is expressed in mature muscle, whereas erythrocytes express
both the M and L subunits. The absence of anemia in PFK
Phosphoenolpyruvate (2) patients is related to the ability of erythrocytes to synthesize
2 ADP a functional enzyme with the L subunit. The defect in the M
2 ATP gene is transmitted as an autosomal trait on chromosome 1.
Pyruvate (2)
XI PHOSPHORYLASE B KINASE DEFICIENCY (TYPE VIII)
Lactate (2) Phosphorylase B kinase has a pivotal role in both the deg-
FIGURE 9-3  Glycogen metabolism and glycolysis. Roman radation and the synthesis of glycogen. The enzyme phos-
numerals refer to glycogenosis enzymatic defects. (Redrawn phorylates glycogen phosphorylase to an active form while
from Tsujinao S, Nonaka I, DiMauro S: Glycogen storage phosphorylating glycogen synthase to an inactive form; thus,
myopathies, Neurol Clin 18:127, 2000.)
when glycogen degradation is turned “on,” synthesis is turned
“off.” Phosphorylase B kinase deficiency can be classified into
the three to five times normal increase in venous lactate ­levels the following groups depending on clinical presentation:
observed when an isolated muscle is made ischemic does not
occur. n Liver disease of childhood exhibiting hepatomegaly, growth
A distinct variant exists that exhibits severe generalized retardation, delayed motor development, hyperlipidemia,
weakness, respiratory insufficiency, and death in infancy. Type and fasting hypoglycemia, inherited as either an X-linked
V deficiency may also be associated with some cases of sudden recessive or an autosomal recessive trait.
infant death syndrome (SIDS). n Liver and muscle disease characterized by hepatomegaly
Phosphorylase initiates glycogen degradation by remov- and nonprogressive myopathy of childhood, inherited as an
ing 1,4-glucosyl residues from the outer branches of the gly- autosomal recessive trait.
cogen molecule, leaving a PLD molecule with four glucosyl n Muscle disease in which the patients exhibit weakness of
units, which are then degraded by the debranching enzyme, exercising muscles with myalgias, cramps, and myoglobin-
leading to glucose-1-phosphate. There are three isoenzymes uria, inherited as an X-linked recessive trait.
expressed in muscle, brain, and liver. The brain contains both n Fatal infantile cardiomyopathy, inherited as an autosomal
muscle and brain isoenzymes, which is why specific brain recessive trait.

The anesthetic considerations would be similar as for the
previously discussed deficits, except when the degree of liver
disease would require modifications.
PHOSPHOGLYCERATE KINASE DEFICIENCY (TYPE IX)
Phosphoglycerate kinase (PGK) catalyzes the formation of
3-phosphoglycerate and ATP. Because the enzyme is tran-
scribed from a single gene that is expressed in all tissues except
sperm, there is considerable clinical variability. The major clin-
ical presentations include hemolytic anemia, CNS dysfunc-
tion (mental retardation, behavioral abnormalities, seizures,
stroke), and exercise myopathies. These major clinical features
occur with equal frequency in enzyme-deficient patients, but
rarely do all appear in the same patient. It is inherited as an
X-linked trait.
PHOSPHOGLYCERATE MUTASE DEFICIENCY (TYPE X)
Phosphoglycerate mutase (PGAM) catalyzes the interconver-
sion of 2-phosphoglycerate and 3-phosphoglycerate. Clinical
features include myopathy with exercise intolerance, cramps,
and myoglobinuria. It is inherited as an autosomal trait, mani-
festing variable heterozygotic symptoms.
MUSCLE LACTATE DEHYDROGENASE DEFICIENCY (TYPE XI)
Lactate dehydrogenase (LDH) is a tetramer composed of two
distinct subunits, M and H, which can be arranged into five
isoenzymes. The M subunit is the predominant form in skel-
etal muscle. Thus, patients with the M-type deficit exhibit
exercise weakness and recurrent myoglobinuria, but no other
tissue pathology.
ALDOLASE DEFICIENCY (TYPE XII)
Aldolase is present as three isoenzymes in skeletal muscle and
erythrocytes; liver, kidney, and small intestine; and neural tis-
sue. Patients with myopathy marked by exercise intolerance
also exhibit hemolytic anemia.
Myoglobinuria
Myoglobinuria is a common metabolic abnormality among
the substrate use muscle diseases. Because of an enzymatic
blockage in glycogen metabolism and glycolysis, the muscle
becomes starved for energy, leading to ischemia, necrosis,
and the release of myoglobin into the circulation. However,
the most common cause of recurrent myoglobinuria is a
lipid metabolism disorder, carnitine palmitoyltransferase II
(CPT-II). Myoglobin is a 17,000-dalton protein with a heme
prosthetic group present in muscle at a concentration of about
1  g/kg and is released during ischemia and cell death. The
normal serum myoglobin concentration is about 20 ng/mL; a
serum concentration of 300 ng/mL is required for renal excre-
tion. Visible brown discoloration of the urine with myoglo-
bin suggests massive muscle destruction (rhabdomyolysis).
Hemolysis is distinguished from myoglobinuria by a positive
urine benzidine test (>500 ng/mL myoglobin) without micro-
scopic red blood cells. Furthermore, if hemolysis is not a factor,
Chapter 9  Muscle Diseases 307
a serum sample should be free of hemolysis. Hypovolemia and
acidosis in combination with myoglobinuria increases the
probability of acute renal failure. The exaggerated response of
muscle fasciculations to succinylcholine, seen in children and
adults with myopathies, places them at risk for myoglobinuria
and renal failure. Arrhythmias may result from the effects of
hyperkalemia, acidosis, and hypocalcemia (from uptake of
­calcium by injured muscle). The hypocalcemia will also be
exacerbated by the IV administration of sodium bicarbon-
ate and the hyperventilation in patients on respirators. These
patients should then receive calcium.
Treatment is aimed at reversing muscle destruction (rest,
in many cases) and the maintenance of adequate urine
­output. Early, vigorous fluid resuscitation reduces the inci-
dence of renal failure during myoglobinuria. Mannitol
should be administered to promote an osmotic diuresis and
to scavenge the free oxygen radicals produced after reperfu-
sion of the ischemic kidney. Alkalinization of the urine with
sodium bicarbonate may prevent the precipitation of myo-
globin acid hematin in the renal tubules and also reduce the
risk of renal failure.
Glycogenosis Type I (von Gierke's Disease)
Patients with this disease lack glucose-6-phosphatase, which
acts primarily in the liver to convert glucose-6-phosphate to
glucose, where it is metabolized by glucose-dependent tissues,
brain, and muscle.30 Therefore, this is not primarily a muscle
disease but rather an “energy deficit” for muscles and other
tissues. Because glycogen synthesis continues without glyco-
gen degradation and glucose utilization, there is excess liver
glycogen deposition resulting in hepatomegaly. Because fast-
ing hypoglycemia can be severe and is associated with acido-
sis, frequent small carbohydrate feedings are required. Von
Gierke's disease is usually accompanied by seizures, men-
tal retardation, and growth impairment; children rarely sur-
vive beyond 2 years. However, some patients have survived
into their teenage years through portocaval shunts, in which
intestinal uptake of glucose will bypass the liver, and with
administration of thyroxine and glucagons to limit glycogen
synthesis. Surgical patients should be permitted to take oral
glucose solutions up to 4 hours before surgery, followed by an
intraoperative glucose infusion. Frequent monitoring of both
blood glucose and pH is required throughout the periopera-
tive period. Lactate-containing solutions should be avoided,
because these patients lack the ability to convert lactic acid to
glycogen.
Glycogenosis Type II (Pompe's Disease)
This lysosomal acid maltase deficiency results in the deposi-
tion of glycogen in smooth, skeletal, and cardiac muscle. The
clinical presentation takes three forms. The infantile form pri-
marily involves cardiomegaly with CHF and death, usually
before age 2 years. A juvenile form results in severe proximal,
truncal, and respiratory muscle weakness. An echocardiogram
 308 ANESTHESIA AND UNCOMMON DISEASES

may reveal cardiac hypertrophy with subaortic stenosis.
Muscle glycogen deposition may lead to an enlarged protrud-
ing tongue, making the patient prone to upper airway obstruc-
tion and a difficult tracheal intubation. Respiratory muscle
weakness may predispose the patient to prolonged postoper-
ative ventilatory support. Once extubated, aggressive pulmo-
nary toilet is required to prevent pneumonia. These patients
often die during the second and third decade. A milder, adult-
onset variant of Pompe's disease simulates limb-girdle dystro-
phy. The etiology of the muscle weakness in these patients is
unclear but may involve the rupture of hypertrophied lyso-
somes, causing muscle destruction.
MITOCHONDRIAL MYOPATHIES
The mitochondrion is an intracellular organelle responsible for
most of the energy-producing pathways. The genetics of mito-
chondria are complex in that the enzymes and proteins of the
organelle are coded for by either mitochondrial genes or cel-
lular genes. In addition, the mitochondrial deoxyribonucleic
acid is exclusively maternally inherited and heterogeneous,
such that multiple different copies of mitochondrial DNA may
exist within the cell. Genetic defects in these mitochondrial
enzymes are devastating to normal muscle action because the
enzymes are responsible for ATP production from the mito-
chondrial respiratory chain and oxidative phosphorylation33
(Fig.  9-4). Thus genetically and phenotypically a heteroge-
neous group, these myopathies have an estimated incidence
of 1 in 4000 births.
Luft34 reported the first case of a mitochondrial disorder
in 1962 in a Swedish woman with evidence of hypermetabo-
lism, but with normal thyroid function. The woman was sub-
sequently found to have a loose coupling of oxidation and
phosphorylation, with abnormal mitochondrial structure.
The 1963 morphologic criteria for this mitochondrial myopa-
thy included ragged-red fiber (RRF) appearance with a mod-
ification of the GÖmÖri trichrome stain.35 It is now known
that not all RRF mitochondrial diseases involve myopathy,
and RRF is not always present in mitochondrial myopathies.
Mitochondrial myopathies can be divided into (1) “pure”
mitochondrial myopathies; (2) mitochondrial encephalomy-
opathies; (3) oxidative phosphorylation disorders; (4) disor-
ders of fatty acid metabolism; and (5) disorders of pyruvate
metabolism.36–40 Myocardial myopathies have been classified
into specific clinical syndrome groups or into specific oxida-
tive phosphorylation enzyme defects.
See Chapter 14 for an in-depth discussion of mitochondrial
myopathies.
OXIDATIVE PHOSPHORYLATION
DISORDERS
The increasing list of neuromuscular disorders associated
with mitochondrial abnormalities especially includes defects
in oxidative phosphorylation.41 OxPhos disorders can be
classified according to the specific site of the biochemical
defect.42 However, patients may have an isolated defect in one
complex, or the genetic defect may affect several complexes.

Complex I II III IV V

NADH: CoQ Succinate: CoQ Ubiquinol– Cytochrome–c ATP

reductase reductase cytochrome–c oxidase synthase
reductase

H H H H

Q
Q Q
Inner Q
Q Q
membrane
Q ETF

NAD
FADH2 ½ O2H2O
Matrix FADH2 FAD
FAD
NADH

TCA e ADP  Pi ATP

cycle
H

-oxidation Fatty acids

FIGURE 9-4  Mitochondrial respiratory chain and oxidative phosphorylation system. (Redrawn from Cooper JM, Clark J: The structural
organization of the mitochondrial respiratory chain. In Shapira AH, Di-Mauro S, editors: Mitochondrial disorders in neurology, Oxford, UK,
1994, Butterworth-Heinemann.)

In  addition, the clinical pictures of these defects often over-
lap. Furthermore, because the genes for OxPhos subunits may
originate in either mitochondrial (mtDNA) or nuclear DNA,
the specific biochemical defect does not indicate the mode
of inheritance. This section discusses important syndromes
associated with mitochondrial OxPhos defects.
Luft's Disease
Luft34 described a 35-year-old woman with symptoms of
hyperthyroidism (hyperhidrosis, polydipsia, polyphagia,
weight loss) with normal thyroid function. She was nonethe-
less treated for hyperthyroidism, including thyroidectomy,
without the expected results. She was subsequently found to
have mitochondria of variable size with increased numbers
of cristae. The biochemical defect was a loose coupling of
­oxidative phosphorylation; for every oxidation of hydrogen,
an ATP was not produced from adenosine diphosphate (ADP).
Thus, more O2 expenditure was required to achieve a normal
amount of energy production. Perioperatively these patients
would be at risk for hyperthermia, increased O2 ­utilization,
metabolic acidosis, and hypovolemia.
Complex I Deficiency
Complex I deficiency is one of the most common OxPhos
deficits (see Fig. 9-4). The presentation may include isolated
myopathy with exercise intolerance and lactic acidosis or a
multisystem disease.43 The multisystem disease includes a
fatal infantile lactic acidosis with cardiomyopathy and CNS
impairment.
Complex IV Deficiency
Complex IV defect usually presents before age 3 years as severe
infantile myopathy, with failure to thrive, weakness, hypoto-
nia, severe lactic acidosis, and associated hepatic, cardiac and
renal involvement.44 The myopathy has improved spontane-
ously after age 3 in some reports. This “benign” reversible
infantile myopathy may be caused by a developmentally regu-
lated OxPhos subunit (see Fig. 9-4).
Coenzyme Q Deficiency
Coenzyme Q is responsible for shuttling electrons between
complexes I, II, and III44 (see Fig. 9-4). The clinical presentation
has included progressive muscle weakness starting in child-
hood, with associated CNS disorders. The patients improved
clinically when administered 150 mg of coenzyme Q daily.
Anesthetic Considerations
Defects in OxPhos may have global physiologic effects that
predispose these patients to anesthetic complications. The
major cardiac manifestation of an OxPhos deficit is hypertro-
phic cardiomyopathy, possibly caused by a specific metabolic
Chapter 9  Muscle Diseases 309
defect in which a translocase exchanges mitochondrial ATP
for cytosolic ADP. These patients should have a preopera-
tive echocardiogram. Hematologic manifestations have also
been associated with OxPhos lesions, specifically sideroblas-
tic anemia in Pearson's syndrome (bone marrow vacuoliza-
tion, pancreatic insufficiency). Proximal tubular defects may
be a common manifestation of pediatric OxPhos diseases.
Diabetes mellitus is also fairly common in pediatric OxPhos
disorders and has been described in the mitochondrial syn-
dromes Kearns-Sayre, Pearson's, Wolfram's, and MELAS
(mitochondrial encephalomyopathy with lactic acidosis and
stroke-like episodes).
Preoperative evaluation of these patients must include their
tendency to develop lactic acidosis, their feeding habits, and
the utility of glucose infusion in maintaining normal metabo-
lism. Similar to other muscle diseases, patients often have a
history of respiratory problems (e.g., recurrent pneumonias,
asthma, dyspnea), which may require pulmonary evaluation
preoperatively and intensive care unit (ICU) monitoring post-
operatively. Succinylcholine should be avoided because of
the low risk of inducing lactic acidosis in myopathic patients.
Propofol has several deleterious effects on the normal phys-
iologic metabolism of mitochondria, including inhibition
of OxPhos complex I, CPT-I, and β-oxidation.45 Therefore,
patients with mitochondrial myopathies are at increased
risk of developing propofol infusion syndrome (PRIS), which
includes metabolic acidosis, refractory cardiac failure, hyper-
thermia, and muscle necrosis. TIVA with propofol should be
used with caution in patients with mitochondrial myopathies.
Regional anesthesia may also increase the risk of periopera-
tive complications in these patients, because local anesthetics
have an inhibitory effect on mitochondrial ATP synthesis. For
patients with known mitochondrial myopathies, an inhala-
tional anesthetic may be the best option.
DISORDERS OF FATTY ACID METABOLISM
Muscles use long-chain fatty acids as a source of energy
(Fig. 9-5; see also Fig. 9-1). The fatty acids are esterified with
coenzyme A (CoA) and then transported across the inner
mitochondrial membrane through three steps: (1) esterifica-
tion to carnitine with carnitine palmitoyltransferase I (CPT-I);
(2) translocation across the membrane with carnitine acylcar-
nitine translocase; and (3) release as CoA by CPT-II. Inherited
defects have been described for each of these enzymatic
steps, as well as for the enzymes involved in β-oxidation.46,47
Presentation is usually in infancy as hypoketotic hypoglyce-
mia, triggered by a fasting or hypermetabolic state (infection).
These defects may also be associated with encephalopathy,
hepatocellular dysfunction, and cardiomegaly.
Carnitine Deficiency
Carnitine is synthesized in the liver and then transported to
skeletal muscle, where it facilitates the transport of long-chain
fatty acids into the mitochondrion. Medium-chain fatty acids
 310 ANESTHESIA AND UNCOMMON DISEASES
CoA  fatty acid
Fatty acid  CoA  carnitine
CPT
CoA  fatty acid  carnitine
Translocase
CoA  fatty acid  carnitine
CPT
Fatty acid  CoA  carnitine
C22  C12 Acetyl-CoA
LC dehydrogenase
C12  C6 Acetyl-CoA
MC dehydrogenase
C4 Acetyl-CoA
SC dehydrogenase
CPT  carnitine palmitoyl transferase
LC  long chain
MC  medium chain
SC  short chain
FIGURE 9-5  Transport of fatty acids into muscle mitochondria.
do not require carnitine for transport. Since skeletal and car-
diac muscle derive most of their resting, fasting, and endur-
ance energy from fatty acid metabolism, a carnitine deficiency
results in weak muscles and the deposition of lipid granules.
Childhood carnitine deficiency myopathy includes progres-
sive dilated cardiomyopathy. In addition, Reye's syndrome has
been associated with this deficiency, which includes vomit-
ing, stupor, and coma. The addition of carnitine and medium-
chain fatty acids to ameliorate the muscle weakness should be
administered perioperatively. Corticosteroids should also be
administered, because they provide an alternative transport
mechanism for long-chain fatty acid metabolism. Prolonged
fasting must be avoided, and glucose-containing infusions
should be used.
Acyl-Coenzyme A Dehydrogenase Deficiency
The dehydrogenases break down mitochondrial fatty acid CoA
to acyl-CoA. Defects in these enzymes lead to the accumula-
tion of fatty acyl-CoA and fatty carnitine acyl-CoA. The most
common form is the medium-chain acyl-CoA dehydrogenase
deficiency, with an incidence of 1 in 10,000 births. It usually
presents as hypoketotic hypoglycemia during the first or sec-
ond year, usually triggered by fasting or a metabolic stress. The
deficiency has been linked to some cases of SIDS. In addition,
patients who survive the childhood crisis often develop myop-
athy and cardiomyopathy.
Carnitine Palmitoyltransferase Deficiency
More common than the CPT-I form, CPT-II deficiency usu-
ally presents in late adolescence as exercise-induced muscle
cramping and myoglobinuria. Prolonged metabolic stress
can result in respiratory insufficiency and renal failure from
rhabdomyolysis. Serum muscle CK levels are elevated dur-
ing attacks but are usually normal between episodes. These
patients exhibit normal work and oxidative capacity as long
as a carbohydrate substrate is available; it is only during fast-
ing or when glycogen stores (glucose) have been depleted that
these patients have a metabolic crisis. Thus, as with several
other substrate deficiency disorders, glucose should be admin-
istered perioperatively. Severe shivering and muscle contrac-
tions (succinylcholine) should also be avoided.
DISORDERS OF PYRUVATE METABOLISM
These metabolic disorders include pyruvate dehydrogenase
and pyruvate carboxylase deficiency. Pyruvate dehydrogenase
deficiency is one of the most common presentations of con-
genital lactic acidosis.48 Clinical presentation can occur in the
newborn as severe persistent lactic acidosis, usually resulting
in death. Later in infancy, it may be associated with develop-
mental delay, hypotonia, seizures, dysmorphic features, and
intermittent episodes of lactic acidosis. It may also present later
in childhood with ataxia, precipitated by high-­carbohydrate
meals and treated with high-fat, low-carbohydrate diets.
MALIGNANT HYPERTHERMIA
Still a cause of anesthesia-related fatalities, malignant hyper-
thermia (MH) was first described in 1960 by Denborough and
Lovell.49 The reported incidence is 1 in 15,000 anesthetics in
children to 1 in 50,000 to 100,000 anesthetics in adults. The
MH syndrome is characterized by generalized muscle rigidity,
unexplained increased CO2 production, metabolic acidosis,
rhabdomyolysis, elevated CK levels, hyperkalemia, and hyper-
thermia.50 An increase in core temperature of 10° C every
5 minutes to a maximum of 46° C has been reported. Although
the degree and duration of core temperature elevation has an
effect on outcome, hyperthermia may be a late sign in the
development of MH.
Pathogenesis. The MH syndrome is triggered by the
administration of volatile anesthetics and the depolarizing
muscle relaxant succinylcholine.51 The initial presentation
may be masseter spasm after administration of succinylcho-
line. If succinylcholine is not administered to facilitate endo-
tracheal intubation, the syndrome may not be recognized until
later into uncomplicated inhalational anesthesia.52 At that
point in the anesthetic, the tachycardia, hypertension, and
rigid muscles might be attributed to “light” anesthesia, leading
the anesthesiologist to increase the concentration of the deliv-
ered anesthetic. Only after the patient becomes red and hot,
and the end-tidal CO2 has risen significantly, is the problem

often recognized. Muscle rigidity may make ventilation dif-
ficult, which in association with increased CO2 production
leads to both respiratory acidosis and metabolic acidosis.
Furthermore, the CO2 absorbance of the breathing circuit
will become hot and exhausted, exacerbating the hyperther-
mia and acidosis. Cardiac arrhythmias are common, including
ventricular tachycardia and fibrillation, the result of acidosis,
hyperthermia, and catecholamine surges. Bleeding may occur
from the surgical site with the development of coagulopathies
(e.g., disseminated intravascular coagulation, thrombocytope-
nia). Acute renal failure ensues from hypotension and rhabdo-
myolysis. Coma will follow as a result of extreme hyperthermia
and cerebral edema. The syndrome is almost always fatal if not
appropriately treated. MH has also been reported in humans
in response to stress or exercise.53
Malignant hyperthermia is a defect in the regulation of
myoplasmic calcium concentration. The triggering event
leads to a release of calcium from the sarcoplasmic reticulum
through a voltage-dependent muscle ryanodine (RYR1) chan-
nel.54 The RYR1 channel is regulated by calcium, ATP, calmod-
ulin, and magnesium. Micromolar concentrations of calcium
activate the RYR1 channel, whereas calcium concentrations
tenfold higher (>10 μM) inhibit the channel. Mutations in
the RYR1 gene on human chromosome 19q13.1 have been
linked to MH-susceptible individuals.55 The mutant RYR1
channel is activated by lower-than-normal concentrations of
calcium and is inhibited by higher-than-normal concentra-
tions of calcium. In addition, modulation of the RYR1 recep-
tor by calmodulin is altered such that its activation threshold
is significantly decreased. This ultimately leads to excess sar-
coplasmic calcium, with persistent contracture of myofibrils,
depletion of ATP, uncoupling of oxidative phosphorylation,
metabolic acidosis, and muscle necrosis. Genetic linkage stud-
ies have demonstrated that about 50% of the cases of MH can
be linked to mutations in the RYR1 gene.
The RYR1 mutation has also been linked to central core
disease and King-Denborough syndrome, an unclassified mus-
cle disease associated with short stature, pectus carinatum,
kyphosis, cleft palate, ptosis, and delayed motor development.
Central core myopathy is a rare congenital myopathy and auto-
somal dominant disease that results in hypotonia and delayed
development. In 124 MH-susceptible individuals, 23% had
mutations in the RYR1 gene in one report.56 In other analysis,
MH susceptibility was linked to the dihydropyridine (DHP)
receptor gene on chromosome 7q, which also regulates skel-
etal muscle calcium flux.57
Thus, although the inheritance of MH is autosomal domi-
nant, the molecular genetics of MH susceptibility may involve
more than one genetic locus.
Diagnosis. The diagnosis of MH is based on the presenta-
tion of the clinical syndrome or the in  vitro contracture test
(IVCT). The IVCT is specific for MH, but its lower sensitivity
eliminates it as a practical screening test for the general sur-
gical population. Furthermore, because many clinical scenar-
ios can produce a hypermetabolic state and mimic MH, the
Chapter 9  Muscle Diseases 311
TABLE 9-4  n Malignant Hyperthermia: Criteria for
Clinical Grading Scale
Process Clinical Criteria
Muscle rigidity Generalized rigidity
Masseter muscle spasm
Muscle breakdown Creatine kinase (CK) >20,000 U/L
Myoglobinuria
Plasma potassium (K) >6 mEq/L
Respiratory acidosis End-tidal CO2 >55 mm Hg
Paco2 >60 mm Hg
Temperature increase Rapidly increasing
Temperature >38.8° C (102° F)
Cardiac involvement Unexplained sinus tachycardia
Ventricular tachycardia/fibrillation
Family history Familial history of malignant
hyperthermia
diagnosis is usually made in individuals with both appropriate
clinical criteria and a positive IVCT. Larach et al.58 developed a
clinical grading scale to assess the probability of MH suscepti-
bility (Table 9-4). This MH scale incorporates six clinical crite-
ria, such that the probability of MH susceptibility increases the
more criteria manifested by the patient. When an individual
manifests enough criteria consistent with MH, it is important
that the individual undergo an IVCT, because many will be
found to be non–MH susceptible. This information is impor-
tant for family counseling.
The IVCT is performed at only two centers in Canada and
six in the United States.* The patient should have the mus-
cle biopsy performed at the IVCT diagnostic center, because
the test must be performed within 4 hours of excision of the
muscle. The caffeine-halothane contracture test (CHCT)
requires 2 g of muscle, usually harvested from the vastus late-
ralis or vastus medialis muscle. Regional anesthesia with seda-
tion is preferable for the procedure, since direct infiltration
of the muscle with local anesthetic is contraindicated. In the
North American protocol, six longitudinal strips of muscle are
hooked to force transducers and three are exposed to 3% halo-
thane and three to caffeine. The development of a contracture
0.7 g or greater for halothane and 0.3 g or greater for caffeine
is considered positive for MH.59 The specificity of this test is
about 98% for tested individuals who have had an unequivocal
MH episode, but the sensitivity is only 85% to 90%. Therefore,
with a low prevalence of the MH syndrome in the general
population and a false-positive incidence of 10% to 15%, the
IVCT cannot be used for routine screening. An ideal solution
for MH would use a simple DNA-based test to screen surgi-
cal patients. However, as noted earlier, more than one genetic
locus has been identified as being associated with MH suscep-
tibility, and at this time the detection rate for gene mutations
is only 23% in known MH-susceptible patients.57
* See www.mhaus.org for the addresses of MH diagnostic centers.
 312 ANESTHESIA AND UNCOMMON DISEASES
Some patients have masseter muscle spasm (MMS) during
induction of anesthesia. Sudden cardiac arrest after adminis-
tration of succinylcholine has been reported in normal patients
with MMS but is much more common in patients with myopa-
thies.60 Children with muscle diseases may have a myotonic
response (MMS) to succinylcholine that also includes elevated
CK levels, metabolic acidosis, hyperkalemia, and dysrhyth-
mias, although this does not necessarily mean they are MH
susceptible. In a study of whether MMS can occur in “normal”
individuals after induction with succinylcholine and inhala-
tional agents, of 5000 anesthetized children, no child induced
with pentothal developed MMS, whereas its incidence was
0.5% with succinylcholine and halothane.61 None of these
patients developed MH. However, others have reported that
60% of patients with MMS tested IVCT positive for MH.62
Because development of MH syndrome can be fatal, a
nontriggering anesthetic should be used for surgery after
the observation of MMS alone during anesthetic induction.
The development of generalized myotonic contractions and
other sequelae after succinylcholine or inhalational agents is
abnormal; if possible, the anesthetic should be terminated,
the patient hospitalized for observation, and MH susceptibil-
ity investigated. Even if the patient is not MH susceptible, the
significant rhabdomyolysis occurring in some muscle diseases
could progress to severe metabolic acidosis, renal failure, and
sudden death.
Treatment. The mortality from an MH syndrome has
fallen from almost 100% to low levels as a result of vigilance,
supportive care, withdrawal of triggering agents, and admin-
istration of dantrolene. When an MH response is suspected,
­dantrolene should be administered at 1 to 2 mg/kg intrave-
nously, with additional doses every 15 to 30 minutes until
evidence of the acute episode has subsided. After the initial
episode, dantrolene should be continued at 1 mg/kg IV every
6 hours, or 0.25 to 0.5 mg/kg/hr IV until the treatment has
produced stable, normal vital signs (possibly for 24 hours,
depending on the severity of the episode). Evidence of an MH
relapse has been reported in about 25% of patients within
24 hours of the initial episode.63 Each 20-mg vial of dantrolene
contains 3 g of mannitol, and the vials are reconstituted in
water. The most common complication of dantrolene admin-
istration is muscle weakness.
Additional responses to an MH episode should include
correction of the metabolic acidosis with bicarbonate
(0.5-2 mEq/kg), hyperventilation with 100% O2, and an initial
fluid bolus of 10 to 20 mL/kg of cooled or room-temperature
normal saline. Continued fluid management will depend on
the patient's urine output, electrolytes, and hemodynamic sta-
bility. Aggressive alkaline diuresis to maintain a urine o­ utput
of 1 to 2 mL/kg may be required to prevent renal failure from
myoglobinuria. The administration of glucose and insulin
will drive potassium intracellularly and provide a substrate
for maintenance of normal cerebral metabolism. ABG analy-
sis and blood samples for electrolytes and CK levels should
be sent regularly. It may be necessary to lavage body cavities
(stomach and bladder) with cooled saline to prevent danger-
ous levels of hyperthermia. Muscle compartments must be
evaluated to allow early treatment of compartment syndrome.
Management of MH-Susceptible Patients. These patients
can safely be administered general anesthesia with nitrous
oxide, IV anesthetics, and nondepolarizing muscle relaxants.
Regional anesthesia with any local anesthetic is also consid-
ered safe for MH-susceptible patients. The anesthetic circuit
should not have been exposed to inhalational agents, includ-
ing new CO2–absorbent drugs, and the anesthesia machine
should have been flushed with a continuous O2 flow at
10 L/min for 20 minutes. Prophylactic loading with dantrolene
appears unnecessary, because MH may still develop, and
effective serum dantrolene levels can be achieved after acute
IV loading.64 Because stress can theoretically trigger an MH
response, patients should be appropriately treated with anx-
iolytics before their arrival in the operating room, and those
receiving a regional anesthetic should be sedated. An MH kit
with sufficient dantrolene to administer 10 mg/kg to a large
adult, several ampules of bicarbonate, equipment for lavaging
body cavities, IV fluids, and ice for topical cooling should be
readily available.
MUSCLE CHANNELOPATHIES
The channelopathies have a common molecular basis in the
impairment of voltage-gated skeletal muscle.65
Hyperkalemic Periodic Paralysis
Hyperkalemic periodic paralysis is inherited as an autosomal
dominant trait with complete penetrance. The paralytic attacks
usually begin infrequently during the first decade of life and
then increase in frequency with age until possibly recurring
daily. They often occur in the morning or after a period of
rest following strenuous exercise. The attacks never occur dur-
ing exercise and may be aborted if the individual begins mild
exercise. The muscle weakness is accompanied by hyperkale-
mia, with levels up to 6 mM and a concomitant decrease in
serum sodium levels. With resolution of the weakness, serum
potassium returns to normal, and the patient may experience
a water diuresis, creatinuria, and myalgias. The attacks can be
precipitated by potassium intake, cold, stress, glucocorticoids,
and pregnancy.
There are three clinical variants of hyperkalemic periodic
paralysis: with myotonia, without myotonia, and with para-
myotonia. Lowering the patient's body temperature will induce
weakness, but not myotonia, in any of the clinical variants. The
myotonia that does occur is mild and rarely interferes with
movement. In the paramyotonia variant the attacks include
generalized weakness and paradoxical myotonia. In paramyo-
tonia congenita the myotonia is induced by cold and includes
hyperkalemia, but differs in that the myotonia appears during
exercise and worsens with continued exercise. These individu-
als have the characteristic lid-lag phenomenon.65

The pathogenesis of hyperkalemic periodic paralysis
involves abnormal activation of sarcolemmal sodium chan-
nels.66 The mutation has been linked to the skeletal muscle
sodium channel gene on chromosome 17q23. The mutant
sodium channel responds to elevated potassium levels by
increased influx of sodium and prolonged depolarization.
This renders the muscle inexcitable (paralyzed) and results
in a compensatory release of potassium from the cells, which
may then activate more sodium channels.
Hyperkalemic periodic paralysis is diagnosed with an exer-
cise stress test. Individuals are exercised for 30 minutes to a
heart rate greater than 120 beats per minute, followed by abso-
lute rest. In normal individuals, serum potassium will rise
during the exercise phase, then decline to baseline during the
rest phase. In periodic paralysis patients, serum potassium will
start to decline at rest, but then rise again in 10 to 20 minutes
with accompanying weakness.67
Individuals with the disease may be able to attenuate
attacks by ingestion of carbohydrates, continuation of mild
exercise, and administration of a potassium-wasting diuretic.
Preventive therapy also includes potassium-wasting diuretics
(hydrochlorothiazide). Preoperative carbohydrate depletion
should be avoided by carbohydrate loading the night before
surgery or by infusion of a glucose solution the day of surgery.
IV solutions free of potassium should be administered. The
ECG may show evidence of peaked T waves before a paretic
attack. At that time, glucose, insulin, and inhaled β-agonists
should be administered in an attempt to abort the paralysis.
Again, the patient must be kept warm and relaxed, because
both cold and stress can trigger paralysis.
A rare variant of hyperkalemic periodic paralysis is nor-
mokalemic periodic paralysis, in which the serum potassium
value does not increase during severe attacks. This condi-
tion includes urinary potassium retention, beneficial effects
of sodium loading, and lack of beneficial effects in glucose
loading. In one family the mutation was linked to the sodium
channel gene on chromosome 17q.67
Hypokalemic Periodic Paralysis
As with the hyperkalemic variant, the attacks in hypokale-
mic periodic paralysis begin before age of 16 with infrequent
attacks, then increase in frequency to possible daily recur-
rence. The attacks usually occur in the second half of the night
or early in the morning. The patient may awaken in the morn-
ing paralyzed except for the cranial muscles, which are usually
spared. However, respiratory function is compromised during
severe attacks, and fatal respiratory failure has been reported.
Attacks are triggered by preceding strenuous physical activity,
high-carbohydrate and high-sodium meals, stress, and cold.
During severe attacks, serum potassium falls to abnormal lev-
els. Attacks can be accompanied by oliguria, constipation, dia-
phoresis, and sinus bradycardia. In addition, many patients
may develop a permanent myopathy.68
Hypokalemic periodic paralysis is inherited as an auto-
somal dominant trait, with higher penetrance in males. The
Chapter 9  Muscle Diseases 313
disease is linked to the l-type calcium channel DHP receptor
on chromosome 1q31-32, but the pathogenesis has not been
well elucidated.
The diagnosis of hypokalemic periodic paralysis is made by
establishing hypokalemia during attacks and normokalemia
between attacks. If an abnormally low serum potassium level is
sustained, the clinician should consider secondary reasons for
paretic attacks, including renal or GI potassium wasting and
thyrotoxic conditions. The administration of glucose and insu-
lin may provoke an attack by driving potassium intracellularly.
Attacks can be prevented or attenuated by ingesting 2 to
10 g of potassium chloride. Patients planning to undergo sur-
gery should not ingest a meal high in carbohydrates the pre-
vious night. Electrolytes should be measured preoperatively
on the day of surgery, and appropriate corrections to serum
potassium should be instituted. Some patients are treated with
acetazolamide to induce a mild metabolic acidosis, preventing
potassium from shifting into the cell. Postoperative hypother-
mia should be avoided. An episode may precipitate respiratory
failure, so these patients should be monitored postoperatively.
MYASTHENIAS
The myasthenias are disorders that affect the neuromuscular
junction (NMJ) and are characterized by fluctuating muscle
weakness and abnormal fatigability. The NMJ consists of the
presynaptic and postsynaptic regions separated by the synap-
tic space. The nerve terminal contains acetylcholine (ACh)
membrane-enclosed synaptic vesicles, which are released in
response to a generated motor nerve action potential. The
ACh molecules then bind to a postsynaptic receptor and
induce a muscle action potential (Fig.  9-6). In addition to
ACh ACh
Prejunctional
nerve terminal
ACh ACh
Acetylcholine receptors
Postjunctional
muscle
membrane
Normal Myasthenia
gravis
FIGURE 9-6  Neuromuscular junction. Density of acetylcholine
(ACh) receptors is shown on the folds of postjunctional muscle
membranes. Compared with normal folds, the density of ACh
receptors is greatly reduced in the presence of myasthenia gravis.
(From Stoelting RK, Dierdorf SF: Anesthesia and co-existing
disease, New York, 1993, Churchill Livingstone, p 440.)
 314 ANESTHESIA AND UNCOMMON DISEASES
acquired myasthenia gravis and the Eaton-Lambert syndrome,
several toxins and medications can produce myasthenic-like
syndromes that affect the NMJ, including botulism, tetanus,
venom poisoning, aminoglycosides, hypermagnesemia, quini-
dine, and organophosphate poisoning.
Myasthenia Gravis
Acquired myasthenia gravis (MG), the classic syndrome, ini-
tially involves muscles innervated by cranial nerves (ocular
muscles), with symptoms worsening during the progression of
the day (Box 9-2). There is considerable variation in the world
prevalence, from 1.2 per 1 million in Japan to 14.2 per 100,000
population in West Virginia, with a 3:2 female/male ratio. MG
may occur at any age, but females under 40 and males over 60
are more often affected.69
The defect is the result of a reduction in the number of
available receptors for ACh at the postsynaptic NMJ. In MG
the ACh receptors are inactivated by circulating antibodies,
which renders them unavailable to ACh binding. Ultimately,
the ACh receptor–immunoglobulin G (IgG) complex will
stimulate a complement-mediated lysis of the receptors at the
junctional folds. Antibodies to ACh receptors are detectable in
the serum in 74% to 94% of MG patients. About two thirds of
patients have thymic hyperplasia, and 10% have thymomas. In
about 10%, MG is associated with another autoimmune dis-
ease, including hyperthyroidism, polymyositis, systemic lupus
erythematosus, Sjögren's syndrome, rheumatoid arthritis,
ulcerative colitis, sarcoidosis, and pernicious anemia. In addi-
tion, MG has developed in patients receiving d-penicillamine
and interferon therapy and after bone marrow transplantation
(Box 9-3).
In about 50% of the MG patients the initial symptoms
involve extraocular muscles, but bulbar and limb muscles may
also be included in the initial presentation. Levator palpebrae
weakness leads to eyelid ptosis, which is often exacerbated by
sustained upward gaze. Individuals often complain of dip-
lopia. The face often appears expressionless with a snarling
smile. Speech is usually hoarse and slowed. Chewing and swal-
lowing of food is difficult, with a risk of aspiration. Dyspnea
BOX 9-2   n  SYMPTOMS OF MYASTHENIA GRAVIS
Fluctuating weakness
Fatigability of ocular and other muscles innervated by cranial nerves
Gender/age
Female/male ratio of 3:2
More common: females <40, males >60
About two-thirds thymic hyperplasia; 10% thymomas
In 50% of patients initial symptoms involve extraocular muscles
Eyelid ptosis
Sustained upward gaze
Diplopia
Face appears expressionless.
Speech is hoarse and slowed.
Chewing and swallowing difficult; risk of aspiration
Dyspnea with mild to moderate exertion
BOX 9-3   n SECONDARY CAUSES OF MYASTHENIA
GRAVIS
Hyperthyroidism
Polymyositis
Systemic lupus erythematosus
Sjögren's syndrome
Rheumatoid arthritis
Ulcerative colitis
Sarcoidosis
Pernicious anemia
Has developed in patients:
Receiving d-penicillamine
Receiving interferon therapy
After bone marrow transplantation
will occur with mild to moderate exercise. The proximal limb
muscles are often more affected than the distal limb muscles.
Muscle weakness is worse with repeated exercise and as the
day progresses. However, the symptoms may vary daily or
from week to week with periods of remission (see Box 9-2).
Although the initial symptoms are usually ocular, in about
90% of patients the disease becomes generalized within the
first year of diagnosis, with the most rapid progression dur-
ing the first 3 years. Before the 1990s, MG progressed to a
complete systemic deterioration and death in one fourth of
patients. With the introduction of more effective therapy, mor-
tality has decreased dramatically. Beckman et  al.69 reported
no fatalities directly related to MG in 100 patients. However,
patients do experience episodes of respiratory failure because
of bulbar involvement. A “myasthenic crisis” is defined as an
acute exacerbation of symptoms with respiratory compromise.
In a series of 53 patients with a myasthenic crisis, 75% of the
patients were extubated within 1 month of being placed on a
respirator, with three deaths during the crisis and four deaths
after extubation.70 Independent risk factors associated with
poor prognosis were identified, such that patients with no risk
factors were all extubated within 2 weeks, whereas patients
with increasing risk factors required longer periods of respira-
tory support (Box 9-4).
To define the severity of MG and the clinical prognosis, a
classification was devised by Osserman in 1958 and then mod-
ified in 1971 (Box 9-5).71 Patients in group I are “medication
responsive” and are not at risk for a crisis. Patients in group
IIB have moderately severe disease, respond poorly to medi-
cations, and are at risk for a crisis. Patients in group III have
rapidly progressive disease over 6 months, are at high risk for
BOX 9-4   n RISK FACTORS ASSOCIATED WITH
PROLONGED INTUBATION AFTER
MYASTHENIA GRAVIS CRISIS
Preintubation serum bicarbonate ( HCO3− ) >30 mg/dL
Peak vital capacity <25 mL/kg
Age >50 years
Comorbidities: atelectasis, anemia, congestive heart failure,
Clostridium difficile infection

BOX 9-5   n  CLASSIFICATION OF MYASTHENIA GRAVIS
I. Ocular myasthenia
II. Chronic generalized
A. Mild
B. Moderate
III. Acute, fulminating
IV. Late, severe
crisis, and often have thymomas. Patients with group IV dis-
ease have milder MG for more than 2 years and then develop
a severe, progressive form.
Neonatal myasthenia develops in about 12% of infants born
to mothers with MG resulting from the passive transfer of
ACh receptor antibodies. The symptoms of poor feeding, gen-
eralized weakness, respiratory distress, and weak cry usually
appear a few hours after birth and last about 18 days. About
30% of women with MG experience a worsening of symptoms
during pregnancy. If possible, pregnancy should be planned
for periods of remission when the patient is no longer receiv-
ing immunosuppressants. If the symptoms during pregnancy
become debilitating, these women can receive plasmapheresis
and increased cholinesterase therapy.
The diagnosis of MG is usually based on the symptoms of
easy fatigability and fluctuating weakness. An edrophonium
chloride (Tensilon) test, however, is sometimes used to confirm
the diagnosis. An initial 2-mg IV dose of edrophonium is admin-
istered to ascertain tolerance, and then 6 to 8 mg is injected. The
patient is observed for an improvement in symptoms or the
ability to complete repetitive functions. The improvement in
symptoms, usually lasting about 10 minutes, suggests a diagno-
sis of MG. Side effects of edrophonium injection include fascic-
ulations, sweating, nausea, abdominal cramps, and bradycardia.
In addition, electrophysiologic studies can be performed, show-
ing a decremental response of the compound action potential to
repetitive electrical stimulation in MG.
Therapeutic options for patients with MG include cholin-
esterase inhibitors, immunosuppressants, plasma exchange,
specific immunoglobulins, and thymectomy. Pyridostigmine
(Mestinon), a cholinesterase inhibitor that prolongs the
action of ACh at the NMJ receptor, is the first line of treat-
ment for the symptomatic relief of MG. Pyridostigmine
is dosed initially at 15 to 60 mg four times daily, with reso-
lution of s­ ymptoms within 15 to 30 minutes and a duration
of 3 to 4 hours. Neostigmine bromide, a shorter-acting cho-
linesterase inhibitor, may be administered parenterally for
acute episodes. Progressive weakness with increasing dosing
of anticholinesterases may indicate the onset of a myasthenic
or a cholinergic crisis. A cholinergic crisis is associated with
­muscarinic effects: abdominal cramps, nausea, vomiting, diar-
rhea, miosis, lacrimation, increased bronchial secretions, and
diaphoresis. Significant bradycardia may also be observed.
These muscarinic symptoms should not be prominent during
a myasthenic crisis and can be distinguished by a 2-mg edro-
phonium test. However, it is often difficult to distinguish these
Chapter 9  Muscle Diseases 315
two crises, and it is best to hold the anticholinesterase and sup-
port the patient's respiration if necessary with intubation and
ventilation.
Thymectomy may improve the remission rate and amelio-
rate the progression of MG. The best responders to thymec-
tomy are female patients with hyperplastic thymus glands and
high ACh receptor antibody titers. Alternate-day prednisone
therapy induces remission and improves the clinical course
of the disease in more than half of patients. Azathioprine
(150-200 mg/day) often improves symptoms as well.
Anesthetic Considerations
Surgical MG patients undergoing anesthesia should be warned
that they may require postoperative ventilatory support. MG
criteria that correlate with postoperative controlled ventila-
tion include duration of disease greater than 6 years, pres-
ence of pulmonary disease, pyridostigmine dose greater than
750 mg/day, and preoperative vital capacity less than 2.9 L.72
If possible, neuromuscular blocking drugs should be avoided
because of the variable response to these medications as a result
of the nature of MG and the treatment with anticholinester-
ases. Patients with MG are usually resistant to s­ uccinylcholine
and sensitive to nondepolarizing muscle relaxants. Thus,
if rapid intubation is required, a larger dose (1.5-2 mg/kg)
of succinylcholine should be administered.73,74 Chronic use
of anticholinesterases will also impair the effect of plasma
cholinesterase. This may result in prolonged neuromuscu-
lar blockade by succinylcholine and mivacurium. It may also
reduce the metabolism of ester local anesthetics. The use of
any nondepolarizing muscle relaxant should be titrated with a
peripheral nerve stimulator.
For maintenance of anesthesia, inhalational agents might
be preferred because they can be eliminated by ventilation and
do not have the depressant effects of narcotics postoperatively.
One approach is to hold the patient's anticholinesterase med-
ication 4 hours before surgery and then begin neostigmine
IV 1 hour before emergence from anesthesia, at 1⁄30 to 1⁄60 the
daily pyridostigmine dose infused over 24 hours. Before extu-
bation the patient should be fully awake, have a full return to
a “train of four” if muscle relaxants were used, and a negative
inspiratory force greater than 30 cm H2O.
Eaton-Lambert Myasthenic Syndrome
Eaton-Lambert myasthenic syndrome (ELMS) was first
described in 1956 in patients with fatigable weakness and
pulmonary malignancies. The weakness usually affects the
proximal limb muscles, predominantly the lower limbs, while
sparing of the extraocular and bulbar muscles. Symptoms are
usually worse in the morning on awakening and improve dur-
ing the day. Unlike in MG, DTRs are usually reduced or absent.
Patients also have autonomic symptoms of dry mouth, ortho-
static hypotension, hyperhidrosis, and reduced papillary light
reflex. ELMS is probably caused by impaired release of ACh
at the nerve terminal, produced by autoantibodies directed
 316 ANESTHESIA AND UNCOMMON DISEASES
against the voltage-gated calcium channels. It is the calcium
influx into the nerve terminal that stimulates the release of
ACh vesicles.75 Because a malignancy is present in about 60%
of ELMS patients, a diagnosis of the myasthenic syndrome
should elicit a search for a neoplasm.
Therapy with cholinesterases alone is usually minimally
effective. Muscle strength and autonomic functions can be
improved with 3,4-diaminopyridine (DAP) therapy. DAP
causes peripheral paresthesias, palpitations, sleeplessness,
cough, diarrhea, and rare seizures. Guanidine hydrochloride,
which increases the release of ACh, has also proved effective,
but the severe side effects of bone marrow depression, renal
tubular necrosis, cardiac arrhythmias, liver failure, and ataxia
have limited its use.
Patients are sensitive to both depolarizing and nondepo-
larizing muscle relaxants. In addition, because ELMS patients
may be treated with both DAP and pyridostigmine, antago-
nism of the neuromuscular blockade at the end of surgery
may prove ineffective. These patients often undergo diagnos-
tic procedures in search of occult malignancies, and because
of their reduced respiratory reserve, they are at risk for respi-
ratory failure with only minimal anesthetics and sedatives.76
INFLAMMATORY MYOPATHIES
Dermatomyositis
Dermatomyositis can present at any age, but usually the child-
hood cases present between 5 and 14 years and the adult form
at 40 to 60 years. Women are usually affected more often than
men. The neck flexors, shoulder girdle, and pelvic girdle mus-
cles are the most severely affected, such that lifting the arms
over the head, climbing stairs, or rising from a chair is difficult.
Children usually also present with fatigue, low-grade fevers,
and a rash that precedes the muscle weakness and myalgia.
The classic rash includes a purplish discoloration of the eyelids
with periorbital edema; scaly, papular, erythematous lesions
over the knuckles; and a flat, erythematous, sun-sensitive rash
over the neck, face, and anterior chest. Children also develop
subcutaneous calcifications. Cardiac conduction abnormali-
ties are common, as are CHF and myocarditis. About 10% of
dermatomyositis patients also develop interstitial lung disease,
with restrictive disease and reduced diffusing capacity. There
may also be evidence of chronic pulmonary aspiration from
oropharyngeal and esophageal weakness. Vasculitis of the GI
tract may result in ulcerations and perforations. In addition,
necrotizing vasculitis may affect the eyes, kidneys, and lungs.
Arthralgias involving all joints are a common complaint. Adult
dermatomyositis is strongly associated (up to 45%) with under-
lying malignancies. Corticosteroids are the major initial ther-
apy, with progression to more powerful immunosuppressants.77
Polymyositis
Polymyositis usually presents after age 20 years, with women
affected more often than men. The patient usually presents
with neck flexor and proximal arm and leg weakness that
develops over weeks and months, but without a characteris-
tic rash as in dermatomyositis. Dysphagia is also a common
symptom. These patients have similar cardiac and pulmonary
complications as in dermatomyositis, but with a much lower
incidence of associated malignancies. Most patients with poly-
myositis improve with immunosuppressive therapy.
Inclusion Body Myositis
Inclusion body myositis (IBM) presents with slowly progres-
sive, distal and proximal muscle weakness, often with years
from onset of symptoms to diagnosis. It is the most common
inflammatory myopathy in men older than 50. Early signs of
the disease include asymmetric quadriceps and wrist/­finger
flexor weakness. At least 40% of patients complain of dys-
phagia. IBM is not associated with cardiac abnormalities or
an increased risk of cancer. The muscle biopsy demonstrates
inflammation with atrophic fibers and eosinophilic cytoplas-
mic inclusions. Patients with IBM do not significantly improve
with immunosuppressive therapy.
Overlap Syndromes
In the “overlap” group of diseases an inflammatory myopa-
thy occurs in association with a connective tissue disease.
The overlap syndromes include scleroderma, Sjögren's syn-
drome, systemic lupus erythematosus, rheumatoid arthritis,
and mixed connective tissue disease. Antinuclear antibodies
are seen in many of these patients.
INFECTIVE AND TOXIC MYOPATHIES
Infections, endocrine abnormalities, environmental tox-
ins, and medications can all potentially produce myalgias
and muscle weakness. In developing countries, infections
from parasitic infestations produce myositis and myopathies.
Exogenous chemicals and the abnormal production of inter-
nal endocrine chemicals can have profound effects of skeletal
muscle function. It is beyond the scope of this chapter to dis-
cuss the action of these agents on the skeletal muscle appara-
tus. Instead, this section discusses three of the more common
agents that result in a myopathy.
Human Immunodeficiency Virus
The spectrum of findings with HIV spans asymptomatic
CK elevation to generalized fatigue to severe proximal limb-­
girdle weakness. In one report, 18% of HIV-infected patients
had muscle involvement, which included a polymyositis-like
myopathy and muscle atrophy.78 These patients are also subject
to bacterial and protozoal myopathies as a result of immuno-
suppressive therapy. The myopathy is progressive, symmetric,
and usually affects the lower extremities. Dysphagia, respira-
tory weakness, and rashes are not part of the syndrome. HIV-
infected patients also are subject to a poorly defined syndrome
characterized by severe muscle wasting with normal or only

mildly reduced muscle strength. This may be the result of gen-
eralized systemic infections, poor nutrition, and the toxins
from antiviral medications.
Necrotizing Myopathy
Cholesterol-lowering medications tend to produce myopathy
and necrotizing myopathy. Lovastatin in combination with
other medications (e.g., cyclosporine) or in patients with hep-
atobiliary or renal dysfunction may produce severe myopa-
thy with rhabdomyolysis. ε-Aminocaproic acid, used during
surgery to inhibit fibrinolysis and reduce bleeding, has been
implicated in a necrotizing myopathy that affects the axial
musculature. The symptoms can begin 4 or more weeks after
administration and may be the result of an ischemic insult to
the muscle.79
Thyrotoxic Myopathy
The incidence of myopathy among thyrotoxic patients is as
high as 82%. Common symptoms include myalgias, fatigue,
and exercise intolerance. The weakness is predominantly
proximal and may be associated with dysphagia and respira-
tory insufficiency. The sudden onset of generalized weakness
with bulbar palsy has been described for thyrotoxic patients
alone, but it should raise the suspicion of associated myasthe-
nia gravis. CK levels are usually normal, except during thy-
roid storm, when rhabdomyolysis could lead to renal failure.
Treatment of patients with thyrotoxic myopathy is to reinstate
a euthyroid condition.
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 C H A P T E R
10
Skin and Bone Disorders
JOHN E. TETZLAFF, MD  n
PAUL X. BENEDETTO, MD  n

n Barbiturates can precipitate Stevens-Johnson syndrome,

Achondroplasia and Dwarfism which can present as life-threatening airway compromise
Behçet's Disease requiring urgent airway intervention.
Epidermolysis Bullosa n Erythema nodosum can be associated with serious pulmo-
Erythema Multiforme, Stevens-Johnson Syndrome, and nary compromise. An infectious etiology requires protection
Toxic Epidermal Necrolysis
of anesthetic equipment.
Erythema Nodosum
n In Fabry's disease the massive lipid deposition can com-
Fabry's Disease
promise pulmonary, cardiovascular, renal, and ocular
Herpes Simplex
systems.
Mastocytosis
n During primary herpes simplex outbreaks, elective anes-
Mucopolysaccharidoses
thesia and surgery should be avoided, if possible. In any
Neurofibromatosis
case, protection of anesthesia equipment is required.
Osteogenesis Imperfecta
n Mastocytosis patients can have massive release of histamine
Osteoporosis, Osteomalacia, and Osteopetrosis
and other vasoactive substances from mast cells, resulting
Paget's Disease of Bone
in serious hemodynamic instability.
Panniculitis
n Patients with mucopolysaccharide metabolism errors
Pemphigus and Pemphigoid
present anesthetic issues because of structural abnor­
Psoriasis
mality, especially the neuraxis and airway. Asymptomatic
Pyoderma Gangrenosum
compression of the spinal cord can result in injury from
routine airway management maneuvers.
n Neurofibromatosis patients present anesthetic issues
related to proliferation of neural tissue and involving air-
way management and respiratory compromise, as well as
KEY POINTS
endocrine and electrolyte abnormalities.
■ Achondroplasia frequently makes airway management n Osteogenesis imperfecta patients present for anesthesia
difficult for patients, and unstable cervical spine anatomy related to fracture and can be easily injured with position-
presents the risk of neurologic injury. Postoperative respi- ing unless special care is taken.
ratory insufficiency may be a challenge. n Patients with lesions of bone formation (osteoporosis,
n Behçet's disease is associated with a variety of cardiovas- osteomalacia, osteopetrosis) have structural skeletal anom-
cular diseases with anesthetic implications. Lesions around alies that make positioning difficult and put them at risk for
the airway can make intubation difficult, and airway injury.
obstruction may require anesthetic intervention. n Paget's disease patients may have calcific changes of the car-
n Epidermolysis bullosa patients present with fragile skin and diovascular system. Some treatment options have specific
potential airway anomalies, including laryngeal stenosis. anesthetic implications.
Airway manipulation can create lesions that compromise n In panniculitis patients the anesthetic management is dic-
the ability to extubate the patient. tated by the site of the lesions. Positioning, monitoring, or
n Erythema multiforme patients may sustain extensive skin regional anesthesia should not be allowed to exacerbate the
injury from minimal trauma. lesions.

319
 320 ANESTHESIA AND UNCOMMON DISEASES
n Many pemphigus patients with acute exacerbations have
airway lesions that make airway management difficult and
that can worsen with maneuvers. Elective anesthesia dur-
ing exacerbations should be avoided because remission can
be induced medically.
n Psoriasis patients have anesthetic issues related to chronic
pharmacologic treatment options.
n Pyoderma gangrenosum patients can present for urgent
surgery when compartment syndrome results from inflam-
matory involvement of extremity skin.
This chapter discusses the diseases and syndromes that involve
the skin and bones in the context of the perioperative period,
defining anesthetic issues during preoperative preparation,
intraoperative management, and postoperative care. Skin dis-
orders and bone disorders both involve an alteration in the
surface of the body, and thus anesthetic care can be challeng-
ing. Many skin and bone disorders are associated with patho-
physiologic changes of the airway. Airway management can be
difficult if the anatomy is abnormal. Regional anesthesia can
also be difficult or impossible for the same reason, or unwise
if the site of the block is abnormal. Alterations in surface anat-
omy present difficult issues for positioning, and routine move-
ment of the patient can cause significant skin injury or bone
fracture. Some of these diseases are associated with comorbid-
ities that require preoperative investigation and perioperative
consideration. Some skin and bone diseases are chronic and
controlled with a variety of medications that can cause organ
toxicity. When surgery is indicated for these diseases, particu-
larly urgent surgery, knowledge of their pathophysiology can
guide management and decrease the risk of morbidity.
ACHONDROPLASIA AND DWARFISM
Pathophysiology. The chondrodysplasias are a group of
related syndromes associated with abnormality of the size
of the trunk, limbs, and skull, resulting in a disproportion-
ate shortness of stature. Achondroplasia is the most common
form of dwarfism.1 The pathophysiology is abnormal carti-
lage formation, particularly at the epiphyseal growth plates.2
Cellular structure of individual cartilage cells is abnormal.3
Classification is based on the site of the dysplasia (e.g., epiphy-
seal, metaphyseal, and diaphyseal).4 Other terms for these dis-
eases include “spondylo” for those that affect the spine, and
TABLE 10-1  n  Achondroplasia and Chondrodysplasias
Type Bone Abnormality
Achondroplasia Limbs, skull, spine
Dystrophic dysplasia Limbs, spine, cleft palate
Hypochondroplasia Limbs
Metaphyseal dysplasia Limbs
Spondyloepiphyseal dysplasia Spine, cleft palate
“cranio” for those that involve the base of the skull. Further
classification is based on age at onset (infantile) and genetic
inheritance (X-linked, recessive, or autosomal dominant)
(Table 10-1). The etiology is unknown but has been associated
with numerous causative factors.2
Differential Diagnosis. Another name for achondroplasia
is “short-limbed dwarfism.” The achondroplastic appearance
is an adult less than 4 feet (1.2 m) tall, with a large head, bulg-
ing forehead, depressed nasal bridge, prominent mandible,
and short arms and legs with normal trunk size. In those who
survive infancy, life expectancy is normal. Affected infants
have shortening of the proximal part of the limbs, protuber-
ance of the frontal skull, and depressed nasal bridge, related
to shortness of the base of the skull. Lordosis, thoracolumbar
kyphosis, and pelvic narrowing are present, and severe spinal
stenosis is common.1 Spinal stenosis can manifest as nerve
root compression, cauda equina syndrome, thoracolumbar
spinal cord compression, or high cervical cord compression
caused by stenosis of the foramen magnum. Quadriplegia
in an achondroplastic infant resulted from stenosis of the
foramen magnum caused by normal range of motion of the
neck.5 Normal range of motion also caused cervical spi-
nal cord injury in an infant with atlantoaxial s­ubluxation.6
Quadriplegia occurred after anesthesia and surgery in a
­diastrophic dwarf with severe kyphosis.7
Achondroplasia is an autosomal dominant syndrome,
although family history is less obvious because fertility is
low.8 The differential diagnosis of short stature (dwarfism) is
based on a combination of clinical and radiographic features.
Numerous comorbidities are associated with these syndromes
(Box 10-1).
Preoperative Preparation (Box  10-2). Because of the
associated congenital defects, abnormalities of the cardio-
vascular and respiratory systems should be suspected in all
patients with chondrodysplasia. Chest radiography, electro-
cardiography, and transthoracic echocardiography are mini-
mum requirements. Difficult airway management is likely,
complicated by anatomic abnormalities of the skull, neck,
and chest. Cleft lip, cleft palate, and micrognathia may also
be contributing factors. Stridor can occur spontaneously, sec-
ondary to laryngomalacia.9 Symptomatic subglottic stenosis
required urgent tracheostomy in one report.10 The potential for
Genetic Transmission
Autosomal dominant
Recessive
Autosomal dominant
Recessive
X-linked recessive
 Chapter 10  Skin and Bone Disorders 321

Because no specific treatment exists for achondroplasia,

BOX 10-1   n ACHONDROPLASIA AND there are no recurring medications. Any medication list is
CHONDRODYSPLASIAS: ASSOCIATED
COMORBIDITIES
related to comorbidities, such as seizure disorder or lung
disease.
Atlantoaxial instability (hypoplastic odontoid)
Cleft palate Intraoperative Considerations. The primary anesthesia
Clubfoot concern in achondroplasia relates to airway management. The
Congenital heart disease high probability of difficult airway management necessitates
Dental abnormalities preparation for awake intubation. Reduced endotracheal tube
Difficult airway criteria
Hydrocephalus
size has been recommended.14 Urgent airway management
Malformation of skull should be avoided because atlantoaxial instability or spinal
Mental retardation canal stenosis puts the cervical spinal cord at risk with tradi-
Obstructive sleep apnea tional airway maneuvers. Laryngeal mask airway (LMA) can
Pulmonary hypertension achieve oxygenation and facilitate endotracheal intubation in
Scoliosis, kyphosis
Seizure disorder
urgent situations when otherwise impossible in these infants.15
Spinal stenosis High spinal cord injury and death have been reported after
Tracheomalacia routine airway management (neck flexion, extension of
occiput) in patients with atlantoaxial instability. Ventilatory
difficulty should be assumed, and because of restrictive pul-
monary disease, general anesthesia may be impossible with-
out tracheal intubation. Mechanical ventilation may require
BOX 10-2   n ACHONDROPLASIA PATIENTS: a high respiratory rate and a reduced tidal volume. Pressure-
PREOPERATIVE ISSUES controlled ventilation may be the best approach.
Anticipated difficult airway All forms of general and regional anesthesia have been per-
Laryngomalacia formed in patients with achondroplasia (Box  10-3). Spinal
Cervical spine instability surgery, especially of the cervical spine, may require neuro-
Kyphoscoliosis
physiologic monitoring (somatosensory/motor-evoked poten­
Obstructive sleep apnea
Abnormal chest mechanisms tials), which modifies anesthetic options. Regional anesthesia
has been reported for achondroplastic patients. Spinal and epi-
dural anesthesia for surgery16–18 and obstetrics19–23 have been
successful, although technically difficult. Successful combined
spinal/epidural anesthesia has also been reported.24 Emergency
s­ ignificant atlantoaxial subluxation from abnormal o ­ dontoid
cesarean section has been accomplished with spinal anesthesia
development1 or congenital absence of the odontoid11 should
when a difficult airway was obvious.25 Extensive spread of small
be investigated with flexion-extension lateral cervical spine
volumes of local anesthetic in the epidural space could lead to
radiographs and open-mouth view of the odontoid. If incon-
dangerously high block if the volume injected is not reduced.26
clusive, magnetic resonance imaging (MRI) of the skull and
Peripheral nerve block and plexus block have been accom-
cervical spine is required. If cervical radicular signs are pres-
plished without incident, although the uncontrolled airway
ent, or if mental retardation makes recognition impossible,
management issues associated with local anesthetic–induced
high cervical stenosis should be evaluated with computed
seizure activity are a concern. Ultrasound guidance for periph-
tomography (CT) or MRI.
eral and plexus block could reduce this risk. The use of ket-
When spinal cord compression is identified, decompres-
amine, succinylcholine, and nitrous oxide for cesarean section
sive laminectomy or decompression of the foramen magnum
has been reported for a full-term achondroplastic parturient
is indicated. Kyphoscoliosis can be severe, and evaluation of
who required general anesthesia.27
pulmonary reserves with chest radiography, arterial blood
gas (ABG) analysis, and pulmonary function tests may be
required. Thoracic dystrophy can be associated with some rare
dwarfism syndromes and can greatly exaggerate the ventila- BOX 10-3   n ACHONDROPLASIA PATIENTS:
tory compromise from kyphoscoliosis secondary to mechan- ANESTHETIC MANAGEMENT ISSUES
ical restriction of thoracic excursion. Tracheomalacia is an Airway management issues
additional source of airway compromise and should be evalu- Difficult ventilation
ated by identification of symptoms, CT, or flow-volume loops. Cervical spinal cord compression
Cervical spine instability
Because of the shape of the head and neck, obstructive sleep
Technical difficulty with neuraxial block
apnea is present in as many as 40% of achondroplastic patients, Extensive spread of neuraxial local anesthetic
even in childhood.12,13 Central sleep apnea has been reported Prolonged postoperative respiratory insufficiency
in patients with high cervical spinal stenosis or stenosis of the Difficult acute pain control because of obstructive sleep apnea
foramen magnum.13
 322 ANESTHESIA AND UNCOMMON DISEASES
Because of the anatomic and functional abnormality of the
chest cage, postoperative ventilatory insufficiency may occur,
and extended mechanical ventilation may be necessary. The
high probability of obstructive sleep apnea12 will increase the
sensitivity to opioids and make postoperative pain manage-
ment challenging.
Summary. Achondroplasia and other dwarfism syndromes
are congenital defects in the development of bones. Patients
present with short stature and a variety of skeletal anomalies.
Other congenital defects include heart disease, cleft lip/­palate,
scoliosis, and clubfoot. Anesthetic management is complicated
by difficult airway issues, spinal abnormalities that include
atlantoaxial instability, and cardiopulmonary compromise.
Prolonged mechanical ventilation may be necessary.
BEHÇET'S DISEASE
Behçet's disease is an autoinflammatory disease character-
ized by iritis28 and mucocutaneous ulceration; it is most aptly
considered a neutrophilic dermatosis with systemic vasculitis
and autoimmune complex deposition.29 Although the diag-
nostic criteria pertain exclusively to skin and eye involvement
(Box  10-4), almost any organ system can be involved, with
reports of cases involving the central nervous system (CNS),
cardiovascular system, lungs, and synovial surfaces.30,31 Less
common lesions can occur in the urogenital and gastrointes-
tinal (GI) tract. In some patients, fibrinolysis is impaired and
recurrent thrombophlebitis and hypercoagulability can occur.
Differential Diagnosis and Clinical Manifestations.
Behçet's disease can have a broad differential diagnosis as
a result of its myriad manifestations. Oral ulcerations can
mimic herpetic stomatitis, pemphigus vulgaris, and Stevens-
Johnson syndrome. Skin lesions may be confused with other
neutrophilic dermatoses such as Sweet's syndrome, but the
triad of iritis, oropharyngeal lesions, and genital mucosal
lesions is more specific.32 CNS involvement can manifest as
parenchymal and nonparenchymal disease.33–34 Serious man-
ifestations include lesions of the spinal cord and brainstem,
BOX 10-4   n BEHÇET'S DISEASE: DIAGNOSTIC
CRITERIA*
Major Criterion
More than three (>3) recurrent episodes of oral ulceration in
12-month period
Minor Criteria
1. Recurrent genital ulceration
2. Eye lesions
3. Skin lesions in addition to oral ulcerations (e.g., erythema
nodosum, papulopustular lesions, pseudofolliculitis)
4. Positive pathergy test (new skin lesion at site of trauma)
Data from International Study Group for Behçet's Disease: criteria for
diagnosis of Behçet's disease, Lancet 335:1078-1080, 1990.
*Diagnosis requires the major criterion plus two of four (2/4) minor criteria.
cauda equina syndrome, aseptic meningitis, seizures, demen-
tia, coma, and intracranial aneurysms and thrombosis. Dural
sinus thrombosis has been reported in a patient with Behçet's
disease.35 Cardiovascular manifestations include myocardi-
tis, vasculitis,36 pericardial effusion, valve lesions,37 arterial
occlusion, aneurysm,38 or dissection of major blood vessels.39
Obstruction of the superior vena cava has been reported,40 as
well as other lesions of major venous structures.41 Pulmonary
manifestations42,43 include chronic obstructive pulmonary dis-
ease (COPD),44 hemoptysis, bronchiectasis, pulmonary artery
aneurysms and thrombosis, and pulmonary hypertension.45
Glomerular lesions can precipitate chronic renal failure.46 In
patients with Behçet's involvement of the GI tract, return of
GI function may be delayed after surgery.47 This should also be
considered in regard to drug absorption, which can be delayed
postoperatively.48
Preoperative Preparation (Box  10-5). When Behçet's dis-
ease presents as major organ system involvement, these systems
should be completely investigated before elective surgery. Severe
neurologic manifestations49 have usually been defined at diag-
nosis with MRI or CT and should be reviewed for anesthetic
issues, including cord compression, increased intracranial pres-
sure (ICP), and risk of herniation. If symptoms have increased
since the last study, the studies may need to be repeated.
Electrocardiography and echocardiography are often needed
because of the cardiovascular involvement.50 If the patient has
significant respiratory symptoms, ABG analysis, spirometry,
and a chest radiography should be considered. Oropharyngeal
ulceration can occur and become symptomatic with onset of
hemorrhage.51 If symptoms such as stridor with exertion sug-
gest airway compromise, indirect laryngoscopy should be con-
sidered before elective anesthesia. Blood urea nitrogen (BUN)
and creatinine levels should be measured to identify or quanti-
tate chronic renal disease and nephrotoxicity of treatment.52–54
Because Behçet's disease is an inflammatory process,
chronic use of anti-inflammatory and antineoplastic drugs
such as corticosteroids, azathioprine, cyclosporine, and cyclo-
phosphamide is common.52 With chronic corticosteroid use,
supplemental corticosteroids are necessary the day of surgery.
Intraoperative Considerations. Skin puncture, such as
at the site of an intravenous (IV) line, is likely to result in
an inflammatory nodule, a phenomenon known as pathergy
(Fig.  10-1); punctures should thus be kept to a minimum.
BOX 10-5   n BEHÇET'S DISEASE PATIENTS:
PREOPERATIVE PREPARATION
Review MRI/CT scan for central nervous system compromise.
Electrocardiogram
Echocardiogram
Pulmonary function tests
Elective evaluation of airway
Blood urea nitrogen/creatinine
Stress-dose steroids

FIGURE 10-1  Positive pathergy response at the site of previous
intravenous line placement.
Thus, regional anesthesia is less ideal but not contraindicated.
With anesthesia of the airway, topical application of local anes-
thetics is preferred to airway blocks because of potential com-
promise of the airway from the inflammatory response to local
injection.
General anesthesia can be challenging if oropharyngeal
lesions are present. In extreme cases, lesions can severely
reduce the lumen of the oropharynx, and tracheostomy might
be necessary for urgent surgery. For elective procedures, awake
fiberoptic intubation is required. Use of an LMA could aggra-
vate lesions in the airway. If spinal cord lesions are symptom-
atic, use of succinylcholine can result in hyperkalemia. With
cervical cord lesions, intraoperative manifestations of auto-
nomic hyperreflexia may occur.
Summary. The anesthetic implications of Behçet's disease
are related to comorbidity, mainly in the CNS, cardiovascu-
lar, and pulmonary systems (Box 10-6). In patients with severe
oropharyngeal lesions, airway management can be difficult or
impossible. Regional anesthesia can be used, but needle punc-
ture may cause inflammation and lesion formation. General
anesthesia is complicated by difficult airway management.
Autonomic hyperreflexia is a risk with spinal cord lesions.
Spinal involvement can exaggerate the hyperkalemic response
to succinylcholine.
BOX 10-6   n BEHÇET'S DISEASE PATIENTS:
ANESTHETIC MANAGEMENT ISSUES
Minimize skin puncture.
Difficult airway management
Difficult ventilation
Lesions from needle used for regional anesthesia
Hyperkalemia with succinylcholine
Autonomic hyperreflexia
Chapter 10  Skin and Bone Disorders 323
EPIDERMOLYSIS BULLOSA
Epidermolysis bullosa (EB) is a group of hereditary disorders
of the skin, mucous membranes, and internal epithelial linings
characterized by skin fragility and blister development. The
most visible abnormalities are vesicles and bullae within skin
and mucous membranes. Abnormal healing with milia forma-
tion, contracted scarring, and chronic erosion and ulceration
are common features. Although skin surfaces are the primary
sites of involvement, the mucous membranes of the upper GI
tract can also be extensively involved. The three major genetic
variants of epidermolysis bullosa55 have numerous subgroups
based on genotypic and phenotypic expression (Table 10-2).
Epidermolysis bullosa results from defects in the structural
integrity of the protein components of the basal keratino-
cytes or dermal-epidermal junction (basement membrane).
In epidermolysis bullosa simplex (EBS) there is a true split
through the cytoplasm of basal cells. In junctional epidermol-
ysis bullosa (JEB) and dystrophic epidermolysis bullosa (DEB)
the split occurs in the lamina lucida and sub–lamina densa of
the basement membrane, respectively. Regardless, the result
is a surface structure with minimal ability to withstand any
shear forces. The genetic basis of EB disorders is defective
protein products of at least 10 different genes encoding for
the components of the basal keratinocytes and basement
membrane.56
All the subtypes of EB typically present at or shortly after
birth. Sites of maximum friction are the most symptomatic.
In some variants, lesions can include the anus, genitouri-
nary tract, and ominously from the anesthesiology perspec-
tive, the larynx and vocal apparatus. Laryngeal scarring with
vocal cord dysfunction has been reported,57 as has laryngo-
tracheal sloughing with airway obstruction on extubation.
In EB patients, lesions of the airway can result from vigorous
laryngoscopy. Esophageal obstruction and webbing,57 as well
as abnormal coagulation,58 have been reported.
Diagnosis. Epidermolysis bullosa is not subtle, and the age
of presentation coupled with the diffuse blistering and ulcer-
ations make the diagnosis apparent. The most severe types of
TABLE 10-2  n Epidermolysis Bullosa: Major Genetic
Variants
Genetic Level of Skin
Syndrome Transmission Split
Epidermolysis bullosa Autosomal Intraepidermal
simplex (EBS) dominant
Junctional Autosomal Subepidermal
epidermolysis recessive
bullosa (JEB)
Dystrophic Autosomal Subepidermal
epidermolysis dominant or
bullosa (DEB) autosomal
recessive
 324 ANESTHESIA AND UNCOMMON DISEASES
recessive DEB involve pseudosyndactyly (“mitten” deformities
of hands with scarring contractures and fusion of web spaces),
often necessitating corrective surgery.59 Also, squamous cell
carcinomas frequently develop in the sites of chronic ulcer-
ation, requiring surgical excision.60 The pediatric patient with
a rare variant of JEB with pyloric atresia may present for sur-
gical repair.61 Although all surface areas are at risk, each EB
patient has areas of the body more affected than others. These
sites should be identified preoperatively to allow periopera-
tive protection. It is particularly important to identify lesions
in the oropharynx or esophagus, because these may predict
laryngeal involvement and risk of acute postoperative airway
compromise from lesions.
Preoperative Preparation (Box  10-7). The major periop-
erative issues for EB patients are skin fragility, risk of infec-
tion, potential for airway involvement and compromise,
chronic malnutrition and impaired GI absorption, potential
esophageal strictures from manipulation, and use of nasogas-
tric tubes. Corticosteroids are not often used chronically in
these patients, and the need for perioperative corticosteroids
should be weighed against the risk for infection. Wound care
and infection management or prevention are key elements for
survival in EB patients and must be continued carefully in the
perioperative period. EB patients with esophageal involve-
ment may have severe dysphasia that can compromise airway
reflexes and increase the risk of aspiration during induction
or emergence from anesthesia.59 Significant laryngeal steno-
sis has been reported with EB.56 If history or symptomatology
suggests an abnormal airway, a preoperative assessment with
indirect laryngoscopy by an otolaryngologist may be neces-
sary to identify existing lesions that could influence subse-
quent plans for airway management.
Intraoperative Care. The key to safe anesthetic care in
EB patients is caution with skin and mucous membranes.
The blood pressure cuff should be applied over padding
and inflated only when needed. Excessive pressure or sus-
tained inflation can cause injury and should be avoided.
Placement of monitors must be done with caution.62,63
Electrocardiogram (ECG) electrode pads can cause lesions.
All positioning and patient transfers must be performed
with the absolute minimum shear force applied to the body
surface, and whenever possible, patients should be encour-
aged to move themselves to decrease the risk of skin injury.64
BOX 10-7   n EPIDERMOLYSIS BULLOSA PATIENTS:
PREOPERATIVE PREPARATION
Stress-dose corticosteroids
Wound care
Handle all skin and mucosal surfaces gently.
Minimize frictional trauma.
Aspiration prophylaxis
Liver function tests
Blood urea nitrogen/creatinine
Spinal anesthesia for surgery has been reported.62 Regional
anesthesia for surgery or obstetrics65 can be an excellent
choice, as long as the skin at the block site is normal.66–69
Successful brachial plexus anesthesia has also been reported
in EB patients.70 Aggressive volume or injecting pressure for
infiltration should be avoided because this can cause skin
lesions.
With general anesthesia, airway management can be
problematic.71 Prolonged mask ventilation can subject the
face to enough friction to cause disfiguring facial lesions; in
fact, a variant of JEB (Herlitz type) manifests with promi-
nent perioral granulation tissue and scarring.72 The physical
maneuvers necessary to place an LMA properly would likely
create lesions in the airway and should probably be avoided.
Endotracheal intubation is the best approach to securing the
airway but has been associated with lesions, edema, and hem-
orrhage.73 This is particularly true with emergency obstetric
care.74 Atraumatic technique, the smallest possible endotra-
cheal tube, and generous lubrication of the tube are neces-
sary. There are no particular advantages among general
anesthetic agents. Intramuscular and intravenous ketamine
have been used as sole anesthesia for minor procedures.75 The
eyes should not be taped closed, but lubricated. The risk to
skin surfaces from stormy emergence makes rapid emergence
techniques valuable. Suctioning during emergence should
be gentle and limited to direct vision to avoid creating oro-
pharyngeal lesions.76 With IV drugs, the patency of IV access
must be continuously verified, because extravasation can be
associated with serious skin injury.
Summary (Box 10-8). The disorders collectively known as
epidermolysis bullosa are caused by genetic defects in the skin
and mucous membranes that decrease the tensile strength of
body surfaces and result in extensive blistering lesions from
minimal trauma. Involvement of the esophagus and orophar-
ynx can make airway management difficult, and even mini-
mal trauma from laryngoscopy, stylets, forceful intubation, or
blind suctioning can create lesions that compromise the air-
way. Regional anesthesia can be used as long as the block site
is clear of lesions. Excessive volume and pressure with infiltra-
tion of local anesthetic for IV placement or nerve block can
cause skin injury. Intravenous extravasation is also associated
with potential skin sloughing.
BOX 10-8   n EPIDERMOLYSIS BULLOSA PATIENTS:
ANESTHETIC MANAGEMENT ISSUES
Padding pressure points
Careful patient transfer to avoid skin injury
Avoidance of high subcutaneous injection pressure
Injury from prolonged mask ventilation
Airway injury and compromise from instrumentation, stormy
emergence
Esophageal injury from nasogastric tube
Perioperative superinfection of skin lesions
Chronic malnutrition and impaired gastrointestinal absorption
 Chapter 10  Skin and Bone Disorders 325

ERYTHEMA MULTIFORME, STEVENS-
JOHNSON SYNDROME, AND TOXIC
EPIDERMAL NECROLYSIS
Erythema multiforme (EM), Stevens-Johnson syndrome
(SJS), and toxic epidermal necrolysis (TEN) have classically
been considered similar entities along a spectrum of related
diseases.77–79 More recent data suggest that EM minor and EM
major are clinically and etiologically distinct diseases from
SJS and TEN, a concept supported by their different progno-
ses.80 Whereas EM (minor and major) is most frequently pre-
cipitated by an infection, SJS and TEN are almost exclusively
initiated by a drug.81 Clinically, however, the entire group of
disorders may appear similar at the outset, and appropri-
ate caution must be taken as soon as any of the diagnoses
are suspected, to ensure early, aggressive treatment and thus
improved clinical outcome.
Pathophysiology and Clinical Manifestations (Table 10-3).
The majority of cases of EM, both minor and major, are trig-
gered by herpes simplex virus (HSV). Less frequently, other
infectious agents may be implicated, such as Mycoplasma
pneumoniae, Histoplasma capsulatum, and human immuno-
deficiency virus (HIV). Rarely, a medication may cause EM,
but this should heighten clinical suspicion for early presen-
tation of SJS.82–87 Also rarely, a response that resembles EM88
can follow radiation therapy.89 Both minor EM and major EM
manifest with typical target lesions classically described for
the disease spectrum. These well-defined, round, 0.5- to 3-cm
papules and plaques have a dusky violaceous center and an
outer concentric ring of erythema separated by a paler zone.
As the lesions progress in number and severity, the central vio-
laceous zone may become bullous, hemorrhagic, or necrotic.
EM minor and EM major are distinguished by the presence
or absence of mucosal involvement and systemic symptoms,
both of which are characteristic of EM major. In general,
however, despite the more serious clinical appearance of EM
major, both EM conditions are characterized by involvement
of relatively minimal body surface area and lack of progression
to the SJS/TEN spectrum.
In contrast, SJS and TEN exist on a clinical spectrum
together, are characterized by significantly greater involve-
ment of body surface area as well as mucous membranes, an
abrupt onset and fulminant course, and most often with cuta-
neous drug reactions.80 SJS is classically described as involv-
ing less than 10% of body surface area (BSA), whereas TEN
involves greater than 30% BSA. The nebulous region between
10% and 30% BSA has been dubbed “SJS-TEN overlap syn-
drome.” Numerous drugs, including antimicrobials,90 anti-
epileptics,91 and antihypertensives, have been reported as
triggers for life-threatening airway compromise from SJS/TEN
(Fig. 10-2), caused by mucocutaneous lesions adjacent to the
airway and mucous membranes within the airway. Respiratory
epithelium is involved in approximately 25% of TEN patients.92
Conjunctivitis, corneal lesions, and uveitis are common.
Acute myocarditis has been associated with EM triggered
by viremia. Mucosal lesions of the trachea or GI tract can
cause perforation,93 resulting in esophageal rupture, medi-
astinitis, pneumothorax, bronchopleural fistula, or mas-
sive GI hemorrhage. Fulminant cases may cause acute renal
failure.94

TABLE 10-3  n Spectrum of Erythema Multiforme (EM) vs. Stevens-Johnson Syndrome (SJS) and Toxic Epidermal
Necrolysis (TEN)

Mucosa
Diagnosis Skin Lesions Involved* Associated Symptoms Usual Precipitator Treatment

EM minor Classic target lesions No None HSV, other Viral suppressive therapy,
infectious agents systemic steroids

EM major Classic target lesions Yes Fever, malaise, myalgias HSV, other Same as EM minor
plus bullous and infectious agents
necrotic lesions

SJS Dusky macules and
patches; atypical
targets; bullae and skin
sloughing (<10% BSA)
Yes Fever, malaise, fluid Medications Controversial; early
and electrolyte identification and
disturbances (generally cessation of culprit
less than TEN) medication; steroids
vs. IVIG

SJS-TEN Similar skin findings to Similar to SJS Medications Same as SJS

overlap SJS (10%-30% BSA)

TEN Large dusky patches, Yes Toxic appearance, fever, Medications Same as SJS
atypical targets, and hypotension, electrolyte
widespread sloughing disturbance, systemic
(>30% BSA) organ involvement

*Oral, ocular, or anogenital.

BSA, Body surface area; HSV, Herpes simplex virus; IVIG, intravenous immune globulin.
 326 ANESTHESIA AND UNCOMMON DISEASES
FIGURE 10-2  Mucous membrane involvement in patient with
Stevens-Johnson syndrome.
Preoperative Preparation (Box  10-9). Erythema multi-
forme minor presents no unique issues for anesthesiology or
surgery. In contrast, EM major, SJS, and TENS are phenomena
that can create the need for anesthetic intervention.95 When
time permits, identifying comorbidity may allow optimiza-
tion, appropriate assessment, or planning, especially if myo-
carditis or renal failure is known.
With EM patients, chronic skin care techniques to prevent
skin injury and infection are important. Continuing this skin
care into the perioperative period reduces the risks of infec-
tion and sepsis. Chronic corticosteroid therapy is common,
and stress-dose corticosteroids are often required in the peri-
operative period. When myocarditis is known or suspected,
echocardiography is required to define ventricular function
and quantify pericardial effusion. If airway lesions are sus-
pected, careful indirect laryngoscopy can identify critical
lesions. In fulminant cases, this is specifically avoided to pre-
vent acute airway compromise. With extensive acute lesions,
transepidermal fluid loss can cause hypovolemia and electro-
lyte imbalances, which should be identified and corrected.
Severe chronic cases can be associated with cachexia and
malnutrition.
Anesthetic Management. No special anesthetic agents or
techniques are indicated in these patients. Barbiturates may
precipitate SJS. Skin care is a primary issue; tissue injury from
BOX 10-9   n ERYTHEMA MULTIFORME PATIENTS:
PERIOPERATIVE ISSUES
Skin care
Stress-dose corticosteroids (in chronic forms of EM)
Echocardiogram to detect pericardial effusion
Detection of airway lesions
Emergency airway care (Stevens-Johnson syndrome)
Hypovolemia, electrolyte abnormality (toxic epidermal necrolysis)
Eye care
minimal trauma is a risk, and all elements of patient handling
must address this concern. Because cutaneous barriers are
incompetent, surfaces must be protected from contamination
because bacteremia and sepsis could be fatal.
In fulminant cases the anesthesia care required is often air-
way management. With SJS and especially with TEN, anesthe-
sia care for airway management is often urgent. All elements of
management of the difficult airway may be required, includ-
ing tracheostomy. Dehydration and electrolyte loss intra-
operatively should be considered likely. Monitoring devices
can injure skin, as with epidermolysis bullosa. Unexplained
arrhythmia could be a sign of acute myocarditis. Ocular care
should reflect the possibility of eye involvement.
When chronic EM patients present for elective surgery,
regional anesthesia is appropriate, as long as the skin at the site
of the block is normal. With general anesthesia, nitrous oxide
should be used with caution because of the risk of occult baro-
trauma. For similar reasons, maximum peak ventilatory pres-
sures should be kept as low as possible. In patients with EM
precipitated by oral HSV infection, contamination of anesthe-
sia equipment should be prevented with filters or a disposable
circuit and carbon dioxide (CO2) absorber.
Summary. Erythema multiforme and SJS/TEN present
along a clinical spectrum. Minor cases have virtually no anes-
thetic implications. Patients with severe EM can present for
emergency airway management. Most anesthetic manage-
ment issues are related to comorbidities such as dehydration,
electrolyte disturbance, renal failure, myocarditis, and ocular
involvement. Most anesthetic techniques are appropriate.
ERYTHEMA NODOSUM
Pathophysiology and Clinical Manifestations. Erythema
nodosum (EN), an acute inflammatory reaction of the subcu-
taneous fat, is the prototypic septal panniculitis.96 The lesions
manifest as red to violaceous, deep, painful nodules most
frequently on the anterior legs. Unlike a disease process, EN
should be considered a type of hypersensitivity reaction to some
other stimulus. The most common causes include infectious
or inflammatory processes such as streptococcal pharyngi-
tis, bacterial gastroenteritis, inflammatory bowel disease, and
sarcoidosis97–99 (Box  10-10). However, despite appropriately
thorough investigations for underlying causes, the majority of
cases continue to be idiopathic in nature. Less common causes
include leptospirosis,100 toxoplasmosis,101 Q fever,102 and sar-
coid.99 A syndrome that resembles EN has been reported as a
sequela of malignancy.103
Some patients with EN have associated joint involvement,
most often of the knees, ankles, and wrists. Permanent joint
deformity is uncommon, but septic arthritis can be an indica-
tion for surgery.
Differential Diagnosis. The lesions of EN may be confused
with other forms of panniculitis, such as pancreatic pannic-
ulitis and erythema induratum, and with bruising, traumatic
fat necrosis, and superficial thrombophlebitis. EN tends to
 Chapter 10  Skin and Bone Disorders 327

BOX 10-10   n ERYTHEMA NODOSUM: ASSOCIATED BOX 10-11   n ERYTHEMA NODOSUM PATIENTS:

DISEASES PERIOPERATIVE ISSUES

Acute myelogenous leukemia Identify infectious etiology.

Bacterial gastroenteritis (Yersinia enterocolitica, Salmonella, Quantify diminished pulmonary reserve.
Campylobacter) Detect myocarditis and encephalitis.
Behçet's disease Prevent contamination of anesthesia gear.
Drugs (oral contraceptives, penicillin, sulfonamides) Laryngospasm
Fungal infections Bronchospasm
Coccidioidomycosis Atelectasis
Histoplasmosis
Gonorrhea, syphilis
Hodgkin's disease
Human immunodeficiency virus (HIV) compromise should be suspected. Because of the possibly
Idiopathic causes infectious etiology, anesthesia equipment should be protected.
Inflammatory bowel disease No specific anesthetic agents or techniques are indicated or
Measles/rubella
contraindicated for EN patients.
Mycoplasma pneumoniae infection
Pregnancy
Sarcoidosis
Streptococcal pharyngitis
FABRY'S DISEASE
Tuberculosis Pathophysiology. Fabry's disease results from a congeni-
Viral hepatitis
tal defect of glycosphingolipid caused by abnormal function
Data from Psychos DN, et al: Erythema nodosum: the underlying conditions, of the enzyme α-galactosidase A. The defect is transmitted
Clin Rheumatol 19:212–216, 2000. as an X-linked autosomal recessive syndrome. The result is
widespread deposition of neutral glycosphingolipids within
most visceral structures and body fluids. The organs most
i­nvolute spontaneously over several weeks to months, but a affected are the vascular endothelium, smooth muscle of the
more chronic form exists termed erythema nodosum migrans. cardiovascular and renal systems, cornea, kidney, reticuloen-
The lesions of EN rarely ulcerate, and secondary morbidity dothelial system, and the ganglion and perineural cells of the
from EN is uncommon. nervous system.

Preoperative Preparation. Because the etiology of EN can Clinical Manifestations (Box  10-12). The consequences
be infectious, presurgical preparation should focus on identi- of lipid accumulation in Fabry's disease include excruciat-
fication and treatment of the infectious etiology. In patients ing pain, blue-black vascular lesions of the superficial lay-
who present for emergency surgery (e.g., infectious arthri- ers of skin and mucous membranes, and organ dysfunction.
tis), other infections should be considered, but not delaying The lesions of the mucous membranes usually occur in the
the surgical procedure. When the precipitating factor is sar- mouth and oropharynx. Some cases can occur without surface
coid, chest radiography and spirometry should be obtained lesions.104
to identify limited pulmonary reserves. ABG analysis may be The affected organ systems present with symptoms of
indicated for severe cases. Because viremia can be etiologic organ dysfunction. Cardiac disease presents early in life,105,106
for EN, other serious sequelae of viremia, such as encephalitis including coronary artery disease (CAD),107 myocarditis, left
and myocarditis, should be considered during preparation for
emergency surgery.
BOX 10-12   n FABRY'S DISEASE: CLINICAL
Intraoperative Considerations (Box  10-11). If respira- MANIFESTATIONS
tory or systemic infections are etiologic, contamination of
Angiokeratomas of skin
anesthesia equipment should be prevented with filters or dis-
Mucous membrane lesions
posable circuit/CO2 absorber. Both regional anesthesia and Coronary artery disease
general anesthesia are possible for EN patients, and there are Myocarditis
no specific recommendations regarding agents. During acute Cardiac conduction lesions
infection, coincident infection of the airway can cause laryn- Valvular heart disease
Congestive heart failure
gospasm, bronchospasm, or atelectatic lobar collapse from
Hypertrophic cardiomyopathy
inspissated secretions. Pulmonary hypertension
Chronic renal failure
Summary. Erythema nodosum is a cutaneous hypersen-
Delayed gastric emptying
sitivity response to a variety of infectious and inflammatory Central hyperthermia/hypohidrosis
disorders. Because joint involvement can occur, septic arthri- Ocular lesions
tis can present as an urgent indication for surgery. When sar- Retinal detachment/thrombosis
coidosis or pulmonary tuberculosis is causative, pulmonary
 328 ANESTHESIA AND UNCOMMON DISEASES
ventricular hypertrophy, conduction abnormalities,108 val-
vular insufficiency,109–111 and congestive heart failure (CHF).
The progress and severity of these diseases are accelerated by
the universal presence of severe hypertension. Hypertrophic
cardiomyopathy has been associated with some cases of
Fabry's disease.112–114 Pulmonary hypertension from lipid
accumulation in the pulmonary vasculature can occur.115,116
Accumulation of lipid in the kidney causes progressive loss
of renal tubular units.117 Tubules lose squamous tissue as well
as the ability to exchange electrolytes. Renal blood vessels are
also involved, with progressive luminal narrowing. The result
is progressive, chronic renal failure and a renovascular com-
ponent for hypertension. Intestinal dysfunction can occur
with obstruction and delayed gastric emptying.108,118
Vascular lesions occur within the CNS and peripheral ner-
vous system. Pain, hyperhidrosis, and GI symptoms can result.
Episodic fever is reported. Abnormalities in the brainstem
and cerebellum cause disequilibrium and abnormal temper-
ature regulation.119 Dementia, seizure disorder, and intracra-
nial hemorrhage can occur. Ocular involvement120,121 includes
corneal opacity, lens involvement, and arterial lesions that can
result in retinal artery thrombosis122,123 and retinal detachment.
Diagnosis. In affected male patients, the diagnosis of Fabry's
disease is made in childhood from skin lesions and fever of
unknown origin. It can be mistakenly attributed to collagen
vascular disease, rheumatic fever, or vasculitis. Fabry's disease
can be diagnosed in the workup of the early onset of cardio-
vascular, renal, or neurologic disease. Biochemical investiga-
tion is confirmatory.
Preoperative Considerations (Box  10-13). Because there
is no specific treatment for Fabry's disease, preoperative
preparation should focus on detection of end-organ dis-
ease. Quantification of ocular involvement should be consid-
ered to avoid the association of postoperative visual defects
with surgical positioning and hemodynamic fluctuation.
Measurement of BUN/creatinine determines the degree of
chronic renal failure. An ECG124,125 and echocardiogram126 are
required to detect myocardial ischemia, valve lesions, CHF,
and ventricular outflow tract obstruction. Silent myocardial
ischemia is likely because of lesions of the autonomic nervous
system. A pharmacologic stress test may be required to deter-
mine if significant CAD is present, especially if the patient is
sedentary. With an abnormal stress test or echocardiographic
evidence of pulmonary hypertension, cardiac catheterization
BOX 10-13   n FABRY'S DISEASE PATIENTS:
PREOPERATIVE PREPARATION
Quantify ocular involvement.
Measure blood urea nitrogen/creatinine.
Electrocardiogram and echocardiogram
Functional cardiac study
May need cardiac catheterization
MRI/CT if neurologic examination abnormal
BOX 10-14   n FABRY'S DISEASE PATIENTS:
ANESTHETIC MANAGEMENT ISSUES
Sedation to avoid sympathetic activations
Invasive monitoring
Temperature monitoring/control
Hemodynamic control
Airway management issues
Need for excellent analgesia
Centrally mediated chronic pain
Autonomic instability with neuraxial block
may be necessary. Careful neurologic examination is impor-
tant to document peripheral lesions,127,128 especially if regional
anesthesia is planned.
Intraoperative Considerations (Box  10-14). Preoperative
sedation should be considered for Fabry's disease patients to
prevent excessive activation of the abnormal autonomic ner-
vous system. Increased levels of monitoring may be required
because of major organ system comorbidity. Abnormal tem-
perature regulation should be assumed, and active warming
and cooling devices should be present. Autonomic neuropathy
is likely, and vasoactive drugs to treat sudden hypotension and
hypertension should be prepared in advance.
With general anesthesia, the airway should be evaluated in
advance because of oropharyngeal lesions. Agent selection is
determined by comorbidity. Excellent pain control should be
planned, particularly in patients with chronic pain from periph-
eral nerve lesions. Pain control may require carbamazepine or
phenytoin.129 If successful in treating prior pain episodes, mor-
phine may be useful postoperatively.130 If chronic pain is treated
with carbamazepine,131 increased metabolism of nondepolariz-
ing muscle relaxants should be assumed and dosing of muscle
relaxants guided by neuromuscular blockade monitoring.
Although regional anesthesia is a consideration in Fabry's
disease patients, autonomic instability could exaggerate the
hemodynamic instability normally associated with sympa-
thectomy from central neuraxial blocks.132 If CNS lesions are
progressive, central neuraxial block is relatively contraindi-
cated because of possible central demyelination.
Summary. Fabry's disease is a congenital defect of glyco-
sphingolipid metabolism that results in massive deposition of
the lipoproteins in visceral structures, causing organ dysfunction.
Cardiovascular, pulmonary, neurologic, renal, and ocular dys-
function are common. Anesthetic preparation and care are deter-
mined by the presence and extent of major organ system disease.
HERPES SIMPLEX
Herpes infections of the skin and mucous membranes are
caused by infection with human herpes simplex virus (HSV-1
and HSV-2). Once systemic infection occurs, a primary out-
break is followed by a dormant state.133 Recurrent outbreaks
result from reactivation of the latent virus. Oral and genital
sites for primary infection are the most common. During the

BOX 10-15   n  HERPES INFECTIONS
Primary gingivostomatitis
Primary genital herpes
Recurrent facial-oral herpes
Herpesvirus cervicitis
Recurrent genital herpes
Herpes associated with HIV
Herpes in immunocompromised patients
Herpetic whitlow
Generalized herpes
Herpetic keratoconjunctivitis
Herpes encephalitis
dormant state, the virus remains in the cells of the neuraxial
ganglia. During the primary and recurrent outbreaks, the
lesions are contagious by contact, but HSV can also be trans-
mitted during periods of asymptomatic viral shedding. After
transfer to other surfaces, the viruses are only briefly contagious.
Genital herpes in an active outbreak can be transferred to
the neonate during transit through the infected birth canal,
with the risk of transmission highest among mothers with
active primary infection around the time of delivery. Neonatal
herpes infections can be classified as localized or disseminated
skin disease and disseminated systemic disease. The progno-
sis is most guarded for neonates with systemic involvement
of the CNS, eyes, and viscera (e.g., liver, adrenals).134 Whereas
genital herpes is almost always directly related to sexual con-
tact, facial-oral herpes infection has many causes and involves
the majority of adults worldwide.135 Reactivation is triggered
by stress, sunlight, fever or illness, contact sports,136 or surgi-
cal manipulation. The viruses move down the nerve by axo-
nal flow and produce lesions. Box 10-15 lists common disease
manifestations of herpes.
Diagnosis. Small, agminated (aggregated) or confluent
vesicopustules on a bright erythematous base are strongly
suggestive of HSV infection, especially when found on the
most common sites of involvement (lips, genitalia). The facial
lesions may be confused with erythema multiforme, impe-
tigo, and vaccinia. Genital herpes must be distinguished from
syphilis, lymphogranuloma venereum, and bacterial urinary
tract infections. Mucopurulent herpes cervicitis is easily con-
fused with infectious vaginitis. Recurrent infections usually
are readily identified because of prior experience.137 A swab
may be performed for viral culture and direct fluorescent anti-
body (DFA) test to confirm the diagnosis.
Preoperative Considerations (Box 10-16). During the pri-
mary herpes outbreak, generalized viremia is present. Elective
surgical procedures are unwise because body fluids are con-
tagious. Patients with herpetic whitlow can present for surgi-
cal drainage of infected finger tissue.138 Oral antiviral drugs
are both therapeutic in acute episodes and part of suppression
therapy to prevent outbreaks. Topical antiviral therapy lacks
proven clinical efficacy. Parenteral antiviral drugs can be life-
saving in generalized herpes and herpes encephalitis.139–141
Chapter 10  Skin and Bone Disorders 329
BOX 10-16   n HERPES-INFECTED PATIENTS:
PERIOPERATIVE ISSUES
Generalized viremia during primary outbreak
Viral transfer with airway management
Central nervous system infection with neuraxial instrumentation
Protection of anesthetic equipment
Universal precautions
Detection of systemic infection is a priority. During viremia,
transmission from primary lesions or systemic viremia is pos-
sible by instrumentation; elective airway management during
acute oral outbreak or neuraxial block during primary genital
herpes would thus be unwise.
Intraoperative Care. When emergency surgery is
required during acute HSV outbreaks, all body fluids from
the patient should be considered contaminated. The anes-
thesia machine should be protected with filters and equip-
ment cleaned as if contaminated. Nurses and equipment
aides should be warned of the risk of transmission. Simple
contact cleaning is effective, and contaminated surfaces
remain contagious only briefly. No particular anesthetic
agents or techniques offer any advantage. Central neuraxial
block during acute or systemic episodes should be avoided.
Other than avoiding viral transmission to other people,
recurrent lesions have no specific issues.
Summary. Acute HSV infections are associated with systemic
viremia. Elective surgery and anesthesia should be avoided to
prevent dissemination of the viruses. In particular, dural punc-
ture could induce herpes meningitis or encephalitis, and caution
is advised when providing regional anesthesia for cesarean birth
in mothers with active primary infection. When emergency sur-
gery is required, the lesions should be considered contagious.
Anesthesia machine protection, appropriate cleaning, and warn-
ings for health care providers at risk for exposure are essential.
No particular anesthetic agents are indicated or contraindicated.
MASTOCYTOSIS
Mastocytosis refers to a group of disorders caused by mast cell
hyperplasia in the liver, spleen, bone marrow, lymph nodes,
skin, and GI tract.142 Mast cells easily degranulate, and symp-
toms related to release of mediators are common, including
urticaria, flushing, abdominal pain, bone pain, diarrhea, nau-
sea, and vomiting. This group of sporadic or familial diseases
is based on abnormal expression of the c-KIT proto-oncogene,
which regulates mast cell production.143 Disease manifesta-
tions of mastocytosis are classified as indolent, hematologic,
and aggressive (Box 10-17).
The clinical features for any given patient are determined by
which mast cell mediators are produced in excess. Most patients
have cutaneous lesions referred to as urticaria ­pigmentosa,
which are small, reddish brown, itchy papules of the trunk and
limbs. The papules tend to urticate, or exhibit a wheal and flare,
 330 ANESTHESIA AND UNCOMMON DISEASES

Systemic mediator release can cause neuropsychiatric

BOX 10-17   n MASTOCYTOSIS: CLASSIFICATION AND
MANIFESTATIONS
Indolent
Syncope
Cutaneous
Ulcer
Malabsorption
Bone marrow aggregate
Skeletal
Liver-spleen
Lymph gland
Hematologic
Myeloproliferative
Myelodysplastic
Aggressive
Mastocytic leukemia
when stroked vigorously, a phenomenon known as Darier's
sign. In aggressive forms, these lesions can become confluent
and involve nasal and oral mucosa. Local heparin release cre-
ates a lesion with easy bruising by light contact.
The noncutaneous manifestations of mastocytosis are
related to mast cell infiltration of various organ systems.
Gastritis and peptic ulcer disease result from hypersecretion
secondary to increased plasma histamine levels. Abdominal
pain, diarrhea, and malabsorption144 are other manifestations
directly related to mast cell invasion of GI mucosa.145 Some
patients have liver and spleen involvement. The most com-
mon liver manifestation is elevated liver enzymes, although
patients with severe mastocytosis can present with ascites and
portal hypertension146 associated with liver fibrosis.147 Marked
enlargement of the spleen occurs in a majority of cases. Bone
lesions are caused by focal deposits of mast cells. Bone pain is
the most common result, but pathologic fracture can occur.148
Numerous hematologic abnormalities are associated with
mastocytosis.149 Systemic response to mediators is as varied as
the mediators are chemically (Table 10-4).
TABLE 10-4  n  Mast Cell Mediators
abnormalities, including irritability, headache, decreased
attention span, memory impairment, and secondary depres-
sion.150,151 An association exists between mastocytosis and
eosinophilic granuloma.152
Diagnosis. Most cases of mastocytosis are diagnosed by
the characteristic skin lesions. Biopsy confirms the role of
mast cells in various lesions (skin, mucous membranes,
bone). Urine studies may reveal increased levels of metab-
olites of mast cell mediators. Without the presence of skin
lesions, CT, bone scan, or endoscopy may be diagnostic.
Because the systemic effects mimic other diseases with vaso-
active release, workup should rule out carcinoid and pheo-
chromocytoma by measuring urine 5-hydroxyindoleacetic
acid and metanephrines.
Preoperative Considerations (Box 10-18). Gastric hyper-
secretion should be suspected in all mastocytosis patients.
Gastric acid blockade and increased gastric emptying with
metoclopramide should be considered. If liver disease is
suspected, assessment of synthetic and coagulation function
is required.153 Anxiolysis may decrease mast cell activation.
If chronic corticosteroid therapy is used, stress-dose corti-
costeroids should be ordered for the perioperative period.
Intraoperative Considerations. Vasodilation makes
hypothermia more likely in mastocytosis patients, and active
temperature support should be planned.154 Furthermore,
rapid and extreme temperature fluctuation can cause gener-
alized mast cell degranulation and hemodynamic instability.
Release of mediators is increased by manipulation of lesions,
which should be kept to the absolute minimum.155 Bone pain
indicates a risk of fracture, which should be considered dur-
ing positioning. Hemodynamic instability may occur from
mast cell mediator release.156 Sudden, profound, intraop-
erative hypotension has been reported,157 and epinephrine
may be the intervention of choice.158 As a result, invasive
monitoring with immediate availability of v­ asoactive drugs
is often required. Histamine release with transfusion can
be massive; pretreatment with diphenhydramine should
be routine.

Mediator Physiologic Response

Histamine Pruritus, bronchoconstriction, gastric

hypersecretion BOX 10-18   n MASTOCYTOSIS PATIENTS:
PERIOPERATIVE ISSUES
Heparin Local anticoagulation, osteoporosis
Gastric acid blockade
Proteases Bone lesions Delayed gastric emptying
Liver function tests
Leukotrienes Vasopermeability, bronchoconstriction,
Coagulation testing
vasoconstriction
Stress-dose steroids
Prostaglandin D2 Vasodilation, bronchoconstriction Temperature support
Hemodynamic instability from histamine release
Platelet-activating Vasopermeability, vasodilation, Invasive monitoring
factor bronchoconstriction Avoidance of histamine-releasing anesthetic agents
Histamine release with blood transfusion
Cytokines Cellular activation

Regional anesthesia is acceptable, but vasodilation may
accentuate the consequences of neuraxial sympathetic block.
Specific agents for general anesthesia should be selected to
avoid further histamine release.159 Light anesthesia may trig-
ger histamine release.
Summary. Mastocytosis presents numerous anes-
thetic implications related to release of mast cell mediators.
Cutaneous, GI, and systemic issues are most prominent. Many
of the mediators have potent vasoactive properties that can
alter the course of any anesthetic procedure.
MUCOPOLYSACCHARIDOSES
Mucopolysaccharidoses occur because of genetic defects in
enzymes that degrade intracellular complex molecules. The
action of the abnormal enzymes leads to accumulation of these
partially degraded compounds and secondary cellular and
organ system pathology.160 The specific enzyme defect deter-
mines the different syndromes (Table  10-5). Accumulation
of mucopolysaccharides (heparan sulfate, dermatan sulfate,
keratan sulfate) is the direct cause of the systemic manifesta-
tions. Accumulation occurs in CNS, peripheral nerves, gan-
glia, cardiac valves, coronary arteries,161 liver, spleen, lymph
nodes, retina, pituitary, and testicles. Skeletal and bony defects
result from abnormal osteocytes and chondrocytes, which are
enlarged and have multiple large vacuoles. In the area of the
growth plates the chondrocytes are disorganized, leading to
decreased growth and early closure.
Differential Diagnosis and Clinical Manifestations.
Although similar, each syndrome has unique features.
Hurler's syndrome (mucopolysaccharidosis IH) results from
accumulation of dermatan, with lesser amounts of hepa-
rin.162 The head is enlarged with abnormal facies and poor
dentition. Upper airway defects are common, and severe
sleep apnea may be seen. Airway obstruction can be pro-
gressive and symptomatic.163 Hypoplasia of the odontoid can
cause atlantoaxial instability, often presenting as quadripare-
sis requiring fusion.164 Short neck, flaring of the thorax, and
kyphoscoliosis characterize the trunk. Flexion contractures
are common. Chronic dislocation and dysplasia of the hip
may be present.
TABLE 10-5  n Mucopolysaccharidoses
Syndrome Enzyme Skeletal Defect
Hunter's Sulfoiduron sulfatase Spine
Hurler's α-l-Iduronidase Face, spine
Morquio's N-acetyl-galactose-6 Face, spine, femur
sulfate sulfatose
Scheie's α-l-Iduronidase Hands, face
Sanfilippo's Heparan sulfatase Chest, clavicle
Chapter 10  Skin and Bone Disorders 331
BOX 10-19   n MUCOPOLYSACCHARIDOSES:
ASSOCIATED COMORBIDITIES
Cardiac conduction defects
Cervical spine instability
Chronic dislocation of hip
Chronic hydrocephalus
Glaucoma
Kyphoscoliosis
Obstructive sleep apnea
Progressive airway obstruction
Retardation
Cardiac defects result from infiltration of cardiac cells,165
and progressive accumulation around the valves, especially the
mitral valve, may be observed.166 Retardation is common, and
MRI of the brain reveals multiple small cystic lesions of white
matter. Acute hydrocephalus has been reported, with deposi-
tion of mucopolysaccharides in the lower brain.167 Glaucoma
from mucopolysaccharide deposition has been reported168
(Box 10-19).
Hunter's syndrome (mucopolysaccharidosis II) results
from accumulation of heparan sulfate. Skeletal defects include
absent thoracolumbar kyphosis, pediatric carpal tunnel syn-
drome,169–171 abnormal facies, structural upper airway obstruc-
tion, and mild to moderate distortion of the chest. Progressive
mucopolysaccharide deposition in the upper airway leads to
airway obstruction and can present as stridor or airway com-
promise.172 Sleep apnea is common.163 In one patient, diffi-
culty with endotracheal intubation during airway surgery was
related to bulging false cords and glottic stenosis from deposi-
tion of mucopolysaccharides.173
Morquio's syndrome (mucopolysaccharidosis IV) results
from accumulation of keratan sulfate and chondroitin-6-
sulfate. These children are normal at birth but demonstrate
spine dysplasia within 12 to 18 months. Severe thoracolum-
bar kyphoscoliosis occurs early in life.174 Abnormality at the
craniocervical junction is almost universal, with hypoplastic
odontoid,174 atlantoaxial instability,175,176 and in some patients,
severe cervical cord compression177,178 or quadriparesis.179
Spinal cord compression and myelopathy represent a common
chronic disability.180 Dwarfism results from limited develop-
ment of the trunk. Joint laxity, abnormal facies, and valgus/
varus deformity of the knees are common. The CNS is usually
not involved; mental retardation is uncommon. Life expec-
tancy is shortened by progressive kyphoscoliosis. Fusion of
the second cervical vertebra (C2) to the occiput is frequently
required because of atlantoaxial instability.181
Preoperative Preparation (Box  10-20). Obstructive sleep
apnea can be associated with pulmonary hypertension and
right ventricular dysfunction. Respiratory mechanics can be
compromised from airway obstruction, pectus deformities,
or mechanical distortion of the thorax182 and deposition of
mucopolysaccharides in the tracheobronchial tree.183 If sus-
pected, transthoracic echocardiogram with attention to the
 332 ANESTHESIA AND UNCOMMON DISEASES

BOX 10-20   n MUCOPOLYSACCHARIDOSES: BOX 10-21   n MUCOPOLYSACCHARIDOSES:

PREOPERATIVE ISSUES ANESTHETIC ISSUES

Pulmonary function tests Difficult airway management

Echocardiogram Difficulty with ventilation
Electrocardiogram Acute airway obstruction
Chest radiograph Difficult positioning/injuries
Cervical spine radiographs in flexion and extension Incomplete epidural block
Cervical spine fusion Complete heart block
Delayed emergence
Obstructive sleep apnea makes acute pain control challenging.

right ventricle and right-sided valves is indicated. If a mur-

mur is detected, echocardiography is also indicated because of
a child with Hurler's syndrome198 in whom intubation could
the potential involvement of the aortic and mitral valves from
not be accomplished. During general anesthesia, recognition
mucopolysaccharide deposition166,184 and the resultant cardio-
of acute cord compression is difficult, and if unrecognized,
myopathy.185 Even in young children, an ECG is important
devastating neurologic injury could result.199 Massive intraop-
because of cardiac defects from accumulation of mucopoly-
erative stroke has also been reported in a child.200 There are
saccharides and early-onset CAD.161,186
no specific issues with anesthetic agents unless comorbidity
Radiographic evidence of severe thoracic deformity sug-
is present, such as cardiac dysfunction. Complete heart block
gests increased risk of postoperative ventilatory insuffi-
during anesthetic management has been reported.201 Delayed
ciency. Radiographic investigation of the cervical spine may
awakening was associated with Hunter's syndrome in one
be required if limited range of motion or abnormal surface
case.202 Progressive respiratory failure leading to death has
anatomy is observed. Because odontoid development may be
been reported after surgery, related to the mechanical limits
abnormal, atlantoaxial instability may be present. Flexion-
of respiratory mechanics.203 Increased sensitivity to opioids
extension cervical spine films are indicated, and if coopera-
should be assumed, and because of the high probability of an
tion is impossible, instability must be presumed. With Hurler's
abnormal upper airway, airway obstruction is even more likely
syndrome, C2-occiput fusion may be required for atlantoax-
during acute pain management (Box 10-21).
ial instability because of odontoid hypoplasia or the onset of
spontaneous quadriplegia.187 Summary. Patients with congenital defects in mucopoly-
saccharide metabolism present with anesthetic issues mainly
Intraoperative Management. A large tongue, thickening of
because of skeletal structural issues. Airway management,
airway structures, and friable tissue can make airway manage-
positioning, and IV access problems are likely. Asymptomatic
ment difficult. Plans for difficult airway management should
compression of the spinal cord may occur, and spinal cord
be made for any patient with mucopolysaccharidosis.188
lesions may result from positioning during general anesthe-
Bronchospasm may be more common.189 In one series, airway
sia. Abnormality of the thorax creates diminished respiratory
issues occurred in 53% of patients.190 Death from inability to
function and increases the probability of postoperative respi-
ventilate or intubate occurred in patients with Hurler's syn-
ratory failure in mucopolysaccharidosis patients.
drome.191,192 Emergency tracheostomy was lifesaving in oth-
ers.186,193 Use of the LMA has been helpful in some of these
children with difficult airway management, to control the NEUROFIBROMATOSIS
airway and to assist with fiberoptic intubation.194 Inability to
Neurofibromatosis is a syndrome caused by the abnormal
achieve ventilation with an LMA has been reported.195 Airway
deposition of neural tissue within the nervous system, endo-
management can be challenging when cervical cord com-
crine system, visceral structures, and skin.204 The origin is con-
pression is symptomatic and the patient is uncooperative.177
genital, with an autosomal dominant mode of transmission.
Transoral decompression of the brainstem and proximal cer-
Two variants are known205: central neurofibromatosis (10%)
vical spine may be the procedure of choice.180 With Hurler's
and von Recklinghausen's neurofibromatosis (90%). 206,207 Both
syndrome, progressive airway obstruction may require trache-
have characteristic skin lesions. The central variant is associated
ostomy if laser decompression is not possible.172
with multiple slow-growing CNS lesions, including bilateral
Contractures may make positioning difficult, and pressure
acoustic neuroma in most cases.208 With von Recklinghausen's
injuries should be actively prevented. Because of tissue depos-
variant, osseous lesions, renal artery involvement, optic nerve
its, contractures, and bony defects, IV access may be prob-
compression,209 and hydrocephalus can occur.210 Involvement
lematic. Deformities of the skeleton make regional anesthesia
of the midbrain can cause a variety of endocrine disorders.
difficult and potentially dangerous. Even with successful cath-
Spinal cord lesions may result in paraplegia.211
eterization of the epidural space, epidural anesthesia can be
incomplete secondary to deposition of mucopolysaccharides Clinical Manifestations (Box  10-22). Deposition of pro-
in the epidural space.196 Continuous spinal anesthesia has been liferating neural tissue causes organ-specific dysfunction in
used successfully in a child with Morquio's syndrome197 and neurofibromatosis. Proliferation in osseous tissue causes cyst

BOX 10-22   n NEUROFIBROMATOSIS: CLINICAL
MANIFESTATIONS
Bone cyst, osteoporosis, fracture
Dysphagia
Airway incompetence
Interstitial lung disease
Hydrocephalus
Retinal artery lesions
Optic nerve compress
Spinal cord compromise
Renal failure
Neuroendocrine disorders
Pelvic outlet obstruction makes obstetric care difficult.
formation, osteoporosis, or fracture. Long-bone fracture,
osteoarthritis of weight-bearing joints, and kyphoscoliosis are
potential pathophysiologic consequences. Deposition of neu-
ral tissue in the oropharynx and larynx can cause dysphagia or
airway incompetence.212,213 Interstitial lung disease can result
from deposition of neural tissue.214 Other respiratory involve-
ment can result from chronic hypoxemia, causing pulmonary
hypertension, right-sided heart strain, and respiratory failure
from cor pulmonale. Obstruction of the urinary tract and renal
artery involvement can cause renal failure. Pelvic obstruction
may complicate obstetric care.215,216 Neuroendocrine prolifera-
tion can lead to pheochromocytoma and other, less common
endocrinopathies.
Diagnosis. The diagnosis of neurofibromatosis can be
delayed by the manifestations in a major organ system. The
most common diagnostic evidence comes from observa-
tion of the classic skin lesions called café-au-lait macules217,218
(Box 10-23).
Preoperative Considerations (Box  10-24). The multiple
sites of involvement of advanced neurofibromatosis determine
the priorities for presurgical preparation. The primary site of
involvement is the nervous system, which must be investigated
completely. CT or MRI of the head219 will identify masses,
BOX 10-23   n NEUROFIBROMATOSIS I (VON
RECKLINGHAUSEN'S DISEASE):
DIAGNOSTIC CRITERIA*
● ≥6 café-au-lait macules (>5 mm in prepubertal children; ≥1.5 cm in
adults)
● ≥2 neurofibromas or >plexiform neurofibromas
● Axillary or inguinal freckling
● Optic glioma
● ≥2 Lisch nodules (hamartoma of iris)
● Bony lesions (sphenoid or long-bone dysplasia)
● First-degree relative with neurofibromatosis I
Data from National Institutes of Health (NIH) Consensus Development
Conference: Neurofibromatosis: conference statement, Arch Neurol
45:575-578, 1988.
*Diagnosis requires two or more (≥2) of seven criteria listed.
Chapter 10  Skin and Bone Disorders 333
BOX 10-24   n NEUROFIBROMATOSIS PATIENTS:
PERIOPERATIVE ISSUES
CT/MRI of head
Cervical spine radiographs in flexion/extension
Pulmonary function tests
Echocardiogram
Blood urea nitrogen/creatinine
Detection of abnormal electrolytes
Difficult airway management
Respiratory compromise with high neuraxial block
Temperature control
Abnormal response to muscle relaxants
midline shift, or increased ICP and demonstrate any poten-
tial risk of herniation. Occult spinal cord tumors have been
reported.220 If spinal cord involvement is suggested by weak-
ness, pain, or other long-tract signs, radiographic investiga-
tion is required. Meningocele and bony anomalies have been
seen.221,222 In particular, quantification of risk for airway man-
agement may require MRI of the cervical spine.223 Discovery of
spinal osseous lesions can further protect the patient from spi-
nal cord injury resulting from fracture, through modification
of the anesthetic technique. The patient history may suggest
the probability of pulmonary involvement. If the history or
physical examination (kyphoscoliosis) is positive,224 spirom-
etry and ABG analysis may be necessary. If there are signs of
cor pulmonale, echocardiography and even right-sided heart
angiography may be required. If the upper airway is involved,
indirect laryngoscopy should be performed by an experienced
endoscopist.
Other issues to consider include renal failure, endocrine
hyperplasia (pheochromocytoma), and optic nerve involve-
ment. If regional anesthesia is a consideration, the site for the
block must be free of lesions and anatomically normal enough
to perform the block. Abnormal pituitary function is possible,
and occult electrolyte abnormalities should be investigated.
Intraoperative Considerations. A compromised airway or
cervical spine requires careful, awake fiberoptic intubation.
The extent of invasive monitoring is determined by the degree
of major organ system compromise. With advanced pulmo-
nary compromise, prolonged postoperative mechanical venti-
lation must be considered.225 In this subset of patients, central
neuraxial block should be undertaken with the understand-
ing that high levels of truncal somatic block could precipitate
respiratory failure. Epidural analgesia for labor has been suc-
cessful.226 With advanced kyphoscoliosis, access for neuraxial
block may be mechanically difficult or impossible. Even with
successful epidural catheterization, the block can be incom-
plete because the epidural space may be partially obliter-
ated. Abnormal temperature regulation should be assumed;
hypothermia is a concern, and active heating is provided.
No special drug indications or contraindications are pres-
ent, although abnormal response to muscle relaxants has been
reported.227–229
 334 ANESTHESIA AND UNCOMMON DISEASES
Summary. Neurofibromatosis is a syndrome related to
deposition and proliferation of abnormal neural tissue.
Consequences are manifest in the central autonomic and
peripheral nervous systems, spine and long bones, airway, kid-
neys, and eyes. Anesthetic management is modified by CNS
pathology, respiratory compromise, difficult airway manage-
ment, endocrine and electrolyte abnormalities, and abnormal
skin surface.
OSTEOGENESIS IMPERFECTA
The majority of patients with osteogenesis imperfecta (OI) have
a genetic defect that creates structural collagen.230 The subclas-
sification of collagen found in the skeletal system, including
ligament, tendon, and bone, is type I collagen. Patients with
OI have either a quantitative defect or a structural deficiency
of type I collagen.231 The four or more genetic variants range
from extreme bone fragility, which leads to death during or
shortly after delivery, to skeletal changes subtle enough to
be confused with child abuse. The consequence of defective
structural collagen is defective formation of enchondral and
intramembranous bone. Ligament and tendon structure is
variably defective or incomplete. The bone trabeculae most
responsible for tensile strength are thin, and the interlinkage
is diminished.
Clinical Manifestations (Box 10-25). In the most extreme
cases, multiple fractures occur during delivery, usually associ-
ated with neonatal demise. In the nonlethal forms of OI, the
most significant feature is brittle bone structure. Fractures
occur from minimal force. More fractures occur in the
lower extremities, perhaps because they are exposed to more
trauma. The femur is fractured more often than the tibia for
the same reason. Deformity of the pelvis can be extreme, and
bowel obstruction from protrusion fracture of the acetabulum
has been reported.232 Spinal deformity develops because of
decreased ligamentous stability, compression fractures, osteo-
porosis, and spondylolisthesis.233 Kyphoscoliosis is the most
common lesion of the spine, but others include cervical spine
instability/fracture234 and upward migration of the odontoid,
causing brainstem compression and altered cerebrospinal
fluid flow.235,236 The teeth are malformed and fracture easily.237
BOX 10-25   n OSTEOGENESIS IMPERFECTA: CLINICAL
MANIFESTATIONS
Multiple fractures with delivery
Fracture with minimal stress
Spinal deformity
Compression fractures
Spondylolisthesis
Abnormal dentition
Ocular lesions
Patent ductus arteriosus
Atrial septal defect
Valvular lesions
Blue sclera, thin sclera and cornea, and exophthalmos
are common ocular abnormalities, and central retinal artery
occlusion in the prone position was seen in an OI patient.238
An association with malignant hyperthermia has been
reported,239–241 although muscle biopsy from a clinical case did
not test positive for malignant hyperthermia susceptibility.242
Platelet dysfunction has been associated with OI.243 Associated
cardiac anomalies include patent ductus arteriosus, atrial sep-
tal defects, ventricular septal defects, and valvular defects.244
Acquired cardiac defects associated with OI include a­ortic
regurgitation,245 mitral regurgitation from chordal rupture,246,247
and cystic degeneration of the proximal aorta.248
Diagnosis. In infancy, OI can be confused with achondro-
plasia or other forms of dwarfism because of skeletal or skull
anomalies with a common appearance. In childhood, idio-
pathic juvenile osteoporosis also presents in a similar manner.
A confounding variable is child abuse, where fracture is also a
feature of diagnosis.249–253 In less severe forms of OI, investiga-
tion for possible child abuse can delay the diagnosis.
Preoperative Preparation (Box  10-26). The anatomic
defects determine the preanesthetic preparation. Because
of the nature of OI, most indications for surgery are urgent,
as in the treatment of fractures. This does not eliminate the
issues of preparation. Creatine phosphokinase (CPK) should
be measured because levels may be elevated if there is risk of
malignant hyperthermia. Because platelet function may be
abnormal,254 complete measurement of coagulation is indi-
cated if there are any signs of coagulopathy, such as excessive
bleeding, easy bruising, or blood with oral hygiene or bowel or
bladder function.255 Unexpected massive bleeding without an
obvious surgical etiology has been reported in a patient with
OI.256 Because cor pulmonale can result from thoracic defor-
mity, and because of associated congenital heart disease, a pre-
operative echocardiogram is required if a normal study is not
previously known.
Severe kyphosis will predict mechanical dysfunction of
the lungs and should be evaluated preoperatively with spi-
rometry.257 Multiple issues with the skull and spinal column
must be investigated radiographically, including brainstem
BOX 10-26   n OSTEOGENESIS IMPERFECTA:
PERIOPERATIVE ISSUES
Creatine phosphokinase: high levels suggest risk of malignant
hyperthermia
Evaluation of coagulation
Electrocardiogram, echocardiogram
Central nervous system and cervical spine evaluation
Pulmonary function tests
Visual acuity
Positioning issues
Airway management issues
Bony injury during neuraxial block
Risk of malignant hyperthermia
Fracture risk with stormy emergence

c­ ompression, atlantoaxial instability, and cervical cord com-
pression. Hypoplasia or fracture of the odontoid leading
to atlantoaxial instability is a significant risk258 influencing
approaches to airway management. Basilar impression may
occur, requiring decompression of the foramen mag-
num.235,259–262 If undetected, normal range of motion with bas-
ilar impression236,263 or hypoplasia of the odontoid264 could
cause neurologic catastrophe.265 Minor trauma has been asso-
ciated with death from brainstem compression by this same
mechanism.235 Congenital or progressive kyphoscoliosis can
interfere with pulmonary function, and spirometry and ABG
analysis may be indicated for major surgery, especially pro-
cedures to stabilize progressive scoliosis. Reports of retinal
artery anomalies associated with OI make assessment of pre-
operative visual activity valuable.
Intraoperative Management. Positioning of OI patients
must be done carefully because long-bone fractures can result
from minor trauma. Fragility of connective tissues makes pad-
ding important, to avoid ligament or tendon injury. Achilles and
patellar tendons are particularly at risk. Any bone is susceptible
to fracture, with potentially serious consequences. A fatal intra-
operative hemorrhage resulted from occult fracture of a rib dur-
ing instrumented spine fusion, resulting in massive transfusion
and coagulopathy.266 In one OI patient, fracture of the femur
from minor trauma caused a compartment syndrome.267
Airway management must be gentle because fractures of
the mandible, maxillary surface, and cervical spine may occur
with excessive force.268 Awake fiberoptic intubation may be the
best option, although an intubating LMA has been successfully
used.269 Regional anesthesia is possible, but needle placement
near bony structures may be problematic. Puncture of bone
could cause fracture postoperatively. Intraosseous injection is
also a risk, is difficult to recognize, and might be associated
with local anesthetic toxicity. However, an epidural catheter
for anesthesia and postoperative analgesia for cesarean section
has been used successfully.270,271 Intramuscular ketamine has
been used in the past as a sole anesthetic for fracture reduc-
tion,244,272 although adequate muscle relaxation was problem-
atic in some patients. Because malignant hyperthermia is a
risk, a nontriggering anesthetic should be planned for gen-
eral anesthesia, and total intravenous anesthesia (TIVA) may
be an excellent option.273 Succinylcholine should be avoided.
Metabolic acidosis without other signs of malignant hyper-
thermia has also been reported.236,274
The risk of hyperthermia243 requires access to active cool-
ing. Smooth emergence should be the goal; coughing, buck-
ing, or excitement could cause multiple fractures. When the
surgical procedure is spine fusion, this is particularly impor-
tant because the fusion instrumentation can be disrupted and
threaten the integrity of the spinal cord.275 Extensive cervico-
occipital decompression with fusion would almost certainly
require prolonged postoperative intubation and sedation
before extubation.235 Any positioning other than supine must
take into account the risk of retinal artery occlusion, and
external pressure on the eyes should be carefully avoided.
Chapter 10  Skin and Bone Disorders 335
Summary. Anesthesia for patients with osteogenesis imper-
fecta is unfortunately a common experience because of the fre-
quency of long-bone fracture, requiring fixation. Anesthetic
issues arise from abnormalities of bone, including cervical
spine instability, brainstem herniation, and kyphoscoliosis.
Positioning must be done carefully because fracture from min-
imal stress can occur. Similar care with airway management is
necessary to avoid fracture of the mandible, maxilla, or cervi-
cal spine. Susceptibility to malignant hyperthermia must be an
element of any plan for general anesthesia. Regional anesthesia
should be performed with care if close to cortical bone to avoid
fracture or unrecognized intraosseous injection.
OSTEOPOROSIS, OSTEOMALACIA,
AND OSTEOPETROSIS
Osteoporosis. A generalized atrophy of bone, osteoporo-
sis results in decreased bone mass without change in the non-
mineralized elements. There is no alteration in the structural
appearance of osteoporotic bone, although the tensile strength is
reduced as bone density decreases. Disproportionate loss of tra-
becular bone is a distinguishing feature of osteoporosis.276 When
the trabecular (structural) bone volume reaches 10% or lower,
osteoporosis is confirmed, and the risk of stress fracture becomes
significant. The most common association is loss of estrogen
in postmenopausal women,277 or as a result of aging or disuse.
Exercise may prevent disuse osteoporosis.278,279 Osteoporosis has
also been associated with both rheumatoid arthritis and osteo-
arthritis.280 Reduced intestinal absorption of calcium can create
osteoporosis with normal aging, in association with primary bili-
ary cirrhosis281,282 or chronic cholestatic liver disease.283
Bone remodeling favors absorption as a function of age.
Although the tensile strength of all bone is reduced in osteopo-
rosis, bones more at risk for fracture include the thoracic and
lumbar spine, proximal femur, proximal humerus, and wrist.
Compression fractures of the thoracic and lumbar spine are
common.284 Midforearm fractures result from minimal trauma
if Colles’ fracture of the wrist does not occur.277 When bone
density is reduced more than 50%, spontaneous fractures of
vertebral bodies may occur in response to minor compression
loading, such as coughing or sneezing. Acute pain and muscle
spasm are the presenting symptoms and may indicate the need
for surgical procedures to stabilize the spine (percutaneous ver-
tebroplasty). There is a clear genetic predisposition to osteopo-
rosis, with women of Northern European descent at highest risk.
Osteomalacia. A generalized softening of bone, osteomala-
cia results in reduced tensile strength of bone. The wide variety
of causes share deficient vitamin D activity, either extrinsic, as
in nutritional deficiency,285,286 or intrinsic, related to malabsorp-
tion.287,288 The result is defective or incomplete mineralization
of bone.
In contrast to osteoporosis, osteomalacia can occur at any
age, including childhood. Bone tenderness, back pain, and
abnormal gait are the most common clinical symptoms. Long-
bone fractures are more likely and occur with less trauma.289
 336 ANESTHESIA AND UNCOMMON DISEASES
Rarely, this occurs with symptoms of hypocalcemia when
inadequate skeletal calcium is available for acute mobiliza-
tion. Severe deformities of the spine (kyphoscoliosis) or pel-
vis (acetabular protrusion) can be the initial presentation and
the indication for surgery. Radiating sciatic pain can also be
both diagnostic and an indication for surgery. Skeletal mus-
cle may have abnormal function in advanced osteomalacia,
and muscle weakness may be significant. Respiratory muscle
groups are not spared, and respiratory muscle failure may be
accelerated.
Using conservative definitions, up to 4% of geriatric hospi-
tal patients have the clinical criteria for osteomalacia. Chronic
corticosteroid use can cause osteopenia,290,291 especially associ-
ated with rheumatoid arthritis.292,293 Comorbidities can cause
osteomalacia. Hepatic osteodystrophy can occur in end-stage
liver disease,294 either based on malnutrition (alcoholism) or
steatorrhea and malabsorption of vitamin D. Chronic inges-
tion of alcohol can impair calcium uptake by the intestine,295,296
and osteomalacia can be the result.297 In cholestasis, impaired
absorption of vitamin D and impaired metabolism can be
expected. Long-term anticonvulsant therapy can result in
osteomalacia from malabsorption of calcium.291,298 End-stage
renal disease or nephrotic syndrome299 can cause renal osteo-
dystrophy from malabsorption of calcium and failure of bone
mineralization, secondary to abnormal vitamin D metabo-
lism.300 Softened bone may result in fractures proximate to
large blood vessels.301 Osteomalacia is associated with meta-
static prostatic cancer.302–304
Osteopetrosis. Also called marble bone disease, osteopetro-
sis is a rare disorder associated with increased bone density
(osteosclerosis), associated with clinical issues related to skel-
etal abnormality.305 The range of severity is wide, from chil-
dren with genetically based, generalized skeletal defects306 to
asymptomatic adults, identified because of easy fracture or
workup for metabolic bone disease.307 Radiographic manifes-
tations include sclerosis of bone, abnormal growth, and sym-
metrically increased bone mass, most obvious near the end of
the long bones and pelvis. In some patients, alternating hyper-
dense and hyperlucent areas can be visible radiographically,
suggesting risk for pathologic or traumatic fracture.308 Cranial
nerve compression may be associated with blindness, deaf-
ness, and facial nerve paralysis.305 Rare presentations include
diffuse idiopathic skeletal hyperostosis (DISH),309 which mani-
fests with increased bone mass and density at ligament and
tendon insertions of the spine.310 Ankylosis can create defor-
mity and decreased mobility.
Hypertrophic osteoarthropathy is an osteopetrosis variant
that occurs secondary to other disease processes, including
COPD, lung cancer,311 bronchiectasis, pulmonary fibrosis, con-
genital heart disease, liver cirrhosis, cystic fibrosis,312 chronic
GI disease, renal tubular acidosis,313 multiple myeloma,314
and other chronic diseases. Long-bone abnormality is more
likely than altered trunk or vertebral column, although spon-
dylolysis has been reported.315 Intracranial calcification has
been observed in children with osteopetrosis, associated with
c­ arbonic anhydrase II deficiency.316 Although fracture is less
common, nonunion of fracture in children is more likely.317
Hyperostosis has been associated with excessive ingestion of
vitamin D.318,319
Differential Diagnosis. The differential diagnosis of these
bone diseases is based on radiographic examination and bone
density studies. A patient with repeated fractures or a post-
menopausal female with bone pain may undergo a skeletal
radiographic survey. The abnormalities may include decreased
bone density (osteoporosis), decreased mineralization (osteo-
malacia), or excessive mineralization (osteopetrosis). All share
a structural weakness of bone and an increased risk of fracture.
Preoperative Preparation (Box 10-27). Patients with struc-
tural defects of bone may have anatomic deformity of the air-
way and thorax. The airway can be abnormal secondary to
decreased range of motion of the neck. Despite diminished
mobility, instability is also possible, caused by fragility of
the structural elements, such as the odontoid. Even if mobil-
ity is normal, tensile strength may be decreased. Structural
abnormality of the thorax may diminish pulmonary reserves.
If kyphosis, scoliosis, or rib cage deformity is present, chest
radiography and spirometry may be indicated. Because bone
pain may indicate structural deficiency, an inventory of bone
pain sites may be a guide to positioning issues in the operat-
ing room.
If osteoporosis is secondary to chronic corticosteroid use,
stress-dose corticosteroids may be indicated. Osteomalacia is
often a secondary condition, and when caused by end-organ
failure, investigation may be required. If secondary to severe
liver disease, the synthesizing functions of the liver should be
measured, including proteins and coagulation testing (pro-
thrombin time, activated partial thromboplastin time). If
related to chronic renal disease, BUN/creatinine measure-
ments are needed to guide anesthetic care. Osteopetrosis also
may be a secondary condition, and primary causes in the
lungs and heart would need to be investigated and evaluated
to guide anesthetic care.
Intraoperative Management. Patients should be positioned
carefully to avoid fracture. The skin is also fragile in some
patients.320 The management of the airway could be either diffi-
cult or dangerous with advanced osteoporosis. Awake ­fiberoptic
BOX 10-27   n PATIENTS WITH STRUCTURAL DEFECTS
OF BONE: PERIOPERATIVE ISSUES
Airway issues
Fragile cervical spine
Diminished pulmonary reserves
Stress-dose corticosteroids
Assessment of causative organ-system
Positioning issues
Risk with routine airway maneuvers
Cervical spine ankylosis
Increased risk of bleeding
Injury to bone with regional anesthesia

intubation may be necessary. Positioning of the patient can be
difficult, and the risk of fracture with minimal stress must be
considered in all these conditions. Instrumentation of osteo-
petrotic bone can be difficult because of its density321 and may
be associated with increased levels of bleeding and prolonged
surgical times.305,322 There is no interaction between anesthetic
agents and structural bone disorders, unless secondary to other
diseases (e.g., end-stage liver disease, chronic renal failure) that
have independent interaction issues. Regional anesthesia can
be used, but the potential for trauma to abnormal bone must
be considered. Chronic compression fractures of the lumbar
and thoracic spine may make access to neuraxial block sites
technically difficult or impossible. Besides injury to bone, the
possibility of intraosseous injection with rapid plasma uptake
of local anesthetic must be considered. In patients with osteo-
petrosis, ankylosis of the dorsal spinal column may be pres-
ent,323,324 making neuraxial block difficult or impossible. There
are no unique recovery issues.
Summary. Osteoporosis, osteomalacia, and osteopetrosis
are associated with reduced tensile strength of bone, result-
ing in indications for surgery. Anesthetic issues focus on the
skeletal anomalies and the primary causative comorbidities.
Anesthetic care is modified by airway issues, risk of posi-
tioning injuries, and potential technical issues with regional
anesthesia.
PAGET'S DISEASE OF BONE
Paget's disease of the bone is a process of unknown etiol-
ogy that causes excessive resorption and subsequent abnor-
mal remodeling, resulting in abnormally thickened bone with
paradoxically reduced tensile strength. The process may be
related to excess parathyroid hormone or decreased calcito-
nin levels.325 Paget's disease clearly has a genetic basis and is
found most frequently in residents of Anglo-Saxon countries
and their descendents.326–328
Paget's disease occurs in phases. The first phase involves
active resorption of bone, and pain may occur.329 Rapidly, new
bone is deposited in an asymmetric pattern. Pain will continue
if present at the start of this phase, or it may occur as a new
sign. The final phase is not usually associated with pain but
is characterized by the proliferation of irregularly shaped tra-
beculae, which create a mosaic appearance in affected bone. In
this final phase the cellular content of bone is reduced, as is the
tensile strength. Fracture through affected bone heals with a
disorganized pattern. Collagen is prominent in the fracture cal-
lus for prolonged intervals. Vascular hypertrophy occurs dur-
ing fracture repair and during the first two phases of the onset
of Paget's disease. During instrumentation of this bone, bleed-
ing will be significantly greater than normal. The abnormal
remodeling of bone has been suggested as etiologic in familial
cases of osteosarcoma that develop in pagetoid bone.330–332
Pain is the most common symptom that leads to the diag-
nosis of Paget's disease. Pain may be related to bone resorption,
inflammation, or microfracture. Weight bearing increases the
Chapter 10  Skin and Bone Disorders 337
pain in affected long bones. Pain may be caused by hyperemia
after microfracture or stretching of periosteum. Weight bear-
ing also leads to deformity, such as acetabular protrusion.333
Osteoporosis of the skull can occur, followed by exuberant
deposition of bone and increased size and weight of the skull.
Changes in the skull are typically associated with hearing
loss.334 Excessive ossification of the foramen magnum can lead
to neurologic symptoms resulting from compression of the
cerebellum in the posterior fossa or cerebral tonsillar hernia-
tion.335 Hydrocephalus or compression of the cervical spine is
possible. Hydrocephalus associated with dementia has resulted
from pathologic changes of the base of the skull related to
Paget's disease.336,337 Anatomically abnormal temporal bones
may result in distorted balance and hearing loss, as well as
optic neuropathy from bony compression.338 Paget's disease
can involve the mandible, maxilla, and teeth, further increas-
ing the abnormal configuration of the head.339 Dental extrac-
tion is usually more difficult and associated with increased
bleeding perioperatively.340 Paget's disease of the upper cer-
vical spine can cause spinal cord compression or atlantoaxial
instability.341 Proliferation of bone can result in compression of
the spinal cord or nerve roots, particularly in the lumbar and
thoracic regions,342 or spondylitis.343 Lumbar spinal stenosis is
a common manifestation of Paget's disease, requiring surgical
intervention.344 Coincident ankylosing spondylitis has been
reported.329 Knee and hip pain associated with sclerosis and
deformity are common in advanced Paget's disease.
Fractures are the most common pathologic manifestation
of Paget's disease after bone pain. The incidence of nonunion
of these fractures is high. Microfracture through an area of
active resorption of bone during early onset of Paget's disease
may lead to spread of the lesions to surrounding bone. Rarely,
malignancy (osteosarcoma) may occur in bone affected by
Paget's disease. Renal calculi and gout are manifestations of
abnormal calcium metabolism. Excessive blood flow to bone
affected by Paget's disease can cause CHF. Calcification of car-
diac structures (especially valves) is common. When calcifi-
cation involves the cardiac structures, arrhythmia and heart
block can result. Patients with Paget's disease are more likely
to develop calcific disease of the aortic valve. Peripheral vas-
cular disease based on arterial calcification has been reported
(Box 10-28).
Diagnosis. Paget's disease can be confused with a variety
of bone disorders, including osteomalacia, osteoporosis, and
osteopetrosis. The unique radiographic presentation of Paget's
disease is usually the element that establishes the diagnosis.
Pharmacologic Therapy. Drug treatment is usually reserved
for patients with symptomatic or advanced Paget's disease.
Antimitotic drugs such as colchicine have been used for symp-
tomatic relief, with the concomitant issues with bone marrow
suppression.345 Bone pain can be modified with calcitonin346
or bisphosphonates.347 High cardiac output can be treated with
either option, but bisphosphonates may be more effective.348
The risk of osteomalacia,349 stress,350 and pathologic fractures351
is higher with bisphosphonates.352–354 A limitation of calcitonin
 338 ANESTHESIA AND UNCOMMON DISEASES
BOX 10-28   n PAGET'S DISEASE: ASSOCIATED
COMORBIDITIES
Abnormal mandible/maxilla
Acetabular protrusion
Bone pain
Calcific cardiac conduction, valve disease
Cervical spine instability
Compression of cerebellum
Compression at foramen magnum
Hearing loss, optic neuropathy
High incidence of fracture
Hydrocephalus
Hypertrophy of skull
Lumbar spine stenosis
Nonunion of fracture
Osteosarcoma
Peripheral vascular disease
therapy is the development of resistance. Mithramycin has been
used in the treatment of hypercalcemia secondary to Paget's
disease.355 It has also been used for severe bone pain refrac-
tory to other pharmacologic options. Administration is chal-
lenging because mithramycin is highly cytotoxic and must be
administered intravenously and carefully. Nausea and vomiting
are often associated with its administration. Abnormal platelet
function, hepatotoxicity, and nephrotoxicity are associated with
mithramycin therapy, which should trigger evaluation of these
systems.356
Preoperative Preparation (Box  10-29). Because of the
abnormal bone metabolism in Paget's disease, the potential
for electrolyte abnormalities should be considered. If the skull
is enlarged, CNS pathology is possible, including increased
ICP and compression of the brainstem, cerebellum, and spi-
nal cord. Although plain radiography of the skull will yield
some information, especially with involvement of the maxilla
or mandible, CT or MRI is needed to identify increased ICP,
mass effect, or impending herniation at the foramen magnum.
If there is bony abnormality of the spine, radiographic exami-
nation is required to look for spinal compression or anoma-
lies that would risk injury to the spinal column during airway
management. Flexion-extension films of the neck to check for
atlantoaxial instability are indicated.
BOX 10-29   n PAGET'S DISEASE PATIENTS:
PERIOPERATIVE ISSUES
Abnormal electrolytes
Central nervous system at risk
Unstable cervical spine
Electrocardiogram, echocardiogram
Carotid ultrasound
Difficult airway management
Risk of injury with routine airway maneuvers
Excessive blood loss
Because of calcific changes in the cardiovascular system,
comorbidities should be sought. Basic electrocardiography
may reveal lesions in the conduction system. Calcific valvular
disease can be detected by cardiac auscultation, and murmurs
may require evaluation by echocardiography. Carotid bruit
may trigger a carotid ultrasound. As described earlier, spe-
cific therapies for Paget's disease may necessitate detection of
renal, hepatic, or platelet function abnormalities. If significant
deformity of the thorax is noted, spirometry may be required
to measure pulmonary reserves.
Intraoperative Issues. Airway management can be difficult
related to bone changes in Paget's disease. Both pain and defor-
mity will make positioning difficult. Excessive force should
be avoided, secondary to the risk of fracture through weak-
ened bone. Regional anesthesia can be used, but radiographic
examination may be required before central neuraxial block
to avoid needle instrumentation through pathologic bone. If
range of motion of the spine is severely restricted, review of
spine radiographs may reveal ankylosis, which presents severe
technical issues for central neuraxial block.329 Excessive bleed-
ing occurs routinely with bone affected by Paget's disease, and
increased blood loss can be expected compared with com-
parable procedures on nonpagetoid bone.357 Preparation for
possible massive transfusion with lower-extremity joint recon-
struction is indicated.358 Sclerotic bone is more difficult to
instrument, which may prolong the surgical time and further
increase blood loss. There are no specific interactions between
Paget's disease and anesthetic agents, except when treatment
causes organ damage or dysfunction.
Summary. The anesthetic management of Paget's disease
is complicated by the structural consequence of the disease,
including fracture, deformity, and CNS dysfunction. The
symptoms of pain and weak bones present perioperative issues
with patient handling. When Paget's disease is symptomatic,
treatment may be necessary, and some options have anesthetic
implications.
PANNICULITIS
Panniculitis is a general term for a group of diseases caused
by inflammation of the subcutaneous fat. Edematous, ten-
der, subcutaneous nodules may be widely spread, depending
on the etiology of the panniculitis, but are often found on the
trunk and lower extremities. Certain forms of panniculitis can
involve the neck and face. The massive inflammatory response
has systemic manifestations, including malaise, myalgia,359
fatigue, and fever.360 In rare cases the fat of visceral organs can
be involved. Inflammation of fat around the spleen, liver, adre-
nals, or myocardium can cause serious organ damage. Diffuse
adenopathy is common. Bone marrow suppression can cause
pancytopenia and bleeding events.
Causes are numerous and include infection, traumatic and
cold-induced panniculitis,361–364 and factitious panniculitis
from self-injection. Subcutaneous fat necrosis of the newborn
occurs in full-term neonates, manifests as one or more firm,

mobile, subcutaneous nodules, and may be accompanied by
laboratory abnormalities such as hypercalcemia and throm-
bocytopenia, but tends to resolve spontaneously with mini-
mal sequelae.365,366 By contrast, sclerema neonatorum occurs in
premature infants, manifests as widespread subcutaneous fat
necrosis and diffuse induration, is accompanied by multior-
gan system involvement, and is fatal, usually as a result of sep-
ticemia, in a majority of cases.367 Some forms of panniculitis
are caused by serious systemic diseases, such as pancreatitis,
lupus,368,369 sarcoidosis,370 renal failure, α1-antitrypsin defi-
ciency, leukemia,371 and lymphoma. One variant is associated
with vasculitis in the same areas where needle trauma induced
panniculitis.372 The vasculitis results in increased severity of
tissue injury and delayed healing.
Erythema nodosum is the most common form of panniculitis
(see previous discussion). Articular lesions have been reported.373
Differential Diagnosis. Classic lesions of panniculitis are
recognized as involving the subcutaneous fat but initially
may be confused with other skin conditions such as vascu-
litis. Hemorrhagic or ulcerative lesions may be mistaken for
pyoderma gangrenosum or calciphylaxis. The differential
diagnosis is extensive because of the numerous causes of pan-
niculitis. Although rare, panniculitis can be diagnosed during
the workup of organ failure associated with fat necrosis.
Preoperative Considerations (Box  10-30). The primary
issue for presurgical preparation of patients with panniculitis
focuses on care of the lesions and identification of any comor-
bidity caused by fat necrosis. Pressure on the lesion could cause
extension. Ulcerated lesions should be protected from infec-
tion. Assessment of liver function and BUN/creatinine should
be obtained to rule out organ dysfunction. An abnormal ECG
and poor exercise tolerance may suggest cardiac involvement.
When the lesions create the need for surgery (abscess, vascular
compromise), evaluation should focus on functional status if
fuller evaluation would delay urgent surgery. Treatment with
corticosteroids suggests the use of stress-dose corticosteroids
perioperatively. When immunosuppressants or antimetabo-
lites are used, organ toxicity should be investigated.
Intraoperative Considerations. Positioning can be an
issue when numerous lesions are present. Anesthetic tech-
nique is dictated by other organ system involvement and
urgency of surgery. If there are clusters of lesions involving
the face or neck, airway compromise should be considered.
BOX 10-30   n PANNICULITIS PATIENTS:
PERIOPERATIVE ISSUES
Identify cause of fat necrosis.
Positioning pressure, causing lesions
Abscess
Vascular compromise
Stress-dose corticosteroids
Inflammation of visceral organs
Chapter 10  Skin and Bone Disorders 339
Regional anesthesia is a reasonable technique, as long as the
needle insertion site is free of lesions. Traumatic placement of
regional anesthesia or invasive monitors can create lesions.
Summary. Panniculitis should be considered not as a single
diagnosis, but rather a variegate group of etiologically distinct
disorders that share a clinical presentation of deep, tender
lesions of fat, which may expand and ulcerate. Although usu-
ally found on the trunk and limbs, lesions can occur on the
neck and face as well, with potential airway issues. If general-
ized inflammation of fat involves fat-insulating viscera, organ
system dysfunction can result. Perioperative care requires that
positioning, regional anesthesia, and invasive monitoring not
compromise lesions or increase the risk of infection.
PEMPHIGUS AND PEMPHIGOID
Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are clin-
ically similar but etiologically distinct diseases characterized
by autoimmune blistering of the skin and mucous membranes.
PV is the prototype of intraepidermal autoimmune blistering
diseases, whereas BP is the most common subepidermal auto-
immune blistering disorder. There are many variants that fall
under the basic heading of “pemphigus and pemphigoid.”
The bullae of BP are large, tense, well formed, often serosan-
guineous, and range in size from 1 cm to several centimeters.
By contrast, the bullae of PV are much more superficial and
flaccid and often rupture, giving way to widespread erosions
instead of intact blisters at presentation. The skin surrounding
the lesions of PV is fragile, and pressure causes extension of
the lesions. BP does not usually manifest with such profound
and reproducible fragility. Mucous membranes are usually
involved in both conditions and are frequently the exclusive
site of involvement in PV patients (Fig. 10-3).
Etiologically, pemphigus and pemphigoid are caused by
antibody binding and interruption of intercellular bonds. In
PV the antibodies bind to desmosomes, disrupting the attach-
ment of keratinocytes to one another, known as intraepider-
mal acantholysis. In BP the antibodies bind to components of
the hemidesmosomes, disrupting the attachment between the
basal layer of the epidermis and the underlying dermis.
Although the most common etiology for PV and BP is
­idiopathic, potential associations include medications, malig-
nancies, autoimmune diseases, and inflammatory dermatoses,
ultraviolet (UV) light, burns, and radiotherapy. Cases of neona-
tal blistering disease may result from transplacental transmis-
sion of maternal antibodies; resolution occurs with antibody
metabolism.374 Frequently implicated causative medications
include nonsteroidal anti-inflammatory drugs (NSAIDs),
diuretics, d-penicillamine, antibiotics, and captopril. In contrast
to other causes, most drug-induced pemphigus resolves rapidly
with elimination of the drug. Myasthenia gravis and thymoma
have been associated with pemphigus. Rheumatoid arthri-
tis, lupus, and cirrhosis of the liver have also been associated
with pemphigus. A type of pemphigus occurs as a paraneoplas-
tic syndrome.375,376 The oral mucosal lesions of paraneoplastic
 340 ANESTHESIA AND UNCOMMON DISEASES
FIGURE 10-3  Oral mucous membrane involvement in patient with
pemphigus vulgaris.
pemphigus are unusually severe, widely affecting the orophar-
ynx and vermilion border of the lips. The triggering neoplasms
are most often lymphoma, typically non-Hodgkin's lymphoma,
and leukemia, or thymoma.377,378 The reverse—pemphigus as a
cause of malignancy—is less likely.379,380
Preoperative Considerations (Box  10-31). Preoperative
preparation of patients with pemphigus or pemphigoid
focuses on care of the lesions, assessment of the airway, and
consequences of treatment. First-line treatment usually begins
with high-dose corticosteroid therapy381 or bolus corticoste-
roid administration,382 which should be continued through
the perioperative period parenterally to deal with adrenal sup-
pression, as well as avoiding acute exacerbation of the lesions.
Following initial control with high dose corticosteroids,
many patients are transitioned to steroid-sparing immuno-
suppressants,383 which increase the risk of infection.384 Because
of the nephrotoxicity of some immunosuppressants (e.g.,
BOX 10-31   n PEMPHIGUS/PEMPHIGOID PATIENTS:
PERIOPERATIVE ISSUES FOR
ANESTHETIC MANAGEMENT
Stress-dose corticosteroids
Patient taking immunosuppressants
Nephrotoxicity
Laryngeal/airway obstruction
Physical trauma with intubation
Airway obstruction during emergence
cyclosporine), renal function (e.g., BUN/creatinine) should
be measured. Cyclophosphamide has reportedly caused hem-
orrhagic cystitis.384 Dapsone has been used in some patients,
but the failure rate, peripheral neuropathy,385 and hemato-
logic complications (anemia, hemolysis, neutropenia) have
made this less common.379,386 Rarer complications of dapsone
include anaphylaxis, thrombocytopenia, and toxic epider-
mal necrolyis.384 Perioperative methemoglobinemia second-
ary to dapsone has been reported.387 Gold therapy388 has been
used and can cause liver failure,384 and these patients should
have liver function tests. A combination therapy with tetra-
cycline and nicotinamide has been used389 and rarely causes
renal toxicity or potential acute tubular necrosis.390 Severe
dehydration and electrolyte abnormalities391 are common in
pemphigus patients, with lesions covering a large surface area,
and assessment of volume status and resuscitation are impor-
tant preanesthetic issues. In patients with oral lesions, indirect
laryngoscopy to evaluate the airway preoperatively is valuable,
recognizing the trauma that could exaggerate oropharyngeal
lesions. Coexisting illnesses should be fully explored.392
Intraoperative Course. Elective surgery should be rare in
these patients.393 Laryngeal and airway obstruction can be the
presentation of pemphigoid requiring anesthetic intervention,
and tracheostomy may be required.394 When emergency sur-
gery is required, management of the airway is potentially life
threatening.395 Intubation could be difficult, and the physical
process of placing the endotracheal tube might create lesions
that could compromise the airway after extubation. Bleeding
within the oropharynx could also result, even from gentle air-
way instrumentation.396 Regional anesthesia is possible if the
site of the block is free of lesions.397,398
Summary. Pemphigus and pemphigoid are autoimmune
diseases of the skin that can present issues when surgery and
anesthesia are required. Oral lesions are common, and airway
compromise is a serious issue. Many treatments create issues
with major organ systems that must be investigated before
surgery. Because pemphigus vulgaris and bullous pemphigoid
can be induced into remission or eliminated, elective surgery
should be uncommon.
PSORIASIS
Pathophysiology. Psoriasis is an inflammatory skin dis-
ease characterized by epidermal proliferation and accumu-
lation. This common chronic skin disease has an estimated
prevalence of 2% worldwide and as high as 5% in the United
States. Psoriasis can be triggered by bacterial infection (e.g.,
Streptococcus), medications (e.g., lithium, beta blockers, inter-
feron), bone marrow transplantation,399 malignancy,400,401 or
emotional stress. Psoriasis is associated with smoking, obesity,
alcoholism, and metabolic syndrome.402
Diagnosis. Psoriasis has several clinical variants, but
the lesions of psoriasis vulgaris (classic psoriasis) are well-­
demarcated, brightly erythematous plaques of varying size

with overlying white or silvery micaceous scales. Psoriasis
vulgaris favors the extensor extremities (knees, elbows,
sacrum), scalp, palms, and soles. Pinpoint bleeding may occur
when the scales are removed (Auspitz sign), and new lesions
of psoriasis may occur at sites of skin trauma (Koebner phe-
nomenon). The differential diagnosis of plaque psoriasis
may include eczema, lichen planus, cutaneous T-cell lym-
phoma, and severe ­seborrheic dermatitis. Psoriatic arthritis,
which can lead to joint erosion, may occur in up to a third of
patients and less often may precede cutaneous involvement.
More recent data link psoriasis to obesity, occlusive heart dis-
ease, metabolic syndrome, and fatty infiltration of the liver
with periportal inflammation. Preoperative evaluation of car-
diac function, blood glucose levels, and transaminases may
be appropriate.
Preoperative Preparation. Systemic corticosteroid therapy
is relatively contraindicated in patients with psoriasis because
it may exacerbate the disease on cessation and produce wide-
spread erythroderma and generalized pustules (Fig.  10-4).
Perioperative stress-dose corticosteroids may be administered
as needed, but a high index of suspicion for erythrodermic or
pustular psoriasis should be maintained, and the patient should
be comanaged by a dermatologist. As a rule, psoriasis is usually
not co-infected or superinfected with bacteria, likely related
to upregulation of antimicrobial peptides such as β-defensins
and cathelicidins.403 Candidal intertrigo may ­coexist with pso-
riasis, and inguinal involvement should be investigated before
FIGURE 10-4  Exfoliative erythroderma and pustular psoriasis
flare in patient treated with systemic corticosteroids.
Chapter 10  Skin and Bone Disorders 341
­ ercutaneous catheterization. Uveitis has been reported and
p
could cause visual delay.404 Immunosuppressants are often
used,405–408 and renal function should be investigated. If meth-
otrexate is used, liver toxicity should be suspected.409,410 More
recently, biologic therapies such as tumor necrosis factor alpha
(TNF-α) inhibitors are being increasingly used in the treatment
of psoriasis and may predispose patients to serious infection.
Intraoperative Considerations. Trauma to psoriatic skin
should be avoided when possible. Regional blocks or invasive
monitors should not be inserted through psoriatic skin. No
specific agents are indicated or contraindicated. Unusual sep-
sis events have been associated with psoriasis411–413 and could
present in the operating room or early postoperative period.
Summary. Psoriasis is a chronic skin disease that results
in large surface areas of inflamed skin. The only anesthetic
issues are protecting the skin and avoiding instrumentation of
­psoriatic skin.
PYODERMA GANGRENOSUM
Pathophysiology. Pyoderma gangrenosum (PG) is a destruc-
tive inflammatory disease of the skin.414 The lesion begins as
painful papulopustules on an erythematous base that rapidly
expand, break down, and ulcerate.415 These ulcers naturally
expand to large sizes. Although almost half of all cases are
idiopathic, most are associated with other systemic illnesses,
such as inflammatory bowel disease, malignancy,416 or other
autoimmune diseases417 (Box  10-32). Neutrophil infiltration
of the dermis is causative.418 Although mucous membranes
are usually spared, lesions of the oral cavity, pharynx, and lar-
ynx have been reported in a rare PG subtype, termed pyosto-
matitis vegetans.419 Intradermal injections, IV catheters, and
surgical incision can cause new lesions (pathergy). Massive
edema from circumferential lesions may indicate surgery if
distal ischemia or compartment syndrome is present. The
lesions can trigger fat necrosis, also causing vascular embar-
rassment of limbs or panniculitis, which can trigger peri-
tonitis. Polyarthritis can occur in PG patients, and septic
arthritis is an occasional presentation for urgent surgery.418
An association with vasculitis can also present urgent need
for surgery.420,421
BOX 10-32   n PYODERMA GANGRENOSUM:
ASSOCIATED DISEASES
Biliary cirrhosis
Carcinoid
Diabetes
Hepatitis
Inflammatory bowel disease
Leukemia
Lupus
Myeloma
Vasculitis
 342 ANESTHESIA AND UNCOMMON DISEASES
Diagnosis. The lesions of PG occur as an idiopathic disease
confined to the skin in a majority of cases. In the other cases, a
systemic illness precedes PG and is causative. Myeloma,422 leu-
kemia,423–425 chronic426 hepatitis, primary427 biliary cirrhosis,
diabetes, carcinoid, lupus,428,429 vasculitis, and inflammatory
small430 or large431 bowel disease are examples of precipitating
causes. PG has been associated with allogenic bone marrow
transplantation.432
Preoperative Considerations. Significant lesions around
the mouth433 can occur and should prompt further evalua-
tion to determine if the airway is involved.434–438 Because PG
lesions are associated with other diseases, presurgical prepara-
tion should focus on identifying comorbidities. Inflammatory
lesions of the lung should be investigated if symptomatic.439,440
Chronic corticosteroid therapy requires stress-dose steroids in
the perioperative period. Some patients receive immunosup-
pressive drugs with side effects of organ toxicity, most nota-
bly nephrotoxicity and hepatotoxicity with methotrexate.441
Antimetabolites can induce pancytopenia and coagulopathies.
Intraoperative Considerations. Pressure on existing
lesions should be avoided to prevent expansion. Lesions of
the oropharynx and airway should be suspected. If abnormal-
ity of voice or swallowing is detected, awake fiberoptic intu-
bation is indicated. Regional anesthesia can be used, but the
possibility of a lesion occurring at the site of the block must
be considered. No particular anesthetic agent is indicated or
contraindicated. Causative comorbidities may alter the anes-
thetic course.
Summary. Pyoderma gangrenosum is an inflammatory
neutrophilic dermatosis characterized by the spontaneous
appearance of large, painful, necrotic ulcers. Many systemic
illnesses with an inflammatory component may be associ-
ated with onset of PG. Oropharyngeal and airway lesions
have potentially serious anesthetic implications. Needle punc-
ture and intradermal injections can initiate new lesions and
limit the use of regional anesthesia. When general anesthesia
is selected, the possibility of lesions of the airway may make
awake fiberoptic intubation the best choice.
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 C H A P T E R
11
Hematologic Diseases
JONATHAN LEFF, MD  n
LINDA SHORE-LESSERSON, MD, FASE  n
GREGORY W. FISCHER, MD  n

n Alterations in the coagulation cascade can result in throm-

Anemias bosis or hemorrhage and should be closely monitored and
Iron Deficiency Anemia
evaluated.
Thalassemia
n Point-of-care testing is useful to determine the patient's
Megaloblastic Anemias
transfusion needs and quickly evaluate the coagulation
Hemolytic Anemias
profile.
Acute Blood Loss/Hemorrhagic Shock
Diseases of Leukocytes The hematologic system plays a central role in maintaining
Lymphomas homeostasis, although its importance is often overlooked by
Leukemias many clinicians. The consideration of pathologies that affect
Myelodysplastic Syndrome hemostasis is critical in caring for a patient in a perioperative
Diseases of Thrombocytes (Platelets) setting. This chapter highlights both common and uncommon
Thrombocytopenia abnormalities of the hematologic system and provides treat-
Thrombasthenic Syndromes ment strategies. Anesthesiologists are often faced with the
Impaired Coagulation daunting task of caring for patients with coagulation abnor-
Thrombotic Disorders malities and must balance the risk of surgical bleeding versus
Monitoring Platelet Function potential thrombosis. An understanding of these diseases will
Conclusion improve patient care.

KEY POINTS
n Preoperative recognition of anemia is essential to provide a
systems approach to treatment.
n The decision to transfuse a patient with blood products
should be based on the entire clinical picture and not the
absolute laboratory value.
n Coexisting diseases of leukocytes can alter anesthetic care.
Careful preoperative evaluation helps avoid complications
from obstructive tumor and radiation and chemotherapy
side effects.
n Thrombocytopenia and diseases related to platelets pres-
ent special anesthetic challenges; preoperative evaluation
is necessary to assess the potential for bleeding and guide
treatment, including possible transfusion.
ANEMIAS
Anemia is defined as hemoglobin (Hb) concentrations less
than 11.5 grams per deciliter (g/dL) in females and 12.5 g/dL
in males. It is a common finding, occurring in 35% to 56%
of patients presenting for surgery and 84% to 90% of patients
postoperatively.1,2 Preoperative testing is often the only way to
diagnose patients with anemia because many are asymptom-
atic. Patients with more severe anemia may refer to a number
of clinical symptoms, including fatigue, depression, anorexia,
nausea, menstrual abnormalities, tachycardia, and exertional
dyspnea.
In the preoperative period the causes of anemia are mul-
tifactorial, and the clinician is responsible for investigating
possible causes of low Hb concentrations. Potential causes
of anemia during this period are iron deficiency, renal
insufficiency, malignancy, chronic disease, gastrointestinal

350
 Chapter 11  Hematologic Diseases 351

(GI) bleeding, and decreased red blood cell (RBC) life

span.3,4 To aid in the differential diagnosis, erythrocyte
indices are used to help categorize anemias and pinpoint
probable causes of anemia (Table 11-1). Erythrocyte (RBC)
indices are defined as follows (Hct, hematocrit):
Mean corpuscular hemoglobin: MCH = Hb × 10/RBC
Mean corpuscular volume: MCV = Hct × 10/RBC
Mean corpuscular hemoglobin concentration: MCHC = Hb/Hct
Anemia in the postoperative setting is common and
often the result of diminished erythropoiesis during early
recovery period, frequent phlebotomies, and untreated
surgical bleeding.3,4 Predictors of perioperative anemia
include African ancestry, female gender, low preoperative
serum levels, and smaller body size.5 Anemia complicates
patient care in the perioperative period by decreasing oxy-
gen (O2) content in circulating blood, which in turn can
reduce O2 delivery to peripheral tissues. To avoid hypoxia,
the cardiovascular system must compensate by increasing
cardiac output.
When interpreting the formula in Box 11-1, one sees that
physically dissolved oxygen (Pao2 × 0.003) results in only a
fraction of the total oxygen content (Cao2) found in blood.
BOX 11-1   n FORMULA FOR CALCULATION OF OXYGEN
DELIVERY
Do2 = CO × (Hb × Sao2 × 1.34 + Pao2 × 0.003)
where Do2 = oxygen delivery; CO = cardiac output; Hb = hemoglobin
concentration; Sao2 = percent of oxygenated hemoglobin; 1.34 = Hüfner
number (constant 1.34-1.36); and 0.003 = dissolved oxygen (mL/mm Hg/dL)
The vast majority of oxygen is bound chemically to hemoglo-
bin. This makes it easy to understand why in states of hypox-
emia, the clinician should treat the anemic patient, provided
a normal arterial oxygen partial pressure (Pao2) exists, with
the administration of erythrocytes, most often given in form
of packed red blood cells (PRBCs). Increasing the fraction of
inspired oxygen (Fio2) and thus increasing Pao2 only leads to
slight increases in Cao2.6
One of the controversial topics in recent years has been
determining the threshold at which anesthesiologists should
transfuse patients in the perioperative setting.7–9 The best
hematocrit at which the O2-carrying capacity is ideally

TABLE 11-1  n  Anemia by Erythrocyte Indices

Anemia RBC Size Chromatic MCH/MCV Reticulocytes Serum Iron

Thalassemia Microcytic Hypo- ↓ ↓ ↑

Myelodysplastic Microcytic Hypo- ↓ ↓ ↑

syndrome

Iron deficiency Microcytic Hypo- ↓ ↓ ↓

Inflammation-infection Micro/ Hypo/normo- ↓/↑ ↓ ↓

normocytic

Tumor Micro/ Hypo/normo- ↓/↑ ↓ ↓

normocytic

Hemolytic anemia Normocytic Normo- Normal ↑ Normal

Hemorrhage Normocytic Normo- Normal ↑ Normal

Aplastic anemia Normocytic Normo- Normal ↓ Normal

Renal failure Normocytic Normo- Normal ↓ Normal

Megaloblastic Macrocytic Hyper- ↑ Normal Normal

Hypochromatic Microcytic Anemia Normochromatic Normocytic Anemia Hyperchromatic Macrocytic Anemia

MCH + MCV reduced MCH + MCV normal MCH + MCV increased

Serum iron increased: thalassemia, Reticulocytes increased: hemolytic anemia, Normal reticulocytes: megaloblastic
myelodysplastic syndrome hemorrhage anemia

Serum iron decreased: iron Deficiency Reticulocytes decreased: aplastic anemia, renal Iron decrease and ferritin increase:
anemia anemia inflammatory, infection, and tumor
anemia

RBC, Red blood cell; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume.
 352 ANESTHESIA AND UNCOMMON DISEASES
matched with the rheologic properties of blood is approxi-
mately 27%. However, the “10/30 rule” (10 g/dL Hb or 30%
Hct), once thought to be the “gold standard” by many clini-
cians, has been challenged by recent studies. There is some
evidence linking low preoperative Hb with adverse events
such as increased risk of death, increased risk of transfusion,
and prolonged hospitalization.10,11 The risk of a low value for
starting Hb must be balanced with the known complications
of allogenic blood transfusion. In fact, patients who receive
transfusion are at high risk for perioperative infection due to
the immunomodulating effects of transfusion. Thus, trans-
fusing RBCs solely on the basis of Hb concentration or Hct is
no longer considered proper care. It is prudent to investigate
the cause of anemia and treat the underlying condition rather
than transfusing PRBCs to reach a target Hb. Indications for
transfusion of RBCs should be based on the O2 supply/
demand ratio in the individual patient. Decreased mixed
venous oxygen saturation (Sv̄o2), serial measurements of lac-
tate showing progressively increasing concentrations, and
electrocardiographic changes suggestive of myocardial isch-
emia are appropriate indications for transfusion of RBCs.12–16
For example, Nelson et al.17 found that Hct less than 27% was
associated with an increased incidence of myocardial isch-
emia and infarction in patients undergoing infrainguinal
bypass surgery.
Despite great advancements in transfusion medicine,
life-threatening complications still do occur. Transfusion
reactions can be divided into three major pathophysiologic
groups. The most common complication is the transfusion of
immunologic incorrectly matched blood, resulting in hemo-
lysis. The ABO and Rhesus antigens are responsible for this
reaction. Patients under general anesthesia will present with
hypotension, tachycardia, and hemoglobinuria, possibly pro-
gressing to acute renal failure (acute kidney injury). Second,
febrile nonhemolytic reactions are seen in 0.5% to 5% after
transfusion of blood products.18 These reactions are caused by
leukocyte and thrombocyte antigens.18,19 Third, transmission
of infectious diseases, including hepatitis B and C viruses and
human immunodeficiency virus (HIV), is a rare phenom-
enon but has serious and long-lasting consequences for the
patient.20–24
The complications of blood product transfusion should
always make the clinician weigh benefits against potential
risks. Strict indications for the transfusion of blood prod-
ucts should be employed. Transfusion solely to achieve vol-
ume expansion or to raise Hct to a certain value cannot be
recommended. Finally, in a society becoming more and more
conscious of the financial burden brought on by its health
care system, avoiding unnecessary transfusions poses a major
source of potential savings.
Treatment. The treatment options for a patient with ane-
mia first focus on discovering the etiology of the disease. The
use of transfusion is only indicated in symptomatic patients or
in those patients who would benefit from a higher O2-carrying
capacity.
TABLE 11-2  n  Anemia and Iron Metabolism
Serum Serum
Disorder Iron Transferrin Ferritin
Iron deficiency ↓ ↑ ↓
Myelodysplastic ↑ ↓ ↑
syndrome
β-Thalassemia Normal-↑ Normal-↓ Normal-↑
Inflammatory ↓ ↓ ↑
or tumor
associated
Iron Deficiency Anemia
Iron deficiency anemia is the most-often diagnosed anemia in
the industrialized world. Its cause is usually chronic blood loss
(e.g., menstruation, chronic GI bleeding) or increased require-
ments seen in pregnancy or infancy. An adult has approxi-
mately 3000 mg (45 mg/kg) of elemental iron in their body.
An adult man requires daily iron intake of 12 mg to absorb
1 mg, to compensate for losses, and a woman requires 15 mg to
absorb 2 mg. During pregnancy, iron intake must be doubled
to compensate for approximately 3 mg of daily iron losses.
Iron deficiency anemia is a microcytic, hypochromatic
anemia with increased serum transferrin, low serum ferri-
tin, and low serum iron concentrations. Microscopic exam-
ination of bone marrow reveals low to missing iron depots.
The differential diagnoses for iron deficiency anemia are listed
in Table  11-2. Clinically, these patients have general anemia
symptoms as well as symptoms from skin and mucous mem-
brane problems. Koilonychia, hair loss, Plummer-Vinson syn-
drome, and perlèche are all symptoms associated with iron
deficiency.
Treatment. Patients with iron deficiency anemia receive
oral or parenteral iron replacement therapy, as the source of
chronic blood loss is located.25,26 The goal of treatment is to
return Hb levels and restore MCV to normal. A complete
investigation should be performed to determine the etiol-
ogy of the microcytic anemia and prevent further iron loss.
The supplementation of iron is with ferrous sulfate, 200 mg
three times daily; alternatively, ferrous gluconate or ferrous
fumarate is used. Ascorbic acid can be given concomitantly
to enhance iron absorption. An Hb increase of 2 g/dL should
occur within 3 to 4 weeks of initiating treatment.
Thalassemia
Thalassemia consists of a group of inherited disorders result-
ing in the inability to produce structurally normal globin
chains. This results in an abnormal hemoglobin molecule with
subsequent hemolysis. The disorder can affect synthesis of
both the alpha (α) and the beta (β) globin chain, and depend-
ing on whether the bearer is homozygous or heterozygous,

the disease is called major or minor. β-Thalassemia major
(Cooley's anemia) is rare and carries a poor prognosis. Patients
of Mediterranean descent present with this illness in early
stages of life. Patients have prehepatic jaundice, hepatospleno-
megaly, and an increased susceptibility to infection. Because
of multiple blood transfusions, patients also develop second-
ary hemochromatosis and die of complications related to car-
diac hemochromatosis (e.g., arrhythmias, congestive heart
failure). β-Thalassemia is not compatible with life.
Patients with minor thalassemias show mild anemic states
with microcytic, hypochromatic erythrocyte indices. Iron
stores are normal or increased. The diagnosis is confirmed by
Hb electrophoresis.27,28
Treatment. In its mild form, thalassemia rarely requires
an intervention. With more severe disease, folic acid and pos-
sible RBC transfusion may become necessary. Patients with
advanced disease require frequent transfusions and folic acid;
some require splenectomy and bone marrow transplantation.
It is important to avoid iron supplementation.
Megaloblastic Anemias
Megaloblastic anemias are anemias with macrocytic, hyper-
chromatic erythrocyte indices. The two most common forms
are vitamin B12 deficiency and folic acid deficiency. Both vita-
min B12 and folic acid are important cofactors in the synthesis
of DNA. A deficiency of either vitamin leads to an insufficient
amount of DNA, resulting in the inability of bone marrow
to produce an adequate amount of blood cells. This in turn
results in large blood cells, each packed with an abnormally
high amount of hemoglobin.29,30
Vitamin B12 deficiency is most often caused by an autoim-
mune disease and results in pernicious anemia.29 An autoanti-
body targeted toward the intrinsic factor leads to the inability
to absorb vitamin B12. Intrinsic factor is produced by gastric
parietal cells and is required to absorb vitamin B12 (extrin-
sic factor) in the terminal ileum. Other causes are rare and
include strict vegetarian diet, malabsorption syndromes, sta-
sis (blind loop) syndrome, and tapeworm (Diphyllobothrium
latum) infection (Box 11-2).
Vitamin B12 deficiency can also lead to neurologic and
gastroenterologic symptoms. An atrophic tongue, known as
Hunter's glossitis, is a typical sequela of vitamin B12 deficiency.
Degeneration of the lateral and posterior spinal cord leads to
BOX 11-2   n DIFFERENTIAL CAUSES OF VITAMIN B12
DEFICIENCY
Vegetarian diet
Reduction in intrinsic factor
Pernicious anemia
Subtotal or partial gastric resection
Malabsorption syndrome
Tapeworm (Diphyllobothrium latum) infection
Stasis (blind loop) syndrome
Chapter 11  Hematologic Diseases 353
peripheral neuropathy and gait ataxia. Depression and psy-
chotic symptoms are also seen. Clinically, the loss of sensation
to vibration is an early warning sign. The diagnosis is obtained
by measuring vitamin B12 concentrations in plasma. At pres-
ent, parenteral administration of vitamin B12 is the only thera-
peutic option.
Folic acid deficiency is the third most common cause of ane-
mia seen in pregnancy, resulting from increased requirements.
Other risk factors for folic acid deficiency are alcoholism,
abnormal dietary habits, and certain medications (methotrex-
ate, phenytoin). Folic acid deficiency does not present with
neurologic sequelae in the adult, although it has been linked
to neural tube defects in early stages of pregnancy. The diag-
nosis is confirmed, as in vitamin B12 deficiency, by measuring
plasma concentrations. Folic acid, however, can be supple-
mented orally.
Nitrous oxide (N2O) can irreversibly oxidize the cobalt ion
found in vitamin B12. Therefore, use of N2O should be avoided
in patients with megaloblastic anemia, to avoid a synergistic
effect. Otherwise, the same principles apply as in treating any
other form of anemia.
Treatment. The treatment of patients with megaloblastic
anemia consists of cobalamin and folate. It is rarely necessary
to transfuse patients because the anemia develops over time,
and patients tend to compensate for their low hemoglobin.
Hemolytic Anemias
Hemolytic anemias can be caused by corpuscular defects of
the erythrocyte or by extracorpuscular pathologic processes.
Typical corpuscular hemolytic anemias are seen with cell
membrane defects (e.g., spherocytosis), hemoglobinopathies
(e.g., thalassemia, sickle cell disease), or enzyme defects within
the erythrocyte (e.g., glucose-6-phosphate dehydrogenase
or pyruvate kinase deficiency). Extracorpuscular hemolytic
anemias are immunologically mediated (Rh incompatibility,
ABO transfusion reactions, autoimmune hemolytic anemias)
and result from consumption of certain medications, infec-
tious diseases, metabolic derangements (Zieve syndrome),
or microangiopathic pathologic processes (hemolytic-uremic
syndrome, thrombotic thrombocytopenic purpura).31,32
Treatment. Patients with hemolytic anemia are treated
according to the cause of their disease. Options include folic
acid, corticosteroids, and intravenous immune globulin
(IVIG).
SPHEROCYTOSIS
Spherocytosis is one of the most common inherited hemolytic
anemias. It is caused by a defect in the erythrocyte membrane,
which leads to an increased permeability for sodium and
water, giving the erythrocyte its characteristic spherical form.
This renders the erythrocytes susceptible to phagocytosis in
the spleen at an early age. Patients are prone to hemolytic cri-
sis and gallstones, formed primarily of bilirubin. Normocytic
anemia accompanied by signs of hemolysis (increased indirect
 354 ANESTHESIA AND UNCOMMON DISEASES
bilirubin, increased lactate dehydrogenase, increased reticulo-
cytes) is the typical laboratory finding. The diagnosis is con-
firmed by osmotic testing of erythrocytes.
Patients with recurrent hemolytic crisis may have under-
gone splenectomy. The anesthesiologist must be aware that
these patients, if not properly vaccinated, are at increased risk
for sepsis (overwhelming postsplenectomy sepsis).33
Treatment. In neonates with hereditary spherocytosis and
hyperbilirubinemia, it may be necessary to initiate photother-
apy to prevent kernicterus. In addition, transfusion of RBCs
and exchange transfusion need to be considered. Aplastic cri-
sis can cause a significant drop in Hb and may require blood
transfusion. Folic acid (1 mg/day) is administered to sustain
erythropoiesis. Splenectomy is often curative and should be
considered in patients with frequent aplastic crisis.
HEMOGLOBINOPATHIES
There are approximately 300 known abnormal hemoglobin
molecules. Most of these pathologic globin molecules differ
from the physiologic α and β chains through exchange of only
one amino acid with another. This section concentrates on the
illnesses most likely seen in daily practice.
Sickle Cell Anemia
Sickle cell anemia is the most common form of inherited
hemoglobinopathy found in humans; 5% to 10% of African
Americans are heterozygotic carriers. The mutation is in the
sixth amino acid in the β chain of the Hb molecule; glutamic
acid is replaced by valine.34 In its deoxygenated form, hemo-
globin S (HbS) tends to precipitate, causing the erythrocytes to
lose their normal biconcaval form and take on a sickled struc-
ture. This leads to sludging and eventually occlusion of the
microvasculature, resulting in end-organ infarction.
Heterozygotic carriers are generally asymptomatic,
expressing only a sickle cell trait found in laboratory test-
ing (HbS <50%). However, homozygotic carriers can display
sickle cell crisis as early as infancy, with signs of hemoly-
sis and painful vaso-occlusive infarctions (spleen, kidney,
bones). Because of an atrophic spleen caused by recurrent
microinfarctions, patients are prone to Streptococcus pneu-
moniae and Haemophilus influenzae infections of the respi-
ratory tract and osteomyelitis. The diagnosis of sickle cell
anemia is made through microscopic sickle cell testing or
Hb electrophoresis.
Conventional anesthetic management is geared toward
avoiding a sickle cell crisis during the perioperative period.35
Patients should be kept well hydrated, warm, and well oxy-
genated. Acidosis should be avoided at all costs.36 Sickle cell
patients presenting for cardiac surgery can be appropriately
managed by maintaining temperature and Hb concentra-
tion. Fast-track or early extubation protocols have been used
with success.37 Many of the practices directed toward avoid-
ing a sickle cell crisis are still followed in current manage-
ment, but some of the classic “dogmas” have been challenged
in the past decade. For example, the use of tourniquets for
orthopedic procedures is no longer considered an absolute
contraindication.38–40 Exchange transfusion solely with the
intent to improve a laboratory value (HbS fraction <30%) can
no longer be considered proper standard of care.41,42 Griffin
and Buchanan43 suggest that transfusion before elective sur-
gery in children may not be necessary at all. They successfully
provided anesthesia for 54 children with sickle cell disease
without a transfusion and found that smaller surgical proce-
dures could be easily performed without complication, but
that pulmonary complications arose after laparotomy, tho-
racotomy, and tonsillectomy.42,43 Although benefits for pain
management and rheology accompany neuraxial anesthe-
sia, many investigators still believe that the patient with more
complex sickle cell anemia is better managed using general
anesthesia.35
The anesthesiologist is sometimes asked to assist as a pain
consultant in managing an acute sickle cell crisis.42 Adequate
oxygenation, normothermia, and euvolemia are the corner-
stones of management. Analgesia is achieved with opiates.
Caution must be used with analgesics such as nonsteroidal
anti-inflammatory drugs (NSAIDs), which can impair renal
function because these patients frequently have renal microin-
farctions with reduced baseline renal function. Vaso-occlusive
crisis of the lower extremities can be managed with continu-
ous neuraxial blocks. Occasionally a partial exchange trans-
fusion with PRBCs is performed to increase the fraction of
HbA greater than 50%. For rheologic reasons, Hct should not
exceed 35%.
In parturients with sickle cell disease, transfusion therapy
is recommended to treat the complications of the disease,
especially those associated with chest pain syndromes, pre-
eclampsia, and multiple gestations.44,45 Antibiotic prophylaxis
for both mother and newborn should be actively practiced.
The avoidance of adverse events during labor does not seem
to be associated with the type of analgesia provided (regional
vs. systemic) but appears more related to careful monitoring
for the known consequences of the disease.46
Newer therapies are being investigated for the anesthetic
management of patients with sickle cell disease. Cytotoxic
agents such as hydroxyurea stimulate the production of fetal
hemoglobin and are being studied in the prevention of vaso-
occlusive crises. Inhaled nitric oxide (iNO) and other investi-
gational drugs have shown promise in reducing the sickling
process and even unsickling cells.
Treatment. As stated, treatment of sickle cell anemia
includes hydroxyurea and folate. Investigational treat-
ments include NO, oral glutamine, butyrate, and arginine.
Exchange or simple transfusion should be considered,
depending on the type and complexity of surgery and
­individual patient needs.
ENZYME DEFICIENCY ANEMIAS
Enzyme defects within erythrocytes can lead to hemoly-
sis. The two most common defects are glucose-6-phosphate
dehydrogenase (G6PD) deficiency and pyruvate kinase (PK)
deficiency.

Glucose-6-Phosphate Dehydrogenase Deficiency
G6PD deficiency is the most common enzyme deficiency
anemia and is seen in individuals of African, Asian, or
Mediterranean descent. The illness is inherited recessively on
the X chromosome. Patients with this defect have erythro-
cytes containing a reduced amount of glutathione, leading to
oxygenation injury of the cell membrane. A hemolytic crisis
can be induced through infections or ingestion of beans and
certain medications (e.g., sulfonamides, aspirin, quinidine).
No specific therapy for G6PD deficiency exists. Avoiding
trigger substances is the only recommendation available at
present.47
Pyruvate Kinase Deficiency
The PK deficiency is the most common defect of the glycoly-
sis pathway. It has an autosomal recessive pattern of inheri-
tance. The normal erythrocyte does not have mitochondria
and relies on glycolysis to produce adenosine triphosphate
(ATP) to maintain cellular integrity. Homozygous carriers for
PK deficiency present with hemolytic anemia, splenomegaly,
and acanthocytes.48
Treatment. Patients with enzyme deficiency anemias are
treated with removal of the precipitating agent. Supportive
care with bed rest and oxygen are helpful while the patient's
Hb levels return to baseline. In those with the most severe
forms of enzyme deficiency anemia, transfusion and splenec-
tomy must be considered.
ANTIBODY-INDUCED HEMOLYSIS
Antibodies can result in two major reactions: hemolysis and
agglutination. Antibodies directed against erythrocytes are
either immunoglobulin M (IgM) or IgG in structure. IgM anti-
bodies are larger (molecular weight, 900,000 daltons) and can
act as a bridge between two erythrocytes. The term complete
antibodies is sometimes used. Examples of IgM antibodies
are ABO isoagglutinins and cold agglutinins. IgG antibod-
ies are smaller in size (150,000 D) and cannot form a bridge
between two erythrocytes (incomplete antibodies). Examples
of IgG antibodies are Rhesus (Rh) agglutinins and warm anti-
bodies. The Coombs test is used to diagnose the presence of
incomplete antibodies either already attached to the surface of
erythrocytes (direct Coombs) or in the patient's serum (indi-
rect Coombs).
Autoimmune Hemolytic Anemia
Autoimmune hemolytic anemias can be caused by either
warm (IgG) or cold (IgM) antibodies; 70% of all autoimmune
hemolytic anemias are caused by warm antibodies. Warm
autoimmune hemolytic anemias are seen in patients with
non-Hodgkin's lymphoma, systemic lupus erythematosus,
viral infection, and after ingestion of certain drugs (penicillin,
α-methyldopa). These antibodies bind to the surface of eryth-
rocytes at body temperature without causing hemolysis. The
erythrocytes undergo phagocytosis in the spleen. The erythro-
cyte survival time can be diminished to only a few days, with
erythropoiesis increased tenfold. About 15% of all patients
Chapter 11  Hematologic Diseases 355
with autoimmune hemolytic anemia present with cold anti-
bodies. These antibodies are seen in patients after Mycoplasma
pneumonias or mononucleosis. These antibodies lead to a
Raynaud-like syndrome (acrocyanosis) and hemolysis as soon
as intravascular temperature drops to below 25° to 30° C (77°-
86° F).49
Treatment. Patients with cold-agglutinin antibod-
ies can often be managed with temperature regulation.
Glucocorticoids are occasionally administered to patients
with warm-antibody-induced hemolysis, but are of limited
benefit with IgM cold antibodies. Chemotherapy and immu-
nosuppressive therapy are generally reserved for patients with
underlying malignancies. Plasmapheresis is useful in tempo-
rarily removing and reducing levels of IgM antibodies from
plasma and can be used before a patient undergoes a hypo-
thermic surgical procedure.
TRAUMATIC HEMOLYSIS
Traumatic injury to erythrocytes leading to premature RBC
destruction can be seen in patients with mechanical heart
valves, intra-aortic balloon pumps, or after severe physical
exertion (e.g., extreme hiking, runner's anemia). Whenever
feasible, remove the cause of hemolysis as quickly as possi-
ble. Other options are supportive treatment, and in the most
severe cases, consider transfusion.
RENAL ANEMIA
Patients presenting for surgery with chronic kidney disease
(CKD, chronic renal failure), with glomerular filtration rate
(GFR) less than 30 mL/min, frequently have a normochro-
mic, normocytic anemia (see Table  11-1) because of inad-
equate production of erythropoietin.50,51 Hb concentration is
generally found to be about 9 g/dL. Transfusion of PRBCs is
necessary should signs of ischemia develop. These patients
are frequently treated with recombinant human erythro-
poietin to raise baseline Hb values.52 Patients often tolerate
anemia caused by CKD. The need for transfusion should be
reserved for those requiring increased O2-carrying capac-
ity or expected blood loss. The use of epoetin alfa and more
recently darbepoetin alpha are helpful options to increase
Hb levels.
ACUTE BLOOD LOSS/HEMORRHAGIC
SHOCK
One of the most challenging situations for the anesthesi-
ologist is to induce anesthesia for a patient in hemorrhagic
or hypovolemic shock. A further complication is that acute
hemorrhage is often difficult to diagnose. Laboratory values
for hemoglobin are normal immediately after an acute blood
loss. Loss of half the circulating blood volume will result in no
change in Hb concentration unless fluid with a different Hb
concentration is added. In clinical practice, fluids are admin-
istered parenterally after obtaining access to the circulatory
system. Advanced Trauma Life Support protocols advise
 356 ANESTHESIA AND UNCOMMON DISEASES
administering 2 L of crystalloid solution to patients in sus-
pected hypovolemic shock. This will lead to dilution of the
original Hb concentration. If intravenous (IV) fluids are not
administered, anemia will result within hours through move-
ment of interstitial fluid into the intravascular space. Because
of this delay, Hb and Hct are not ideal parameters for detect-
ing acute blood loss.
In addition to laboratory problems with diagnosis of acute
blood loss, the volume state of a patient is also extremely dif-
ficult to assess clinically. Especially in young patients, the sym-
pathetic nervous system is capable of masking even extreme
states of hypovolemia, giving the clinician a false sense of
security. Subtle signs such as orthostatic hypotension, tachy-
cardia, narrowing pulse pressure, alterations of cerebral func-
tion, and low urine output must be sought before induction of
anesthesia is indicative of hypovolemia. In an attempt to main-
tain adequate perfusion to the brain and myocardium, the
autonomic nervous system compromises perfusion to the kid-
neys, skeletal muscular system, and gut. This redirection in
blood flow is achieved by increasing the sympathetic adrener-
gic tone of the vegetative nervous system, resulting in increased
heart rate, systemic peripheral resistance (SVR), and narrow-
ing pulse pressure. As a result of impaired tissue perfusion,
lactate concentrations increase while urine output and Sv̄o2
decrease.
The treatment of acute blood loss is primarily aimed at
replacing lost volume. This can be achieved by administer-
ing either crystalloid or colloid solutions. Whether p ­ rimarily
crystalloid or colloid solutions should be employed to
replace lost blood volume is controversial. Blood products
need to be administered because of the rapid dilution of
RBCs and coagulation factors. The goal of therapy is aimed
at restoring adequate perfusion and O2 delivery to all organ
systems. A successful course of treatment can be seen by
normalization of vital signs, urine output, lactate concentra-
tions, and Sv̄o2. Vasopressors should be used only as a tem-
porary resort in maintaining perfusion pressure to the
myocardium and cerebrum until adequate volume replace-
ment can be achieved.
Inducing a hypovolemic patient is especially challenging to
anesthesiologists because all induction agents can potentially
reduce the adrenergic tone needed by the organism to main-
tain adequate perfusion pressure to the brain and myocardium.
If not corrected quickly, a vicious cycle is started that will lead
to further hemodynamic deterioration. Invasive monitoring
and use of induction agents with the least suppressive effect
on hemodynamics are recommended; ketamine and etomi-
date are good choices. If perfusion pressure declines, a vaso-
pressor might be indicated until adequate access is obtained
and volume loading begins.
Treatment. As previously described, treatment of acute
blood loss is with transfusion of PRBCs. The clinician should
consider the benefit of blood transfusion increasing O2-
carrying capacity against possible transfusion-related adverse
effects.
DISEASES OF LEUKOCYTES
Although leukocyte abnormalities rarely alter an anesthetic
plan, a few exceptions exist.
Lymphomas
Lymphomas are neoplasms of the lymphatic system clinically
divided into two groups: Hodgkin's disease and non-Hodgkin's
lymphoma (NHL). The primary localization of these tumors is
in the lymph nodes. As the disease progresses, metastatic lesions
can be found in every organ. A major concern to the anesthesi-
ologist is that lesions may obstruct the airway. Large tumor bulks
can be found in the mediastinum, growing undetected until vital
organs (blood vessels, heart, airway) are compressed. Mediastinal
mass syndrome is the acute obstruction of the trachea or large ves-
sels (superior vena cava, right atrium, right ventricle) by tumor
mass after induction of general anesthesia. Patients frequently
complain of dyspnea while in the supine position. The supine
position in combination with muscle relaxation can lead to posi-
tional changes of the tumor mass and result in airway obstruc-
tion. Careful preoperative evaluation and review of the patient's
computed tomography (CT) scan can alert the anesthesiologist
to this potential complication. Discussing these concerns with
the patient and surgeon can result in alternative means of analge-
sia (e.g., local anesthesia in monitored anesthesia care).
If a general anesthetic is deemed necessary, inhalational
induction with sevoflurane is prudent, keeping the patient
breathing spontaneously and avoiding muscle relaxation. If air-
way compromise still occurs, the anesthetic should be aborted
and the patient awakened immediately. Awake f­ iberoptic intu-
bation is another alternative, as long as the bronchoscope can
be passed distal to the lesion. A distal lesion, however, poses
the same problems seen in conventional intubation, because
the end of the endotracheal tube will lie proximal to the lesion.
In an urgent situation, a rigid ventilating bronchoscope must
be passed immediately.
Treatment. The treatment options for patients with lym-
phoma vary depending on the type and staging of the disease.
The mainstay therapies include radiation, chemotherapy, stem
cell transplantation, surgery, and immunosuppressive drugs. It
is important to recognize that each specific treatment option
has the potential to affect anesthetic management.
HODGKIN'S DISEASE
Hodgkin' disease has an incidence of 3 per 100,000 population,
showing a double-peaked distribution in Western countries
during the third and sixth decades of life. Males are more fre-
quently affected than females (3:2). Whether the Ebstein-Barr
virus plays a similar role in the etiology as in the development
of Burkitt's lymphoma remains unclear. Hodgkin's disease
leads to immunosuppression, with increased susceptibility for
tuberculosis and fungal and viral infections. Oncologists use
the Ann Arbor Classification to describe the progression of
Hodgkin's disease (Table 11-3).

TABLE 11-3  n Ann Arbor Staging System for Hodgkin's
Disease
Stage* Description
I Involvement in single lymph node region or single
extralymphatic site
II Involvement in two or more lymph node regions on
same side of diaphragm
III Involvement of lymph node regions on both sides of
diaphragm; may include spleen
IV Disseminated involvement of one or more
extralymphatic organs with or without lymph node
involvement
*Subtypes: A = Symptoms: without general symptoms of disease. B = Symptoms:
fever, loss of weight, night sweats, pruritus.
This classification can also be used to assess patient prog-
nosis; the higher the grading, the worse the prognosis. Patients
with stage I or II Hodgkin's disease are primarily treated with
radiation therapy; those with stage III or IV additionally
receive chemotherapy. As a result of improved medical man-
agement, long-term survival has increased dramatically over
the past decade. Unfortunately, the cure of Hodgkin's lym-
phoma comes with a price. An increasing number of “sur-
vivors” are presenting with long-term complications of the
medical treatment (e.g., second neoplasms, cardiotoxicity
induced by chemotherapy [doxorubicin], pulmonary toxic-
ity through bleomycin). For patients with a history of doxo-
rubicin therapy, assessment of cardiac function should be
made, including cardiovascular testing if appropriate. Surgical
patients who have been exposed to bleomycin therapy should
have a complete set of pulmonary function tests (PFTs) if they
exhibit pulmonary symptoms. This is especially helpful in
patients presenting for pulmonary resection. The PFT profile
of bleomycin toxicity will demonstrate a severe restrictive lung
disease pattern with small lung volumes and a reduced carbon
monoxide diffusion ratio.
NON-HODGKIN'S LYMPHOMA
In contrast to Hodgkin's disease, NHL cannot be regarded as
a single malignant entity but as a heterogeneous collective of
neoplasia originating from T lymphocytes in lymphatic tissue.
About 30% of NHL cases present with a leukemic element.
The incidence is 5 to 10 per 100,000 population, increasing
with age. As in Hodgkin's disease, male gender is more prone
than female (1.5:1). HIV-positive patients are 1000 times more
susceptible to developing NHL than a control population.
MULTIPLE MYELOMA
Also known as plasmacytoma or Kahler's disease, multiple
myeloma is a malignant disorder of plasmacytes. It is classified
into the group of non-Hodgkin's lymphomas. The neoplas-
tic plasmacytes produce either a monoclonal immunoglob-
ulin (IgG, IgA, IgD) or isolated light chains (Bence Jones
Chapter 11  Hematologic Diseases 357
plasmacytoma). During this process, bone marrow is displaced
by infiltration of the tumor, resulting in a loss of functioning
peripheral blood cells. The tumor also leads to osteolysis with
a loss of normal bone architecture, resulting in an increased
risk of pathologic fractures. Patients present with high eryth-
rocyte sedimentation rates, Bence Jones proteinuria, or altered
protein or immunoglobulin electrophoresis. Patients will typi-
cally be anemic and have signs of coagulopathy due to throm-
bocytopenia, thrombocytopathy, and decreased functional
plasmatic coagulation factors. Renal failure caused by toxic
deposition of immunoglobulin in renal tubuli is the most
common cause of mortality. Hypercalcemia resulting from
increased osteoclastic activity supports the development of
renal failure and can lead to hypercalcemic crisis. About 10%
of patients will develop amyloidosis. Treatment includes radi-
ation therapy and/or chemotherapy. Prognosis is poor at pres-
ent for patients with multiple myeloma.
MACROGLOBULINEMIA
Also known as Waldenström's disease, macroglobulinemia
is generally seen in the aging population and is caused by
malignant plasmacytes producing IgM. Macroglobulinemia
is four times less common than multiple myeloma and is
not as aggressive. Osteolysis and hypercalcemia are not seen;
however, hemorrhagic diathesis is caused by disorders of
thrombocyte aggregation and binding of coagulation factors.
Hyperviscosity syndrome leading to Raynaud-like acral per-
fusion deficits and visual disturbances is also seen. Prognosis
for patients with macroglobulinemia is better than for mul-
tiple myeloma.
Leukemias
Leukemia means “white blood” and refers to an increased
amount of leukocytes seen in peripheral blood. Leukemias
are divided into acute or chronic and myeloplastic or lym-
phatic forms, depending on the cell row of neoplasmic ori-
gin. All leukemias lead to impaired immune reactions, making
patients more prone to infection. Because of possible infil-
tration of leukemic cells into virtually all organs, patients
may have reduced organ function. Leukemia is treated clas-
sically with chemotherapy. The anesthesiologist should be
aware of the agents employed during chemotherapy cycles.
Doxorubicin is known to cause systolic dysfunction that can
affect the anesthetic technique. Emerging techniques used to
treat leukemia are allogenic bone marrow and stem cell trans-
plantation. Treatment is generally more successful in children,
with 5-year survival reaching 80%.
ACUTE LEUKEMIA
The cornerstone for the diagnosis of an acute leukemia is
the presence of immature hematopoietic cells in ­peripheral
blood. The incidence is 4:100,000 per year. About 80% of
acute leukemias in childhood originate from lymphatic
cells; in adulthood, 80% are myelocytic. The etiology is
­multifactorial. Retroviruses, bone marrow damage caused
 358 ANESTHESIA AND UNCOMMON DISEASES
by radiotherapy or chemical substances, and genetic compo-
sition of the patient (e.g., Down or Klinefelter's syndrome)
have all been linked to an increased risk for developing acute
leukemia.
CHRONIC MYELOPROLIFERATIVE DISEASE
Chronic myeloproliferative disease incorporates four illnesses:
chronic myelocytic leukemia, polycythemia vera, essential
thrombocythemia, and osteomyelosclerosis. All these diseases
show a monoclonal proliferation from a myelocytic stem cell.
Initially, all three cell rows are increased in number (leuko-,
erythro-, and thrombocytosis). Splenomegaly is common.
Eventually, sclerosis of the patient's bone marrow occurs,
leading to loss of its function. Extramedullary hematopoiesis
is seen (liver, spleen). In the terminal phase a blast crisis often
occurs.
Chronic leukemias develop over a prolonged period,
sometimes taking a decade to manifest clinically. Chronic
myelocytic leukemia presents as the highest concentration
of leukocytes (>500,000/μL), resulting in organ infarction.
Chronic lymphatic leukemia is the most common form of leu-
kemia and increases in incidence with increasing age. Chronic
myelocytic leukemia has a low degree of malignancy, allowing
patients to survive for many years without impairing quality of
life. Lymphadenopathy and splenomegaly are common mani-
festations in chronic leukemia.
Myelodysplastic Syndrome
Myelodysplastic syndrome represents a heterogenic clonal
stem cell pathology with qualitative and quantitative changes
of hematopoiesis, peripheral cytopenia, and a high propor-
tional amount of blast in bone marrow. It is primarily seen
in the elderly population, at 20 to 50 per 100,000 per year in
those older than 70.
DISEASES OF THROMBOCYTES
(PLATELETS)
Circulating platelets are anucleate discoid cells created
from megakaryocytes. The normal platelet count is 140,000
to 450,000 cells/μL. Platelets have many different roles in
TABLE 11-4  n Disease States Associated with Thrombocytopenia
Impaired Production Increased Destruction
Megakaryocyte dysfunction Autoimmune (immune thrombocytopenic purpura)
Aplastic anemia Immune (posttransfusion)
Drug (ticlopidine) Drug (chemotherapy)
Vitamin B12/folate deficiency Disseminated intravascular coagulation
Myelodysplastic disorders Thrombotic thrombocytopenic purpura
Hemolytic-uremic syndrome Hemodilution
maintaining circulation and hemostasis. Platelets form the pri-
mary phase of hemostasis, the platelet plug. This initial adhe-
sion of platelets to the injured endothelium is responsible for
the physical “healing” of the wound and for the biochemical
signaling that occurs when other cells and coagulation factors
are summoned to the site of injury. The platelet surface phos-
pholipid is a critical surface on which the coagulation cascade
proteases become activated and form a fibrin clot. On physical
examination, absence of normal platelet number or function
can be detected by the presence of petechiae. Conversely, an
excessive number of platelets or excessively activated platelets
will predispose to arterial occlusive disease. Patient and fam-
ily history are the most important factors in assessing platelet-
related disorders.
Routine screening for platelet abnormalities is not recom-
mended in the absence of any sign or symptom. In the presence
of signs or symptoms of a bleeding diathesis, a platelet count
is obtained. A minimal platelet count of 50,000 to 100,000
cells/μL is recommended before elective surgery. Spontaneous
bleeding can occur with platelet counts less than 30,000/μL.
Further testing, such as the bleeding time and other aggrega-
tion studies, are described as they relate to individual disease
states.
Thrombocytopenia
Thrombocytopenia is caused by decreased production of
platelets, excessive destruction of platelets, or splenic or other
sequestration. A common cause of decreased production is
the result of bone marrow hypoplasia or marrow-toxic drugs.
Increased destruction may be drug induced or autoimmune.
Thrombocytopenia also occurs in the parturient and may rep-
resent risks to maternal or fetal well-being if not recognized
early.53 Common causes of thrombocytopenia are listed in
Table 11-4.
IMMUNE (IDIOPATHIC) THROMBOCYTOPENIC PURPURA
Immune or idiopathic thrombocytopenic purpura (ITP)
is a common abnormality causing a low platelet count. It
affects 0.01% of the population and is the result of autoan-
tibodies that bind to the platelet surfaces, thus decreasing
their life span.54 ITP frequently affects young women and is
Sequestration
Hypersplenism
Splenomegaly
Adhesion to synthetic surfaces
Platelet-platelet adhesion
Heparin-induced thrombocytopenia type 1
Heparin-induced thrombocytopenia type 2

thus encountered in the parturient.55 Cutaneous signs such
as petechiae are often the presenting feature. The goal of
treatment is to prevent complications associated with a low
platelet count (i.e., hemorrhage). Corticosteroids remain the
drug of choice for initial treatment of patients with acute
ITP. Steroids decrease platelet destruction and facilitate
primary hemostasis while reducing bleeding and bruising.
Alternative treatment includes IV immunoglobulins and
recently the use of thrombopoietin receptor analogs for
chronic ITP.56
Treatment is not usually recommended until the plate-
let count is less than 30,000/μL, unless the patient is hav-
ing uncontrolled bleeding or major surgery. In the patient
with catastrophic bleeding, platelet transfusion can be given
in conjunction with corticosteroid therapy or IVIG ther-
apy to decrease the immunologically mediated destruc-
tion. Plasmapheresis has also been used with other therapies
with some success. Emergent splenectomy is reserved for the
patient who fails therapies and has life-threatening bleeding.57
Again, transfusion of platelets is generally avoided unless the
risk of spontaneous bleeding is imminent.
THROMBOTIC THROMBOCYTOPENIC PURPURA
The signs and symptoms of thrombotic thrombocytopenic
purpura (TTP) consist of fever, hemolytic anemia, thrombo-
cytopenia, renal disease, and central nervous system disease.
Management consists of corticosteroids, plasmapheresis, and
plasma transfusion. When presenting during pregnancy, TTP
can appear identical to toxemia of pregnancy. The antiplate-
let drug clopidogrel is a potential cause in patients d
­ eveloping
TTP.58 During the last trimester of pregnancy, treatment of
this constellation of symptoms is delivery of the infant. The
treatment of choice for TTP is plasma exchange with fresh-
frozen plasma. Steroids are often administered to these
patients. Transfusion of platelets is avoided except in extreme
circumstances.
TABLE 11-5  n Platelet Disorders and Available Testing Modalities
Disorder Pathophysiology
Bernard-Soulier syndrome Absent GPIb
Glanzmann's thrombasthenia Absent GPIIbIIIa
Von Willebrand's disease Von Willebrand factor (vWF)
Gray platelet syndrome Alpha-granule depletion
DRUG THERAPY
Aspirin ingestion Cyclo-oxygenase inhibition
Clopidogrel ingestion ADP P2Y12 inhibition
Abciximab GPIIbIIIa blockade
Nitroglycerin Increased nitric oxide
ADP, Adenosine diphosphate; GP, glycoprotein; PFA, Platelet Function Analyzer; TEG, thromboelastography.
Chapter 11  Hematologic Diseases 359
PLATELET SEQUESTRATION
Platelet count is reduced because of sequestration of plate-
lets in the spleen. This clinical condition is similar to a pseu-
dothrombocytopenia because the platelets are present in the
body but are not circulating in the bloodstream. Platelets
adhere to extracorporeal surfaces such as a cardiopulmo-
nary bypass (CPB) circuit, which, along with hemodilu-
tion, accounts for most of the thrombocytopenia seen after
cardiac surgery.57 The common cause of platelet sequestra-
tion is hypersplenism, and all therapies should be aimed at
resolving this issue. In some patients, surgical splenectomy
is indicated.
Thrombasthenic Syndromes
In contrast to thrombocytopenia, clinical conditions in which
the platelet count often falls to levels less than 30,000 cells/μL
before treatment is initiated, patients with thrombasthenic
syndromes (Table 11-5) require treatment with platelet trans-
fusion at much higher levels of platelet count because platelet
function is severely compromised.
Bernard-Soulier syndrome is a thrombasthenic disorder
marked by deficiency of the GPIb receptor, the major receptor
responsible for platelet adhesion to collagen, vWF, and other
ligands.59 Patients have hemorrhagic tendencies.
GLANZMANN'S THROMBASTHENIA
Patients with this rare autosomal recessive disorder have
severely impaired platelet aggregation, prolonged bleeding
time, and normal platelet count. Glanzmann's thrombasthe-
nia is marked by the absence of the GPIIbIIIa receptor (α2bβ3
integrin).59 Either component of this receptor, the α or the β
component, may be absent or abnormal for the disease to be
expressed. Fibrinogen binding to GPIIbIIIa induces a con-
formational change in the receptor, making it more likely
to bind fibrinogen and further enhancing the aggregation
Testing
Flow cytometry, bleeding time, PFA-100
Flow cytometry, aggregation, Ultegra, TEG
Bleeding time, PFA-100
Flow cytometry, aggregation
Aggregation, bleeding time, PFA-100, modified TEG
Aggregation, bleeding time, modified TEG
Aggregation, flow cytometry, Ultegra
Aggregation, flow cytometry
 360 ANESTHESIA AND UNCOMMON DISEASES

VON WILLEBRAND'S DISEASE

process. GPIIbIIIa is the major receptor whereby fibrinogen
Von Willebrand factor (vWF) is synthesized in the endothe-
bridges adjacent platelets. Thus, patients with Glanzmann's
lium and in the platelet and acts as a ligand for platelet adhesion
thrombasthenia have lifelong bleeding histories and require
via the GPIb receptor. Von Willebrand's disease is a common
platelet transfusions to achieve normal platelet aggregation.
vWF disorder that frequently manifests as a bleeding disor-
In certain clinical scenarios such as percutaneous cardio-
der. It is inherited as an autosomal dominant trait. Laboratory
logic intervention, pharmacologic agents are prescribed that
analysis of von Willebrand's disease consists of the measure-
competitively or permanently block the GPIIbIIIa recep-
ment of vWF activity, vWF antigen, factor VIII activity, vWF
tor. The effect achieved is one of extreme platelet “pare-
multimeric analysis, and bleeding time. The vWF multimeric
sis.” If large enough doses are administered, almost 100%
analysis is important for the classification of the subtype of von
of GPIIbIIIa receptors can be blocked, and platelet aggre-
Willebrand's disease (Table  11-6). If only factor VIII level is
gation to raw atherogenic surfaces (coronary arteries) will
reduced, von Willebrand's disease can be confused with hemo-
not occur. During drug infusion, patients are susceptible to
philia A.60 If only the bleeding time is prolonged, it can be con-
bleeding, but careful monitoring and drug dosing minimize
fused with a primary platelet disorder. Different subtypes of the
this risk. Examples of these drugs include abciximab, tirofi-
disease respond differently to therapy; thus, it is important to
ban, and eptifibatide.
know which von Willebrand's subtype exists in a patient.
Anesthetic management of the patient with absent
Patients with von Willebrand's disease have a prolonged
GPIIbIIIa function includes the transfusion of allogeneic
bleeding time. Clinically, they can have a range of abnormali-
platelets. In patients who have received GPIIbIIIa antagonist
ties, from mild bleeding to hemorrhagic symptoms. They often
drugs, additional fibrinogen in the form of cryoprecipitate
have increased mucocutaneous bleeding (during dental proce-
may be transfused to compete with the drug for the platelet
dures), and women frequently present with menorrhagia.61
receptor. However, this is often not done because the drugs
Type I von Willebrand's disease is marked by a reduced
have a higher affinity for the receptor than does the fibrino-
quantity of normal vWF. The large multimers of vWF that
gen ligand. In emergency surgery, antifibrinolytic drugs have
are so critical for platelet adhesion are normal in size but
been used to minimize the amount of bleeding seen in these
reduced in quantity. Treatment of type I includes desmopres-
patients, but the data supporting this practice come from ani-
sin (d-arginine vasopressin [DDAVP]), which increases the
mal and in-vitro studies. The degree of platelet inhibition
release of vWF from the endothelium and the platelet.62,63
can be measured using laboratory and point-of-care tests so
Desmopressin is available in intranasal or IV forms, and the
that an approximation of the patient's transfusion needs can
IV form is often given intranasally. In patients with type I dis-
be made. Laboratory testing of platelet function is discussed
ease, a doubling of vWF activity (and factor VIII) and short-
earlier.
ening of the bleeding time occur within 15 to 30 minutes of
Treatment. Patients with Glanzmann's thrombasthe- administration of desmopressin. The IV dose is 0.3 μg/kg over
nia often require multiple transfusions in their lifetime. As a 30 minutes. Desmopressin must be infused slowly, or it will
result, these patients should be immunized with the hepati- cause hypotension.
tis B vaccine. The use of oral contraceptives helps to control In type IIA von Willebrand's disease a qualitative abnormal-
female menorrhagia. In the face of life-threatening bleeding, ity of vWF leads to defective platelet-vWF interactions, caused
factor VII has been administered at varying doses to promote by the absence of high- and middle-molecular-weight vWF
hemostasis. multimers. Patients may have normal levels of vWF protein,

TABLE 11-6  n  Von Willebrand's Disease: Laboratory Analysis and Therapy

Type vWF Activity Antigen Bleeding Time Factor VIII Therapy

Type 1 ↓ ↓ ↑ ↓ Desmopressin

Type 2A ↓ ↓ ↑ ↓ Factor VIII concentrates

Type 2B ↓ ↓ ↑ ↓ Factor VIII concentrates

Type 2 N Normal Normal ↑ ↓ Factor VIII concentrates

Type 3 ↓↓ ↓↓ ↑ ↓↓ Factor VIII concentrates plus desmopressin

Platelet* ↓ ↓ ↑ ↓ Platelets

Hemo A Normal Normal Normal ↓ Factor VIII concentrates

*Pseudo–von Willebrand's disease.

hemo A, Hemophilia A; vWF, von Willebrand's factor.

but the protein is dysfunctional. These variants account for
15% to 30% of cases.64–66 In type IIB von Willebrand's disease
a qualitative abnormality of vWF results in increased plate-
let-vWF interaction, caused by an increased affinity of vWF
for its platelet receptor, GPIb. The hallmark of type IIB is an
enhanced aggregation of the patient's platelets in the presence
of reduced concentrations of ristocetin. In type IIB disease, a
low concentration of ristocetin stimulates a full aggregation
response. This form of disease can be marked by thrombo-
cytopenia, but there may also be increased adhesiveness and
thrombosis. Thus, the administration of desmopressin as
therapy is not recommended in patients with type IIB von
Willebrand's. In type IIN disease, there may be qualitative
variants with greatly decreased affinity for factor VIII. The
measured vWF activity and antigen may be normal.
Type III is a severe form of von Willebrand's disease, with
near-complete deficiency of vWF. Usually, vWF activity and
antigen are undetectable, and factor VIII levels are greatly
reduced. The bleeding time is prolonged, usually to more than
20 minutes. Patients with type III disease have essentially no
vWF multimers. This severe form of von Willebrand's disease
may be the result of a homozygous defect or a complex hetero-
zygous defect. Desmopressin is not of benefit in patients with
type III disease because they have almost no endogenous pro-
duction of vWF.
Platelet-type or pseudo–von Willebrand's disease is a pri-
mary platelet disorder involving the platelet receptor for vWF,
GPIb. Although this is primarily a platelet disorder, patients
with pseudo disease have absent high-molecular-weight mul-
timers, reduced factor VIII, reduced vWF activity, and pro-
longed bleeding time. The laboratory analysis is similar to
patients with type IIB disease. Aggregation is enhanced in
response to low concentrations of ristocetin (0.3-0.5 mg/mL),
and mild thrombocytopenia is common. Von Willebrand's
disease can also be acquired. This is thought to occur by anti-
bodies to vWF that neutralize vWF activity.
Surgery. In the patient with von Willebrand's disease, base-
line factor VIII and bleeding time should be obtained within
1 week of surgery. From 1 to 2 hours before surgery, treatment
with desmopressin at 0.3 μg/kg should be infused. If baseline
factor VIII and bleeding time were abnormal, these measures
should be confirmed normal after desmopressin treatment
and before surgery is begun. After surgery, these measures
should be repeated once daily until wound healing is complete.
Desmopressin may need to be given once daily after surgery.
For more extensive surgery, factor VIII concentrates may be
necessary so that desmopressin can enhance vWF activity of
the administered product. Patients with type II or III disease
should receive factor VIII concentrates along the same timeline
as described for the treatment of type I disease. Desmopressin
may cause thrombocytopenia or increased aggregation67 in
these patients, but some still suggest that it may be effective
therapy in addition to replacement therapy for patients with
type II and III disease. After surgery, treatment is continued
every 12 hours until wound healing is complete.
Chapter 11  Hematologic Diseases 361
Treatment. Treatment for von Willebrand's disease depends
on the subtype. The most common form (type I) is treated with
desmopressin. However, desmopressin is contraindicated with
type IIB because the enhanced aggregation effect may cause
platelet count to paradoxically decrease. The administration
of factor VIII concentrate is an option for patients unrespon-
sive to DDAVP. The options for replacement include highly
purified vWF concentrates, cryoprecipitate, and a recombinant
vWF product that is still in development. The use of antifi-
brinolytic drugs is helpful in preventing the breakdown of
formed clot.
CONCOMITANT DRUGS
In patients with thrombocytopenia or platelet dysfunction,
other drugs that impair platelet function should be avoided.
However, many drugs and drug classes have been shown to
impair platelet function in vitro.68 The most common class of
drugs would be the nitric oxide (NO) donors.69,70 This class
of drugs includes nitrates (sodium nitroprusside, nitroglyc-
erin),71 phosphodiesterase inhibitors (milrinone),72 and NO
itself. NO has such a short half-life that its effects on plate-
let function would be short-lived.73,74 However, NO donors
such as nitroprusside may clinically impair platelet func-
tion to a measurable degree in a patient whose platelet activ-
ity is already compromised.75 Despite that NO donors impair
platelet function in the laboratory, this does not translate
into a clinical problem.70,76,77 In fact, when NO was compared
with control inhalation after cardiopulmonary bypass, NO
patients had preserved platelet counts and lower expression of
GPIb. Aggregation was no different between NO and control
groups.78 The acute effects of milrinone on platelet function
in  vivo were also not measurable by standard laboratory or
clinical tests.79
ANTITHROMBOTIC DRUG THERAPY
The glycoprotein IIbIIIa (GPIIbIIIa) receptor is responsible
for mediating platelet-platelet aggregation through fibrinogen
bridging. Drugs that inhibit this receptor in a reversible or an
irreversible manner are potent inhibitors of platelet aggrega-
tion and include abciximab (Reopro), eptifibatide (Integrilin),
and tirofiban (Aggrastat). They are frequently infused to pre-
vent thrombus formation in patients who have undergone a
high-risk coronary interventional procedure. Large-scale mul-
ticenter studies have shown that rethrombosis and infarction
rates after percutaneous angioplasty and after stent procedures
have been reduced with the use of these drugs.80 Reduced mor-
tality and reinfarction rates have been shown in such patient
groups as diabetics and those with prior cardiac surgery.81
Of the three intravenous GPIIbIIIa inhibitors, abciximab
is a large monoclonal antibody (mAb) that binds and causes
permanent dysfunction of the GPIIbIIIa receptor, while also
blocking other receptors because of its large size. Comparative
studies and one-to-one comparisons have shown that abcix-
imab is superior to the other agents in preventing isch-
emic complications, which explains its prevalence of use.82
 362 ANESTHESIA AND UNCOMMON DISEASES
However, its potent platelet-inhibiting properties also render
abciximab likely to cause increased episodes of major bleed-
ing. Patients who present for surgery after having received
abciximab often require a prolonged operative time to achieve
hemostasis and an increased incidence of platelet transfu-
sions.83 By contrast, the small-molecule agents eptifibatide
and tirofiban are competitive blockers whose small size and
half-life of approximately 2 hours make it possible to conduct
cardiac surgery without an increased risk of bleeding. Studies
have documented lower myocardial infarction rates84 and
similar bleeding rates in emergency coronary bypass patients
who received eptifibatide compared with those that received
placebo before surgery.85
Antiplatelet therapy has been rapidly advancing owing to
the introduction of the thienopyridine derivatives ticlopidine
and clopidogrel (Plavix, Sanofi). Clopidogrel has almost com-
pletely replaced ticlopidine for this use because clopidogrel
has a wider therapeutic index and a lesser side effect profile
and is more efficacious at doses used clinically. Clopidogrel
is a prodrug and requires metabolism by cytochrome P450
subtype 3A4 to form the active drug.86-88 These drugs act by
noncompetitive antagonism at one of the platelet adenosine
diphosphate (ADP) receptors, the P2Y12 receptor.89 There
are three known ADP receptor subtypes: the P2X receptor is
a calcium ion channel; the P2Y1 receptor is the major recep-
tor responsible for regulating calcium influx and subsequent
aggregation,90–92 and the P2Y12 receptor inhibits cyclic ade-
nosine monophosphate production and potentiates platelet
aggregation (Fig. 11-1).
The duration of antiplatelet activity is the life span of the
platelet because the P2Y12 receptor is permanently altered.
The effects of clopidogrel plus aspirin are additive and some-
times synergistic, depending on the model of platelet function
studied. This may explain why cardiac surgical patients hav-
ing received this combination of drugs seem to have excessive
postoperative bleeding.93 Patients taking these medications
at the time of cardiac surgery are at increased risk for bleed-
ing complications and have a documented increase in trans-
fusions and reoperations for bleeding.87,94–99 This increase
ADP
Blocked by
clopidogrel
P2X1 P2Y1 P2Y12
Gi
Gq
Shape
Inhibit adenyl
Ca change Ca
cyclase
Platelet aggregation Potentiate platelet
aggregation
FIGURE 11-1  Role of clopidogrel in antiplatelet therapy. ADP,
Adenosine diphosphate.
in transfusion is seen despite the careful implementation of
a transfusion algorithm97 or strict guidelines for transfusion
therapy.16,100
The logical solution to an increased occurrence of bleed-
ing would seem to be cessation of antithrombotic therapy in
preparation for an elective surgical procedure. However, anti-
thrombotic therapy is critical for at least 6 weeks when a bare
metal stent is in situ.101 After this period, it is believed that the
stent surface has sufficient surface of neo-endothelium and is
not thrombogenic.102 The minimum period during which anti-
thrombotic therapy is suggested in patients with drug-eluting
stents (DES) is less well defined. The current recommendation
for patients with a coronary DES provided by the 2007 ACC/
AHA guidelines is to avoid elective surgery and discontinua-
tion of antiplatelet agents for 12 months.103 The antiprolifera-
tive drugs embedded in these stents prolong the development
of new endothelium and thus require longer periods (per-
haps years) of antiplatelet medication.104 Retrospective and
case reporting suggests that cessation of antiplatelet therapy in
patients whose stent has not developed endothelium leads to
thrombosis and acute myocardial infarction.
Specific monitoring of the platelet defect induced by these
antithrombotic drugs would be advantageous for several rea-
sons. For therapeutic efficacy, the degree to which patients
are protected from thrombotic events is related to the degree
of platelet inhibition. Thus, platelet function monitoring can
be used for titrating drug effect. Alternatively, patients taking
these medications who present for surgery can be assayed for
their degree of platelet dysfunction and their risk of bleeding
and need for transfusion.
Impaired Coagulation
Hemophilia A is the most common form of hemophilia and
is inherited as an X-linked disorder. Patients with hemophilia
A have insufficient production of factor VIII and thus severe
impairments in intrinsic coagulation. This can be detected by
laboratory analysis by a prolonged partial thromboplastin time
(PTT). Clinically, the disease manifests as hematuria, hemar-
throses, and spontaneous hemorrhage when factor VIII levels
are less than 3% of normal. It is important to measure the factor
VIII level so that replacement therapy can be initiated before
surgery.105 The goal of replacement therapy is to achieve 100%
activity by transfusion of factor VIII concentrates. Assuming a
plasma volume of 40 mL/kg, and the need for 100% functional
factor VIII before surgery, the required number of units of fac-
tor VIII can be calculated. Plasma contains 1 unit of procoagu-
lant factor per milliliter; cryoprecipitate contains 5 to 10 U/mL,
and factor VIII concentrates contain up to 40 U/mL. Factor
VIII levels of greater than 30% are considered adequate for
hemostasis after major surgery. Replacement therapy is needed
twice daily in the perioperative period because the elimination
half-life of factor VIII is 10 to 12 hours. Some forms of hemo-
philia are not easily treated with replacement factors because
patients can have circulating inhibitors.

Hemophilia B is a disorder of the production of factor IX.
The inheritance pattern for hemophilia B is similar to that for
hemophilia A. The laboratory abnormalities are also similar
in that activated PTT is prolonged. Replacement of factor IX
is with specific procoagulant concentrates or complexes that
contain high concentrations of factor IX.
Other isolated factor deficiencies are rare. Specific peri-
operative treatment for these disorders includes preoperative
measurement of the deficient factor quantity. Replacement of
that factor with factor concentrates or a pooled plasma prod-
uct should bring factor levels to 100% before surgery. Even the
heat-treated factor concentrates that are manufactured carry a
small risk of viral transmission because they are derived from
human blood products.
Thrombotic Disorders
ANTITHROMBIN III DEFICIENCY
Antithrombin III (AT-III) deficiency can be inherited or
acquired. The inherited form is usually marked by extremely
low levels of this endogenous anticoagulant. It inhibits
thrombin, but antithrombin III also effectively inhibits fac-
tors XI, X, and IX. Heparin works as an anticoagulant by
enhancing the activity of AT-III by 1000-fold. Patients with
congenital AT-III deficiency present with venous thromboses
throughout life. They develop many complications because of
their hypercoagulable state and are unresponsive to heparin.
Patients “acquire” AT-III deficiency as a result of recent hepa-
rin administration. The continued dosing of heparin, usually
intravenously, causes consumption of AT. Thus, AT-III levels
can be low and its activity can also be impaired. When these
patients present for cardiac surgery, they often have reduced
dose-responsiveness to heparin.106 Treatment is replacement
of AT.107 Specific AT-III concentrates are often available.
If they are not, transfusion of plasma will replace AT-III.108
Each unit of plasma contains one unit of antithrombin III.
Measurement of preoperative levels and attempted replace-
ment to 100% before cardiac surgery is recommended in con-
genital AT-III deficiency. In the acquired form, it is unclear if
replacement therapy is actually indicated.109
Treatment. The treatment for patients with AT-III defi-
ciency is the administration of antithrombin III. Antithrombin
III is available in a plasma-derived solution or recombinant
formula. Fresh-frozen plasma also contains AT-III, but has a
higher degree of viral transmission than other replacement
options. Long-term treatment of patients with AT-III defi-
ciency is warfarin administration.
PROTEIN C AND S DEFICIENCY
Proteins C and S are anticoagulant proteases that form a feed-
back mechanism to the coagulation cascade so that clotting
does not occur unchecked. These two proteases are activated
by the presence of thrombin and fibrin. It was once thought
that protein C and S deficiencies were common in patients
with hypercoagulable disorders. Now it is accepted that many
Chapter 11  Hematologic Diseases 363
of the patients previously classified as “protein C deficient”
actually had the factor V Leiden mutation.
Treatment. The treatment following an acute thrombotic
event consists of heparin with transition to warfarin. It is con-
troversial whether lifetime anticoagulation with warfarin is
necessary, but the decision usually depends on the severity of
the initial thrombotic event.
FACTOR V LEIDEN MUTATION
Factor V Leiden mutation is now known to be a common,
familiar disorder in European and Western cultures. Once
thought to be an abnormality of activated protein C, the fac-
tor V Leiden mutation confers activated protein C resistance
by virtue of the factor V molecule, which is resistant. Factor
V Leiden mutations, which occur in 3% to 5% of the popula-
tion, yield a resistance to activated protein C, which impairs
the signaling for anticoagulation and fibrinolysis. Using a
clot-based assay, in  vitro analyses evaluating the response
to activated protein C in cardiac surgical patients indicate
that aprotinin induces a factor V Leiden–like defect in nor-
mal plasma. In  vitro analyses from factor V Leiden patients
suggest that aprotinin further exacerbates this defect in the
plasma. Corroborating clinical data demonstrate that patients
with factor V Leiden mutation have lesser amounts of medi-
astinal tube drainage and allogeneic transfusions.110 One case
report describes a patient with factor V Leiden mutation who
experienced thrombosis of coronary artery revascularization
grafts within 1 month of surgery, and other case series have
described aortic thromboses after aortic replacement.111
Treatment. Only patients who present with a thrombotic
event require anticoagulation. The use of lifetime warfarin is
reserved for the few patients with recurrent and severe throm-
botic events.
HEPARIN-INDUCED THROMBOCYTOPENIA
The syndrome known as heparin-induced thrombocytopenia
(HIT) develops in 5% to 28% of patients receiving heparin.
HIT is typically categorized into two subtypes. Type I is char-
acterized by a mild decrease in platelet count and is the result
of the proaggregatory effects of heparin on platelets. Type II is
considerably more severe, most often occurs after more than
5 days of heparin administration (average onset time, 9 days),
and is mediated by antibody binding to the complex formed
between heparin and platelet factor 4 (PF4).112,113 Associated
immune-mediated endothelial injury and complement acti-
vation cause platelets to adhere, aggregate, and form platelet
clots, or “white clots.” Among patients developing HIT type
II, the incidence of thrombotic complications approximates
20%, which in turn may carry a mortality rate as high as 40%.
Demonstration of heparin-induced proaggregation of plate-
lets confirms the diagnosis of HIT type II. This can be accom-
plished with a heparin-induced serotonin release assay or a
specific heparin-induced platelet activation assay. A highly
specific enzyme-linked immunosorbent assay (ELISA) for the
heparin/PF4 complex has been used to delineate the course
 364 ANESTHESIA AND UNCOMMON DISEASES
of IgG and IgM antibody responses in patients exposed to
unfractionated heparin during cardiac surgery.114
Few options exist for treating these patients.115 If the hepa-
rin can be discontinued for 90 days, often the antibody will
disappear and allow a brief period of heparinization for CPB
without complication.116 Some types of low-molecular-weight
heparin have been given in HIT, but reactivity of the partic-
ular heparin with the patient's platelets should be confirmed
in  vitro. Supplementing heparin administration with phar-
macologic platelet inhibition using prostacyclin, iloprost,
aspirin, or aspirin and dipyridamole has been reported with
favorable outcomes. Recently, the use of tirofiban with unfrac-
tionated heparin has been used in this clinical circumstance.
Plasmapheresis may be used to reduce antibody levels. The
use of heparin could be avoided altogether by anticoagulat-
ing with direct thrombin inhibitors such as argatroban, hiru-
din, or bivalirudin. These thrombin inhibitors have become
the standard of care in the management of the patient with
HIT type II.117–119
Treatment. The goal of treatment in patients with HIT is to
stop the immune response by the discontinuation of heparin
and treat thrombosis. The treatment of thrombosis is with the
use of direct thrombin inhibitors. In patients with HIT II the
discontinuation of heparin alone is not adequate in preventing
further thrombotic events.
Monitoring Platelet Function
PLATELET FUNCTION TESTS
Point-of-care (POC) platelet function testing is critical to have
an impact on acute medical management. The need for small
sample size, rapid turnaround, ease of use, and clinical appli-
cability make POC monitoring the “gold standard” in the peri-
operative setting. Platelet function monitors can be divided
into three basic and non–mutually exclusive categories: static
tests, dynamic tests (nonactivated), and tests of the platelet
response to an activating stimulus.
Static Tests. Static tests, such as measurement of
β-thromboglobulin, ADP release, or number of platelet recep-
tors on the surface, capture only a single point in time and do
not accurately reflect the dynamic environment encountered
after CPB. Static tests also do not reflect the platelet ability to
respond to an agonist.
Dynamic Tests. Dynamic tests, such as the bleeding time or
viscoelastic measures of clot formation, better reflect the con-
tribution of platelet function to overall clot formation because
the time-dependent nature of platelet-mediated hemostasis
are taken into account. However, dynamic tests are nonspe-
cific in nature because of the absence of a platelet-specific ago-
nist, but the tests can generally be modified to overcome this
limitation.
Thromboelastography (TEG) (Haemonetics, Braintree,
Mass) is a whole-blood test of viscoelastic blood clot forma-
tion used in many clinical scenarios to diagnose coagulation
abnormalities. Within 10 to 20 minutes, information is obtained
regarding the integrity of the coagulation cascade, platelet
function, platelet-fibrin interactions, and fibrinolysis. Whole
blood (360 μL) is placed into an oscillating cuvette. Movement
of a piston connected to a transducer and oscillograph and
immersed into the blood sample couples with the oscillating
cuvette as the blood clots. This generates a signature tracing
with parameters of reaction time (R value), coagulation time
(K value), α angle, maximum amplitude (MA), and amplitude
60 minutes after the maximal amplitude (A60). Respectively,
these parameters measure fibrin formation, fibrinogen turn-
over, speed of clot formation, platelet-fibrin interactions, and
fibrinolysis.
Recent modifications to the TEG have allowed for
improved monitoring capabilities. Use of recombinant human
tissue factor as an activator accelerates the rate of thrombin
formation and shortens the time required for development of
MA. Because MA primarily reflects clot strength and plate-
let function, this information can be obtained more quickly
with tissue factor enhancement (5–10 minutes). A TEG appli-
cation in the clinical arena is its use in monitoring fibrinolysis
and antiplatelet therapy using the GPIIbIIIa receptor block-
ers, aspirin, or clopidogrel. This has predominantly been done
using modifications to POC system and is being further devel-
oped. In vitro addition of a large dose of abciximab to the test
cuvette enhances the diagnostic ability of the test to discrimi-
nate between hypofibrinogenemia and platelet dysfunction as
a cause of decreased MA.120,121
PLATELET RESPONSE TO AGONIST STIMULUS
The newest group of platelet function tests includes POC
monitors specifically designed to measure agonist-induced
platelet-mediated hemostasis.
The platelet-activated clotting time, Hemostatus
(Medtronic, Parker, Colo), measures the activated clotting
time without platelet activator and compares this value to the
activated clotting time obtained when increasing concentra-
tions of a platelet-activating factor (PAF) are added. The per-
cent reduction of the activated clotting time resulting from
the addition of PAF is related to the ability of platelets to be
activated and to shorten clotting time.122 The test is performed
using a specific cartridge in a Heparin Management System
(HMS) (Medtronic) device, and the Hemostatus cartridge is
useful for monitoring platelet function during cardiac sur-
gery.123 Hemostatus is an ideal way to assess platelet respon-
siveness to specific agonists and was used in other tests with
other activators. This particular assay did not penetrate the
marketplace at the time of its release, however, and thus has
been discontinued.
The Platelet Function Analyzer, PFA-100 (Dade Behring,
Miami), is a monitor of platelet adhesive capacity that is valu-
able in its diagnostic abilities to identify drug-induced platelet
abnormalities, Bernard-Soulier syndrome, von Willebrand's
disease, and other acquired and congenital platelet defects.123,124
The test is conducted as a modified in  vitro bleeding time.
Whole blood is drawn through a chamber by vacuum and is

perfused across an aperture in a collagen membrane coated
with an agonist (epinephrine or ADP). Platelet adhesion and
formation of aggregates will seal the aperture, thus indicating
the “closure time” measured by the PFA-100. This test may be
useful in detecting pharmacologic platelet dysfunction before
cardiac surgery and has been used successfully to reduce
transfusions in a transfusion algorithm after cardiac surgery.125
Ultegra (Accumetrics, San Diego) has been renamed
VerifyNow and is a POC monitor designed specifically to
measure the platelet response to a thrombin receptor agonist
peptide (TRAP). In whole blood, it measures TRAP activa-
tion-induced platelet agglutination of fibrinogen-coated beads
using an optical detection system. Because of the importance
of the GPIIbIIIa receptor in mediating fibrinogen-platelet
interactions, the Ultegra assay has been especially useful in
accurately measuring receptor inhibition in invasive cardiol-
ogy patients receiving GPIIbIIIa-inhibiting drugs.126–128
The VerifyNow-P2Y12 test (Accumetrics) was designed to
measure the effective platelet inhibition by antithrombotic
drug therapy. It can be used to assess the effects of clopi-
dogrel on PGY12 receptor and to assess aspirin inhibition.
Clopidogrel acts by noncompetitive antagonism at one of the
platelet ADP receptors, the P2Y12 receptor. The VerifyNow sys-
tem uses ADP to stimulate platelets in the presence of prosta-
glandin E1 (PGE1). This addition of PGE1 to the assay inhibits
the ADP receptor P2Y1 and thus allows for a specific assess-
ment of clopidogrel's effect at the P2Y12 receptor. The test can
be applied to identify patients who are nonresponders to the
clopidogrel and at increased risk for thrombosis. In addition,
the timing of surgery can be best determined using the test to
determine individual patient response to clopidogrel.129
Plateletworks (Helena Laboratories, Beaumont, Texas) uses
the principle of the platelet count ratio to assess platelet reac-
tivity. The instrument is a Coulter counter that measures the
platelet count in a standard EDTA-containing tube. Platelet
count is also measured in tubes containing the platelet ago-
nists (e.g., ADP, collagen). Addition of blood to these agonist
tubes causes platelets to activate, adhere to the tube, and to
be effectively eliminated from the platelet count. The ratio of
the activated platelet count to the nonactivated platelet count
is a function of the reactivity of the platelets. Early investi-
gation in cardiac surgical patients indicates that this assay is
useful in providing a platelet count and that it is capable of
measuring the platelet dysfunction that accompanies CPB.129
Plateletworks has also been used to study the pharmacokinet-
ics and pharmacodynamics of clopidogrel in conjunction with
other drug therapy.87
PLATELET AGGREGOMETRY
Platelet aggregometry utilizes a photo-optical instrument to
measure light transmittance through a sample of platelet-rich
plasma. When exposed to a platelet agonist, the initial reversible
aggregation phase results in increased light transmittance due to
the platelet aggregates that decrease the turbidity of the sample.
Aggregometry is considered a gold standard of platelet function
measure.130 It is rather labor and time intensive, however, and
Chapter 11  Hematologic Diseases 365
is not practical for the immediate perioperative period. This is
the reason for the surge in the number of point-of-care platelet
function monitors being developed.
Whole-blood aggregometry is also used to assess platelet
function. Its accuracy does not approach that of platelet-rich
plasma aggregometry It is a highly sensitive and user-friendly
instrument, however, and can be very useful as a POC platelet
analyzer.
A recent application of whole-blood aggregation is in the
Multiplate platelet analyzer (DiaPharma, West Chester, Ohio).
The instrument has five channels, a computer, monitor, and
electronic pipette. Each test cell has two sensor units, each
consisting of two electrodes on which platelets aggregate in
response to agonist stimulation. Blood is collected into citrate-
containing tubes. Blood is pipetted into the test cell and stirred.
After addition of the agonist (arachidonic acid, TRAP, ADP, ris-
tocetin), the recording begins. The platelets adhere to the elec-
trodes, which changes the electrical resistance between the two
electrodes. Alternating current is used. The impedance change
between the electrodes is recorded as an area under the curve,
which is proportional to platelet function. The results reported
are the mean of the two test electrode pairs, in aggregation units
(AU). Use of the Multiplate analyzer has been shown to mea-
sure aspirin-induced platelet inhibition accurately,131 as well as
being predictive for excessive bleeding after cardiac surgery.130
CONCLUSION
Hematologic disorders can present with bleeding or throm-
bosis. Both are perioperative complications to be avoided,
and thus an understanding of the hematologic system is criti-
cal in maintaining homeostasis. It is important to appreciate
the many different functions, ranging from oxygen trans-
port and hemostasis to immunity and thermoregulation. The
hematologic diseases can be recognized perioperatively and
may be amenable to diagnosis and selective treatment by the
anesthesiologist.
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 C H A P T E R
12
Infectious Diseases and Biologic Weapons
PATRICK NELIGAN, MA, MD, FCAI  n

n Patients with multiorgan dysfunction syndrome (MODS)

Sepsis and Systemic Inflammatory Response Syndrome become confused, delirious, and ultimately stuporous and
Pathophysiology of Sepsis
comatose.
Multiorgan Dysfunction Syndrome
n The four main pillars in the management of the patient with
Treating the Patient with Septic Shock
severe sepsis are immediate resuscitation, empiric therapy,
Transmissible Infections source control, and prevention of further complications.
Hepatitis B
n Infection with HIV is the most feared of all occupation-
Hepatitis C
ally acquired diseases. Management of HIV-seropositive
Human Immunodeficiency Virus
pregnant women includes minimizing the infant's risk of
Tuberculosis
acquired infection. Patients with HIV are at particular risk
Prions
for biliary tract disease.
Intra-Abdominal Infections and Anesthesia n A patient with active tuberculosis represents major infec-
Pyogenic Liver Abscess
tion risk for other patients and health care workers.
Amebic Liver Abscess
n Intra-abdominal abscesses are walled-off collections of
Hydatid Disease
pus or parasites surrounded by fibrotic tissue, induced by
Splenic Abscess
inflammation.
Appendiceal Abscess
n Anesthesiologists are involved with necrotizing fasciitis
Diverticular Abscess
patients at initial presentation (fulminant sepsis) or during
Necrotizing Soft Tissue Infections subsequent OR visits (tissue debridement).
Necrotizing Fasciitis
n Soft tissue infections of the neck are of particular impor-
Clostridial Myonecrosis (Gas Gangrene)
tance to anesthesiologists because of possibly significant
Soft Tissue Infections of Head and Neck
airway obstruction.
Epiglottitis
n In epiglottitis patients, intubation should be performed
Infectious Agents as Biologic Weapons by the most skilled anesthesiologist, with a full airway
Anthrax
team, including otolaryngologist, and open tracheostomy
Smallpox
pack.
Tularemia
n In a terrorist biologic attack, the anesthesiologist is involved
Plague
with triage and resuscitation of injured patients and should
Biologic Toxins be familiar with potential bioweapons.
Sarin
n Anesthesiologists may be involved with the critical care
Ricin
management of the patient with inhalational anthrax, for
Botulinum
intubation and supportive care. There is no risk of person-
to-person transmission.
n With plague patients, the anesthesiologist should wear a
gown, mask, and eye protection because of the potential for
KEY POINTS contagion.
n Patients with severe sepsis are at particular risk for hepatic n In emergency care of patients with organophosphate poi-
and renal injuries. soning, the anesthesiologist usually secures the airway, ini-
n The major cardiovascular events in sepsis are vasoplegia, tiates mechanical ventilation, and transfers the patient to
reduced stroke volume, and microcirculatory failure. the ICU.
369
 370 ANESTHESIA AND UNCOMMON DISEASES
n Infection has killed more soldiers in war than gunfire.
Although the age of infectious diseases has all but passed in
the Western world, infection, and the means by which the
body deals with it, remains a major problem in critical care
and perioperative medicine.
A clear distinction must be made between infections, sep-
sis, infectiousness, and carrier states. Infection refers to the
host response to the presence of microorganisms or tis-
sue invasion by microorganisms. The microorganisms
may be bacteria, viruses, fungi, parasites, or prions. Sepsis
is a syndrome—the systemic inflammatory response to the
microorganism and associated toxins. Infectiousness or con-
tagiousness refers to the transmissibility of pathogens from
one host to another. A carrier state refers to the persistence
of a contagious organism within a host who may not demon-
strate signs of infection.
Each of these situations is of importance to anesthesiolo-
gists. For example, patients with fulminant surgical sepsis
(e.g., necrotizing pancreatitis or gas gangrene) may come to
the operating room (OR) for debridement and source con-
trol. Anesthesia management is significantly influenced by the
immunologic and hemodynamic impact of sepsis. Likewise,
patients with transmissible diseases (e.g., tuberculosis, HCV,
HIV) represent a significant risk to health care personnel,
who may contract the disease.1 The anthrax fatalities after
September 2001 refocused attention of previously eradicated
infectious organisms as potential weapons of terrorism.2
SEPSIS AND SYSTEMIC INFLAMMATORY
RESPONSE SYNDROME
Physicians managing intensive care units (ICUs) have long
used a variety of terms to describe illnesses associated with
infection or with infectious-appearing illnesses. These terms
included sepsis, septicemia, bacteremia, infection, septic
shock, and toxic shock. Unfortunately, there were no strict def-
initions for the terms used, which were often used incorrectly,
and emerging evidence indicated that systemic inflammation,
rather than infection, was responsible for multiple-organ fail-
ure. In the 1990s the American College of Chest Physicians
(ACCP) and Society for Critical Care Medicine (SCCM) rede-
fined inflammation and sepsis (Box 12-1).3
The host response to both infectious and noninfectious
injuries is similar4; the clinical signs are essentially the same.
This inflammatory response is determined, qualitatively and
quantitatively, by genetic and environmental factors.5 Thus,
the term “sepsis” had come to be used, incorrectly, to describe
the host response to a variety of infectious and noninfectious
injuries (Fig. 12-1). The term systemic inflammatory response
syndrome (SIRS) was introduced to describe the process of
inflammation without infection.3 This terminology is now
accepted, with some reservations.6,7
Infection is a microbial phenomenon characterized by
an inflammatory response to the presence of microorgan-
isms or the invasion of normally sterile host tissue by those
organisms.3 Sepsis is the presence of a systemic inflammatory
BOX 12-1   n SEPSIS AND ORGAN FAILURE: DEFINITIONS
AND THERAPEUTIC GUIDELINES
Infection
A host response to the presence of microorganisms or tissue
invasion by microorganisms.
Bacteremia
The presence of viable bacteria in circulating blood.
Systemic Inflammatory Response Syndrome (SIRS)
The systemic inflammatory response to a wide variety of severe
clinical insults, manifested by two or more of the following conditions:
Temperature >38° C or <36° C
Heart rate >90 beats/min
Respiratory rate >20 breaths/min or Paco2 <32 mm Hg
WBC count >12,000/mm,3 <4000/mm,3 or >10% immature (band)
forms
Sepsis
The systemic inflammatory response to infection. In association with
infection, manifestations of sepsis are the same as those previously
defined for SIRS. It should be determined whether they are a direct
systemic response to the presence of an infectious process and
represent an acute alteration from baseline in the absence of other
known causes for such abnormalities. The clinical manifestations
would include two or more of the following conditions as a result of a
documented infection:
Temperature >38° C or <36° C
Heart rate >90 beats/min
Respiratory rate >20 breaths/min or Paco2 <32 mm Hg
WBC count >12,000/mm,3 <4000/mm,3 or > 10% immature
(band) forms
Severe Sepsis/SIRS
Sepsis (SIRS) associated with organ dysfunction, hypoperfusion, or
hypotension. Hypoperfusion and perfusion abnormalities may include,
but are not limited to, lactic acidosis, oliguria, or an acute alteration
in mental status.
Refractory (Septic) Shock/SIRS Shock
A subset of severe sepsis (SIRS) and defined as sepsis (SIRS)–
induced hypotension despite adequate fluid resuscitation, along with
the presence of perfusion abnormalities that may include, but are not
limited to, lactic acidosis, oliguria, or an acute alteration in mental
status. Patients receiving inotropic or vasopressor agents may no
longer be hypotensive by the time they manifest hypoperfusion
abnormalities or organ dysfunction, yet they would still be considered
to have septic (SIRS) shock.
Multiple Organ (Multiorgan) Dysfunction Syndrome (MODS)
Presence of altered organ function in an acutely ill patient such that
homeostasis cannot be maintained without intervention.
From Bone RC, et al: Crit Care Med 20:864-874, 1992.
Paco2, Partial pressure (tension) of carbon dioxide in arterial blood; WBC,
white blood cell.
response to infection. A second consensus conference in 20015
addressed the ongoing problem with the vagueness of the defi-
nition of SIRS.8 The strengths and weaknesses of the current
sepsis definitions were reviewed. The definitions were left
unchanged with the exception of an expansion in the list of
signs and symptoms of sepsis to reflect the spectrum of man-
ifestations at the bedside. These definitions have significant
 Chapter 12  Infectious Diseases and Biologic Weapons 371

Microbes possess specific virulence factors to overcome

host defenses. The cell wall of gram-negative bacteria consists
Bacteremia of an inner phospholipid bilayer and an outer layer that con-
Other
tains lipopolysaccharide (LPS). This consists of polysaccharide
SIRS O, which protrudes from the exterior cell surface, a core poly-
Fungemia saccharide, and a lipid component (lipid A) that faces the cell
INFECTION
SEPSIS Trauma interior. Lipid A, or endotoxin, is responsible for the toxicity of
this molecule. It is released with cell lysis. In meningococce-
Parasitemia mia, plasma levels of endotoxin correlate well with the devel-
opment of multiorgan dysfunction syndrome (MODS).
Viremia Burns Gram-positive organisms, such as Staphylococcus, Strept­
ococcus, and Enterococcus species, actively secrete an exotoxin,
Other which consists of two polypeptide components: the first binds
Pancreatitis
the protein to the host cell, and the second has toxic effects.
Staphylococcus aureus produces four cytolytic exotoxins, the
FIGURE 12-1  Infection and sepsis. SIRS, Systemic inflammatory most important of which—α toxin—punctures holes in the
response syndrome. (From Bone RC, et al: Crit Care Med 20:864- membranes of cells, leading to osmotic lysis. In addition,
874, 1992.) S. aureus produces a number of superantigens that have an
affinity for T-cell receptor major histocompatibility complex
epidemiologic value: there is a clear increase in mortality as (MHC) class II antigen complexes. They activate a large num-
patients pass from SIRS, with progressive organ failure, to sep- ber of T cells, leading to massive release of cytokines and toxic
sis, to septic shock (Box 12-2).9,10 shock. Clostridium difficile produces two exotoxins: toxin A
and toxin B.
In addition to toxins, bacteria possess a variety of viru-
Pathophysiology of Sepsis lence factors that contribute to the establishment of infection.
The presence of pathogens in the bloodstream or tissues elic- For example, group A streptococci produce hyaluronidase
its an inflammatory response. There are five stages4: (1) estab- and various proteases and collagenases, which facilitate the
lishment of infection, (2) preliminary systemic inflammatory spread of the bacteria along tissue planes. Staphylococcus
response, (3) overwhelming systemic inflammatory response, ­epidermidis produces a biofilm that coats intravascu-
(4) compensatory anti-inflammatory response, and (5) immu- lar devices and endotracheal tubes, making elimination
nomodulatory failure. by antibiotics almost impossible. Coliform bacteria and

BOX 12-2   n  DIAGNOSTIC CRITERIA FOR SEPSIS*

General Coagulation abnormalities (INR >1.5 or aPTT >60 seconds)

Fever (core temperature >38.3°C) Ileus (absent bowel sounds)
Hypothermia (core temperature <36°C) Thrombocytopenia (platelet count <100,000/μL)
Heart rate >90 beats/min or >2 SD above normal value for age Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 mmol/L)
Tachypnea
Tissue Perfusion
Altered mental status
Hyperlactatemia (>1 mmol/L)
Significant edema or positive fluid balance (>20 mL/kg over 24 hours)
Decreased capillary refill or mottling
Hyperglycemia (plasma glucose >120 mg/dL or 7.7 mmol/L) in absence
of diabetes
From Levy MM, et al: Crit Care Med 31:1250-1256, 2003.
Inflammatory
Leukocytosis (WBC count >12,000/μL) Note: Diagnostic criteria for sepsis in the pediatric population are signs and
Leukopenia (WBC count <4000/μL) symptoms of inflammation plus infection with hyperthermia or hypothermia
Normal WBC count with >10% immature forms (rectal temperature >38.5° C or <35° C), tachycardia (may be absent in
Plasma C reactive protein >2 SD above the normal value hypothermic patients), and at least one of the following indications of altered
organ function: altered mental status, hypoxemia, increased serum lactate
Plasma procalcitonin >2 SD above the normal value
level, or bounding pulses.
Hemodynamic variables *Infection, documented or suspected, and defined as a pathologic process
Arterial hypotension† (SBP <90 mm Hg, MAP <70 mm Hg, or SBP induced by a microorganism, and some of the criteria listed.
decrease >40 mm Hg in adults or <2 SD below normal for age) †Sv o >70% is normal in children (normal, 75%-80%), and cardiac index of
2
Svo2 >70%† 3.5 to 5.5 L/min/m2 is normal in children; therefore, neither should be used
Cardiac index >3.5 L/min/m2 as a sign of sepsis in newborns or children.
SD, Standard deviation; WBC, white blood cell; SBP, systolic blood pressure;
Organ Dysfunction MAP, mean arterial pressure; Sv o2, mixed venous oxygen saturation;
Arterial hypoxemia (Pao2/Fio2 <300) Pao2, arterial oxygen partial pressure; Fio2, fraction of inspired oxygen
Acute oliguria (urine output <0.5 mL/kg/hr for at least 2 hr) concentration; INR, international normalized ratio; aPTT, activated partial
Creatinine increase >0.5 mg/dL thromboplastin time.
 372 ANESTHESIA AND UNCOMMON DISEASES
Predisposition Response
Genetics Physiologic
Chronic illness Specific mediators
Cultural attitudes Generic markers
PIRO
Insult Organ dysfunction
Shock, ARDS, renal
Infection
Endotoxin failure, etc.
Injury, ischemia
FIGURE 12-2  The PIRO model of sepsis and SIRS. ARDS,
Acute respiratory distress syndrome. (Modified from Levy MM
et al: Crit Care Med 31:1250-1256, 2003.)
Pseudomonas species have pili that allow the organism to
bind and anchor to the epithelium, potentially a mechanism
of bacterial translocation.
Fungal infections are common in the hospitalized popula-
tion. Commensal organisms, such as Candida spp., become
pathogenic as a result of host factors (e.g., immunosuppres-
sion, concomitant infection, diabetes) and iatrogenic factors
(e.g., multiple antibiotics, critical illness, parenteral nutrition,
abdominal surgery). The gastrointestinal (GI) tract appears to
be an important source of Candida; the mechanism of candi-
demia is unclear (Fig. 12-2).
THE INFLAMMATORY CASCADES
Tissue injury or pathogens (bacteria, viruses, fungi, or para-
sites) cause monocyte activation, which produces interleukin
(IL-1, IL-6), tumor necrosis factor alpha (TNF-α), plasmino-
gen activator inhibitor 1 (PAI-1), and interferon-γ (IFN-γ).11,12
These cytokines subsequently modulate the release and activa-
tion of a medley of different agents: interleukin-8 (IL-8), com-
plement, histamine, kinins, serotonin, selectins, eicosanoids,
and neutrophils. This leads to local vasodilation, release of
various cytotoxic chemicals, and destruction of the invading
pathogen. The release of cytotoxic material and proinflamma-
tory cytokines results in the systemic inflammatory response:
fever or hypothermia, tachypnea, tachycardia, and leukocyto-
sis or neutropenia.
A subgroup of patients has an abnormal (“malignant”)
inflammatory response: tissue destruction by neutrophils,
endothelial cell destruction, and massive systemic release of
mediators. The result is vasoplegia, capillary leak, and activa-
tion of clotting cascades.
Damage to the endothelium exposes a procoagulant fac-
tor known as tissue factor. Tissue factor exists in the suben-
dothelial space and has a reparative role after tissue damage.
In sepsis, there is massive exposure. Tissue factor binds to
activated factor VII. The resulting complex activates in turn
factors IX and X. Factor X converts prothrombin into throm-
bin, which cleaves fibrinogen into fibrin—a blood clot. At
the same time, the fibrinolytic system is inhibited. Cytokines
and thrombin stimulate the release of PAI-1 from platelets
and the endothelium. In the human body, when a clot forms, it is
ultimately broken down by plasmin, which is activated by tis-
sue plasminogen activator (t-PA) from plasminogen; PAI-1
inhibits t-PA.
Thrombin itself is an activator of inflammation and
inhibitor of fibrinolysis. The latter is achieved by the activa-
tion of thrombin-activatable fibrinolysis inhibitor (TAFI).
Thrombomodulin, another modulator of fibrinolysis, is
impaired by inflammation and endothelial injury. The func-
tion of this compound is to activate protein C. Activated pro-
tein C modifies the inflammatory and coagulant response at
several different levels; a deficiency results from inhibition of
thrombomodulin in sepsis.
HEMODYNAMIC DERANGEMENT IN SEPSIS
Three major cardiovascular events occur in sepsis, as follows:
1. Vasoplegia. Pathologic vasodilation results from loss of
normal sympathetic tone, caused by the combination of
local vasodilator metabolites. There is activation of ade-
nosine triphosphate–sensitive potassium channels, lead-
ing to hyperpolarization of smooth muscle cells.13,14 There
is increased production of inducible nitric oxide synthetase
(iNOS), which manufactures massive amounts of nitric
oxide. In addition, there is acute depletion of vasopressin.15
Vasoplegia leads to relative hypovolemia. Vascular tone is
characteristically resistant to catecholamine therapy but
very sensitive to vasopressin.
2. Reduced stroke volume. This results from the presence of a
circulating myocardial depressant factor, probably TNF-α.
There is reversible biventricular failure, a decreased ejec-
tion fraction, myocardial edema, and ischemia. Cardiac
output is maintained by a dramatic increase in heart rate.16
3. Microcirculatory failure.17 The small blood vessels vasodi-
late, and there is widespread capillary leak, maldistribution
of flow, arteriovenous shunting, and oxygen (O2) utilization
defects.18 These abnormalities are incompletely understood.
In addition, there is initial activation of the coagulation sys-
tem and deposition of intravascular clot, causing ischemia.
The relative hypovolemia of early sepsis is virtually indis-
tinguishable from hypovolemic or hemorrhagic shock. In
response to intravascular volume depletion (distributive or
hypovolemic shock), the precapillary arterioles and postcap-
illary venules vasoconstrict, increasing blood flow velocity,
which draws fluid in from the interstitium (a net influx of fluid
into the circulation). This is known as transcapillary refill.
Fluid effectively shifts from the extravascular to the intravas-
cular space. An O2 debt is incurred, and there may be lactic
acidosis. At this stage, patients are highly sensitive to volume
resuscitation.
Eventually, persistent release of cytokines leads to deple-
tion of reserve: there is hyperpolarization of vascular smooth
muscles, massive release of iNOS, vasopressin depletion,
and widespread increase in vascular permeability. The
result is vasoplegia and sequestration of intravascular fluid
into extracellular space. The patient has interstitial edema,
hemoconcentration, and increased blood viscosity. There is

50
45
40
35
30
Percent
25
20
15
10
5
0 In addition to lower mortality, this group had a significantly
No SIRS2 SIRS3 SIRS4 Sepsis Severe
SIRS sepsis
FIGURE 12-3  Mortality in SIRS/sepsis/septic shock. SIRS,
Systemic inflammatory response syndrome. (From Rangel-Frausto M,
et al: JAMA 273:117-125, 1995.)
parallel activation of clotting cascades, intravascular throm-
bosis, and bleeding. The capacity of mitochondria to extract
O2 is impaired, and multiorgan dysfunction results (Fig. 12-3).
Multiorgan Dysfunction Syndrome
The brain and kidneys are normally protected from swings
in blood pressure (BP) by autoregulation. In early sepsis the
autoregulation curve shifts rightward (because of an increase
in sympathetic tone). In late sepsis, vasoplegia occurs and
autoregulation fails, making these organs susceptible to the
swings that occur in systemic BP. In addition, “steal” phe-
nomena may occur (areas of ischemia may have their blood
“stolen” by areas with good perfusion). This is known as
vasomotor neuropathy. Acute tubular necrosis results from
cellular apoptosis, toxic injury (mechanism unclear, pos-
sibly cellular lysosomes and debris), hypotension, and
hypovolemia.19
Patients with multiorgan dysfunction syndrome (MODS)
become confused, delirious, and ultimately stuporous and
comatose as a result of a variety of insults: hypoperfusion
injury, septic encephalopathy, metabolic encephalopathy, and,
of course, drugs used for sedation.
Myocardial O2 supply is dependent on diastolic BP,
which falls following vasoplegia, and on intravascular vol-
ume depletion. This may lead to ischemia. There is revers-
ible biventricular dilation, decreased ejection fraction, and
decreased response to fluid resuscitation and catecholamine
stimulation. A circulating myocardial depressant substance
is responsible for this phenomenon. This substance has been
shown to represent low concentrations of TNF-α and IL-1β
acting in synergy on the myocardium through mechanisms
that include nitric oxide and cyclic guanosine monophos-
phate generation.
Chapter 12  Infectious Diseases and Biologic Weapons 373
In the lungs, ventilation/perfusion mismatches occur, ini-
tially from increased dead space (caused by hypotension and
fluid shifts) and subsequently from shunt.20 There is increased
extravascular lung water and widespread disruption of the
alveolar-capillary basement membrane, leading to acute
lung injury. Up to 70% of patients develop nosocomial pneu-
monia. Cytokines released as a result of ventilator-induced
lung injury may have adverse effects at distant organs.21 This
hypothesis was confirmed from data in the Acute Respiratory
Distress Syndrome (ARDS) Network trial supported by the
National Institutes of Health.22 Blood samples were obtained
from 204 of the first 234 patients for measurement of plasma
IL-6 concentration. Levels of this cytokine were significantly
higher in the “high stretch” (tidal volume, 10- 12 mL/kg) com-
pared with the “low stretch” (tidal volume, 5-6 mL/kg) group.
Septic
shock lower incidence of nonpulmonary organ injury (the lung ori-
gin theory of sepsis).
There is significant hepatic dysfunction in sepsis. Uncon­
trolled production of inflammatory cytokines by the Kupffer
cells (of the liver), primed by ischemia and stimulated by
endotoxin (derived from the gut), leads to cholestasis and
hyperbilirubinemia. There is decreased synthesis of albumin,
clotting factors, cytochrome P450, and biliary transporters.
Impaired ketogenesis, ureagenesis, and gluconeogenesis are
caused by decreased expression of genes encoding gluconeo-
genic, β-oxidative, and ureagenic enzymes.23 Gut mucosa is
usually protected from injury by autoregulation. Hypotension
and hypovolemia lead to superficial mucosal injury. This
results in atrophy and possible translocation of bacteria into
the portal circulation, stimulating liver macrophages, causing
cytokine release, and amplifying SIRS (the gut origin theory
of sepsis).24,25
Metabolic abnormalities in sepsis include hyperglyce-
mia caused by glycogenolysis, insulin resistance, and massive
release of catecholamines and lactic acidosis. A generalized
catabolic state leads to muscle breakdown, not unlike maras-
mus. The patient has relative hypothyroidism, hypopituita-
rism, and adrenal insufficiency.26,27
ACTIVATED PROTEIN C
Protein C is an important anticoagulant and anti-­
inflammatory protein. The main effect of activated protein
C (APC) is to reduce the production of thrombin, by inac-
tivating factors Va and VIII. Thrombin is proinflammatory,
procoagulant, and antifibrinolytic.28 In addition, protein C
inhibits the influence of tissue factor on the clotting system,
reduces the production of IL-1, IL-6, and TNF-α by mono-
cytes, and has profibrinolytic properties through the inacti-
vation of PAI-1.24 The Prowess trial suggested that exogenous
administration of APC to patients, in severe sepsis, may
improve outcome.29 However, the results of the single trial
have been controversial, and there is no survival benefit in
patients with severe sepsis and Apache II scores less than 25.
The major clinical drawback of treatment with APC is bleed-
ing, particularly in perioperative patients.
 374 ANESTHESIA AND UNCOMMON DISEASES

Treating the Patient with Septic Shock Early Phase

Behaves like hypovolemic shock
Patients with acute severe sepsis (e.g., necrotizing fasciitis or Absolute and relative hypovolemia
gas gangrene) are infrequently brought to the OR for emer- Increased oxygen extraction
gent source control. In this circumstance, the anesthesiolo- Lactic acidosis
gist will be required to both administer anesthesia, ensuring
amnesia, analgesia, and hypnosis, and resuscitate the patient.
Later Phase
A familiarity with modern resuscitation practices is thus Vasoplegia
important. The four main pillars in the management of Continued fluid sequestration
the patient with severe sepsis are immediate resuscitation, Mitochondrial dysfunction ( O2 extraction)
Multiorgan dysfunction
empiric therapy, source control, and prevention of further Neuroendocrine failure
complications (Fig. 12-4).
FIGURE 12-5  Two phases of sepsis resuscitation.
STAGE 1: IMMEDIATE RESUSCITATION
Immediate Stabilization (Airway and Breathing). crystalloid, to replete interstitial fluid debt. Subsequent efforts
The initial treatment priority in patients with severe sepsis is to are directed at maintenance of intravascular volume. If crys-
reverse life-threatening physiologic abnormalities. The airway talloid resuscitation is continued, there is significant extrava-
must be controlled and the patient oxygenated and ventilated. sation of fluid, and the patient becomes edematous.31,32 Many
This usually requires endotracheal intubation and initiation favor high-molecular-weight (“colloid”) compounds as a
of mechanical ventilation. Care must be taken when admin- means of minimizing resuscitation volume and for potential
istering anesthetic agents for gaining airway control. Propofol positive oncotic effects.31 Although the use of colloid is con-
usually causes dramatic hypotension, from peripheral vasodi- troversial,33,34 evidence supports its use in perioperative medi-
lation and vagotonia, and should be avoided. Etomidate and cine and critical illness as part of a goal-directed paradigm.35–39
ketamine are reasonable choices. Although frequently used The main limiting factors for colloids are availability (gelatins
in cardiac anesthesia for hemodynamic stability, opioids have and pentastarches are not available in the United States) and
significant antiadrenergic effects in sepsis and may cause dra- cost. Available colloids include blood products, hydroxyethyl
matic hypotension. Therapies directed at slowing heart rate starches, and albumin. Previous concerns regarding albumin
should be avoided, because tachycardia is the main compensa- safety are unfounded.40
tory mechanism in maintenance of cardiac output. The goal-directed approach to resuscitation involves the
After intubation, extreme care must be taken with institu- use of specific monitors to measure input (fluid loading), tis-
tion of positive-pressure ventilation. The increase in intratho- sue blood flow, and response (Fig. 12-6). Arterial and central
racic pressure will reduce venous return: aggressive “bagging” lines are placed, and goals for resuscitation are set: these
invariably leads to severe hypotension. include a central venous pressure (CVP) of 8 to 12 cm H2O; a
Re-establishing the Circulation mean arterial pressure (MAP) of more than 65 mm Hg; and, if
Volume Resuscitation. In early sepsis, hypotension is the appropriate device is placed, a mixed venous oxygen satu-
caused by relative hypovolemia, secondary to peripheral vaso- ration (S o2) of more than 70%; and stroke volume (SV)
dilation. Later, hypotension is caused by myocardial depres- between 0.7 and 1 mL/kg.
sion, vasoplegia, and absolute hypovolemia secondary to
capillary leak (Fig.  12-5). Regardless, the initial resuscitative
effort is to attempt to correct the absolute and relative hypo- Response
volemia by refilling the vascular tree. Volume resuscitation
should be early (in OR or emergency department), aggressive,
and goal directed.30 Input Flow
The choice of fluids early in resuscitation remains con-
troversial. Initial resuscitation should include isotonic CVP Objective: Laboratory:
PAOP MAP Base deficit
PADP UO Lactate
Mentation
Maintain oxygenation SV
Empiric therapy
Restore the circulation FVT
CO/Ci
SvO2
Source control
FIGURE 12-6  Goal-directed resuscitation. CVP, Central venous
pressure; PAOP, pulmonary artery opening “wedge” pressure;
PADP, pulmonary artery diastolic pressure; MAP, mean arterial
Prevent further complications
pressure; UO, urine output; SV, stroke volume; FVT, flow velocity
time; CO, cardiac output; Ci, cardiac index; Sv o2, mixed venous
FIGURE 12-4  Treating sepsis: the four pillars of therapy. oxygen saturation.
 Chapter 12  Infectious Diseases and Biologic Weapons 375

Supplemental oxygen/
Endotracheal intubation/IPPV

Central venous and arterial

catheter placement

Fluid load to
8 cm H2O 12 cm H2O
CVP Crystalloid of colloid

65 mm Hg Norepinephrine targeted

to65 mm Hg
MAP Vasoactive agents

65 mm Hg

70% Transfuse to
hemoglobin10 g/L
SvO2 RBC transfusion
70% Hb10 g/L
70% Dobutamine
No
Goals achieved

FIGURE 12-7  Goal-directed resuscitation using oximetric central venous pressure (CVP) catheter based on the Surviving
Sepsis Campaign. IPPV, Intermittent positive-pressure ventilation; MAP, mean arterial pressure; Sv o2, mixed venous oxygen saturation;
RBC, red blood cell.

Central Venous and Pulmonary Artery Catheters. The
Surviving Sepsis Campaign41 promotes the use of oximetric
CVP catheters to monitor input and flow (Fig. 12-7) based on
the work of Rivers et al.42 Fluid is administered until the CVP
reaches and stays in the target range: 8 to 12 cm H2O for the
majority of patients (Fig.  12-8). Once fluid loading has been
achieved, hypotension is managed with vasopressors (norepi-
nephrine or dopamine; see later) to a target MAP of 65 mm Hg. If
S o2 is less than 70%, with CVP and MAP in the target range,
blood is transfused until the hematocrit exceeds 30% (hemoglo-
bin [Hb] 10 g/L). If this fails to restore the S o2, an inotrope is
added, such as dobutamine or a phosphodiesterase inhibitor.
Stroke volume
A more elegant approach involves insertion of an oximetric
pulmonary artery catheter rather than a CVP line. In this par-
adigm, SV is used as the main end point of resuscitation, and
CVP or pulmonary artery pressure is used to determine the
presence of heart failure (Fig. 12-9); a Starling curve is con-
structed (Fig. 12-10). Fluid is administered to the patient until
SV is a sustained 0.7 to 1 mL/kg (Fig. 12-11).
Overfilled
Target range

Target range
Central venous pressure (cm H2O)

Fa

ed
ilin

fill I
g

r
de D
Un E
8 A
L
Pulmonary
edema

Filling pressure
(CVP, PCWP, LVEDP, PADP)
2 FIGURE 12-9  Using stroke volume to construct Starling
Bolus 1 Bolus 2 Bolus 3 curves. CVP, Central venous pressure; PCWP, pulmonary capillary
FIGURE 12-8  Goal-directed approach using central venous wedge pressure; LVEDP, left ventricular end-diastolic pressure;
pressure. PADP, pulmonary artery diastolic pressure.
 376 ANESTHESIA AND UNCOMMON DISEASES

Supplemental oxygen/
Endotracheal intubation/IPPV

Oximetric PAC and arterial

catheter placement
Fluid load to SV
0.7–1 mL/kg
Crystalloid of colloid
SV 0.7 mL/kg
0.7–1.5 mL/kg:
CVP SV hold fluids

Fluid load to CVP 16 cm H2O 1.5 mL/kg: hold

fluids and diurese
0.7 mL/kg
CVP16 SV0.7 mL/kg
65 mm Hg Norepinephrine targeted
to MAP65 mm Hg
MAP Vasoactive agents

Inotrope required
65 mm Hg

70%
Transfuse to hemoglobin10 g/L
Dobutamine SvO2 RBC transfusion

70% Hb10 g/L 70%

No
Goals achieved

FIGURE 12-10  Algorithm for goal-directed resuscitation. Using stroke volume as a measure of flow. IPPV, Intermittent positive-
pressure ventilation; PAC, pulmonary artery catheter; CVP, central venous pressure; SV, stroke volume; MAP, mean arterial pressure; Svo2,
mixed venous oxygen saturation; RBC, red blood cell.

Stroke Clinical
the body (brain, heart, splanchnic organs, kidneys). Currently,
CVP SVO2 norepinephrine is the agent of choice in the fluid-resuscitated
Volume Impression
patient.
Underfilled
8 cm H2O 55% 45 mL Underresuscitated Norepinephrine. Norepinephrine has pharmacologic
effects on both α1 and β1 adrenoceptors. In low-dosage
Filled
ranges, the beta effect is noticeable, with a mild increase in
12 cm H2O 70% 79 mL Resuscitated cardiac output. In most dosage ranges, vasoconstriction and
increased MAP are evident. Norepinephrine does not increase
heart rate. The main beneficial effect of norepinephrine is to
Overfilled
18 cm H2O 80% 110 mL Overresuscitated
increase organ perfusion by increasing vascular tone. Studies
comparing norepinephrine to dopamine favored the former
FIGURE 12-11  Goal-directed approach to determine
in terms of overall improvements in O2 delivery, organ per-
effectiveness of fluid resuscitation. In this situation, the goal fusion, and O2 consumption. Norepinephrine is more effec-
for stroke volume was 65 to 80 mL and for Svo2 it was 70. CVP, tive at fulfilling targeted end points than dopamine,43 is less
central venous pressure; Svo2, mixed venous oxygen saturation. metabolically active than epinephrine, and reduces serum lac-
tate levels. Norepinephrine significantly improves renal perfu-
Overresuscitation. An SV in excess of 1 mL/kg is indica- sion and splanchnic blood flow in sepsis,44,45 particularly when
tive of overresuscitation, and fluids are withheld until the SV combined with dobutamine.45
drifts back into normal range. If the SV exceeds 1.5 mL/kg,
Dopamine. Dopamine has predominantly β-adrenergic
serious consideration should be given to the administration
effects in low to moderate dose ranges (up to 10 MIC/kg/ min),
of diuretics.
although there is much interpatient variability. This effect
Vasopressor Therapy may result from its conversion to norepinephrine in the
Hypotension, unresponsive to fluid therapy, in patients with myocardium and its activation of adrenergic receptors. In
sepsis is an indication for vasopressor use (Table  12-1). The higher dose ranges, α-adrenoceptor activation increases
ideal pressor agent would restore BP while maintaining car- and causes vasoconstriction. Dopamine is thus a mixed ino-
diac output and preferentially perfuse the midline structures of trope and vasoconstrictor. At all dose ranges, it is a potent
 Chapter 12  Infectious Diseases and Biologic Weapons 377
TABLE 12-1  n  Pharmacologic Support of the Circulation in Sepsis
Agent a1 b1
Epinepthrine ++++ ++++
Norepinephrine ++++ ++++
Dopamine ++ ++
Phenylephrine ++ — —
chronotrope. Much controversy has surrounded other meta-
bolic functions of this agent. Dopamine is a potent diuretic;
it neither saves nor damages the kidneys.46 Dopamine has
complex neuroendocrine effects; it may interfere with thy-
roid47 and pituitary47 function and may have an immuno-
suppressive effect.48 Overall, there is no benefit to dopamine
administration over norepinephrine.
Dobutamine. Dobutamine is a potent β1 agonist, with pre-
dominant effects in the heart, where it increases myocardial
contractility and thus SV and cardiac output. Dobutamine is
associated with much less increase in heart rate than dopa-
mine. In sepsis, dobutamine, although a vasodilator, increases
O2 delivery and consumption. Dobutamine appears partic-
ularly effective at splanchnic resuscitation, increasing pHi
(gastric mucosal pH) and improving mucosal perfusion in
comparison with dopamine.49
Epinephrine. Epinephrine has potent β1-, β2-, and α1-
adrenergic activity, although the increase in MAP in sepsis is
mainly from an increase in cardiac output (SV). Epinephrine
has three major drawbacks: (1) it increases myocardial oxy-
gen demand; (2) it increases serum glucose lactate, which may
be caused by a worsening of perfusion to certain tissues or by
a calorigenic effect (increased release and anaerobic break-
down of glucose); and (3) it appears to have adverse effects on
splanchnic blood flow,50 redirecting blood peripherally as part
of the “fight or flight” response. The metabolic and hemody-
namic effects make epinephrine an unsuitable first-line agent
in sepsis.
Phenylephrine. Phenylephrine is an almost pure α1 agonist
with moderate potency. Although widely used in anesthesia to
treat iatrogenic hypotension, it is an ineffective agent in sep-
sis. Phenylephrine is a less effective vasoconstrictor than nor-
epinephrine or epinephrine. Compared with norepinephrine,
phenylephrine reduces splanchnic blood flow, O2 delivery, and
lactate uptake.51
Vasopressin. Vasopressin has emerged as an additive vaso-
constrictor in septic patients who have become resistant to cat-
echolamines.52 There appears to be a quantitative deficiency of
this hormone in sepsis,15,53–55 and administration in addition to
norepinephrine surprisingly increases splanchnic blood flow
and urine output. The most efficacious dose appears to be
0.04 unit/min,56 and this is not titrated. This relatively low
dose has little or no effect on normotensive patients.
b2 Heart Rate Organs Perfused
++++ ↑↑↑↑ Skin, muscle
++ ↑↑ Central organs
++++ ↑↑↑↑ Skin, muscle
— No real change
STAGE 2: EMPIRIC THERAPY—ANTIBIOTICS
The selection of specific antibiotics depends on the following:
1. The presumed site of infection (see Box 12-1)
2. Gram's stain results
3. Suspected or known organisms
4. Resistance patterns of the common hospital microbial
flora
5. Patient's immune status (especially neutropenia and immu-
nosuppressive drugs), allergies, renal dysfunction, and
hepatic dysfunction
6. Antibiotic availability, hospital resistance patterns, and
clinical patient variables to be treated
Suggested Antimicrobial Regimens
Sepsis Source Unknown. Combining either an antipseu-
domonal cephalosporin (ceftazidime) or an antipseudomonal
penicillin (piperacillin + tazobactam) (particularly if anaer-
obes are suspected) with either an aminoglycoside (gentami-
cin or amikacin) or a fluoroquinolone (ciprofloxacin) can be
done. If an antipseudomonal cephalosporin is used and anaer-
obes are a possible cause, the addition of metronidazole or
clindamycin should be considered.
n Piperacillin + tazobactam/imipenem + gentamicin/
ciprofloxacin
Catheter-Related Bloodstream Infection. There is a strong
possibility of infection with staphylococci, coagulase positive
or negative.
n Vancomycin should be added to, for example, piperacillin +
tazobactam.
Once the infecting organisms have been isolated, the
spectrum of antimicrobials should be narrowed; if methicillin-
resistant S. aureus (MRSA) is isolated, the piperacillin +
tazobactam should be discontinued.
n Vancomycin + piperacillin + tazobactam or ciprofloxacin
Community-Acquired Pneumonia. The most likely organ-
isms are pneumococci, Mycoplasma, and Legionella. The
patient requires coverage for both gram-positive and atypical
organisms (IV, intravenously; PO, orally).
n Cephalosporin IV + macrolide PO or fluoroquinolone
n Cefuroxime/ceftriaxone IV + azithromycin PO or
levofloxacin
 378 ANESTHESIA AND UNCOMMON DISEASES
Intra-Abdominal Sepsis. The most likely infecting organ-
isms are Enterobacteriaceae, enterococci, S. pneumoniae, and
anaerobes. Broad-spectrum treatment is required, without
cover for Pseudomonas.
n Penicillin + β-lactam inhibitor or ampicillin + aminoglyco-
side + antianaerobic agent
n Ampicillin + sulbactam or piperacillin + tazobactam or
ampicillin + gentamicin/aztreonam + metronidazole or
imipenem
Urosepsis. The most common organisms causing urinary
tract infections are Enterobacteriaceae and enterococci, and
the treatment is ciprofloxacin or ampicillin and gentamicin. In
this case, however, the patient has been admitted from a nurs-
ing home, and Pseudomonas is a strong possibility. Twin ther-
apy is often required, not mixing β-lactam antibiotics:
n Antipseudomonal quinolone or aminoglycoside + antipseu-
domonal penicillin or cephalosporin
n Ciprofloxacin/gentamicin/amikacin + piperacillin or ceftazidime
Cellulitis. The most likely organisms are streptococci and
staphylococci. If the infection is community acquired, cloxa-
cillin is adequate. Again, this patient was institutionalized, and
the infection must be treated as hospital acquired:
n Vancomycin + gentamicin
Necrotizing Fasciitis. Type 1 (see later) is caused by group
A streptococci, and type 2 is polymicrobial and caused by
streptococci, staphylococci, Bacteroides, and Clostridium.57
n Penicillin (high dose) or ciprofloxacin (if penicillin allergic) +
clindamycin
n Add ampicillin + sulbactam or piperacillin + tazobactam
Meningococcemia. Bacterial meningitis is meningococcal
septicemia until proved otherwise. The most likely alterna-
tive organisms are pneumococci, Haemophilus influenzae, and
rarely, Enterobacteriaceae and Listeria.
n Third-generation cephalosporin + vancomycin (if penicillin-
resistant S. pneumoniae suspected) + ampicillin (if Listeria
suspected)
n Cefotaxime + vancomycin
STAGE 3: SOURCE CONTROL
Source control is the essential curative measure in the man-
agement of sepsis and the associated inflammatory response.
Although there is a myriad of potential causes of sepsis,
beyond medical causes, such as pneumonia or meningitis,
source control can be neatly summarized by applying the
“four Ds” rule (Fig.  12-12)41: abscesses should be drained,
necrotic tissue should be debrided, infected devices removed,
and recurrent sources of infection/inflammation (e.g., cho-
lecystitis or diverticulitis) definitively controlled. This repre-
sents the major involvement of anesthesiologists within the
sepsis paradigm: patients travel to the OR for source control
under anesthesia.
Source Control–4 Ds
Intra-abdominal abscess
Drainage Thoracic empyema
Septic arthritis
Pyelonephritis, cholangitis
Necrotizing soft tissue
Debridement infections
Pancreatic necrosectomy
Mediastinitis
Infected intravascular device
Device removal Urinary catheter
Colonized endotracheal tube
Infected IUCD
Bowel resection
Definitive control
Cholecystectomy
FIGURE 12-12  The “four Ds” of source control.
IUCD, Intrauterine contraceptive device.
STAGE 4: PREVENTION OF FURTHER COMPLICATIONS
A significant aspect of the critical care management of sep-
tic patients is prevention of complications. This applies also
to their perioperative care. Many patients with acute severe
sepsis have a concomitant hypoxic lung injury (e.g., ARDS)
requiring intensive mechanical ventilatory support. This usu-
ally involves the application of high mean airway pressures to
prevent derecruitment of involved lung tissue. It is imperative
that lung volume be maintained perioperatively. If the patient
is requiring more than 10 cm H2O of positive end-expiratory
pressure (PEEP) or is on inverse-ratio pressure-controlled or
airway pressure–release ventilation, the following guidelines
should be followed58:
1. The OR mechanical ventilator must be of sufficient capac-
ity to maintain high mean airway pressure. Although some
modern ventilators have this capacity, the majority of “bag
in bottle” bellows are insufficient. When there is doubt,
the patient should be transferred to the OR with their ICU
ventilator.
2. Extreme care must be taken to avoid disconnection from
the ventilator; even short periods of disconnection (i.e., for
changing from ventilator to anesthesia machine) may result
in significant derecruitment of the lung and life-­threatening
hypoxemia.
3. The endotracheal tube should be clamped before discon-
nections to maintain lung recruitment.
4. If accidental disconnection should occur, sustained infla-
tion maneuvers should be performed to re-recruit the lung.
5. Critically ill patients are usually nursed in the semirecum-
bent position. Patients lie supine in the OR. This often
results in an increase in chest wall elastance, requiring
higher levels of PEEP to maintain lung volumes.
6. The standard of care in the management of patients with
ARDS is to limit end inspiratory lung volumes to a plateau
pressure of 30 cm H2O or less and tidal volume of 6 mL/kg
or less.31 This is to avoid “volutrauma,” a ventilator-associated
lung injury.
 Chapter 12  Infectious Diseases and Biologic Weapons 379
Care must be taken to maintain circulating volume and
blood flow to tissues. During surgical debridement of, for
example, necrotizing pancreatitis or fasciitis, handling of
inflamed or infected tissues usually leads to significant sys-
temic release of cytokines, worsening vasoplegia and increas-
ing myocardial depression. The anesthesiologist must be
careful to titrate vasopressors and bolus fluids in response to
rapidly changing hemodynamics.
Patients with severe sepsis are at significant risk of sec-
ondary organ injuries, particularly to the liver and kid-
neys. Medications that are renally metabolized or excreted
(e.g., pancuronium, morphine) should be used with cau-
tion. Aminoglycosides and glycopeptides (e.g., vancomycin)
must be administered with reference to pharmacokinetics.
Nonsteroidal anti-inflammatory drugs should be avoided
because NSAIDs may precipitate acute renal failure, worsen
coagulopathy, and induce upper GI bleeding in a vulnerable
population. Although hepatic metabolism is well preserved in
patients with liver dysfunction in sepsis, consideration should
be given to the use of agents metabolized independently of
the liver (e.g., cisatracurium rather than vecuronium or pan-
curonium; remifentanil rather than fentanyl or morphine).
The choice of anesthesia agents depends on several fac-
tors. Many patients are transported to the OR in an induced
coma (e.g., lorazepam or midazolam plus morphine or hydro-
morphone infusions), and minimal additional anesthesia is
required. In the awake patient being induced, care should be
taken as described previously. For maintenance of anesthesia,
sufficient agents must be administered to maintain hypno-
sis and amnesia. Frequently, this is not possible with volatile
agents because of peripheral vasodilation and hypotension.
Ketamine is a good alternative, particularly if accompanied by
an infusion of fentanyl or remifentanil, or hydromorphone.
Patients with acute severe sepsis are at high risk for peri-
operative bleeding as a result of sepsis-induced coagulopathy
and thrombocytopenia. Aggressive volume repletion with red
blood cells, thawed plasma, and platelets is recommended.
APC (drotrecogin alfa activated) significantly increases the
risk of bleeding and must be discontinued at least 2 hours
before surgical procedures and not restarted until at least
2 hours after surgery (Box 12-3).
TRANSMISSIBLE INFECTIONS
Hepatitis B
Hepatitis B virus (HBV) is a small, double-stranded (ds) DNA
hepadnavirus. HBV is spread by sexual intercourse, with a
high degree of infectivity, via secretions and blood products.
Health care workers are at particularly high risk of exposure
through handling of blood/tissue or needlestick injuries. The
outer core of the virus contains a surface antigen (HBsAg) that
elicits production of a neutralizing antibody (anti-HBs). In
addition, the body generates a separate antibody (anti-HBc)
against the viral core antigen (HBcAg). A third viral antigen—
the hepatitis B e antigen (HBeAg)—is also released from the
BOX 12-3   n PERIOPERATIVE CARE OF THE PATIENT
WITH ESTABLISHED SEVERE SEPSIS
Monitoring: Continuation of all monitoring procedures in ICU
Fluid administration: Goal directed, based on predetermined end points
Anesthesia agents: Determined by hemodynamic stability, whether
the patient will tolerate volatile agents, pre-existing infusions (e.g.,
lorazepam, morphine), and pharmacokinetics
Mechanical ventilation: Transport with ICU ventilator if PEEP >10 cm
H2O, inverse-ratio pressure-controlled or airway pressure–release
ventilation in use
Avoid ventilator disconnection (use clamp)
Accidental disconnection should be followed by recruitment maneuvers
Inhaled nitric oxide or prostacyclin should be continued
Vasopressors: Therapy should be continued; additional bags of
medication should be available to avoid catastrophic cessation
Corticosteroids (for adrenal insufficiency) should be continued
Nutrition: Gastric feeding should be discontinued 6 hours before
surgery; postpyloric feeding may be continued (at anesthesiologist's
discretion)
Total parenteral nutrition should be continued
Coagulation: All anticoagulants should be stopped before surgery
Activated protein C should be stopped 2 hours before surgery
Renal replacement therapy: Continuous therapy should be stopped
6 hours before surgery to allow autoreversal of heparin
Antimicrobials: Dosage based on predicted microbes, resistance
patterns of patient and hospital, renal function, and
pharmacokinetics
ICU, Intensive care unit; PEEP, positive end-expiratory pressure.
core. The presence of this antigen in the serum is indicative
of active viral replication. The presence of the antibody to
this particle (anti-HBe) is indicative of the end of active viral
replication.
One to 6 weeks after exposure, HBsAg appears in the
serum; its disappearance after 6 months indicates recovery
(Fig. 12-13). The presence of HBsAg for greater than 6 months
indicates chronic disease/carrier status (5%-10% of infec-
tions). Past exposure of immunization can be detected by
anti-HBs. In the majority of patients, anti-HBs does not rise to
detectable levels until several weeks after the disappearance of
the surface antigen and remains detectable for life. There may
be a window in which neither antibody nor antigen is detect-
able. Consequently, another test is required to ensure diagno-
sis. This is to detect the presence of immunoglobulin M (IgM)
antibody directed against the core antigen (IgM anti-HBc),
which is the earliest discernible anti–hepatitis B antibody. The
presence of HBeAg implies high infectivity; it is usually pres-
ent from 11⁄2 to 3 months after acute infection. The presence of
anti-HBc indicates past exposure (see Fig. 12-13).
After exposure, the incubation period is approximately
12 weeks, with resolution of symptoms after 30 to 60 days.
Symptoms include a prodrome of pyrexia, anorexia, myalgia,
urticaria, and nausea, followed by jaundice, hepatosplenomeg-
aly, and lymphadenopathy. There is an increase in serum bili-
rubin and hepatic transaminases. From 5% to 10% of patients
go on to develop chronic active hepatitis.
 380 ANESTHESIA AND UNCOMMON DISEASES
Acute Hepatitis B
Anti-HBc Anti-HBs
Jaundice IgM anti-HBc
Symptoms
HBeAg
HBV DNA (PCR)
HBsAg
0 1 2 3 4 5 6 12
Months after exposure
FIGURE 12-13  Serologic course of acute hepatitis B
virus (HBV) infection. PCR, Polymerase chain reaction. (From
Goldman L, Bennett JC, editors: Cecil textbook of medicine, ed 21,
Philadelphia, 2002, Saunders.)
ANESTHETIC CONSIDERATIONS
Patients with acute HBV infection who present for surgery
represent a unique risk for health care personnel, particularly
anesthesiologists. Universal precautions should be taken when
dealing with tissues or body fluids (Box 12-4). Following needle-
stick injury, the risk of developing clinical hepatitis B or sero-
logic conversion, in a worker who is not immune, if the blood
BOX 12-4   n  UNIVERSAL PRECAUTIONS
1. Use barrier protection at all times to prevent skin and mucous
membrane contamination with blood, body fluids containing visible
blood, or other body fluids (cerebrospinal, synovial, pleural, peritoneal,
pericardial, and amniotic fluids, semen and vaginal secretions).
a. Barrier protection should be used with all tissues.
b. The type of barrier protection used should be appropriate for
the type of procedures being performed and the type of expo-
sure anticipated. Examples of barrier protection include dispos-
able laboratory coats, gloves, and eye/face protection.
2. Wear gloves when the potential exists for hand or skin contact
with blood, other potentially infectious material, or items and
surfaces contaminated with these materials.
3. Wear face protection (face shield) during procedures that are
likely to generate droplets of blood or body fluid to prevent
exposure to mucous membranes of the mouth, nose, and eyes.
4. Wear protective body clothing (disposable laboratory coats) when
there is a potential for splashing of blood or body fluids.
5. Wash hands or other skin surfaces thoroughly and immediately if
contaminated with blood, body fluids containing visible blood, or
other body fluids to which universal precautions apply.
6. Wash hands immediately after gloves are removed.
7. Avoid accidental injuries caused by needles, scalpel blades, and
laboratory instruments when performing procedures, cleaning
instruments, handling sharp instruments, and disposing of used
equipment (e.g., needles, pipettes).
8. Used needles, disposable syringes, scalpel blades, pipettes, and
other “sharps” are placed in puncture-resistant containers marked
with a biohazard symbol for disposal.
is positive for both HBsAg and HBeAg, is approximately 25%
and 50%, respectively. If the blood is HBsAg positive and HBeAg
negative, however, the respective risks are only 3% and 30%.
Health care workers who have antibodies to HBV either
from pre-exposure vaccination or prior infection are not at
risk. In addition, if a susceptible worker is exposed to HBV,
postexposure prophylaxis with hepatitis B immune globulin
and initiation of hepatitis B vaccine is more than 90% effective
in preventing HBV infection (Table 12-2).
Hepatitis C
Hepatitis C is the most common chronic blood-borne viral
infection in the United States. It affects 300 million people
worldwide, including 4 million Americans. Hepatitis C virus
(HCV), a single-strand (ss) RNA, was first identified in 1989.
HCV infection is primarily spread by parenteral adminis-
tration of blood, blood products, and needle sharing among
intravenous (IV) drug users. The incubation period for HCV
is 6 to 10 weeks. The majority of patients remain asymptom-
atic. From 50% to 70% of HCV-infected patients develop
chronic hepatitis C, of which 50% will develop cirrhosis over
20 to 30 years. Hepatitis C is a leading cause of hepatic fail-
ure in the United States. About 40% of patients who undergo
hepatic transplantation have hepatitis C.
The nosocomial risk of hepatitis C seroconversion after a
single incident of a needlestick in the health care setting is esti-
mated to be in the 2% to 8% range. Needlestick injury with hol-
low needles is associated with a 6- to 10-fold greater likelihood
of transmission than when it occurs from contaminated solid-
bore needles. There is no vaccine or effective immunoglobulin
for these patients. Seroconversion is confirmed by the detection
of HCV RNA in the serum. Treatment is targeted at a sustained
virologic response using interferon alfa and ribavirin. This results
in normalization of serum transaminase levels in 50% of patients.
ANESTHETIC CONSIDERATIONS
The anesthesiologist and OR staff are particularly vulnerable
to acquiring hepatitis C by way of needlestick injury or from
­contaminated blood or tissues. Patients with a known history
of hepatitis B or C or high-risk patients (e.g., IV drug abusers)
should be managed with strict barrier precautions (see Box 12-4).
­High-quality gloves (or two pairs of gloves) should be worn.
Hands must be rigorously washed after gloves are removed,
and contaminated gloves should be disposed of rapidly. Barrier
protection of the eyes and mouth is imperative. Contaminated
needles should not be recapped, manipulated with both hands,
or manually removed from a syringe. They should be dis-
posed of, alongside contaminated sutures and other sharps, in
a solid, ­carefully marked container adjacent to the operative site.
Human Immunodeficiency Virus
About 40 million people (range, 34-46 million) were living
with human immunodeficiency virus (HIV) infection and
acquired immunodeficiency syndrome (AIDS) at the end of
 Chapter 12  Infectious Diseases and Biologic Weapons 381

TABLE 12-2  n  Recommended Postexposure Prophylaxis for HBV Infection

TREATMENT

Vaccination and Antibody

Response Status of Exposed Source HBsAg Source Unknown or Not Available
Workers* Source HBsAg† Positive Negative for Testing

Unvaccinated HBIG‡ × 1 and initiate HB vaccine Initiate HB Initiate HB vaccine series

series§ vaccine series

Previously vaccinated known No treatment No treatment No treatment

responder||

Known nonresponder¶ HBIG × 1 and initiate revaccination or No treatment If known high risk source, treat as if
HBIG × 2** source were HBsAg positive

Antibody response unknown
Test exposed person for anti-HBs††
1. If adequate,|| no treatment is
necessary.
2. If inadequate,¶ administer HBIG × 1
and vaccine booster.
No treatment Test exposed person for anti-HBs
1. If adequate,|| no treatment is
necessary.
2. If inadequate,¶ administer
vaccine booster and recheck titer
in 1-2 months.

Data from Updated U.S. Public Health Service Guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for
postexposure prophylaxis, MMWR 50(RR-11):22, 2001.
*Persons who have previously been infected with hepatitis B virus (HBV) are immune to reinfection and do not require postexposure prophylaxis.
†Hepatitis B surface antigen.
‡Hepatitis B immune globulin; dose is 0.06 mL/kg intramuscularly.
§Hepatitis B vaccine.
||A responder is a person with adequate levels of serum antibody to HBsAg (i.e., anti-HBs ≥10 mIU/mL).
¶A nonresponder is a person with inadequate response to vaccination (i.e., serum anti-HBs <10 mIU/mL).
**The option of giving one dose of HBIG and reinitiating the vaccine series is preferred for nonresponders who have not completed a second three-dose vaccine
series. For persons who previously completed a second vaccine series but failed to respond, two doses of HBIG is preferred.
††Antibody to HBsAg.

2003, with 5 million new cases that year. An estimated 20%
to 25% of HIV-positive patients will require surgery during
their illness.59
After entering the cell, HIV type 1, an ssRNA retrovirus, is
copied by a reverse transcriptase (RT), enabling the virus to
produce dsDNA, which then integrates into the host's cells.
The most common mode of infection is sexual transmis-
sion through the genital mucosa. HIV may also be spread by
transfusion of contaminated blood or by needle sharing or
needlestick injury. Within 2 days the virus can be detected
in the internal iliac lymph nodes, and within 5 days (range,
4-11 days) the virus can be cultured from the plasma. There
is rapid dissemination to lymphoid tissue and the brain. The
CD4+ T lymphocytes (T-helper cells) are the primary target of
infection. Progression of HIV illness is defined by the decline
in CD4+ cell count leading to immune deficiency and mani-
fest by opportunistic infections and unusual neoplasia. Thus,
progression is followed by monitoring the cell count per cubic
millimeter.
Plasma viral load (which can be quantified) is initially
extremely high and then declines in the clinical latency period.
This early acute infection, the seroconversion illness, is tran-
sient; symptoms include fever, fatigue, rash, headache, lymph-
adenopathy, pharyngitis, myalgia or arthralgia, and nausea,
vomiting, and diarrhea. This may be confused with a flulike
illness. The clinical latency period may last 7 to 12 years, dur-
ing which billions of virions and CD4+ cells are destroyed
each day. The T lymphocytes are replenished, and immune
status remains functional.
Before the development of “full-blown AIDS,” the patient
enters a stage of persistent generalized lymphadenopathy. In
this stage, nodes greater than 1 cm in more than two nonin-
guinal sites are present for more than 3 months. The patient
may lose weight and develop seborrheic dermatitis. AIDS is
diagnosed by a CD4+ count of less than 200 cells/μL or the
presence of one or more defining illnesses (Box  12-5). The
patient is at significant risk for opportunistic infections and
malignancies, including toxoplasmosis, cryptococcal menin-
gitis, progressive multifocal leukoencephalopathy, cytomega-
lovirus (CMV) infection, herpes simplex virus infection, brain
lymphomas, and tuberculosis. HIV is thus a multisystem dis-
ease (Box 12-6).
With the development of constitutional symptoms (physi-
ologic reserve is depleted), viral load again increases, and the
patient becomes extremely infectious. This has significant
implications for health care providers.
ANESTHETIC CONSIDERATIONS
Perioperative risk correlates well with immune function. A
CD4+ cell count of less than 200 cells/μL puts the patient at
significant risk for opportunistic infections and increased
infectious risk associated with surgery.60 The presence of
­pulmonary, cardiac, or renal disease may also lead to periop-
erative complications. Consequently, the patient with AIDS
 382 ANESTHESIA AND UNCOMMON DISEASES

BOX 12-5   n  AIDS-DEFINING ILLNESSES BOX 12-6   n COMPLICATIONS OF HIV MULTIORGAN

DISEASE
Candidiasis of bronchi, trachea, lungs, or esophagus
Invasive cervical cancer Respiratory
Coccidioidomycosis, disseminated or extrapulmonary Pneumocystis jiroveci (formerly P. carinii)
Cryptococcosis, extrapulmonary Bacterial pneumonia
Cryptosporidiosis, chronic intestinal (>1 month) Tuberculosis
Cytomegalovirus disease (other than liver, spleen, or nodes) Aspergillosis
Cytomegalovirus retinitis (with loss of vision) Cytomegalovirus
Encephalopathy, HIV related Oropharyngeal candidiasis, herpetic infections
Herpes simplex: chronic ulcer(s) (>1 month); or bronchitis, pneumonitis,
Hematologic
or esophagitis
Leukopenia, lymphopenia
Histoplasmosis, disseminated or extrapulmonary
Thrombocytopenia
Isosporiasis, chronic intestinal (>1 month)
Anemia
Kaposi's sarcoma
Drug toxicity, bone marrow suppression
Lymphoma, Burkitt's (or equivalent term)
Lymphoma, immunoblastic (or equivalent term) Cardiac
Lymphoma, primary, of brain Pericarditis effusion
Mycobacterium avium-intracellulare complex or Mycobacterium Pericarditis
kansasii, disseminated or extrapulmonary Myocarditis (late stages of infection)
Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary) Dilated cardiomyopathy
Mycobacterium, other species or unidentified species, disseminated Endocarditis (intravenous drug use)
or extrapulmonary Pulmonary hypertension
Pneumocystis jiroveci (P. carinii) pneumonia Drug-related cardiotoxicity
Pneumonia, recurrent Thromboembolitic events
Progressive multifocal leukoencephalopathy Myocardial infarction
Salmonella septicemia, recurrent
Gastrointestinal
Toxoplasmosis of brain
Infectious diarrhea, proctitis
Gastrointestinal bleeding
Acalculous cholecystitis
requires significant preoperative workup. This should include Vomiting, loss of appetite, cachexia
complete blood cell count, a coagulation panel, and liver and Dysphagia (Candida albicans, cytomegalovirus), esophagitis
Liver disease, hepatitis B and C, other infections
renal function tests. The patient should have an electrocar-
diogram and chest radiograph, regardless of age and gender. Neurologic Problems in AIDS Patients
Distal, symmetric sensory neuropathy: numbness, tingling, painful
If there is a history of pulmonary disease, and the patient is
dysesthesias and paresthesias
undergoing major surgery, pulmonary function testing is Chronic, inflammatory demyelinating polyneuropathy
necessary. AIDS encephalopathy or AIDS dementia complex: cognitive, motor,
There are numerous airway complications of HIV/AIDS: and behavioral changes
oral candidiasis, herpes simplex ulcers (risk of transmission Vacuolar myelopathy: sensory disturbance, spasticity and
hyperreflexia (acute or chronic progression)
to the laryngoscopist), and hemorrhagic Kaposi's sarcoma
Segmental (focal) myelopathy, acute or subacute (less common)
lesions. Lung parenchyma may be damaged by Pneumocystis,
histoplasmosis, CMV, or tuberculosis, with significant impact Data from Hughes SC: Anesthesiol Clin North Am 22:379-404, 2004.
on gas exchange. This may lead to a higher Fio2 requirement
intraoperatively, and prolonged postoperative mechanical
ventilation.
The cardiovascular system may be affected by autonomic A variety of opportunistic infections of the GI tract mani-
neuropathy (inadequate heart rate response to vasodilatory fest in HIV/AIDS. Chronic diarrhea is common and associated
effects of anesthetic agents), cardiomyopathy, and myocardial with hypokalemia and volume depletion. Colonic perforation
lymphoma. If cardiac involvement is suspected, the patient has been associated with cytomegalic colitis. Lymphoma has
should have preoperative echocardiography to determine been associated with bowel obstruction, increasing the risk
both systolic and diastolic function. The presence of signif- of aspiration pneumonitis. Patients with HIV/AIDS have a
icant cardiac dysfunction is an indication for invasive peri- predisposition for anemia, as a consequence of bone marrow
operative monitoring. Neurologic problems associated with suppression, associated with chronic disease, malnutrition
HIV/AIDS include delirium, headache, localized or general- (GI involvement impairs iron, vitamin B12, and folate absorp-
ized seizures, limb weakness, and visual loss. It is important tion), and drug therapy (zidovudine).
to document, preoperatively, the presence or absence of focal Past medical/social history is of particular importance in
neurologic deficit to avoid confusion with complications of this patient population. Substance abuse, and IV drug abuse
anesthesia and surgery. The presence of AIDS-related demen- in particular, remains the most significant risk factor. The
tia may preclude the patient consenting to both surgery and concurrent presence of sexually transmitted diseases such
anesthesia.61 as hepatitis B, hepatitis C (severe hepatic involvement), and
 Chapter 12  Infectious Diseases and Biologic Weapons 383

Abdominal Surgery. Patients with HIV may develop

TABLE 12-3  n Antiretroviral Drug Therapy: Side Effects
with Anesthetic Significance
abdominal pain for a variety of reasons, rarely requiring
­laparotomy. Surgery may be required for resection of neo-
Side Effects Responsible Antiretroviral Drug plasm, particularly if there is bowel obstruction, drainage of
intra-abdominal abscess, and appendectomy. The presence of
Neutropenia Ganciclovir immunodeficiency may mask the signs (leukocytosis) of infection,
Trimethoprim/sulfamethoxazole
leading to delayed diagnosis.65 Moreover, these patients may
Thrombocytopenia Isoniazid mount a less dramatic SIRS response than expected, leading to
Phenytoin dramatic development of severe sepsis without warning. Low
Rifampin
CD4+ count independently predicts an increased incidence of
Zidovudine
postoperative sepsis.60
Electrolyte disturbances Protease inhibitors Patients with HIV are at particular risk for biliary tract dis-
Pentamidine ease: cholecystitis, cholangitis, and infections with opportunis-
Hepatic dysfunction Ethambutol tic organisms such as Salmonella, CMV, and Cryptosporidium.
Phenytoin Risk of extrahepatic biliary obstruction is increased by exter-
Peripheral neuropathy Didanosine
nal compression of the common bile duct by enlarged portal
Lamivudine lymph nodes (or lymphoma).66 Laparoscopic cholecystectomy
Stavudine or choledochojejunostomy may be required.
Zalcitabine Patients infected with HIV, or with AIDS, frequently
Bronchospasm Pentamidine require anorectal surgery for excision of extensive condy-
lomata, anal fistulas, or perirectal abscesses. The patient is
Cardiac dysrhythmias Pentamidine positioned in the prone-jackknife position. General or spinal
Data from Kuczkowski KM: J Clin Anesth 15:224-233, 2003. anesthesia (assuming the patient does not have a coagulopa-
thy) can be safely administered, as with patients who are not
infected. Postoperative wound healing in patients with HIV,
syphilis (neurologic deficits in late stage) may alter anesthetic
but not AIDS, is not impaired.67
management.62
The current standard therapy for HIV/AIDS is highly active Neurosurgery. Intracranial pyogenic abscess, toxoplasmo-
antiretroviral therapy (HAART), which involves combination sis, or lymphoma may cause neurologic symptoms in HIV-
chemotherapy. These drugs fall into four categories: nucleo- infected patients. Infrequently, stereotactic needle biopsy is
side analog reverse transcriptase inhibitors, nonnucleoside required for diagnosis. The procedure is usually carried out
analog reverse transcriptase inhibitors, protease inhibitors, under monitored anesthesia care, for example with a remifen-
and the new category of fusion inhibitors (Table 12-3). From tanil-propofol infusion and spontaneous ventilation.
the anesthesiologist's perspective, protease inhibitors are the
Thoracic Surgery. The HIV-infected patient will occa-
most important agents. These potent CYP450 inhibitors pro-
sionally require open-lung biopsy to clarify the diagnosis in
long duration of action of hepatically metabolized drugs, such
the event of respiratory failure. Opportunistic infections can
as fentanyl, midazolam, and morphine. Judicious dosing and
usually be diagnosed by sputum examination or bronchoal-
careful titration are recommended.
veolar lavage. However, the identification, classification, and
The anesthesia care plan should take into account immu-
staging of lymphoma may require surgery. Additional risk of
nosuppression, systemic disease, and the risk of HIV transmis-
recurrent pneumothorax and empyema can be managed by
sion to health care providers. There is no evidence of increased
video-assisted thoracoscopic surgery (VATS). It is important
anesthesia risk in this patient population or of increased com-
to assess and clarify the extent of the respiratory insult and the
plications associated with regional anesthesia.63,64
degree of hypoxemia in these patients before surgery. Careful
Surgery attention must be placed in the ventilation strategy in the pres-
Splenectomy. Patients with HIV may develop a variant of ence of hypoxemic respiratory failure. The patient with signif-
thrombocytopenia purpura (ITP) known as HIV-associated icant parenchymal lung disease may be intolerant of one-lung
immune ITP. This characteristically does not respond to corti- anesthesia.
costeroid therapy and may occur with HIV infection or AIDS.
The treatment of choice is combination retroviral therapy; in Pregnancy
refractory cases, however, splenectomy is required.64 The anes- Management of HIV-seropositive pregnant women includes
thesiologist must be aware that the patient is at significantly attempts to minimize the infant's risk of acquired infection.
increased risk of bleeding, and that the platelet count cannot Perinatal HIV transmission occurs antepartum, intrapartum,
be raised by administration of corticosteroids or platelet trans- or postpartum. High maternal viral load increases the likeli-
fusion. Consequently, epidural anesthesia should be avoided, hood of perinatal transmission of HIV. Most perinatal HIV
as should the placement of large-bore IV catheters in noncom- transmissions occur during labor and vaginal delivery. Thus,
pressible vessels. obstetric care is targeted at minimizing exposure to maternal
 384 ANESTHESIA AND UNCOMMON DISEASES
TABLE 12-4  n Elective Cesarean Delivery to Reduce
HIV Transmission: Rates of Vertical
Transmission
Elective Cesarean Other Mode
Delivery of Delivery
No antiretroviral 10.4% 19.0%
therapy
Antiretroviral 2.0% 7.3%
therapy
Data from International Perinatal HIV Group: N Engl J Med 340:977-987, 1999.
blood and genital secretions. This involves avoiding percuta-
neous umbilical cord sampling, fetal scalp clips (when pos-
sible), fetal scalp sampling, delivery techniques that could
produce abrasions in the infant's skin (e.g., vacuum or for-
ceps), and immediate removal of maternal blood and fluids
from the infant.59 There is a relationship between the mode
of delivery and risk of transmission: the risk is significantly
reduced by elective cesarean section68,69 (Table  12-4). This
benefit may be lost if spontaneous rupture of the membranes
has occurred. HIV may be transmitted through breast milk so
breast feeding is discouraged.
Elective cesarean section should be performed under spinal
anesthesia, as in noninfected parturients.61,63
RISK TO ANESTHESIOLOGIST
Infection with HIV is the most feared of all occupa-
tionally acquired diseases. It is important to note that
patients with HIV/AIDS represent a reservoir of poten-
tial infectious exposures, in addition to the virus itself.
The most important of these is tuberculosis. The patient
may also be simultaneously infected with hepatitis B or
C, or both.
Universal precautions should be employed when handling
body fluids, tissue, blood, and blood products (see Box 12-4).
The anesthesiologist must wear gloves at all times when in
contact with the patient, the patient's blood, or tissues.70
Where there is significant risk of exposure to the patient's
body ­fluids—inserting arterial or central lines, performing
bronchoscopy or fiberoptic intubation, or using epidural, spi-
nal or regional anesthetic—a gown and face mask with eye
protection is recommended. Contaminated needles should
not be recapped by hand.
The risk of HIV transmission from a needlestick injury
with HIV-infected blood is approximately 0.32%, a much
lower risk than with hepatitis C.70 Immediately after
needlestick injury, the health care worker should be treated
with antiretroviral drugs (within 1 hour); this can reduce
the rate of seroconversion by 80%.1 Factors determining
the risk to the exposed health care provider include type of
procedure using needle, depth of needlestick injury, quan-
tity of blood involved, and viral titers in the HIV-infected
patient.61
Tuberculosis
Tuberculosis (TB) remains a major worldwide scourge.
Approximately one third of the world's population has been
exposed, and there are about 8 million new cases per year and
4 million deaths. Nevertheless, until the AIDS epidemic, the
prevalence of TB declined dramatically from the 1950s to the
1980s. There was a 20% increase in the incidence of TB in
the United States between 1985 and 1992, principally caused
by AIDS but also associated with immigration from coun-
tries with endemic TB, poverty, and limited health services in
impoverished areas. After peaking at 25,287 cases in 1993, the
number of reported cases began to fall again. In 2001, 15,989
cases of TB were reported to the U.S. Centers for Disease
Control and Prevention (CDC). Three fourths of cases among
foreign immigrants came from seven countries: Vietnam, the
Philippines, India, China, South Korea, Mexico, and Haiti.
Mycobacterium tuberculosis is an aerobic rod that thrives in
an aerobic environment, at a Po2 of 140 mm Hg. Consequently,
it preferentially infects the anterior apical segments of the lung.
The bacilli are transmitted via droplet infection as a result of
coughing or sneezing. TB may also be transmitted from one
patient to another through anesthesia breathing systems or
mechanical ventilators.
The principal site of infection of tuberculosis is the lung,
but the bacterium may infect other organs, including the kid-
neys, brain, bones, joints, spine, and genitourinary tract.
Pulmonary TB typically presents as general malaise,
anorexia, weight loss, fever, night sweats, productive cough,
and hemoptysis. Diagnosis is made by serial sputum s­ ampling
for detection of acid-fast bacilli. In active primary TB, chest
radiography reveals lobar pneumonia, with subsegmental
atelectasis and ipsilateral hilar adenopathy. The more classic
“reactivation” form of TB manifests with cavitating lesions
in the posterior segment of the right upper lobe and apical
segments of the lower lobes. A normal radiograph does not
exclude TB, and in the presence of HIV the lesions are often
atypical. If TB is suspected, respiratory isolation precautions
should be instituted immediately, until the patient is deemed
not to be infectious (acid-fast bacillus negative on three suc-
cessive sputum samples, improving symptoms, and improving
chest radiograph).
Current therapeutic regimens for TB involve four-drug
therapy, over 6 months, as follows:
n Initial 2 months (all oral doses): isoniazid (INH), 300 mg/
day; rifampin (RIF), 600 mg/day; pyrazinamide (PZA), 2 g/
day); and ethambutol (ETB), 2 g/day.
n Final 4 months (if initial 2 months are successful by smear
conversion and resolving symptoms): INH, 300 mg/day,
and RIF, 600 mg/day, or alternatively, INH, 900 mg, and RIF,
600 mg, twice weekly.
Patients suspected of having active TB are nursed in respi-
ratory isolation, in special negative-pressure isolation rooms.
Precautions can be supplemented with high-efficiency par-
ticulate air (HEPA) filters and ultraviolet irradiation devices
 Chapter 12  Infectious Diseases and Biologic Weapons 385
installed near the ceiling. Clear infection control guidelines
must be in place and followed rigorously. The patient should
wear a surgical mask when outside an isolation room.
ANESTHETIC CONSIDERATIONS
A patient with active TB represents major infection risk
for other patients and health care workers. Elective surgery
should be avoided and postponed until the patient is no lon-
ger infectious. For emergent or semi-emergent surgery, spe-
cial precautions should be taken. Contact with health care
workers should be minimized; the number of staff in the OR
should be kept to a minimum. The OR doors should be kept
closed and infectious risk signs placed prominently as alerts
to unwitting staff. The anesthesia breathing system should
be separated from the mechanical ventilator by a HEPA fil-
ter. The breathing system should be disposed of at the end
of the case.
Standard surgical face masks provide insufficient pro-
tection from droplet infection; the anesthesiologist should
wear a National Institute for Occupational Safety and Health
(NIOSH) N95 standard face mask and eye protection. The
mask should fit snugly over the face such that all inspired air
passes through it. Extreme care should attend the disposal of
soiled endotracheal tubes, suction tubing, and so on. If laryn-
geal mask anesthesia is performed, the mask should not be
recycled. The patient should undergo recovery in isolation. If
no isolation room is available, recovery is in the OR or an ICU
isolation room (Box 12-7).
BOX 12-7   n ASA GUIDELINES FOR OPERATIVE CARE
OF TUBERCULOSIS PATIENT
1. Elective surgical procedures on a patient who has tuberculosis
should be delayed until the patient is no longer infectious.
2. Patients should be transported to the OR wearing surgical masks
to prevent respiratory secretions from entering the air.
3. The doors of the OR should be closed, and traffic into and out of
OR should be minimized.
4. Perform the procedure at a time when other patients are not
present in the OR suite and when minimal personnel are present
(e.g., end of workday).
a. Ideally, the OR should have an anteroom that is negative pres-
sure to the corridor and the OR.
b. The anesthesiologist and other health care workers should
wear a NIOSH N95–compatible face mask.
5. Exhausted air should be diverted away from hospital.
6. A bacterial filter between the anesthesia circuit and the patient's
airway will prevent contamination of anesthesia equipment or
discharge of tubercle bacilli into the ambient air.
7. These filters can be placed between the Y-connector and the
mask, laryngeal mask, or endotracheal tube.
8. During recovery from anesthesia, the patient should be monitored
and placed in an isolation room.
9. Alternatively, the patient should undergo recovery in the OR or in
own room.
ASA, American Society of Anesthesiologists; OR, operating room; NIOSH,
National Institute for Occupational Safety and Health.
Prions
Prions (proteinaceous infective particles) are infectious
proteins without (known) nucleic acid genomes. A num-
ber of these agents infect mammals, preferentially target-
ing neurologic tissue, causing spongiform encephalopathies.
These include Creutzfeldt-Jakob disease (CJD), Gerstmann-
Straussler-Scheinker syndrome, and kuru in humans; scrapie
in sheep; and bovine spongiform encephalopathy (BSE) in cat-
tle (“mad cow disease”). These neurodegenerative diseases are
universally lethal.
Renewed interest in these agents followed the 1996 descrip-
tion of a new form of CJD, known as variant CJD (vCJD),
which appears to have crossed over from BSE.71,72 After a clus-
ter of reported cases in the United Kingdom, the specter of
perioperative transmission of CJD and vCJD has emerged.
Moreover, emerging data suggest that these diseases may be
spread by blood transfusion.73 Variant CJD affects mainly
young people (average age 29), and the median duration of ill-
ness is 14 months. Since first reported in the United Kingdom
in 1996, by 2005 there were 151 cases of definite or probable
vCJD and 146 deaths, with 1010 reported cases of CJD of all
causes in the UK alone.
Creutzfeldt-Jakob disease causes progressive neuropsy-
chiatric degeneration, associated with gradual reduction in
consciousness, myoclonus, ataxia, chorea, or dystonia. In the
late stages the patient progresses to a near catatonic state. The
prions causing vCJD are found in high concentration in the
brain, spinal cord, and eye. They are also found in lymphore-
ticular tissue, a potential source of infectiousness.
Diagnosis of vCJD is difficult with no reliable investiga-
tion available. Diagnosis is made by a combination of clinical
symptoms and signs and a positive tonsillar biopsy or by the
presence of bilateral high pulvinar signal on magnetic reso-
nance imaging (MRI).
ANESTHETIC CONSIDERATIONS
Anesthesia may be required for patients with vCJD for tonsillar
or brain biopsy, tracheostomy, or placement of a percutaneous
endoscopic gastrostomy (PEG) feeding tube. This has signifi-
cant implications for the performance of anesthesia and for the
OR staff. Most important is the potential for transmission of
disease between patients through contaminated instruments.
Prions are small enough to reside in the microscopic crypts on
stainless steel instruments and are not removed easily by stan-
dard washing techniques; furthermore, they are resistant to
deactivation by traditional methods of decontamination. Novel
approaches have been suggested but not widely adopted.74
All unnecessary equipment and staff should be removed or
excluded from the OR, and warning signs placed outside. Staff
must take extraordinary barrier measures such as double glov-
ing, eye protection, aprons, and disposable liquid-repellent
gowns. Where possible, disposable equipment should be used
(e.g., laryngoscopes, face masks, orolaryngeal mask airways)
and incinerated. If the diagnosis of CJD or vCJD is confirmed,
all instruments should be disposed of immediately.75
 386 ANESTHESIA AND UNCOMMON DISEASES
In the anesthetic setup, it is preferable to use an ICU-style
ventilator, which can be stripped afterward, with disposables
incinerated. If the patient is already intubated, the ventilator
from the ICU should travel with the patient. Total intrave-
nous anesthesia can be administered. Although there are no
specific contraindications to anesthesia agents, succinylcho-
line should be avoided when degenerative myopathy exists.
Pipeline vacuum systems should not be used, and a portable
machine should accompany the patient in the OR, recovery,
and ward.76 During surgery, all needles, clamps, sutures, and
sharps should be directly disposed of into a suitable receptacle.
Tissue matter should be carefully disposed of in clearly labeled
bags. The patient proceeds to the recovery room or is returned
directly to the ICU.
INTRA-ABDOMINAL INFECTIONS AND
ANESTHESIA
Intra-abdominal abscesses are walled-off collections of pus
or parasites surrounded by fibrotic tissue, induced by inflam-
mation, occurring within the abdomen. They may be located
within viscera, in the peritoneum, between loops of bowel, or
in the retroperitoneal space. Intraperitoneal infections result
from postsurgical anastomotic leakage, viscus perforation
(e.g., a ruptured diverticulum), resolution of diffuse peritoni-
tis into multiple small abscesses, or infection with parasites.
Pyogenic Liver Abscess
Liver abscesses are divided into pyogenic and parasitic (ame-
bic and hydatid). The incidence of hepatic abscess is estimated
as 13 to 20 cases per 100,000.77 Most pyogenic liver abscesses
are secondary to infection originating in the abdomen
(Box 12-8). Cholangitis resulting from stones or strictures is
the most common cause, followed by abdominal infection
from diverticulitis or appendicitis. In 15% of cases, no cause
can be found.
In the United States 80% of cases of liver abscess are pyo-
genic. The majority of pyogenic liver abscesses are polymi-
crobial infections, usually with gram-negative aerobic and
anaerobic organisms. Most organisms are of bowel origin, with
Escherichia coli, Klebsiella pneumoniae, Bacteroides, entero-
cocci, anaerobic streptococci, and microaerophilic streptococci
being most common. In approximately 50% of cases there is
infection with anaerobic organisms. In patients with pre-exist-
ing infections such as dental abscess or endocarditis, infection
with hemolytic streptococci, staphylococci, or Streptococcus
milleri may occur. In the immunosuppressed population, such
as patients undergoing chemotherapy, with AIDS, or after
transplantation, opportunistic organisms or fungi may infect
the liver.78 The classic presentation of pyogenic liver abscess
is with abdominal pain, swinging fever, night sweats, nausea,
vomiting, anorexia, anergia, and malaise. There is usually hep-
atomegaly, tenderness in the right upper quadrant, and raised
right hemidiaphragm (with sympathetic pleural effusion) on
chest radiography. There is leukocytosis, anemia, and in the
BOX 12-8   n ORIGINS AND CAUSES OF PYOGENIC
LIVER ABSCESS
Liver and Biliary Tract
Gallstones
Biliary strictures
Cholangiocarcinoma
Blocked biliary stent
Liver biopsy
Gallbladder empyema
Secondary infection of hepatic cyst
Extrahepatic Causes
Appendicitis
Diverticulitis
Crohn's disease
Trauma
Abscess Extension
Perforated peptic ulcer
Subphrenic abscess
Disseminated sepsis
Catheter-related bloodstream infection
Infective endocarditis
Dental infection
Data from Krige JEJ, Beckingham IJ: BMJ 322:537-540, 2001.
presence of biliary tree compression caused by mass effect,
increased serum transaminase and alkaline phosphatase (ALP)
levels. Ultrasonography is the preferred imaging technique,
because internal septations or daughter cysts (hydatid disease)
are more clearly visualized.
Treatment is determined by the size, number, and nature
of the lesions within the liver. Multiple small abscesses are
treated by antimicrobial therapy alone, which must include
a penicillinase-resistant penicillin, an anti–gram-negative
agent, and metronidazole. In the absence of an intra-abdominal
source, aspiration of the abscess under ultrasound or com-
puted tomography (CT) can be performed. Usually a con-
tinuous-drainage catheter is left in place. If an abdominal
source is present, if there is a very large abscess or multilocular
abscesses, or if antibiotics fail, surgical drainage is necessary.
Amebic Liver Abscess
About 10% of the world's population is chronically infected
with Entamoeba histolytica.78 Amebiasis is the third most com-
mon parasitic cause of death, surpassed only by malaria and
schistosomiasis. The prevalence of infection varies widely,
occurring most often in tropical and subtropical climates.
Overcrowding and poor sanitation are the main predisposing
factors.
The parasite is transmitted through the fecal-oral route
with the ingestion of viable protozoal cysts. The cyst wall dis-
integrates in the small intestine, releasing motile trophozoites.
These migrate to the large bowel, where pathogenic strains
may cause invasive disease. Mucosal invasion results in the
formation of flask-shaped ulcers through which amebae gain
 Chapter 12  Infectious Diseases and Biologic Weapons 387
access to the portal venous system. The abscess is usually soli-
tary and affects the right lobe in 80% of cases. The abscess con-
tains sterile pus and reddish brown (“anchovy paste”) liquefied
necrotic liver tissue. Amebae are occasionally present at the
periphery of the abscess.
Patients may have had symptoms from a few days to several
weeks before presentation. Pain is a prominent feature, and the
patient appears toxic, febrile, and chronically ill.
The diagnosis is based on clinical, serologic, and radiologic
features. The patient is usually resident in an endemic area
or has visited one recently, although there may be no history
of diarrhea. Patients typically have leukocytosis, with 70% to
80% polymorphs (eosinophilia is not a feature), a raised eryth-
rocyte sedimentation rate, and moderate anemia. In patients
with severe disease and multiple abscesses, ALP activity and
bilirubin concentration are raised. Stools may contain cysts, or
in the case of dysentery, hematophagous trophozoites.
Chest radiography usually shows a raised right hemidia-
phragm with atelectasis or pleural effusion. Ultrasonography
shows the size and position of the abscess and is useful when
aspiration is necessary and to assess response to treatment.
Serologic tests provide a rapid means of confirming the diag-
nosis, but the results may be misleading in endemic areas
because of previous infection. Indirect hemagglutination
titers for Entamoeba are raised in more than 90% of patients.
In areas where amebiasis is uncommon, failure to consider the
infection may delay diagnosis.
Serious complications occur as a result of secondary infec-
tion or rupture into adjacent structures such as pleural, peri-
cardial, or peritoneal spaces. Two thirds of ruptures occur
intraperitoneally and one third are intrathoracic.
About 95% of uncomplicated amebic abscesses resolve
with metronidazole alone (800 mg three times daily for
5 days). Supportive measures such as adequate nutrition and
pain relief are important. Clinical symptoms usually improve
greatly within 24 hours. Lower doses of metronidazole are
often effective in invasive disease but may fail to eliminate
the intraluminal infection, allowing clinical relapses to occur.
After the amebic abscess has been treated, patients are pre-
scribed diloxanide furoate, 500 mg every 8 hours for 7 days, to
eliminate intestinal amebae.
Patients should have ultrasonographically guided nee-
dle aspiration if serology gives negative results or the abscess
is large (>10 cm), if they do not respond to treatment, or if
there is impending peritoneal, pleural, or pericardial rupture.
Surgical drainage is required only if the abscess has ruptured
causing amebic peritonitis or if the patient has not responded
to drugs despite aspiration or catheter drainage.
ANESTHESIA CONSIDERATIONS
Abnormal liver function is unusual except in the event of bil-
iary obstruction or parenchymal compression. The presence
of jaundice or increased serum transaminase levels likely has
minimal effect on the conduct of anesthesia, because inher-
ent liver metabolic function is usually intact. The patient may
have evidence of low-grade or frank sepsis, in which case
the guidelines established for the management of the septic
patients, described earlier in the chapter, should be followed. If
the patient is bacteremic, epidural analgesia and placement of
CVP catheters should be avoided, to prevent the development
of catheter-related infection.
Hydatid Disease
Hydatid disease in humans is caused by the dog tapeworm
Echinococcus granulosus. Dogs are the definitive host. Ova
are shed in the feces and then infect the natural intermedi-
ate hosts such as sheep or cattle. Hydatid disease is endemic
in many sheep-raising countries. Increasing migration and
world travel have made hydatidosis a global problem of
increasing importance. Human infection follows accidental
ingestion of ova passed in dog feces. The ova penetrate the
intestinal wall and pass through the portal vein to the liver,
lung, and other tissues. Hydatid cysts can develop anywhere
in the body, but two thirds of cysts occur in the liver and one
fourth in the lungs.
Patients with a liver hydatid may present either with liver
enlargement and right upper quadrant pain caused by pressure
from the cyst or acutely with a complication. Complications
include rupture of the cyst into the peritoneal cavity, which
results in urticaria, anaphylactic shock, eosinophilia, and
implantation into the omentum and other viscera. Cysts may
compress or erode into a bile duct, causing pain, jaundice, or
cholangitis, or the cyst may become infected secondary to a
bile leak.
Ultrasonography and CT will show the size, position, and
number of liver cysts and any extrahepatic cysts. Classically,
“daughter cysts” are visualized within the main collection.
About 10% of patients with a liver cyst will also have a lung
hydatid on chest radiography. The diagnosis is confirmed by
hemagglutination and complement fixation tests. Aspiration
of the cyst for diagnostic purposes is avoided until the diagno-
sis is confirmed. Biliary tree compression may increase serum
bilirubin and transaminase levels. Eosinophilia is present in
40% of patients.
Surgery. All symptomatic cysts require surgical removal
to prevent complications. Radiologic cyst drainage has been
described but is not widely practiced.79 Consequently, the
majority of these patients require general anesthesia. The
primary goal of surgery is careful dissection and removal of
the intact cyst, avoiding spillage of its contents, which would
result in the development of secondary cysts in the perito-
neum. The patient is treated with albendazole for 4 weeks pre-
operatively, to shrink the cyst. The surgical field is carefully
isolated by abdominal swabs soaked in scolicidal fluid. The
cyst fluid is aspirated and replaced by a scolicidal agent such as
0.5% sodium hypochlorite, 0.5% cetrimide, 0.5% silver nitrate,
30% hypertonic saline, or sodium hydroxide. This sterilizes
the cyst cavity. After decompression, the cyst and contents are
carefully shelled and the cavity filled with isotonic saline or
omentum and closed.
 388 ANESTHESIA AND UNCOMMON DISEASES
ANESTHETIC CONSIDERATIONS
Liver dysfunction caused by an enlarging cyst rarely interferes
with metabolic function. There may be compressive atelecta-
sis in the lower segments of the right lung, leading to hypox-
emia, which worsens after induction of anesthesia. PEEP is
recommended. There is no contraindication to epidural cath-
eter placement, although epidural infusion should be delayed
until the cyst has been successfully excised. An arterial line
should be placed to monitor beat-to-beat BP variation. Two
major intraoperative complications are cyst rupture, leading to
anaphylactic shock,80 and hyperosmolar coma, following the
administration of hypertonic saline.81,82 Anaphylaxis is treated
with IV fluid, epinephrine, antihistamines, and corticoste-
roids, all of which should be at hand in the OR. Pretreatment
with H1 and H2 antagonists may be beneficial.83
Splenic Abscess
Splenic abscesses are rare. There are five major causes: (1)
metastatic spread from septic foci—including IV drug use,
endocarditis, salmonella (in AIDS), osteomyelitis, TB, den-
tal extractions, infected intravascular devices; (2) spread from
adjacent organs—pancreatic and subphrenic abscesses, gas-
tric and colonic perforations; (3) infection of splenic infarct—
seen in hemoglobinopathies, including sickle cell disease
and splenic artery embolization; (4) splenic trauma, and (5)
immunocompromise. Patients present with fever, leukocyto-
sis, and right upper quadrant pain. It may be associated with
raised left hemidiaphragm, pleural effusion, and pain referred
to the left shoulder. Splenic abscess is most effectively diag-
nosed by CT or MRI. In approximately 50% of patients, blood
cultures are positive. In the majority of abscesses, strepto-
cocci or staphylococci are present; gram-negative rods are
present in 30%, anaerobes in 12%, and mixed organisms in
25%. Antimicrobial treatment includes penicillinase-resistant
β-lactam, aminoglycoside, or aztreonam and metronidazole.
Appendiceal Abscess
Appendiceal abscesses result from acute rupture of an acutely
inflamed appendix. Appendicitis is the consequence of
obstruction of the appendiceal lumen by a fecalith. There is
increased intraluminal pressure associated with bacterial pro-
liferation. There is venous congestion, distention of the organ,
and eventually arterial compromise. Ischemia and gangrene
result. In the majority of cases this results in abscess forma-
tion. However, rupture may also result in diffuse peritonitis,
which represents a surgical emergency.
Patients present with lower abdominal pain, guarding, leu-
kocytosis, and low-grade fever. The diagnosis is confirmed by
CT. If a contrast agent is given, abscesses are well defined with
rim enhancement; a phlegmon does not enhance. This will also
provide information regarding the feasibility of percutaneous
drainage. Antimicrobial therapy is targeted at the polymicrobial
nature of the abscess—a combination of gentamicin or amika-
cin plus either metronidazole or clindamycin is recommended.
There are two surgical approaches to appendiceal abscess:
(1) immediate appendectomy with abscess drainage, the
major risk of which is pus dissemination through the perito-
neum caused by the friability of tissues, and (2) delayed sur-
gery, awaiting abscess organization. If the second approach is
planned, spontaneous resolution of the abscess is anticipated
and appendectomy planned at 6 to 8 weeks. If the abscess per-
sists, however, it should be drained percutaneously.
Diverticular Abscess
Diverticular abscesses form after perforation of a diverticu-
lum. Perforation into the peritoneum leads to diffuse peritoni-
tis, requiring immediate surgery. Often, however, the abscess
may be contained by mesentery or local structures. The patient
thus presents with malaise, pyrexia, leukocytosis, and general-
ized abdominal pain. The diagnosis is confirmed by CT. The
most common site of diverticular disease is the sigmoid colon.
The patient usually develops a colonic ileus.
In the early stages, after perforation, when there is fecal
soiling of the peritoneum, the patient may remain surpris-
ingly well, leading to a false sense of security. This “honey-
moon” period lasts 24 to 48 hours, followed by a dramatic
SIRS response, fluid sequestration, and hypoxemia. This is
the clinical manifestation of the proliferation of bowel bacte-
ria in the peritoneum. Early laparotomy allows for peritoneal
irrigation and colonic resection. At this stage, mild to moder-
ate vasodilation may be present, but patients rarely have overt
signs of sepsis.
Diverticular abscesses are usually drained radiologically,
using CT guidance. This may require sequential proce-
dures. Once the initial inflammatory response has resolved
and the source is controlled, laparotomy and bowel resec-
tion are performed. Antimicrobial coverage should include
therapy for gram-positive organisms and anaerobes and
includes ampicillin/sulbactam or ampicillin, gentamicin, and
metronidazole.
NECROTIZING SOFT TISSUE INFECTIONS
Necrotizing soft tissue infections (NSTIs) represent a group
of diseases characterized by rapidly spreading necrotizing
infection of subcutaneous tissue, fascial planes, and muscle.
NSTIs are classified anatomically, determined by the depth
of infection and the tissues involved84 (Box  12-9). The his-
tory is usually minor trauma or surgery in a vulnerable
patient.85 Often-unexplained pain that increases rapidly over
time is the first manifestation. The patient may develop early
dramatic symptoms and signs of sepsis (confusion, delirium,
tachycardia, tachypnea, hypotension, oliguria). The source
may not be readily apparent. Clinical findings include ery-
thema, edema, and induration of the tissues, occasionally
with bullae formation. NSTIs share the features of extensive
tissue destruction, thrombosis of blood vessels, abundant
bacteria spreading along fascial planes, and relatively few
acute inflammatory cells.
 Chapter 12  Infectious Diseases and Biologic Weapons 389

response. There may be a history of surgery, trauma, or minor

BOX 12-9   n  NECROTIZING SOFT TISSUE INFECTIONS injury, for example, in a diabetic patient. Infection rapidly
Classification
spreads throughout the subcutaneous tissues and along fas-
Infections of Skin and Subcutaneous Tissue cial planes. Localized thrombosis of blood vessels may lead to
Progressive synergistic bacterial gangrene loss of perfusion and necrosis/gangrene. Crepitus may result
Chronic undermining burrowing ulcer (Meleney's ulcer) from gas production in the tissues. The natural progression of
Idiopathic scrotal gangrene (Fournier's gangrene) necrotizing fasciitis is severe sepsis, septic shock, multiorgan
Infections Involving Subcutaneous Tissue and Fascia failure, and death. Early aggressive skin debridement is imper-
Hemolytic streptococcal gangrene ative, often with the patient in extremis. In addition to source
Necrotizing fasciitis
control, empiric antibiotics must be administered, principally
Gram-negative synergistic necrotizing cellulitis
Clostridial cellulitis
clindamycin, aminoglycosides, or third-generation cephalo-
sporins and metronidazole. Supportive care usually involves
Infections Involving Muscle
Clostridial myonecrosis
aggressive volume resuscitation and vasopressors, which can
Streptococcal myositis usually be weaned with removal of necrotic tissue. Surgical
debridement of necrotic tissue is often extensive and usually
Risk Factors
Diabetes
involves multiple OR trips. Amputation of limbs may be nec-
Peripheral vascular disease essary. In addition, when anaerobic, gas-producing bacteria
Chronic liver disease are involved, hyperbaric O2 therapy may be indicated.
Cancer
AIDS
ANESTHETIC CONSIDERATIONS
Collagen vascular diseases
Chronic renal failure
Anesthesiologists may be involved with patients with necro-
Recent surgery tizing fasciitis either during the initial presentation, where
Penetrating trauma fulminant sepsis is the major manifestation, or during subse-
Systemic sepsis (the “second hit”) quent visits to the OR for tissue debridement. Surgery should
Corticosteroids
not be delayed by the anesthesiologist, because resuscitation
Advanced age
Malnutrition
and hemodynamic stabilization is usually impossible without
Alcoholism surgical debridement. The incision is made directly over the
Intravenous drug use area of skin involved or the most indurated region. The skin
Postoperative infection incision parallels the neurovascular bundles and carries down
Morbid obesity
to the fascia. The underlying muscle and fascia is inspected
Data from Kuncir EJ, Tillou A, St. Hill CR, et al: Emerg Med Clin North Am
and all necrotic tissue excised in all directions until healthy
21:1075-1087, 2003. tissue is reached. Debridement is adequate when a finger can
no longer easily separate the subcutaneous fat from the fascia.
The wound is left exposed, without skin flaps, for subsequent
assessment.
Necrotizing Fasciitis
The patient may be intolerant of the vasodilatory effects of
Necrotizing fasciitis is a deep-seated infection of the subcu- volatile agents and may require massive volume resuscitation
taneous tissue that results in progressive destruction of fascia plus vasopressor therapy, as described earlier. Importantly, as
and fat, although it may spare the skin. It usually involves the debridement progresses, cytokine release is reduced, and the
extremities, abdominal wall, or perineum. Much confusion patient usually becomes hemodynamically more stable. In the
surrounds nomenclature; for example, necrotizing infection absence of a volatile agent, ketamine is a suitable alternative
of the perineum is often called Fournier's gangrene. Other to maintain hypnosis during surgery, along with fentanyl or
names used include progressive bacterial synergistic gangrene hydromorphone for analgesia.
(PBSG) and Meleney's ulcer. It is simpler to classify necrotiz-
ing fasciitis according to the type of microbes involved. There
are two types of necrotizing fasciitis, as follows:
Clostridial Myonecrosis (Gas Gangrene)
Type 1: Polymicrobial form is an infection with mixed Clostridial species are obligate anaerobes that infect devital-
bowel organisms. Microbes may be aerobic (e.g., staphylo- ized tissue. Three types of clostridial infections have been
cocci, group A streptococci, Escherichia coli) or anaerobic identified: simple wound contamination or colonization,
(e.g., Clostridium, Bacteroides, Peptostreptococcus). anaerobic cellulitis, and clostridial gas gangrene. Myonecrosis
Type 2: Monomicrobial form is caused by group A strepto- is caused by Clostridium perfringens, an exotoxin-secreting
cocci, which produces a number of cellular components and and spore-forming bacterium found in the soil. This infection
exotoxins that lead to the destruction of tissue and spread of is often called “gas gangrene” because of the palpable crepitus
infection. caused by liberation of gas. Muscle is remarkably resistant to
The patient usually presents with pain out of proportion to infection. Infection follows significant loss of barrier function,
the apparent tissue injury and malaise with significant SIRS as occurs with contamination of deep-seated wounds, as in
 390 ANESTHESIA AND UNCOMMON DISEASES
trauma, knife wounds, septic abortions, immunocompromise,
and surgery. The introduction of the organism is comple-
mented by the presence of an anaerobic environment with a
low oxidation-reduction potential and acid pH, which is ideal
for the growth of clostridial organisms. Another form of myo-
necrosis, spontaneous gangrenous myositis, is caused by group
A streptococci.
The toxic effects of clostridial organisms result from the
release of toxins (12 in number). Alpha toxin is lecithinase
(phospholipase C), which degrades lecithin in cell membranes
causing lysis. In addition, C. perfringens produces a variety of
hydrolytic enzymes (proteases, DNases, hyaluronidase, colla-
genases) that liquefy tissue, thus promoting spread of infec-
tion. The patient presents with sudden onset of malaise and
painful swelling of the affected area. There may be a smelly
purulent discharge and discoloration of skin. Gram stain of
infected material reveals gram-positive rods. Exotoxins and
proteolytics released by the organism cause fermentation of
tissue carbohydrates and accumulation of gas bubbles in the
subcutaneous space, resulting in crepitus.
Treatment of patients with clostridial myonecrosis is extensive
surgical debridement of all infected tissue and IV antibiotics:
benzylpenicillin, 2.4 g every 4 hours, plus clindamycin, 500 mg
every 6 hours. Again, hyperbaric O2 may have a role, but this
has not been proved by prospective clinical trials. Anesthesia
care of the patient with myonecrosis is similar to that of the
patient with necrotizing fasciitis.
Soft Tissue Infections of Head and Neck
Soft tissue infections of the neck are of particular importance
to anesthesiologists because of the potential for significant airway
obstruction. The most common sources of life-threatening
infections of the head and neck are the teeth and tonsils. The
majority are polymicrobial, usually oral flora (Bacteroides,
Peptostreptococcus, Actinomyces, Fusobacterium, and micro-
aerophilic streptococci) that become virulent. Infection
spreads along facial planes to distant sites.
The most well-known neck space infection was described
by Wilhelm von Ludwig in 1836 and is known as Ludwig's
angina. This severe cellulitis of the mouth floor tissue, with
involvement of the submandibular and sublingual spaces, is
marked by edema of the neck and tongue, cellulitis, and grad-
ual airway compromise. The source of infection is almost
always the second and third mandibular molars. If the infec-
tion is allowed to continue, there may be local lymphadenitis,
systemic sepsis, and extension of the disease to involve deep
cervical fascia with a cellulitis that extends from the clavicle to
the superficial tissues of the face. The disease is almost always
polymicrobial, including α-hemolytic streptococci and anaer-
obes such as Peptostreptococcus, Prevotella melaninogenica,
and Fusobacterium nucleatum. Most patients with Ludwig's
angina are young, healthy adults. Patients usually present with
mouth pain, dysphagia, drooling, and stiff neck. The patient
often maintains the neck in an extended position and may
have a muffled or “hot potato” voice.
ANESTHETIC CONSIDERATIONS
Urgent airway control is usually advised in the Ludwig's angina
patient. Traditionally, tracheostomy has been performed
under local anesthesia but this may be technically difficult
because of extensive edema and inflammation, as well as inev-
itable infection and inflammation of the stoma site. Incision
and drainage is indicated if suppurative infection develops,
or if fluctuance, crepitus, and soft tissue gas mandate surgical
intervention. CT can be used to help identify these suppura-
tive complications. Surgical drainage has been required in 50%
of patients, performed under local anesthesia or cervical block.86
Any suggestion of airway compromise demands the airway be
secured. From 40% to 60% of patients with Ludwig's angina
require tracheostomy or endotracheal intubation.87
Conventional IV induction and neuromuscular blockade is
unacceptable; spontaneous ventilation should be maintained.
An awake fiberoptic “look see” approach appears optimal. The
airway is visualized after appropriate topical preparation. If
the glottis and supraglottic area are patent, the anesthesiolo-
gist proceeds to intubation. If not, awake tracheostomy is per-
formed. An alternative approach is inhalational induction of
anesthesia with sevoflurane; the major drawback is difficulty
in maintaining airway patency (from edematous neck tissue),
obstruction, and hypoxemia. Cricothyroidotomy is extremely
difficult in this situation. Penicillin with a β-lactamase inhibi-
tor is the agent of choice for patients with Ludwig's angina:
ampicillin/sulbactam or piperacillin-tazobactam, with
clindamycin or metronidazole.
Epiglottitis
Acute epiglottitis is inflammation of the epiglottis secondary
to bacterial infection, usually Haemophilus influenzae type B.
Infection results in significant edema and airway compromise,
which may be life threatening. Inflammation can also occur in
the arytenoid cartilage, false vocal cords, or pharyngeal wall,
resulting in acute supraglottitis. The mean age at presentation
ranges from 42 to 50 years, with male predominance and an
association with cigarette smoking.
Patients typically present after approximately 2 days of
symptoms and sore throat and pain in swallowing (Table 12-5).
Thickening of the epiglottis is the classic radiographic finding
and is present on 73% to 86% of lateral neck radiographs.88
Other radiographic findings strongly suggestive of acute epi-
glottitis and supraglottitis include enlargement of aryepiglottic
folds, arytenoid enlargement, prevertebral soft tissue swelling,
and an emphysematous epiglottitis.
ANESTHETIC CONSIDERATIONS
Although generally avoided in children, laryngoscopy appears
to be safe in adults and can be used to evaluate patients with
a clinical suspicion of acute epiglottitis but with a negative
neck radiograph. A “cherry red” epiglottitis is the classic find-
ing, and most patients have supraglottic inflammation and
edema. The need to sit upright, bacteremia, and a rapid onset
of serious symptoms have been associated with the need for
 Chapter 12  Infectious Diseases and Biologic Weapons 391
TABLE 12-5  n Acute Epiglottitis: Signs, Symptoms, and
Frequency (Adults)
Sign/Symptom % Frequency
Muffled voice 54-79
Pharyngitis 57-73
Fever 54-70
Tenderness of anterior neck 79
Dyspnea 29-37
Drooling 22-39
Stridor 12-27
Data from Bansal A, Miskoff J, Lis RJ: Crit Care Clin 19:55-72, 2003.
airway intervention: intubation or tracheostomy (5%-20% of
patients). The patient should continue to breathe spontane-
ously while the airway is secured. Therefore, awake fiberoptic
intubation or inhalational induction with sevoflurane should
be performed. Care should be taken with topicalization to
prevent precipitation of acute airway obstruction. Intubation
should be performed by the most skilled anesthesiologist and
a full airway team, including an otolaryngologist, with an open
tracheostomy pack, should be present.
The antimicrobial of choice is a second- or third-generation
cephalosporin with activity against H. influenzae. Additional
therapy, such as racemic epinephrine or dexamethasone, is of
undetermined utility.89
INFECTIOUS AGENTS AS BIOLOGIC
WEAPONS
Biologic agents have been weaponized to wage war and pro-
mote terror throughout history. In the 6th century bc the
Assyrians poisoned enemy wells with rye ergot. In 1347 ad the
Tartar army catapulted the bodies of bubonic plague victims
over the walls of the city of Kaffa in the Crimea, leading to
a plague epidemic. In 1495 the Spanish infected French wine
with blood from leprosy patients. In the mid-1600s a Polish
military general reportedly put saliva from rabid dogs into
hollow artillery spheres for use against his enemies. Smallpox
was used as a biologic weapon in South America in the 15th
century and during the French-Indian and Civil wars in the
United States. In each case, clothes from smallpox victims
were given to natives or prisoners.
In World War I, horses, mules, and cattle were deliberately
infected with anthrax and glanders to infect Allied military
personnel in 1915. In World War II the Japanese military exten-
sively used aerosolized anthrax and air-dropped 150 million
plague-infected fleas over villages in China and Manchuria in
1941, resulting in several plague outbreaks. In 1942 the Soviet
military used weaponized tularemia on German soldiers
during the battle of Stalingrad. From 1975 to 1983, Soviet-
backed forces in Laos, Cambodia, and Afghanistan allegedly
used trichothecene mycotoxins (T-2 toxins), called “yellow
rain.” In 1979 an outbreak of pulmonary anthrax occurred in
Yekaterinburg in the Soviet Union as a result of an accidental
release of anthrax in aerosol form from a bioweapons facil-
ity. Iraq is suspected to have used bombs and scud warheads
filled with Botulinum toxin, anthrax, and aflatoxin against
Kurds in 1991.
In the 21st century, interest in biologic weapons has
increased with the rise of terror networks and the produc-
tion of such weapons by “rogue states.” Successful attacks have
included sarin in Japan (1994-1995) and salmonella (1984)
and anthrax (2001) in the United States. In 2004, Viktor
Yushchenko, the opposition candidate of the presidency of
Ukraine, was poisoned with dioxin, leading to severe facial
disfiguration, abdominal pain, and extensive GI ulceration.
In the event of a terrorist biologic attack, the anesthesiolo-
gist will be intensely involved with triage and resuscitation of
the injured patient. A familiarity with potential bioweapons
is necessary (Table 12-6). An ideal biologic weapon is robust,
highly infectious, and highly potent and can be delivered as an
aerosol. A vaccine should be available. In addition, the weapon
is one that should be able to be manufactured quickly and eas-
ily. In general, the primary difficulty is not the production of
the biologic agent but rather the development of an effective
delivery system to infect the intended target (Table 12-7).
Anthrax
Bacillus anthracis is a gram-positive rod that primarily infects
animals, particularly herbivores. Humans can contract the
disease from infected animals or animal products. In most
countries, however, domestic animal vaccinations have all
but eliminated the disease. In an unfavorable environment,
anthrax endospores are formed that are highly resistant to dis-
infectants, temperature, and alkali. These spores have been
manufactured by a number of countries as biologic weapons.
In fall 2001, letters with spores were sent from Trenton, NJ, to
five media offices and two U.S. senators; 22 individuals devel-
oped anthrax infections, mainly cutaneous, and five died of
inhalation anthrax from cross-contamination of the mail.
Infection occurs with the introduction of the spore through
a break in the skin, causing cutaneous anthrax, or through
the mucosa of the GI tract. To cause pulmonary infection,
weapons-grade anthrax spores must be used. The reason for
this is that anthrax must be delivered as single spores, which
can work their way down into small airways, where they are
phagocytosed and transported to the hilar lymph nodes, where
bacteria proliferate. To deliver single spores, anthrax must be
treated, to “unclump” the spores by making them electrostati-
cally neutral. Proliferating bacteria produce three exotoxins;
protective antigen binds to cell surface receptors, facilitating
entry of other the two exotoxins into the cell through a chan-
nel; edema factor causes cell swelling; and lethal factor has
­protease activity, which causes cell lysis.
 392 ANESTHESIA AND UNCOMMON DISEASES

Expiratory stridor, from tracheal compression by enlarged

TABLE 12-6  n Agents of Concern for Use as Biologic
Weapons
paratracheal nodes, may accompany other respiratory symp-
toms. The diagnosis of inhalational anthrax is suspected by
Microbe or Toxin Disease circumstances (e.g., mail worker with acute respiratory fail-
ure), sepsis, and respiratory failure in a patient with a widened
HIGHEST PRIORITY (CATEGORY A) mediastinum (i.e., adenopathy) on chest radiography.90
Bacillus anthracis Anthrax Cutaneous anthrax presents as a painless, pruritic papule
on the skin up to 1 week after infection. Progression of the dis-
Variola virus Smallpox
eased lesion involves the development of one or more vesicles
Yersinia pestis Plague and edema surrounding the primary lesion, fever, and mal-
Clostridium botulinum Botulism
aise. The vesicles subsequently rupture, revealing a necrotic
ulcer and a characteristic black eschar. This dries and falls off
Francisella tularensis Tularemia after 1 week to 10 days. The most important clinical approach
Filoviruses Ebola hemorrhagic fevers, to cutaneous anthrax is to avoid surgical debridement, which
Marburg disease may be associated with bacteremia and systemic infection.91
Gastrointestinal anthrax is contracted by ingesting food
Arenaviruses Lassa fever, South American
hemorrhagic fevers contaminated with anthrax spores; 3 to 5 days after infec-
tion the patient develops fever, malaise, nausea, vomiting, and
Bunyaviruses Rift Valley fever, Congo-Crimean diarrhea, associated with abdominal pain. Ulcers may develop
hemorrhagic fevers
in the intestinal mucosa, leading to profuse bleeding, mesen-
MODERATELY HIGH PRIORITY (CATEGORY B) teric lymphadenitis, and ascites.
Coxiella burnetti Q fever
Definitive diagnosis is the identification of encapsulated
broad gram-positive bacilli on examination of skin smears,
Brucella spp. Brucellosis blood, or cerebrospinal fluid.
Burkholderia mallei Glanders Treatment of inhalational anthrax is ciprofloxacin plus
clindamycin, rifampicin, or vancomycin.92 For postexposure
Alphaviruses Viral encephalitides
chemoprophylaxis, ciprofloxacin, doxycycline, and penicil-
Ricin Ricin intoxication lin G have been recommended. Amoxicillin is recommended
for cutaneous anthrax. Information is negligible regarding
Staphylococcus aureus Staphylococcal toxin illness
enterotoxin B hospital infection control and anthrax. There is no risk of
person-to-person transmission with inhalational anthrax. If
Salmonella spp., Shigella Food-borne and water-borne discharging skin lesions are present, contact precautions are
dysenteriae; E. coli O gastroenteritis
157:H7; Vibrio cholerae,
necessary. Contaminated surfaces should be treated with spo-
Cryptosporidium parvum ricidal solutions.
CATEGORY C
ANESTHETIC CONSIDERATIONS
Hantaviruses Viral hemorrhagic fevers The anesthesiologist may be involved with the critical care
management of the patient with inhalational anthrax—for
Flaviviruses Yellow fever
intubation and supportive care. There is no risk of person-to-
Mycobacterium tuberculosis Multidrug-resistant tuberculosis person transmission (Table 12-8).
MISCELLANEOUS

Genetically engineered vaccine-resistant and/or antimicrobial- Smallpox

resistant category
A or B agents
Human immunodeficiency virus type 1 (HIV-1)
Adenoviruses
Influenza
Rotaviruses
Hybrid pathogens (e.g., smallpox-plague, smallpox-Ebola)
Anthrax is a biphasic disease. Inhalational anthrax manifests,
following an incubation period of 3 to 6 days, as nonspecific
symptoms of pyrexia, malaise, myalgia, and dry cough. The
second stage begins 2 days thereafter, with fulminant ­sepsis
associated with pyrexia, dyspnea, and vasoplegic shock.
Smallpox is caused by the variola virus. The disease was eradi-
cated worldwide in 1977 but exists in two known repositories,
at the CDC in Atlanta and at the Institute of Viral Preparations
in Moscow. It is feared that stockpiles of this virus are in the
hands of others and may be used as a biological weapon.
Smallpox is spread from person to person without animal
vector. The virus is inhaled into the respiratory tract and makes
its way into the blood, to all body organs, through pulmonary
lymph nodes. During the incubation period of 1 to 2 weeks,
the virus replicates in the reticuloendothelial system, followed
by a prodromal syndrome (i.e., fever, backache, headaches,
malaise, rigors, delirium, nausea and vomiting), after which a
rash appears. At this point and for several weeks, the disease is
 Chapter 12  Infectious Diseases and Biologic Weapons 393

TABLE 12-7  n  Differential Diagnosis for Inhalational Anthrax

Diagnosis Distinguishing Features

Pneumonic plague (Yersinia pestis) Hemoptysis relatively common with pneumonic plague but rare with
inhalational anthrax

Tularemia (Francisella tularensis) Clinical course usually indolent, lasting weeks; less likely to be fulminant

Community-acquired bacterial pneumonia Rarely as fulminant as inhalational anthrax

Mycoplasmal pneumonia (Mycoplasma pneumoniae)
Pneumonia caused by Chlamydia pneumoniae
Legionnaires’ disease (Legionella pneumophila or other
Legionella spp.)
Psittacosis (Chlamydia psittaci)
Other bacterial agents (e.g., Staphylococcus aureus,
Streptococcus pneumoniae, Haemophilus influenzae,
Klebsiella pneumoniae, Moraxella catarrhalis)
Legionellosis and many other bacterial agents (S. aureus, S. pneumoniae,
H. influenzae, K. pneumoniae, M. catarrhalis) usually occur in persons with
underlying pulmonary or with other disease or in elderly patients.
Bird exposure occurs with psittacosis.
Gram stain of sputum may be useful.
Community outbreaks caused by other etiologic agents not likely to be as
explosive as pneumonic plague outbreak.
Outbreaks of S. pneumoniae usually institutional.
Community outbreaks of legionnaires’ disease often involve exposure to
cooling towers.

Viral pneumonia Influenza generally seasonal (October-March in United States) or involves

Influenza history of recent cruise ship travel or travel to tropics
Hantavirus Exposure to mice droppings, feces with hantavirus
Respiratory syncytial virus (RSV) RSV usually occurs in children (although may be cause of pneumonia in
Cytomegalovirus (CMV) elderly); tends to be seasonal (winter/spring)
CMV usually occurs in immunocompromised patients

Q fever (Coxiella burnetii) Exposure to infected parturient cats, cattle, sheep, goats
Severe pneumonia not prominent feature

communicable. The most prominent manifestation of small-

TABLE 12-8  n Infection Control Issues for Select
Bioweapons
pox is its characteristic centrifugal rash, which appears on the
extremities first and then the trunk. This initially appears as a
Incubation Person to Infection widespread macular eruption, with associated skin edema. An
Disease Period Person Precautions extensive pustular eruption follows; after 14 days these lesions
rupture, necrose, and leave prominent pockmark scars.
Inhalational 2-43 days No Standard
anthrax
Death from smallpox results from septic shock and multi-
organ dysfunction syndrome.
Botulism 12-72 No Standard The rash of smallpox must be differentiated from that of
hours
chickenpox (varicella zoster). In varicella infection there is a
Primary 1-6 days Yes Droplet shorter prodrome, lesions appear predominantly on the trunk
pneumonic with facial sparing, and the rash is different. The lesions in
plague chickenpox are soft and do not scar and are at different stages
Smallpox 7-17 days Yes Contact and of development; in smallpox the lesions progress in synchrony.
airborne There is no known treatment for smallpox. Patients should
Tularemia 1-14 days No Standard
be managed supportively, with full isolation and barrier pre-
cautions, in a negative-pressure room. Meticulous contact
Viral 2-21 days Yes Contact and tracing is imperative. A vaccine is available, based on live vac-
hemorrhagic airborne
cinia virus. Routine vaccination of children was abandoned
fevers
in the 1960s because of the high incidence of vaccine-related
Viral 2-14 days No Standard complications. If the affected patient is in the early phase of
encephalitides the disease, he or she should be vaccinated.93
Q fever 2-14 days No Standard

Brucellosis 5-60 days No Standard Tularemia

Glanders 10-14 days No Standard Tularemia is an acute, febrile, granulomatous, infectious zoo-
Data from Cohen J, Powderly W: Infectious diseases, ed 2, St Louis, 2004, nosis caused by the aerobic gram-negative pleomorphic bacil-
Mosby, p 101. lus Francisella tularensis. Its name relates to the description
 394 ANESTHESIA AND UNCOMMON DISEASES
in 1911 of a plaguelike illness in ground squirrels in Tulare
County, California. The disease commonly infects rab-
bits and rodents, including mice, groundhogs, squirrels, and
sheep. There are 150 to 300 tularemia cases reported in the
United States annually, with a majority of those from Alaska,
Arkansas, Illinois, Oklahoma, Missouri, Tennessee, Texas,
Utah, and Virginia.
Francisella tularensis was weaponized by the United States
(until the 1960s) and the former Soviet Union (until the
1990s). Other countries have been or are suspected to have
weaponized this bacterium. This organism can be produced
in wet or dry form and is introduced by aerosolization or con-
tamination of food and water sources.
Many routes of human exposure to the tularemia organism
are known to exist. The common routes include direct contact
with blood or tissue while handling infected animals, the bite
of arthropods (e.g., ticks, mosquitoes), and handling or eating
undercooked small game animals (e.g., rabbit). Less common
means of transmission are drinking or swimming in contami-
nated water, from animal scratches or bites of animals contam-
inated from eating infected animals, and inhaling dust from
contaminated soil or handling contaminated pelts or paws of
animals. Tularemia is not directly transmitted from person
to person. Laboratory workers exposed to the bacteria are at
higher risk. The clinical form of tularemia reflects the mode
of transmission. Some classify the disease as typhoidal (pre-
dominance of systemic symptoms), pneumonic (pulmonary
f­ indings), or ulceroglandular (regional symptoms).
Weaponized tularemia is most likely acquired by inhala-
tion or consumption of contaminated food. The most com-
mon form of tularemia is usually acquired through the bite of
blood-sucking arthropods or from contact with infected ani-
mals. Inhalation of the organism will result in sudden chills,
fever, weight loss, abdominal pain, fatigue, and headaches.
Inhalation of F. tularensis may result in tularemic pneumonia.
Patchy, poorly defined infiltrates appear in one or more lobes
on chest radiography. Bilateral hilar adenopathy may be pres-
ent. Bloody pleural effusions are characteristic and demon-
strate a mononuclear cellular response. This may progress to
acute respiratory distress syndrome (ARDS). Ingestion of the
organism in contaminated food or water may result in pain-
ful pharyngitis, abdominal pain, diarrhea, and vomiting. As
many as 20% of patients have a rash that may begin as blotchy,
macular, or maculopapular and progress to pustular lesions.
Erythema nodosum and erythema multiforme rarely occur.
Involvement of other systems may lead to meningitis, pericar-
ditis, peritonitis, and osteomyelitis.
Symptoms generally appear between 1 and 14 days, but
usually within 3 to 5 days. Diagnosis is exceedingly difficult
to make. It is usually based on serology (the tularemia tube
agglutination test). However, there is a 12- to 14-day delay in
receiving the result of this test. Treatment is with gentamicin
or streptomycin. Otherwise, therapy is supportive. Mortality
in untreated patients is 5% to 15% and in treated patients,
1% to 3%.
Plague
Yersinia pestis is a gram-negative bacillus that causes plague.
As with B. anthracis, Y. pestis primarily infects animals, par-
ticularly rodents. Plague is spread to humans through the
bite of infected rodent fleas. In this form, known as bubonic
plague, approximately 10 cases per year are reported in the
United States (Table  12-9). Numerous epidemics of bubonic
plague have swept the world in the last 1000 years. One third
of the European population succumbed in the 14th century
to plague, commonly known as the Black Death. Plague was
used as a biologic weapon during World War II when infected
fleas were released. The United States and the Soviet Union
developed an aerosolized version during the Cold War and
still maintain stockpiles.
The bubonic plague typically presents 2 to 8 days after
exposure, with sudden onset of fever, chills, weakness, and
acutely swollen lymph nodes, termed buboes, usually in the
groin, axillae, or cervical regions. Buboes are egg shaped,
1 to 10 cm in length, and often exquisitely tender. The patient
develops acute severe sepsis, progressing over 2 days to mul-
tiorgan failure, characterized by microvascular thrombosis.
Peripheral tissue necrosis is seen, similar to that in meningo-
coccemia (i.e., necrotitis fulminans). Person-to-person spread
of bubonic plague does not occur.
When Yersinia is spread by aerosolized droplets, the sub-
sequent disease is known as pneumonic plague. It is highly
contagious. This would be the route of attack by a terrorist or
military group.
After exposure there is an incubation period of 2 to 4
days, with sudden onset of fever, rigors, and muscular pain.
Within 24 hours the patient develops hemoptysis, resulting
from the production of coagulase and fibrolysin by the bac-
terium, leading to tissue necrosis. The patient may complain
of abdominal pain, chest pain, nausea, and vomiting. The dis-
ease progresses to ARDS, with severe hypoxemia, and to sep-
tic shock. Without appropriate antibiotics within 18 hours,
the patient will die.
The diagnosis of plague may be difficult in isolated
cases; the symptoms and signs may be indistinguishable
from other forms of acute severe sepsis (e.g., meningococ-
cemia, ­pneumococcal pneumonia). A history of hemoptysis
on ­presentation should alert the clinician to the possibility
of plague. Moreover, if a biologic attack is carried out with
Yersinia, multiple patients will begin presenting to the emer-
gency department with symptoms of rapidly progressing
pneumonia and hemoptysis. Sputum Gram stain reveals
gram-negative rods. Blood cultures are usually positive, but
the diagnosis is usually retrospective because, by the time the
cultures emerge, without treatment the patient will be dead.
The treatment of choice for plague is streptomycin, gen-
tamicin, doxycycline, or ciprofloxacin. These agents are not
routinely used or recommended for community-acquired
pneumonia. If the patient has symptoms or signs of menin-
gitis, chloramphenicol should be used. Strict isolation with
droplet precautions should be enforced for 48 hours.

TABLE 12-9  n  Select Bioweaponized Diseases: Clinical Presentation and Differential Diagnosis
Clinical Presentation
Nonspecific “flulike” symptoms with nausea,
emesis, cough with or without chest discomfort,
without coryza or rhinorrhea, leading to abrupt
onset of respiratory distress with or without
shock, mental status changes, with chest
radiographic abnormalities (wide mediastinum,
infiltrates, pleural effusions)
Pruritic, painless papule, leading to vesicle(s), leading
to ulcer, leading to edematous black eschar with
or without massive local edema and regional
adenopathy and fever, evolving over 3 to 7 days
Rapidly progressive respiratory illness with cough,
fever, rigors, dyspnea, chest pain, hemoptysis,
possible GI symptoms, lung consolidation with or
without shock
Sepsis, disseminated intravascular coagulation
(DIC), purpura, acral gangrene
Fever, malaise, prostration, headache; myalgias
followed by development of synchronous,
progressive papular leading to vesicular and
then pustular rash on face, mucous membranes
(extremities more than trunk); rash may become
generalized, with hemorrhagic component and
systemic toxicity
Nonspecific flulike, febrile illness with
pleuropneumonitis, bronchiolitis with or without
hilar lymphadenopathy; variable progression to
respiratory failure
Acute onset of afebrile, symmetric, descending
flaccid paralysis that begins in bulbar muscles;
dilated pupils, diplopia or blurred vision;
dysphagia, dysarthria, ptosis; dry mucous
membranes, leading to airway obstruction with
respiratory muscle paralysis; clear sensorium
and absence of sensory changes
Acute-onset fevers, malaise, prostration, myalgias,
headache, GI symptoms, mucosal hemorrhage,
altered vascular permeability, DIC; hypotension
leading to shock, with or without hepatitis and
neurologic findings
GI, Gastrointestinal; TTP, thrombotic thrombocytopenic purpura.
ANESTHESTIC CONSIDERATIONS
The anesthesiologist may be involved with airway manage-
ment and initiation of mechanical ventilation. Extreme pre-
cautions should be taken to avoid contact with patients’
secretions. The anesthesiologist should wear a gown, mask,
and eye protection because of the potential for contagion. All
health care workers involved in face-to-face contact must be
Chapter 12  Infectious Diseases and Biologic Weapons 395
Disease Differential Diagnosis
Inhalation anthrax Bacterial mediastinitis, tularemia, Q fever,
psittacosis, legionnaires’ disease, influenza,
Pneumocystis jiroveci pneumonia, viral
pneumonia, ruptured aortic aneurysm,
superior vena cava syndrome, histoplasmosis,
coccidioidomycosis, sarcoidosis
Cutaneous anthrax Recluse spider bite, plague, staphylococcal
lesion, atypical Lyme disease, orf, glanders,
tularemia, rat-bite fever, ecthyma gangrenosum,
rickettsialpox, atypical mycobacteria, diphtheria
Primary pneumonic plague Severe community-acquired bacterial or viral
pneumonia, inhalational anthrax, inhalational
tularemia, pulmonary infarct, pulmonary
hemorrhage
Septicemic plague Meningococcemia; gram-negative streptococcal,
pneumococcal, or staphylococcal bacteremia
with shock; overwhelming postsplenectomy
sepsis; acute leukemia; Rocky Mountain spotted
fever; hemorrhagic smallpox; hemorrhagic
varicella (in immunocompromised patients)
Smallpox Varicella, drug eruption, Stevens-Johnson syndrome,
measles, secondary syphilis, erythema
multiforme, severe acne, meningococcemia,
monkeypox (with African travel history),
generalized vaccinia, insect bites, coxsackievirus
infection, vaccine reaction
Inhalational tularemia Inhalational anthrax, pneumonic plague, influenza,
mycoplasmal pneumonia, legionnaires’ disease,
Q fever, bacterial pneumonia
Botulism Myasthenia gravis, brainstem cerebrovascular
accident, polio, Guillain-Barré syndrome variant,
tick paralysis, chemical intoxication
Viral hemorrhagic fever Malaria, meningococcemia, leptospirosis, rickettsial
infection, typhoid fever, borreliosis, fulminant
hepatitis, hemorrhagic smallpox, acute leukemia,
TTP, hemolytic uremic syndrome, systemic lupus
erythematosus
given chemoprophylaxis with doxycycline for at least 7 days.
Patients are managed supportively in the ICU. There are
no indications for surgery in the early stages. In particular,
buboes should not be incised or debrided because of the risk
of spreading the infection. Peripheral necrosis requires surgi-
cal debridement or amputation, but this is delayed until the
patient is in the recovery stage of the disease.
 396 ANESTHESIA AND UNCOMMON DISEASES
BIOLOGIC TOXINS
Sarin
Sarin (GB) is an organophosphate nerve agent first devel-
oped by Nazi German scientists in 1938. A number of simi-
lar agents exist, such as tabun (GA), soman (GD), cyclosarin
(GF), and VX toxin. VX is the most potent known biotoxin.
Sarin is one of the few biologic weapons known to have been
used in military and terrorist attacks. Sarin was probably used
by the Iraqi military against Kurdish villagers in 1988 as well
as during the Iraq-Iran War.94 A Japanese terrorist cult known
as Aum Shinrikyo used sarin against civilians in Japan, first
in Matsumoto in 1994, killing eight people, then in the Tokyo
subway system in 1995, killing 13 and injuring hundreds.95
At room temperature, sarin is a volatile liquid that can be
aerosolized by explosive devices. Exposure to sarin occurs by
one of two routes: topically/transdermally or inhaled into the
lungs.96 Once acquired, organophosphate nerve agents bind to
and inactivate acetylcholinesterase (AChE). This leads to toxic
accumulation of acetylcholine at nicotinic, muscarinic, and
CNS synapses. Thus, sarin is a noncompetitive agonist at neu-
romuscular junctions, parasympathetic nerve terminals, and
nicotinic adrenergic receptors. The result is a medley of symp-
toms97 (Table 12-10).
Initial symptoms and signs depend on the route of expo-
sure and quantity of agent involved.96 Transdermal poisoning
causes insidious symptoms—initially vasodilation, sweating,
localized muscle fasciculations, and paralysis and then gener-
alized muscle weakness, paralysis, and respiratory depression.
TABLE 12-10  n Sarin or Organophosphate Poisoning
Symptoms
System Symptom(s)
Respiratory Dyspnea, cough, chest tightness,
wheezing (bronchospasm)
Cardiovascular* Tachycardia, hypertension
Neurologic Headache, weakness, fasciculations,
extremity numbness, decreased level
of consciousness, vertigo, dizziness,
convulsions
Ophthalmic Eye pain, blurred vision, dim vision,
conjunctival injection, tearing
Ear, nose, throat Rhinorrhea
Gastrointestinal Nausea, vomiting, diarrhea, tenesmus,
fecal incontinence
Genitourinary Urinary incontinence
Dermal Sweating
Psychological Agitation
General Fatigue
Data from Lee EC: JAMA 290:659-662, 2003.
*Adrenal medullary stimulation.
Inhalation of large quantities of nerve agent leads to acute
respiratory distress, loss of consciousness, flaccid paralysis,
convulsions, and coma. Physical signs include dyspnea, tachy-
pnea, and wheezing. There may be tachycardia or bradycardia,
reduced levels of consciousness, weakness, muscle fascicula-
tion, flaccid paresis. Examination of the eyes reveals miosis
and lacrimation.
If a sarin gas attack is suspected, it is imperative that
health care providers take extraordinary measures. Personal
protective equipment (PPE) includes protective suits, heavy
butyl rubber gloves, and self-contained breathing apparatus.
Aggressive decontamination of victims is required to prevent
further exposure to them and others. Goals of decontami-
nation are to prevent further absorption of nerve agents by
victims and to prevent the spread of nerve agents to others.
Decontamination is necessary only with topical exposure. The
skin should be washed with an alkaline solution of soap and
water or 0.5% hypochlorite solution (made by diluting house-
hold bleach 1:10). This chemically neutralizes the nerve agent.
ANESTHETIC CONSIDERATIONS
The anesthesiologist's involvement in the emergency care of
patients poisoned with organophosphates usually involves
securing the airway, commencing mechanical ventilation,
and transferring the patient to the ICU. The patient should
be treated with supplemental oxygen before intubation.
A hypnotic agent is administered to facilitate intubation.
Succinylcholine should be avoided because it is metabolized
by cholinesterase and will have a prolonged duration of action.
Neuromuscular blockade is usually unnecessary. Intubation
may be made more difficult because of excessive salivation
and airway secretions.
Two essential antidotes are required to treat organophos-
phate poisoning.96 Atropine reverses the muscarinic effects
of the poison, which include bronchoconstriction, abdomi-
nal pain, nausea, vomiting, and bradycardia. Pralidoxime acts
by disrupting covalent bonds between nerve agent and AChE
before they become permanent; thus, AChE is reactivated and
skeletal muscle weakness is reversed. Convulsions are treated
with benzodiazepines.97
Ricin
Ricin is a plant carbohydrate-binding protein (lectin) found
in high concentration in castor beans. Ricin is active orally or
on inhalation and thus could be aerosolized or used to poi-
son food. Ricin has relatively low potency, although it has been
used as a bioweapon, most famously in the assassination of
Georgi Markov in 1978 after skin perforation with the tip of an
umbrella. Ricin and castor bean extraction equipment found
during a police raid of a UK apartment and in a U.S. postal
facility suggests interest by terrorist organizations.
Ricin is composed of two hemagglutinins and two tox-
ins. The toxins, RCL III and RCL IV, are dimers of approxi-
mately 66,000 daltons. The toxins have an A and a B chain,
which are polypeptides and joined by a disulfide bond. The
 Chapter 12  Infectious Diseases and Biologic Weapons 397

B chain binds to cell surface glycoproteins and affects entry
into the cell by an unknown mechanism. The A chain acts
on the 60 S ribosomal subunit and prevents the binding of
elongation factor-2. This inhibits protein synthesis and leads
to cell death.
After inhalation exposure there is an incubation period of
4 to 8 hours, followed by fever, cough, dyspnea, nausea, and
the development of ARDS. By the oral route there is necrosis
of the GI tract and significant bleeding. In parenteral expo-
sure there is induration, erythema, and gradual development
of systemic symptoms.
Mortality and morbidity depend on the delivery route and
amount of ricin exposure. Therapy is supportive. The airway is
secured, and ventilation is ensured. Decontamination for ricin
exposure is similar to that for sarin infection.
Following infection, the neurotoxin is absorbed through
the intestinal mucosa and is widely distributed throughout the
body. Initial presentation includes GI problems that rapidly
progress to cranial nerve abnormalities (e.g., diplopia, dys-
phagia, dysarthria), particularly bulbar deficits. A progressive,
bilateral, descending motor neuron flaccid paralysis ensues,
followed by respiratory failure and death. The toxin combines
irreversibly with peripheral cholinergic synapses, preventing
acetylcholine release98 and leading to flaccid paralysis resem-
bling that seen with neuromuscular blockers. There are no
antiadrenergic effects. Blockade of neurotransmitter release
at the terminal is permanent, and recovery only occurs when
the axon sprouts a new terminal to replace the toxin-damaged
one. Mortality is less than 5% if the infection is treated but
approaches 60% if untreated (Table 12-11).

Botulinum
Botulism is caused by the toxin of Clostridium botulinum, an
aerobic, spore-forming bacterium. The bacterium occurs nat-
urally in soil. Botulism is a neuroparalytic disease. Although
manufactured as a bioweapon, botulinum toxin has never
been used as such. The most likely bioterrorism dissemination
scenarios include contamination of food and aerosolization.
ANESTHETIC CONSIDERATIONS
Treatment of botulism involves immediate administration of
antitoxin, respiratory monitoring, and mechanical ventilation.
Once forced vital capacity falls below 30% of predicted value,
intubation is necessary. No specific interventions are required
for intubation. The administration of neuromuscular blockers
is unnecessary. Patients with botulism may require mechani-
cal ventilation for up to 6 weeks. Full recovery may take 1 year.

TABLE 12-11  n  Differential Diagnosis of Botulism

Condition Features that Distinguish Each Condition from Botulism

Guillain-Barré syndrome (GBS)
(particularly Miller-Fisher
variant)
Usually an ascending paralysis, although Miller-Fisher variant may be descending with pronounced
cranial nerve involvement
Abnormal CSF protein 1 to 6 weeks after illness onset, although may be normal early in clinical course
Paresthesias typically occur (often stocking/glove pattern)
EMG shows abnormal nerve conduction velocity; facilitation with repetitive nerve stimulation does not
occur (as with botulism)
History of antecedent diarrheal illness (suggestive of Campylobacter infection)

Myasthenia gravis Dramatic improvement with edrophonium chloride (although some botulism patients may exhibit
partial improvement following administration of edrophonium chloride)
EMG shows decrease in muscle action potentials with repetitive nerve stimulation

Tick paralysis Ascending paralysis; paresthesias common

Careful examination reveals presence of tick attached to skin
Recovery occurs within 24 hours after tick removal
EMG shows abnormal nerve conduction velocity and unresponsiveness to repetitive stimulation
Usually does not involve cranial nerves

Lambert-Eaton syndrome Typically associated with carcinoma (often oat cell carcinoma of lung)
Although EMG findings are similar to those in botulism, repetitive nerve stimulation shows much
greater augmentation of muscle action potentials, particularly at 20 to 50 Hz

Stroke or CNS mass lesion Paralysis usually asymmetric

Brain imaging (CT or MRI) usually abnormal
Sensory deficits common
Altered mental status may be present

Poliomyelitis Febrile illness present

CSF shows pleocytosis and increased protein
Altered mental state may be present
Paralysis often asymmetric

(Continued)
 398 ANESTHESIA AND UNCOMMON DISEASES

TABLE 12-11  n  Differential Diagnosis of Botulism—Cont'd

Condition Features that Distinguish Each Condition from Botulism

Paralytic shellfish poisoning or History of shellfish (i.e., clams, mussels) or puffer fish ingestion within several hours before symptom
ingestion of puffer fish onset
Paresthesias of mouth, face, lips, and extremities occur

Belladonna toxicity History of recent exposure to belladonna-like alkaloids

Fever: tachycardia
Altered mental status

Aminoglycoside toxicity History of recent exposure to aminoglycoside antibiotics

More likely to occur in patient with renal insufficiency
Most often seen with neomycin administration
Most frequently associated with other neuromuscular blockers (e.g., succinylcholine, paralytic agents)

Other toxicities History of exposure to toxic agents

(hypermagnesemia, Carbon monoxide toxicity: Altered mental status may occur; cherry-colored skin
organophosphates, nerve gas, Hypermagnesemia: History of cathartic or antacid use may be present, elevated serum magnesium
carbon monoxide) level
Organophosphate toxicity: Fever, excessive salivation, altered mental status, paresthesias, miosis

Other conditions CNS infections (particularly brainstem infections)

Inflammatory myopathy
Hypothyroidism
Diabetic neuropathy
Viral infections
Streptococcal pharyngitis (pharyngeal erythema and sore throat can occur in botulism as a result of
dryness caused by parasympathetic cholinergic blockade)

Data from Infections Disease Society of North America. www.cidrap.umn.edu/cidrap/content/bt/botulism/biofacts/botulismfactsheet.html.

CSF, Cerebrospinal fluid; EMG, electromyogram; CT, computed tomography; MRI, magnetic resonance imaging; CNS, central nervous system.

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 C H A P T E R
13
Diseases of the Endocrine System
SHAMSUDDIN AKHTAR, MBBS  n

n If rapid parathyroid hormone assay is contemplated intra-

Parathyroid Glands operatively (to determine effectiveness of resection), pro-
Physiology
pofol use is discouraged and should be stopped at least 5
Hypercalcemia
minutes before the assay is drawn.
Hypocalcemia
n Before thyroid surgery the anesthesiologist must know
Thyroid Gland the gland's functional status; hyperthyroidism and
Physiology
hypothyroidism have significant preoperative implica-
Hyperthyroidism
tions. Imaging studies delineate anatomy, determine
Hypothyroidism
if other structures are involved, and help plan surgical
Thyroid Nodules and Carcinoma
management.
Anesthetic Considerations
n The major considerations regarding anesthesia for
Pituitary Gland patients with thyroid disorders are (1) attainment of a
Physiology
euthyroid state preoperatively, (2) preoperative prepara-
Anterior Pituitary Disease: Hypopituitarism and
tion and attention to disease characteristics, and (3) nor-
Hyperpituitarism
malization of cardiovascular function and temperature
Posterior Pituitary Disorders: Diabetes Insipidus and SIADH
perioperatively.
Adrenal Cortex
n Thyroid storm is a medical emergency with significant
Physiology
mortality. Therapy includes blocking the synthesis of thy-
Excessive Adrenocortical Hormones: Hyperplasia,
Adenoma, and Carcinoma roid hormones with antithyroid drugs.
Adrenocortical Hormone Deficiency n Myxedema coma is a rare complication associated with
Perioperative Stress and Corticoid Supplementation profound hypothyroidism and occasionally accompanied
Adrenal Medulla by pericardial effusion and congestive heart failure.
Pheochromocytoma n Pituitary adenomas are three to five times more com-
Pancreas mon than previously reported (5%-20% of primary CNS
Physiology tumors). Pituitary surgery treats the hyperfunctioning
Hypoglycemia and Hyperinsulinism (Islet Cell Tumors gland, cancer, or mass effect.
of Pancreas) n Pituitary surgical complications include temperature
Diabetes Mellitus dysregulation and abnormalities of endocrine function,
requiring immediate treatment of steroid deficiency,
hypoglycemia, and excessive or deficient secretion of
vasopressin.
n Abnormalities of vasopressin (ADH) function that affect
KEY POINTS
perioperative management involve a relative or absolute
n Anesthetic management of endocrine surgical patients lack or an excess of vasopressin.
should consider not only the organ of interest but also the n Special preoperative considerations for patients with
end-organ consequences of the endocrine dysfunction and Cushing's syndrome include regulating diabetes and hyper-
possible rare syndromes. tension, ensuring normal intravascular fluid volume and
n Severe symptomatic hypercalcemia (especially > 14 mg/dL) electrolyte concentrations, and careful patient positioning.
constitutes a medical emergency, often mandating treat- n Withdrawal of steroids or suppression of their adre-
ment before completing the diagnosis. nal synthesis by steroid therapy is the leading cause
401
 402 ANESTHESIA AND UNCOMMON DISEASES

of underproduction of corticosteroids. If not stressed,

TABLE 13-1  n Syndromes Associated with Parathyroid
­glucocorticoid-deficient patients usually have no periop- Gland Tumors
erative problems.
n Pheochromocytoma and paragangliomas are c­ atecholamine- Syndrome Clinical Features
producing nervous system tumors. Preoperative α-blockade Multiple endocrine Primary hyperparathyroidism
alleviates symptoms, with β-blockade and phenoxy- neoplasia type I (MEN-I) Enteropancreatic tumors
benzamine for patients with persistent dysrhythmias or Pituitary tumors
tachycardia. Thymic or bronchial endocrine
n Signs and symptoms in patients with insulinomas usually tumors
Adrenocortical tumors
are directly related to prolonged hypoglycemic states.
n Surgical mortality rates for diabetic patients average MEN-IIA Medullary thyroid carcinoma
five times higher than for nondiabetic patients. Acute Pheochromocytoma
Parathyroid hyperplasia
diabetic complications include hypoglycemia, diabetic
ketoacidosis, and hyperglycemic hyperosmolar nonke- Hereditary Primary hyperparathyroidism
totic coma. hyperparathyroidism– Parathyroid carcinoma
n For management of hyperglycemia in the ICU, recom- jaw tumor syndrome Ossifying fibromas of jaw
Renal cysts
mended threshold to initiate insulin infusion is 180 mg/dL, Renal solid tumors
then 140 to 180 mg/dL as the target range. Glucose control Uterine fibromas
by insulin infusion is recommended preoperatively and for
Familial isolated Associated with MEN-I
critically ill patients.
hyperparathyroidism

Neonatal severe Occurs in childhood

The endocrine system directly or indirectly influences many
critical functions of the body, especially energy homeostasis,
metabolism, and the cardiovascular system. Electrolyte and
fluid balance and immune system function are intricately con-
trolled by hormones. Disorders involving the endocrine sys-
tem can present as primary disorders of the endocrine organ
(common) or can be part of a syndrome (rare). The man-
agement of a patient who presents for surgery on endocrine
organs should not only focus on the organ of interest, but
also consider the end-organ consequences of the endocrine
dysfunction and its possible relationship to rare syndromes.
Perioperative outcome in many of these patients also involves
the anesthesiologist's understanding of the surgery and the
potentially dramatic pathophysiologic effects of removing the
endocrine organ.
PARATHYROID GLANDS
Parathyroid glands are intricately involved in calcium and
phosphate metabolism. Disorders of serum calcium concen-
tration are relatively common and often serve as a harbinger
of underlying parathyroid disease. However, many diseases
can cause hypercalcemia or hypocalcemia.1 Most surgeries
on the parathyroid gland are performed for primary hyper-
parathyroidism. However, surgery may also be needed for sec-
ondary hyperparathyroidism, inherited parathyroid diseases,
or familial hyperparathyroidism syndromes. Patients with
primary carcinoma of the parathyroid gland, multiple endo-
crine neoplasia type I (MEN-I, parathyroid hyperplasia with
lesions of pancreas and pituitary), and MEN-IIA (medullary
thyroid cancer, pheochromocytoma, and primary hyperpara-
thyroidism) may also present for parathyroid surgery.2-4 Other
parathyroid syndromes that may require surgery include
hereditary hyperparathyroidism–jaw tumor, familial isolated
hyperparathyroidism Extreme hypercalcemia caused by:
  Diffuse chief cell hyperplasia
 Demineralization and pathologic
 fractures
 Multiglandular parathyroid
  hyperplasia vs. adenoma
Familial hypocalciuric Mild to moderate hypercalcemia
hypercalcemia (FHH) Most common cause of hereditary
hypercalcemia
Histologically, parathyroid glands
removed from FHH patients are
normal or occasionally hyperplastic.
hyperparathyroidism, neonatal severe hyperparathyroidism,
and familial hypocalciuric hypercalcemia (Table  13-1). To
appreciate perioperative considerations for patients undergo-
ing parathyroid surgery, it is important to know about calcium
metabolism.
Physiology
The calcium ion (Ca++) plays a critical role in diverse cellu-
lar functions such as cardiac contractility, hormone secretion,
blood coagulation, and neuromuscular signaling. Total (bound
and free) serum calcium concentration is maintained at the
normal level of 9.5 to 10.5 mg/dL through a series of feedback
mechanisms that involve parathyroid gland, bone, kidney, and
gastrointestinal (GI) tract5 (Fig.  13-1). Approximately 50%
of the serum calcium is bound to serum proteins (albumin),
40% is ionized, and the remaining 10% is bound to such che-
lating agents as citrate. If the serum protein concentration
decreases, the total serum calcium concentration will also
decrease. The rule of thumb is that for every 1-g decrement
in albumin, a 0.8-mg/dL decrement in total serum calcium
concentration occurs. Likewise, if the serum proteins increase
 Chapter 13  Diseases of the Endocrine System 403

increasing calcium reabsorption from bone and by promot-

Increased Decreased
extracellular calcium extracellular calcium ing synthesis of 1,25(OH)2D3, which in turn enhances calcium
reabsorption from the gut. Finally, PTH directly increases cal-
Intestines cium reabsorption from the renal tubule. Thus, PTH accel-
1,25(OH)2D3 erates the breakdown of bone by a complex mechanism that
absorption includes a fast component and a slow component (involving
protein synthesis and cellular proliferation). In addition, PTH
Kidney Bone Parathyroid has an anabolic effect on bone formation, and in tissue culture
absorption resorption glands it increases the number of active osteoblasts, the maturation of
cartilage, and osteoid formation within the bone shaft.

Increased PTH
Hypercalcemia
FIGURE 13-1  Factors involved in extracellular calcium
homeostasis. 1,25[OH]2D3, 1,25-dihydroxycholecalciferol; PTH, Etiology. The many causes of hypercalcemia can be grouped
parathyroid hormone (parathormone). pathophysiologically into six broad categories (Fig  13-2).
Excessive PTH production is seen in (1) primary hyperpara-
thyroidism, caused by adenoma, hyperplasia, or rarely carci-
(as in myeloma), total serum calcium will increase. Acidosis
noma; (2) tertiary hyperparathyroidism, caused by long-term
tends to increase the ionized calcium, whereas alkalosis tends
stimulation of PTH secretion in renal insufficiency; (3) ecto-
to decrease it. Serum calcium tends to decrease slightly with
pic PTH secretion (rare); (4) inactivation mutations at the cal-
age, with a concomitant elevation of the serum parathyroid
cium sensor receptor (CaSR), as seen in familial hypocalciuric
hormone (PTH, parathormone), perhaps contributing to the
hypercalcemia (FHH); and (5) alteration in CaSR function, as
osteoporosis associated with the aging process.6
seen with lithium therapy.
When the ionized calcium concentration decreases or
Parathyroid hyperplasia, usually involving all four para-
the serum phosphate level rises, release of PTH is stimulated
thyroid glands, may be a major cause of the hyperparathyroid
through activation of the calcium sensor receptor on para-
syndrome. Carcinoma of the parathyroid glands is extremely
thyroid cells. PTH is secreted by the four parathyroid glands,
rare. All adenomas might begin as hyperplasia;8 therefore, for
which are usually located posterior to the upper and lower
the individual patient, where surgery occurs in the natural his-
poles of the thyroid gland. PTH increases tubular reabsorption
tory of the disease may determine whether hyperplasia or an
of calcium and decreases tubular reabsorption of phosphate
adenoma is found. Hypercalcemia can also be seen in solid
to raise the serum calcium concentration. PTH also increases
malignancies caused by overproduction of PTH-related pep-
the resorption from the bone. Another effect of PTH on the
tide (PTHrP) or lytic skeletal metastases, as seen in myeloma
kidney is the increase in active form of vitamin D, which in
or breast cancer. Excessive 1,25(OH)2D3 production can also
turn increases the absorption of calcium from the intestines.
cause hypercalcemia. This is typically observed with lym-
A renal phosphate leak is the result of excessive PTH secretion.
phomas, granulomatous diseases, or vitamin D intoxication.
Vitamin D plays an important role in calcium homeosta-
Primary increase in bone resorption, as seen with immobi-
sis. Cholecalciferol is synthesized in the skin by the effects
lization, Paget's disease, and hyperthyroidism, can also lead
of ultraviolet light. Cholecalciferol is hydroxylated in the
to hypercalcemia. Excessive calcium intake, which can occur
liver to form 25-hydroxycholecalciferol. The 25-hydroxy
with total parenteral nutrition (TPN) and milk-alkali syn-
derivative is further hydroxylated in the kidney to form
drome, can also cause hypercalcemia. Hypercalcemia also
1,25-­dihydroxycholecalciferol (1,25[OH]2D3). 1,25(OH)2D3
results from other endocrine disorders (e.g., adrenal insuf-
stimulates absorption of both calcium and phosphorus from
ficiency, pheochromocytoma, VIPomas) and medications
the GI tract.7 Thus, vitamin D provides the substrates for the
(e.g., antiestrogens, vitamin A, thiazides). Thiazides increase
formation of mineralized bone. 1,25(OH)2D3 may also directly
renal tubular reabsorption of calcium and may even enhance
enhance mineralization of newly formed osteoid matrix in
the PTH effects on the renal tubule. Most patients with sig-
bone. Vitamin D derivatives also seem to work synergisti-
nificant hypercalcemia associated with thiazide diuretics have
cally with PTH to increase resorption of bone. This is clinically
hyperparathyroidism.
important because immobilization alone increases bone resorp-
tion, and if the patient is receiving a vitamin D derivative, bone Clinical Presentation. Patients with hypercalcemia present
resorption may be increased further. with a variety of symptoms. The level of blood calcium is fre-
Hydroxylation of 25-hydroxycholecalciferol is controlled quently related to the degree and severity of symptoms. Mild
in the kidney by PTH and the phosphorus level. Elevated hypercalcemia (up to 11-11.5 mg/dL) is usually asymptomatic
PTH and hypophosphatemia tend to accentuate the synthe- and detected on routine calcium measurement. Patients may
sis of 1,25(OH)2D3, whereas low levels of PTH and high lev- have vague complaints of depression, poor concentration, and
els of phosphate turn off the synthesis of 1,25(OH)2D3 in the personality changes. Other patients may present with neph-
kidney. PTH maintains a normal calcium level in blood by rolithiasis or peptic ulcer disease. Nephrolithiasis occurs in
 404 ANESTHESIA AND UNCOMMON DISEASES
Hypercalcemia
Excessive Excessive Excessive
PTH production calcium intake 1, 25(OH)2D3
production
Primary
hyperparathyroidism Granulomatous diseases
(sarcoidosis, tuberculosis,
Tertiary silicosis)
hyperparathyroidism
Lymphomas
Ectopic PTH secretion
Vitamin D intoxication
Inactivating mutations
in the CaSR
Alterations in CaSR Milk-alkali
function syndrome
Total parenteral
nutrition
FIGURE 13-2  Causes of hypercalcemia. CaSR, Calcium sensor receptor; PTHrP, parathormone-related peptide; VIPoma, vasoactive
intestinal polypeptide tumor (usually islet cell).
60% to 70% of patients with hyperparathyroidism. Sustained
hypercalcemia can result in tubular and glomerular disorders.
Polyuria and polydipsia are common complaints. Patients
with calcium levels above 12 to 13 mg/dL, especially develop-
ing acutely, have anorexia, nausea, vomiting, abdominal pain,
constipation, polyuria, tachycardia, and dehydration.1,9
Hypercalcemia can also result in significant echocardio-
graphic (ECG) changes, including bradycardia, atrioventricu-
lar block, and short QT interval. Psychosis and obtundation
are usually the end results of severe and prolonged hypercal-
cemia. Band keratopathy is a most unusual physical finding.
Bone disease in hyperparathyroidism, such as subperiosteal
resorption, can also be seen in radiographs of the teeth and
hands in patients with prolonged hypercalcemia.10 Severe
bone disease in hyperparathyroidism, such as osteitis fibrosa
cystica, is only rarely seen and usually in older patients with
long-standing disease (up to 20 years). The older patient with
severe osteopenia, and perhaps vertebral compression frac-
tures, should prompt suspicion of hyperparathyroidism.
Patients with hyperparathyroidism have elevated calcium
and low serum phosphate levels. Very mild hyperchloremic
acidosis may be present. The PTH level is usually elevated,
particularly with respect to the level of calcium concentration,
and PTH reduction is the hallmark of successful surgery.11,12
The only two situations in which hypercalcemia would be
associated with a high PTH level are hyperparathyroidism
and the ectopic PTH syndrome (usually secondary to a tumor
of the lung or kidney that produces a biologically active frag-
ment of PTH).1 All other causes of hypercalcemia are associ-
ated with either “normal” or, more appropriately, low levels of
Primary increase in Hypercalcemia Other
bone resorption of malignancy causes
Overproduction
of PTHrP
(many solid
tumors)
Lytic skeletal
metastases
(breast myeloma)
Hyperthyroidism Other endocrine
disorders (adrenal
Immobilization insufficiency,
pheochromocytoma,
VIPoma)
Medications
(thiazides, vitamin A,
antiestrogens)
PTH. When a patient presents with an extremely high blood
calcium level (> 14 mg/dL), the patient likely has a distant can-
cer rather than hyperparathyroidism. Overall, about 50% of all
cases of hypercalcemia are caused by cancer invading bone. In
these patients, prognosis is poor; more than 50% die within 6
months. Treating hypercalcemia does not prolong survival but
usually improves quality of life.13,14
Evaluation for bony metastases includes a technetium
diphosphonate bone scan, which is positive in a large percent-
age of cancers that have metastasized. In addition to serum
calcium and phosphate, the bony fraction of alkaline phos-
phatase, creatinine, electrolyte, and urinary calcium levels are
obtained, as well as the appropriate skeletal radiographs and
isotope bone scan (by endocrinologist) to aid diagnosis.
Management. Severe symptomatic hypercalcemia, espe-
cially levels greater than 14 mg/dL, constitutes a medical emer-
gency, and often treatment must be begun before the diagnosis
is complete. The signs and symptoms in any one patient can-
not be related to serum calcium level. One patient with total
calcium of 14 mg/dL may be almost asymptomatic, whereas
another may have severe polyuria, tachycardia, dehydration,
and even psychosis. Age seems to be a factor; that is, for any
given calcium level, the older patient is more likely to be symp-
tomatic than younger patients.
The first step in the management of hypercalcemia is hydra-
tion. Infusion of 4 to 6 L of intravenous (IV) saline may be
required in the first 24 hours. Loop diuretics may be required
to enhance sodium and calcium excretion.1 Complications of
these interventions include hypomagnesemia and hypokalemia.
 Chapter 13  Diseases of the Endocrine System 405
Extreme care must be exercised in the use of digitalis deriva-
tives for patients with hypercalcemia. Digitalis intoxication
occurs quite readily in the presence of hypercalcemia, and dys-
rhythmias from digitalis toxicity are common (Box 13-1).
If there is increased calcium mobilization from bone, as in
malignancy or severe hyperparathyroidism, drugs that inhibit
bone resorption should be considered. Zoledronic acid (e.g.,
4 mg intravenously [IV] over 30 minutes), pamidronate (e.g.,
60–90 mg IV over 2-4 hours), and etidronate (e.g., 7.5 mg/kg/
day for 3-7 consecutive days) can be used in the treatment
of hypercalcemia of malignancy in adults. Onset of action
is within 1 to 3 days, with normalization of serum calcium
levels occurring in 60% to 90% of patients. Because of their
effectiveness, bisphosphonates have replaced calcitonin and
plicamycin, which are rarely used in current practice for the
management of hypercalcemia.1 In rare cases, dialysis may be
necessary. Finally, although IV phosphate chelates calcium
and decreases serum calcium levels, this therapy can be toxic
because calcium-phosphate complexes may deposit in tissues
and cause extensive organ damage.
In patients with 1,25(OH)2D3-mediated ­hypercalcemia,
glucocorticoids are the preferred therapy because they
decrease 1,25(OH)2D3 production. IV hydrocortisone (100-
300 mg daily) or oral prednisone (40-60 mg daily) for 3 to 7
days are used most often. Other drugs, such as ketoconazole,
chloroquine, and hydroxychloroquine, may also decrease
1,25(OH)2D3 production and are used occasionally.
Patients with Hyperparathyroidism
Preoperative Considerations. Patients with moderate hyper-
calcemia who have normal renal and cardiovascular function
present no special preoperative problems. ECG findings can
be examined preoperatively and intraoperatively for shortened
PR or QT interval.15 Because severe hypercalcemia can result
in hypovolemia, normal intravascular volume and electrolyte
status should be restored before anesthesia for elective surgery.
BOX 13-1   n  MANAGEMENT OF HYPERCALCEMIA
Provide hydration: 4-6 L of IV saline in first 24 hours.
Administer loop diuretics to enhance sodium excretion.
Inhibit bone resorption by bisphosphonates (zoledronic acid,
pamidronate, etidronate).
Rarely, plicamycin may be indicated.
Correct hypokalemia and hypomagnesemia that may develop with
treatment of hypercalcemia.
Anesthetic Considerations
Correct hypovolemia.
Correct electrolyte disorders.
Note risk of aspiration if patient has altered mental status.
Take special care in positioning (risk of pathologic fractures).
Avoid or discontinue propofol if rapid PTH assay is going to be
conducted intraoperatively.
Postoperatively, note risk of recurrent laryngeal nerve injury, glottic
edema, hypocalcemia, hypophosphatemia and hypomagnesemia.
IV, Intravenous; PTH, parathormone.
Aspiration precautions must be taken because the hypercalce-
mic patient with altered mental status may have a full stomach
or may be unable to protect the airway. Radiographs of the
cervical spine should be taken to rule out lytic lesions when
hypercalcemia results from cancer.16 Laryngoscopy in a patient
with an unstable cervical spine may result in quadriplegia.
Intraoperative and Postoperative Considerations. There
have been significant advances in parathyroid surgery. With
newer imaging and radionuclide techniques and rapid intra-
operative PTH assay, it is no longer necessary to remove all
four parathyroid glands. Unilateral removal of the glands is
now possible with less invasive techniques.17 Surgery can be
performed under general, regional, or local anesthesia based
on institutional approach. Although no controlled study
has demonstrated clinical advantages of one anesthetic over
another, if rapid intraoperative PTH assessment is contem-
plated (to determine the effectiveness of resection), propofol
use is discouraged. If propofol is used, it should be stopped at
least 5 minutes before the assay is drawn.
Maintenance of anesthesia usually presents little diffi-
culty. No special intraoperative monitoring for hyperparathy-
roid patients is required. Because of the proximity of surgical
retraction to the face, however, meticulous care is taken to
protect the eyes. The possibility of lytic or pathologic frac-
tures warrants careful positioning. Response to neuromuscu-
lar blocking agents may be unpredictable when calcium levels
are elevated; reversal of the effects may be difficult.18 Failure to
remove all the parathyroid adenomas may necessitate single
or multiple reoperations. Sestamibi scanning and venous sam-
pling of PTH levels in thyroidal venous beds may provide use-
ful information to the surgeon at reoperation.19 Unusual sites
of parathyroid adenoma include areas behind the esophagus,
in the mediastinum, and within the thyroid.
Of the many possible postoperative complications (nerve
injuries, bleeding, metabolic abnormalities), bilateral recur-
rent nerve trauma and hypocalcemic tetany are most seri-
ous. Bilateral recurrent laryngeal nerve injury (from trauma
or edema) causes stridor and laryngeal obstruction as a result
of unopposed adduction of the vocal cords and closure of
the glottic aperture. Immediate endotracheal intubation is
required in these patients, usually followed by tracheostomy
to ensure an adequate airway. This rare complication of bilat-
eral recurrent nerve injury occurred only once in more than
30,000 operations at the Lahey Clinic (Tufts University School
of Medicine, Burlington, Mass). Unilateral recurrent laryn-
geal nerve injury often goes unnoticed because of compensa-
tory overadduction of the uninvolved cord. Because bilateral
injury is rare and clinically obvious, laryngoscopy after thy-
roid or parathyroid surgery need not be performed routinely;
however, the clinician can easily test vocal cord function after
surgery by asking the patient to say “e” or “moon.” Unilateral
nerve injury is characterized by hoarseness, and bilateral nerve
injury is characterized by aphonia. Selective injury of adduc-
tor fibers of both recurrent laryngeal nerves leaves the abduc-
tor muscles relatively unopposed, and pulmonary aspiration is
 406 ANESTHESIA AND UNCOMMON DISEASES
a risk. Selective injury of abductor fibers, on the other hand,
leaves the adductor muscles relatively unopposed, and airway
obstruction can occur.
Bullous glottic edema is edema of the glottis and phar-
ynx, which occasionally follows parathyroid surgery. This is
an additional cause of postoperative respiratory compromise;
it has no specific origin, and there is no known preventive
measure.
Unintended hypocalcemia during surgery for parathyroid
disease occurs in rare cases, usually from the lingering effect
of vigorous preoperative treatment. This effect is especially
important for patients with advanced osteitis because of the
calcium affinity of their bones. After parathyroidectomy, mag-
nesium or calcium ions may be redistributed internally (into
“hungry bones”), thus causing hypomagnesemia, hypocalce-
mia, or both. Risk factors for the development of hypocal-
cemia (and hypocalcemic tetany) after parathydroidectomy
include subtotal or 3½-gland parathyroidectomy, bilateral
neck exploration, removal of the parathyroids together with
thyroid glands, or history of previous neck dissection.17 In
high-risk situations, management after parathyroid surgery
should include serial determinations of serum calcium, inor-
ganic phosphate, magnesium, and PTH levels.20-25 Serum cal-
cium levels fall by several milligrams per deciliter in the first 24
hours. The lowest level usually is reached within 4 or 5 days. In
some patients, hypocalcemia may be a postoperative problem.
Causes include insufficient residual parathyroid tissue, surgi-
cal trauma or ischemia, postoperative hypomagnesemia, and
delayed recovery of function of normal parathyroid gland tis-
sue. It is particularly important to correct hypomagnesemia in
patients with hypocalcemia because PTH secretion is dimin-
ished in the presence of hypomagnesemia.22,23 Potentially
lethal complications of severe hypocalcemia include laryngeal
spasm and hypocalcemic seizures.
In addition to monitoring total serum calcium or ionized
calcium postoperatively, the clinician can test for Chvostek and
Trousseau signs. Because Chvostek sign is present in 10% to
20% of individuals who do not have hypocalcemia, an attempt
should be made to elicit this sign preoperatively. Chvostek sign
is a contracture of the facial muscles produced by tapping
the ipsilateral facial nerves at the angle of the jaw. Trousseau
sign is elicited by application of a blood pressure (BP) cuff at
a level slightly above the systolic pressure for a few minutes.
The resulting carpopedal spasm, with contractions of the fin-
gers and inability to open the hand, stems from the increased
muscle irritability in hypocalcemic states, which is aggravated
by ischemia produced by the inflated BP cuff. Because a post-
operative hematoma can compromise the airway, the neck and
wound dressings should be examined for evidence of bleeding
before a patient is discharged from the recovery room.
Hypophosphatemia may also occur postoperatively. It is par-
ticularly important to correct this deficiency in patients with
congestive heart failure (CHF). In a group of patients with
severe hypophosphatemia, correction of serum phosphate con-
centration from 1.0 to 2.9 mg/dL led to significant improve-
ment in left ventricular contractility at the same preload.20
Other complications of hypophosphatemia include hemolysis,
platelet dysfunction, leukocyte dysfunction (depression of che-
motaxis, phagocytosis, and bactericidal activity), paresthesias,
muscular weakness, and rhabdomyolysis.23 In patients with
both hypocalcemia and hypomagnesemia, correction of the
hypomagnesemia may cause greatly increased PTH secretion,
resulting in dramatic hypophosphatemia. Serum phosphate
levels should be monitored closely in such patients.22,23
Hypomagnesemia may occur postoperatively. Clinical
sequelae of magnesium deficiency include cardiac dysrhyth-
mias (principally ventricular tachydysrhythmias), hypocal-
cemic tetany, and neuromuscular irritability independent of
hypocalcemia (tremors, twitching, asterixis, seizures).21 Both
hypomagnesemia and hypokalemia augment the neuromus-
cular effects of hypocalcemia. Often, just restoring the magne-
sium deficit corrects the hypocalcemia. It is preferable to use
oral calcium (1 or 2 g of calcium gluconate four times daily)
when the patient is able to take oral fluids.
During the first week or 10 days after surgery, vitamin D
derivatives are avoided to allow the suppressed parathyroid tis-
sue (if present) to function. Vitamin D derivatives are always
started if the patient has significant hypocalcemia 2 weeks after
surgery. The management of hypoparathyroidism is not easy,
and careful follow-up of patients is mandatory. Oral calcium
and vitamin D analogs are used for long-term management.
Hypocalcemia
Etiology. Probably the most common cause of hypocalce-
mia is hypoalbuminemia, followed by surgical removal of the
parathyroids. However, causes of hypocalcemia can be dif-
ferentiated based on high or low PTH levels. Low PTH lev-
els (hypoparathyroidism) are associated with (1) parathyroid
agenesis (DiGeorge syndrome); (2) parathyroid gland destruc-
tion from surgery, radiation, autoimmune disease, or infiltra-
tion by metastatic or inflammatory diseases; and (3) reduced
parathyroid function caused by hypomagnesemia or activat-
ing calcium sensor receptor mutations (Fig. 13-3).
Hypocalcemia can lead to a compensatory increase in PTH
levels (secondary hyperparathyroidism). The causes for hypo-
calcemia in patients with high PTH level include the following:
1. Vitamin D deficiency or impaired 1,25(OH)2D3 produc-
tion or action, as seen in nutritional deficiency, renal
insufficiency with impaired 1,25(OH)2D3 production, or
resistance to vitamin D, including receptor defects.
2. Parathyroid hormone resistance syndromes, includ-
ing PTH receptor mutations and G-protein mutations
(pseudohypoparathyroidism).
3. Drugs such as calcium chelators, inhibitors of bone resorp-
tion, and agents that alter vitamin D metabolism (e.g., phe-
nytoin, ketoconazole).
4. Acute pancreatitis, acute rhabdomyolysis, “hungry bone”
syndrome after parathyroidectomy, or osteoblastic metas-
tases with marked stimulation of the bone (prostate
cancer).
 Chapter 13  Diseases of the Endocrine System 407

Causes of hypocalcemia

Low parathyroid hormone levels High parathyroid hormone levels

(hypoparathyroidism) (secondary hyperparathyroidism)

Parathyroid Parathyroid Reduced Vitamin D PTH hormone Drugs Other

agenesis destruction parathyroid function deficiency/ resistance causes
impaired syndromes
1,25(OH)2D3
production/
action
Isolated Surgical Hypomagnesemia PTH receptor Acute
mutations pancreatitis
DiGeorge Radiation Activating
syndrome CaSR Pseudo- Acute
Infiltration mutations Nutritional hypoparathyroidism Calcium rhabdomyolysis
metastases/ vitamin D (G protein mutations) chelators
systemic deficiency Hungry bone
diseases (poor intake or Inhibitors of syndrome
absorption) bone resorption
Autoimmune (bisphosphonates, Osteoblastic
Renal insufficiency with plicamycin) metastases
impaired 1,25(OH)2D3 production (prostate
Altered vitamin D cancer)
Vitamin D resistance, metabolism
including receptor defects (phenytoin, ketoconazole)
FIGURE 13-3  Causes of hypocalcemia.

In DiGeorge syndrome, thymic hypoplasia is associated
with hypoparathyroidism.26 Pseudohypoparathyroidism is an
unusual entity associated with short stature, round facies, and
short metacarpals, as well as parathyroid hyperplasia. It rep-
resents in part as end-organ resistance to the action of PTH
resulting from G-protein defects. 1,25(OH)2D3 levels are low in
pseudohypoparathyroidism, and replacement of this vitamin
D derivative can partially reverse the end-organ resistance.
Hypomagnesemia impairs PTH release and thus can cause
profound hypocalcemia. Hypomagnesemia is common in
patients with alcoholism, malnutrition, or chronic severe
malabsorption states. The calcium level may be restored by
replacing magnesium. The vitamin D deficiency of the mal-
absorption syndrome, osteomalacia (adults) and rickets
(children), is associated with a low serum phosphorus con-
centration. In all other causes of hypocalcemia, serum phos-
phorus tends to be elevated. It is disproportionately elevated
in chronic renal failure. Cataracts and basal ganglion calcifi-
cation are seen in both hypoparathyroidism and pseudohy-
poparathyroidism. Subperiosteal resorption, the hallmark of
excessive PTH secretion, is seen mainly in chronic renal fail-
ure associated with secondary hyperparathyroidism and in
some forms of pseudohypoparathyroidism.
Clinical Presentation. Most of the clinical manifestations
of hypoparathyroidism are attributable to hypocalcemia.
Hypocalcemia occurs because of a fall in the equilibrium level
of the blood-bone calcium relationship, in association with a
reduction in renal tubular reabsorption and GI absorption of
calcium. PTH inhibits renal tubular reabsorption of phosphate
and bicarbonate; thus, serum phosphate and bicarbonate lev-
els are elevated in patients with hypoparathyroidism.
The manifestations of acute hypoparathyroidism are dis-
cussed earlier in the context of the postoperative management
of hypercalcemia. A nerve exposed to low calcium concentra-
tion has a reduced threshold of excitation, responds repeti-
tively to a single stimulus, and has impaired accommodation
and continuous activity. Tetany usually begins with paresthe-
sias of the face and extremities, which increase in severity.
Spasms of the muscles in the face and extremities follow. Pain
in the contracting muscle may be severe. Patients often hyper-
ventilate, and the resulting hypocapnia worsens the tetany.
Spasm of laryngeal muscles can cause the vocal cords to be
fixed at the midline, leading to stridor and cyanosis. Chvostek
and Trousseau signs are classic signals of latent tetany, and
manifestations of spasm distal to the inflated BP cuff should
occur within 2 minutes (see earlier discussion).
Hypocalcemia delays ventricular repolarization, thus
increasing the QTc interval (normal, 0.35-0.44). With electri-
cal systole thus prolonged, the ventricles may fail to respond
to the next electrical impulse from the sinoatrial (SA) node,
causing 2:1 heart block. Prolongation of the QT interval is a
moderately reliable ECG sign of hypocalcemia, not for the
population as a whole but for individual patients. Thus, follow-
ing the QT interval as corrected for heart rate is a useful but
not always accurate means of monitoring hypocalcemia. CHF
may also occur with hypocalcemia, but this is rare. Heart fail-
ure in patients with coexisting heart disease can be improved
 408 ANESTHESIA AND UNCOMMON DISEASES
when calcium and magnesium ion levels are restored to nor-
mal, and these levels should be normal before surgery. Sudden
decreases in blood levels of ionized calcium (as with chelation
therapy) can result in severe hypotension.
Patients with hypocalcemia may have seizures. These may
be focal, jacksonian, petit mal, or grand mal in appearance,
indistinguishable from those that occur in the absence of hypo-
calcemia. Patients may also have a type of seizure called cere-
bral tetany, which consists of generalized tetany followed by
tonic spasms. Therapy with standard anticonvulsants is inef-
fective. In long-standing hypoparathyroidism, calcifications
may appear above the sella, representing deposits of calcium
in and around small blood vessels of the basal ganglia, and
may be associated with various extrapyramidal syndromes.
Other common clinical signs of hypocalcemia include
clumsiness, depression, muscle stiffness, paresthesias, dry
scaly skin, brittle nails, coarse hair, and soft tissue calcifica-
tions. Patients with long-standing hypoparathyroidism some-
times adapt to the condition well enough to be asymptomatic.
The symptoms related to tetany seem to correlate best with
the level of the ionized calcium. If alkalosis is present, the total
calcium level may be normal, but the ionized calcium may be
low. This can result in symptoms of neuromuscular irritabil-
ity (i.e., hyperventilation syndrome). With slowly developing
chronic hypocalcemia, the symptoms may be very mild despite
severe hypocalcemia, which may partly result from adaptive
changes in the level of the ionized calcium. Even with calcium
levels of 6 to 7 mg/dL, minor muscle cramps, fatigue, and mild
depression may be the only symptoms. Many patients with a
calcium level of 6 to 6.5 mg/dL are asymptomatic aside from
some mild depression of intellectual function.
Management. The approach to treatment of patient with
hypocalcemia depends on the rate of decline and clinical pre-
sentation. For example, seizure and laryngospasm require
acute treatment. Acute, symptomatic hypocalcemia is initially
managed with calcium gluconate, 10 mL 10% wt/vol (90 mg or
2.2 mmol) IV, diluted in 50 mL of 5% dextrose or 0.9% sodium
chloride, IV over 5 minutes. Continuing hypocalcemia often
requires a constant IV infusion (typically 10 ampules of cal-
cium gluconate or 900 mg of calcium in 1 L of 5% dextrose or
0.9% NaCl administered over 24 hours). Accompanying hypo-
magnesemia, if present, should be treated with appropriate
magnesium supplementation (Box 13-2).
BOX 13-2   n  MANAGEMENT OF HYPOCALCEMIA
Acute Treatment
10% calcium gluconate over 5 minutes, then IV calcium gluconate
infusion of 900 mg over 24 hours
Chronic Therapy
Calcium supplements
Vitamin D supplements in large doses
Anesthetic Considerations
Correct electrolyte imbalance: calcium, phosphate, and magnesium
Chronic hypocalcemia from hypoparathyroidism is treated
with calcium supplements (1000-1500 mg/day of elemental
calcium in divided doses) and either vitamin D2 or vitamin
D3 (25,000-100,000 U daily) or calcitriol (1,25[OH]2D3, 0.25-2
μg/day). Other vitamin D metabolites (dihydrotachysterol,
alfacalcidiol) are now used less frequently. Vitamin D defi-
ciency, however, is best treated using vitamin D supplemen-
tation, with the dose depending on the severity of the deficit
and the underlying cause. Thus, nutritional vitamin D defi-
ciency generally responds to relatively low doses of vitamin
D, 50,000 U two or three times per week for several months,
whereas vitamin D deficiency caused by malabsorption may
require much higher doses (≥ 100,000 U/day).1 The treatment
goal is to bring serum calcium into the low-normal range and
to avoid hypercalciuria, which may lead to nephrolithiasis.
Perioperative Considerations
Patients with Hypoparathyroidism. Because treatment of
hypoparathyroidism is not surgical, hypoparathyroid patients
require surgery for an unrelated condition. Their calcium, phos-
phate, and magnesium levels should be measured both pre-
operatively and postoperatively. Patients with symptomatic
hypocalcemia should be treated with IV calcium gluconate before
surgery, as previously detailed. Initially, 10 to 20 mL of 10% cal-
cium gluconate may be given at a rate of 10 mL/min. The effect on
serum calcium levels is of short duration, but a continuous infu-
sion with 10 mL of 10% calcium gluconate in 500 mL of solution
over 6 hours may help to maintain adequate serum calcium levels.
The objective of therapy is to have symptoms under control
before surgery and anesthesia. In patients with chronic hypo-
parathyroidism, the objective is to maintain the serum calcium
level in at least the lower half of the normal range. A preopera-
tive electrocardiogram (ECG) can be obtained and the QTc
interval calculated. The QTc value may be used as a guide to
the serum calcium level if a rapid laboratory assessment is not
possible. The choice of anesthetic agents or techniques does
not appear to influence outcome, with the exception of avoid-
ance of respiratory alkalosis, because this tends to decrease
ionized calcium levels further.
Patients with DiGeorge Syndrome. These patients can
have congenital thymic hypoplasia and hypoparathyroidism;
associated anomalies are usually vascular, such as tetralogy
of Fallot, persistent truncus arteriosus, or right aortic arch.
Furthermore, airway abnormality and compression of the
trachea by abnormal vessels are possibilities. Thorough pre-
operative workup to rule out lower airway abnormalities and
cardiovascular anomalies is warranted before elective surgery.
These patients are also prone to sepsis caused by depressed
cellular immunity, so leukocyte-depleted, irradiated blood is
indicated for such patients.26
THYROID GLAND
Thyroidectomy is typically performed (1) to treat benign and
malignant thyroid tumors or establish definitive diagnosis of a
thyroid nodule; (2) to alleviate pressure symptoms or respiratory
 Chapter 13  Diseases of the Endocrine System 409

difficulties associated with a benign or malignant process (e.g., almost all emergency situations, and certainly in all elective
large or substernal goiters); or (3) as therapy for hyperthyroid- situations, stabilization of any endocrine abnormality affect-
ism (thyrotoxicosis) in some patients, both those with Graves' ing the patient's preoperative state may improve outcome.27-29
disease and others with hot nodules. Thyroid tumors can be
part of rare familial syndromes such as phosphatase and tensin
Physiology
homolog (PTEN) hamartoma tumor syndrome, familial ade-
nomatous polyposis syndrome, Carney's complex, Pendred's Thyroid hormone biosynthesis involves five steps30,31:
syndrome, and Werner's syndrome (Table 13-2). (1) iodide trapping, (2) oxidation of iodide and iodination of
As with other endocrinopathies, two themes guide anes- tyrosine residues, (3) hormone storage in the colloid of the
thesia for patients with thyroid disease. First, the organ system thyroid gland as part of the large thyroglobulin molecule,
that most influences the anesthetic management of patients (4) proteolysis and release of hormones, and (5) conversion
with endocrinopathy is the cardiovascular system. Second, in of less active prohormone thyroxine (T4) to the more potent
3,5,3-tri-iodothyronine (T3). The first four steps are regulated
by pituitary thyroid-stimulating hormone (TSH, thyrotropin).
TABLE 13-2  n Syndromes Associated with Thyroid Proteolysis of stored hormone in the colloid is inhibited by
Gland Tumors iodide (Fig. 13-4).
The major thyroid products are the prohormone T4, a
Syndrome Clinical Features product of the thyroid gland, and T3, a product of both the
MEN-IIB Pheochromocytoma thyroid and the extrathyroidal enzymatic deiodination of
Mucosal neuromas T4. Approximately 85% of T3 is produced outside the thy-
Ganglioneuromatosis of intestine roid gland. Production of thyroid hormones is maintained by
Marfanoid habitus
secretion of TSH by the pituitary gland, which in turn is reg-
Carney's complex Mucocutaneous pigmented lesion ulated by secretion of thyrotropin-releasing hormone (TRH)
(syndrome, triad) Myxomas in the hypothalamus. The production of thyroid hormone is
Multiple thyroid follicular adenomas
Primary pigmented nodular
adrenocortical disease
Pituitary growth hormone-producing 
adenoma Hypothalamus

PTEN hamartoma tumor Multiple adenomatous nodules
syndrome Lymphocytic thyroiditis ?

Familial adenomatous Papillary thyroid carcinoma TSH (short feedback)

polyposis syndrome Adrenal adenomas
?
Colon polyps
Desmoid tumors
Osteomas TRF
Hepatoblastomas
Retinal pigmented epithelial
hypertrophy 
Anterior
Pendred's syndrome Thyroid goiter
Thyrotroph pituitary
Bilateral sensorineural hearing loss 
Werner's syndrome Papillary thyroid carcinoma
Follicular thyroid carcinoma
Anaplastic thyroid carcinoma T4 T3 TSH
Premature aging
Skin atrophy
Bilateral cataracts 

Cowden's disease Thyroid cancer Thyroid

(multiple hamartoma Breast cancer gland
syndrome) Hamartomas
Uterine leiomyoma
Megacephaly T4, T3
Thyroid adenoma
Benign breast disease
Mucocutaneous lesions
Endometrial carcinoma
Lhermitte-Duclos disease FIGURE 13-4  Hypothalamic-pituitary-thyroid axis.  TSH,
Thyroid-stimulating hormone (thyrotropin); TRF, thyrotropin-
PTEN, Phosphatase and tensin homolog gene. releasing hormone.
 410 ANESTHESIA AND UNCOMMON DISEASES
initiated by absorption of iodine from the GI tract, where the
iodine is reduced to an iodide and released into plasma. It is
then concentrated up to 500-fold by the thyroid gland.
Once in the gland, the iodide is oxidized by a peroxidase
to iodine (organification) and then bound to tyrosine, form-
ing either monoiodotyrosine or di-iodotyrosine. Both these
are then coupled enzymatically to form T4 or T3. The T3 and
T4 are bound to the protein thyroglobulin and stored as col-
loid in the gland. A proteolytic enzyme releases T3 and T4 from
the ­thyroglobulin as the prohormones pass from the cell to the
plasma. T3 and T4 are transported through the bloodstream on
thyroxine-binding globulin (TBG) and thyroxine-binding pre-
albumin. The plasma normally contains 4 to 11 μg of T4 and
0.1 to 0.2 μg of T3 per deciliter (dL; 100 mL). Secretion of TSH
and TRH appears to be regulated by T3 in a negative feedback
loop. Most of the effects of thyroid hormones are mediated by
T3; again, T4 is both less potent and more protein bound, thus
having lesser biologic effect, and is considered a prohormone.26
In peripheral tissues there exists a ubiquitous deiodinase
that converts T4 to T3. Thus, T4 appears to be a prohormone
for T3. Monodeiodination can remove either the iodine at the
5′ position to yield T3 or the iodine at the 5 position to yield
reverse T3 (rT3), which is totally inactive biologically. In gen-
eral, when T3 levels are depressed, rT3 levels are elevated. In
several situations, rT3 levels are increased, such as during ges-
tation, malnutrition, chronic disease, and surgical stress.32
A feedback circuit exists between the pituitary gland and the
circulating thyroid hormones. High levels of thyroid hor-
mones reduce release of pituitary TSH, whereas low levels
result in more TSH release (see Fig. 13-4).
Energy-dependent transport systems move T3 across the
target cell membrane into the cytoplasm. It then diffuses to
receptors in the cell nucleus, where its binding to high-affinity
nuclear receptors (TRα and TRβ) alters the production of spe-
cific messenger ribonucleic acid (mRNA) sequences, resulting
in physiologic effects. Thyroid hormone has anabolic effects,
promotes growth, and advances normal brain and organ
development. Thyroid hormone also increases the concentra-
tion of adrenergic receptors,33 which may account for many
of its cardiovascular effects. They also bind to specific target
genes that code for structural and regulatory proteins (myosin,
β-receptors, Ca++-activated adenosine triphosphatase, phos-
pholamban) and for calcium, sodium, and potassium chan-
nels in the heart, which are important for systolic contractile
function and diastolic relaxation.
Before undertaking surgery on the thyroid gland, it is
important to know its functional status. Hyperthyroidism and
hypothyroidism both have significant preoperative implica-
tions. Furthermore, imaging studies are undertaken to delin-
eate the anatomy of the gland, determine if other structures
are involved, and plan the best possible surgical management.
Thyroid Function Tests
The current generation of the TSH assay is very sensitive and
now considered the single best test of thyroid hormone action
at the cellular level. Small changes in thyroid function cause
significant changes in TSH secretions. Most of the T4 is bound
to the plasma protein TBG; changes in TBG can affect the
total T4 level. Estrogens, infectious hepatitis, and genetic fac-
tors can elevate TBG level and thus secondarily raise total T4.
Androgens, nephrosis, hypoproteinemia, and genetic factors
can lower TBG and thus secondarily lower total T4. Thus, it is
more important to know the value of free T4 and free T3. The
normal level of TSH is 0.4 to 5.0 mU/L. A TSH level of 0.1 to
0.4 with normal levels of free T3 and free T4 is diagnostic of
subclinical hyperthyroidism. A TSH level less than 0.03 mU/L
with elevated T3 and T4 is diagnostic of overt hyperthyroidism.
Overt hypothyroidism is diagnosed if TSH levels are more
than 20 mU/L (even as high as 200-400 mU/L) with reduced
levels of T3 and T4. Subclinical hypothyroidism is defined by
TSH levels in the range of 5 to 10 mU/L, with normal levels of
free T3 and free T4.34 Ultrasound, radioactive iodine uptake,
magnetic resonance imaging (MRI), and thin-slice computed
tomography (CT) thyroid scan can be useful in the diagnosis
and management of thyroid masses. Functioning thyroid nod-
ules are rarely malignant, whereas “cold” or hypofunctioning
nodules have a greater probability of malignancy.
The diagnosis of pituitary or hypothalamic disease can be
complicated. The procedure is often aided by the use of TRH.
This tripeptide is the hypothalamic factor that brings about
release of TSH from the pituitary. It may also be used to con-
firm the diagnosis of hyperthyroidism. Thyroid antibodies
(antithyroglobulin and antimicrosomal) are useful in arriving
at the diagnosis of Hashimoto's thyroiditis. Serum thyroglob-
ulin levels tend to be elevated in patients with thyrotoxicosis.
Painless thyroiditis is associated with transient hyperthyroid-
itis. Measurement of the α subunit of TSH has been helpful in
identifying the rare patients who have a pituitary neoplasm and
who usually have increased α-subunit concentrations. Some
patients are clinically euthyroid in the presence of elevated
levels of total T4 in serum. Certain drugs, notably gallbladder
dyes, corticosteroids, and amiodarone, block the conversion to
T3 to T4, thus elevating T4 levels. Severe illness also slows the
conversion of T4 to T3. Levels of TSH are often high when the
rate of this conversion is decreased. In hyperthyroidism, car-
diac function and responses to stress are abnormal; the return
of normal cardiac function parallels the return of TSH levels
to normal values.
Hyperthyroidism
Hyperthyroidism is usually caused by multinodular diffuse
enlargement of the gland, as in Graves' disease, which is also
associated with disorders of the skin and eyes. Hyperthyroidism
may be associated with pregnancy, thyroiditis (with or with-
out neck pain), thyroid adenoma, choriocarcinoma, or TSH-
secreting pituitary adenoma (Fig. 13-5).
Major manifestations of hyperthyroidism are weight loss,
diarrhea, warm moist skin, weakness of large muscle groups,
menstrual abnormalities, nervousness, intolerance of heat,
tachycardia, cardiac dysrhythmias, mitral valve prolapse, and
heart failure. When the thyroid is functioning abnormally, the
 Chapter 13  Diseases of the Endocrine System 411

Causes of thyrotoxicosis

Primary Thyrotoxicosis without Secondary

hyperthyroidism hyperthyroidism hyperthyroidism

Graves’ disease Subacute TSH-secreting

thyroiditis pituitary adenoma
Toxic multinodular
goiter Silent Thyroid hormone
thyroiditis resistance syndrome;
Toxic adenoma occasional patients may
Amiodarone, have features of
Functioning thyroid radiation, thyrotoxicosis
carcinoma metastases infarction of adenoma
Chorionic
Activating mutation Ingestion of excess gonadotropin-
of the TSH receptor thyroid hormone secreting tumors
(thyrotoxicosis factitia)
Activating mutation or thyroid tissue Gestational
of Gs (McCune-Albright thyrotoxicosis
syndrome)

Struma ovarii

Drugs: iodine excess

(Jod-Basedow phenomenon)
FIGURE 13-5  Causes of hyperthyroidism (thyrotoxicosis). Jod-Basedow, iodine-induced hyperthyroidism.

cardiovascular system is most threatened. Severe diarrhea can
lead to dehydration, which can be corrected before surgery.
Mild anemia, thrombocytopenia, increased serum alkaline
phosphatase, hypercalcemia, muscle wasting, and bone loss
frequently occur in patients with hyperthyroidism.
Muscle disease usually involves proximal muscle groups;
hyperthyroidism has not been reported to cause respiratory
paralysis. In the “apathetic” form of hyperthyroidism, seen
most often in persons over age 60, cardiac effects dominate
the clinical picture.35,36 The signs and symptoms include tachy-
cardia, irregular heartbeat, atrial fibrillation, heart failure, and
occasionally, papillary muscle dysfunction. Atrial fibrillation
of unknown origin is a special concern in patients with apa-
thetic hyperthyroidism because “thyroid storm” can occur
when they have surgery for other diseases.
Although β-adrenergic receptor blockade can con-
trol heart rate, its use is fraught with hazards in a patient
already experiencing CHF. However, decreasing heart rate
may improve the cardiac pump function. Thus, hyperthy-
roid patients who have high ventricular rates, who have CHF,
and who require emergency surgery are given propranolol in
doses guided by changes in pulmonary artery wedge pressure
and the overall clinical condition. If slowing the heart rate
with a small dose of esmolol (50 μg/kg) does not aggravate
heart failure, additional esmolol (50-500 μg/kg) is adminis-
tered. The aim is to avoid imposing surgery on any patient
whose thyroid function is clinically abnormal. Therefore,
only “life or death” emergency surgery should preclude mak-
ing the patient pharmacologically euthyroid, a process that
can take 2 to 6 weeks.
Preparation of Hyperthyroid Patient for Elective Surgery
A number of patients refuse radioactive iodine treatment and
undergo surgery for hyperthyroidism. However, it is impor-
tant to make these patients euthyroid before surgery. Typical
treatment for hyperthyroidism includes the antithyroid drug
methimazole or propylthiouracil (PTU). These drugs inhibit
both thyroid hormone synthesis and the peripheral conversion
of T4 to T3. A usual dose takes full effect in about 6 to 8 weeks,
although it may take much longer in a patient with a large thy-
roid gland. About 10 days before surgery, the patient typically
receives a potassium iodide saturated solution (3 drops three
times daily) to decrease gland vascularity and block release of
stored hormone. A β-blocker, typically propranolol, is added
to control adrenergic symptoms31 (Box 13-3).
BOX 13-3   n  MANAGEMENT OF HYPERTHYROIDISM
Treat with antithyroid medication (e.g., methimazole, propylthiouracil/
PTU) for 6-8 weeks.
Prescribe potassium iodide, 3 drops three times daily for 10 days
before surgery.
Treat sympathetic symptoms with beta-adrenergic blockers
(e.g., propranolol).
Anesthetic Considerations
Ensure patient is euthyroid before elective surgery.
Correct hypovolemia.
Correct electrolyte abnormalities.
Treat sympathetic symptoms with β-blockers (e.g., propranolol,
esmolol).
Monitor for cardiac failure and cardiac arrhythmias.
Patient may require glucocorticoids and active cooling.
 412 ANESTHESIA AND UNCOMMON DISEASES
If the clinical situation demands, preoperative preparation
with propranolol and iodides can yield comparable results.37-39
This approach is less time-consuming than methimazole/PTU
therapy (7-14 days vs. 6-8 weeks); it causes the thyroid gland
to shrink, as does the more traditional approach; and it treats
symptoms, but abnormalities in left ventricular function may
not be corrected.38,39 Regardless of the approach used, antithy-
roid drugs should be administered both chronically and on
the morning of surgery.
If emergency surgery is necessary before the euthyroid
state is achieved, or if the hyperthyroidism is not well con-
trolled during surgery, 50 to 500 μg/kg of IV esmolol can be
titrated for restoration of a normal heart rate (assuming that
CHF is absent; see previous discussion). Larger doses may
be required, and in the absence of better data, the return of
a normal heart rate and the absence of CHF serve as guides
to therapy. In addition, intravascular fluid volume and elec-
trolyte balance should be restored. Importantly, administering
propranolol may not prevent “thyroid storm.”40
Thyroid Storm
Thyroid storm refers to the clinical diagnosis of a life-threatening
illness in a patient whose hyperthyroidism has been severely
exacerbated by illness or surgery. Mortality results from car-
diac failure, arrhythmia, or hyperthermia and is as high as
30% even with treatment. Thyroid storm manifests with
hyperpyrexia, tachycardia, and striking alterations in con-
sciousness.40,41 No laboratory tests are diagnostic of thyroid
storm, and the precipitating (nonthyroidal) cause is the major
determinant of survival. Therapy usually includes blocking
the synthesis of thyroid hormones by administration of anti-
thyroid drugs, blocking release of preformed hormone with
iodine, meticulous attention to hydration and supportive
therapy, and correction of the precipitating cause. Survival is
directly related to the success of treatment of the underlying
cause. Blocking of the sympathetic nervous system with α-
and β-receptor antagonists may be exceedingly hazardous and
requires skillful management and constant monitoring of the
critically ill patient. Additional therapeutic measures include
use of glucocorticoids, treatment of the underlying precipitat-
ing event (infection), IV fluids, and active cooling.
Management of Thyrotoxicosis during Pregnancy
The management of the thyrotoxicosis of Graves' dis-
ease during pregnancy presents some special problems.42,43
Radioactive iodine therapy is usually considered contraindi-
cated because it crosses the placenta. The physician's choice
is between antithyroid drugs and surgery. Antithyroid drugs
also cross the placental barrier and can cause fetal hypothy-
roidism. This problem may theoretically be obviated by the
simultaneous administration of l-thyroxine or T3. However,
most of the evidence indicates that neither T4 nor T3 crosses
the placental barrier. The occurrence of fetal hypothyroid-
ism when small doses of antithyroid drugs alone are used is
unusual as long as the mother remains euthyroid. It is typi-
cally better to err on the side of undertreatment than over-
treatment with antithyroid drugs. Small amounts of PTU are
often sufficient. Chronic use of iodide in the mother is usually
contraindicated because fetal goiter and hypothyroidism may
result. The use of propranolol during pregnancy is controver-
sial, with case reports of intrauterine growth retardation and
low Apgar score in infants whose mothers received proprano-
lol. Bradycardia and hypoglycemia also have been described
in these infants.
The thyrotoxicosis of pregnancy tends to be mild and often
improves in the second and third trimesters. Surgery is an
acceptable alternative to treatment, usually postponed until
neural development and organogenesis of the first trimester
are complete. After pregnancy, it is impossible to predict the
thyroid status of the mother. Whereas some patients remain
hyperthyroid, some become hypothyroid after delivery.
A reported 5% of women have transient thyrotoxic effects 3 to
6 months postpartum and tend to have recurrences with sub-
sequent pregnancies.44
The status of the neonate after delivery needs attention.
Either hypothyroidism or hyperthyroidism may be present.
Neonatal hypothyroidism is characterized by a low total T4
(< 7 μg/dL) and an elevated TSH. At times the T4 may be per-
fectly normal, with only the TSH elevated. Amniotic fluid
rT3 levels tend to be low in the hypothyroid fetus in the third
trimester, and likewise, serum rT3 concentration is low after
birth if hypothyroidism exists.
Management of neonatal hypothyroidism consists of the
immediate replacement with l-thyroxine in the range of 9 μg/
kg/day. This dose is relatively large but often required to nor-
malize the TSH level and T4 concentration. Normally, total T4
level (8-15 μg/dL) tends to be high in the first year of life, then
slowly but progressively drops until after puberty. Likewise,
thyroid hormone replacement doses tend to be higher than in
the average adult until puberty is complete.
Neonatal hyperthyroidism is unusual and always associ-
ated with high levels of thyroid-stimulating immunoglobu-
lins. These immunoglobulins cross the placental barrier and
are probably the cause of fetal hyperthyroidism; therefore they
are usually measured in thyrotoxic women in the third trimes-
ter. Controlling maternal hyperthyroidism seems to prevent
the development of hyperthyroidism in infants.
Amiodarone and Thyroid Function
Depending on the iodine intake, up to 13% of patients
treated with the antiarrhythmic amiodarone develop thyroid
dysfunction, either hyperthyroidism or hypothyroidism.29
Approximately 39% of the drug's weight is iodine, and a 200-
mg tablet releases about 20 times the optimal daily dose of
iodine. This iodine can lead to reduced synthesis of thyrox-
ine or to increased synthesis. In addition, amiodarone inhib-
its the conversion of T4 into the more potent T3. Patients
receiving amiodarone may require special attention preop-
eratively to ensure no perioperative dysfunction exists, or
unsuspected thyroid hyperfunction or hypofunction. Many
patients with amiodarone thyrotoxicosis receive corticoste-
roids for a time, so the anesthesiologist should determine if
steroids were used.
 Chapter 13  Diseases of the Endocrine System 413

Usually, symptoms of hypothyroidism are subclinical,

Hypothyroidism
Hypothyroidism is a common disease. The apathy and leth-
argy that often accompany hypothyroidism often delay its
diagnosis, so it may be detected the first time in the periop-
erative period. Usually, hypothyroidism is subclinical; serum
concentrations of thyroid hormones are in the normal range,
and only serum TSH levels are elevated (5-15 mU/L).45,46 In
such cases, hypothyroidism may have minimal or no periop-
erative significance.
Hypofunction of the thyroid gland can be caused by surgi-
cal ablation, radioactive iodine administration, irradiation to
the neck (e.g., for Hodgkin's disease), iodine deficiency or toxic-
ity, genetic biosynthetic defects in thyroid hormone production,
antithyroid drugs (e.g., PTU), amiodarone pituitary tumors,
or hypothalamic disease (Fig. 13-6). The most common cause
of primary thyroid hypofunction may be a form of thyroiditis,
often chronic lymphocytic thyroiditis, or Hashimoto's disease
(Hashimoto's thyroiditis). The thyroid is usually enlarged, non-
tender, and extremely firm and indurated. A variety of antithyroid
antibodies are found in the serum, including antithyroglobulin
and antimicrosomal antibodies in high titer. Hypothyroidism
seems to be the most common consequence of Hashimoto's dis-
ease; indeed, it is the most common cause of hypothyroidism
in adults.46 Patients with Hashimoto's thyroiditis are extremely
susceptible to iodides and to antithyroid drugs, and overt severe
hypothyroidism can be exacerbated by these maneuvers.
with serum concentrations of thyroid hormones in the nor-
mal range and only serum TSH levels elevated.30,45,46 In the
less frequent cases of overt hypothyroidism, the deficiency
of thyroid hormone results in slow mental functioning, slow
movement, dry skin, intolerance to cold, depression of the
ventilatory responses to hypoxia and hypercarbia,47 impaired
clearance of free water, slow gastric emptying, and brady-
cardia. In extreme cases, cardiomegaly, heart failure, and
pericardial and pleural effusions are manifested as fatigue,
dyspnea, and orthopnea.48 Hypothyroidism is often associ-
ated with amyloidosis, which may cause enlargement of the
tongue, abnormalities of the cardiac conduction system, and
renal disease. The tongue may be enlarged in the hypothy-
roid patient even in the absence of amyloidosis, and this may
hamper intubation.49
Full-blown myxedema presents as a variety of symp-
toms, including cold intolerance, apathy, hoarseness, con-
stipation, impaired movement, anemia, hearing loss, and
bradycardia. Myxedema coma is a rare complication associ-
ated with profound hypothyroidism and extreme lethargy,
severe hypothermia, bradycardia, and alveolar hypoventila-
tion with hypoxia and occasionally accompanied by peri-
cardial effusion and CHF. Hyponatremia associated with
marked decrease in free-water clearance by the kidney is
also often part of the syndrome. This is the only indication
for IV T4 therapy.

Causes of hypothyroidism

Primary Transient Secondary

Autoimmune hypothyroidism:
Hashimoto’s thyroiditis,
atrophic thyroiditis
Iatrogenic:
131l treatment,
subtotal or total thyroidectomy,
external irradiation of neck
Drugs:
iodine-containing
contrast media, amiodarone,
lithium, antithyroid drugs,
p-aminosalicylic acid,
interferon, and other cytokines,
aminoglutethimide, sunitinib
Congenital hypothyroidism:
absent or ectopic thyroid gland,
dyshormonogenesis, TSH-R mutation
Silent thyroiditis,
including postpartum Tumors, pituitary surgery, or irradiation
thyroiditis
Subacute thyroiditis
Withdrawal of thyroxine
treatment in individuals with
an intact thyroid after
131I treatment or
subtotal thyroidectomy
for Graves’ disease
Hypopituitarism:
Infiltrative disorders
Sheehan’s syndrome
Trauma
Genetic forms of combined
pituitary hormone deficiencies
Isolated TSH deficiency
or inactivity
Bexarotene treatment
Hypothalamic disease:
Tumors, trauma
Infiltrative disorders
Idiopathic

Iodine deficiency

Infiltrative disorders:
amyloidosis, sarcoidosis,
hemochromatosis, scleroderma,
cystinosis, Riedel’s thyroiditis
FIGURE 13-6  Causes of hypothyroidism.
 414 ANESTHESIA AND UNCOMMON DISEASES
Preparation of Hypothyroid Patient for Surgery
Hypothyroidism decreases anesthetic requirements. Ideal pre-
operative management of the hypothyroid patient consists
of restoring euthyroid status; the normal dose of T3 or T4 is
administered on the morning of surgery, even though these
drugs have long half-life (1.4-10 days). The usual daily replace-
ment dose in adults is 0.1 to 0.2 mg of l-thyroxine (Synthroid).
The T4 level itself can be used as a guide to therapy. Both T4
and TSH serum levels are usually in the normal range in ade-
quately treated patients.
For patients in myxedema coma who require emergency
surgery, T3 or T4 can be given IV (with the risk of precipitating
myocardial ischemia) while supportive therapy is undertaken
to restore normal intravascular fluid volume, body tempera-
ture, cardiac function, respiratory function, and electrolyte
balance. l-Thyroxine is given in a single IV dose of 300 to 500
μg. IV T3 liothyronine may also be given in the dose range of
25 to 50 μg every 8 hours until the blood level of T3 is nor-
mal. Intravenous T3 is probably superior to IV T4 because T3
is the most physiologically active thyroid hormone therapy
and bypasses the normal conversion pathway, which usually
is greatly depressed in patients with serious systemic illnesses
(Box 13-4).
Hypothyroid Patients with Coronary Artery Disease
Treating hypothyroid patients who have symptomatic coro-
nary artery disease (CAD) poses special problems and may
require compromises in the general practice of preoperatively
restoring euthyroidism with drugs. Although both T4 and
esmolol may be given, adequate amelioration of both ischemic
heart disease and hypothyroidism may be difficult to achieve.
The need for thyroid therapy must be balanced against the risk
of aggravating anginal symptoms. One review suggests early
consideration of coronary artery revascularization.50 It advo-
cates initiating thyroid replacement therapy in the intensive
care unit (ICU) soon after the patient's arrival from the operat-
ing room after myocardial revascularization surgery. However,
several deaths from dysrhythmias and CHF, as well as cardio-
genic shock with infarction, have occurred while patients who
were not given thyroid therapy were awaiting surgery. Thus,
BOX 13-4   n MANAGEMENT OF HYPOTHYROIDISM
(MYXEDEMA COMA)
Treat with l-thyroxine (300-500 μg) or intravenous T3 (25-50 μg) every
8 hours until T3 level is normal.
Monitor for cardiac ischemia.
Patient may require stress-dose steroids.
Anesthetic Considerations
Consider surgery only in emergency situations.
Large tongue may create difficult airway.
Decrease dose of anesthetics, opioids, and benzodiazepines;
hypothyroid patients are sensitive to these agents.
Correct intravascular volume.
Correct electrolyte imbalance.
Correct hypothermia.
there is a need to consider “truly” emergency coronary artery
revascularization in patients who have both severe CAD and
significant hypothyroidism.
In the presence of hypothyroidism, respiratory control mech-
anisms do not function normally.48 However, the response to
hypoxia and hypercarbia and the clearance of free water nor-
malize with thyroid replacement therapy. Drug metabolism was
slowed in anecdotal reports, and awakening times after admin-
istration of sedatives were prolonged during hypothyroidism.
These concerns disappear when thyroid function is normalized
preoperatively. Addison's disease (with its relative steroid defi-
ciency) is more common in hypothyroid than in euthyroid indi-
viduals, and some endocrinologists routinely treat patients who
have noniatrogenic hypothyroidism by giving stress doses of
corticosteroids perioperatively. This steroid deficiency should be
considered if the patient becomes hypotensive perioperatively.
Thyroid Nodules and Carcinoma
Thyroid carcinoma is the most common malignancy of the
endocrine system. Based on the staging, many patients would
undergo total or partial thyroidectomy. Papillary carcinoma
accounts for more than 70% of all carcinomas. Simple excision
of lymph node metastases appears to be as efficacious for patient
survival as radical neck procedures.51 Medullary carcinoma is
the most aggressive form of thyroid carcinoma, accounting for
5% to 10% of all thyroid cancers, and is associated with a famil-
ial incidence of pheochromocytoma, as are parathyroid adeno-
mas. For this reason, a history should be obtained for patients
who have a surgical scar in the thyroid and parathyroid region,
to rule out the possibility of occult pheochromocytoma.
Anesthetic Considerations
The major considerations regarding anesthesia for patients
with thyroid disorders are (1) attainment of a euthyroid state
preoperatively, (2) preoperative preparation and attention to
the characteristics of the diseases mentioned previously, and
(3) normalization of cardiovascular function and temperature
perioperatively.
No controlled study has demonstrated clinical advantages
of any one anesthetic drug over another for surgical patients
who are hypothyroid. Thus, no data on human subjects imply
that the choice of anesthetic affects patient outcome in the
presence of thyroid disease. Some recommend avoiding anti-
cholinergic drugs (especially atropine) because they interfere
with the sweating mechanism and cause tachycardia.
A patient who has a large goiter and an obstructed air-
way can be treated as would any patient whose airway man-
agement is problematic. Preoperative medication need not
include “deep” sedation, and an airway can be established,
often with the patient awake. A firm, armored endotracheal
tube is preferable and should be passed beyond the point of
extrinsic compression. It is most useful to examine CT, MRI,
or ultrasound scans of the neck preoperatively to determine
the extent of compression.
 Chapter 13  Diseases of the Endocrine System 415
Maintenance of anesthesia usually presents little diffi-
culty. Body heat mechanisms are inadequate in hypothyroid
patients, and temperature can be monitored and maintained,
especially in patients who require emergency surgery before
the euthyroid state is attained. Because incidence of myasthe-
nia gravis is increased in hyperthyroid patients, a twitch moni-
tor to guide muscle relaxant administration may be advisable.
Postoperatively, extubation should be performed under
optimal circumstances for reintubation, in case the tracheal
rings have been weakened and the trachea collapses. Possible
postoperative complications are those for hyperparathyroid-
ism (see earlier).
PITUITARY GLAND
Tumors involving the pituitary gland are rare. The exact inci-
dence is not known, although with recent advances in brain
imaging, more asymptomatic pituitary adenomas are being
discovered. By some estimates the incidence of pituitary ade-
nomas is three to five times higher than previously reported.52
Although most pituitary adenomas are sporadic, approximately
5% of all cases occur in a familial setting, and more than half of
these are caused by MEN-1 and Carney's complex. A non-
MEN-I/Carney's disorder called familial isolated pituitary ade-
noma (FIPA) syndrome is also described52 (Table 13-3). As in
other endocrine disorders, surgical intervention is undertaken
to treat a hyperfunctioning gland or cancer or to alleviate mass
effect. Pituitary adenomas constitute 5% to 20% of the primary
central nervous system (CNS) tumors.
Physiology
The pituitary gland is divided into anterior and posterior por-
tions that have substantially different organization. The anterior
pituitary is connected to the hypothalamus through a complex
portal vascular system. Hypothalamic releasing or inhibitory
TABLE 13-3  n Syndromes Associated with Pituitary
Gland Tumors
Syndrome Clinical Features
MEN-I Primary hyperparathyroidism
Enteropancreatic tumors
Pituitary tumors
Thymic or bronchial endocrine tumors
Adrenocortical tumors
Carney's complex Mucocutaneous pigmented lesion
(syndrome) Myxomas
Multiple thyroid follicular adenomas
Primary pigmented nodular
adrenocortical disease
Pituitary growth hormone–producing
adenoma
Familial isolated Early onset, aggressive tumor growth
pituitary adenoma Prolactin-secreting tumor
(FIPA) Somatotropin tumors
factors are synthesized in the hypothalamus, are secreted into the
portal system, and reach the anterior pituitary in extremely high
concentrations. Functional activity in the posterior pituitary
depends on specialized neurons in the hypothalamus that syn-
thesize vasopressin (ADH) and oxytocin. These two hormones
are then secreted through specialized axons down the stalk of the
pituitary and are stored in the posterior pituitary gland.
Each pituitary hormone has a specific releasing factor asso-
ciated with it, as well as a specific inhibitory factor in some
cases. Specific hypothalamic-releasing hormones have been
defined for TSH, adrenocorticotropic hormone (ACTH),
and the gonadotropins (both luteinizing hormone [LH] and
follicle-stimulating hormone [FSH]). Both a releasing and
an inhibitory hypothalamic factor have been discovered for
growth hormone (GH). Prolactin is primarily associated with
an inhibitory hypothalamic factor, probably the neurotrans-
mitter dopamine. Generally there is no overlap in function of
the hypothalamic hormones, except for the positive effect of
TRH on both TSH and prolactin secretion. In disease states
such as acromegaly, however, both somatotropin-releasing
factor and thyrotropin-releasing factor can bring about release
of GH. In the normal state, this would not occur. An addi-
tional factor involving hypothalamic control of the pituitary is
the pulsatile periodic operation of the hypothalamus. Probably
the most important biologic rhythm is the sleep or light-dark
pattern; for example, GH and ACTH show specific nocturnal
bursts in males. Prolactin also tends to increase in concentra-
tion in the blood immediately after sleep begins. LH shows a
sleep pattern especially during puberty.
The three monoamine neurotransmitters—dopamine, nor-
epinephrine, and serotonin—can profoundly affect hypotha-
lamic function and are found in high concentration in major
hypothalamic centers. There is essentially no blood-brain bar-
rier in either the pituitary or the hypothalamus, and target
organ products such as estrogen, testosterone, thyroid, and
adrenal hormones can exert feedback at either the hypotha-
lamic or the pituitary level (Fig. 13-7).
Anterior Pituitary Disease: Hypopituitarism and
Hyperpituitarism
HYPOFUNCTION OF THE PITUITARY GLAND
All or several of the trophic hormones may be involved in
hypopituitary states. The causes of hypopituitarism can be
grouped into two broad pathophysiologic categories: those
that involve the pituitary gland and those caused by hypotha-
lamic diseases (Fig. 13-8). Mass lesions that can cause hypo-
pituitarism include pituitary adenomas, cysts, lymphocytic
hypophysitis, metastatic cancer, and other lesions (e.g., chro-
mophobe adenoma, Rathke's pouch cysts, craniopharyngioma
in children). Necrosis following circulatory collapse results
from hemorrhage after delivery (Sheehan's syndrome), surgi-
cal hypophysectomy, irradiation to the skull or brain, granu-
lomatous diseases, other infectious diseases, surgical or other
trauma, and hemochromatosis.53-55 Metastatic disease (espe-
cially from breast cancer) is only rarely seen.
 416 ANESTHESIA AND UNCOMMON DISEASES

Input from internal Major causes of hypopituitarism

and external stimuli

Central
nervous Pituitary diseases Hypothalamic diseases
system
Biological clock

Mass lesions: Mass lesions:

Neural Hypothalamus
Pituitary adenomas Craniopharyngiomas
stimuli
Other benign tumors Metastatic
Cysts malignant tumors

Pituitary surgery Radiation:

CNS and
Pituitary radiation nasopharyngeal
Hypothalamic CRF MIF malignancies
Releasing factors LHRF Somatostatin Infiltrative lesions:
and GHRF PIF Lymphocytic Infiltrative lesions:
Inhibitory factors TRF hypophysitis Sarcoidosis
Hemochromatosis Langerhans cell
histiocytosis
Anterior Infarction
GH pituitary (Sheehan’s syndrome) Trauma:
Prolactin Fracture of the
MSH Apoplexy skull base

Genetic diseases: Infections:

Anterior pit-1 mutation Tuberculous
pituitary ACTH FSH FSH Estrogen meningitis
hormones LH
Thyroid FSH FIGURE 13-8  Major causes of hypopituitarism. CNS, Central
Cortisol hormones LH nervous system.

Destruction of the pituitary by tumor (i.e., chromophobe

Adrenals Thyroid Testis Ovary adenoma) is probably the most common cause of hypopituita-
Adrenal Testosterone rism. One third to one half of all patients with chromophobe
hormones Thyroid Estrogen adenoma secrete excessive quantities of prolactin. GH defi-
hormones Progesterone ciency in a child results in severe growth failure. Loss of TSH
Tissue metabolism or ACTH function usually occurs later in life, when variable
Other tissues and metabolic features related to thyroid deficiency or lack of cortisol inevi-
fuel (e.g., glucose)
tably manifest. If a tumor exists, it may grow above the sella
Excitatory response Inhibitory response
Known
turcica (suprasellar extension), and headaches and visual field
Suspected defects, notably bitemporal hemianopsia, will occur.
Genetic disorders of hypothalamopituitary development
Pituitary Hypothalamic
can lead to congenital hypopituitarism and single isolated defi-
hormone regulatory hormones ciencies of specific pituitary hormones (see Table 13-3). These
typically involve specific genes that are intricately involved in
Adrenocorticotropic Corticotropin-releasing factor hypothalamopituitary organogenesis. These disorders include
hormone (ACTH) (CRF)
septo-optic dysplasia, Kallmann's syndrome, Bardet-Biedl
Thyroid-stimulating Thyrotropin-releasing factor syndrome, and Prader-Willi syndrome. Septo-optic syndrome
hormone (TSH) (TRF) results from dysgenesis of septum pellucid or corpus callosum.
These children exhibit variable combinations of cleft palate,
Follicle-stimulating Gonadotropin-releasing factor
hormone (FSH) and (GHRF) syndactyly, ear deformities, hypertelorism, optic atrophy, and
luteinizing hormone anosmia. Well-known Kallmann's syndrome is associated with
(LH) gonadotropin deficiency related to loss of the sense of smell
Growth hormone Growth hormone−releasing factor (anosmia). The syndrome may also be associated with color
(GH) (GHRF), somatostatin (inhibitory) blindness, optic atrophy, nerve deafness, cleft palate, renal
abnormalities, and cryptorchidism. Bardet-Biedl (Laurence-
Prolactin Prolactin inhibitory factor Moon) syndrome is a rare genetic disorder characterized by
(PIF)
mental retardation, renal abnormalities, obesity, and hexadac-
FIGURE 13-7  Basic feedback mechanism: hypothalamic-pituitary- tyly. It is also associated with diabetes insipidus and growth
adrenal axis. hormone deficiency. Prader-Willi syndrome is associated
 Chapter 13  Diseases of the Endocrine System 417
with hypogonadotropic hypogonadism, hyperphagia-obesity,
chronic muscle hypotonia, mental retardation, and adult-
onset diabetes mellitus.
Biochemical diagnosis of pituitary insufficiency is made by
demonstrating low levels of trophic hormones in the setting of
low target hormones. It is possible to measure virtually all the
hormones of the anterior pituitary gland (GH, TSH, LH, FSH,
prolactin, ACTH). Low LH and FSH associated with estrogen
deficiency in a female patient or low testosterone in a male
patient indicates a hypothalamic or pituitary deficiency, even
of ACTH. Low TSH with a low T4 also indicates either hypo-
thalamic or pituitary deficiency. An elevated prolactin level is
often associated with chromophobe adenomas. Provocative
tests may be required to test pituitary reserve. Hypoglycemia
induced by insulin (0.1 unit/kg IV) can also be used to test not
only ACTH reserve but also GH reserve. Hypoglycemia (blood
glucose concentration < 50 mg/dL) should result in significant
rises in both plasma cortisol and GH if the pituitary gland is
functioning normally. Failure of the plasma cortisol level to rise
after IV insulin indicates that ACTH reserve is low.
However, evaluation of the hypothalamic-pituitary-adrenal
(HPA) axis can be difficult. The metapyrone test has long been
a standard test for determination of the pituitary-adrenal axis.
Metapyrone blocks the conversion of 11-deoxycortisol to cor-
tisol. Normally, 11-deoxycortisol is not measurable. A single
oral dose of metapyrone (3 g) is given at midnight, and plasma
cortisol and 11-deoxycortisol concentrations are measured
the following morning. If the 11-deoxycortisol level is greater
than 10 μg/mL, ACTH stimulation must have occurred,
and the patient has a normal pituitary-adrenal axis. If both
11-deoxycortisol and cortisol are low, this means that ACTH
was not stimulated and the patient has little or no ACTH pitu-
itary reserve. The test can also be performed using the mea-
surement of urinary 17-hydroxycorticoids while 750 mg of
metapyrone is given every 4 hours for six doses.
HYPERFUNCTION OF THE PITUITARY GLAND
There are three major hyperfunctioning pituitary gland
tumors: (1) prolactin-secreting chromophobe adenoma, (2) an
ACTH-secreting tumor associated with Cushing's disease (see
Adrenal Cortex), and (3) acromegaly associated with exces-
sive GH secretion. Gonadotropin-secreting and thyrotropin-
secreting pituitary tumors are extraordinarily rare.
Acromegaly
Acromegaly is a syndrome that presents as characteristic
facies, weakness, enlargement of the hands (often rendering
usual oximeter probes difficult to use) and feet, thickening of
the tongue (often making endotracheal intubation difficult),
and enlargement of the nose and mandible with spreading of
the teeth (often requiring larger-than-normal laryngoscope
blades).56-59 The patient may even appear myxedematous. Other
findings include abnormal glucose tolerance, carpal tunnel syn-
drome, and osteoporosis. The most specific test for acromegaly
is measurement of GH before and after glucose administration.
The typical acromegalic patient has elevated fasting levels of GH
(usually > 10 mg/mL), and the levels do not change appreciably
after oral glucose is administered. In the normal state, glucose
greatly suppresses the GH level. A few patients with active acro-
megaly have normal levels of fasting GH that are not suppressed
after glucose is administered. The drug l-dopa, which nor-
mally increases GH in healthy subjects, either has no effect or
decreases GH levels in the acromegalic patient.
Therapy for acromegaly includes the options of pituitary
irradiation (heavy particle or implants) and transsphenoidal
hypophysectomy.60 If suprasellar extension exists, conventional
transfrontal hypophysectomy is often employed. Surgery is the
preferred primary treatment. Medical treatment includes soma-
tostatin analogs (octreotide, lanreotide) or specific GH receptor
antagonists (e.g., pegvisomant).56 The dopaminergic agonist bro-
mocriptine or cabergoline can lower GH levels in some patients.
Prolactinomas
Prolactin has been one of the most interesting markers for
identifying patients with pituitary tumors.54 Elevated prolac-
tin levels are often (but not invariably) associated with galac-
torrhea. Female patients typically have amenorrhea, and male
patients have impotence. Therapy for prolactin-secreting
tumors includes bromocriptine or cabergoline, which can be
extremely effective in controlling prolactin level and restoring
gonadotropin function. However, in women considering preg-
nancy, the concern that pregnancy will cause rapid growth of
these tumors may favor a surgical procedure.
ANESTHETIC CONSIDERATIONS
In patients with abnormal anterior pituitary function, the basic
approach of rendering normal endocrine functions before sur-
gery holds for endocrine abnormalities originating in the pitu-
itary as well as in the end organ. The most common approach
for pituitary surgery is transsphenoidal hypophysectomy. For
the patient undergoing craniotomy, the appropriate concerns
include provision of patent airway, adequate pulmonary ven-
tilation, control of circulating blood volume, inhibition of
increased brain size, and effective constant monitoring for
adverse complications associated with posture, anesthesia, and
surgery. Acromegalic patients can be difficult to intubate.60-62
Premedication, use of anesthetic agents and techniques, and
monitoring as indicated for pituitary procedures are essen-
tially the same as for any craniotomy. The effects of anesthetic
agents on secretion of pituitary hormones do not constitute
an important factor in the selection of perioperative anesthet-
ics. Disorders arising from pituitary surgery include temper-
ature deregulation and abnormalities of endocrine function,
including the need for immediate treatment of steroid defi-
ciency, hypoglycemia, and excessive or deficient secretion of
vasopressin, also called antidiuretic hormone (ADH).
Posterior Pituitary Disorders: Diabetes Insipidus
and SIADH
DIABETES INSIPIDUS
Deficiency of arginine vasopressin (AVP) synthesis results
in diabetes insipidus (DI). Clinically, DI is characterized by
the excretion of a large volume of hypotonic urine, which in
turn necessitates the intake of equally large amounts of fluid
 418 ANESTHESIA AND UNCOMMON DISEASES
or prevention of hyperosmolarity of body fluids and dehydra-
tion.63 The many causes of DI are broadly classified as central
DI (pituitary DI, neurophyseal DI), nephrogenic DI, or primary
polydipsia. Each category is further classified into subcatego-
ries. In central DI, AVP deficiency is caused by decreased AVP
production, whereas nephrogenic resistance to AVP action is
seen in nephrogenic DI. Primary polydipsia refers to second-
ary deficiency of AVP resulting from inhibition of secretion by
excessive fluid intake, caused by psychogenic factors or abnor-
mal thirst mechanisms.
A number of drugs have been shown to alter the release
and action of ADH. The sulfonylurea agents, notably chlor-
propamide, have been shown to augment release of ADH and
are used in the treatment of patients with partial nephrogenic
DI. Likewise, clofibrate, carbamazepine (Tegretol), vincris-
tine, and cyclophosphamide all either release ADH or potenti-
ate its action on the renal tubule. Ethanol as well as phenytoin
(Dilantin) and chlorpromazine inhibit the action of ADH
and its release. Lithium, a drug widely used to treat bipolar
(manic-depressive) disorders, can inhibit the formation of
cyclic adenosine monophosphate (cAMP) in the renal tubule
and probably inhibits synthesis of ADH directly, thus resulting
in a DI-like picture.
The classic test to distinguish patients with DI from com-
pulsive water drinkers and patients with nephrogenic DI is the
water deprivation test.63 Following dehydration, DI patients
can only minimally concentrate their urine. When the serum
osmolarity rises to 295 mOsm/L (osmotic threshold), all nor-
mal patients release vasopressin into the blood and concentrate
their urine to conserve water. Simultaneous measurements of
urine and plasma osmolarity are made as water deprivation
continues. Once the urine and plasma osmolarity have stabi-
lized (usually with 3%-5% loss in body weight), the patient is
given an injection of vasopressin. If vasopressin is being maxi-
mally secreted by the posterior pituitary, exogenous vasopres-
sin will have no effect. The patient with vasopressin deficiency
never quite reaches stable plasma osmolarity, and the urine
osmolarity rarely rises much above 500 mOsm/L. Moreover,
even after severe dehydration, exogenous vasopressin causes a
significant increase in urine osmolarity only in patients with
true DI. Thus, this sensitive test even distinguishes patients
who have partial diabetes insipidus.
Compulsive water drinkers may at times present a diag-
nostic problem, because they often cannot concentrate their
urine well, and the water deprivation test must be carried out
until the osmotic threshold is reached. Tests employing hyper-
tonic saline as a physiologic stimulus to ADH are cumbersome
and difficult to interpret. Adrenocortical insufficiency can
mask the polyuria of partial DI, because it lowers the osmotic
threshold for vasopressin release. Institution of corticosteroid
therapy in such patients unmasks the diabetes insipidus, and
severe polyuria may result.
The treatment of DI usually consists of replacement of
AVP. Desmopressin (1-deamino-8-d-arginine vasopressin
[DDAVP]) is used for the treatment of central DI. It can be
administered IV, subcutaneously (SC), intranasally, or orally.
BOX 13-5  n MANAGEMENT OF DIABETES
INSIPIDUS (DI)
Remove underlying cause.
Central DI: Administer desmopressin (0.3 μg/kg) intravenously or
intranasally.
Nephrogenic DI: Thiazide diuretic with low sodium diet.
Primary polydipsia: Do not administer desmopressin (can cause water
intoxication).
Anesthetic Considerations
If desmopressin is administered, monitor serum osmolality.
Administer isotonic fluids.
Nephrogenic DI is not affected by desmopressin. Thiazide
diuretics in conjunction with low-sodium diet may be indi-
cated for nephrogenic DI patients. Prostaglandin inhibitors are
also effective in some patients. Desmopressin can be harmful
if used for the treatment of primary polydipsia and can pro-
duce water intoxication within 24 to 48 hours. If DDAVP is
used preoperatively to treat DI, serum osmolality should be
monitored (Box 13-5).
HYPERSECRETION OF VASOPRESSIN (SIADH)
Excessive secretion of AVP, known as the syndrome of inap-
propriate secretion of AVP (or of antidiuretic hormone,
SIADH) is a disorder characterized by hyponatremia that
results from water retention, which in turn is caused by AVP
release that is inappropriately high for the plasma osmolal-
ity or serum sodium concentration.63 Because patients with
SIADH are unable to excrete dilute urine, they retain ingested
fluids, and expansion of extracellular fluid volume with or
without edema. The hallmark of SIADH is hyponatremia in
the presence of urinary osmolality that is higher than plasma
osmolality.
The most common cause of SIADH is production of ecto-
pic AVP by neoplasms. The AVP produced by neoplasms is
identical to the arginine vasopressin secreted by the normal
neurohypophysis. The most common of the neoplasms pro-
ducing AVP are small cell carcinomas of the lungs. SIADH
is also associated with various nonmalignant and inflam-
matory conditions of the lungs and CNS. Any patient with
suspected SIADH should be screened for possible adrenal
insufficiency or hypothyroidism. The diagnosis is essentially
one of exclusion. A wide variety of drugs can cause hyperse-
cretion or augmentation of ADH and result in SIADH, most
often chlorpropamide, clofibrate, psychotropics, thiazides,
and the antineoplastic agents vincristine, vinblastine, and
cyclophosphamide.
Most of the clinical features associated with SIADH are
related to hyponatremia and the resulting brain edema; these
features include weight gain, weakness, lethargy, mental con-
fusion, obtundation, and disordered reflexes, which may prog-
ress to convulsions and coma. This form of edema rarely leads
to hypertension. SIADH should be suspected when any patient
with hyponatremia excretes urine that is hypertonic relative to
 Chapter 13  Diseases of the Endocrine System 419
BOX 13-6   n MANAGEMENT OF EXCESS VASOPRESSIN
SECRETION*
Fluid restriction: 500-1000 mL/day
Administer hypertonic saline (3% N/S) for severe hyponatremia.
Correct at a rate of no more than 1 mEq/hr, with no more than 12 mEq
in 24 hours.
Monitor serum sodium every 2 hours.
Anesthetic Considerations
Correct fluid and electrolyte imbalances as possible before surgery.
Monitor fluid status (CVP, TEE); patients are at risk of developing
hypervolemia.
Be alert to the possibility of delayed awakening and emergence
delirium.
*Syndrome of inappropriate antidiuretic hormone secretion (SIADH).
plasma. The following laboratory findings further support the
diagnosis:
n Urinary sodium greater than 20 mEq/L
n Low blood urea nitrogen and serum levels of creatinine, uric
acid, and albumin
n Serum sodium less than 130 mEq/L
n Plasma osmolality less than 270 mOsm/L
n Hypertonic urine relative to plasma
The response to water loading is a useful means of evaluat-
ing the patient with hyponatremia. Patients with SIADH are
unable to excrete dilute urine, even after water loading. Assay
of ADH in blood can confirm the diagnosis.
Patients with mild to moderate symptoms of water intoxi-
cation can be treated with restriction of fluid intake to 500 to
1000 mL/day. Patients with severe water intoxication and CNS
symptoms may need vigorous treatment, with IV administra-
tion of 3% saline solution over several hours at a rate no more
than 0.05 mL/kg/min, followed by fluid restriction. Sodium
should be monitored every 2 hours and stopped when it
increases by 12 mmol or increases to 130 mmol/L (Box 13-6).
Treatment should be directed at the underlying problem.
If SIADH is drug induced, the agent should be withdrawn.
Inflammation should be treated with appropriate measures,
and neoplasms should be managed with surgical resection,
irradiation, or chemotherapy, as indicated.
ANESTHETIC CONSIDERATIONS
The abnormalities of ADH function that affect perioperative
management involve either a relative or absolute lack of ADH
or an excess of ADH. Regardless of the cause, the perioper-
ative management problems can be grouped into situations
with insufficient ADH and situations with excess ADH.
Insufficient Antidiuretic Hormone
Diabetes insipidus, and thus an insufficient ADH (AVP) level,
is a problem in children undergoing posterior fossa craniot-
omy and is the most significant complication after hypoph-
ysectomy. The severity and duration of DI depend on the
degree of injury to the adjacent hypothalamus. The major-
ity of patients who develop DI after hypophysectomy recover
within a few days to 6 months. Patients with DI second-
ary to head trauma or surgery usually recover after a short
period. Those who continue to have symptoms, and patients
with a long history of DI who require surgery, present a chal-
lenge for the anesthesiologist with regard to perioperative
management.
Perioperative management of DI patients is based on the
extent of the AVP deficiency. Management of a patient with
complete DI and a total lack of AVP usually does not pres-
ent any major problems as long as side effects of the drug are
avoided and as long as that status is known before surgery.
Just before surgery, such a patient is given the usual dose
of desmopressin intranasally. All the IV fluids given intra-
operatively should be isotonic, to reduce the risk of water
depletion and hypernatremia. Plasma osmolality should
be measured every hour, both intraoperatively and in the
immediate postoperative period. If the plasma osmolality
increases above 290 mOsm/L, hypotonic fluids should be
administered.
Excessive Antidiuretic Hormone
Patients with SIADH resulting from malignancy have the
usual problems present in malignancy, such as anemia and
malnutrition, often with fluid and electrolyte imbalance as
well. Perioperatively, they usually have low urine output, high
urine osmolality, low serum osmolality, and delayed awaken-
ing from anesthesia or awakening with mental confusion.
When a patient with SIADH comes to the operating room
for any procedure, fluids are managed by measuring the cen-
tral volume status using central venous pressure (CVP) or pul-
monary artery catheter, transesophageal echocardiography
(TEE), and frequent assays of urine osmolarity, plasma osmo-
larity, and serum sodium, often into the immediate postopera-
tive period (see Box  13-6). Despite the common impression
that SIADH is frequently seen in elderly patients in the post-
operative period, the patient's age and the type of anesthetic
have no role in the postoperative development of SIADH. It
is not unusual to see many patients in the neurosurgical ICU
suffering from this syndrome. The diagnosis is usually one
of exclusion. Patients with SIADH usually require only fluid
restriction; hypertonic saline is rarely needed.
ADRENAL CORTEX
Physiology
Three major classes of hormones—glucocorticoids, mineralo-
corticoids, and androgens—are secreted by the adrenal cortex.
An excess or a deficiency of each hormone class is associ-
ated with a characteristic clinical syndrome. Glucocorticoids
are responsible for modulating metabolism and immune
responses. Blood pressure, vascular tone, fluid volume, and
electrolytes are maintained by mineralocorticoids, and andro-
gens play a role in secondary sexual characteristics and sexual
function.64
 420 ANESTHESIA AND UNCOMMON DISEASES

GLUCOCORTICOIDS Overproduction of glucocorticoids can be caused by adre-

The principal glucocorticoid, cortisol, is an essential regulator
of carbohydrate, protein, lipid, and nucleic acid metabolism.
Cortisol exerts its biologic effects by a sequence of steps initi-
ated by its binding to stereospecific intracellular cytoplasmic
receptors. This bound complex stimulates nuclear transcription
of specific mRNA. These mRNAs are then translated to give rise
to proteins that mediate the ultimate effects of these hormones.64
Most cortisol is bound to corticosteroid-binding globu-
lin (CBG, transcortin). It is the relatively small amounts of
unbound cortisol that enter cells to induce actions or to be
metabolized. Conditions that induce changes in the amount
of CBG include liver disease and nephrotic syndrome, both
of which result in decreased circulating levels of CBG, as well
as estrogen administration and pregnancy, which result in
increased CBG production. Total serum cortisol levels may
become elevated or depressed under conditions that alter the
amount of bound cortisol and yet the unbound, active form of
cortisol is present in normal amounts. The most accurate mea-
sure of cortisol activity is the level of urinary cortisol, that is,
the amount of unbound, active cortisol filtered by the kidney.
The serum half-life of cortisol is 80 to 110 minutes; how-
ever, because cortisol acts through intracellular receptors,
pharmacokinetics based on serum levels is not a good indi-
cator of cortisol activity. After a single dose of glucocorticoid,
the serum glucose level is elevated for 12 to 24 hours.
The HPA axis is shown in Figure  13-7. Secretion of glu-
cocorticoids is regulated exclusively by pituitary ACTH.65
ACTH is synthesized from a precursor molecule (preopi-
omelanocortin) that breaks down to form an endorphin
(β-lipoprotropin) and ACTH. ACTH secretion has a diur-
nal rhythm; it is normally greatest during the early-­morning
hours in men (afternoon in women) and is regulated at least
in part by sleep-wake cycles. Its secretion is stimulated by
release of corticotropin-releasing factor (CRF) from the
hypothalamus. Cortisol and other glucocorticoids exert neg-
ative feedback at both pituitary and hypothalamic levels to
inhibit secretion of ACTH and CRF.
nal tumors (primary Cushing's disease) or by overstimula-
tion of normal adrenal glands by elevated levels of ACTH
from pituitary microadenomas (secondary Cushing's disease).
Inappropriately low levels of glucocorticoids may result from
destruction or atrophy of the adrenal gland itself (primary
adrenal insufficiency) or from diminished levels of ACTH in
pituitary dysfunction (secondary adrenal insufficiency).
Treatment schedules for glucocorticoid replacement are
therefore based not on the measured serum half-life, but on
the well-documented, prolonged end-organ effect of these ste-
roids. In the past, hospitalized patients who required chronic
glucocorticoid replacement therapy were usually treated
twice daily, with a slightly higher dose in the morning than
in the evening to simulate the normal diurnal variations in
cortisol levels. For patients who require parenteral “steroid
coverage” during and after surgery (see later), administra-
tion of glucocorticoid every 8 to 12 hours seems appropriate.
Cortisol is inactivated primarily in the liver and is excreted as
17-hydroxycorticosteroid. Cortisol is also filtered and excreted
unchanged into the urine. Table 13-4 lists relative potencies of
glucocorticoids.
The synthetic glucocorticoids vary in their binding specific-
ity in a dose-related manner. When given in supraphysiologic
doses (> 30 mg/day), cortisol and cortisone bind to mineralo-
corticoid receptor sites and cause salt and water retention and
loss of potassium and hydrogen ions.65,66 When these steroids
are administered in maintenance doses of 30 mg/day or less,
patients require a specific mineralocorticoid for electrolyte
and volume homeostasis. Many other steroids do not bind
to mineralocorticoid receptors, even in large doses, and have
minimal mineralocorticoid effect66 (Table 13-4).
MINERALOCORTICOIDS
Aldosterone, the major mineralocorticoid secreted in humans,
comes from the zona glomerulosa of the adrenal cortex,
causes reabsorption of sodium and secretion of potassium and
hydrogen ions, and thus contributes to electrolyte and volume

TABLE 13-4  n  Cortisol and Synthetic Analogs: Relative Potency and Half-Life

ESTIMATED POTENCY

Common Name Glucocorticoid Mineralocorticoid Biologic Half-Life (hours)

Cortisol 1 1  8-12

Cortisone 0.8 0.8  8-12

Prednisone 4 0.25 12-36

Methylprednisolone 5 0.25 12-36

Triamcinolone 5 0.25 12-36

Dexamethasone 20-30 −/+ 26-54

Fluorohydrocortisone 5 200 —

Desoxycorticosterone 0 15 —
 Chapter 13  Diseases of the Endocrine System 421
homeostasis. This action is most prominent in the distal renal
tubules, but it also occurs in salivary and sweat glands. The
main regulator of aldosterone secretion is the renin-angiotensin
system. Juxtaglomerular cells in the cuff of the renal arterioles
are sensitive to decreased renal perfusion pressure or volume
and consequently secrete renin. Renin splits the precursor angio-
tensinogen (from the liver) into angiotensin I, which is further
split by converting enzyme, primarily in the lung, to angiotensin
II. Mineralocorticoid secretion is increased by increased levels
of angiotensin.
ANDROGENS
Androstenedione and dehydroepiandrosterone, which are
weak androgens arising from the adrenal cortex, constitute
major sources of androgens in women. These androgens are
converted outside the adrenal glands to testosterone, a potent
virilizing hormone.67 Excess secretion of androgen in women
causes masculinization, pseudopuberty, or female pseudo-
hermaphroditism. Some tumors convert this androgen to an
estrogenic substance, and feminization results. Some congen-
ital enzyme defects that cause abnormal levels of androgens
in blood also result in glucocorticoid and mineralocorticoid
abnormalities.
The altered sexual differentiation in the presence of such
defects requires no specific modification of anesthetic tech-
nique. All syndromes related to abnormal androgen levels
are associated with cortisol deficiency. In patients who have
associated alterations in glucocorticoid or mineralocorticoid
activity, anesthetic plans should be modified as outlined in the
following sections.
Excessive Adrenocortical Hormones: Hyperplasia,
Adenoma, and Carcinoma
SEX HORMONE–SECRETING TUMORS OF ADRENAL GLANDS
Hirsutism in female patients may be caused by either adrenal
or ovarian tumor. Adrenal virilizing tumors are almost always
associated with elevated 17-ketosteroid urinary excretion,
whereas functioning ovarian tumors tend to produce potent
androgens such as testosterone and dihydrotestosterone,
which are not measured as part of the 17-ketosteroids. Rarely,
adrenal tumors produce only testosterone and are stimulated
by human chorionic gonadotropin. Similarly, some androgen-
producing ovarian tumors respond to dexamethasone sup-
pression. A common cause of hirsutism in females is polycystic
ovarian disease, which is associated with bilaterally enlarged
ovaries. Extreme feminization in males can occasionally result
from an estrogen-producing tumor of the adrenal gland.
Functioning sex hormone–producing tumors of the adrenal
gland almost always tend to be unilateral. Pelvic B-mode ultra-
sonography, CT, and MRI are useful modalities for localizing
lesions. Most patients do not have to be managed with gluco-
corticoids during or after surgery. The only exception is the
patient who has associated Cushing's syndrome with cortisol
excess, for whom management should be as outlined later for
tumors of the adrenal gland.
Adrenal genital syndrome should be ruled out as a p ­ ossible
cause of hirsutism. These patients are not surgical candidates.
Generally, in addition to high 17-ketosteroid levels in the urine,
these patients have very high urinary pregnanetriol levels and
elevated 17-OH progesterone blood levels. Patients with
adrenal genital syndrome are usually managed with mildly
suppressive doses of corticosteroids.
EXCESSIVE GLUCOCORTICOIDS
Glucocorticoid excess, or Cushing's syndrome, resulting from
either endogenous oversecretion or long-term treatment
with large doses of glucocorticoids, produces a characteris-
tic appearance and a predictable complex of disease states.68
The individual appears moon faced and plethoric, having a
centripetal distribution of fat and thin extremities because
of muscle wasting. The heart and diaphragm apparently are
spared the effects of muscle wasting. The skin is thin and eas-
ily bruised, and striae are often present. Hypertension (from
increases in renin substrate and vascular reactivity caused
by glucocorticoids) and fluid retention are present in 85% of
patients. Almost two of every three patients also have hyper-
glycemia resulting from inhibition of peripheral glucose use,
with concomitant stimulation of gluconeogenesis. Patients
with Cushing's syndrome often have osteopenia as a result
of decreased bone matrix formation and impaired calcium
absorption. One third of these patients have pathologic frac-
tures (Table 13-5).
Special preoperative considerations for patients with
Cushing's syndrome include regulating diabetes and hyperten-
sion and ensuring that intravascular fluid volume and electro-
lyte concentrations are normal.69 Ectopic ACTH production
from sites other than the pituitary may cause marked hypoka-
lemic alkalosis. Treatment with the aldosterone antagonist spi-
ronolactone halts the potassium loss and helps mobilize excess
fluid. Because of the high incidence of severe osteopenia and
the risk of fractures, meticulous attention to patient position-
ing is necessary. In addition, glucocorticoids are lympholytic
and immunosuppressive, perhaps increasing the patient's sus-
ceptibility to infection.70-72
Specific considerations pertain to the surgical approach for
each cause of Cushing's syndrome. For example, almost three
fourths of the cases of spontaneous Cushing's disease result
from a pituitary adenoma that secretes ACTH. Perioperative
considerations for patients with Cushing's disease caused by
pituitary microadenoma may differ from patients with other
adenomas because they may bleed more easily and may have a
higher central venous pressure. Thus, during transsphenoidal
tumor resection in Cushing's patients with pituitary microad-
enoma, monitoring central venous pressure may be indicated
to maintain pressure in the low-normal range. Such monitor-
ing is needed only infrequently in other cases of transsphenoi-
dal resection of microadenoma.
From 10% to 15% of patients with Cushing's syndrome
have adrenal overproduction of glucocorticoids (adrenal
adenoma or carcinoma). Patients with Cushing's syndrome
who require bilateral adrenalectomy have a high incidence of
 422 ANESTHESIA AND UNCOMMON DISEASES

replacement therapy, with the goal of complete adrenal sup-

TABLE 13-5  n Clinical Features of Hyperadrenalism
(Cushing's Syndrome) and Hypoadrenalism
Cushing's Syndrome
Central obesity
Proximal muscle weakness
Osteopenia at young age and
back pain
Hypertension
Headache
Psychiatric disorders
Purple stria
Spontaneous ecchymoses
Plethoric facies
Hyperpigmentation
Hirsutism
Acne
Hypokalemic alkalosis
Glucose intolerance
Kidney stones
Hypoadrenalism
Weight loss
Weakness, fatigue, lethargy
Muscle and joint pain
Postural hypotension and
dizziness
Headache
Anorexia, nausea, abdominal
pain, constipation, diarrhea
Hyperpigmentation
Hyperkalemia, hyponatremia
Occasional hypoglycemia
Hypercalcemia
Prerenal azotemia
pression. These patients should be considered to have sup-
pressed adrenal function, and glucocorticoid replacement
should be administered preoperatively.
EXCESSIVE MINERALOCORTICOIDS
Excess mineralocorticoid activity leads to sodium reten-
tion, potassium depletion, hypertension, and hypokalemic
alkalosis. These symptoms constitute primary hyperaldoste-
ronism, or Conn's syndrome, a cause of low-renin hyperten-
sion because renin secretion is inhibited by the effects of the
high aldosterone levels. Primary hyperaldosteronism is pres-
ent in 0.5% to 1% of hypertensive patients who have no other
known cause of hypertension. Primary hyperaldosteronism is
most often the result of a unilateral adenoma, although 25%
to 40% of patients may have bilateral adrenal hyperplasia.
Spironolactone therapy should restore intravascular fluid vol-
ume, electrolyte concentrations, and renal function to within
normal limits preoperatively. The effects of spironolactone are
slow to appear over 1 to 2 weeks. In addition, patients with
Conn's syndrome have a high incidence of ischemic heart
disease, and hemodynamic monitoring appropriate for their
degree of cardiovascular impairment should be undertaken.
A retrospective study indicated that intraoperative stability,
with preoperative control of blood pressure and electrolytes,
was better with spironolactone than with other antihyperten-
sive agents.74

Polyuria
Menstrual disorders
Increased leukocyte count
postoperative complications. The incidence of pneumothorax
approaches 20% with adrenal carcinoma resection, requiring
treatment before the wound is closed. Ten percent of patients
with Cushing's syndrome who undergo adrenalectomy are
found to have an undiagnosed pituitary tumor. After reduc-
tion of high levels of cortisol by adrenalectomy, the pituitary
tumor enlarges (Nelson's syndrome).73 These pituitary tumors
are potentially invasive and may produce large amounts of
ACTH and melanocyte-stimulating hormone, thus increasing
pigmentation.
Adrenal tumors are discovered incidentally 85% of the
time during screening (and largely unindicated) CT scans.
Nonfunctioning adrenal adenomas are found in as many as
10% of autopsies. Adrenal adenomas are usually treated sur-
gically, and often the contralateral gland will resume func-
tioning after several months. Frequently, however, the effects
of carcinomas are not cured by surgery, and such patients
may require administration of inhibitors of steroid synthe-
sis such as mitotane (o,p′-DDD[2,2-bis-(2-chlorophenyl-
4-chlorophenyl)-1,1-dichloroethane]). Patients given these
adrenal suppressants also receive chronic glucocorticoid
Adrenocortical Hormone Deficiency
GLUCOCORTICOID DEFICIENCY
Withdrawal of steroids or suppression of their adrenal syn-
thesis by steroid therapy is the leading cause of underpro-
duction of corticosteroids. The management of this type of
glucocorticoid deficiency is discussed later (see Perioperative
Stress and Corticoid Supplementation). Other causes of adre-
nocortical insufficiency include destruction of the adrenal
gland by cancer (including AIDS), tuberculosis, hemorrhage,
or an autoimmune mechanism; some forms of congenital
adrenal hyperplasia; and administration of cytotoxic drugs
(see Table 13-5).
Primary adrenal insufficiency (Addison's disease) is caused
by a local process within the adrenal gland that leads to destruc-
tion of all zones of the cortex and causes both glucocorticoid
and mineralocorticoid deficiency if bilateral. Autoimmune
disease is the most common cause of primary (nonendoge-
nous) bilateral ACTH deficiency. Autoimmune destruction of
the adrenals may be associated with other autoimmune dis-
orders, such as Hashimoto's thyroiditis. Enzymatic defects
in cortisol synthesis also cause glucocorticoid insufficiency,
compensatory elevations of ACTH, and congenital adrenal
hyperplasia. Adrenal insufficiency usually develops slowly.
Patients with Addison's disease can develop marked pigmen-
tation (because excess ACTH is present to drive an unproduc-
tive adrenal gland) and cardiopenia, apparently secondary to
chronic hypotension.
 Chapter 13  Diseases of the Endocrine System 423
BOX 13-7   n MANAGEMENT OF ACUTE ADRENAL
CRISIS (ADDISON'S DISEASE)
Treat precipitating cause.
Correct hypovolemia.
Correct hyponatremia and hyperkalemia.
Administer 0.9% normal saline with dextrose.
Administer IV hydrocortisone, 100 mg every 8 hours, then start oral
prednisone or taper as dictated by clinical situation.
Secondary adrenal insufficiency occurs when ACTH secre-
tion is deficient, often because of a pituitary or hypothalamic
tumor. Treatment of pituitary tumors by surgery or radiation
may result in hypopituitarism and consequent adrenal failure.
If glucocorticoid-deficient patients are not stressed, they
usually have no perioperative problems. However, acute adre-
nal (Addisonian) crisis can occur.75 In the preparation of such
a patient for anesthesia and surgery, hypovolemia, hyper-
kalemia, and hyponatremia should be corrected. Because
these patients cannot respond to stressful situations, tradi-
tionally they are given a maximum stress dose of glucocor-
ticoids (hydrocortisone, 300 mg/70 kg/day) perioperatively.
Symreng et al.76 gave 25 mg of hydrocortisone phosphate IV
to adults at the start of surgery, followed by 100 mg IV over
the next 24 hours. Because using the minimal drug dose that
will cause an appropriate effect is desirable, this latter regimen
seems attractive. Evidence supports that less steroid supple-
mentation does not cause problems (Box 13-7).
MINERALOCORTICOID DEFICIENCY
Hypoaldosteronism, a condition less common than glucocorti-
coid deficiency, can be congenital or can occur after unilateral
adrenalectomy or prolonged administration of heparin. It may
also be a consequence of long-standing diabetes and renal fail-
ure. Nonsteroidal inhibitors of prostaglandin synthesis may also
inhibit renin release and exacerbate this condition in patients
with renal insufficiency. Levels of plasma renin activity are below
normal and fail to rise appropriately in response to sodium
restriction or diuretics. Most patients have low blood pressure;
rarely, however, a patient may be normotensive or even hyper-
tensive. Most symptoms are caused by hyperkalemic acidosis
rather than hypovolemia. Patients with hypoaldosteronism can
have severe hyperkalemia, hyponatremia, and myocardial con-
duction disturbances. These defects can be treated successfully
with mineralocorticoids (9α-fluorocortisone, 0.05-0.1 mg/day)
preoperatively. Doses must be carefully titrated and monitored
so that hypertension can be avoided.
Perioperative Stress and Corticoid
Supplementation
Many reports (mostly anecdotal) concerning normal adre-
nal responses during the perioperative period and responses
of patients taking steroids for other diseases indicate the
following:
1. Perioperative stress is related to the degree of trauma and
the depth of anesthesia. Deep general or regional anesthe-
sia causes the usual intraoperative glucocorticoid surge to
be postponed until the postoperative period.
2. Few patients with suppressed adrenal function have peri-
operative cardiovascular problems if they do not receive
supplemental steroids preoperatively.
3. Occasionally, a patient who habitually takes steroids will
become hypotensive perioperatively, but this event has only
rarely been documented sufficiently to implicate glucocor-
ticoid or mineralocorticoid deficiency as the cause.
4. Although it occurs rarely, acute adrenal insufficiency can
be life threatening.
5. High-dose corticosteroid coverage perioperatively poses
minimal risk to these patients.
Usually, laboratory data defining pituitary-adrenal ade-
quacy are not available before surgery. However, rather than
delay surgery or test most patients, it is assumed that any
patient who has taken corticosteroids at any time in the
preceding year has pituitary-adrenal suppression and will
require perioperative supplementation. The current recom-
mendation is 100 mg/70 kg/24 hr until a prospective, ran-
domized, double-blind trial in patients receiving physiologic
doses of corticosteroids is performed. A smaller dose prob-
ably can be used.
The physiology of the HPA axis is dramatically altered
during critical illnesses such as trauma, surgery, sepsis, and
shock. Under perioperative conditions, the adrenal glands
secrete 116 to 185 mg of cortisol daily. Under maximum
stress, adrenals may secrete 200 to 500 mg daily. Good cor-
relation exists between the severity and duration of surgery
and the response of the adrenal gland during major surgery
(e.g., colectomy) and minor surgery (e.g., herniorrhaphy).
In one study the mean maximal plasma cortisol level ­during
major surgery in 20 patients was 47 μg/dL (range, 22-75 μg/dL).
Values remained above 26 μg/dL for a maximum of 72 hours
postoperatively. The mean maximal plasma cortisol level
during minor surgery was 28 μg/dL (range, 10-44 μg/dL).77
If random plasma cortisol is measured during acute stress,
a value greater than 34 μg/dL indicates normal pituitary-
adrenal responsiveness. A value of 15 μg/dL indicates relative
adrenal insufficiency.
The most sensitive test of adrenal reserve is the ACTH stim-
ulation test. To test pituitary-adrenal sufficiency, after deter-
mining baseline plasma cortisol level, 250 μg of synthetic
ACTH (cosyntropin) is given and plasma cortisol measured
30 to 60 minutes later. An increment in plasma cortisol of 7
to 20 μg/dL or more is normal. A normal response indicates a
recovery of pituitary-adrenal axis function. A lesser response
usually indicates pituitary-adrenal insufficiency, possibly
requiring perioperative supplementation with corticosteroids.
One approach to these patients is to administer 50 to 75 mg
of hydrocortisone every 6 hours for 1 week and then taper. In
patients who survive their critical illness, the pituitary-adrenal
function can be re-evaluated after resolution.
 424 ANESTHESIA AND UNCOMMON DISEASES

ADRENAL MEDULLA than 0.1% of all cases of hypertension, pheochromocytomas

have important implications to the anesthesiologist. Patients
Pheochromocytomas and paragangliomas are catecholamine- with unrecognized pheochromocytomas can have high mor-
producing tumors derived from the sympathetic and para- bidity and mortality.
sympathetic nervous system. Cells of neural crest origin are In more than 85% of cases, pheochromocytomas are spo-
capable of developing into catecholamine-secreting tumors; radic tumors of unknown cause that are localized in the
indeed, catecholamine tumors have been reported in neu- medulla of one adrenal gland; however, these vascular tumors
ral crest sites ranging from the neck to the inguinal ligament. can occur anywhere. They are found in the right atrium,
About 10% of the pheochromocytomas are bilateral, 10% spleen, broad ligament of the ovary, or Zuckerkandl organs
extra-adrenal, and 10% malignant. (bodies) at the bifurcation of the aorta. Malignant spread
occurs in less than 15% of patients with pheochromocytoma,
Pheochromocytoma
usually through venous and lymphatic channels, with a predi-
Pheochromocytomas have been reported as part of the lection for the liver. Often, bilateral tumors are present in the
MEN-IIA and MEN-IIB syndromes and in association with familial form.78
neuroectodermal dysplasias, including neurofibromatosis 1 Catecholamines, are the physiologic transmitters released
(NF1), tuberous sclerosis, Sturge-Weber syndrome, and von from the terminals of the postganglionic sympathetic nervous
Hippel–Lindau disease (Table  13-6). Although causing less system. Synthesis of catecholamines begins in the postgangli-
onic nerve cell bodies when tyrosine is hydroxylated in the
rate-limiting step to DOPA; DOPA is decarboxylated to dopa-
TABLE 13-6  n Syndromes Associated with Adrenal mine, and, in most cells dopamine is hydroxylated to norepi-
Gland Tumors nephrine. In the adrenal gland, in rare parts of the CNS, and
at some ganglia, norepinephrine can be converted by phenyl-
Syndrome Clinical Features ethanolamine-N-transferase to epinephrine. The release of
Bechwith-Wiedemann Adrenocortical carcinoma dopamine, norepinephrine, and epinephrine occurs both
syndrome Omphalocele basally and in response to physiologic and pharmacologic
Macroglossia stressors such as hypotension (through baroreceptors), low tis-
Macrosomia
sue perfusion, hypoxia, hypoglycemia, anger, determination,
Hemihypertrophy
Hypoglycemia fear, and anxiety. Such release from the sympathetic nervous
Visceromegaly system can be generalized or localized. Most pheochromocy-
Renal abnormalities tomas are independent of these physiologic stressors. Some
Li-Fraumeni syndrome Adrenocortical carcinoma
pheochromocytomas are under neurogenic control, with
Breast cancer increased release of catecholamines stimulated by physiologic
Leukemia and pharmacologic stressors. However, much of the release of
Sarcoma catecholamines from pheochromocytomas is not controlled
Brain tumors by neurogenic influence. This lack of neurologic control is
Carney's complex Mucocutaneous pigmented lesion used in the clonidine suppression test for pheochromocytoma.
Myxomas Several studies found that the triad of paroxysmal sweat-
Multiple thyroid follicular ing, hypertension, and headache strongly suggests pheochro-
adenomas
mocytoma. These are the symptoms experienced when given
Primary pigmented nodular
adrenocortical disease an infusion of epinephrine. Physical examination of a patient
Pituitary growth hormone– with a pheochromocytoma is usually unrewarding unless the
producing adenoma patient is observed during an attack. Occasionally, palpation of
MEN-II Pheochromocytoma
the abdomen causes the bladder or rectum to rub against the
Mucosal neuromas tumor and stimulates release of catecholamines; however, lab-
Ganglioneuromatosis of intestine oratory measurement of catecholamines or their metabolites
Marfanoid habitus has been the standard method of diagnosis. Half of all patients
Neurofibromatosis 1 Pheochromocytoma with pheochromocytoma have continuous hypertension with
(NF1) Neurofibromas occasional paroxysms, and another 40% have paroxysmal
Café au lait spots hypertension. Labile hypertension or the triad (hypertension,
Optic gliomas headache, sweating) usually is an indication for urine testing.
Lisch nodules
Urine tests have become a mainstay of diagnosis. The usual
Short stature
Learning disabilities urine tests used measure 3-methoxy-4-hydroxymandelic acid,
Macrocephaly or metanephrines, or native catecholamines per milligram
of creatine secreted. If the results of three 24-hour collec-
von Hippel–Lindau Same as for NF1
disease
tions of urine are normal, a pheochromocytoma can usually
be ruled out. Catecholamine levels in urine and plasma are
 Chapter 13  Diseases of the Endocrine System 425
diagnostic when elevated to three times the normal median
value. Sensitivity and specificity of biochemical tests vary
greatly and are important when considering borderline eleva-
tions; the results of various tests may be combined to reach a
diagnosis.79
Once the diagnosis of pheochromocytoma is made, the
tumor must be localized and pretreated before surgical resec-
tion. The protocol for localizing these often small tumors now
favors MRI, which replaced CT, which in turn had replaced
urography and venous sampling. When such techniques do
not yield definitive results, m-iodobenzylguanidine (ioben-
guane) iodine 129 (129I) scanning or positron emission tomog-
raphy (PET) is considered.
ANESTHETIC CONSIDERATIONS
Complete tumor removal is the therapeutic goal. Perioperative
morbidity and mortality associated with pheochromocytoma
are well reported.80-83 Mortality for patients with pheochromo-
cytoma is usually the result of myocardial failure, myocardial
infarction, or hemorrhage (hypertensive) into the myocardium
or brain. Persistently elevated catecholamine levels may result
in catecholamine myocarditis. This cardiomyopathy appears to
pose an extra risk for patients, but it can be treated success-
fully by alpha-adrenergic blockade preoperatively. Patients
with pheochromocytoma should receive α-blockers preop-
eratively to reduce the perioperative complications of hyper-
tensive crisis, the wide fluctuations in blood pressure during
intraoperative manipulation of the tumor (especially until
venous drainage is obliterated), and perioperative myocardial
dysfunction. Perioperative mortality associated with the exci-
sion of pheochromocytoma was reduced with the introduction
of preoperative α-blocker therapy and when it was recognized
that these patients often had hypovolemia preoperatively.84
Preoperative therapy consisting of α-adrenergic blockade
with phenoxybenzamine, prazosin, or labetalol alleviates the
patient's symptoms, favors a successful outcome, and allows
re-expansion of intravascular plasma volume by eradicating
the vasoconstrictive effects of high levels of catecholamines.
This re-expansion of fluid volume is often accompanied by
a decreased hematocrit. Because some patients are sensitive,
phenoxybenzamine should initially be administered at 10 to
20 mg orally two or three times daily. Most patients require
60 to 250 mg/day. The efficacy of the therapy is judged by the
reduction of symptoms (especially sweating) and by BP sta-
bilization. For patients with catecholamine myocarditis, as
evidenced by often-localized ST-segment and T-wave ECG
changes, preoperative and long-term α-blockade (15 days to
6 months) has been effective in resolving the clinical and ECG
alterations80 (Box 13-8).
Beta-adrenergic receptor blockade with concomitant
administration of phenoxybenzamine is suggested for patients
with persistent dysrhythmias or tachycardia. The β-receptor
blockade should not be started without α-blockade, because
unopposed β-blockade could produce dangerous vasocon-
striction and hypertension; with hypertension reported only
rarely, however, perhaps no firm rules are necessary.
BOX 13-8   n  MANAGEMENT OF PHEOCHROMOCYTOMA
Treat hypertension with alpha-adrenergic blockers
(phenoxybenzamine, prazosin, labetalol).
Add β-blockers after initiation and titration of α-blockers.
Metyrosine can be used to decrease production of catecholamines.
Correct hypovolemia, if indicated.
Anesthetic Considerations
Prepare for intraoperative hypertension and hypotension
(nitroprusside infusion, IV phentolamine, phenylephrine, and
norepinephrine).
Consider invasive monitoring of blood pressure (A-line).
Consider central venous pressure monitoring and central line for
delivery of vasoactive drugs.
Most patients require treatment for 10 to 14 days, as deter-
mined by the time needed for BP stabilization and amelio-
ration of symptoms. The patient who does not complain of
nasal stuffiness is not ready for surgery. Pheochromocytomas
spread slowly, allowing the patient's preoperative condition to
be optimized with medical therapy. Painful or stressful events
such as intubation often cause an exaggerated catecholamine
response in less-anesthetized patients with pheochromocy-
toma. This response is caused by release of catecholamines
from nerve endings that are “loaded” by the reuptake process.
Stresses may cause catecholamine levels of 200 to 2000 pg/mL
in normal patients. For the patient with pheochromocytoma,
even simple stresses can lead to blood catecholamine levels of
2000 to 20,000 pg/mL. Squeezing the tumor, however gently,
or infarction of the tumor with release of products onto peri-
toneal surfaces, can result in blood levels of 200,000 to 1 mil-
lion pg/mL, a potentially disastrous situation that should be
anticipated and avoided. The physician should ask for a tem-
porary delay of surgery, if at all possible, during which the
rate of nitroprusside infusion will be increased. Although spe-
cific anesthetic drugs have been recommended for patients
with pheochromocytoma, optimal preoperative preparation,
careful and gradual induction of anesthesia, and good com-
munication between surgeon and anesthesiologist are most
important.
Virtually all anesthetic agents, muscle relaxants, and tech-
niques have been used successfully for patients with pheochro-
mocytoma, and all are associated with a high rate of transient
intraoperative dysrhythmias. The theoretic advantages or dis-
advantages of some agents have not been demonstrated clini-
cally. It is prudent to avoid drugs that cause histamine release,
including morphine and droperidol (which can cause tran-
sient hypertension).
Phenylephrine or dopamine is used for treatment of hypo-
tension, whereas nitroprusside is preferable when hypertension
occurs.29 Phentolamine, previously a mainstay of intraopera-
tive therapy, has overlong onset and duration of action. After
the venous supply has been secured, some patients become
hypotensive and occasionally require a relatively large infu-
sion of catecholamines. On rare occasions, patients remain
hypertensive intraoperatively. Postoperatively, about 50% of
 426 ANESTHESIA AND UNCOMMON DISEASES
patients have hypertension for 1 to 3 days and have greatly ele-
vated but declining plasma catecholamine levels. After 3 to 10
days, all but 25% become normotensive. Catecholamine levels
do not return to normal for 10 days; therefore, early measure-
ment of urine concentrations is usually not helpful in ensuring
complete catecholamine removal from tissue.
Because pheochromocytomas may be hereditary, it is
important to screen other family members. They are advised
to inform the anesthesiologist about their potential for occult
pheochromocytoma should they require surgery in the future.
PANCREAS
Physiology
Pancreatic islets are composed of at least three cell types:
alpha cells that secrete glucagon, beta cells that secrete insu-
lin, and delta cells that contain secretory granules. Insulin is
first synthesized as proinsulin, converted to insulin by pro-
teolytic cleavage, and then packaged into granules within the
β cells. A large quantity of insulin, normally about 200 units,
is stored in the pancreas, and continued synthesis is stimu-
lated by glucose. There is basal, steady-state release of insulin
from the β granules and additional release that is controlled
by stimuli external to the β cell. Basal insulin secretion
continues in the fasted state and is key to the inhibition of
catabolism and ketoacidosis. Glucose and fructose are the
primary regulators of insulin release. Other stimulators of
insulin release include amino acids, glucagon, GI hormones
(gastrin, secretin, cholecystokinin-pancreozymin, enteroglu-
cagon), and acetylcholine. Epinephrine and norepinephrine
inhibit insulin release by stimulating α-adrenergic receptors,
and they stimulate its release at β-adrenergic receptors.
A normal plasma glucose level requires adequate endog-
enous substrate for glucose production, normal enzymatic
mechanisms capable of converting glycogen and other sub-
strates to glucose, and normal hormonal modulation of glu-
coneogenesis.85 The rise in glucose levels after a meal causes
release of insulin from β cells in the pancreas. The mag-
nitude of the insulin response depends partly on other GI
hormones secreted after food intake, the action of which
accounts for the greater rise in insulin levels after oral than
after parenteral administration of glucose. Release of insu-
lin can also be triggered by β-adrenergic stimuli believed to
act by increasing cAMP levels. Insulin release is inhibited by
α-adrenergic stimuli. The action of insulin tends to return
the levels of plasma glucose to normal within 1 to 2 hours
after completion of a meal.
When endogenous nutrients are not available, plasma glu-
cose levels are maintained by hepatic glycogenolysis and then
gluconeogenesis.86 Insulin levels are low in these patients, and
glucagon, GH, cortisol, and catecholamines play important
roles in gluconeogenesis. Insulin is normally secreted from
the pancreas in response to elevated levels of blood glucose as
a prohormone (proinsulin). This hormone is rapidly cleaved
into C peptide and insulin in the portal vein. Patients with
insulinoma tend to have high levels of proinsulin (> 20% of
total insulin) in plasma and C-peptide levels that parallel insu-
lin levels.
Hypoglycemia and Hyperinsulinism (Islet Cell
Tumors of Pancreas)
Almost all the signs and symptoms in patients with insuli-
nomas are directly related to prolonged hypoglycemic states.
Hypoglycemia is a clinical syndrome with many causes that
results in plasma glucose levels sufficiently low to promote
secretion of catecholamines and to impair CNS function
(Fig. 13-9). The two major classifications of hypoglycemia can
be distinguished by the relationship of symptoms to meals.
Reactive hypoglycemia occurs 2 to 4 hours after ingestion of
food and is associated primarily with adrenergic symptoms.
Fasting hypoglycemia occurs more than 6 hours after a meal,
is precipitated by exercise, and is often associated with CNS
symptoms.
Insulinomas usually cause fasting hypoglycemia. Reactive
hypoglycemia can be caused by alimentation, impaired glu-
cose tolerance, or functional causes. Alimentary hypoglycemia
is associated with low levels of plasma glucose 2 to 3 hours
after ingestion of food by patients who have rapid gastric
emptying (e.g., after subtotal gastrectomy, vagotomy, or pylo-
roplasty). Rapid gastric emptying and rapid absorption of glu-
cose may result in excessive release of insulin, falling glucose
levels, and reactive hypoglycemia. Impaired glucose tolerance
resulting in hypoglycemia, an early symptom of diabetes, usu-
ally occurs 4 to 5 hours after ingestion of food. Because the
brain is extremely sensitive to glucose utilization, CNS effects
often manifest with hypoglycemia. Most patients show CNS
symptoms that include visual disturbances, dizziness, confu-
sion, epilepsy, lethargy, transient loss of consciousness, and
coma. Perhaps because of the many CNS manifestations of
insulinomas, many patients with these tumors have been mis-
diagnosed as having psychiatric illness.
Less frequent but nevertheless important manifestations
of insulinomas involve the cardiovascular system. More than
10% of insulinoma patients have palpitations, tachycardia,
or hypertension (or all three). These symptoms are probably
related to catecholamine release secondary to hypoglycemia,
and about 9% of the patients have either severe hunger or GI
upset, including cramping, nausea, and vomiting. Other inves-
tigators have noted obesity or weight gain as a symptom. The
symptoms of hypoglycemia caused by insulinoma may occur
at a particular time of day that is associated with a low blood
glucose level, especially 6 hours or more after eating, after fast-
ing for a time, or in the early morning.
Fasting hypoglycemia results from inadequate hepatic
glucose production or from overutilization of glucose in the
peripheral tissues. The causes of inadequate production of
glucose during the fasting state may be hormone deficiencies,
enzyme defects, inadequate substrate delivery, acquired liver
disease, or drugs. Overutilization of glucose may occur in the
presence of either elevated or appropriate insulin levels.
 Chapter 13  Diseases of the Endocrine System 427
Causes of hypoglycemia
Fasting (postabsorptive)
hypoglycemia
Drugs:
Insulin, sulfonylureas, ethanol,
quinine, pentamidine
Critical illnesses:
Hepatic, renal, and cardiac failure,
sepsis
Hormone deficiencies:
Cortisol, growth hormone,
glucagon, and epinephrines
Non-beta cell tumors
Hyperinsulinism:
Insulinoma
Other beta-cell disorders
Insulin secretagogues
Autoimmune
Ectopic insulin secretion
Disorders of infancy or childhood:
Congenital hyperinsulinism
Inherited enzyme deficiencies
FIGURE 13-9  Causes of hypoglycemia.
To define the diagnosis of insulinomas, Whipple intro-
duced a triad of diagnostic criteria, which have been mod-
ified to include (1) symptoms of hypoglycemia brought
on by fasting and exercise; (2) blood glucose levels, while
symptoms are present, of less than 40 mg/dL in females
and less than 45 mg/dL in males; and (3) relief of these
symptoms by administration of glucose, either orally or
intravenously. If an insulinoma is suspected and Whipple's
triad is confirmed, several tests may be done with which
one can differentiate insulinoma from other causes of
hypoglycemia.
With the ability to determine insulin levels as well as glu-
cose levels, the diagnosis is made with even more certainty.
During a prolonged fast in patients with insulinoma, hypo-
glycemia develops because of a relative underproduction
of glucose by the liver rather than because of increased glu-
cose utilization. High levels of C peptide and proinsulin levels
greater than 20% of total insulin measured in blood are also
helpful. Selective celiac CT angiography or MRI of the pan-
creatic region is often used for localization of tumors before
surgical exploration.
Medical management of insulin-secreting tumors is often
difficult but has been simplified by somatostatin, before
and during surgery and when surgery fails to remove all the
tumor(s). Surgical treatment of insulin-secreting islet cell
tumors involves their removal, usually from the pancreas,
their usual location. About 13% of patients have more than
one adenoma. Most insulinomas are benign; approximately
one third of malignant tumors are found at laparotomy to have
metastasized to the liver.
Reactive (postprandial)
hypoglycemia
Alimentary (postgastrectomy)
Noninsulinoma pancreatogenous
hypoglycemia syndrome:
Following Roux-en-Y gastric bypass
Hereditary fructose intolerance
Idiopathic
ANESTHETIC CONSIDERATIONS
Most patients who come to surgery with the diagnosis of
reactive or fasting hypoglycemia do not require special
intraoperative care other than frequent assays of blood glu-
cose levels and adequate infusion of dextrose. The varia-
tions in plasma glucose levels are exaggerated in patients
with functional islet cell adenoma. An intraoperative rise
in blood glucose, sometimes quite striking, is thought
to be evidence of tumor removal.87 Therefore, two other
methods of intraoperative glucose management have been
designed not to mask this hyperglycemic rebound. In the
first approach, glucose infusion is stopped approximately 2
hours before surgery. Blood glucose is monitored frequently,
but no glucose is administered unless the level drops below
a certain value.
Administration of insulin to hyperglycemic patients dur-
ing and after surgery is aimed at short-term control of glu-
cose levels. Intraoperatively, the aim should be to keep the
blood glucose levels above 100 mg/dL but less than 180 mg/
dL, administering regular insulin intravenously. Frequent
monitoring of glucose is continued and glucose infusion
titrated to achieve the goal. The aim is to keep the blood glu-
cose level higher than the level at which the patient becomes
symptomatic while awake. Blood glucose also is monitored in
the postoperative period because hyperglycemia and its com-
plications can occur. Muir et  al.88 reviewed 39 patients who
underwent surgery for insulinoma. After tumor removal, all
patients except one had an increase in plasma glucose concen-
tration. All patients subsequently proved to be cured, whereas
the patient who had a hyperglycemic response was later shown
 428 ANESTHESIA AND UNCOMMON DISEASES

not to be cured. In six patients whose blood glucose concen-
tration increased after tumor resection, the rise was less sharp
than that before tumor removal.
Perioperative control of glucose levels is aimed at euglyce-
mia, with either glucose infusion or an artificial β cell.
Diabetes Mellitus
Diabetes mellitus (DM) is a common condition with far-
reaching implications. “Diabetes mellitus” refers to a group
of common metabolic disorders that share the phenotype of
hyperglycemia. Several distinct types of DM are caused by a
complex interaction of genetics and environmental factors.
Depending on the etiology of the DM, factors contributing to
hyperglycemia include reduced insulin secretion, decreased
glucose utilization, and increased glucose production. The
metabolic dysregulation associated with DM causes second-
ary pathophysiologic changes in multiple organ systems. In
the United States, DM is the leading cause of end-stage renal
disease (ESRD), nontraumatic lower-extremity amputations,
and adult blindness. It also predisposes to cardiovascular dis-
eases. Surgical mortality rates for the diabetic population aver-
age five times higher than for the nondiabetic population.89
Diabetes mellitus is classified on the basis of the patho-
genic process that leads to hyperglycemia, in contrast to
earlier criteria such as age at onset or type of therapy. The
two broad categories of DM are designated type 1 and type
2 (Fig.  13-10). Both types of diabetes are preceded by a
phase of abnormal glucose homeostasis as the pathogenic
processes progress. Type 1 DM is the result of complete or
near-total insulin deficiency. Type 2 DM is a heterogeneous
group of disorders characterized by variable degrees of insu-
lin resistance, impaired insulin secretion, and increased glu-
cose production. Other etiologies for DM include specific
genetic defects in insulin secretion or action, metabolic
abnormalities that impair insulin secretion, mitochondrial
abnormalities, and a host of conditions that impair glucose
tolerance. The fourth variety is related to glucose intoler-
ance that develops during pregnancy and is called gesta-
tional diabetes. It is important to know the various types of
diabetes because of their distinct therapeutic implications.
Furthermore, ­ classifying patients into insulin-dependent
(IDDM) and non-insulin-dependent (NIDDM) groups is
confusing and now considered obsolete.
ACUTE COMPLICATIONS
Diabetic patients are subject to a series of long-term com-
plications resulting from cataracts, retinopathy, neuropathy,
nephropathy, and angiopathy and leading to considerable
morbidity and premature mortality. Many complications
bring the diabetic patient to surgery; more than 50% of all dia-
betic patients require surgery at some time. However, acute

Etiologic classification of
diabetes mellitus

Type I Type II Specific types Gestational

diabetes diabetes of diabetes diabetes

Immune-mediated
idiopathic

Genetic defects of Genetic defects Genetic syndromes Uncommon Drug or chemical Diseases of Infections Endocrinopathies
beta-cell function in insulin action associated with forms of induced exocrine pancreas
diabetes immune-mediated
Hepatocyte nuclear diabetes Glucocorticoids Congenital rubella
transcription factor (HNF)4 Wolfram’s syndrome Pentamidine Cytomegalovirus
Glucokinase Down syndrome Nicotinic acid Coxsackievirus
HNF-1 Klinefelter’s syndrome Diazoxide
Turner’s syndrome Beta-adrenergic agonists
Insulin promoter factor-1 Friedreich’s ataxia Thiazides
Neuro01 Huntington’s chorea Hydantoins
Mitochondrial DNA Laurence-Moon-Biedl syndrome Asparaginase
Subunits of ATP-sensitive Myotonic dystrophy Alpha-interferon
potassium channel Porphyria Protease inhibitors
Proinsulin or insulin Prader-Willi syndrome Antipsychotics
Epinephrine

Type A insolin resistance “Stiff-person” syndrome, Pancreatitis Acromegaly

Leprechaunism anti-insulin receptor Pancreatectomy Cushing’s syndrome
Rabson-Mendenhall syndrome antibodies Neoplasia Glucagonoma
Lipodystrophy syndromes Cystic fibrosis Pheochromocytoma
Hemochromatosis Hyperthyroidism
Fibrocalculous pancreatopathy Somatostatinoma
Mutations in carboxyl ester lipase Aldosteronoma
FIGURE 13-10  Etiologic classification of diabetes mellitus.
 Chapter 13  Diseases of the Endocrine System 429
complications are most life threatening and include hypogly-
cemia, diabetic ketoacidosis, and hyperglycemic hyperosmo-
lar nonketotic coma.
Hyperglycemic Hyperosmolar State
Hyperglycemic hyperosmolar nonketotic diabetic coma is
characterized by elevated serum osmolality (> 330 mOsm/L)
and elevated blood glucose level (> 600 mg/dL) with mild or no
acidosis. Trauma or infection in type 2 diabetic patients usually
leads to this state rather than to ketoacidosis. Hyperglycemia
induces marked osmotic diuresis and dehydration, enhanc-
ing the hyperosmolar state; this can result in failure to emerge
from anesthesia and persistent coma. Serum electrolyte values
are often normal, although a widened anion gap may indicate
lactic acidosis or a uremic state.
Ketoacidosis
Many diabetic patients who need emergency surgery for
trauma or infection have significant metabolic decompen-
sation, including ketoacidosis. Often the time available for
patient stabilization is limited, but even a few hours may be
sufficient to correct potentially life-threatening fluid and elec-
trolyte disturbances. It is futile to delay surgery in an attempt
to eliminate ketoacidosis completely if the underlying sur-
gical condition will lead to further metabolic deterioration.
Intraoperative cardiac dysrhythmias and hypotension result-
ing from ketoacidosis are less likely to occur if volume deple-
tion and hypokalemia are at least partly treated.
Insulin therapy is initiated with an IV bolus of regular
insulin, 0.1 unit/kg, followed by continuous insulin infusion
at 0.1 unit/kg/hr. Regular monitoring of glucose, potassium,
and pH is recommended. Because the number of insulin-
binding sites is limited, the maximum rate of glucose decline
is fairly constant, averaging 75 to 100 mg/dL/hr, regardless of
the insulin dose. During the first 1 to 2 hours of fluid resusci-
tation, the glucose level may fall more precipitously. When the
serum glucose concentration reaches 250 mg/dL, 5% dextrose
should be added to the IV fluid.90
The volume of fluid required for therapy varies with over-
all deficits, ranging from 3 to 5 L but as high as 10 L. Despite
losses of water in excess of losses of solute, sodium levels are
generally normal or reduced. Factitious hyponatremia caused
by hyperglycemia or hypertriglyceridemia may result in this
seeming contradiction. The plasma sodium concentration
decreases by about 1.6 mEq/L for every 100-mg/dL increase
in plasma glucose concentration above normal. Initially, nor-
mal saline is infused at 250 to 1000 mL/hr, depending on the
degree of volume depletion and the patient's cardiac status.
About one third of the estimated fluid deficit is corrected in
the first 6 to 8 hours, with the other two thirds corrected over
the next 24 hours. It may be prudent to monitor left ventricu-
lar volume in diabetic patients who have a history of signifi-
cant myocardial dysfunction.91
The degree of acidosis is determined by measurement of
arterial blood gases and an increased anion gap. Acidosis
with an increased anion gap (at least 16 mEq/L) in an acutely
ill diabetic patient may be caused by ketones in ketoacidosis,
lactic acid in lactic acidosis, increased organic acids from renal
insufficiency, or all three. In ketoacidosis the plasma levels of
acetoacetate, β-hydroxybutyrate, and acetone are increased.
Plasma and urinary ketones are measured semiquantitatively
with Ketostix and Acetest tablets. The role of bicarbonate ther-
apy in diabetic ketoacidosis is controversial. Myocardial func-
tion and respiration are known to be depressed at a blood pH
below 7.0 to 7.10; however, rapid correction of acidosis with
bicarbonate therapy may result in alterations in CNS func-
tion and structure. The alterations may be caused by (1) para-
doxical development of cerebrospinal fluid and CNS acidosis
resulting from rapid conversion of bicarbonate to carbon diox-
ide and diffusion of the acid across the blood-brain barrier,
(2) altered CNS oxygenation with decreased cerebral blood
flow, and (3) development of unfavorable osmotic gradients.
After treatment with fluids and insulin, β-hydroxybutyrate
levels decrease rapidly, whereas acetoacetate levels may remain
stable or even increase before declining. Plasma acetone levels
remain elevated for 24 to 42 hours, long after blood glucose,
β-hydroxybutyrate, and acetoacetate levels have returned to
normal; the result is continuing ketonuria. Persistent keto-
sis, with a serum bicarbonate level of less than 20 mEq/L in
the presence of a normal glucose level, represents a contin-
ued need for intracellular glucose and insulin for reversal of
lipolysis.
The most important electrolyte disturbance in diabetic
ketoacidosis is depletion of total body potassium. The defi-
cits range from 3 mEq/kg up to 10 mEq/kg. Rapid declines in
serum potassium level occur, reaching a nadir within 2 to 4
hours after the start of IV insulin administration. Aggressive
replacement therapy may be required. The potassium admin-
istered moves into the intracellular space with insulin as the
acidosis is corrected. Potassium is also excreted in the urine
with the increased delivery of sodium to the distal renal tubules
that accompanies volume expansion. Phosphorus deficiency
in ketoacidosis caused by tissue catabolism, impaired cellular
uptake, and increased urinary losses may result in significant
muscular weakness and organ dysfunction. The average phos-
phorus deficit is approximately 1 mmol/kg. Replacement may
be needed if the plasma concentration falls below 1.0 mg/dL.
PREOPERATIVE MANAGEMENT OF HYPERGLYCEMIA
Prior to the past decade, little attention was paid to the control
of hyperglycemia in the perioperative period or in the acute
phase of critical illness managed in the ICU. “Permissive” or
stress-induced hyperglycemia was generally accepted as the
norm, defined as a transient response to the stress of an acute
injury or illness.92 Observational studies have reported sig-
nificant prevalence of hyperglycemia in hospitalized patients;
70% of diabetic patients with acute coronary syndrome and
80% of cardiac surgery patients in the perioperative period
may develop hyperglycemia.93 Van den Berghe's landmark
2001 paper94 demonstrated for the first time a mortality ben-
efit of tight glucose control in the ICU. From this study origi-
nated the concept of intensive insulin therapy (IIT) as a means
of normalizing elevated glucose levels in critically ill patients.
 430 ANESTHESIA AND UNCOMMON DISEASES
IIT is defined by a target glucose range of 80 to 110 mg/dL,
and standard care implies a target glucose range of 180 to
200 mg/dL in the early studies addressing this issue. Over the
next few years, however, several studies comparing IIT to stan-
dard care failed to demonstrate a difference in mortality; the
IIT groups also demonstrated high incidence of hypoglycemia
(8%-28%).95-99 The 2009 Normoglycemia in Intensive Care
Evaluation-Survival Using Glucose Algorithm Regulation
(NICE-SUGAR), the largest trial yet of tight glucose control
in the ICU (6104 patients in 42 centers), demonstrated an
absolute increase in mortality and an increased incidence of
hypoglycemia in the IIT group compared to controls.100 This
resulted in a paradigm shift in the glycemic management away
from IIT in the perioperative and critically ill patient.101,102
Subsequent studies underscored the NICE-SUGAR find-
ings. Annane et  al.103 found no reduction in mortality and
increased hypoglycemia in a randomized controlled trial of
IIT with glucocorticoids in the treatment of septic shock. The
control group was given standard insulin therapy plus gluco-
corticoid. Three recent meta-analyses of randomized trials
investigating IIT demonstrated no overall effect on mortal-
ity and increased hypoglycemia rates in the IIT groups com-
pared to controls.104-106 An observational cohort study before
the NICE-SUGAR trial compared outcomes before and after
institution of an IIT policy. Hypoglycemia was increased and
no survival benefit noted with the institution of IIT.107
The NICE-SUGAR trial and other recent reports dem-
onstrate that IIT does not improve survival; in fact, it may
increase mortality and is associated with more hypoglycemia
than standard insulin therapy. Given that in NICE-SUGAR
the standard insulin therapy control group (140-180 mg/dL)
had similar outcomes (if not better) than the IIT group, 140 to
180 mg/dL is now generally accepted as the new target range.
The American Association of Clinical Endocrinologists and
American Diabetes Association (AACE/ADA) recommend a
threshold to initiate insulin infusion of no higher than 180 mg/dL
in managing the hyperglycemic ICU patient.108 Once insulin
therapy has been initiated, the 140 to 180–mg/dL range is tar-
geted. Control of glucose by insulin infusion is recommended
in the preoperative period and for critically ill patients. More
precise methods of glucose measurement are also advised.109
ACKNOWLEDGEMENTS
Parts of this chapter have been revised from Roizen MF,
Enany NM: Diseases of the endocrine system. In Fleisher LA
(ed): Anesthesia and Uncommon Diseases, 2nd ed. Philadelphia,
WB Saunders, 2006, p 413.
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 C H
Mitochondrial Disease
Background
Effect of Anesthetics on Mitochondrial Function
Inhalational and Local Anesthetics
Barbiturates, Propofol, Etomidate, Ketamine, Midazolam
Other Effects
Anesthesia-Induced Neurotoxicity
Inherited Disorders with Childhood Onset
Inherited Disorders with Adult Onset
Preoperative Evaluation
Anesthetic Management
Conclusion
KEY POINTS
n Oxidative phosphorylation is critical to aerobic cellular
energy production.
n Five enzyme complexes make up the electron transport
chain, encoded by nuclear DNA (nDNA) and mitochon-
drial DNA (mtDNA). Mutations in mtDNA or nDNA can
result in defective oxidative phosphorylation and under-
lie inherited mitochondrial myopathies, encephalomyopa-
thies, and cytopathies.
n Most volatile and intravenous anesthetic agents inhibit
complex I of the electron transport chain.
n Inherited mitochondrial diseases with childhood onset often
present in the newborn period, with variable clinical features.
n Inherited mitochondrial diseases with adult onset can
appear during the early to middle adult years, often with a
decline in brain and retinal function caused by high rates of
metabolic activity.
n Preoperative evaluation for patients with suspected mito-
chondrial myopathy includes screening (lactate/pyruvate
and ketone ratios), serum and spinal fluid lactate, skeletal
muscle biopsy, and assessment of glucose metabolism.
A P T E R
14
SRIJAYA K. REDDY, MD  n
RICHARD J. LEVY, MD  n
n For pediatric patients, initial investigation involves blood
and urine testing, although normal lactate and glucose do
not rule out mitochondrial disease. Confirmatory diagnos-
tic studies include skin or muscle biopsies for microscopic
evaluation and mtDNA analysis.
n With adult-onset mitochondrial disease, extensive preop-
erative assessment of organ system functional reserve is
more useful than traditional tests.
n Surgical patients with mitochondrial disease are at greater
risk of stroke, deteriorating neurologic status, coma,
­seizures, respiratory failure, arrhythmias, and death.
n Avoid long fasting times in children, and use dextrose-
containing intravenous fluids. Follow malignant hyper-
thermia precautions, and avoid spontaneous intraoperative
ventilation.
“Mitochondrial myopathy” and “inherited mitochondrial
encephalomyopathy” originally encompassed a group of pedi-
atric neurologic syndromes produced by maternally inherited
mitochondrial genetic defects. However, it is now clear that
respiratory chain deficiencies undermine metabolic energy
production, produce excessive levels of “free radical” reactive
oxygen species (ROS), and may generate almost any symptom,
in any organ system, at any stage of life. Therefore, the scope of
human disease attributable to the inherited, acutely acquired,
or insidious onset of impaired mitochondrial function may be
much broader than previously believed.
In addition to the energy production essential for life, the
hundreds of mitochondria found in every cell also provide a
variety of metabolic and cell regulatory functions. For exam-
ple, hepatic mitochondria provide detoxification of ammonia.
In neurons, mitochondria are essential for neurotransmitter
synthesis. Therefore, mitochondrial dysfunction is emerging
as a pivotal factor in the etiology of sepsis, neurodegenerative
disorders, diabetes, arteriosclerotic disease, and even normal
human aging.1,2 This chapter provides an overview of the peri-
operative assessment and anesthetic management of patients
433
 434 ANESTHESIA AND UNCOMMON DISEASES
with inherited mitochondrial disorders of either childhood
or adult onset. The effects of common anesthetic agents on
mitochondrial function are discussed, with a review of the
mitochondrial basis of anesthesia-induced neurotoxicity in
the developing brain.
BACKGROUND
Mitochondria produce adenosine triphosphate (ATP) by oxi-
dative phosphorylation through the electron transport chain,
which is composed of five enzyme complexes located on the
inner mitochondrial membrane (Fig.  14-1). Reduction of
molecular oxygen is coupled to phosphorylation of adenosine
diphosphate (ADP), resulting in ATP synthesis.3 The reduced
cofactors NADH and FADH2, generated by the Krebs cycle
and by fatty acid oxidation, donate electrons to complex I
(NADH dehydrogenase) and complex II (succinate dehydro-
genase). Electrons are then transferred to coenzyme Q and
subsequently to complex III. From complex III, reduced cyto-
chrome c donates its electrons to complex IV (cytochrome-c
oxidase), resulting in the reduction of molecular oxygen to
water. Complexes I, III, and IV actively pump hydrogen ions
(H+) across the inner membrane of the mitochondrion into
the intermembrane space, creating an electrochemical gra-
dient. Influx of protons back into the mitochondrial matrix
through complex V results in ATP synthesis.4 This process of
oxidative phosphorylation is the major intracellular source of
the free radicals (O2−, H2O2, and OH−) that are generated as
byproducts of the interaction between excess electrons and
oxygen.
H+ H+ H+ H+
O2
I Q III C IV V the target tissues during embryogenesis. For the mitochon-
II
NAD NADH H2O
Pi
FADH2
ADP
Krebs
cycle Fatty acid
oxidation
Intermembrane space
FIGURE 14-1  The electron transport chain needed for oxidative
phosphorylation consists of complexes I to V located on the
inner mitochondrial membrane. The Krebs cycle and fatty acid
oxidation yield NADH and FADH2, which initiate electron transfer
to the respiratory chain. Coenzyme Q (Q) and cytochrome c (C)
transport electrons to complex III and complex IV, respectively.
Complex V uses the hydrogen ion gradient (H+) created by
hydrogen pumps within complexes I, III, and IV to phosphorylate
adenosine diphosphate (ADP) to synthesize adenosine
triphosphate (ATP).
The enzymes, membranes, and other molecular compo-
nents of these five major enzyme/protein complexes needed
for mitochondrial oxidative phosphorylation are encoded
in a complementary manner by the circular genome found
within the mitochondrion itself, as well as by the much
larger nuclear genome of the host cell. The mitochondrial
genome encodes for 13 essential subunits of the ­electron
transport chain, two types of ribosomal ribonucleic acid
(rRNA), and 22 forms of transfer RNA (tRNA). Each mito-
chondrion ­contains multiple copies of mitochondrial deoxy-
ribonucleic acid (mtDNA). Nuclear DNA (nDNA) encodes
an additional 900 proteins that are needed for ­ normal
­mitochondrial function.
The complementary relationship between two genomes
within each cell and the putative evolution of the mitochon-
drion from a free-living organism into an organelle within
the cell have been known and discussed by cell biologists
only within the past three or four decades. The implications
of this biologic curiosity with regard to our understand-
ing of embryology, evolution, aging, and even the mecha-
nism of death itself may be profound. The mitochondrion,
through a central role in the modulation of bioenergetics
and cellular apoptosis, may also serve as both a “biosensor”
for oxidative stress and as the final determinant of cellular
viability.
The most severe inherited mitochondrial disease syn-
dromes become clinically apparent during infancy, but a
few were eventually described in which symptoms did not
appear until early adulthood. The original descriptions
of the mitochondrial diseases of childhood assumed that
there was maternal transmission of mitochondria and of
both normal (“wild type”) and mutant mtDNA. Because
mutant mtDNA coexists with wild-type mtDNA, vari-
ability in the severity of all these inherited conditions is
thought to reflect heteroplasmy, the random differences in
the proportion of mutant mtDNA distributed throughout
drial disorders of adult onset, variability in disease s­ everity
and an exceptionally wide range of phenotypic symptom
­patterns are thought to reflect both heteroplasmy and the
much different, progressively changing metabolic demands
ATP of target tissues during adulthood. Hundreds of mtDNA
mutations have already been identified in detail and clas-
sified as mitochondrial myopathies, encephalomyopathies,
or cytopathies.5,6
A report of a patient with mutated mtDNA of paternal
origin, however, suggests that some paternal mtDNA also
survives in the zygote and therefore may also contribute to
the mtDNA pool.7 Recently, the important role of defects in
nDNA in disorders characterized by declining mitochon-
drial bioenergetics has also been clarified, reflecting a bet-
ter understanding of the interaction between nuclear and
mitochondrial genomes.8 It is now clear that there are sub-
units of the electron transport chain not encoded by mtDNA
that arise from nDNA. Diseases caused by nuclear genes that

do not encode subunits but affect mtDNA stability are an
­especially interesting group of mitochondrial disorders. In
these syndromes, a primary nuclear gene defect causes sec-
ondary mtDNA ­information loss or deletion, which leads to
subsequent tissue dysfunction in the form of disrupted oxi-
dative phosphorylation. Therefore, some genetically deter-
mined defects in oxidative phosphorylation follow classic
mendelian patterns of dominant recessive genetic transmis-
sion rather than the maternal patterns usually associated
with mtDNA defects.
EFFECT OF ANESTHETICS ON
MITOCHONDRIAL FUNCTION
The effects of anesthetics on mitochondrial function were
first investigated in the 1930s. Although all the mechanisms
of action are still not established, virtually all v­ olatile, local,
and intravenous (IV) anesthetics clearly have s­ignificant
depressant effects on mitochondrial energy production.
These effects are believed to occur primarily at the level
of the electron transport chain on the inner membrane
of ­mitochondria. Early studies reported inhibition of the
­oxidation of glucose, lactate, and pyruvate by narcotics,
and more recent work explores the mechanism of reduced
­oxygen consumption in the brain after treatment with barbi-
turates.9 A common final pathway of depressed bioenergetic
activity, possibly through intracellular or mitochondrial
­mechanisms, may also help explain the primary anesthetic
effects of these drugs.10
However, these data must be interpreted cautiously,
because much of the work examining anesthetic-induced
mitochondrial dysfunction has been done in vitro, in isolated
mitochondria, and not in functioning cells. Furthermore,
the anesthetic concentrations used to inhibit mitochondrial
function experimentally have been up to 10-fold higher than
concentrations used clinically, although anesthetics seem to
inhibit m
­ itochondria in a dose-dependent manner. The reader
must take these major limitations into consideration when
reviewing the subject.
Inhalational and Local Anesthetics
Nitrous oxide (N2O) and the potent inhalational agents have
significant effects on mitochondrial respiration.11–14 In car-
diac mitochondria, halothane, isoflurane, and sevoflurane
have all been shown to inhibit complex I of the electron
transport chain.15 At concentrations equal to 2 MAC (mini-
mal alveolar concentration), complex I activity is reduced by
20% after exposure to halothane and isoflurane, and by 10%
after exposure to sevoflurane. Oxidative phosphorylation in
liver mitochondria is also measurably disrupted after expo-
sure to halothane. Concentrations of 0.5% to 2% halothane
lead to reversible inhibition of complex I (NADH: ubiqui-
none oxidoreductase). Halothane-induced mitochondrial
inhibition in the liver is exacerbated by the addition of N2O.16
Chapter 14  Mitochondrial Disease 435
Local anesthetics also disrupt oxidative phosphorylation and
significantly degrade bioenergetic capacity in mitochondrial
isolates.17–19
Barbiturates, Propofol, Etomidate, Ketamine,
Midazolam
Barbiturate effects have been well studied in the brain,
heart, and liver. As with the inhalational agents, barbiturates
inhibit complex I of the electron transport chain. This inhi-
bition, however, occurs at serum levels that greatly exceed
those required to produce the anesthetic effect. Propofol
disrupts electron transport in the respiratory chain.20
Decreased oxygen consumption and inhibited electron flow
have been demonstrated in cardiac mitochondria exposed
to propofol.21 Similarly, work with mitochondria from the
liver has demonstrated that propofol inhibits complex I
of the electron t­ransport chain.22 Etomidate has also been
shown to inhibit oxidative ­phosphorylation in isolated rat
hepatic ­mitochondria.23 The inhibitory effect of etomidate
occurs mostly at the level of complex I and to a lesser extent
at complex III. In addition, low concentrations of ketamine
inhibit the NAD+-linked oxidation of glutamate and malate
in rat hepatic mitochondria, but can also uncouple oxidative
phosphorylation.24 Midazolam, a common benzodiazepine,
inhibits complexes I, II, and III.25 Box  14-1 summarizes
the effect of various a­nesthetic agents on ­mitochondrial
function.
Other Effects
Exposure to the volatile anesthetics also alters the ability of
the mitochondrion to respond to rising levels of ROS, a “pre-
conditioning” effect that may protect the cell if exposed later
to periods of hypoxia or ischemia. Although the mechanism
of “anesthetic preconditioning” remains speculative, anes-
thetic agents appear to disrupt mitochondrial bioenergetics
sufficiently that they produce the low levels of oxidative stress
that induce short-term genetic expression of heat shock protein
(HSP) or other protective substances. HSP can also be induced
by brief, sublethal episodes of ischemia or hypoxia, suggest-
ing that the prophylactic administration of HSP or ­similar
BOX 14-1   n EFFECT OF ANESTHETICS ON
MITOCHONDRIAL FUNCTION
Volatile agents inhibit complex I.
Barbiturates inhibit complex I.
Propofol inhibits complex I and slows electron transport chain.
Etomidate inhibits complex I and complex III.
Ketamine inhibits complex I.
Midazolam inhibits complexes I, II, and III.
Local anesthetics disrupt oxidative phosphorylation by unknown
mechanisms.
 436 ANESTHESIA AND UNCOMMON DISEASES
interventions may provide cardiac and neural p ­rotection
­during major surgery when tissue perfusion or oxygenation
is disrupted.26
Therefore, anesthetics may not only depress bioenergetic
activity, but also affect other functions of the mitochon-
drion, such as the role of this organelle as a “biosensor” for
oxidative stress, or the mitochondrion as an effector organ-
elle for cellular apoptosis. Accumulation of ROS increases
outer-membrane permeability of the mitochondrion and
leads to the ingress of potassium and ionized calcium and
the release of cytochrome c and other “pro-apoptotic” sol-
uble proteins. Release of cytochrome c from mitochondria
not only rapidly degrades the bioenergetic capacity of the
cell by removing a key component of the respiratory chain,
but also appears to trigger the release of caspases, cysteine-
containing protease enzymes. Caspases in turn activate
other enzymes that digest nDNA, the final step in “cell sui-
cide,” or apoptosis.
Anesthesia-Induced Neurotoxicity
Recent studies show that common anesthetics (benzodiaz-
epines, barbiturates, ketamine, inhaled volatile anesthetics,
N2O) induce widespread neuronal apoptosis in the devel-
oping brain in a variety of experimental newborn animal
models (rodents, guinea pigs, piglets, primates) raising seri-
ous concern among anesthesiologists.27–31 Although anes-
thesia-induced neurotoxicity has never been demonstrated
in human infants, two studies suggest a potential associa-
tion between anesthesia exposure and developmental and
behavioral disorders in younger children. In the first study,
almost 600 children were retrospectively compared to 4764
controls.32 Those who received two or more general anes-
thetics before age 4 years were at increased risk for having
a learning disability. In another retrospective analysis, 383
children who underwent inguinal hernia repair under gen-
eral anesthesia within the first 3 years of life were compared
to 5050 age-matched ­ controls.33 The anesthesia-exposed
cohort was more than twice as likely to have a subsequent
diagnosis of developmental or behavioral disorder than con-
trols. Although no causative relationship was established,
these studies question the safety of anesthesia exposure dur-
ing infancy and childhood.
The mechanism of anesthesia-induced neurotoxicity
appears to be caspase activation through the mitochondrial
pathway of apoptosis, followed by activation of the “death
receptor pathway” and neurotrophic factor–activated path-
ways34 (Fig.  14-2). This results in massive caspase-3 acti-
vation, subsequent nDNA fragmentation, and cell death.
Although chemically dissimilar, many different anesthetic
agents inhibit neuronal activity and synaptic transmission
through interaction with γ-aminobutyric acid (GABA) and
N-methyl-d-aspartate (NMDA) receptors in the brain.31
After this GABA and NMDA receptor interaction, Bax pro-
tein translocates to mitochondria, causing release of cyto-
chrome c from the mitochondria intermembrane space into
Anesthetic
agents
GABA NMDA
receptor receptor
Bax
Activated
caspase-3
DNA
fragmentation
Apoptosome C
Procaspase-9 dATP APAF-1
FIGURE 14-2  The mechanism of anesthesia-induced neurotoxicity
is initiated by the mitochondrial pathway of apoptosis. A variety
of anesthetic agents interact with γ-aminobutyrate (GABA) and/
or N-methyl-d-aspartate (NMDA) receptors. This in turn leads to
Bax translocation to mitochondria and release of cytochrome c
(C) from the mitochondrial intermembrane space into the cytosol.
Cytochrome c then complexes with apoptotic protease activation
factor 1 (APAF-1) and dATP. This complex then oligomerizes and
recruits and activates procaspase-9. Subsequent procaspase-3
recruitment forms the apoptosome and activates caspase-3.
Activation of caspase-3 results in nDNA fragmentation.
the cytosol. Cytochrome  c then complexes with apoptotic
protease activation factor 1 (APAF-1) and deoxyadenosine
triphosphate dATP. This complex then oligomerizes and
recruits and activates procaspase-9. Subsequent procaspase 3
recruitment forms the apoptosome and activates caspase 3.
This results in nDNA fragmentation.
All the experimental data to date indicate that the vulnera-
bility of the newborn mammalian brain to anesthesia-induced
neurotoxicity coincides with synaptogenesis.34 Furthermore,
anesthesia-induced neuroapoptosis has resulted in signifi-
cant neuronal loss, behavioral impairments, and cognitive
deficits.29,34 Whether such neurotoxicity occurs in the human
­system is unknown, however, so future investigations need
to focus on identifying evidence of anesthesia-induced neu-
roapoptosis in human infants and assess neurodevelopmen-
tal outcome after anesthetic exposure during infancy and
childhood.
INHERITED DISORDERS WITH CHILDHOOD
ONSET
Mitochondrial diseases with childhood onset often present in
the newborn period. The clinical features may vary because a
single organ system or multiple organ systems may be affected.
The organ systems most often involved are the central ner-
vous system (CNS), peripheral nervous system (PNS), liver,

heart, kidneys, muscle, gastrointestinal (GI) tract, the skin,
and a number of endocrine glands. Nonspecific signs include
lethargy, irritability, hyperactivity, and poor feeding. The pre-
sentation can be very abrupt and dramatic, with acute onset
of hypothermia or hyperthermia, cyanosis, seizures, emesis,
diarrhea, or jaundice. Box 14-2 lists some of the more insidious
signs and symptoms of mitochondrial disease in the newborn.
The mtDNA depletion syndrome (MDS) is a severe dis-
ease of childhood characterized by liver failure and neuro-
logic abnormalities involving tissue-specific loss of mtDNA.
MDS is thought to be caused by a putative nuclear gene that
controls mtDNA replication or stability.35 Similarly, chil-
dren with mitochondrial neurogastrointestinal encephalo-
myopathy (MNGIE) may have multiple mtDNA deletions
and mtDNA depletion resulting from an nDNA mutation.36
Although found in most mitochondrial disorders, non-
specific GI and hepatic symptoms are among the cardinal
manifestations of primary mitochondrial diseases such as
MDS and MNGIE.
The CNS manifestations of mitochondrial disorders
include encephalopathy, a cardinal feature of Leigh's syn-
drome. Seizures and ataxia also occur with myoclonic epilepsy
with ragged-red fibers (MERRF). Dementia and stroke-like
symptoms are major features of mitochondrial encephalomy-
opathy with lactic acidosis and stroke-like episodes (MELAS).
When the PNS is involved, there may be axonal sensory
­neuropathies. Cardiac involvement with pediatric mitochon-
drial disease may produce hypertrophic cardiomyopathy, seen
with MELAS, or dilated cardiomyopathy, heart block, and
pre-excitation syndrome, features of Leber's hereditary optic
neuropathy (LHON). Impaired renal bioenergetics p ­ roduces
tubular acidosis; muscle abnormalities present largely as
myopathies. Hepatic failure, dysphagia, ­pseudo-obstruction,
and constipation all suggest GI impairment. Vision and hear-
ing are often impaired by ophthalmoplegia, ptosis, cataracts,
optic atrophy, pigmentary retinopathy, and s­ensorineural
deafness. Endocrine organ involvement manifests with
­diabetes mellitus, hypoparathyroidism, hypothyroidism, and
gonadal failure.
BOX 14-2   n MITOCHONDRIAL DISORDERS:
DIFFERENTIAL DIAGNOSIS OF SIGNS AND
SYMPTOMS IN NEWBORN PERIOD
Unexplained sepsis or recurrent severe infection
Unexplained hypotonia, weakness, failure to thrive, and metabolic
acidosis
Organic acidemias such as maple syrup urine disease and
methylmalonic aciduria
Urea cycle defects such as ornithine transcarbamylase deficiency
Carbohydrate disorders such as galactosemia and hereditary fructose
intolerance
Aminoacidopathies such as homocystinuria, tyrosinemia, and
nonketotic hyperglycemia
Endocrinopathies such as congenital adrenal hyperplasia and
congenital diabetes
Chapter 14  Mitochondrial Disease 437
Table  14-1 lists typical symptoms and signs of the most
well-known mtDNA-related syndromes.
INHERITED DISORDERS WITH ADULT
ONSET
Inherited neurologic/metabolic syndromes produced by
genetic defects that disrupt mitochondrial energy produc-
tion are typically seen during infancy, although some become
apparent many years later. They can appear during the early
to middle adult years in the form of declining organ system
reserve in tissues (e.g., brain, retina) that require mainte-
nance of relatively high rates of metabolic activity for normal
functioning. Symptoms include progressive motor weakness
and lethargy, decreased color or night vision, and ataxia.
As with most syndromes of infancy, adult mitochondrial
­syndromes such as NARP are caused by maternally transmit-
ted mutations of mtDNA. In neuropathy, ataxia, and retinitis
pigmentosa (NARP) syndrome, a point mutation at base-
pair position 8993 of mtDNA produces defects in adenosine
­triphosphatase (ATPase). Consequently, reduced enzymatic
activity and lower rates of ATP production are found in
mitochondrial isolates of lymphoblastoid cell lines from
NARP patients. Also, increased brain levels of phosphocre-
atine and inorganic phosphate occur in NARP patients com-
pared with age- and gender-matched controls, suggesting
generalized impairment of the efficiency of oxidative meta-
bolic pathways.37 The ­specific genetic defects that produce
NARP and several other ­mitochondrial disorders have been
identified (Fig. 14-3).
Some of the pathognomonic features of adult-onset mito-
chondrial disorders may also occur long after the syndrome
itself is established by secondary characteristics. For exam-
ple, stroke-like episodes may not appear until decades after
initial clinical onset of MELAS.38 A progressive decrease in
cardiac, muscle, and nervous system functional reserve prob-
ably begins long before the appearance of overt signs or symp-
toms, but this can usually be confirmed by careful and detailed
review of the patient's history and ability to accomplish the
normal activities of daily life.
Even when the focus of mitochondrial disease was
­limited to the inherited disorders of childhood, mtDNA
missense mutations were suspected to play an etiologic role
in a wide range of neurodegenerative disorders.39 Among
the adult neurodegenerative diseases, a mitochondrial focus
has now been clearly established for Parkinson's disease,40
Alzheimer's dementia, and amyotrophic lateral sclerosis.41
More recently, the spinal cord atrophy of multiple sclero-
sis has been attributed to inflammation that may be con-
trolled by a m ­ itochondrion-driven, genetically determined
­mechanism similar to that of other neurodegenerative dis-
orders.42 However, other important processes are impli-
cated in neurodegenerative ­disorders, and several involve
degradation of proteins or compromise of mechanisms that
remove damaged proteins from within neurons. Oxidative
modification of proteins, perhaps by increased levels of
 438 ANESTHESIA AND UNCOMMON DISEASES

TABLE 14-1  n  Symptoms and Signs of Mitochondrial Disorder

Disease Mutation Inheritance Signs and Symptoms

Kearns-Sayre syndrome
Large-scale mtDNA Sporadic Ataxia, peripheral neuropathy, muscle weakness, ophthalmoplegia,
deletion ptosis, pigmentary retinopathy, sideroblastic anemia, diabetes
mellitus, short stature, hypoparathyroidism, cardiomyopathy,
conduction defects, sensorineural hearing loss, Fanconi syndrome,
lactic acidosis, ragged-red fibers on muscle biopsy

Progressive external Large-scale mtDNA Sporadic Muscle weakness, ophthalmoplegia, ptosis, lactic acidosis, ragged-
ophthalmoplegia deletion red fibers on muscle biopsy

Pearson's syndrome Large-scale mtDNA Sporadic Ophthalmoplegia, sideroblastic anemia, pancreatic dysfunction, Fanconi
deletion syndrome, lactic acidosis, ragged-red fibers on muscle biopsy

Myoclonic epilepsy with mtDNA point Maternal Seizures, ataxia, myoclonus, psychomotor regression, peripheral
ragged-red fibers mutation, tRNA neuropathy, muscle weakness, short stature, sensorineural hearing
(MERRF) abnormality loss, lactic acidosis, ragged-red fibers on muscle biopsy

Mitochondrial mtDNA point Maternal Seizures, ataxia, myoclonus, psychomotor regression, hemiparesis,
encephalopathy with mutation, tRNA cortical blindness, migraine, dystonia, peripheral neuropathy,
lactic acidosis and abnormality muscle weakness, diabetes mellitus, short stature,
stroke-like episodes cardiomyopathy, conduction defects, intestinal pseudo-obstruction,
(MELAS) sensorineural hearing loss, Fanconi syndrome, lactic acidosis,
ragged-red fibers on muscle biopsy

Aminoglycoside-induced tRNA abnormality — Cardiomyopathy, sensorineural hearing loss

deafness

Neuropathy, ataxia, mtDNA point Maternal Ataxia, peripheral neuropathy, muscle weakness, pigmentary
and retinitis mutations, mRNA retinopathy, optic atrophy, sensorineural hearing loss
pigmentosa (NARP) abnormality

Maternally inherited mtDNA point Maternal Seizures, ataxia, psychomotor regression, dystonia, muscle
Leigh's syndrome mutation, mRNA weakness, pigmentary retinopathy, optic atrophy, cardiomyopathy,
abnormality lactic acidosis

Leber's hereditary optic Multiple mtDNA point Maternal Dystonia, optic atrophy, conduction defects
neuropathy (LHON) mutations, mRNA
abnormality

mtDNA, Mitochondrial DNA; tRNA, transfer RNA.

Leigh’s syndrome Age-related

Age- or ischemia-
skeletal muscle induced
and hepatic
Single mtDNA cardiomyopathy
dysfunction
point mutation
at bp8993

“NARP” Large-scale mtDNA

encephalomyopathy insertions or deletions
syndromes
FIGURE 14-3 Inherited
mitochondrial syndromes and
disorders can reflect single- “MELAS” syndrome Single mtDNA Pearson’s Kearns-Sayre
point, multipoint, or large-scale of epilepsy point mutation syndrome syndrome
errors in mitochondrial DNA and stroke at bp3243
(mtDNA).
Multiple mtDNA
“MERRF” syndrome Single mtDNA point mutation
of epilepsy point mutation at bp's 3460, 4160,
and myopathy at bp8344 11778, 15257

Single mtDNA
“MMC” syndrome point mutation “LHON” syndrome
of myopathy at bp3260 of optic neuropathy

ROS, makes them dysfunctional and targets for selective
destruction by the ­proteolytic machinery of the proteasomal
system. This system is distributed in the cytosol, nucleus,
and endoplasmic reticulum of the neuron and contains a
multicatalytic protease complex and various regulatory and
control elements.43
Several adult-onset clinical syndromes associated with
multiple mtDNA deletions have been characterized; the
syndrome most frequently described is autosomal dominant
progressive external ophthalmoplegia (adPEO). Alpers’ dis-
ease, Pearson's marrow-pancreas syndrome,44 and Navajo
neuropathy are proven or suspected primary mitochondrial
hepatopathies. Less well-described, s­econdary mitochon-
drial hepatopathies involve mitochondrial dysfunction
caused by alcohol abuse, drugs, or other h ­ epatotoxins.
Mitochondrial defects are now also associated with predis-
position to two types of inherited neoplasia s­ yndromes.45
There is growing evidence that mitochondrial dysfunc-
tion plays a pivotal, if not necessarily etiologic, role in
renal disease, adult-onset diabetes, and perhaps various
cardiomyopathies. The most common renal symptom is
proximal tubular dysfunction, usually as de Toni-Debre-
Fanconi s­ yndrome, and less often in renal tubular acido-
sis, Bartter's syndrome, chronic tubulointerstitial nephritis,
and nephrotic syndrome.46
Examination of mitochondrial respiration in the skeletal
muscle of patients with occlusive peripheral arterial disease
suggests that mitochondrial respiratory activity is abnormal.
Impaired bioenergetics may be a pathophysiologic component
of these disorders.47 Similarly, an increase in oxidative stress
is now thought to contribute to the pathology of vascular dis-
ease in stroke, hypertension, and diabetes.48 A 40% reduction
in oxidative phosphorylation, as assessed in  vivo by nuclear
magnetic resonance (NMR) spectroscopy, suggests that age-
associated decline in mitochondrial function contributes to
the reduced insulin-stimulated muscle glucose metabolism
that characterizes insulin resistance in elderly patients.49 This
insulin resistance appears to reflect an inherited defect of fatty
acid metabolism.50
PREOPERATIVE EVALUATION
Because of the heteroplasmy of mitochondria in tissues, as
previously discussed, patients with mitochondrial disor-
ders may present with a wide variety of symptoms; many are
extremely vague or subtle, even if a defined mtDNA mutation
is involved. Mitochondrial cytopathy should be included in
the differential diagnosis whenever clinical signs and symp-
toms include persistent muscle pain associated with weak-
ness or fatigue,51 or if diffuse multisystem involvement does
not clearly fit an established pattern of conventional disease.52
Subclinical hepatic and renal involvement is common, but
the diagnosis of a mitochondrion-based respiratory chain
­deficiency is rarely entertained, even when renal symptoms
are present, unless associated with evidence of skeletal muscle
weakness or encephalopathy.
Chapter 14  Mitochondrial Disease 439
If a mitochondrial myopathy is suspected, diagnostic
investigations should include screening for increased lac-
tate/pyruvate and ketone body molar ratios and measure-
ment of serum and cerebrospinal fluid (CSF) lactate. With
a very high index of suspicion, skeletal muscle biopsy may
confirm the presence of characteristic “ragged-red fibers,”
which reflect accumulation of defective mitochondria,
excess g­ lycogen granules, and cytochrome-c oxidase–defi-
cient cells. The biopsy can also provide material for genetic
analysis and subsequent genetic counseling. Because mito-
chondrial cytopathies involve ­enzymatic defects in ATP pro-
duction that lead to organ dysfunction, common sequelae
are lactic acidosis and abnormalities in g­ lucose metabo-
lism. For pediatric patients, initial i­ nvestigation to confirm
the diagnosis involves blood and urine testing, although
normal lactate and glucose do not necessarily rule out the
presence of mitochondrial disease. Box 14-3 lists the most
common laboratory tests used to detect m ­ itochondrial
disorders.53 As in adults, ­confirmatory ­diagnostic studies
include skin or muscle biopsies for m ­ icroscopic evaluation
and mtDNA analysis.
To define the extent that declining mitochondrial energy
production has produced clinical compromise in patients with
adult-onset mitochondrial disease, extensive preoperative
assessment of organ system functional reserve is more use-
ful than traditional preoperative tests used to screen for spe-
cific disease entities. Unique concerns regarding comorbidity
include decreased anesthetic requirement and susceptibility to
prolonged drug-induced nervous system depression because
of impaired neuronal bioenergetics, even when overt enceph-
alopathy has not yet developed, as well as intrinsic skeletal
muscle hypotonia and cardiomyopathy with increased risk of
sudden death from conduction abnormalities. Skeletal m ­ uscle
weakness may produce a general decrease in aerobic work
capacity that may compromise postoperative ventilation after
upper abdominal or thoracic surgery.54 Subclinical erosion of
BOX 14-3   n INITIAL LABORATORY INVESTIGATION
FOR SUSPECTED MITOCHONDRIAL
DISORDERS
Glucose
Electrolytes with anion gap
Complete blood count
Blood urea nitrogen
Lactate, pyruvate, and lactate/pyruvate ratio
Ammonia
Creatinine kinase
Biotinidase level
Blood and urine amino acids
Blood and urine organic acids
Plasma acylcarnitines
Skin and muscle biopsies, muscle coenzyme Q levels
Proton magnetic resonance spectroscopy
Mitochondrial DNA analysis
Serum lactate during physical exertion
 440 ANESTHESIA AND UNCOMMON DISEASES

hepatorenal reserve may further predispose these patients to ANESTHETIC MANAGEMENT

prolonged drug effects and delayed recovery from anesthesia,
muscle relaxants, and opioids. Surgical patients with mitochondrial disease should be
Many of these clinical concerns may be exacerbated by ­considered at significantly increased risk of adverse outcome
acute or sustained stress (Box 14-4). Many neurologists rec- compared to the general surgical population. Perioperative
ommend a diet and nutritional supplements rich in antioxi- adverse events in these patients include stroke, deteriorating
dants, as well as vitamins and cofactors such as coenzyme Q neurologic status, coma, seizures, respiratory failure, arrhyth-
(Box  14-5), although few data support this approach as a mias, and death. Therefore, informing the patient and fam-
mandatory preoperative regimen. Therefore, optimization ily of these risks is an important part of the preoperative
of the patient's physical status and treatment of the stig- evaluation. Although patients with inherited mitochondrial
mata of acquired or adult-onset mitochondrial diseases encephalomyopathies have been exposed to many different
remain supportive. Preoperative therapy should focus on general anesthetic regimens without apparent adverse conse-
serious overt clinical manifestations, such as cardiac dys- quences,56,57 it still remains unclear whether there is a “safe”
rhythmias,55 muscle weakness and postural imbalance, and or “best” anesthetic for these patients. Whether the anesthetic
endocrinopathy. plan should or should not include neuromuscular blockade,
especially in children, remains controversial (Box 14-6).
Susceptibility to malignant hyperthermia (MH) and
myasthenia-like sensitivity to neuromuscular blockade are
­
BOX 14-4   n QUESTIONS TO ASK PRIMARY PHYSICIAN, issues typically considered for patients with more familiar
NEUROLOGIST, OR METABOLIC SPECIALIST
muscular dystrophies and neurogenic myopathies, although
Any existing comorbidities involving: these concerns are probably not crucial for most forms of
Central nervous system? inherited mitochondrial encephalopathy and myopathy.58,59
Heart? Nevertheless, one report suggests increased sensitivity to non-
Lungs?
depolarizing blockade,60 and many discussions of anesthe-
Skeletal muscle?
Hepatorenal systems? sia for mitochondrial disease recommend MH precautions.61
Any abnormalities with glucose regulation? Only the rare mitochondrial myopathies with “multicore”
Any recent illnesses, infection, or sustained stress? or “minicore” histology may actually be associated with
Any previous adverse drug reactions and allergies? MH.62 Avoidance of depolarizing muscle relaxants may fur-
Any prior anesthetic exposure or complications? (Obtain anesthesia
ther reduce the possibility of MH, but the residual effects of
records.)
nondepolarizing agents in patients with compromised hepa-
torenal function may ­exacerbate intrinsic muscle weakness.
Therefore, anesthetic techniques requiring spontaneous intra-
operative ventilation that could cause airway obstruction
intraoperatively should probably be avoided. Muscle weak-
ness may also increase the risk of ventilatory failure post-
BOX 14-5   n POSSIBLE CONCURRENT THERAPY
FOR PATIENTS WITH MITOCHONDRIAL operatively. Endotracheal intubation with positive-pressure
DISORDERS ventilation will prevent intraoperative ventilatory failure, but
the anesthesiologist must decide if the patient should be extu-
Coenzyme Q
bated immediately after surgery or should remain i­ntubated
l-Carnitine
Riboflavin (vitamin B2)
Acetyl-l-carnitine
Thiamine (vitamin B1)
Nicotinamide (vitamin B3) BOX 14-6   n MITOCHONDRIAL DISEASE:
Vitamin E INTRAOPERATIVE ANESTHETIC
Vitamin C MANAGEMENT
Lipoic acid
Selenium Consider ICU for postoperative ventilation or monitoring.
Beta-carotene Use glucose containing intravenous fluid.
Biotin Maintain normal temperature and pH.
Folic acid Avoid natural airway or prolonged spontaneous ventilation during
Calcium, magnesium, phosphorous anesthesia.
Vitamin K Consider adding arterial cannula for ABGs, glucose, and lactate to
Succinate routine monitors.
Creatine Have dantrolene or MH cart available.
Citrates Consider total intravenous anesthetic with avoidance of MH “triggers.”
Prednisone
Bicarbonate ICU, Intensive care unit; ABGs, arterial blood gases; MH, malignant
Dialysis hyperthermia.

and receive prolonged recovery in an intensive care unit.
“Late-onset mitochondrial myopathy” may be age related yet
still reflect primary mitochondrial dysfunction because of the
clonal expansion of different mtDNA deletions in individual
fiber segments. Although the origin of these mtDNA muta-
tions is not clear, the phenotype seems to represent an exag-
gerated form of that observed in the normal aging process.63
Patients with mitochondrial cytopathy are usually
instructed not to fast for long durations and to eat small, fre-
quent meals, a regimen that can be problematic in the setting
of perioperative NPO guidelines. To avoid metabolic crisis in
children, an IV infusion of glucose should be initiated during
preoperative fasting. Choice of IV fluids may also be impor-
tant intraoperatively, with most anesthesiologists choosing to
avoid Ringer's solution because of the lactate load. Monitoring
and controlling normal blood glucose, body temperature, and
acid-base values are crucial intraoperatively and postopera-
tively, and as with any anesthetic, electrocardiogram (ECG),
blood pressure, pulse oximetry, temperature, and exhaled-
gas concentrations as well. Arterial catheterization should be
considered to facilitate frequent sampling for blood glucose,
­arterial blood gases, and serum lactate levels.
Few reports describe the anesthetic approach in adult-onset
or acquired mitochondrial encephalomyopathy;64 for example,
only one deals with NARP syndrome.65 Clinical reports sug-
gest that patients with other mitochondrial disorders “do well”
with regional anesthetics, despite that these agents, as with
those used for general anesthesia, depress mitochondrial bio-
energetics. In addition, evidence suggests that some effects of
anesthetics on mitochondria may be beneficial in the event
of tissue hypoxia or ischemia. As stated earlier, the phenom-
enon of anesthetic preconditioning, in which prior exposure
to volatile anesthetics reduces tissue injury after an ischemic
or hypoxic episode, is clearly mediated through the effects on
the mitochondria, either directly or by several possible signal-
ing pathways.66
The nervous system may play a particularly prominent
role in understanding the consequences of altered mitochon-
drial function, whether inherited or acquired. Consciousness
is the most complex manifestation of nervous system func-
tion. Because cortical neurons and deeper nervous system
tissues with high rates of neurotransmitter synthesis have
very high rates of oxygen utilization, depression of mitochon-
drial bioenergetics or organelle injury caused by oxidative
stress usually compromises nervous system function before
other tissues appear to be affected. Therefore, “resistance to
loss of consciousness,” one possible definition of anesthetic
requirement, might allow the clinician to assess remaining
nervous system functional reserve. Preliminary data do sug-
gest that extreme sensitivity to anesthetics may reflect greatly
reduced reserve and a high risk of susceptibility to neuro-
degenerative disorders, postoperative cognitive decline, and
even long-term mortality in elderly patients.67 Increasing age
and deeper levels of anesthesia are also ­independently but
­significantly ­predictive of increased mortality within 1 year
of surgery.68
Chapter 14  Mitochondrial Disease 441
Basic genetic manipulation in subprimates has shown a
direct link between mitochondrial genetics and a­ nesthetic
requirement.69 Children with inherited mitochondrial
­disorders have significantly increased sensitivity to ­volatile
anesthetics.70 In addition, a general relationship between
declining anesthetic requirement and increasing age has
been unequivocally established for adults in the general
population.
CONCLUSION
Mitochondrial dysfunction may be fundamental to a broad
spectrum of human disease, both inherited and acquired, and
perhaps even to aging and death itself. Full understanding of
the status of mitochondrial bioenergetics may eventually play
a critical role in caring for patients with mitochondrial disor-
ders, in anticipating how children and adults respond to anes-
thetics, and in avoiding perioperative ischemic or hypoxic
injuries. At present, however, the basic principles of anes-
thetic management of children and adults with genetically
transmitted mitochondrial disorders include awareness of the
decreased bioenergetic capacity of major organ systems, with
special attention to the clinical implications of generalized
weakness and myopathy, cardiac arrhythmias and dysfunc-
tion, sensorineural compromise, and impaired hepatorenal
function.
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67. Lennmarken C, Lindholm ML, Greenwald S, et al: Confirmation that low
intraoperative BIS levels predict increased risk of postoperative mortality,
Anesthesiology 99:A303, 2003.
Chapter 14  Mitochondrial Disease 443
68. Weldon BC, Mahla ME, van der Aa MT, et al: Advancing age and deeper
intraoperative anesthetic levels are associated with higher first-year death
rates, Anesthesiology 96:A1097, 2002.
69. Kayser EB, Morgan PG, Sedensky MM: GAS-1: a mitochondrial protein
controls sensitivity to volatile anesthetics in the nematode Caenorhabditis
elegans, Anesthesiology 90:545–554, 1999.
70. Morgan PG, Hoppel CL, Sedensky MM: Mitochondrial defects and anes-
thetic sensitivity, Anesthesiology 96:1268–1270, 2002.
 C H A P T E R
15
Psychiatric and Behavioral Disorders
ALAN D. KAYE, MD, PhD  n
HENRY LIU, MD  n
CHARLES FOX, MD  n
AMIR BALUCH, MD  n
PATRICIA B. SUTKER, PhD  n

n Mental disorders and their associated use of psychotropic

Mental Disorders medications, including antidepressants, anxiolytics, major
Epidemiology
tranquilizers, anticonvulsants, and mood stabilizers, intro-
Characterization
duce neurochemical, behavioral, cognitive, and emotional
Preoperative Evaluation
factors that complicate medical or surgical tasks.
Mood Disorders n Anesthesiologists face unique challenges assessing patients
Major Depression
with psychiatric disease, in all steps of patient treatment,
Dysthymic Disorder
regardless of the pathology.
Bipolar Disorders
n Pharmacologic therapy for major depression includes
Anxiety Disorders selective serotonin reuptake inhibitors, tricyclic antidepres-
Generalized Anxiety Disorder
sants, monoamine oxidase inhibitors, and serotonin and
Social Phobia
norepinephrine reuptake inhibitors. Each class has poten-
Obsessive-Compulsive Disorder
tially lethal interactions with other medications, including
Posttraumatic Stress Disorder
nutraceuticals.
Panic Attacks
n Patients with bipolar disease, psychotic disorders (schizo-
Anesthetic Considerations
phreniform, schizoaffective), dementia, and substance
Nonaffective Psychoses abuse may be taking medications that affect anesthetics
Schizophrenia
or may present in states with altered anesthesia require-
Delusional Disorder
ments, posing problems perioperatively.
Substance-Related Disorders n Medications for anxiety, posttraumatic stress disorder,
Cognitive Disorders panic attacks, and social phobias can cause tolerance and
Delirium after Surgery
have similar effects as some anesthesia agents.
Dementia
n Patients undergoing electroconvulsive therapy must have
Other Cognitive Disorders
careful medication evaluation to prevent drug interactions
Disorders Identified in Developmental Stages and possible inability to seize from anticonvulsant proper-
Mental Retardation
ties of routine medicines.
Attention-Deficit/Hyperactivity Disorder
Problem Behaviors in Late Life
Conclusion Mental illnesses, cognitive disorders, and mental health prob-
lems affect persons in all walks of life; few families in America
are untouched by mental illness.1 An estimated 26.2% of
KEY POINTS
Americans age 18 years and older suffer from a diagnosable
n An estimated 26.2% of Americans age 18 and older have mental disorder in a given year.2 When applied to the 2009
a diagnosable mental disorder in a given year (58 million U.S. Census residential population estimate for ages 18 and
people). older, this figure translates to approximately 58.1 million
444
 Chapter 15  Psychiatric and Behavioral Disorders 445
people.3 Mental disease interferes with life activity and ability
to ­function and constitutes a pervasive and prevalent health
problem among varied American population subsets, includ-
ing young and elderly groups. The presence of mental disor-
ders, associated symptoms, possible concomitant pathology,
and prescribed medications are of significance to all health
care providers, not only mental health care professionals.
The burden of mental disease on health care utilization and
effectiveness has become a topic of worldwide interest and
concern.4
Beyond concerns about the adequacy of treatment for
mental illnesses, both in the United States and globally,
special considerations involve management of patients with
serious mental illness in emergency care and inpatient treat-
ment situations, general medicine, family practice and pain
clinics, and the operating room (OR).5 Important to anes-
thesiologists managing patient care is knowledge about the
patient's mental and physical illnesses; history of alcohol,
drug, and tobacco use; use and abuse of prescription medi-
cations, over-the-counter drugs, and herbal products; pre-
vious physical and mental traumas; and potential areas of
cognitive impairment or compromise before, during, and
after surgical procedures and in other treatment circum-
stances. It is important that anesthesiologists recognize the
factors involved in determining the presence of the true
mental disorder; medical conditions that can mimic psy-
chiatric disturbances6 include endocrine diseases (hypothy-
roidism, Cushing's syndrome); neurologic diseases (seizure,
demyelinating disease, encephalitis, CNS tumor/mass, head
trauma); alcohol and drug abuse; metabolic disorders; and
chemical or drug intoxication.
This chapter reviews the major types of mental disorders
and outlines issues and concerns that face anesthesia care pro-
viders in planning case management. Specifically, the focus
is on appropriate perioperative management of patients with
mental disorders undergoing surgical procedures requiring
anesthetic intervention.
MENTAL DISORDERS
The use of psychotropic medications (e.g., antidepressants,
anxiolytics, major tranquilizers, anticonvulsants, mood
stabilizers) introduces neurochemical, behavioral, cogni-
tive, and emotional factors that increase the complexity of
medical or surgical tasks. For example, patients with men-
tal disorders may not communicate well about their dis-
eases, symptoms, medications, and history; may present
with difficult behaviors; and often bring a background of
polypharmacy that requires unraveling.7 The use of psycho-
tropic medications has increased significantly over the last
several decades, with psychiatrists and family practice phy-
sicians prescribing tranquilizers, neuroleptics, and antide-
pressants, even to young persons.6–8 With depression alone,
numerous complexities exist in prescribing medications and
understanding side effect and adverse effect profiles, as well
as drug interactions with other medications prescribed for
mental and physical problems.
Epidemiology
The National Comorbidity Survey Replication (NCS-R) esti-
mates the incidence of mental illness for Americans aged 18
and older is 26.2%.9 The President's Commission on Mental
Health concluded in 1978 that the annual prevalence of spe-
cific mental disorders in the United States was about 15%.1
Bourdon et al.10 assessed that in any 6-month period, 19.5%
of the adult population, or one in five individuals, suffers from
a diagnosable mental disease. Epidemiologic estimates have
shifted over time because of changes in the definitions and
diagnosis of mental health and mental illness. For more than
two decades, scientists have used well-structured lay inter-
views as part of community-wide surveys to diagnose mental
disorders and determine the incidence and prevalence of seri-
ous mental illnesses.
Mandated by the U.S. Congress, the National Comorbidity
Study (NCS) included administration of a structured psychi-
atric interview to a representative sample of noninstitution-
alized persons age 15 to 54 years in the 48 contiguous states,
along with a survey of campus-housing students. Data were
collected between 1990 and 1992 for 8089 respondents. The
study's purpose was to assess comorbidity of substance use dis-
orders and non-substance-based psychiatric disorders using a
modified version of the Composite International Diagnostic
Interview.11 Morbidity rates were higher than the 1980–1985
Epidemiologic Catchment Area (ECA) project estimates, pos-
sibly because of methodologic and illness-defining differences
in study implementation. Nevertheless, results were impres-
sive toward developing an understanding of mental disor-
der prevalence and comorbidity. Almost 50% of respondents
reported at least one lifetime disorder, and almost 30% at least
one 12-month disorder, the most common being a major
depressive episode, alcohol dependence, social phobia, and
simple phobia. Morbidity was concentrated in approximately
one sixth of the population who evidenced history of three or
more comorbid disorders.9 Factors of age, gender, race, socio-
economic status, and geographic region influenced prevalence
trends. Women had elevated rates of affective and anxiety dis-
orders compared with men, who showed higher rates of sub-
stance use disorders and antisocial personality. The majority
of individuals with psychiatric disorders failed to obtain pro-
fessional treatment, suggesting that patients with mental dis-
orders may not be identified readily by medical health care
providers.
Characterization
A mental disorder is a clinically significant psychological or
behavioral pattern generally associated with subjective dis-
tress or disability, likely with significantly increased risk of
suffering death, pain, disability, or loss of freedom,12 and not
a part of normal development or culture. The recognition and
 446 ANESTHESIA AND UNCOMMON DISEASES
understanding of mental health conditions has changed over
time and across cultures, and the definition, assessment, and
classification of mental disorders still vary, although standard
guideline criteria are widely accepted. A few mental disorders
are diagnosed based on the harm to others, regardless of the
patient's perception of distress. More than one third of people
in most countries report meeting criteria for the major mental
disorder categories at some point in their life.
Mental disorders constitute an enormous public health
problem, interfering with life activities and functions.5 U.S.
Public Law 102-321 defines “serious mental illness” as the
presence of any DSM mental disorder (see later), substance
use disorder, or developmental disorder that leads to “sub-
stantial interference” with “one or more major life activities.”
This framework is used to characterize mood and anxiety
disorders, nonaffective psychoses, substance abuse disorders,
difficult-to-define personality disorders, and disorders affect-
ing development and “life course phenomena,” such as those
identified in infancy or childhood (e.g., mental retardation)
and associated with physical trauma leading to organic brain
syndrome, as well as cognitive disorders, such as dementia of
midlife to late-life stages. Clinicians may also need to attend to
other forms of mental disorder resulting from a general medi-
cal condition, somatoform disorders, and disorders of eating,
sleep, impulse control, and adjustment.
This discussion also clarifies the clinical status of pri-
mary care patients with symptoms of mental distress that
fall below the threshold criteria for a mental disorder. Olfson
et  al.13 found that in primary care patients, the morbidity of
subthreshold symptoms was often explained by confounding
mental, physical, or demographic factors. However, depres-
sive symptoms and panic symptoms tended to be disabling,
and these patients may have been at increased risk for devel-
opment of major depression, even though they were a hetero-
geneous group.
Preoperative Evaluation
Practicing clinical anesthesiologists face unique challenges
when they assess patients with psychiatric diseases, regardless
of the pathologic nature of the disease. Such issues may arise
during all steps of patient treatment, including history taking,
obtaining informed consent, and physical examination.
PATIENT HISTORY
Many of these patients will not communicate well with the
anesthesiologist either because they are unable to do so (e.g.,
if they suffer from profound psychosis, delirium, memory
disturbances, and so on), or because they choose not to talk
(e.g., out of embarrassment or hostility). It may be difficult
to establish rapport with such patients even if they seem oth-
erwise cooperative. Often, anesthesiologists find that it is
easier to obtain data from medical records (history, medi-
cations, previous interventions). A few patients with mental
disorders, however, will present without clinicians having
access to their medical records. When medical records are
available, clinicians must review these records carefully and be
prepared to measure this information against patient-reported
history. Often, patient records provide more accurate infor-
mation than can be obtained otherwise. Likewise, physicians
may trust the objective data obtained from a careful physical
examination more than the history obtained.6
In some cases the anesthesiologist evaluating the psychiat-
ric patient may consult directly with the primary care physi-
cian or psychiatrist in charge of care and address preoperative
concerns. In addition, the anesthesiologist should establish
rapport with the patient to minimize emotional trauma in the
OR.6 In this regard the anesthesiologist's role as consultant
cannot be overstated. Some patients may present for surgery
with an undiagnosed disease that mimics psychopathology.
Appropriate history-taking skills, physical examination, and
laboratory tests may reveal a mental disorder. Furthermore,
many substances, including both illicit drugs and legal phar-
maceuticals, may produce signs and symptoms that mimic
psychiatric disease. Any organic cause for symptoms must be
eliminated fastidiously before subjecting patients to anesthesia
because of the potential for adverse outcomes from inappro-
priate management of such disorders.6
INFORMED CONSENT
Another issue is obtaining informed consent from patients
with psychiatric diseases. Informed consent is ethically and
legally required before surgery, and surgery without consent
may be considered civil or possibly criminal assault and battery.
Criteria for informed consent dictate that (1) the patient must
possess sufficient decision-making capacity, (2) it must be a
voluntary decision (free from coercion), and (3) sufficient
information must have been provided to the patient prior to
the final decision. Competent patients have a right to decide
whether to accept or reject proposed surgery, even if aware
that it could be lifesaving.
When the patient is incapable of informed consent and does
not refuse surgery, surgeons seek permission from next of kin
or a legally designated surrogate. Only the court can legally
declare a patient incompetent, but psychiatric consultants
can evaluate a patient's decision-making capacity. Frequently,
when psychiatric consultation is requested to determine the
capacity of a patient refusing surgery, the reason for refusal
is unrelated to the patient's decision-making capacity (e.g.,
it is deemed that insufficient information has been provided
to the patient, or that the patient displays fear or emotional
unreadiness).14
UNDERRECOGNIZED PERIOPERATIVE PSYCHIATRIC
PROBLEMS
Considering the high prevalence of mental disorders in the
American population, it is not surprising that many surgi-
cal patients are taking antipsychiatric medications at the time
of surgery. However, many patients’ psychiatric history is
not obtained or even considered until problems arise post-
operatively. One reason for this retrospective evaluation is
underrecognition of psychological distress by the surgical
 Chapter 15  Psychiatric and Behavioral Disorders 447
team preoperatively. A psychiatric history should be rou-
tinely obtained during the general preoperative evaluation
and as an outpatient before admission when the surgery is
elective. Disorders may flare during the postoperative period,
and abrupt discontinuation of psychiatric medication, as a
result of oversight or the patient's inability to take oral medi-
cation for a sustained period, adds to the risk of relapse of
psychiatric disorders as well as symptoms of medication
discontinuation.14
MOOD DISORDERS
Mood disorder is the term designated to a set of diagnoses in
the American Psychiatric Association (APA) Diagnostic and
Statistical Manual of Mental Disorders, fourth edition (DSM-IV)
classification system in which disturbance in a person's mood
is hypothesized to be the main underlying feature. Mood disor-
ders were formerly called “affective disorders,” a name initially
proposed by British psychiatrist Henry Maudsley. Mood disor-
ders are further categorized into major depression and bipolar
disorders based on depressive or manic episodes.12
A mood disorder is characterized by a depressed mood,
a lack of interest in activities normally enjoyed, changes in
weight and sleep, fatigue, feelings of worthlessness and guilt,
difficulty concentrating, and thoughts of death and suicide.
If a person has experienced most of these symptoms for
longer than 2 weeks, they may be diagnosed as having had a
“major depressive episode.” In the DSM-IV a person h ­ aving
one or more major depressive episodes is considered to have
major depression. After one episode, “major depressive dis-
order (single episode)” would be diagnosed. After more than
one episode, the diagnosis becomes “major depressive dis-
order (recurrent).” Depression without periods of mania is
also called unipolar depression because the mood remains
at one emotional state, or “pole.”12 Specifiers can be added to
describe severity, other features (e.g., postpartum onset), and
course of recurrent episodes.
Major Depression
Among the mood disorders, the most studied is major depres-
sion, a common and disabling psychiatric disorder in the
United States. The prevalence of major depression is estimated
to be as high as 5.3% in adults (17 million patients) and 4%
in adolescents. Major depression has a 17% lifetime preva-
lence in the general U.S. population.9 Lifetime risk of an epi-
sode for women is 20%.15 In the 2001–2002 NCS-R, Kessler
et al.16 reported the prevalence and correlates of major depres-
sion using DSM-IV criteria in 9090 household residents age
18 years and older. They calculated a prevalence of lifetime
major depression of 16.2% and of 6.6% for a 12-month period,
estimated to affect 32 to 35 million and 13 to 14 million adults,
respectively.
As many as 74% of NCS respondents with lifetime depres-
sion showed one or more coexisting disorders, with anxi-
ety (58%) and substance abuse (38%) most common. The
prevalence of depression in cancer patients is twofold to three-
fold the rate documented in the general population, and as
many as 25% of patients in extended care facilities may have
major depression.8,17,18 The incidence of major depression
appears to have increased, reaching younger persons, yet often
going undetected and undiagnosed in all age groups.
CHARACTERISTICS
Depressive mood disorders include feelings of sadness, hope-
lessness, and discouragement, but sadness may be bypassed
with complaints of somatic problems, persistent anger or
increased irritability, disinterest or lack of pleasure in ­activities,
changes in appetite and sleep patterns, and altered psychomo-
tor behaviors, such as agitation. Decreased energy, tiredness,
and fatigue are common, as are feelings of ­worthlessness and
guilt. There may be concentration problems, ­difficulties in
decision making, thoughts of death and suicide, and ­varied
degrees of social and work impairment. In many cases,
depressed persons present with tearfulness, irritability, rumi-
nations, anxiety, phobias, concern over physical health, pain
complaints, and brooding. Major depression is usually dif-
ferentiated from “mood disorders due to general medical
condition,” substance abuse–induced mood disorders, demen-
tia, and adjustment disorders with depressed mood and s­ imple
bereavement.
At the opposite end of the spectrum, manic episodes are
characterized by inflated self-esteem or grandiosity, decreased
need for sleep, pressured speech, flights of ideas, distractibility,
increased involvement in goal-directed activities, and psycho-
motor agitation. Expansiveness and unwarranted optimism
coupled with poor judgment may lead to imprudent excesses,
as discussed later.
RISK FACTORS
Factors associated with increased risk for major depression
are female gender, genetic inheritance, history of trauma,
homemaker status, sexual abuse, physical abuse, physical dis-
ability, bereavement at a young age, alcoholism, insufficient
family structure, unemployment or disability, lack of mar-
riage history, lower education, and living in or near poverty
levels. Risk seems to be low until the early teenage years, but
depressive disorders can occur throughout the life cycle.
Major depression is highly comorbid with other mental dis-
orders. As many as 72% of respondents with lifetime major
depression met criteria for at least one other disorder, such
as anxiety disorder (59%), substance abuse disorder (24%),
and ­impulse-control disorder (30%). Approximately 90% of
12-month major depression cases were classified as moderate,
severe, or very severe.
Depression is also associated with physical illness, affecting
multiple domains of functioning and well-being. Patients with
depressive conditions have poorer mental, emotional, and
social functioning than even those with chronic medical con-
ditions.19,20 For example, depressed patients may report higher
levels of fatigue and fatigue-related interferences than cancer
patients.21
 448 ANESTHESIA AND UNCOMMON DISEASES
PHARMACOLOGIC THERAPY
Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs) are undoubt-
edly the most commonly prescribed antidepression medica-
tions. The U.S. Centers for Disease Control and Prevention
(CDC) found that of 2.4 billion drug prescriptions in 2005, 118
million were for antidepressants.22 Antihypertensive prescrip-
tions came in second with 113 million. Depressed patients pre-
scribed psychotropic medications rose from 44.6% in 1987 to
79.4% in 1997, with the increase attributed primarily to SSRIs,
which were unavailable in 1987 (Table 15-1).8,23–28
Discoveries from psychopharmacologic research have
altered depression treatment protocols, particularly over the
past 20 years, and use of antidepressants increased threefold
to fivefold from 1988 to 1994 among those under age 20.29 In
recent decades, primary care physicians have initiated more
antidepressant pharmacotherapy than psychiatrists. The phar-
macology of depression treatment is well detailed, including
side effects, adverse drug effects, and drug-drug interactions,
as well as patient-specific factors such as gender, age, and other
illnesses.8
Antidepressants act on multiple receptors and induce var-
ious neurochemical modulating effects (Table  15-2).30 The
SSRIs are the most frequently encountered antidepressants
by practicing anesthesiologists. SSRIs selectively potentiate
the transmission of central nervous system (CNS) impulses
along serotonergic pathways while having little effect on
other neuroendocrine pathways, such as those involving nor-
epinephrine or acetylcholine. Thus, SSRIs lack many of the
side effects associated with other classes of antidepressants.
However, SSRIs may cause nausea, diarrhea, headache, sex-
ual dysfunction, agitation, and besides some mild sedative
effects, insomnia. Specifically, escitalopram may be associ-
ated with hyponatremia. Fluoxetine is a potent inhibitor of the
cytochrome P450 2D6 (CYP2D6) isoenzyme.31 The inhibition
of this enzyme leads to a rise in the plasma concentration of
drugs that depend on hepatic metabolism for clearance, such
as β-blockers, benzodiazepines, and some antidysrhythmic
drugs. The most obvious results of this inhibition derive from
treatment of the patients’ depression itself, because patients
may be treated with several antidepressants from different
classes. Concomitant treatment of depressed patients with
both fluoxetine and a tricyclic drug may result in substan-
tial rises in tricyclic plasma concentrations. Combining SSRIs
with monamine oxidase inhibitors may precipitate serotonin
syndrome, which is similar to neuroleptic malignant syndrome
both in presentation and mortality and is marked by flush-
ing, restlessness, anxiety, chills, ataxia, insomnia, and hemo-
dynamic instability. Combination of fluoxetine with the mood
stabilizer carbamazepine or lithium may also precipitate sero-
tonin syndrome. Whether SSRIs potentially increase the risk
of suicide in a small subgroup of depressed patients is an
ongoing debate.32,33
For anesthetic management, SSRIs do not pose too much
challenge. SSRIs have no effect on seizure threshold. Some
attentions should be paid to drug combinations and the effects
of drugs taken by patients on the CYP450 system if patient has
been taking barbiturates, benzodiazepines, and certain neuro-
muscular blocking drugs.
Tricyclic Antidepressants
The tricyclic antidepressants (TCAs) were the most widely
used drugs to treat clinical depression prior to the SSRIs, after
imipramine (Tofranil) was shown to be effective for treating
depression in the 1950s. TCAs primarily work by increasing
the level of norepinephrine in the brain and, to a lesser extent,
serotonin levels. Some TCAs also are antihistamines (which
block the action of histamine) or anticholinergic (which
blocks the action of acetylcholine, a neurotransmitter). These
additional actions allow for uses of TCAs other than for treat-
ing depression, as well as introducing additional side effects.
A TCA's chemical structure is composed of three conjoined
rings. If the nitrogen atom on the center ring is a tertiary
amine, the drug belongs to the first-generation TCAs; most
side effects associated with TCAs are more pronounced with
first-generation TCAs. If it is a secondary amine, the drug is a
second-generation TCA.
Tricyclics may inhibit the antihypertensive effect of cloni-
dine (Catapres). Therefore, combining TCAs with clonidine
may lead to dangerous elevations in blood pressure (BP).
TCAs may affect the heart's electrical conduction system.
Combining TCAs with drugs that also affect the heart's con-
duction system (disopyramide, pimozide, procainamide) may
increase the frequency and severity of an abnormal heart rate
and rhythm. Combining TCAs with carbamazepine (Tegretol)
may result in lower TCA blood levels because carbamaze-
pine increases the breakdown of TCAs, potentially reduc-
ing their effect. TCAs may increase the BP-elevating effect of
epinephrine, norepinephrine, dopamine, phenylephrine, and
dobutamine.
It is generally believed that the TCAs are equally potent
in treatment of depression. On the other hand, all the TCAs
cause some anticholinergic symptoms, orthostatic hypoten-
sion, cardiac dysrhythmia, and sedation. However, they do
so in varying degrees when compared with their efficacy as
antidepressants. This differing side effect profile serves as the
basis for much of the strategy employed by practitioners pre-
scribing these drugs. For example, a drug that causes a greater
degree of sedation might be chosen preferentially for patients
experiencing insomnia as part of their symptomatology.
Similarly, practitioners might avoid drugs that have greater
anticholinergic activity in patients who have glaucoma or
reflux disease. The degree of cardiac dysrhythmia potential
is essentially the same for TCAs, which should be avoided in
patients with known cardiac conduction abnormalities, such
as second-degree or higher atrioventricular block. Despite
their potential for causing cardiac dysrhythmias, TCAs may
paradoxically show some antidysrhythmic activity.34 Also, the
electrocardiographic (ECG) changes that occur with these
drugs tend to dissipate with ongoing treatment, implying
some form of tolerance by the cardiac conduction system to
these effects.35

TABLE 15-1  n  Common Antidepressants by Class and Side Effects
Class
Selective serotonin reuptake
inhibitors (SSRIs)
Tricyclic antidepressants
(TCAs)
Monoamine oxidase inhibitors
(MAOIs)
Reversible inhibitors of MAO-
type (RIMAs)
Noradrenaline reuptake
inhibitor (NARI)
Norepinephrine and dopamine
reuptake inhibitor (NDRI)
Serotonin and noradrenaline
reuptake inhibitors (SNRIs)
Combined reuptake inhibitors and
receptor blockers (CRIRBs)
Noradrenergic and specific
serotonergic antidepressant
NSSA (NaSSA)
Herbal
Atypical
Data from www.clinical-depression.co.uk/dlp/treating-depression/side-effects-of-antidepressants.
GI, Gastrointestinal; SIADH, syndrome of inappropriate secretion of antidiuretic hormone (vasopressin).
Chapter 15  Psychiatric and Behavioral Disorders 449
Generic (Trade) Names Common Side Effects; Comments
Citalopram (Celexa, Cipram, Cipramil, Serostat) SSRIs are safer when overdosed.
Escitalopram (Lexapro) Nausea, diarrhea, headache
Fluvoxamine (Dumirox, Feverin, Floxyfral, Luvox) Loss of libido, erectile dysfunction, failure to reach
Fluoxetine (Prozac, Sarafem) orgasm
Paroxetine (Paxil) Increase in suicidal ideation
Sertraline (Zoloft) Serotonergic syndrome
Amitriptyline (Elavil, Endep, Entrofen) Cardiac: increased heart rate and blood pressure
Amoxapine (Asendin) Dry mouth, blurred vision, drowsiness, dizziness,
Clomipramine (Anafranil) skin rash
Desipramine (Norpramin, Pertofran) Weight gain or loss
Doxepin (Adapin, Sinequan) Sexual problems
Imipramine (Norfranil, Tofranil, Tipramine)
Maprotiline (Ludiomil)
Nortriptyline (Aventyl, Noratren, Pamelor)
Protriptyline (Vivactil)
Trimipramine (Surmontil)
Deprenyl (Eldepryl) Heart attack, liver inflammation, stroke, seizure
Phenelzine (Nardil) Severe hypertension if taking together with tyramine-
Selegiline (Emsam) rich foods or beverages
Tranylcypromine (Parnate) Weight gain, constipation, dry mouth, dizziness,
headache, drowsiness, insomnia, sexual side effects
Moclobemide (Aurorix) Urticaria, angioedema, asthma; insomnia, anxiety,
agitation; vertigo, headache, seizure; nausea,
diarrhea; hypertension
Reboxetine (Edronax, Vestra) Dry mouth, constipation, headache, drowsiness,
dizziness, sweating, insomnia, hypertension
Bupropion (Wellbutrin, Wellbutrin SR) Restlessness, insomnia, headache, worsening of
migraine conditions, tremor, dry mouth, agitation,
confusion, rapid heartbeat, dizziness, nausea,
constipation, menstrual complaints, rash
Venlafaxine (Effexor) Nervousness, agitation, headache, insomnia,
Duloxetine (Cymbalta) seizure
Milnacipran (Ixel, Savella, Dalcipran,Toledomin) Nausea, diarrhea, rash
Sexual side effects: problems with arousal or
satisfaction
↓Sexual function; headache, ↑heart rate,
hyperhidrosis, mood swing to mania
Nefazodone (Dutonin, Serzone) Drowsiness, nausea/vomiting, headache and dry
Trazodone (Desyrel, Trazon, Trialodine) mouth
Mirtazapine (Remeron) Dizziness, blurred vision, sedation, somnolence,
malaise/lassitude, ↑appetite and weight gain,
dry mouth, constipation, ↑libido/sexual function;
vivid, bizarre, lucid dreams or nightmares
Gingko biloba remedies Nausea, diarrhea, dizziness, headache, bleeding,
Ginseng weakness, seizure, headache
Hypericum perforatum (St. John's wort) Nervousness, excitability, headache, euphoria,
bleeding
GI symptoms, dizziness, confusion, tiredness,
sedation
Amisulpride (Deniban, Solian, Sulamid) Amenorrhea, galactorrhea, nausea, weight gain,
Viloxazine (Vivalan, Vivarint) akathisia, sexual dysfunction
GI symptoms; dysarthria, tremor, agitation, SIADH,
↑libido
 450 ANESTHESIA AND UNCOMMON DISEASES

TABLE 15-2  n  Pharmacology of Common Antidepressants*

Anti- Anti- Anti–α1- REUPTAKE INHIBITION

histamine muscarinic adrenergic
Drug Activity (H1)† Activity† Activity NE 5-HT Elimination Half-Life (hr)

Amitriptyline 3 3 3 2 4 32-40

Doxepin 4 2 3 1 2 8-25

Imipramine 1 2 1 2 4 6-20

Trimipramine 4 2 3 1 1 9

Desipramine 0 1 1 4 3 12-54

Nortriptyline 1 1 2 2 3 15-90

Protriptyline 0.5 3 1 3 3 54-92

Amoxapine 1 1 2 2 2 8-30

Maprotiline 2 1 1 2 1 27-58

Trazodone 0.5 0 2 0 3 3-9

Fluoxetine 0 0.5 0 1 4 168-210

Bupropion 0 0 0 0 0 8-24

Data from Haddox JD, Chapkowski SL: Neuropsychiatric drug use in pain management. In Raj PP, editor: Practical management of pain, ed 3, St Louis, 2000, Mosby,
pp 489-512.
* Relative scale of 1 to 4 with 1 = least effect.
† Relative agents: atropine = 4 (antimuscarinic activity), diphenhydramine = 2 (antihistamine activity, phentolamine = 4 (anti–α1-adrenergic activity).
NE, Norepinephrine; 5-HT, 5-hydroxytryptamine (serotonin).

These changes are a concern, however, during the early
phase of treatment of depressed patients with suicidal ide-
ation. A frequently chosen method of suicide is overdose, and
the medications chosen are those in patients’ possession, in
this case, possibly their antidepressants. Overdose with TCAs
may be achieved by ingesting 5 to 10 times the daily dosage,
resulting in fatal arrhythmia or resistant myocardial depres-
sion. Despite these facts, overdose with TCAs typically pres-
ents as CNS depression, including seizures, hypoventilation,
and coma. Anticholinergic symptoms are also present and
may confuse the diagnosis. Normally, when patients pres-
ent to the OR, these problems are not present. In the trauma
patient, however, there may be need for concern if acute drug
ingestion is present as part of a suicide attempt or abuse of
these drugs.
Anesthetic management of patients taking TCAs focuses
on side effects and drug-drug interactions. The mechanism
of the antidepressant effects of TCAs involves enhancement
of serotonergic and noradrenergic activity. TCAs’ inhibition
of histaminergic, cholinergic, and α1-adrenergic activity is
responsible for many of their side effects. The main concerns
for these patients being treated with a TCA involve the cardio-
vascular system and the interaction of the drug with a specific
neurotransmitter, such as norepinephrine. Administration of
TCAs increases storage of this neurotransmitter in noradren-
ergic nerve terminals, and thus administration of indirect-act-
ing vasopressors such as ephedrine may cause an exaggerated
release of epinephrine. This effect is most pronounced with
acute treatment and gradually dissipates after the first 2 to 3
weeks. Caution is therefore advised when administering drugs
with sympathomimetic effects to patients receiving TCAs.
The anticholinergic effects of TCAs can cause problems
because many drugs used by anesthesiologists are anticho-
linergics or have anticholinergic effects. Preoperatively, some
anesthesiologists employ scopolamine for its sedative, anxio-
lytic, and antisialogogic properties. Intraoperatively, glyco-
pyrrolate and atropine are both used for their anticholinergic
properties. Pancuronium, which has significant anticholiner-
gic effects, is still used for procedures requiring a long period
of muscle relaxation, especially cardiac surgery. Atropine and
glycopyrrolate have been noted to have increased muscarinic
activity in the presence of TCAs, and administration of pan-
curonium has been documented to precipitate tachydysrhyth-
mias in a sample of patients studied.32 Furthermore, there is
the possibility that preoperative treatment with scopolamine
may increase the incidence of emergence delirium, although
there are no formal studies that support this suspicion.
Monoamine Oxidase Inhibitors
The monoamine oxidase inhibitors (MAOIs) were the first
class of antidepressants to be developed. MAOIs elevate the
levels of norepinephrine, serotonin, and dopamine by inhib-
iting the enzyme monoamine oxidase. MAO breaks down
norepinephrine, serotonin, and dopamine. When MAO is
inhibited, norepinephrine, serotonin, and dopamine are
metabolized significantly less, increasing the concentration
 Chapter 15  Psychiatric and Behavioral Disorders 451
of all three neurotransmitters in the brain. As a consequence,
they act to extend the effect of norepinephrine at the nerve
terminals. MAOIs fell from favor because of concerns about
interactions with certain foods and numerous drugs, as well as
the introduction of newer and safer antidepressants. MAOIs
are reserved primarily for patients who have failed treatment
with other antidepressants.
The MAOIs are devoid of many side effects of other classes of
antidepressants. Their principal side effect is profound hyperten-
sive crisis, as well as serotonin syndrome when the patient con-
sumes tyramine-containing foods (most often wines or cheeses)
or when combined with drugs having intrinsic sympathomi-
metic effects (e.g., meperidine, certain β-blockers). Tyramine
and sympathomimetic drugs stimulate the release of norepi-
nephrine from noradrenergic nerve terminals, enhancing the
α-adrenergic effects. Other side effects include orthostatic hypo-
tension, sedation, blurry vision, and peripheral neuropathy.
Anesthetic Considerations. Formerly, MAOIs were discon-
tinued 2 to 3 weeks before any elective procedure involving
general anesthesia. This precaution is no longer encouraged
or practical for many procedures, because discontinuation of
the drug may acutely place patients at greater risk for suicide.36
The MAOIs can also significantly increase the minimum
alveolar concentration (MAC). Furthermore, serum cholin-
esterase activity may be impaired, requiring the dose of suc-
cinylcholine to be reduced.37 Liver function indices may
become elevated during treatment with MAOIs. As with TCAs,
indirect-acting vasopressors as well as epinephrine-containing
local anesthetics should be avoided because of their poten-
tial to cause severe hypertension. Finally, because MAOIs are
known to interact with opioids, their use should be limited
by necessity. Meperidine is the narcotic most often involved,
but with the exception of fentanyl, all opioids can precipitate
a hyperpyrexic response that may be confused with malignant
hyperthermia and has similar potential for mortality.38
Postoperative pain control can be achieved with minimal
use of opioids and by employing alternatives (e.g., NSAIDs);
regional anesthesia is preferred whenever possible.
Second-Generation Antidepressants
The second-generation antidepressants such as venlafaxine,
trazodone, bupropion, and mirtazapine are reserved for the
treatment of patients who have failed other pharmacologic
management (e.g., SSRIs). Again, these drugs’ side effect pro-
file can guide choice of drug. For example, venlafaxine may
be linked to seizures and constipation as two side effects.
Trazodone is the most sedating of the second-generation
antidepressants and might be chosen to treat patients with
insomnia. Unlike the TCAs, these alternative agents possess
almost no anticholinergic effects or potential for cardiac dys-
rhythmias. For patients receiving more than one drug as part
of therapy, avoidance of MAOIs in those undergoing therapy
with a second-generation antidepressant is recommended.
Caution is warranted regarding St. John's wort (Hypericum
perforatum), used by many people to treat what they think
is depression. Most of these individuals have never been
diagnosed by a psychologist or psychiatrist as having depres-
sion. Recent studies indicate St. John's wort is no more effective
than a placebo in the treatment of major depressive disorder.39
Its efficacy for less severe cases is disputed. However, patients
encountered in clinical practice still take this nutraceutical.
The side effect profile is extensive, but the only major concern
for anesthesiologists is the similarity of H. perforatum to the
MAOIs in precipitating hypertension and hyperpyrexia.
Kudoh et al.40 compared 80 depressed patients with 50 con-
trols undergoing orthopedic surgery and found that cortisol
response to surgery is associated with postoperative confu-
sion, and that the use of fentanyl during anesthesia decreases
the incidence of postoperative confusion, related to the inhi-
bition of cortisol secretion by fentanyl. Another study eval-
uated 80 patients age 35 to 63 with major depression who
underwent anesthesia during orthopedic surgery, divided
into those who continued or discontinued antidepressants 72
hours before surgery.41 Depressed patients were taking imip-
ramine, clomipramine, maprotiline, and mianserin. Results
revealed a low incidence of intraoperative hypotension and
arrhythmias in depressed patients, whether antidepressant
treatment was ceased preoperatively or not, but that discon-
tinued use of antidepressants was associated with increased
incidence of delirium, confusion, and depressive symptoms
postoperatively. Kudoh et  al.42 observed temperature regula-
tion during anesthesia and postoperative shivering in chroni-
cally depressed patients undergoing orthopedic surgery who
were taking imipramine, clomipramine, maprotiline, or mian-
serin for more than 1 year, compared to a control sample. The
intraoperative core temperature and incidence of shivering in
the depressed group were significantly higher.
Dysthymic Disorder
Dysthymic disorder tends to be a long-lasting illness and is
considered a chronic depression, but with less severity than
major depressive disorder. The term was first used by James
Kocsis during the 1970s. Dysthymia, also known as neurotic
depression, is a serious state of chronic depression; how-
ever it is less acute and severe than major depressive disorder.
DSM-IV defines dysthymia as a chronically depressed mood
that occurs for most of the day, more days than not, for at least
2 years.12 Dysthymic disorder can be found in children who
may exhibit irritability rather than depression, or in addition
to sadness. When depressed mood prevails, at least two addi-
tional symptoms may be present, such as poor appetite or over-
eating, insomnia or hypersomnia, low energy or fatigue, low
self-esteem, difficulties concentrating or making decisions, and
feelings of hopelessness. Often, patients with dysthymia see
their symptoms as characterizing their personality over time.
Lifetime prevalence is approximately 6%, and ­dysthymic
disorder is often marked by early, insidious onset and a chronic
course.12 Dysthymia may be superimposed on major depres-
sion; and many patients are prescribed medications similar
to those used for major depression. Loss of interest, feelings
of guilt or brooding about the past, excessive anger, and
 452 ANESTHESIA AND UNCOMMON DISEASES
decreased activity, effectiveness, and productivity are com-
mon; and with time, dysthymic disorder may be associated
with multiple physical illnesses.
Bipolar Disorders
Bipolar disorder, or manic-depressive disorder, also referred to
as “bipolar affective disorder” or “manic depression,” is a psy-
chiatric diagnosis that describes a category of mood disorders
defined by the presence of one or more episodes of abnormally
elevated energy levels, cognition, and mood with or without
one or more depressive episodes. When individuals exhibit
bouts or episodes characterized as “manic,” often in sequence
with depressive episodes, they are characterized within this
category. A manic episode is seen as a distinct period mani-
fested by abnormally, persistently elevated, expansive, or irri-
table mood accompanied by such additional symptoms as
inflated self-esteem or grandiosity, decreased need for sleep,
pressured speech, flights of ideas, distractibility, and increased
involvement in goal-directed activities with high potential for
painful consequences. The disturbance is sufficiently severe
to cause marked impairments in social or occupational func-
tioning and may present psychotic features. Mood in manic
episodes may be seen as euphoric, unusually cheerful, or
high; the expansive quality is described as seemingly unceas-
ing and indiscriminate, particularly in interpersonal, sexual,
or occupational interactions. Uncritical self-acceptance may
hold firm, and individuals may not recognize that they are ill
and may resist efforts to be treated. Mood may shift rapidly to
anger or depression.
Depending on the length, severity, and course of symp-
tom complexes over time, individuals may be diagnosed as
bipolar I or bipolar II disorder. Bipolar I disorder is character-
ized by one or more manic or mixed episodes, usually with
major depressive episodes. The diagnosis of bipolar II disor-
der suggests recurrent depressive episodes and at least one
hypomanic episode. Designated subtypes within the bipolar
spectrum reflect severity, psychosis, remission, catatonic fea-
tures, and postpartum onset. Seasonal patterns and the nature
of cycling (rapid or not) are also considered, and thus the his-
tory of current and past episodes determines diagnosis of
actual mood disorder.
RISK FACTORS
It is likely that genetic factors play an important role in bipo-
lar disorder. About 80% to 90% of individuals with bipolar
disorder have a blood relative with either depression or bipo-
lar disorder. Bipolar disorder is not caused by a single gene
change, however, but rather is probably the result of multiple
gene abnormalities. Carney and Jones43 found that patients
with bipolar disorder were also more likely to reside in an
urban setting. Additionally, the younger population has a
higher risk for bipolar disorder, which is encountered signifi-
cantly more often between ages 15 and 30. Stressful major life
changes (e.g., death of loved one) also increase the risk for
bipolar disorder.
Some common medications may be related to bipolar dis-
order, such as corticosteroids and cancer medications. Certain
medical conditions are also associated with a higher preva-
lence of bipolar disorder, such as thyroid disease, vitamin defi-
ciency, end-stage renal disease, and some neurologic diseases
(e.g., Parkinson's, dementia).44
COMORBIDITIES
Substance abuse, cardiovascular diseases, obesity, and diabetes
often coexist with bipolar disorder.44 Carney and Jones43 stud-
ied 3557 patients with bipolar disorder, 61% women (2162)
and 39% men (1395). The control population of 726,262 was
53% female (381,116 subjects). The percentage of patients
with bipolar disorder who had three or more chronic medical
comorbidities was more than threefold higher than for con-
trols (40.5% vs. 12.1%; p <.0001).
Many people with bipolar disorder also have alcohol or
drug problems. Nicotine abuse/dependence was 192% more
likely among patients with bipolar disorder than in subjects
without mental health problems. The odds ratio (OR) were
also much higher for alcohol abuse/dependence (19.63; 95%
confidence interval [CI], 17.59-21.90) and polysubstance dis-
orders (42.91; 95% CI, 37.83-48.66). Conditions related to
alcohol use, such as peptic ulcer disease, liver disease, and
pancreatitis, were also more common in patients with bipo-
lar disorder. Liver disease and pancreatitis likely resulted from
anticonvulsant use in this population. Street drugs or alcohol
may seem to ease symptoms but can actually trigger, prolong,
or worsen depression or mania.43
Cardiovascular disease could be the expected result of
weight gain, unhealthy diet, and increased nicotine use in
patients with bipolar disorder. About 23% of these patients
have hypertension, representing a 185% increase in stroke.
Patients diagnosed with bipolar disorder also are more likely
to have endocrine diseases such as diabetes, thyroid problems,
and obesity
Comorbid anxiety disorders include posttraumatic stress
disorder (PTSD), social phobia, and generalized anxiety dis-
order. Attention-deficit/hyperactivity disorder (ADHD) has
symptoms that overlap with bipolar disorder, which therefore
can be difficult to differentiate from ADHD. Sometimes one is
mistaken for the other; other persons may be diagnosed with
both conditions.
PREVALENCE
The lifetime community prevalence of bipolar disorder is 4%
to 6.4%,43–45 which is significantly higher than for schizophre-
nia (0.5%-1.5%). Interestingly, race, ethnicity, and gender have
no effect on the prevalence of bipolar disorder, but women are
more likely to experience rapid cycling, mixed states, depres-
sive episodes, and bipolar II disorder than men. Patients with
bipolar disorder have high rates of disability and higher rates
of mortality than individuals without bipolar disorder. Natural
causes such as cardiovascular disease and diabetes, as well as
suicide and other “unnatural” causes, are key contributors to
the high mortality rate. Judd and Akiskal45 found subthreshold
 Chapter 15  Psychiatric and Behavioral Disorders 453
cases were at least five times more prevalent than DSM-defined
core syndromal diagnoses. These researchers emphasized that
bipolar disorders are associated with significant service utili-
zation and psychosocial impairment.
LITHIUM
Bipolar disorder is usually treated with medication and coun-
seling, and for refractory cases, electroconvulsive therapy is
used. Pharmacologic management includes one set of drugs
for mania symptoms, another set to treat depression, and
some medications for maintenance. Medications typically used
include lithium carbonate and antidepressants. Lithium car-
bonate was the first and is still the most important antimanic
agent.8,24–28
Although its mechanism of action is still imprecisely
understood, lithium is widely distributed throughout the
­ Usually, once an electrical stimulus has been applied to the brain,
CNS, where it is believed to have a variety of effects. Lithium
interacts with many neurotransmitter systems, increas-
ing the s­ynthesis of serotonin while decreasing norepineph-
rine release; these effects are likely responsible for its clinical
effect. Despite its efficacy in the treatment of mania, lithium
has a very narrow therapeutic index, and plasma levels must
be monitored routinely. A serum concentration of 0.6 to
0.8 mEq/L is considered therapeutic for the treatment of stable
mania. Slightly higher levels, up to 1.2 mEq/L, are acceptable
for treatment of acute episodes. Levels of 2 mEq/L are consid-
ered toxic and require withdrawal of the drug and aggressive
hydration with sodium-containing solutions or administra-
tion of osmotic diuretics such as mannitol.46
Lithium toxicity is evidenced by weakness, sedation, ataxia,
and widening of the QRS complex on the electrocardiogram
(ECG). These symptoms in patients receiving lithium demand
drug withdrawal and testing of serum lithium levels, because
with greater toxicity, atrioventricular blockade, cardiovascular
instability, seizures, and death may result. Besides the possibil-
ity of toxicity, lithium also has long-term effects that require
periodic monitoring. Lithium is known to inhibit the release
of thyroid hormones, resulting in hypothyroidism in as many
as 5% of patients receiving the drug. It may also cause nephro-
genic diabetes insipidus unresponsive to vasopressin therapy.
In a small percentage of patients, leukocytosis may develop,
noted as a white blood cell (WBC) count of 10,000 to 14,000
cells/mm3. All these effects resolve with withdrawal of the drug
but mandate periodic testing of thyroid level, urine osmolality,
and WBC count. In patients with known sinus nodal dysfunc-
tion, it may be prudent first to place a permanent pacemaker
secondary to possible disturbances of the cardiac conduction
system by lithium treatment.
ELECTROCONVULSIVE THERAPY
The mechanism of action for electroconvulsive therapy (ECT)
is still unknown, and thus it is still a controversial treatment
for depression and other mental disorders. Nevertheless, ECT
remains one way to address the symptoms of major depression
and bipolar disorder.47 ECT may also be applied in patients
with schizophrenia, particularly when they do not respond
to other therapeutic efforts.48 The therapeutic mechanism of
ECT may be related to the generalized seizures it induces, and
potentially important interactions occur among psychotro-
pics, anesthetics, and ECT. Several studies have investigated
combinations of anesthetics with ECT to facilitate favorable
outcomes.49 In general, ECT is regarded as a treatment of last
resort, applied when either other treatments have failed or if
patients develop suicidal ideations acutely.50
Although most practitioners believe that seizure duration is
the most important factor relating to ECT efficacy,51 newer stud-
ies cast doubt on this theory.52 The only absolute contraindications
to ECT are elevated intracranial pressure and pheochromocy-
toma. Relative contraindications include recent cerebrovascular
accident (CVA, stroke), aortic disease, cerebral aneurysms, car-
diac conduction disturbances, and certain high-risk pregnancies.
a grand mal seizure is induced. A brief initial tonic phase is fol-
lowed by a more prolonged clonic phase that lasts 30 seconds to
several minutes. Another technique is to induce three seizures at
one sitting and use intubation with hyperventilation to decrease
carbon dioxide. By hyperventilating and decreasing CO2 levels,
the seizure threshold can be lowered. On average, eight treat-
ments are necessary to treat most patients, with a response rate
of almost 75%. Over the course of ECT, the only significant side
effect is memory loss. To minimize this complication, the stimu-
lus can be applied to the nondominant hemisphere only, although
efficacy is reduced by this maneuver.
During ECT, several physiologic consequences mandate
close monitoring of patients. Initially, a substantial vagal
­discharge is noted with consequent bradycardia and hypoten-
sion. This is immediately followed by a much longer period
during which sympathetic activity predominates, resulting in
­hypertension and tachycardia; cardiac ischemia or significant
tachydysrhythmias may develop. In fact, the most frequent
cause of mortality in patients receiving ECT is myocardial
infarction.53 Several treatments have been suggested to address
these side effects, including short-acting β-blockers, narcot-
ics, and nitrates. Careful consideration must be given to such
agents (e.g., propranolol), because profound bradycardia and
asystole have been reported after their administration.54
Patients undergoing ECT are often receiving other psy-
chotropics. These medications may influence the physiologic
implications of ECT and interact with medications used to
anesthetize patients during ECT. For example, the effects of
TCAs on the sympathetic nervous system and cardiac con-
duction system may predispose patients receiving ECT to a
more significant risk of profound hypertension and dysrhyth-
mias. Patients taking MAOIs may find themselves at a simi-
larly increased risk of hypertension. Lithium treatment may
prolong the effect of benzodiazepines or barbiturates used
for induction of general anesthesia while increasing the like-
lihood of treatment-induced cognitive side effects. Also,
preprocedural treatment with centrally acting anticholiner-
gics may increase the likelihood of postprocedural delirium.
Clearly, the anesthetic record must be complete, including
descriptions and quantities of drugs administered, especially
 454 ANESTHESIA AND UNCOMMON DISEASES
those used to treat hemodynamic fluctuations. The induction
stimulus, length of the induced seizure, and length of time to
recovery must be assiduously documented. This is particularly
important because ECT is administered repeatedly over sev-
eral weeks, and the events of the previous treatment can serve
to guide modifications of future treatment.
ANESTHETIC CONSIDERATIONS
Lithium is the most commonly prescribed drug for bipolar
disorder and interacts with several classes of anesthetic agents.
First, lithium prolongs the duration of several nondepolariz-
ing neuromuscular relaxants because of its ability to replace
sodium in propagation of action potentials.55 Therefore, cli-
nicians need to adjust the dosing and select the appropriate
nondepolarizing muscle relaxants. Second, because of the
blocking effects of lithium on the release of epinephrine and
norepinephrine from the brainstem, the MAC of many volatile
agents is reduced in patients receiving lithium. The patient's
emergence from general anesthesia thus may be affected.56
Third, nutraceuticals and herbal agents are also used to treat
mood disorders, and again, anesthesiologists must evaluate for
these agents. In this regard, fish oils have had positive results
in bipolar disorder and can affect the coagulation cascade.57
Concerns also surround the metabolic changes in the acute
phase of bipolar disorder. Guan et al.58 studied the p ­ revalence
of metabolic abnormalities in acute-phase patients start-
ing treatment and found abnormal levels of triglycerides
(>1.7 mmol/L) in 29.1% of patients versus 15.4% of controls,
of high-density lipoprotein (HDL <0.91 mmol/L) in 15.5%
patients versus no controls, of fasting glucose (>6.1 mmol/L)
in 5.4% patients versus no controls, and for body mass index
(BMI) in 34.5% patients versus 10.8% controls.
Clinicians who administer anesthesia for ECT need to be
aware of untoward physiologic responses and must be prepared
to treat them. They also need to know the effects of different
anesthetic agents on administration of the therapy. Traditionally,
methohexital was thought to be superior to other agents because
of its ability to decrease seizure threshold. More recent research,
however, indicates that etomidate provides a longer window of
seizure activity than either methohexital or propofol.59 Until
agreement is reached about the exact mechanism of action of
ECT, which agent is superior remains unknown. Ketamine,
with its ability to lower seizure threshold, may seem to provide
some benefit, but studies do not support this.60
Given the tonic-clonic nature of seizures, muscle relaxation
is essential, and because of the ultrashort duration of action,
succinylcholine is an almost perfect agent for this purpose; it
may be administered as a single bolus or by infusion. However,
succinylcholine may cause mild vagal blockade, and its poten-
tial to amplify the initial vagal phase of the induced seizure
must be carefully monitored. The administration of glycopyr-
rolate preprocedurally may help circumvent this complication.
Mivacurium has also been used for this purpose but has the
disadvantage of causing prolonged relaxation and increasing
the total anesthetic requirements.
In addition to the standard monitors for general anesthe-
sia, most practitioners also use electromyography (EMG)
and electroencephalography (EEG) to monitor the length of
induced seizure activity, both peripherally and centrally. The
inflation of a tourniquet on the limb used to monitor EMG
before administration of the muscle relaxant increases moni-
toring efficacy. Intubation of the trachea is usually not required
unless the patient has a history of gastroesophageal reflux or
hiatal hernia, but ventilation must be supported during the
procedure because of the need for muscle relaxation. Thus, the
antisialogogic effect of glycopyrrolate is an additional benefit
of pretreatment with this medication.
Stress from surgery may psychologically and physiologi-
cally destabilize bipolar disorder, and acute relapse into mania
in the postoperative period can be extremely disruptive to
care, even life threatening.4 Patients unable to take oral med-
ication for prolonged periods preoperatively or postopera-
tively (e.g., recurrent abdominal abscesses and fistulas) cannot
receive lithium, antidepressants, some antipsychotics, or most
anticonvulsant mood stabilizers. During this time, parenteral
antipsychotics serve as the primary choice for mood stabili-
zation (although valproic acid can be given intravenously as
well). For patients taking medication orally, lithium poses a
safety issue for those with rapid fluid shifts (e.g., acute burns).14
ANXIETY DISORDERS (TABLE 15-3)
Generalized Anxiety Disorder
Generalized anxiety disorder (GAD) is categorized as an anxi-
ety disorder and characterized by excessive, uncontrollable, and
often irrational worry about everyday life that is disproportion-
ate to the actual source of worry. This excessive worry often
affects daily functioning because individuals with GAD typi-
cally anticipate disaster and are overly concerned about everyday
matters such as health, money, death, family, and problems with
friends, relationships, or work. They often exhibit a variety of
physical symptoms, including fatigue, fidgeting, headaches, nau-
sea, numbness in hands and feet, muscle tension, muscle aches,
difficulty swallowing, bouts of difficulty breathing, difficulty
concentrating, trembling, twitching, irritability, agitation, sweat-
ing, restlessness, insomnia, hot flashes, and rashes and inability
to control the anxiety. These symptoms must be consistent and
persist at least 6 months for a formal diagnosis of GAD.12
An estimated 5% of the general population has GAD. Studies
over the past two decades have shown that anxiety disorders over-
all are the most prevalent mental disorders, affecting as many as
one in four individuals in American society at some time in their
life.9 Although differing by subtype and among the most diverse,
anxiety disorders are more often found in women, less educated
persons, unmarried persons, and those without children.61
Besides being a persistent and troublesome condition,
GAD also is associated with a high percentage of comor-
bidities, as both the result of and a risk factor for other dis-
orders, often major depression. Many patients with GAD

TABLE 15-3  n  Medications Used to Treat Anxiety Disorders
Drug Class
β-Adrenergic blockers
Barbiturate anxiolytic
Dibenzothiazepine
Benzodiazepines
Herbal and natural remedies
Monoamine oxidase
inhibitors (MAOIs)
5-HT2C antagonist and
melatonin receptor agonist
Selective serotonin reuptake
inhibitors (SSRIs)
Tricyclic antidepressants
(TCAs)
Chapter 15  Psychiatric and Behavioral Disorders 455
Generic (Trade) Names
Propranolol (Inderal)
Atenolol (Tenormin)
Phenobarbital
Quetiapine (Seroquel)
Alprazolam (Xanax)
Loprazolam (Triazulenone)
Lorazepam (Ativan)
Midazolam (Versed)
Flurazepam (Dalmane)
Nitrazepam (Nitrazepam,
Mogadon)
Oxazepam (Serax)
Prazepam (Centrex)
Quazepam (Doral)
Clonazepam (Klonopin)
Chlordiazepoxide (Librium)
Flunitrazepam (Rohypnol)
Lormetazepam (Loramet,
Noctamid)
Kava kava (Piper
methysticum)
Melatonin
Valerian (Valeriana
officinalis)
Deprenyl (Eldepryl, Selegiline)
Isocarboxazid (Marplan)
Moclobemide (Aurorix)
Phenelzine (Nardil)
Tranylcypromine (Parnate)
Agomelatine (Valdoxan)
Citalopram (Celexa, Cipram,
Cipramil)
Escitalopram (Lexapro)
Fluoxetine (Prozac, Sarafem)
Fluvoxamine (Dumirox,
Feverin, Floxyfral, Luvox)
Paroxetine (Paxil)
Sertraline (Zoloft)
Amitriptyline (Elavil,
Endep, Entrofen, Loroxyl,
Tryptizol)
Amoxapine (Asendin)
Clomipramine (Anafranil)
Desipramine (Norpramin,
Pertofran)
Doxepin (Adapin,
Sinequan)
Imipramine (Norfranil, Tofranil,
Tipramine)
Maprotiline (Ludiomil)
Nortriptyline (Aventyl,
Noratren, Pamelor)
Protriptyline (Vivactil)
Trimipramine (Surmontil)
Drug Class Generic (Trade) Names
Sedative-hypnotics Chloral hydrate (Noctec)
Diphenhydramine (Benadryl)
Doxylamine (Unisom)
Estazolam (ProSom)
Hydroxyzine (Atarax, Vistaril)
Mirtazapine (Remeron)
Nefazodone (Dutonin,
Serzone)
Quazepam (Doral)
Estazolam (ProSom)
Temazepam (Restoril)
Trazodone (Desyrel, Trazon,
Trialodine)
Triazolam (Halcion)
Zaleplon (Sonata)
Zopiclone (Imovane)
Zolpidem (Ambien)
Clonidine (Catapres)
Clobazam (Frisium, Mystan)
Clorazepate (Tranxene)
Meprobamate (Miltown)
Others Brotizolam (PIM 919)
Buspirone (BuSpar)
seek treatment from their primary care physicians. Therapy
includes cognitive-behavioral therapy, SSRIs, pregabalin,
benzodiazepines, and other antidepressants (e.g., duloxetine,
venlafaxine, buspirone).62
Social Phobia
Social phobia may refer to social anxiety, specific social phobia,
or social anxiety disorder. Social phobia is a relatively common
disorder associated with significant impairment in a number
of areas; prevalence estimates differ dramatically depending
on measurement instruments, duration under consideration,
and other methodologic features. Lifetime prevalence ranges
from 0.5% to 16% in one report63 and 3% to 13% in DSM-IV.12
Social phobia is characterized by marked and persistent fear
of social or performance situations leading to possible embar-
rassment, and exposure to the threatening situation provokes
an immediate anxiety response such as panic attack. Usually,
individuals avoid the feared situations, and the disorder inter-
feres significantly with normal routines, academic/occupa-
tional functioning, and social activities/relationships. Social
phobia has been identified in 2.9% to 7% of primary care
patients.64 The disorder may be unrecognized by medical pro-
viders across settings, particularly when patients present for
surgery. Patients with social phobia are usually treated with
tranquilizers, anxiolytics, and TCAs (see Table 15-3).
Obsessive-Compulsive Disorder
Obsessive-compulsive disorder (OCD) is an anxiety disorder
characterized by intrusive thoughts that produce uneasiness,
apprehension, fear, or worry; by repetitive behaviors aimed
 456 ANESTHESIA AND UNCOMMON DISEASES
at reducing anxiety; or by a combination of such thoughts
(obsessions) and behaviors (compulsions). Symptoms may
include repetitive handwashing; extensive hoarding; preoccu-
pation with sexual or aggressive impulses, or with particular
religious beliefs; aversion to odd numbers; and nervous h
­ abits.
The symptoms of OCD can potentially alienate patients and
cause severe emotional and financial distress. OCD can be
managed with behavioral therapy (exposure and ritual pre-
vention), SSRIs (paroxetine, sertraline, escitalopram), TCAs
(clomipramine), and occasionally ECT.
Posttraumatic Stress Disorder
Posttraumatic stress disorder (PTSD) is an anxiety disorder
that can develop after exposure to an event or ordeal involv-
ing actual or threatened physical harm. Traumatic events
that may trigger PTSD include violent personal assaults,
natural or human-caused disasters, motor vehicle crashes,
and military combat. Patients with PTSD have persistent
frightening thoughts and memories of their ordeal and feel
emotionally detached or numb, especially with family and
friends. They are easily startled and may experience sleep
problems.
In recent years, PTSD has received increased attention
with more reported domestic violence, worldwide civil unrest,
deadlier natural disasters (e.g., tornadoes, hurricanes), acts
of terrorism, and repeated exposure to war and other trau-
matic events.12 Mental health professionals recognized PTSD
officially in 1980; psychoanalysts have long postulated that
traumatic events may have long-lasting effects on the human
psyche, with implications for mental and physical functioning,
particularly when stressful events are prolonged, severe, life
threatening, and gruesome. Trauma exposure is a ­necessary
condition for diagnosis in DSM-IV, and the critical deter-
minant is individual cognitive and affective reactivity to the
trauma, with the event eliciting severe and incapacitating
psychological distress, such as feelings of “intense fear, help-
lessness, or horror.”12 Symptoms include high levels of anxiety;
distressing thoughts, feelings, and images that recapitulate the
trauma; avoidance of stimuli associated with the event; emo-
tional numbing of responsiveness; restricted range of affect;
sense of foreshortened future; interpersonal anomalies; and
stress-related symptoms of distress, arousal, fear, and irrita-
bility. Data suggest that traumatic events are not unusual and
that the average American is likely to suffer one or multiple
exposures.65 PTSD may occur following a range of stressful
events, including participating in war, torture, rape, and other
criminal victimization; air and motor vehicle crashes; indus-
trial accidents; and devastating acts of nature (e.g., tsunami,
earthquake). The lifetime prevalence for PTSD in the commu-
nity may vary from 1% to 14%, depending on the population
sampled and study methodology.12
In preparation for the May 2013 release of DSM-V, a draft
version of diagnostic criteria was released for public comment,
followed by a 2-year period of field testing. Proposed changes
to the criteria for PTSD include the following66:
1. Criterion A (prior exposure to traumatic events) is more
specifically stated, and evaluation of an individual's emo-
tional response at the time (current criterion A2) is dropped.
2. Several items in criterion B (intrusion symptoms) are
rewritten to add or augment certain distinctions now con-
sidered important.
3. Special consideration is given to developmentally appro-
priate criteria for use with children and adolescents, espe-
cially in the restated criterion B (intrusion symptoms).
Development of age-specific criteria for diagnosis of PTSD
is ongoing at this time.
4. Criterion C (avoidance and numbing) has been split into
criteria C and D:
New version of criterion C now focuses solely on avoidance
of behaviors or physical or temporal reminders of the
trauma; two symptoms are now three because of slight
changes in descriptions.
New criterion D focuses on negative alterations in cogni-
tion and mood associated with the trauma and contains
two new symptoms, one expanded symptom, and four
symptoms previously specified.
5. Criterion E (formerly D), increased arousal and reac-
tivity, contains a revised symptom, a new one, and four
unchanged symptoms.
6. Criterion F (formerly E) still requires symptom duration of
at least 1 month.
7. Criterion G (formerly F) still stipulates symptom impact
(“disturbance”).
8. The “acute” versus “delayed” distinction is dropped; the
delayed specifier is considered appropriate if clinical symp-
tom onset is no sooner than 6 months after trauma.
9. “Developmental trauma disorder” is a proposed new diag-
nosis still under discussion.
Research focusing on special groups at high risk, such
as survivors of natural disaster, combat veterans, former
­prisoners of war (POWs), and soldiers assigned graves reg-
istration duties in the war zone reveal highly variable rates,
depending on the severity and nature of the stressful expe-
rience and, to a lesser degree, individual difference factors.
The National Vietnam Veterans Readjustment Study showed
that 15% and 30% of men and 9% and 27% of women met
criteria for current and lifetime PTSD, respectively.67 Sutker
et  al.68,69 found current rates of PTSD as high as 48% in a
small sample of Gulf War veterans who performed graves
registration duties in the war zone, and up to 70% and 86%,
respectively, for current PTSD in former POWs held by
the Japanese during World War II and by the Koreans and
Chinese in the Korean War.67–69
Treatment for PTSD has often incorporated a variety of
medications, including antidepressants such as the SSRIs,
TCAs, and MAOIs. Adrenergic inhibitors (e.g., clonidine,
propranolol) have been used. Thus, patients with PTSD and
possibly other comorbid disorders (dysthymia, other anxiety
disorders, substance abuse) may present for medical treatment
 Chapter 15  Psychiatric and Behavioral Disorders 457
and surgery with a complex array of prescriptions for anes-
thesiologists to understand. Behavioral complications may
pose barriers to effective communication and cooperation
with physicians, and PTSD patients may become irritable,
anxious, confused, and belligerent when they experience mis-
understandings, lack of control, and potential exposure to life-
threatening stress. Medical outcomes may be diminished by
the direct effects of PTSD psychopathology.
Panic Attacks
Panic attacks are episodes of intense fear or apprehension
that are of sudden onset and of relatively brief duration. Panic
attacks usually begin abruptly, peak within 10 minutes, and are
over in 30 minutes. Panic attacks can be as short as 15 seconds
or can be cyclic, lasting for an extended period, sometimes
hours.12 Patients often experience significant anticipatory
anxiety and limited symptoms between attacks, often associ-
ated with phobic avoidance of situations where they occurred.
Therefore, patients who associate medical treatment and ill-
ness with panic attacks may be particularly vulnerable to such
attacks in a medical situation. As with anxiety disorders overall,
panic attacks represent psychopathology that should be evalu-
ated in patients presenting for surgery and anesthesia. Patients
with a history of panic attacks may describe history of using
of TCAs, MAOIs, SSRIs, and benzodiazepines.70,71 Common
side effects of these medications include drowsiness and lack of
energy, clumsiness and slow reflex, slurred speech, confusion
and disorientation, depression, dizziness and lightheadedness,
impaired thinking and judgment, memory loss and forgetful-
ness, nausea, blurred or double vision, abuse potential, aggres-
sion, intoxication, respiratory problems, withdrawal symptoms
(e.g., diaphoresis), rebound insomnia, and tremor.
Anesthetic Considerations
Patient with anxiety as the fundamental symptom of their men-
tal disorder may experience heightened fear, worry, and anxi-
ety before anesthesia and surgery, associated with high levels of
­circulating catecholamines, behavioral and autonomic agitation,
and fearful behaviors. Heart palpitations and peripheral vasocon-
striction may be evident. The treatment of choice is with benzo-
diazepines and β-blockers continued throughout the operative
period.7 Careful preoperative consultation and appropriate pre-
medication using benzodiazepines or opiates are necessary, and
additional anesthetic requirements may be needed because of
elevated circulating catecholamines and risk of cardiac dysrhyth-
mias. Benzodiazepines and barbiturates may be used for anxiety
as premedicants, with the caution that patients taking barbitu-
rates may have withdrawal phenomena and increased tolerance
to some intravenous (IV) induction agents (e.g., thiopental).
HERBAL REMEDIES
Many people use herbal products for their anxiety, most with-
out prescription.72,73 Herbal therapy can help support a positive
mood balance and reduce nervousness and nervous tension,
occasional anxiety, irritability and agitation, mental and physi-
cal fatigue caused by stress and anxiety, and mild to moderate
mood changes caused by everyday stress.74 These anxiolytic
herbal remedies include a variety of natural agents. For exam-
ple, rhodiola (Rhodiola rosea) is recognized for its broad spec-
trum of action to relieve occasional anxiety and support the
body during stress. Valerian root (Valeriana officinalis) pro-
motes relaxation to relieve nervousness, nervous tension, and
occasional anxiety. Winter cherry (Withania somnifera) is
thought to relieve intermittent anxiety and other emotional
stress responses without causing drowsiness. Passion flower
(Passiflora incarnata) is a natural, nondrowsy sedative that
relieves nervousness and occasional mild to moderate anxi-
ety and panic. 5-Hydroxytryptophan (5-HT) is also a naturally
derived nutrient (plant-based source) that acts as a precursor
to serotonin, a neurotransmitter that regulates mood balance.74
Kava
Contrary to what many herbal users believe, these products
also cause untoward effects. Dozens of case reports link-
ing the kava plant (kava kava, Piper methysticum) to hepatic
failure have been reported worldwide, thus requiring anes-
thesiologists to obtain a detailed history and maintain high
index of suspicion. The mechanism for kava-induced hepatic
­dysfunction appears to be linked to the kava alkaloid piper-
methystin, which has a strong negative effect on cultured
­hepatocytes. Furthermore, four alkaloids with similar struc-
tures to p ­ipermethystin are known cytotoxic agents. It is
thought that epoxidation of pipermethystin may lead to hepa-
totoxic products. Herb-drug interactions may also be linked
to kava toxicity; it is rarely administered alone and typically
taken with other supplements or drugs. Case reports and the-
oretic considerations warrant concern regarding kava intake
with alcohol, certain herbal agents, alprazolam, fluoxetine,
paroxetine, acetylsalicylic acid, oral contraceptives, celecoxib,
omeprazole, paracetamol, and others, with either reported or
associated side effects (e.g., hepatotoxicity, CNS depression).
Genetic polymorphism of the CYP2D6 enzyme may also play
a role in kava-induced liver toxicity. Different ethnicities have
varying frequency of deficiency of this metabolizer of kava-
lactones. About 10% or more of whites have a deficiency
in CYP2D6, whereas the Polynesian population (with no
reported kava-induced liver failure) does not demonstrate this
enzyme deficiency (kava is native to South Pacific islands).75–78
NONAFFECTIVE PSYCHOSES
Schizophrenia
A clinically complex and heterogeneous disorder, schizo-
phrenia is defined by disturbances in emotional, behavioral,
and cognitive arenas manifested in almost every aspect of
life functioning, including sense of well-being, social adapta-
tion, health, and self-sufficiency.79 With a community preva-
lence rate of about 1%, schizophrenia takes its toll on thinking,
attention, language, communication, behavioral monitoring,
affect, hedonic capacity, motivation, and general productivity
 458 ANESTHESIA AND UNCOMMON DISEASES
in thought, speech, emotion, and behavior.12 Symptoms have
been classified into three broad categories: positive, negative,
and cognitive. Positive symptoms reflect an excess or distor-
tion of normal functions, particularly referring to sensory and
perceptual experiences, thoughts, and behaviors that include
hallucinations, delusions, and bizarre, strange, or grossly dis-
organized behaviors. Negative symptoms reflect diminution or
loss of normal functions or absence of emotions and behav-
iors ordinarily present, such as anhedonia, apathy, social with-
drawal, and blunted affect. Negative symptoms also include
restrictions in thought productivity and speech and in ini-
tiation of goal-directed activities. The cognitive category of
symptoms involves impairment in attention, information pro-
cessing, and memory.
A review of the biopsychological aspects reveals the het-
erogeneity of schizophrenia and the complexities in unravel-
ing its components.80 Although disturbances of language and,
by inference, perception and thought are probably the most
salient clinical phenomena, research summaries reveal comor-
bid problems with depression, anxiety, and PTSD.79 Treatment
has advanced with increased understanding of the multifacto-
rial nature of schizophrenia and its various presentations and
subtypes, bolstered by voluminous research in psychopharma-
cology, neuropsychiatry, neuropsychology, and neurobiology.
Kane81 described the gains resulting from research and
development that yielded a new generation of antipsychotics
that have been associated with less negative side-effect pro-
files. He observed that the first three decades of widespread
antipsychotic use, dating from the 1950s, were marked by
major deficiencies, such as elevated incidence of acute and
chronic neurologic effects, frequently poor or only partial out-
come responses, and high rates of noncompliance. He empha-
sized that the introduction of clozapine helped to set the stage
for new perspectives on antipsychotic drug treatment and
development as well as outcome assessment.82–86 The success
TABLE 15-4  n  Typical Neuroleptics for Nonaffective Psychoses
Structure Generic Name Proprietary Name
Phenothiazine (aliphatic) Chlorpromazine Thorazine
Phenothiazine (piperidine) Thioridazine Mellaril
Phenothiazine (piperazine) Fluphenazine Prolixin
Phenothiazine (piperazine) Perphenazine Trilafon
Phenothiazine (piperazine) Trifluoperazine Stelazine
Thioxanthene Thiothixene Navane
Butyrophenone Haloperidol Haldol
Diphenylbutylpiperidine Pimozide Orap
Dibenzoxazepine Loxapine Loxitane
Dihydroindolone Molindone Moban
*Parenteral doses (IM, intramuscular) are generally twice as potent as oral (PO) doses; SC, subcutaneous.
†Dosage information from Tarascon pocket pharmacopoeia, Lompoc, Calif, 2006, Tarascon Publishing.
of clozapine in some refractory patients led to renewed inter-
est in developing better treatment strategies, particularly for
patients thought to be “poor responders.” Some treatment
options have included adjunctive lithium, benzodiazepines,
anticonvulsants, and ECT; however, the second-generation
antipsychotics such as risperidone and olanzapine, marketed
initially in 1994 and 1996, respectively, and quetiapine offer
new hope for patients with schizophrenia. Tables 15-4, 15-5,
and 15-6 list typical, atypical, and newer neuroleptic medica-
tions, respectively, for nonaffective psychoses.
ANESTHETIC CONSIDERATIONS
Patients with a history of schizophrenia or schizophrenic dis-
orders, such as schizoaffective disorder, require careful workup
for medications taken over time as well as tactful and thought-
ful management in the medical situation. Preoperative discon-
tinuation of antipsychotics was common practice because it
was believed to decrease the incidence of perioperative hypo-
tension, but it also increased psychotic symptoms such as
hallucinations and agitation.87,88 Recent studies indicate that
discontinuation of antipsychotics preoperatively does not sig-
nificantly decrease hypotension compared with continuing
antipsychotic medication throughout this period.88
Stressful events of all types may exacerbate symptoms of
distrust, disorganization, and fears among these patients, and
diagnosis of medical illnesses and prospects of surgery may
trigger symptom exacerbation. In one case report a 40-year-
old man treated for schizophrenia who underwent podiatric
surgery with an ankle block regional technique threatened
violence to his wife and father when sedative effects were
decreasing, necessitating appropriate management and psy-
chiatric consultation.89 An investigation of the relationship
between postoperative confusion and plasma norepinephrine
and cortisol response to surgery found higher rates of confu-
sion 72 hours after surgery in schizophrenic patients (28%)
Route* PO Dosage† (mg/day)
PO, IM 20-800
PO 105-800
PO, IM, SC 1-20
PO, IM 12-64
PO, IM 4-20
PO 6-60
PO, IM 1-20
PO 1-10
PO 20-250
PO 50-225
 Chapter 15  Psychiatric and Behavioral Disorders 459

TABLE 15-5  n  Atypical Neuroleptics for Nonaffective Psychoses

Structure Generic Name Proprietary Name Route* PO Dosage† (mg/day)

Benzisoxazole Risperidone Risperdal PO, IM 1-16

Dibenzodiazepine Clozapine Clozaril PO 12.5-900

Thienobenzodiazepine Olanzapine Zyprexa PO, IM 5-20

Dibenzothiazepine Quetiapine Seroquel PO 50-800

Indole Ziprasidone Geodon PO, IM 40-160

*Parenteral doses (IM, intramuscular) are generally twice as potent as oral (PO) doses.
†Dosage information taken from Tarascon Pocket Pharmacopoeia.

TABLE 15-6  n  Newer FDA-Approved Atypical Neuroleptics for Nonaffective Psychoses*

Structure Generic name Proprietary name Route† Usual Dosage Range

Piperidinyl-benzisoxazole Paliperidone Invega PO 3-12 mg/day

Iloperidone Invega Sustenna IM 39-234 mg/mo
Fanapt PO 2-24 mg/day

Dibenzo-oxepino pyrroles Asenapine Saphris SL 10-20 mg/day

Piperidinyl-benzoisothiazole Latuda Lurasidone PO 40-120 mg/day

*Pertinent side effects of these medications: Acute and late-onset (tardive) extrapyramidal side effects, agranulocytosis, anticholinergic effects, disturbances
of cardiac rhythm, dry mouth, dysregulation of temperature, hypersalivation, orthostatic hypotension, sedation, seizures, thromboembolism, tremors, withdrawal
symptoms.
†PO, Oral; IM, intramuscular; SL, sublingual.

than in controls (6%).40 The researchers concluded that the
occurrence of confusion in patients with schizophrenia was
associated with an increase in plasma norepinephrine and cor-
tisol levels during and after surgery.
The increase in abnormal behaviors, including threats
of violence and confusion postoperatively, is a concern to
anesthesiologists and surgeons.90 Chronic administration
of antipsychotics is associated with other anomalies, such as
alterations in autonomic functioning and pituitary-adrenal
activity after surgery, as well as abnormal secretion of vaso-
pressin (ADH), aldosterone, and atrial natriuretic peptide
during anesthesia.91,92 Such difficulties result from the multi-
ple potential adverse effects of the antipsychotic agents, such
as behavioral toxicity, motor aberrations, cardiovascular and
autonomic nervous system (ANS) effects, and hepatotoxic-
ity. Disturbances in ANS function, ECG abnormalities, and
onset of diseases such as diabetes also occur in association
with long-term use of antipsychotics. Beyond the effects of
the antipsychotics themselves, drug-drug interactions occur
between certain psychotropics and anesthetics (Table 15-7).6
Additionally, a dose-response relationship exists between the
number of physical problems and the risk of self-harm, neces-
sitating physicians to consider suicidal ideation in patients
with physical illnesses complicated by schizophrenia, depres-
sion, or another mental disorder.93
The method of action of all antipsychotics is direct interfer-
ence with the centrally located dopaminergic neurotransmitter
system. Furthermore, these drugs stimulate the parasympathetic
nervous system and block the effects of a­ lpha-adrenergic stimu-
lation of the sympathetic nervous system (SNS). This implies
the possibility for cardiovascular side effects, including hypo-
tension, tachycardia, prolongation of the QT interval on the
ECG, and, although rare, ventricular fibrillation and torsades de
pointes. Because of the functional hypovolemia induced dur-
ing general or regional anesthesia, or the blood loss and fluid
shifts for acutely injured and septic patients, respectively, these
concerns become heightened intraoperatively. Again, most anti-
psychotics are metabolized by the CYP2D6 isoenzyme. Several
of the newer drugs are metabolized by several CYP450 isoen-
zymes concurrently (e.g., 1A2 and 3A4).
The incidence of extrapyramidal side effects is higher with
older, more potent agents such as haloperidol. With the advent
of clozapine, the incidence of these side effects has greatly
decreased. However, these still occur and can be life threaten-
ing. One such reaction seen rarely is laryngospasm, requiring
treatment with an anticholinergic medication or diphenhy­
dramine. More frequently seen are acute dystonic reactions
such as oculogyric crisis, torticollis, or tremor. A more serious
dystonic reaction is tardive dyskinesia, characterized by invol-
untary choreoathetoid movements of the neck and face. Once
begun, these movements may never resolve, even with with-
drawal of the medication responsible. Almost every neurolep-
tic medication may cause tardive dyskinesia, with clozapine
posing the least risk.
 460 ANESTHESIA AND UNCOMMON DISEASES
TABLE 15-7  n  Interactions between Psychotropic Medications and Anesthetic Agents
Psychotropic Class/Drug Anesthetic Agent
Tricyclic antidepressants (TCAs) Halothane and pancuronium
Anticholinergics
Sympathomimetics
Monoamine oxidase inhibitors (MAOIs) Meperidine
Sympathomimetics
Phenothiazines Enflurane, isoflurane
Lithium Barbiturates
Nondepolarizing relaxants
Depolarizing relaxants
Donepezil Depolarizing relaxants
Modified from Derrer SA, Helfaer MA: Evaluation of the psychiatric patient. In Rogers MC, Tinker JH, Covino BG, Longnecker DE, editors: Principles and practice of
anesthesiology, St Louis, 1993, Mosby, pp 567-574.
Intraoperative management involves hemodynamic con-
trol, thermoregulation, and prevention of postoperative con-
fusion. From 5% to 20% of chronic schizophrenic patients
experienced profound hypotension during and after induction
of anesthesia, particularly those taking chlorpromazine.89,94
Antipsychotics inhibit autonomic thermoregulation. One
study showed that schizophrenic patients receiving chronic
antipsychotic therapy had lower intraoperative core temper-
atures than controls, which could affect postoperative mor-
bidity and mortality rates for these patients.95 Kramer et al.96
reported 54 deaths associated with hypothermia in patients
taking antipsychotics. Ketamine was avoided in these patients
for years because of its association with prolonged hallucina-
tions or delirium after surgery; however, the incidence of post-
operative confusion decreased in the group receiving total IV
propofol, ketamine, and fentanyl (30%) compared with the
groups anesthetized with sevoflurane (54%).97
NEUROLEPTIC MALIGNANT SYNDROME
Perhaps the most feared complication of treatment with anti-
psychotics is neuroleptic malignant syndrome (NMS).98 NMS
is very similar to malignant hypothermia (MH) and may share
a similar etiologic mechanism. This syndrome most often
occurs within the first several weeks of treatment with, or a
significant dosage increase of, antipsychotics. NMS manifests
as increased body temperature, skeletal muscle rigidity, and
SNS instability (BP fluctuations, diaphoresis, tachydysrhyth-
mias). Often, liver function tests are abnormal, although the
mechanism is uncertain. Because of the severe muscle rigidity,
creatinine kinase (CK) levels may be elevated and the kidneys
damaged by myoglobinuria. If these concerns become signifi-
cant, muscle relaxation with a nondepolarizing neuromuscu-
lar blocker and subsequent mechanical ventilation of the lungs
may become necessary. Treatment of NMS requires withdrawal
of the offending agent and initiation of bromocriptine or dan-
trolene therapy. Of these two therapies, dantrolene is preferred
by some practitioners because of bromocriptine potentially
Interaction
Tachydysrhythmias
Exaggerated anticholinergic responses
Hypertension
Hypertension, seizures, hyperpyrexia
Hypertension
Hypotension
Prolonged somnolence
Prolonged blockade
Prolonged blockade
Prolonged blockade
precipitating hypotension. ECT may also have a therapeutic
effect on these patients as well. Additional treatments are sup-
portive and include antipyretics, IV hydration, and dialysis, in
addition to the measures just described. Mortality in untreated
patients can be as high as 20%. If the patient survives, further
treatment with antipsychotics is usually not suggested because
of possible recurrence. In these patients, alternative therapies
(e.g., lithium, ECT) are advocated.
Anesthesia personnel must be aware of the similarity of
NMS to MH and especially vigilant when providing care to
patients with a documented history of NMS because of their
potential predisposition to MH development. Despite this
unproven possibility, administration of succinylcholine to
patients receiving ECT for NMS is safe.99 Although evidence
is lacking to support NMS and MH having a similar molecu-
lar mechanism, caution is advised when administering general
anesthesia to patients with NMS and more broadly to patients
receiving neuroleptics.
Delusional Disorder
Other psychotic disorders include schizophreniform and
schizoaffective disorders, both sharing features with schizo-
phrenia and depression, psychotic disorders directly resulting
from a general medical condition, and the unusual delusional
disorder. The notion of delusion is plagued by conceptual con-
fusion, but DSM-IV calls attention to a condition character-
ized by the presence of one or more nonbizarre delusions that
persist for at least 1 month, but not in the context of a history of
schizophrenia.12 Apart from the direct impact of the delusions,
psychosocial functioning is not greatly impaired, and behav-
ior may not be seen as odd or bizarre. Delusional disorder is
often marked by erotomanic, grandiose, jealous, persecutory,
and somatic themes.99 Thus, patients may maintain unusual
beliefs about romantic love or idealized spiritual union or
hold a view of themselves as having great but unrecognized
talents or insights. Persecutory delusions may be found, with
 Chapter 15  Psychiatric and Behavioral Disorders 461
the central delusional theme involving beliefs that one is being
cheated, conspired against, or surveilled.
Although uncommon in clinical settings, delusional dis-
orders may appear unexpectedly to anesthesiologists or
­surgeons, particularly in adult patients in midlife to late life.
The pain and anxiety of surgery may unmask underlying
psychiatric disorders perioperatively.100 Evaluation of delu-
sions is d­ ifficult, especially in the absence of marked psy-
chopathology; clinicians must consider associations with
affective disorders, schizophrenia, and organic brain disor-
ders (e.g., epilepsy) and a range of other disorders. Reported
cases of somatic delusions include patients with temporal
lobe ­ epilepsy, narcolepsy, Huntington's chorea, cerebral
malaria, multiple sclerosis, encephalitis, chronic liver disease,
pellagra, and thyroid disorders.99
SUBSTANCE-RELATED DISORDERS
The substance-related disorders in DSM-IV include side effects
of medications, toxin exposure, and use and abuse of prescrip-
tion and illicit drugs, as well as alcohol.12 The substances are
classified in 11 categories: alcohol, amphetamine or similarly
acting sympathomimetics, caffeine, cannabis, cocaine, hallu-
cinogens, inhalants, nicotine, opioids, phencyclidine or sim-
ilarly acting arylcyclohexylamines, and sedatives, hypnotics,
or anxiolytics. Use of substances may be seen as “abuse” or
“dependence” based on behavioral and psychological patterns,
and assessment of features of both tolerance and dependence
are critical in defining abuse and dependence.
The evaluation of patients for anesthesia may uncover
problems resulting from substance intoxication or recent
ingestion of (or exposure to) a substance. The first national
prevalence estimates of DSM-IV alcohol use disorders among
2040 inpatient admissions to 90 acute care, nonfederal U.S.
general hospitals12 found an estimated 1.8 million annual
admissions met criteria for current alcohol use disorder,
with an overall prevalence of 7.4%.100 Moreover, among current-­
drinking admissions, estimated prevalence was 24%.101
Although alcohol is one substance patients might ingest
over time, possibly concomitant with hospital admission or
TABLE 15-8  n  Lifetime Occurrence of Psychiatric Disorders with Alcohol Dependence
MEN
Disorder % OR
Anxiety 35.8 2.2
Mood disorder 28.1 3.2
Drug dependence 29.5 9.8
Antisocial personality disorder 16.9 8.3
Modified from Kessler RC, Crum RM, Warner LA, et al: Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the
National Comorbidity Survey, Arch Gen Psychiatry 54:313-321, 1997.
OR, Odds ratio.
preoperative evaluation, the potential complications to health
and medical treatment associated with alcohol effects are
enormous. Patients identified with chronic alcohol use may
have multisystem organ damage, so meticulous preoperative
evaluation is warranted.102
Often faced with patients who abuse substances of extreme
variety, primary health care providers need to detect mani-
fest mental problems when patients present for anesthesia
and surgery, as well as covert substance use patterns that may
impact response to anesthetics and procedures. The perioper-
ative period may be an opportunity to intervene and educate
patients on the possible benefits of perioperative and long-term
cessation and the harm caused by continuing their substance
abuse.103,104 Comprehensive anesthesia screening procedures
are necessary to uncover patterns of alcohol use and abuse,
as well as use of other drugs, many illegal and glossed over
by patients. A recent study shows that illicit substance use by
patients presenting for preoperative evaluation is underes-
timated by anesthesiologists and identified more accurately
by a computer-based self-assessment inventory.105 Wu et al.106
reported that 2% of adults responding to the 1997 National
Household Survey on Drug Abuse reported using services for
alcohol or drug problems in the previous year. One approach
is application of the Alcohol Use Disorders Identification Test
(AUDIT) for anesthesia screening. This 10-item measure
was developed from a six-country collaborative project as a
screening instrument for hazardous and harmful alcohol con-
sumption and provides a simple method of detection for anes-
thesia screening.107
Alcohol dependence and psychiatric disorders coexist in
a relatively high percentage of the American population. It
is estimated that slightly more than 50% of individuals who
experience alcohol, drug, or mental health disorders will
have two or more psychiatric disorders over their lifetime.
A particularly high prevalence of morbidity is concentrated in
about one sixth of the population with three or more comor-
bid lifetime disorders (Table 15-8). In particular, female psy-
chiatric patients have higher comorbidity rates with alcohol
dependence.108 This comorbidity of mental disorders and alco-
hol dependence further complicates anesthetic management
WOMEN
% OR
60.7 3.1
53.5 4.4
34.7 15.8
7.8 17
 462 ANESTHESIA AND UNCOMMON DISEASES
if these patients need surgery. History of alcohol abuse or
dependence may be found in surgical emergency and trauma
patients with psychiatric disorders, because both alcohol and
mental disorders play important roles in traumatic injuries
(e.g., motor vehicle crashes, falls, fighting, hunting accidents)
and self-inflicted injuries (e.g., gunshot wounds).
Alcohol is also a major risk factor for many diseases that
result in the need for surgery or surgical evaluation (e.g., gas-
trointestinal cancers, peptic ulcers, cirrhosis, pancreatitis).
However, a genuine alcohol use/abuse history is often difficult
to obtain from acute trauma patients because of injury (which
may include traumatic brain injury), shock, subsequent endo-
tracheal intubation, and paralysis, as well as from patients with
other surgical emergencies. Available family members should
be asked about the patient's alcohol use. A high index of sus-
picion is often required. Acute intoxication can be detected
by breath alcohol test or blood alcohol level. Chronic abuse
of alcohol is suggested by the complications of alcoholism
(e.g., gastritis, pancreatitis, frequent prior accidents) and cer-
tain routine laboratory results (e.g., increased red blood cells
indicating corpuscular volume or liver enzymes, especially
γ-glutamyltransferase), as well as possible liver dysfunction.
Chronic alcohol intake may increase the requirement
of anesthetic agents, but acute alcohol intoxication usually
requires less anesthetic medication. The effects of anesthet-
ics on alcoholic patients depend on the amount of alcohol
ingested, relative affinity of the anesthetic for particular hepatic
microsomal enzymes, and severity of any underlying liver dis-
ease.109 Alcoholic patients usually need more analgesics in the
postoperative period, and have more tolerance to opioids.
Alcohol-dependent patients are more likely to leave the hos-
pital prematurely against medical advice and are less likely to
adhere to postdischarge instructions, medication, and follow-
up visits.
Development of an alcohol withdrawal syndrome in the
preoperative period may change an expectedly benign surgi-
cal course into a life-threatening one, with seizures, aspiration,
delirium, and cardiovascular collapse. Alcohol withdrawal is
caused by the sudden rebound of the γ-aminobutyric acid
(GABA) system. Because chronic use of alcohol suppresses
the neurotransmitter GABA, the absence of alcohol postop-
eratively will cause unopposed sudden rebound of the GABA
system. In addition, alcohol misuse is associated with nutri-
tional deficiencies, cardiomyopathy, neuropathy, greater infec-
tion risk, impaired healing, and higher risk for bleeding (due
to coagulopathy from liver disease and platelet dysfunction).
For elective surgery, prevention of alcohol withdrawal can
be achieved by tapering the alcohol use for a certain period.
Appropriate management of alcohol withdrawal is critical
in preventing mortalities. Alcohol infusion has been used to
treat withdrawal but is losing popularity. Benzodiazepines,
antipsychotics (haloperidol), anticonvulsants (carbamaze-
pine), baclofen, barbiturates, clonidine, trazodone, multivi-
tamins, and magnesium have all been used to treat alcohol
withdrawal. Not surprisingly, with all these potential adverse
effects, alcohol abuse is associated with higher surgical mor-
bidity and mortality. However, other reports conclude no sig-
nificant differences exist in surgical outcome in patients with
excessive alcohol intake.110
Comprehensive but efficient screening is clearly needed for
all possible drugs of use and abuse that may impact response
to anesthesia and surgery. Identification of addiction and
issues in pain management are critical to the safe and effec-
tive clinical management of anesthesia in surgical situations,
as well as pain management more generally.
COGNITIVE DISORDERS
Delirium after Surgery
Delirium is a disturbance of consciousness accompanied by
changes in cognition of multiple causes. The disturbance
develops over the course of the day and may fluctuate during
the day and over time. Awareness of the environment, abil-
ity to reason, and clarity of expression and thought are com-
promised. Disorientation, memory impairment, rambling
speech, and perceptual distortions can occur. Although the
broad range and type of disorders leading to delirium states
are beyond the scope of this chapter, postoperative delirium is
a major problem in many surgical patients, particularly elderly
patients or those with multiple illnesses or debilitation.
An acute disorder of attention and cognition, delirium after
surgery may be found in 28% to 50% of patients undergoing hip
fracture repair. Zahriya et al.111 reported that an inability to mount
a stress response or lack of increase in WBC count and abnormal
serum sodium levels were risk factors for occurrence of postop-
erative delirium in elderly hip fracture patients. Other risk fac-
tors for postoperative delirium include older age, alcohol abuse,
pre-existing cognitive dysfunction (particularly dementia), sleep
deprivation, malnutrition (particularly hypoalbuminemia), dura-
tion of anesthesia use, type of anesthesia, certain medications
(e.g., sedatives, anticholinergics), second operation, pain, and
hypoxia.14,112 Perioperative pain management with multimodal
analgesia and regional anesthesia may reduce the incidence of
postoperative delirium in elderly patients.113 Preoperative use
of statins for patients undergoing cardiac surgery significantly
reduces the rate of early postoperative delirium.114
Clarifying the diagnosis of postoperative delirium in patients,
especially those with a psychiatric history, can be a daunting task.
Postoperative delirium (excluding emergence from anesthesia)
appears to be most frequently on day 3 and typically resolves
within a week. Delirium is often not diagnosed, or medical staff
may misdiagnose delirium as a psychiatric disorder (hypoactive
delirium as depression; hyperactive delirium as schizophrenia
or personality disorder). Other conditions associated with acute
confusional states and altered mental states include dementia,
alcoholism, severe medical illness, vision or hearing impair-
ments, advanced age, institutionalization, and depression.111,115
Treatment of postoperative delirium follows the same principles
as for other deliria14 (Fig. 15-1).
 Chapter 15  Psychiatric and Behavioral Disorders 463

Unresponsive postoperative patient

Clinical evaluation
ABGs
Chart review
Glucose
All drugs received
Serum electrolytes, Ca, Mg
Anesthetics
History of seizures, Serum ethanol (ethanol)
diabetes toxicology screen
Renal, hepatic disease Liver function tests
Vital signs, temperature BUN, creatinine
Neurologic examination Thyroid function tests
Lateralizing signs EEG

Assess ventilation; support if needed

Assess cause of DE

Drug effects Metabolic disorders Neurologic disorders

Narcotics Hypoglycemia Cerebral ischemia

Sedatives
Cerebral hemorrhage
Glucose
Naloxone Cerebral embolism
Nalbuphine
Electrolytes After hypoxemia
Physostigmine
NA
Muscle relaxants Ca Intracranial lesions
Mg
Hypothermia
Reverse; support Neurologic or
ventilation neurosurgical consultation
Hypoxia
Central anticholinergic Seizure disorder
syndrome (atropine, Hypercarbia
scopolamine)
Acidosis Anticonvulsants;
treat underlying problem
Physostigmine Hypothyroidism or
hyperthyroidism
Inhalation anesthetics
Liver disease, hepatic
encephalopathy
Support ventilation
Kidney disease
Neurally applied opiates
Adrenal function decreased

Naloxone Sepsis Cultures

Surgical consultations
Alcohol, other
substance abuse
Hyperosmolar nonketotic coma
Assess serum ethanol
level Malignant hyperthermia
Toxicology screen

Other drugs
FIGURE 15-1  Approach to the patient with delayed emergence (DE). ABGs, Arterial blood gases; BUN, blood urea nitrogen; EEG,
electroencephalogram. (Data from Bready LL: Delayed emergence. In Bready LL, Smith RB, editors: Decision making in anesthesiology, ed 2,
St Louis, 1992, Mosby, pp 364-365.)
 464 ANESTHESIA AND UNCOMMON DISEASES

Dementia dementia. For example, neuropsychological assessment may

reveal evidence of weaknesses in executive functions, work-
The DSM-IV defines dementia as characterized by mul-
ing memory, and semantic processing associated with head
tiple cognitive deficits that include memory impairment.12
trauma or other CNS insult. Patients with cognitive disorders
Classification is often determined by presumed etiology, such
require identification and special attention in preoperative
as dementia of the Alzheimer's type, vascular dementia, and
and postoperative conditions, because cognitive deficits place
dementia from other general medical conditions (e.g., head
them at risk for confusion, behavioral agitation, depression,
trauma, Parkinson's disease, Huntington's disease). Other
and other problems before and after surgery or after adminis-
symptoms of dementia include aphasia, apraxia, agnosia, and
tration of anesthetics. These patients may also be more vulner-
“executive function” disturbances or deficit. Problems with
able to anesthetic damage or drug interaction.
judgment and insight are common, and patients with dementia
Clinicians and researchers have observed that anesthe-
may exhibit little or no awareness of memory loss or cognitive
sia may provoke persistent alterations in cognitive perfor-
deficits. Motor disturbances leading to falls, neglect of personal
mances in individuals at risk, including those with multiple
hygiene, misplaced possessions, disinhibited behavior, and
illnesses, elderly patients, and dementia patients who have
disregard of societal conventions may be observed. Because
neuronal changes that may exacerbate pharmacotoxic effects.
physical and mental stressors may exacerbate symptomatol-
Anesthesiologists need to recognize that acute and interme-
ogy, diagnosis of medical illness and receiving medical, surgi-
diate psychiatric problems may be associated with surgery
cal, and anesthesia treatments can be particularly stressful and
or hospitalization. For example, patients may experience
disorganizing. Community studies reveal a 1-year prospective
delirium with psychotic elements as a result of the surgical
prevalence of almost 3% with severe cognitive impairment, and
or medical condition or experience anxiety as a result of the
an estimated 2% to 4% of American adults older than 65 have
imminent surgery. Another source of preoperative stress is
Alzheimer's disease, which increases with age.12
“intensive care unit psychosis.” The ICU setting may be linked
Medical care of patients with limited and declining cogni-
to delirium in perioperative or extremely ill patients because
tive resources and adaptability caused by ongoing dementia
of decreased sleep, increased arousal, social isolation, and
is complicated by patient difficulties in expression, language,
mechanical ventilation.119
and memory, from being unable to describe past and pres-
An assessment of 140 patients older than 64 who completed
ent illnesses to complete inability to communicate, or mut-
cognitive tests before and at 9 days and 3 months after surgery
ism. Physicians must rely on reports of significant others
found a decline in performance 9 days postoperatively in 5.8%
and f­amily members to provide information pertinent to
to 70.3%, depending on the cognitive domain explored.120 Also
physical status or the basic data of the history and physical
after 9 days, 29% of patients showed no significant alteration
examination. Patients with dementia may become irritable,
on any test score, and 44% showed no deficit after 3 months.
behaviorally agitated, and difficult to manage before surgical
Type of anesthesia was the most significant determinant of
procedures, and delirium and postoperative confusion may
decline in verbal fluency, semantic prompt, visuospatial analy-
impede ­recovery. Patients in the early stages of dementia may
sis, and implicit memory scores. Researchers concluded that
be taking antidementia medications such as donepezil. Clinical
anesthesia and orthopedic surgery are related to long-term
anesthesiologists should be aware that donepezil is a cholines-
(3-month) postoperative decline in elderly patients, with sec-
terase inhibitor and may exacerbate succinylcholine-induced
ondary and implicit memory and visuospatial and linguistic
muscle relaxation. Cholinesterase inhibitors may have vago-
tasks most frequently impacted. High-risk factors included age
tonic effects and cholinomimetic effects116,117 (see Table 15-7).
older than 75, less education, high levels of depressive symp-
This complex presentation requires additional effort to work
toms, and recent history of cognitive impairment. Although
toward safe and effective delivery of anesthetic agents.
not evaluated, the stress of surgery and effects of pain may
In the treatment of Alzheimer's disease, memantine, a non-
influence cognitive decline.
competitive N-methyl-d-aspartate (NMDA) receptor antag-
Other research has showed cognitive decline after major
onist, represents a novel pharmacologic approach and has
noncardiac surgery, with impairment most notable immedi-
shown promising results.118 A randomized, double-blind, pla-
ately after surgery but sometimes persisting. In 29 patients
cebo-controlled clinical trial of 404 patients with moderate to
undergoing thoracic and vascular procedures who were
severe Alzheimer's disease receiving donepezil showed signifi-
assessed preoperatively and at 6 to 12 weeks postoperatively,
cant improvement in cognition, activities of daily living, global
Grichnik et al.121 found that 44.8% had cognitive deficits, with
outcome, and behavior after memantine administration. Drugs
severity of decline averaging 15%.
such as tramiprosate (Alzhemed), currently in Phase 3 trials,
Historically, cognitive decline is most notable in cardiac
may provide further defense against Alzheimer's disease.
surgery patients. In 127 patients undergoing coronary artery
bypass graft (CABG) evaluated preoperatively and at 1 month
Other Cognitive Disorders
and 1 year across several cognitive domains, less than one-
Mild to moderate cognitive impairments can result from head third showed significant cognitive change at 1 year compared
injury, specific medical conditions, and CNS dysfunction, but with baseline performance.122 Change was associated with both
these deficits may not be sufficiently severe to meet criteria for medical and surgical variables, with the nonspecific effects of
 Chapter 15  Psychiatric and Behavioral Disorders 465
anesthesia and prolonged surgery interacting with the specific
effects of the procedure. Diabetes was associated with short-
term and long-term change in executive functions and psycho-
motor speed. However, postoperative cognitive decline after
cardiac surgery is controversial in more recent investigations.
Of 127 consecutive CABG patients who had neuropsychologi-
cal testing the day before surgery and 7 to 9 days after surgery,
46% showed postoperative cognitive decline; risk factors were
increasing age, asymptomatic carotid artery stenosis greater
than 50%, longer surgical duration, longer ICU stay, and lon-
ger mechanical ventilation time.123 Seines et al.124 compared
the rate of postoperative decline in patients after cardiac sur-
gery with a demographically similar nonsurgical control group.
These patients underwent a battery of neuropsychological tests
to determine baseline and were restudied 3 and 12 months
later. The prospective longitudinal neuropsychological per-
formance did not differ at 3 months or 1 year between the two
groups. The Cache County Study of Memory Health and Aging
enrolled 5092 individuals from the general population age 65 or
older. After baseline studies were obtained, these patients were
studied 3 years later and again 4 years after that. Patients who
had undergone CABG were compared to those who had not.
No linkage was found between postoperative cognitive decline
and CABG 5 years after baseline studies were obtained.125
Lidocaine infused at induction of anesthesia and contin-
ued for 48 hours may provide cerebral protection for cardiac
patients, unrelated to any effect on depression or anxiety and
at a level noticed by patients.126 Similarly, cognitive dysfunction
decreased in patients treated with lidocaine in the early post-
operative period.127 Finding protective agents against cogni-
tive decline or impairment associated with the stress of surgery
or anesthetics and their delivery is a high priority, particularly
for patients at risk because of various vulnerabilities. Although
controversy persists regarding cardiac surgery outcomes, lido-
caine may have neuroprotectant effects in focal neurologic
injury and in reducing adverse neurobehavioral outcomes.128
DISORDERS IDENTIFIED IN
DEVELOPMENTAL STAGES
Mental Retardation
Mental retardation is characterized by significantly subaverage
general intellectual functioning with limitations in adaptive
functioning, such as in communication, self-care, home living,
interpersonal skills, and self-direction. Many causes and differ-
ent levels of severity can be found, but patients are severely lim-
ited in their abilities to manage the exigencies of life. In all cases,
patients require custodial care at some level of supervision
and generally are managed by a guardian or family member.
Although many patients with mental retardation do not pose
extreme behavioral problems, preparing them for surgery and
anesthesia demands special precautions. For example, Chan
and Chilvers129 described inducing anesthesia in a combative,
intellectually impaired adult whose needs suggested that anes-
thesia induction in the home was helpful to facilitate essential
surgery. This adult, with a history of escalating violence toward
hospital personnel, was administered an anesthetic in his home
before hospital transfer for surgery, illustrating an innovative
approach to improving response to treatment. Although rarer,
autistic disorder may also be identified, marked by abnormal
and impaired development in social interaction and communi-
cation and often associated with moderate mental retardation.
Intraoperative management and perioperative complica-
tions are influenced by mental retardation in specific patient
populations. Patients receiving general anesthesia revealed
no significant difference in intraoperative bispectral index
scale (BIS) scores between groups, classified as having mild,
moderate, or severe mental retardation using APA criteria.130
However, the study did show a longer emergence to extubation
time in the more severely affected groups. In 61 infants with
and 61 infants without Down syndrome undergoing congeni-
tal heart surgery, the Down syndrome group had a higher rate
of unsuccessful peripheral venous cannulation and a lower rate
of successful peripheral arterial catheterization.131 In a study of
74,000 anesthetic inductions, patients with Down syndrome
at a tertiary children's hospital experienced a higher incidence
of bradycardia on induction, natural airway obstruction, and
postintubation croup.132
Attention-Deficit/Hyperactivity Disorder
Often diagnosed in young children and now in adults,
­attention-deficit/hyperactivity disorder (ADHD) is character-
ized by persistent patterns of inattention and/or ­hyperactivity
and impulsivity greater than might be expected, typically
appearing before age 7 years. ADHD affects an estimated 3%
to 5% of school-age children, and diagnosis requires e­ vidence
of problems in social, academic, or occupational function-
ing.12 Inattention may manifest as failing to notice details,
sustain attention, or persist with tasks to completion, and
affected children may not follow through on requests, may be
disorganized, and may avoid activities that require sustained
self-application and mental effort. Frequent shifts in conversa-
tion, not listening, and failures to listen and follow rules may
be seen. Impulsivity and hyperactivity may present as impa-
tience, difficulty delaying responses, interrupting others, being
constantly on the go, fidgeting and squirming, and avoiding
sedentary activities. Found in a variety of contexts and thought
to be familial, these behaviors are usually seen in two settings,
such as home and school. In many cases, primary care physi-
cians identify ADHD using reports of parents and teachers;
and over time there has been increased treatment of symptoms
with antidepressants and stimulants116,117 (Table 15-9).
Although ADHD is a significant health complication,
mental health disorders more generally constitute a common
cause of disability and distress in both children and adoles-
cents. One group reported that 20% of outpatients age 18 and
younger met criteria for psychiatric diagnosis in a given year,
and that psychotropic medications accounted for a substantial,
increasing fraction of outpatient costs.133 Multipsychotropic
therapy among children and adolescents in various settings
demands careful screening of minors for medications as part
 466 ANESTHESIA AND UNCOMMON DISEASES
TABLE 15-9  n Medications for Delirium, Dementia,
Other Cognitive Disorders
Drug Class Generic (Trade) Name
Attention deficit d-Amphetamine (Dexedrine, Dexedrine
disorder (ADD) Spansule, DextroStat)
medications Methylphenidate (Ritalin)
Central nervous d-Amphetamine (as above)
system (CNS) Methylxanthines (caffeine,
stimulants theobromine, theophylline)
Memory enhancers Donepezil (Aricept)
Galanthamine (Reminyl)
Physostigmine (Antilirium)
Rivastigmine (Exelon)
Tacrine (Cognex)
Herbal/natural Ginkgo biloba
remedies
Pertinent side effects of these medications: Addiction potential, bradycardia,
cardiac arrhythmias, circulatory collapse, diaphoresis, hypertension, reflex
hyperactivity, skeletal muscle paralysis, vertigo.
of anesthesia evaluation. Nutraceuticals, or herbal agents,
have shown some positive results with ADHD.134,135 A study of
anesthesia induction, emergence, and postoperative behavior
in 268 children with ADHD (ages 4-17) and a control group
found that the ADHD patients were less cooperative on induc-
tion and exhibited a higher rate of maladaptive behaviors
postoperatively (greater difficulty concentrating and making
decisions, more disobedient, more temper tantrums).136
Problem Behaviors in Late Life
Aggressive and inappropriate behaviors in older people are
associated with varied physical and psychological conditions
and added risk in those receiving medical or surgical therapy.
Behavior problems pose complex challenges for caregivers in
the home and in medical settings. Although often reported in
clinical or nursing home settings or in patients with demen-
tia, problem behaviors are increasingly described at the end of
life. A study of 6748 deceased patients found that 20% exhib-
ited problem behaviors in the last year of life, with risks being
higher for those with dementia, mental illness, alcohol abuse,
and bronchitis or emphysema.137 Violent threats and destroyed
property were identified as “relatively common,” with implica-
tions for health care providers in general and particularly sur-
geons and anesthesiologists.
CONCLUSION
Patients of all ages and with diverse mental and physical condi-
tions may present for anesthesia under many, and unexpected,
circumstances. Mental and cognitive disorders may disrupt
normal physician-patient communication and ­ complicate
medication and anesthesia decisions. Thorough periopera-
tive management is required for all patients, but special care is
needed in those with mental or physical impairment, complex
history of drug use, mental disorder symptoms, and other risk
factors for anesthesia delivery and surgical recovery. Drug-drug
interactions between anesthetics and mental disorder agents are
of great concern, and anesthesiologists must know the behav-
iors that characterize mental illness. Many surgical candidates
take p
­ sychiatric medications or drugs that possess potential neu-
robehavioral effects. With poor self-disclosure to health care
providers, anesthesiologists are required to assess each patient
thoroughly. In this regard, many psychiatric drugs can alter MAC
requirements, affect sedation levels, and influence anesthetic
techniques, such as successful delivery of regional anesthesia.
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 C H A P T E R
16
Mineral, Vitamin, and Herbal Supplements
ALAN D. KAYE, MD, PhD  n
AMIR BALUCH, MD  n
ADAM M. KAYE, PharmD, FASCP, FCPhA  n

KEY POINTS
Minerals
Calcium n With use of alternative medicines such as minerals,
Chromium v­ itamins, and herbals increasing worldwide, the medical
Magnesium community needs a more comprehensive understanding of
Iron these agents.
Selenium n Anesthesiologists need to recognize the potential for bleed-
Zinc ing, drug interactions, and end-organ damage in ­surgical
Vitamins patients taking supplements (e.g., kava linked to liver
Vitamin A ­failure; St. John's wort and meperidine causing serotoner-
Vitamin B12 gic crisis; “G” herbals causing dose-dependent anticoagu-
Vitamin C lant effects).
Vitamin D n Although beneficial for some patients, these compounds
Vitamin E may alter normal physiologic functions in others, with
Folate potentially deleterious consequences.
Herbals n In our survey, approximately one in three surgical patients
Saw Palmetto was taking some form of herbal supplement, although 70%
St. John's Wort did not admit to its use during routine questioning.
Echinacea n Patient education on supplement-supplement and drug-
Feverfew supplement interactions should be part of anesthesia
Ephedra preoperative assessment. Any patient uncertain about
­
Ginger some herbal should bring the container for the anesthesi-
Garlic ologist to review.
Ginkgo biloba n All herbals should be discontinued 2 to 3 weeks before
Kava ­elective surgery (half-life usually unknown).
Ginseng n Lax regulations in some countries result in poorly
Cloves ­categorized and standardized preparations with a high risk
Black Pepper of adverse effects when used by an uninformed or misin-
Capsicum annuum formed public. Over the decades, hundreds of deaths have
White Willow Bark been linked to these agents, specifically the herbals.
Devil's Claw n Given that the FDA considers herbals as “foods” and that
Boswellia this industry has developed into a multibillion-dollar
Conclusion ­business, the anesthesiologist needs a basic understanding
of the more than 29,000 supplements and herbals available
without prescription (OTC) in the United States.
n Less than 1% of adverse effects associated with herbals are
reported in the United States.

470
 Chapter 16  Mineral, Vitamin, and Herbal Supplements 471
n In general, whether the patient is taking minerals, ­vitamins,
or herbals, an open line of communication should exist
between anesthesiologist and patient, to ensure quality
treatment, secure rapport, and a properly informed and
educated general public.
The use of alternative medicines such as minerals, ­vitamins,
and herbals has increased dramatically in recent years. Reasons
include anecdotal reports on efficacy, impressive advertise-
ment, lower cost of products than prescription medications,
and easy access to the supplements. Regardless of the reasons,
it is important that all physicians, particularly the anesthesiol-
ogist, recognize the effects of these agents, whether b ­ eneficial
or harmful. The clinician needs to obtain a good history before
anesthesia induction in a patient taking ­ over-the-counter
(OTC) supplements, especially herbals.
MINERALS
Table 16-1 lists side effects and anesthetic concerns associated
with popular OTC vitamin supplements.
TABLE 16-1  n  Mineral Supplements: Side Effects and Anesthetic Concerns
Potential Side Effects
Calcium May antagonize effects of calcium channel blockers.
May decrease levels of β-blockers.
Reports of dysrhythmias in patients taking digitalis.
Decreased levels of certain antibiotics, levothyroxine,
and bisphosphonates.
Chromium Generally well tolerated; possible mild nervous
system symptoms.
Rare case of anemia, thrombocytopenia, and
hemolysis.
Magnesium May potentiate effects of muscle relaxants and oral
hypoglycemic.
May interfere with antibiotic absorption, ACE
inhibitors, and H2 blockers.
Iron High concentrations may worsen neuronal injury
secondary to cerebral ischemia and cause
preterm labor
Inhibits absorption of certain drugs
Selenium Halitosis, hair and fingernail loss, GI upset, CNS
changes
Zinc Toxicity may lead to anemia, neutropenia, cardiac
abnormalities, acute pancreatitis; may also
interfere with absorption of tetracyclines,
quinolones, penicillamines
ACE, Angiotensin-converting enzyme; H2, histamine-2; GI, gastrointestinal; CNS, central nervous system.
Calcium
It may be reasonable for patients to supplement their diet with
calcium, because calcium supplementation has been shown
to promote bone health and may be lacking in certain diets.1
Many women supplement with calcium to improve symptoms
associated with premenstrual syndrome and premature bone
breakdown.2
However, calcium may interfere with a host of common
drugs. The anesthesiologist must be aware of patients with
cardiac problems who may be taking calcium channel block-
ers or beta-adrenergic blockers. The effects of calcium channel
blockers may be affected by calcium supplementation; c­ alcium
has been shown to antagonize the effects of verapamil.3 In
fact, calcium has recently been used in the successful man-
agement of calcium channel blocker overdose.4 Calcium
supplementation may also decrease levels of β-blockers,
­
­leading to a greater chronotropic and inotropic presentation
than would be expected.5
Thiazide diuretics increase serum calcium concentrations,
possibly leading to hypercalcemia as a result of increased reab-
sorption of calcium in the kidneys. Dysrhythmias may occur
Anesthetic/Analgesic Considerations
Careful use of calcium channel blockers and β-blockers
intraoperatively.
Tetracyclines, quinolones, bisphosphonates, and l-thyroxine
should not be taken within 2 hours of calcium intake.
In rare cases, chromium may lead to toxicity. causing mild
neural or humoral symptoms.
May need to attenuate doses of muscle relaxants
intraoperatively.
Use caution with oral hypoglycemics; check blood sugar
levels in diabetics.
Use caution with ACE inhibitors, H2 blockers, tetracyclines,
quinolones, nitrofurantoins, and penicillamines.
Avoid magnesium supplementation within 2 hours of
administering other medications.
Avoid in patients with risk of stroke.
Be aware of preterm labor and higher chances of transfusion
in patients taking iron supplements.
May see decreased blood levels of methyldopa,
penicillamines, thyroid hormones, ACE inhibitors,
quinolones, and tetracyclines.
Few interactions with other pharmacologic agents
Avoid ingestion within 2 hours of antibiotic administration.
 472 ANESTHESIA AND UNCOMMON DISEASES
in patients taking digitalis and calcium together. The antibi-
otic effect of tetracyclines and quinolone and pharmacologic
blood levels of bisphosphonates and levothyroxine may be
decreased with calcium supplementation; these medications
should not be taken within 2 hours of calcium intake.6,7
Calcium supplementation may also affect the choice of
anesthesia used in surgical procedures. Recent data suggest
that propofol may have a protective effect on erythrocytes in
patients with elevated calcium levels.8 Documenting the use of
calcium by patients preoperatively may prevent many of these
drug interactions.
Chromium
Chromium is an essential nutrient involved in metabolism of
carbohydrates and lipids. Recently, chromium has received
attention from consumers in the belief that it may improve
glucose tolerance in diabetics, reduce body fat, and reduce
atherosclerotic formation. These purported effects stem from
chromium's effect on insulin resistance. However, the evi-
dence regarding use of chromium for insulin resistance and
mildly impaired glucose tolerance is inconclusive.9–12
A double-blind trial with 180 patients concluded that high
doses of chromium supplementation (1000 mg) may have
beneficial effects on hemoglobin A1c, insulin, cholesterol,
and overall glucose control in type 2 diabetic patients.13 The
­practitioner should consider asking all diabetic patients if they
­supplement with chromium. Because of chromium's effects on
insulin resistance and impaired glucose control, some patients
will supplement with this mineral to reduce risk of cardiovas-
cular disease. Human studies have shown decreased total cho-
lesterol and triglyceride levels in elderly patients taking 200 μg
of chromium twice daily.14
Chromium is generally well tolerated; however, some
patients may experience central nervous system (CNS) symp-
toms (e.g., perceptual, cognitive, and motor dysfunction) with
doses as low as 200 to 400 μg.15 In addition, toxicity has been
reported with chromium consumption. In one case, a woman
developed anemia, thrombocytopenia, hemolysis, weight
loss, and liver and renal toxicity when attempting weight
loss with 1200 to 2400 μg of chromium picolinate. These
problems resolved after discontinuation of chromium inges-
tion.16 A lower dose of only 600 μg was demonstrated to have
resulted in interstitial nephritis in another female patient17
(see Table 16-1).
Magnesium
Magnesium plays many important roles in structure, ­function,
and metabolism and is involved in numerous essential physi-
ologic reactions in the human body. Supplemental magnesium
has been used extensively by patients for cardiovascular ­disease,
diabetes, osteoporosis, asthma, and migraines, although most
individuals consume adequate levels in their diet.18 Patients
with a history of these illnesses may be supplementing with
magnesium and therefore should be questioned.
The most obvious anesthesia-related consideration in treat-
ing a patient taking magnesium involves its effect on muscle
relaxants in the operating room (OR). The mineral can poten-
tiate the effects of both depolarizing and nondepolarizing
skeletal muscle relaxants. Therefore, it may be advisable to ask
patients about their magnesium use preoperatively to avoid
potential complications in the OR.6
When caring for obstetric patients, the clinician must
be aware of the effects of magnesium sulfate in the patient
­undergoing cesarean section. Duration of action of relaxant
anesthetics may be affected even by subtherapeutic serum
magnesium levels.19 Rapid inadvertent infusion of magne-
sium can lead to hypermagnesemia, especially during an
urgent cesarean section, resulting in respiratory muscle weak-
ness and inability to extubate safely. For this patient, an inten-
sive care unit (ICU) stay and time will restore strength as the
magnesium is cleared from the patient and will ensure a good
outcome.
Magnesium may also interfere with the absorption of
antibiotics such as tetracyclines, fluoroquinolones, nitro-
furantoins, penicillamine, angiotensin-converting enzyme
(ACE) inhibitors, phenytoin, and histamine-2 (H2) block-
ers. Absorption problems can be ameliorated by not taking
doses of magnesium within 2 hours of these other medica-
tions.20–22 Current studies also support that intake of oral
magnesium favorably affects both exercise tolerance and left
ventricular (LV) function in stable patients with coronary
artery disease23 and may be useful for high-risk surgeries in
this subpopulation. Magnesium may also make oral hypogly-
cemics, s­ pecifically sulfonylureas, more effective when used
concomitantly, thus increasing the risk of hypoglycemic epi-
sodes.24 Recent s­ tudies suggest magnesium supplementation
for patients ­taking long-term proton pump inhibitors (PPIs),
with the potential for hypermagnesemic or hypomagnesemic
states for these patients.
Iron
In both developed and underdeveloped countries, iron defi-
ciency is the most common nutrient deficiency. Worldwide,
at least 700 million individuals have iron deficiency
­anemia.25 More than just a constituent of hemoglobin and
myoglobin, iron is a key component in almost every l­iving
organism and in humans is associated with hundreds of
enzymes and other protein structures. People have supple-
mented with iron for many reasons, including treating iron
deficiency anemia, a­lleviating poor cognitive function in
children, increasing athletic performance, and suppressing
restless legs syndrome (RLS).
High concentrations of iron in the blood may worsen
neuronal injury secondary to cerebral ischemia.26 Increased
iron levels during pregnancy may lead to preterm delivery
and neonatal asphyxia.27 These complications may occur
even with normal iron intake if the patient also takes vita-
min C, because high doses of vitamin C can increase iron
absorption.28
 Chapter 16  Mineral, Vitamin, and Herbal Supplements 473
Iron may inhibit absorption of many drugs, including
levodopa, methyldopa, carbidopa, penicillamine, thyroid hor-
mone, captopril, and antibiotics in the quinolone and tetracy-
cline family.29–32 Moreover, iron deficiency anemia may lead
to increased risk of blood transfusion; studies have demon-
strated the benefits of intravenous (IV) iron preoperatively
to help decrease the risk.33 Some medications may decrease
iron absorption and lead to decreased therapeutic levels.
This includes antacids, H2 receptor antagonists, PPIs, and
c­ holestyramine resin.6,7 Oral iron should not be given within
2 hours of other pharmaceuticals, to avoid alterations in drug
or mineral absorption (see Table 16-1).
Selenium
Selenium, an essential trace element, functions in a variety of
enzyme-dependent pathways, especially those using selenopro-
teins. Much of its supplemental efficacy results from its antioxi-
dant properties. Glutathione peroxidase incorporates selenium
at its active site, and as dietary selenium intake decreases, glu-
tathione levels drop.34 Patients supplement with selenium for a
variety of reasons, most notably for improvement in immune
status; elderly patients may be inclined to supplement with
selenium for this reason. Toxicity with selenium supplementa-
tion begins at intake greater than 750 μg/day and may manifest
TABLE 16-2  n  Vitamin Supplements: Potential Side Effects and Anesthetic Concerns
Potential Side Effects
Vitamin A (retinol) Increased risk of bleeding with other
anticoagulants
May cause birth defects
Vitamin B12 Clinical features of deficiency (anemia, neuropathy)
may be exaggerated with N2O use
Vitamin C May reduce anticoagulant effect of warfarin or
(ascorbic acid) heparin
May increase inotropic effect of dobutamine
May increase acetaminophen levels
Vitamin D Hypervitaminosis: nausea, vomiting, loss of
appetite, polydipsia, polyuria, muscular
weakness, joint pain
Vitamin D/calcium combination may antagonize
effect of calcium channel blockers and exacerbate
arrhythmias in patients taking digitalis
Vitamin E Platelet dysfunction; enhancement of insulin
sensitivity
Folate (folic acid) No significant side effects reported
as garliclike breath, loss of hair and fingernails, gastrointestinal
(GI) distress, or CNS changes.35,36 Few ­interactions with other
pharmacologic agents have been found.6
Zinc
Zinc deficiency was first described in 1961, associated with
“adolescent nutritional dwarfism” in the Middle East.37 Zinc
deficiency is thought to be quite common in infants, ado-
lescents, women, and elderly populations.38–41 The most
well-known use for zinc supplementation is in treatment
of the common cold, caused principally by the rhinovirus.
Patients self-medicating with zinc supplements may inadver-
tently overmedicate with zinc. Signs of zinc toxicity include
­anemia, neutropenia, cardiac abnormalities, unfavorable lipid
­profiles, impaired immune function, acute pancreatitis, and
c­ opper deficiency.42,43 Zinc supplements may interfere with
the absorption of antibiotics such as tetracyclines, fluoroqui-
nolones, and penicillamines.42 Zinc should not be ingested
within 2 hours of antibiotics7 (see Table 16-1).
VITAMINS
Table 16-2 lists side effects associated with major OTC vitamin
supplements and corresponding anesthetic concerns.
Anesthetic/Analgesic Considerations
Avoid use in patients taking anticoagulants, especially
warfarin
May have increased chance of toxicity in alcoholic patients
Avoid use of nitrous oxide if B12 deficiency is suspected
Supplementation should be limited to 1 g/day to avoid
subtherapeutic levels of anticoagulants in patients
May increase cardiac work in patients taking dobutamine
Use caution in patients taking acetaminophen for pain or
fever
Check for concomitant use of calcium, and instruct patients
not to use supplement while taking calcium channel
blockers
Caution when used in patients taking digitalis
May increase risk of bleeding, especially in patients taking
other anticoagulants
May need to lower dose of oral hypoglycemics in diabetic
patients
Check blood sugar levels preoperatively
May increase blood pressure in patients with hypertension
May decrease seizure threshold in patients taking
phenytoin
Use caution with N2O; may decrease absorption or utilization
of folate
 474 ANESTHESIA AND UNCOMMON DISEASES
Vitamin A
The term “vitamin A” refers to a large number of related
compounds, including preformed retinol (an alcohol) and
­ soluble vitamin. The symptoms of scurvy, which include
retinal (an aldehyde). Vitamin A deficiency is common in
teenagers, lower socioeconomic groups, and in developing
countries.44 Furthermore, some studies indicate that diabetic
patients are at an increased risk for deficiency.45 Vitamin A defi-
ciency may manifest as night blindness, immune deterioration,
birth defects, or decreased red blood cell (RBC) ­production.46
Purported therapeutic uses for vitamin A include diseases of
the skin, acute promyelotic leukemia, and viral infections.
Retinoids are used as pharmacologic agents to treat skin
disorders; psoriasis, acne, and rosacea have been treated
with natural or synthetic retinoids. Moreover, retinoids are
effective in treating symptoms associated with congenital
­keratinization-disorder syndromes. Therapeutic effects stem
from their antineoplastic activity.47 Patients with these illnesses
may be supplementing with vitamin A, and their dosages should
be explored. Vitamin A may increase anticoagulant effects of
warfarin,48 which could increase the risk of bleeding in these
patients. Bleeding complications may therefore be avoided by
informing the patient about this effect preoperatively.
Excess vitamin A intake during pregnancy, as well as defi-
ciency, may lead to birth defects. Pregnant woman who are not
vitamin A deficient should not consume more than 2600 IU/day
of supplemental retinol.49 Patients using isotretinoin and
­pregnant women taking valproic acid are likewise at increased
risk for vitamin A toxicity.46,50 Also, alcohol consumption
decreases the liver toxicity threshold for vitamin A, narrowing
its therapeutic window in alcoholic patients.51
Vitamin B12
Vitamin B12, the largest and most complex of all vitamins, is
unique in that it contains cobalt, a metal ion. Vitamin B12 defi-
ciency may affect almost 5% of the general adult population.52
B12 deficiency manifests as pernicious anemia. This syndrome
includes a megaloblastic anemia as well as neurologic symp-
toms. The neurologic manifestations result from degenera-
tion of the lateral and posterior spinal columns and include
symmetric paresthesias with loss of proprioception and vibra-
tory sensation, especially involving the lower extremities.46
The most documented use of vitamin B12 is in the treatment
of pernicious anemia. Many of the neurologic, cutaneous,
and thrombotic clinical manifestations have been successfully
treated with oral or intramuscular (IM) cyanocobalamin.53
The common anesthetic nitrous oxide (N2O) inhibits vita-
min B12–dependent enzymes and may produce clinical features
of deficiency, such as megaloblastic anemia and neuropathy.
Some experts believe that vitamin B12 deficiency should be
ruled out before N2O use because many elderly patients will
present to the OR with this deficiency.52,54 The colchicines as
well as metformin, phenformin, and zidovudine (AZT) may
decrease the levels of vitamin B12.55–58 H2 receptor blockers and
PPIs may decrease absorption of vitamin B12 from food, but
not absorption from dietary supplements59–61 (see Table 16-2).
Vitamin C
Ascorbic acid, also known as vitamin C, is an essential water-
bleeding and easy bruising, can be prevented with only 10 mg
of vitamin C because of its association with collagen, but it
can also be used to prevent a host of other disease p
­ rocesses.62
Numerous people supplement their diet with vitamin C
to ­prevent infection from viruses responsible for the com-
mon cold; however, research over the last 20 years conclude
that vitamin C has no significant impact on the i­ncidence of
i­ nfection.63 A few studies show that certain groups suscep-
tible to low dietary intake of vitamin C, such as marathon
­runners, may be less susceptible when supplementation is
used. Furthermore, vitamin C may decrease the duration or
severity of colds through an antihistamine effect when taken
in large doses.64
Patients taking vitamin C supplements may have a
reduced anticoagulant effect from warfarin or heparin.
Increased doses of these anticoagulants might be advised
to achieve therapeutic levels.65,66 It is recommended that
patients r­eceiving anticoagulation therapy should limit
vitamin C intake to 1 g/day. As always, the precise dosage
regimen must be monitored by the appropriate laboratory
studies. High doses of vitamin C may also interfere with
tests, such as serum bilirubin, c­ reatinine, and stool guaiac
assay; therefore it is crucial to inquire about any OTC
supplementation.6 Vitamin C may increase the i­notropic
effect of dobutamine in patients with abnormal LV func-
tion. Infusion of vitamin C into individuals with normal
heart function was shown to increase contractility of the
left ventricle.67 High doses of vitamin C may increase acet-
aminophen levels, whereas aspirin and oral contraceptives
may lower serum levels of v­ itamin C.68,69 Also, vitamin C's
antioxidant effects can improve c­ linical outcomes in criti-
cally ill patients by optimizing cellular and microcircula-
tory function.70
Vitamin D
Vitamin D deficiency does occur in elderly persons and
shows increased incidence in people that live in n ­ orthern
l­ atitudes.71,72 The main function of vitamin D is calcium
homeostasis. Patients with osteoporosis frequently have
­vitamin D deficiency.73 With increasing age, vitamin D and
calcium metabolism increase the risk of deficiency. Studies
show a clear benefit of vitamin D and calcium supplemen-
tation for older postmenopausal women. Supplementation
results in increased bone density, decreased bone turnover,
and decreased nonvertebral fractures, as well as decreases in
risk of falls and body sway.74
Hypervitaminosis D can occur with high doses; s­ ymptoms
include nausea, vomiting, loss of appetite, polydipsia, poly-
uria, itching, muscular weakness, and joint pain; severe cases
may lead to coma and death.46 To prevent the syndrome,
the U.S. Food and Nutrition Board has set an upper limit of
­supplementation at 2000 IU/day for adults.75
 Chapter 16  Mineral, Vitamin, and Herbal Supplements 475
The cardiac patient taking calcium channel blockers may
present to the OR while taking supplemental vitamin D and
calcium. The combination of vitamin D and calcium may
interfere with calcium channel blockers by antagonizing its
effect. Hypercalcemia exacerbates arrhythmias in patients tak-
ing digitalis. A state of hypercalcemia may be induced by the
concomitant use of thiazide diuretics with vitamin D, which
may lead to these complications. Conversely, a­ nticonvulsants,
cholesterol-lowering medications, and the fat ­substitute ­olestra
may decrease the absorption of vitamin D76 (see Table 16-2).
Vitamin E
Antioxidant properties define the primary function of v­ itamin
E. Dietary deficiency is quite prevalent, even in the d
­ eveloped
world; therefore supplementation is reasonable.77 The anes-
thesiologist must be aware of a patient's vitamin E supple-
mentation because it may increase the effects of anticoagulant
and antiplatelet drugs. Concomitant use of vitamin E with
these drugs may increase the risk of hemorrhage.78 Further,
­preliminary evidence suggests that type 2 diabetic patients
may have an increased risk of hypoglycemia because ­vitamin
E may enhance insulin sensitivity.79,80 Cholestyramine, colesti-
pol, isoniazid, mineral oil, orlistat, sucralfate, and the fat
substitute olestra may decrease the absorption of vitamin E,
leading to decreased levels in the serum.6
Folate
Folic acid and folate have been used interchangeably, although
the most stable form that is used by the human body is folic
acid. This water-soluble, B-complex vitamin occurs naturally
in foods and in metabolically active forms.81 Since 1998, the
fortification of cereal with folate has decreased the p ­ revalence
of folate deficiency significantly.82 Excess folate intake has
not been associated with any significant adverse effects.
Patients taking large doses of nonsteroidal anti-inflammatory
drugs (NSAIDs), such as aspirin or ibuprofen, e­xperience
­interference in folate metabolism, although regular use shows
no significant changes. Patients subject to seizures who
use ­phenytoin for therapy may report a decrease in seizure
­threshold when taking folate supplements.83 The body's abil-
ity to absorb or utilize folate may be decreased if taking N2O,
antacids, bile acid sequestrants, H2 blockers, certain anticon-
vulsants, and high-dose triamterene. Supplementation of folic
acid may also correct for megaloblastic anemia because of B12
deficiency, but the neurologic damage will not be p ­ revented.
In these patients, the clinician must be careful to pinpoint the
true cause of the anemia to prevent neurologic c­ omplications43
(see Table 16-2).
HERBALS
Table 16-3 lists side effects and anesthetic concerns associated
with herbal medications. Box 16-1 lists popular OTC herbal
supplements associated with bleeding abnormalities.
Saw Palmetto
Saw palmetto is used mainly for treatment of benign ­prostatic
hyperplasia (BPH), with free fatty acids and sterols being
the main components.84 Despite an uncertain ­mechanism, the
literature does demonstrate antagonism at the ­
­ androgen
receptor for dihydrotestosterone and 5α-reductase enzyme.84
Although prostate size and prostate-specific antigen (PSA)
level are not decreased by saw palmetto, biopsies have
demonstrated decreases in transitional-zone epithelia in
­
the prostate of men treated with this agent compared with
p
­ lacebo.84 When c­ ompared with finasteride, a 5α-reductase
inhibitor, saw ­palmetto use resulted in fewer side effects and
increased urine flow.84 However, one study reported that
more patients with prostatitis or chronic pelvic pain opted
to continue finasteride rather than saw palmetto treatment.
In patients with the studied condition, saw palmetto had no
appreciable long-term improvement and, with the exception
of voiding, patients receiving finasteride experienced signifi-
cant improvement in all other analyzed parameters.85
Adverse reactions to saw palmetto are rare, with reports of
mild GI symptoms and headaches.84 Recommended doses
of saw palmetto are not likely to alter the pharmacokinetics of
coadministered medications dependent on the cytochrome
P450 isoenzymes 2D6 or 3A4, such as dextromethorphan and
alprazolam.86 Further, there are few herbal-drug ­interactions
in the literature regarding saw palmetto, but as always, care and
responsibility should be exercised when taking this agent.84
St. John's Wort
St. John's wort (Hypericum perforatum) is used to treat anxiety,
mild to moderate depression, and sleep-related disorders.84,87
Other uses have included treatment of cancer, fibrositis, head-
ache, obsessive-compulsive disorder, and sciatica.88 Active
compounds in H. perforatum include the naphthodihydro-
dianthrones hypericin and pseudohypericin; the flavonoids
quercitrin, rutin, and hyperin; and xanthones.84,89 Extracts
of St. John's wort, such as WS 5570, are widely used to treat
mild to moderate depression.90,91 Such extracts are standard-
ized based on their hypericin content and have demonstrated
an effectiveness superior to placebo and potentially as great as
selective serotonin reuptake inhibitors (SSRIs) and low-dose
tricyclic antidepressants (TCAs).88
The exact mechanism of action of St. John's wort remains
controversial; it demonstrates irreversible inhibition of mono-
amine oxidase (MAO) in vitro, but such inhibition has yet to
be observed in-vivo.92 In the feline lung vasculature, St. John's
wort showed a vasodepressor effect mediated or modulated by
both γ-aminobutyric acid (GABA) receptor and L-type cal-
cium channel–sensitive mechanism.93 In vitro studies showed
GABA receptor inhibition by hypericum. This finding may
indicate that a GABA inhibitory mechanism is responsible
for the antidepressant effect.94 However, another theorized
pathway includes inhibition of serotonin, dopamine, and
­norepinephrine ­reuptake in the CNS, making the mechanism of
action of St. John's wort similar to traditional antidepressants.84
 476 ANESTHESIA AND UNCOMMON DISEASES

TABLE 16-3  n  Herbal Supplements: Potential Side Effects and Anesthetic Concerns

Potential Side Effects Anesthetic/Analgesic Considerations

Saw palmetto Mild GI symptoms and headache Does not appear to alter pharmacokinetics of drugs
dependent on P450, CYP2D6, or CYP3A4 enzymes

St John's wort Dry mouth, dizziness Pseudoephedrine, MAOIs, SSRIs should be avoided;
Affects cytochrome P450 enzyme may prolong anesthesia (anecdotal)
Constipation, nausea, serotonergic syndrome

Echinacea Unpleasant taste, tachyphylaxis Can potentiate barbiturate toxicity

Affects CYP450 enzyme
Hepatotoxicity

Feverfew Aphthous ulcers, GI irritability, headache Can increase risk of intraoperative hemodynamic
instability

Ephedra Hypertension, tachycardia, cardiomyopathy, Can interact with anesthetics (i.e., halothane) and
stroke, cardiac arrhythmias cause cardiac dysrhythmias, increased risk of
hypertension with oxytocin

Ginger Increases in bleeding time Can increase risk of intraoperative hemodynamic

instability

Garlic Halitosis, increases in bleeding time, Can increase risk of intraoperative hemodynamic
hypotension instability
Affects CYP450 enzyme

Ginkgo biloba Platelet dysfunction Can increase perioperative bleeding tendencies and
decrease effectiveness of intravenous barbiturates

Kava Dermopathy Can potentiate effect of barbiturates and

Affects cytochrome P450 enzyme benzodiazepines, resulting in excessive sedation
Hepatotoxicity

Ginseng Hypertension, increased bleeding time, Can increase risk of intraoperative hemodynamic
hypoglycemia, insomnia, vomiting, epistaxis instability

Cloves Topical: Tissue irritation May potentiate bleeding with coadministered

Oral: Gingival damage and irritation anticoagulants
Theoretic: Increased risk of bleeding

Black pepper Eye irritation possible. Use caution with CYP3A4-dependent drugs: propranolol,
Decreases activity of CYP4A4 enzyme theophylline, calcium channel blockers, fentanyl,
midazolam, omeprazole, ondansetron

Capsicum annuum Cough, dyspnea, nasal congestion, eye
irritation, burning, stinging, erythema
Exacerbation of ACE inhibitor cough
May increase risk of bleeding with concomitant
use of garlic, ginseng, ginkgo, or cloves
Use with caution in patients on anticoagulants as it may
increase risk of bleeding
Patients taking ACE inhibitors may have exacerbation of
cough

White willow bark Platelet dysfunction May potentiate bleeding with coadministered
anticoagulants

Devil's claw Generally well tolerated; diarrhea is most Use caution with drugs dependent on CYP450, such as
common complaint NSAIDs, warfarin, losartan
Rare cases of nausea, vomiting, abdominal pain,
headache, tinnitus, anorexia, loss of taste,
dysmenorrhea, hemodynamic instability
Inhibits CYP2C9 enzyme

Boswellia GI upset Insufficient evidence to comment on pharmacologic

Topical: May cause contact dermatitis interactions

Modified from Kaye AD, et al: J Clin Anesth 12:468–471, 2000.

GI, Gastrointestinal; MAOIs, monoamine oxidase inhibitors; SSRIs, selective serotonin reuptake inhibitors; ACE, angiotensin-converting enzyme; NSAIDs, nonsteroidal
anti-inflammatory drugs.
 Chapter 16  Mineral, Vitamin, and Herbal Supplements 477
BOX 16-1   n HERBAL DRUGS ASSOCIATED WITH
BLEEDING ABNORMALITIES
Bilberry (Vaccinium myrtillus)
Bromelain (Bromeliaceae)
Chamomile (Matricaria recutita, M. chamomilla)
Cloves (Eugenia aromatic)
Dandelion root (Taraxacum officinale)
Dong quai (Angelica sinensis)
Fenugreek (Trigonella foenum-graecum)
Feverfew (Tanacetum parthenium)
Fish oil
Flax (Linum usitatissimum; flaxseed oil)
Garlic (Allium sativum)
Ginger (Zingiber officinale)
Ginkgo (Ginkgo biloba)
Ginseng (Panax spp.)
Grape seed extract (Vitis spp.)
Horse chestnut (Aesculus hippocastanum)
Kava (Piper methysticum; kava kava)
Meadowsweet (Filipendula ulmaria)
Motherwort (Leonurus cardiaca)
Red clover (Trifolium pratense)
Tamarind (Tamarindus indica)
Turmeric (Curcuma longa)
Willow (Salix spp.)
St. John's wort is typically well tolerated.84 Side effects
include photosensitivity, restlessness, dry mouth, ­dizziness,
fatigue, constipation, and nausea84,87 (see Table  16-3).
St. John's wort induces the CYP450 system (34A), ­affecting
serum ­ levels of cyclosporine in patients after organ
transplantation, and the potential threat of serotonergic
­ ing URIs and related symptoms in pediatric patients, age 2 to
­syndrome in patients taking prescription antidepressants.84
The ­serotonergic ­syndrome is characterized by hypertonicity,
myoclonus, autonomic d ­ysfunction, hallucinosis, t­remors,
hyperthermia, and potentially death.95–97 Specifically, use
of St. John's wort is not recommended with photosensitiz-
ing drugs such as tetracyclines, antidepressants (e.g., MAO
inhibitors, SSRIs), and β-sympathomimetics (e.g., ephedra,
pseudoephedrine). Studies demonstrate that the supplement
greatly reduces the plasma concentrations of oral oxycodone,
which may be clinically significant when treating chronic pain
patients.95 Furthermore, anecdotal unpublished reports detail
meperidine–St. John's wort–induced serotonergic crisis, with
­morbidity and mortality.
Echinacea
Echinacea is part of the daisy family found throughout North
America. Of nine species of Echinacea, the medicinal prepara-
tions are derived from three: Echinacea purpurea ­(purple cone-
flower), E. pallida (pale-purple coneflower), and E. ­angustifolia
(narrow-leaved coneflower).96,98,99 Echinacea is recommended
as a prophylactic and treatment substance for upper respi-
ratory tract infections (URIs); current data are insufficient
to support prophylaxis.84 Echinacea has alkylamide and
­polysaccharide, which possess significant in vitro and in vivo
immunostimulation properties from enhanced phagocytosis
and nonspecific T-cell stimulation.100
The consumption of echinacea at the onset of ­symptoms
has been clinically shown to decrease both the severity and the
duration of the “cold” and the “flu.” Quantitative ­polymerase
chain reaction (PCR) has identified in  vivo alterations in
expression of immunomodulatory genes in response to
e­ chinacea.101 In vivo gene expression within peripheral leuko-
cytes was evaluated in six nonsmoking healthy subjects. Blood
samples were obtained at baseline and subsequent to con-
sumption of a ­commercial echinacea product. The overall gene
expression pattern between 48 hours and 12 days after taking
echinacea was consistent with an anti-inflammatory response.
The expression of interleukin-1 beta (IL-1β), intracellular
adhesion molecule, tumor necrosis factor alpha ­ (TNF-α),
and interleukin-8 was modestly depressed up through day 5, and
returned to baseline by day 12. Further, the expression of
interferon-α consistently increased through day 12, thus indi-
cating an antiviral response. Therefore, initial data yielded a
gene expression response ­pattern consistent with the ability of
echinacea to decrease both intensity and duration of cold and
flu symptoms.101
Aside from the effects of Echinacea on innate immunity, few
studies have examined the ability for enhancement of humoral
immunity. Using female Swiss mice as the model, however, one
study found support for the use of E. purpurea, as suggested by
anecdotal reports, and demonstrated p ­ otential enhancement
of humoral immune responses, in addition to innate immune
responses.102 However, it is important to note that the use of
E. purpurea, as dosed in one study, was not effective in treat-
11 years. Further, consumption of E. purpurea was associated
with an increased risk of rash.103
Echinacea is usually well tolerated, with the most com-
mon side effect being its unpleasant taste.84,104 Echinacea
use longer than 2 months may lead to tachyphylaxis.105
Anaphylaxis has also been reported with a single dose of
this herbal agent.96 Further, echinacea use has been associ-
ated with hepatotoxicity if taken with hepatotoxic agents,
including anabolic steroids, amiodarone, ketoconazole,
­
and methotrexate.106 Further, ­flavinoids from E. purpurea
can affect the hepatic CYP450 and sulfonyltransferase sys-
tems.107,108 For example, one ­investigation found that echi-
nacea decreased the oral clearance of substrates of CYP1A2
but not the oral clearance of substrates of 2C9 and 2D6 iso-
enzymes in  vivo. The herbal also selectively modulates the
activity of the CYP3A isoenzyme at both hepatic and intesti-
nal sites. The researchers therefore urged caution when echi-
nacea is combined with medications dependent on CYP3A
or 1A2 systems for elimination.109 Drug levels may become
elevated with concomitant use of Echinacea. Some drugs
metabolized by CYP3A enzyme include lovastatin, clarithro-
mycin, cyclosporine, diltiazem, estrogens, indinavir, and
­triazolam. Taking midazolam and Echinacea together seems
to increase levels of the sedative.109 Echinacea use should not
exceed 4 weeks, and it should not be used in patients with
 478 ANESTHESIA AND UNCOMMON DISEASES
systemic or autoimmune disorders, pregnant women, or
immunocompromised patients.84
The immunostimulatory effects of echinacea may antag-
onize the immunosuppressive actions of corticosteroids and
cyclosporine.110 Echinacea may also lead to inhibition of the
hepatic microsomal enzyme system; as such, its use with
drugs such as phenobarbital, phenytoin, and rifampin, which
are metabolized by these enzymes, should be avoided because
toxicity may result (see Table 16-3).
Feverfew
Feverfew is used to treat headache, fever, rheumatism, asthma,
stomach pains, and other conditions related to inflamma-
tion.111 The name is derived from the Latin febrifugia, “fever
reducer.”112 Although feverfew is often used for migraine head-
aches, the literature is inconclusive regarding its efficacy.113,114
A review of double-blind randomized controlled trials (RCTs)
of the clinical efficacy of feverfew versus placebo for migraine
prophylaxis found insufficient evidence to suggest a bene-
fit of feverfew over placebo for the prevention of migraine.115
As with most herbal compounds, analyses of feverfew-based
products have yielded significant variations in the partheno-
lide contents, believed to be the active ingredients.116 The anti-
inflammatory lactone parthenolide may support T-cell survival
by downregulating the CD95 system, a critical component of
the apoptotic, or programmed cell death, pathway of activated
T cells. Further, pathenolide may have therapeutic potential
as an antiapoptotic substance blocking the activation-induced
death of T cells.117 Feverfew also has demonstrated inhibition of
serotonin release from aggregating platelets. This mechanism
may be related to the inhibition of arachidonic acid release via
a phospholipase pathway.118–120 Also, feverfew decreases 86% to
88% of prostaglandin production without exhibiting inhibition
of the cyclo-oxygenase (COX) enzyme.121
Adverse reactions to feverfew include aphthous ulcers,
abdominal pain, nausea, and vomiting. A rebound headache
may occur with abrupt cessation of this herbal.111,112 Better
tolerance to feverfew than to conventional migraine medica-
tions has been suggested because feverfew use resulted in no
alteration in heart rate, blood pressure, body weight, or blood
chemistry as did conventional migraine drugs.111 A condition
known as “post-feverfew syndrome” can occur in long-term
users, manifesting as fatigue, anxiety, headaches, insomnia,
arthralgias, and muscle/joint stiffness.111,122
Feverfew may inhibit platelet action; therefore it is reason-
able to avoid its concomitant use in patients taking heparin,
warfarin, NSAIDs, aspirin, and vitamin E.123,124 Further, herbs
such as feverfew can interact with iron preparations, reducing
their bioavailability106 (see Table 16-3).
Ephedra
Since the U.S. Government's ban on ephedra-based products,
there has been an obvious decline in its use. However, patients
may still present for anesthesia evaluation with a history of
ephedra use or of taking related compounds, many of which are
readily available and possess potent dose-dependent increases
in heart rate and in blood pressure. Ma huang, an ephedra-
based alkaloid, is similar in structure to amphetamines and
is traditionally indicated for the treatment of various respira-
tory disorders, such as the flu, common cold, allergies, and
bronchitis. Additionally, ma huang is commonly used as an
appetite suppressant.84 Ma huang, or ephedra, acts as a sympa-
thomimetic agent and exhibits potent positive ionotropic and
chronotropic responses. In addition to its antitussive actions,
ephedra may also possess bacteriostatic properties.112 As a
cardiovascular and respiratory sympathomimetic, ­ ephedra
uses an α- or β-adrenergic sensitive pathway.125 Data using
the feline lung vascular bed indicate that ephedra-mediated
pulmonary hypertension depends on α1-adrenoreceptor–­
­
sensitive mechanisms.126
The appetite suppressant and metabolic enhancer effects of
ma huang made it a potent ingredient of various OTC weight
loss compounds. However, even before the U.S. Federal ban on
ma huang, many herbal manufacturers were already promot-
ing their ephedra-free supplements because of the numerous
reported adverse effects of ephedra.
Dangerous side effects of ma huang include systemic
hypertension, pulmonary hypertension, tachycardia, cardio-
myopathy, cardiac dysrhythmias, myocardial infarction (MI),
cerebrovascular accident (CVA, stroke), seizures, psychosis,
and death.84 Many of these complications have been attrib-
uted to a lack of standardization in formulations and their
varied potency.127 Moreover, studies show ephedra's weight
loss effect is mostly negative in the long term.128 Before the
U.S. ban on ma huang, approximately 16,000 cases of adverse
events, including 164 deaths, had been reported to the U.S.
Food and Drug Administration (FDA) since 1994.129 Further,
the Bureau of Food and Drug Safety of the Texas Department
of Health reported eight ephedra-associated fatalities dur-
ing a 21-month period (1993–1995); seven secondary to MI
or stroke.89 Many large lawsuits for ephedra-linked MI, CVA,
and pulmonary hypertension were filed in recent years. Those
at highest risk of side effects include pregnant women and
patients with hypertension, coronary vascular disease, sei-
zures, glaucoma, anxiety, or mania.84
The use of ma huang, still available over U.S. borders,
is highly relevant to the practitioner in the perioperative
period. The possibility of hypertension causing myocardial
­ischemia or stroke needs to be considered. Further, ephedra or
­similar compounds readily available OTC may interact with
­general anesthetic agents (halothane, isoflurane, ­desflurane)
or ­cardiac glycosides (digitalis) to cause cardiac dysrhyth-
mias. Patients taking ephedra for prolonged periods can also
deplete their peripheral catecholamine stores. Therefore,
under general anesthesia, these patients might experience
­profound intraoperative hypotension, which can be controlled
with a direct vasoconstrictor (e.g., phenylephrine) instead of
­ephedrine. Use of ephedra with phenelzine or other MAO
inhibitors may result in insomnia, headache, and tremulous-
ness. Concurrent use with the obstetric drug oxytocin has
 Chapter 16  Mineral, Vitamin, and Herbal Supplements 479
resulted in hypertension.130 The synthetic analog of ephedra,
ephedrine, is a sympathomimetic amine that has been used by
anesthesiologists to raise blood pressure intraoperatively for
about 85 years.
Ginger
Ginger has been used to treat nausea, vomiting, motion sick-
ness, and vertigo.87 A study of the effects of ginger found that
no subjects with vertigo taking ginger experienced nausea
after caloric stimulation of the vestibular system, in contrast
to those taking placebo.131 Ginger may be superior to dimen-
hydrinate in decreasing motion sickness.132 For vomiting
­episodes, ginger has also been effective in decreasing symp-
toms associated with hyperemesis gravidarum.133
The effect of ginger on the clotting pathway has also been
investigated. Ginger has exhibited potent inhibition of throm-
boxane synthetase, which increases bleeding time and may
cause morbidity.134 The ability of ginger constituents and
related substances to inhibit arachidonic acid–induced plate-
let activation in human whole blood has been studied as well
(see Box 16-1). The data revealed that ginger compounds and
derivatives are more potent antiplatelet agents than aspirin
under the conditions employed. [8]-Paradol, a constituent of
ginger, was identified as the most potent antiplatelet aggrega-
tion agent and COX-1 inhibitor.135 In another study, adminis-
tration of ginger resulted in decreases in blood pressure, serum
cholesterol, and serum triglycerides in diabetic rats.136 Further
investigation into these effects in diabetes is warranted.
Adverse effects of ginger include bleeding d ­ysfunction,
and its use is contraindicated in patients with ­coagulation
­abnormalities or those taking anticoagulants (NSAIDs, a­ spirin,
warfarin, heparin).87 Ginger may increase bleeding risk,
enhance barbiturate effects, and, as a result of an i­notropic
effect, interfere with cardiac medications. Large quanti-
ties of ginger may also cause cardiac arrhythmias and CNS
d ­ epression137 (see Table 16-3).
Garlic
Used prevalently, garlic is available in powdered, dried, and
fresh forms.84 Allicin, the main active ingredient in g­arlic,
contains sulfur, and crushing the clove activates the enzyme
allinase, thus facilitating the conversion of alliin to a­ llicin.96
Recommended uses for garlic have focused on treating
hypercholesterolemia, hypertension, and cardiovascular
­disease, ­targeting its hypocholesterolemic and vasodilatory
­activity.84,138–142 Garlic may lead to inhibition of the HMG-CoA
reductase and 14α-demethylase enzyme systems, ­ exerting
a lipid-reducing effect.84 Garlic may also be used for its
­antiplatelet, antioxidant, and fibrinolytic actions.140,143,144 Data
are m­ inimal to support the use of garlic for hypertension;
its depressor effects on systolic and diastolic blood pressure
appear to range from minimal to modest.84,96
Chronic oral use of garlic has been reported to augment
the endogenous antioxidants of the heart.145,146 A recent study
hypothesized that garlic-induced cardiac antioxidants may
provide protection against acute doxorubicin (Adriamycin)–
induced cardiotoxicity. Using the rat model, researchers
­discovered an increase in oxidative stress, as evidenced by a
significant increase in myocardial thiobarbituric acid reactive
substances (TBARS) and a decrease in myocardial superoxide
dismutase (SOD), catalase, and glutathione peroxidase activity
in the doxorubicin group. In the garlic-treated rats, however,
the increase in myocardial TBARS and a decrease in endog-
enous antioxidants by doxorubicin were significantly attenu-
ated. Therefore, garlic administration may help prevent this
form of drug-induced cardiotoxicity.145
Allicin has shown significant vasodepressor activity in the
pulmonary vascular bed of the rat and cat.146 Further, although
allicin has been found to lower blood pressure, ­ insulin,
and ­triglyceride levels in fructose-fed rats, it has also been
­considered important to investigate its effect on the weight of
animals.
Data indicate garlic may be an effective treatment against
methicillin-resistant Staphylococcus aureus (MRSA) infection.
The garlic extracts diallyl sulfide and diallyl disulfide showed
protective qualities against MRSA infection in mice. Such con-
clusions, coupled with further investigation, may result in the
use of such extracts in MRSA infection treatment.147
Side-effects of garlic are minimal, with odor and GI
discomfort most common.84 Induction of the CYP450
­
­system may occur, as evidenced by reduction of serum ­levels
of one medication.84 Pain prevention practitioners must be
aware that garlic may augment the effects of warfarin, hep-
arin, or ­aspirin and may result in an abnormal bleeding
time. This effect can result in increased risk of perioperative
hemorrhage or ­
­ catastrophic hematoma on interventional
pain procedures.148
Ginkgo biloba
There are many active components present in ginkgo, includ-
ing the flavonoid glycosides and terpenoids. The flavonoids
demonstrate antioxidant activity and the terpenoids, antago-
nism to platelet action.84 Ginkgo (Ginkgo biloba) has been used
to treat intermittent claudication and vertigo and to enhance
memory.89 Subjects report decreased pain in the affected
lower extremities and increased symptom-free distance in
­ambulation. In addition to inhibiting platelet-­activating ­factor,
ginkgo may also mediate nitric oxide release and decrease
inflammation.84,149–154
To evaluate the efficacy of ginkgo biloba on dementia, a
double-blind placebo-controlled RCT found that the extract
EGB761 had the potential to stabilize and modestly improve
cognitive performance and social functioning.84,155 In addition,
the improvement in cognition was comparable to the effect
of donepezil on dementia.84 This effect on cognition function
and memory may be related to activation of cholinergic neu-
rotransmitters. However, data are inconclusive regarding the
ability of this herbal to improve memory in subjects without
dementia.
 480 ANESTHESIA AND UNCOMMON DISEASES
Although the pathogenesis of acute pancreatitis is not well
understood, numerous data suggest a role for oxygen free
radicals in the progression and complications of pancreatitis.
The effects of EGB761 have shown a positive effect on acute
­pancreatitis, which may be linked to a free-radical scavenger
effect by ginkgo.156
Ginkgo is generally well tolerated in healthy adults for about
6 months.84 However, aside from the mild GI distress, the poten-
tial effect of ginkgo on antiplatelet activating factor has resulted
in G. biloba–induced spontaneous hyphema (bleeding from iris,
anterior chamber of eye), spontaneous bilateral subdural hema-
tomas, and subarachnoid hemorrhage.84,87,157–160 Therefore, use
of anticoagulants and ginkgo should be strictly monitored and
possibly avoided when patients are scheduled for surgery.84
An open-label crossover RCT was conducted on healthy
human volunteers to determine if ginkgo alters the phar-
macokinetics of digoxin. Concurrent use of oral ginkgo and
digoxin had no significant effect on digoxin in the subjects.161
Concomitant use of G. biloba with aspirin, NSAIDs, warfarin,
or heparin is not recommended because ginkgo may increase
the potential for bleeding in these patients. It is also advisable to
avoid ginkgo with anticonvulsant drugs such as carbamazepine,
phenytoin, and phenobarbital because the herbal may decrease
the effectiveness of these medications.106 Concurrent use of
ginkgo and TCAs is also not advised because of the potential to
lower the seizure threshold in these patients106 (see Table 16-3).
Kava
Kava (or kava kava), an extract of the Piper methysticum plant,
is employed for its proposed anxiolytic, antiepileptic, antide-
pressant, antipsychotic, and sedative properties.162–164 Some of
the active ingredients of kava include the lactones or pyrones,
kawain, methysticin, dihydrokawain, and dihydromethys-
ticin.165,166 Kava extracts available commercially are usually
found to c­ ontain 30% to 70% kava lactones.165 The extract WS
1490 has been shown effective in anxiety disorders as a treat-
ment alternative to benzodiazepines and TCAs, without the
problems associated with these two drug classes.166 However,
therapeutic effect may take up to 4 weeks, with treatment for 1
to 8 weeks to obtain significant improvement.165,167
Although the exact mechanism of kava kava's effects on the
CNS is largely unknown, the pyrones have demonstrated com-
petitive inhibition of the MAO-B.165 Inhibition of this enzyme
may result in the psychotropic effects related to kava use
because MAO-B is responsible for the breakdown of amines
that play a role in psychoses.168
Patients who experience hepatic adverse reactions are
known as “poor metabolizers.” Typically, these patients
have a deficiency in the CYP2D6 isozyme.165 Therefore, it is
­recommended that patients who use kava receive routine liver
function tests to monitor for hepatotoxicity.165 Furthermore,
24 cases of hepatotoxicity after use of kava kava were
­documented as of 2002, and death or liver transplant occurred
after 1 to 3 months of use in some patients.165 In countries such
as Germany and Australia, kava kava use longer than 3 months
is not recommended.167 Other side effects of kava use include
visual changes, a pellagra-like syndrome with characteristic
ichthyosiform dermopathy, and hallucinations.165,169,170
Kava may react adversely with the benzodiazepine alpra-
zolam, other CNS depressants, statins, alcohol, and levodopa,
resulting in excessive sedation and other side effects. Therefore
the supplement should be avoided in patients with endoge-
nous depression.165,171–173 Kava may also affect platelets in an
antithrombotic manner by inhibiting COX and thus attenu-
ating thromboxane production.165 Pain relief mechanisms
­utilized by kava may be similar to local anesthetic responses
and might depend on a nonopiate-sensitive pathway.174,175
Ginseng
There are three main groups of ginseng that are classified
based on their geographic origin.84 These are Asian ginseng,
American ginseng, and Siberian ginseng, with the pharmaco-
logically active ingredient in ginseng being ginsenosides.84,89,112
Asian and American ginsengs have been used to increase resis-
tance to environmental stress, promote diuresis, stimulate the
immune system, and aid digestion.176,177 Further, while Asian
ginseng has shown promise in improving cognition when
combined with the herbal agent ginkgo, American ginseng has
been studied for its potential to stimulate human TNF-α pro-
duction in cultured white blood cells.177,178 American ginseng
may also possess hypoglycemic activity.179,180 Such effects have
been observed in both normal and diabetic subjects and may
be attributed to ginsengs components, specifically ginsenoside
Rb2 and panaxans I, J, K, and L.181–185
Typically, ginseng is well tolerated, but side effects such
as bleeding abnormalities secondary to antiplatelet effects,
headache, vomiting, Stevens-Johnson syndrome, epistaxis,
and hypertension have been reported.186–192 Drug interactions
between Asian ginseng and calcium channel blockers, warfa-
rin, phenelzine, and digoxin have also been noted.84 Ginseng
should be avoided in patients receiving anticoagulants (warfa-
rin, heparin, aspirin, NSAIDs). Further, because of ginseng's
association with hypertension and the deleterious outcomes
linked to chronic hypertension, the anesthesiologist should
be aware of which patients and for how long they may have
been taking this herbal product. Since many agents can cause
­generalized vasodilation, hemodynamic lability may be seen.
Regarding ginseng's interaction with antidepressants (e.g.,
MAO inhibitors), concurrent use of ginseng with phenelzine
should be avoided because manic episodes have been reported
with routine use of both.193,194 Because it can cause decreased
blood glucose levels, ginseng should be used cautiously in
diabetic patients taking insulin or other oral hypoglycemic
agents, and levels should be monitored (see Table 16-3).
Cloves
Cloves, also known as clove oil, have been used orally for
stomach upset, its antiplatelet effect, and as an expecto-
rant. Cloves may also be used topically for pain relief from
 Chapter 16  Mineral, Vitamin, and Herbal Supplements 481
mouth and throat inflammation, as well as athlete's foot. Its
­constituent, eugenol, has long been used topically for tooth-
ache, but the FDA has classified this drug into category III
(inadequate data to support efficacy).195 More evidence is
necessary to rate cloves for this purpose. Topically, cloves
can cause tissue irritation and in some people even aller-
gic dermatitis.196 Moreover, repeated oral application may
result in gingival damage and skin and mucous membrane
­irritation.195,197 The eugenol c­ onstituent in cloves may theo-
retically increase the risk of b ­ leeding in some people who
are concomitantly using herbs such as ­garlic, ­ginger, ginkgo,
and white willow bark.198 Likewise, patients taking anti-
platelet agents such as aspirin, clopidogrel, d ­ ipyridamole,
­ticlopidine, ­heparin, and warfarin may also experience an
increase risk of bleeding.
Black Pepper
Black pepper, also known as Piper nigrum, has been used to
treat upset stomach, bronchitis, and even cancer. Some have
used black pepper topically to treat pain associated with neu-
ralgia and skin irritation, and it may also possess antimicrobial
and diuretic properties.199,200 The putative compounds include
volatile oils (sabinene, limonene, caryophyllene, β-pinene,
α-pinenes), acid amines (e.g., piperines), and fatty acids. Eye
contact with black pepper may lead to redness and swelling.
Large amounts have even been reported to cause death sec-
ondary to aspiration.201
Black pepper may decrease the activity of the CYP3A4
enzyme, increasing levels of drugs metabolized by the enzyme
(e.g., phenytoin, propranolol, theophylline). The piperine con-
stituent of pepper seems to inhibit CYP3A4 in vitro.202 Other
drugs that may be affected include calcium channel ­blockers,
chemotherapeutic agents, antifungals, glucocorticoids,
­cisapride, alfentanil, fentanyl, losartan, fluoxetine, midazolam,
omeprazole, and ondansetron. Caution is advised if patients
are taking these drugs concomitantly because their doses may
need to be decreased.
Capsicum annuum
Capsicum (Capsicum annuum), also known as cayenne
­pepper, has been used orally for upset stomach, toothache,
poor c­irculation, fever, hyperlipidemia, and heart disease
­prevention. Capsicum can be used topically to treat pain
associated with osteoarthritis, shingles, rheumatoid a­ rthritis,
post-herpetic neuralgia, trigeminal neuralgia, diabetic
­neuropathy, fibromyalgia, and back pain. Others have used
capsicum for relief of muscle spasms and even as a gargle for
laryngitis.195,203–205
Capsaicinoids, carotinoids, flavonoids, and steroid sapo-
nins are the putative compounds involved. The mechanism
of action involves the binding of nociceptors in the skin,
which initially causes neuronal excitation and heightened
sensitivity (itching, burning) followed by cutaneous vasodi-
lation. Selective stimulation of afferent C fibers, which act as
thermoreceptors and nociceptors, and release of s­ ubstance P,
a sensory neurotransmitter that mediates pain, are impli-
cated. This excitatory period is followed by a refractory
period with reduced sensitivity, possibly from desensiti-
zation secondary to substance P depletion.203,206,207 Cough,
­dyspnea, nasal congestion, and eye irritation may occur
through ­stimulation of unmyelinated, slow C-fibers of the
sensory nervous system.208
About 10% of patients who use capsaicin topically
­discontinue its use secondary to adverse effects such as burn-
ing, stinging, and erythema.203 Exacerbation of ACE inhibitor
cough has been reported in patients using topical capsaicin
and taking ACE inhibitors.209 Skin contact with fresh capsicum
fruit can cause irritation or contact dermatitis.210 Furthermore,
concomitant use of herbs and supplements (garlic, ginseng,
ginkgo, cloves) may increase the risk of bleeding by decreasing
platelet aggregation (see Table 16-3).
White Willow Bark
From the family of salicylates, white willow bark is used to treat
headache, mild feverish colds, influenza, muscle and joint pain
caused by inflammation, arthritic conditions and systemic
connective tissue disorders. Preliminary research suggests
that willow bark extracts have analgesic, a­ nti-inflammatory,
and antipyretic effects.211
Evidence demonstrates that willow bark extract provid-
ing 120-240 mg of the salicin constituent daily can reduce
low back pain in some patients with the higher concentration
being more effective. Of note, it may take up to 1 week for sig-
nificant relief.212 Salicin's therapeutic effect had in fact been
reported to be comparable to rofecoxib (Vioxx – now discon-
tinued) for low back pain.213
Research is conflicting concerning white willow bark's
efficacy on osteoarthritis, with some studies suggesting a
moderate analgesic effect while others consider it similar to
placebo.214,215 More studies must be conducted to identify its
use in these conditions.
n Flavonoids, tannins, and salicylates are attributed to the
antiinflammatory, antipyretic, and antiuricosuric activities
of white willow bark. Salicin is eventually metabolized to
salicylic acid, which then shares the same metabolic path-
way as aspirin.216
n An ethanolic extract of willow bark seems to inhibit cyclo-
oxygenase (COX)-2 indirectly by mediating prostaglandin
release, while other constituents of white willow bark may
have lipoxygenase-inhibiting and antioxidant properties
that could contribute to analgesia.212 Moreover, other litera-
ture suggest that they may also prevent prostaglandin and
cytokine release.211
Willow bark inhibits platelet aggregation, but to a lesser
degree than aspirin,217 thus, concomitant use with other herb-
als such as ginkgo, ginseng, garlic, or cloves may increase the
risk of bleeding, as will use with anticoagulants and antiplate-
let drugs.
 482 ANESTHESIA AND UNCOMMON DISEASES
Devil's Claw
Devil's claw has been used to treat pain symptoms from osteoar-
thritis, rheumatoid arthritis, gout, myalgia, fibrositis, ­lumbago,
tendonitis, pleuritic chest pain, and gastrointestinal upset. The
active constituent, harpagoside, seems to reduce nonspecific
low-back pain when used in a dose range from 50 to 100 mg. In
fact, its use in this range has been compared to 12.5 mg of the
discontinued drug, rofecoxib.218–220 Additionally, oral dosing of
devil's claw either alone or in combination with NSAIDs may
lessen pain associated with osteoarthritis218,221,222 and may even
need lower doses of NSAIDs to achieve the same level of pain
relief.222 More evidence is needed to substantiate its use or dis-
use for rheumatoid arthritis-related pain although preliminary
data suggests it may be ineffective.223
Besides containing harpagoside, devil's claw contains ­iridoid
glycoside constituents and procumbide that add to its effect,
as well as the phenylethanol derivatives acteoside (verbasco-
side) and isoaceteoside, and the ­oligosaccharide ­stachyose.224
The iridoid glycoside constituents seem to p ­rovide an
­anti-inflammatory effect.221 Current evidence implies that
harpagoside inhibits both the cyclo-oxygenase (COX) and
lipoxygenase inflammatory pathways.225 Devil's claw seems to
inhibit only COX-2, not COX-1, and also inhibits the inflam-
mation modulating enzyme nitric oxide synthetase.226 An
increased synthesis and release of tumor necrosis factor alpha
(TNF-α) by compounds other than harpagoside aid in the
anti-inflammatory effect; however, research in humans shows
no effect of devil's claw on the arachidonic acid pathway.227
The most common reported side effect of devil's claw is diar-
rhea, but the supplement is generally well tolerated.221 Other
generalized complaints include nausea, vomiting, and abdomi-
nal pain, headache, tinnitus, anorexia, and loss of taste. Some
people have experienced dysmenorrhea and h ­emodynamic
instability.218
Possible drug interactions may stem from devil's claw ability
to inhibit CYP2C9, although the effect has not been reported
in humans.228 Drugs metabolized by CYP2C9 such as nonste-
roidal anti-inflammatory drugs (NSAIDs) (diclofenac, ibupro-
fen, meloxicam [Mobic], and piroxicam [Feldene]); c­ elecoxib
(Celebrex); amitriptyline (Elavil); warfarin (Coumadin); glipi-
zide (Glucotrol); losartan (Cozaar); and others may need to be
reduced or even eliminated (see Table 16-3).
Boswellia
Boswellia, also known as Indian frankincense (Boswellia ­serrata),
has been used to manage pain associated with osteoarthritis,
rheumatoid arthritis (RA), rheumatism, bursitis, and tendon-
itis. Non-pain related uses include ulcerative ­colitis, dyspep-
sia, asthma, allergic rhinitis, sore throat, syphilis, ­pimples, and
cancer.
There is preliminary evidence that taking Indian frank-
incense extract orally might reduce osteoarthritis symptoms
such as knee pain and swelling,229 while its use in rheumatoid
arthritis is controversial. More evidence is needed for use of
boswellia in both these conditions.
The principal constituents, boswellic acid and α- and
β-boswellic acid, come from the resin. These constituents have
anti-inflammatory properties230 that aid in pain management
with arthritic patients, but not all extracts of Indian frank-
incense show antiarthritis, anti-inflammatory, or antipyretic
effects.229 The mechanism behind boswellic acids comes from
inhibition of 5-lipoxygenase and leukotriene synthesis, along
with the inhibition of leukocyte elastase. Some have suggested
that the acids may have disease modifying effects, thereby
decreasing glycosaminoglycan degradation and cartilage
damage. Boswellia seems to decrease production of antibodies
and cell-mediated immunity.229,231
Side effects include GI upset such as e­pigastric pain,
nausea, and diarrhea, while topical use may cause ­contact
dermatitis.229,232 Not enough studies have been done to
­comment on pharmacologic interactions with other drugs
(see Table 16-3).
CONCLUSION
The growing use of alternative medicines such as m
­ inerals, vita-
mins, and herbals in the world warrants a more ­comprehensive
understanding of these agents by the medical community. It
is important for the anesthesia practitioner to recognize cer-
tain facts regarding these supplements. For example, there
are about 1300 g of calcium in a 70-kg adult and the mineral
magnesium activates approximately 300 enzyme systems in
the human body—most of these ­systems involved in energy
metabolism.233 Aside from this, the a­nesthesia practitioner
must appreciate the effect of these supplements on such func-
tions on a regular basis as well as during various operative
procedures. As demonstrated in this chapter, the use of these
compounds may prove beneficial for some patients, but result
in alterations in normal physiologic functions in others, thus
potentially resulting in deleterious consequences. Moreover,
in our own survey, in patients undergoing operative surgery,
including interventional pain procedures, approximately
one in three patients take some form of herbal supplement
although 70% of these patients did not admit to its use during
routine questioning.234
For this reason, these agents, in addition to all other
­medications taken by the patient, should be screened for by
medical practitioners vigorously, in particular anesthesia
practitioners, as some of these compounds may interact with
chosen anesthetics during the stages of anesthesia or can affect
treatment or, even worse, cause harm to the patient. In this
regard, education of patients regarding the serious poten-
tial supplement-supplement and drug-supplement interac-
tions should be an integral component of pain assessment and
ongoing pain management. Currently the American Society of
Anesthesiologists (ASA) suggests that all herbal ­medications
should be discontinued 2 to 3 weeks before an elective s­ urgical
procedure. If the patient is not sure of the contents of the
herbal medicine, he or she should be urged to bring the con-
tainer so that the anesthesiologist can review the contents of
the herb or preparation.235
 Chapter 16  Mineral, Vitamin, and Herbal Supplements 483
Because current regulations are lax in some countries,
some of these agents are poorly categorized and standardized,
thus resulting in a high risk of adverse effects when used by
an uninformed or misinformed public. Within the last few
decades, hundreds of deaths have been linked to the use of
these agents, specifically the herbals. Given that the Federal
Drug Administration considers herbals as foods and that this
industry has developed into a multibillion dollar business, it
is imperative for the anesthesiologist to have a basic under-
standing of issues related to the over 29,000 supplements and
herbal related agents available without prescription in the
United States. Worldwide there are varying levels of scrutiny
and protection for consumers. Data also suggest that less than
1% of adverse effects associated with herbals are reported in
the United States. In general, whether the patient is taking
minerals, vitamins, and/or herbals, one thing is for certain:
an open line of communication between anesthesiologist and
patient should exist regarding all of these agents. This com-
munication is essential to ensure quality patient treatment, a
stable and secure rapport, and a properly informed and edu-
cated general public. Though only recently being taught in
many medical schools, anesthesia practitioners will be well
advised to gain a solid foundation in this most important and
relevant topic.
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 C H A P T E R
17
Trauma and Acute Care
MAUREEN MCCUNN, MD, MIPP, FCCM  n
CORRY J. KUCIK, MD, DMCC, FCCP  n
JOSHUA M. TOBIN, MD  n
THOMAS E. GRISSOM, MD, FCCM  n
RICHARD P. DUTTON, MD, MBA  n

require surgery to reduce complications; nonurgent cases

Basic Considerations can be safely delayed.
Team Organization and Multiple-Trauma Priorities
n The first priority is assurance of a patent airway, with all
Airway Management
trauma patients assumed to have a full stomach. Rapid-
Damage Control and Fluid Resuscitation
sequence intubation is recommended with cricoid ­pressure
Specific Conditions (CP), but with release of CP if the mask ventilation or
Traumatic Brain Injury
­visualization becomes difficult.
Spinal Cord Injury
n Direct laryngoscopy with manual in-line stabilization is
Ocular Trauma
unlikely to aggravate cervical injury and is safe and appro-
Complex Facial Injuries
priate for most trauma patients.
Penetrating Trauma
n Fluid resuscitation after massive hemorrhage will result
Traumatic Aortic Injury
in extensive hemodilution and coagulopathy; hypotensive
Orthopedic Injuries
resuscitation is indicated until hemorrhage is controlled.
Near-Drowning
n Traumatic brain injury (TBI) causes at least half of all trauma
Smoke Inhalation and Carbon Monoxide Poisoning
deaths. Severe TBI (GCS <8) is highly lethal, and even single
The Pregnant Trauma Patient
episodes of hypotension or hypoxemia can increase mortality.
Geriatric Trauma n Patients with complete spinal cord injury deficits ranging
Prehospital Anesthetic Care from C4 to C7 are likely to require early intubation.
Acute Care Anesthesiology n With implied application of substantial force, pelvic
Conclusion ­fractures may be life threatening due to hemorrhage, and
early stabilization will restore blood pressure.
n Some lung dysfunction occurs in almost all patients with
long-bone fractures, including life-threatening fat ­embolism
KEY POINTS (3%-10%); supportive care is the only treatment.
n Trauma is the 10th leading cause of death globally (16,000 n Elderly persons (≥75) have the highest injury-related ­mortality.
people daily). Motor vehicle crashes, firearms, poisoning, However, for geriatric trauma patients who respond favorably
falls, and suffocation account for 81% of all trauma deaths. to aggressive resuscitative efforts, ­prognosis for ­survival and
n Every anesthesiologist will likely care for injured patients return to preinjury function is good.
acutely or for follow-up surgery. n More than 50% of surgeries are not elective (40% urgent,
n Trauma deaths occur in a trimodal distribution: at the 11% emergency, 8% trauma), for patients with intra-
scene, hours after injury, and days to months after injury. abdominal sepsis, soft tissue infection, acute abdominal
n The trauma/acute care anesthesiologist is facile in multiple pathology, and acute hemorrhage. The acute care anesthesi-
settings (ED, OR, ICU, transport, pain clinic, military). ology subspecialty will develop the aspects of practice that
n Emergent trauma cases require surgery as soon as ­possible; are likely to assume a greater prominence in future health
urgent cases are not immediately life threatening but care systems.
488

n Trauma and acute care anesthesiology practice requires
training and knowledge from all anesthetic disciplines.
Trauma patients often require emergent interventions and
advanced techniques of management and coordination of
care among multiple surgical specialties.
BASIC CONSIDERATIONS
The World Health Organization (WHO) estimates that 16,000
people die of injury each day, making trauma the 10th leading
cause of death globally.1 Trauma—disruption of anatomy and
physiology resulting from application of external energy— is
classified as intentional (e.g., violent injuries) or unintentional
(e.g., motor vehicle crashes, falls). Unintentional injuries are
the fifth leading cause of death overall in the United States
and the leading cause for those under 45 years of age.2 The five
leading mechanisms of injury death are motor vehicle crash,
firearm, poisoning, falls, and suffocation, accounting for
81% of all trauma deaths. Persons 75 years and older have the
­highest injury-related mortality rate.
Anesthesiologists may see trauma patients in the field, in
the emergency department (ED), in the operating room (OR),
in the intensive care unit (ICU), in transport, in the pain clinic,
and in the military setting. Specialists in trauma anesthesia
are rare, but every anesthesiologist will see trauma patients at
times and must be aware of the specific medical issues associ-
ated with this challenging population.
This chapter begins with an overview of team organiza-
tion and approach to the injured patient; the ABCDE priori-
ties (airway, breathing, circulation, disability, environment)
are considered to determine whether injuries are life or limb
threatening. Further management strategies include second-
ary and tertiary patient care issues, as well as uncommon
trauma situations. Perioperative management of nontrauma
patients who present to the OR for emergent procedures is
also discussed.
Team Organization and Multiple-Trauma
Priorities
Trauma care outcomes depend as much on the c­ oordination
of services as on the quality of each individual practitioner.
Studies show the more organized and experienced the trauma
service, the better the outcomes.3,4 Practicing anesthesiologists
should understand how the local trauma service or deployed
unit is organized and the role of anesthesia ­personnel in the
larger team. The approach to the initial management of a
trauma patient, as developed through the American College
of Surgeons (ACS) Advanced Trauma Life Support (ATLS)
course,5 is a “vertical” resuscitation: one provider perform-
ing each step of the primary and secondary survey alone
and in sequence. However, modern health care facilities in
highly developed countries have the resources to support
“­horizontal” resuscitation: multiple trauma team members
working ­cohesively and simultaneously on the primary and
secondary survey in an effort to reduce the time to diagnosis
Chapter 17  Trauma and Acute Care 489
A – airway provider
D– doctor
N – nurse
T– team leader
Open circles – additional support staff (fellows, residents,
students, paramedics) to assist with workup
FIGURE 17-1  Trauma team approach for “horizontal”
resuscitation. Multiple personnel perform concurrent and
coordinated tasks of evaluation and management of the injured
patient.
and treatment of traumatic injuries. Figure  17-1 illustrates a
team approach to the injured patient.
Trauma is considered a surgical disease, and in the United
States, seriously injured patients are usually managed by a
general surgeon or a fellowship-trained trauma surgeon. The
­surgeon generally is responsible for the sequencing of diag-
nostic and therapeutic procedures and for resource allocation
among multiple patients. Anesthesiologists may be involved in
initial airway management, vascular access, procedural seda-
tion, hemodynamic resuscitation, and the timing and extent
of any surgery. Some team members, including surgeons, may
have incomplete understanding of anesthetic implications,
mass casualties, and triage, or other related factors; therefore it
is incumbent on anesthesiologists to advise the team through-
out clinical decision making. Close communication with the
surgeon and consultant subspecialties is essential to the appro-
priate allocation of scarce OR resources.
Trauma deaths occur in a trimodal distribution: (1) at the
scene, (2) hours after injury, and (3) days to months after
injury.6 The deaths occurring at the scene result from severe
central nervous system (CNS) or major vascular (aorta, great
vessels) disruption and can be impacted only by improved
­prevention. The second peak of injury deaths is impacted
by efficient prehospital trauma systems and emergent, coor-
dinated care on arrival to the trauma center. Mortality in the
third “wave” occurs more than 24 hours after injury and results
from sepsis and/or multiple-organ failure. As OR coordina-
tor, the anesthesiologist is required to determine how trauma
cases will be accommodated in a busy elective schedule, and
understanding surgical priorities based upon these patterns of
death is essential to this process.
 490 ANESTHESIA AND UNCOMMON DISEASES
Emergent-Urgent-Nonurgent. Table  17-1 is an outline of
trauma case priorities.7 Emergent cases must reach the OR
as soon as possible. Although surgical airway access and
­resuscitative thoracotomy usually occur in the ED, immediate
­follow-up in the OR will be necessary if the patient ­survives.
Also considered emergent are any exploratory surgeries (lap-
arotomy or thoracotomy) in a hemodynamically unstable
patient and craniotomy in a patient with a depressed or dete-
riorating mental status, when evacuation of blood or decom-
pression of severe cerebral edema will result in a survival
benefit. Limb-threatening orthopedic and vascular injuries
should undergo surgical exploration as soon as the necessary
diagnostic studies have been performed and interpreted.
Urgent cases are not immediately life threatening but require
surgery as soon as possible to reduce the incidence of subse-
quent complications. Examples include exploratory laparotomy
in stable patients with free abdominal fluid; irrigation, debride-
ment, and initial stabilization of open ­fractures; and repair of
contained rupture of the thoracic aorta. Angiographic proce-
dures have increasingly replaced open surgeries for splenic,
hepatic, pelvic, and aortic injuries in hemodynamically stable
patients. Early fixation of closed fractures, especially spine and
long-bone fractures, has been shown to benefit trauma patients
by reducing the incidence of subsequent pulmonary compli-
cations. Definitive repair within 24 hours is recommended in
otherwise stable and ­non–brain-injured patients.
TABLE 17-1  n  Surgical Priorities in Trauma Patients
Priority Procedure
Immediate Airway access
Available OR or at Thoracotomy or laparotomy to control
bedside hemorrhage
Evacuation of epidural or subdural
hematoma
Urgent Perforated viscus
First available OR Unstable spine with no deficit or partial
deficit
Decompressive craniotomy or
laparotomy
Fasciotomy or limb-salvage procedure
As soon as possible Open fractures
Next unscheduled Irrigation; debridement of soft tissue
OR wounds
Open-globe injury or entrapped ocular
muscle
Isolated closed long-bone fracture
Elective Small-bone fractures: wrist, ankle,
Next scheduled OR hand, foot
Facial surgery
Second-look laparotomy or thoracotomy
Acetabular reconstruction
Fixation of stable spinal fractures
Plastic surgery and wound reconstruction
Repeat irrigation; debridement of open
wounds
OR, Operating room.
Nonurgent cases are those that can be safely delayed until a
scheduled OR time is available. Although immediate fixation
of face, wrist, and ankle fractures may shorten the patient's
length of stay, early surgeries may be technically more d
­ ifficult
because of swelling and distortion of the surrounding tissue.
Therefore, such procedures are typically postponed days to
weeks after injury, when tissue edema has resolved and the
patient's condition is improved. Early pain control is critical
to mitigate the inflammatory response and development of
­long-term pain syndromes.
Damage Control Approach. In addition to facilitating
timely surgery in patients who require it, the anesthesiologist,
surgeon, and other specialists work together to determine the
extent of surgery allowed by the patient's physiology. The con-
cept of “damage control” has revolutionized s­ urgical thinking
in the last two decades, limiting initial therapeutic procedures
only to those required for the achievement of hemostasis and
homeostasis, while delaying reconstructive p ­ rocedures until
adequate resuscitation has been achieved, and in a­ ppropriate
cases, edema has subsided.8 In a typical example, the ­surgeon
treating an unstable patient with blunt trauma might p ­ erform
an exploratory laparotomy, rapid ­splenectomy, ­staple ­resection
of injured bowel (without attempt at reanastomosis), ligation
of bleeding large vessels, and packing of the abdomen. The
abdomen would be left open under a sterile, watertight wound
vacuum and the patient taken to the ICU. Angiographic
embolization might be necessary to facilitate hemostasis in the
liver and retroperitoneum (e.g., because of pelvic f­ ractures).
The goal with “damage control” surgery is to avoid the
“lethal triad” of hemorrhage, acidosis, and coagulopathy
that can r­ apidly develop in a patient with massive bleeding
and resuscitation. After resolution of shock, warming, and
normalization of laboratory values, the patient would return
serially to the OR in 24 to 48 hours for further exploration
and debridement of nonviable tissue, reconstruction of the
bowel, placement of enteral feeding access, and a­ bdominal
closure.
The concept of damage control may also be applied to
orthopedic injuries: initial external fixation of the pelvis and
long bones is adequate for temporary stabilization of f­ ractures,
without assuming the additional physiologic risks of intra-
medullary nailing or open fixation.9 The damage control
approach should be considered in any patient with persistent
­hypoperfusion, elevated lactate, or transfusion requirement in
excess of one blood volume.
Airway Management
The first priority in the care of any trauma patient is assur-
ance of a patent airway that can provide adequate oxygenation
and ventilation.5 Anesthesiologists are expert consultants for
­airway management, including those in which trauma patients
are managed initially by emergency medicine physicians.
Whether in the ED or the OR, the ability to intubate injured
patients swiftly and safely may be lifesaving.

Pathophysiology. Baseline indications for intubation of the
trauma patient are similar to those of any critically ill patient
and can be organized under basic categories of (1) inability
to oxygenate, (2) inability to ventilate, and (3) inability to
maintain a patent airway. Indications may also include need
for pain control (multiple fractures), diagnostic workup, or
plan to proceed to the OR. Box  17-1 lists specific examples.
Hypoxemia may be the result of impaired respiratory effort,
obstruction of the upper airway, aspiration of blood or gastric
contents, mechanical disruption of the chest cavity, or severe
hemorrhagic shock. Traumatic brain injury (TBI) and intox-
ication with alcohol or other drugs contribute to impaired
effort, upper airway obstruction, and aspiration, whereas
direct trauma to the face, neck, or chest may cause bleeding,
anatomic disruption of the airways or lung tissue, pneumo-
thorax, or severe pulmonary contusions. Ventilatory failure is
common in trauma patients, both at initial presentation and
in the following days. Pulmonary contusion, with subsequent
consolidation of alveolar space, may take hours to develop and
may not be obvious until after fluid resuscitation and initial
surgeries have been completed. Ventilatory failure may also
result from exacerbation of underlying chronic cardiac or
pulmonary disease or from other acute causes, such as pul-
monary embolus (PE). Trauma patients are at very high risk
for PE from their hypercoagulable state, vascular trauma, or
fat emboli, and PE should be suspected in any patient with
an abrupt decline in respiratory status. Patients with multiple
injuries are at increased risk of developing the systemic inflam-
matory response syndrome (SIRS), which can be complicated
by progressive respiratory compromise and recurrent sepsis
and may lead to multiorgan system failure.
BOX 17-1   n  INDICATIONS FOR INTUBATION
Apnea
Hypoxemia
Airway obstruction
Upper airway injury or hemorrhage
Airway burn
Pulmonary injury
Contusion
Hemothorax/pneumothorax
Aspiration
Cardiac contusion/ischemia with pulmonary edema
Neurologic injury with decreased cough or respiratory effort
Severe traumatic brain injury (GCS <8)
Cervical spine injury with deficit
Intoxication
Medication effect
Carbon monoxide poisoning
Need for Anesthesia
Painful injuries
Urgent surgical procedures
Combative or uncooperative patient
GCS, Glasgow Coma Scale score.
Chapter 17  Trauma and Acute Care 491
All trauma patients must be assumed to have a full stomach;
obtaining an accurate history in the injured patient is difficult,
and trauma itself will lead to a drastic decrease of gastrointes-
tinal (GI) motility, with ileus persisting for hours to days after
injury.10 Trauma patients are also at risk for aspiration of blood
from open fractures or penetrating wounds of the face and air-
way. Impaired mental status resulting from TBI or intoxication
may make aspiration more likely, particularly when combined
with the use of sedative or analgesic drugs given to facilitate
diagnostic procedures such as computed tomography (CT)
or minor surgical procedures such as reducing a fracture or
suturing a laceration.
Evaluation. Ideally, assessment of the patient before airway
management is no different than assessment of an elective sur-
gery patient. However, it must often be adjusted for the urgency
of the situation. A thorough history and ­physical examination
of the face, neck, and chest is appropriate when possible. Any
suggestion that intubation will be ­difficult ­warrants the need
for additional equipment or personnel. Presence of a cervi-
cal collar, facial fractures, or blood or vomitus in the airway
add to traditional predictors of difficult i­ntubation. When the
urgency of the situation does not allow for a thorough assess-
ment, the anesthesiologist must gather what information is
immediately available from other providers, make a quick
assessment of the patient, and then proceed as necessary.
Box 17-2 summarizes factors predicting a ­difficult airway.
The need for “discretionary” intubation in the combative
or uncooperative patient is controversial, and the provider
must carefully assess the risks and benefits of intervention.
Induction of anesthesia will allow for immediate diagnos-
tic studies and more rapid identification of life-threatening
conditions, such as epidural hematoma or splenic rupture.
Induction and intubation may also prevent the patient from
injuring self or ­others and may allow for deeper, safer levels of
sedation during diagnostic studies. Induction, l­aryngoscopy,
and intubation are not without risks. However, h ­ emodynamic
instability may be ­precipitated even in previously normotensive
BOX 17-2   n FACTORS PREDICTING A DIFFICULT
INTUBATION
Emergency setting
Presence of hypoxemia
History of difficult intubation (may be noted on Medic-Alert bracelet)
Obesity
History of sleep apnea
Presence of a cervical collar and backboard
Soft tissue injury to the neck or face
Known cervical spine injury (possibility of prevertebral edema)
Limited mouth opening
Limited neck extension (ankylosing spondylitis, previous cervical
fusion)
Upper airway hemorrhage
Tongue injury
Foreign bodies in the airway
Previous attempts at intubation
 492 ANESTHESIA AND UNCOMMON DISEASES
patients with either the induction agent or the institution
of ­positive-pressure ventilation (PPV) with a subsequent
decrease in venous return and cardiac output. Also, technical
complications of rapid-sequence intubation (aspiration, oral
trauma, need for surgical airway) may exacerbate the care of
an ­otherwise ­minimally injured patient.11,12
Early intubation, diagnostic imaging, and rapid extubation
of the intoxicated patient without significant trauma are pos-
sible in some settings but can carry a substantial economic
burden. Ultimately, the trauma team, including the anesthesi-
ologist, must evaluate the potential for life-threatening trauma,
the patient's ability to tolerate CT (with or without additional
sedation), and the likely ease of intubation when deciding how
to proceed. No matter what course is elected, close monitor-
ing of the patient's neurologic status and ­respiratory effort is
required.
Preparation. Sufficient trained personnel must be avail-
able to manage the airway physically, administer induction
drugs, provide cricoid pressure (now controversial), and sta-
bilize the cervical spine. The anesthesiologist performing or
directing the intubation coordinates this process to ensure
that all participants know their role. When possible, the plan
of care should be discussed with the patient and family and
any ­questions answered.
While other preparations are being made, preoxygenation
should be maximized to the extent possible, whether through
use of blow-by oxygen (O2), assisted bag-valve-mask (BVM)
support of spontaneous ventilations, or ideally, a tight-fitting
face mask. Although an apneic patient often must be pre-
oxygenated through BVM ventilation, inspiratory pressures
should be kept as low as possible to minimize the chance of
gastric insufflation, regurgitation, and pulmonary aspiration
of stomach contents. A high-flow suction device should be
immediately available should regurgitation occur. All neces-
sary intubating equipment, including primary and backup
­airway equipment, reliable sources of O2 and PPV, induction
and emergency medications, and confirmatory equipment,
should be close at hand.
Patient positioning can greatly facilitate intubation and
is often overlooked in the emergent situation. The bed or
stretcher should be placed at a convenient height for the anes-
thesiologist, with enough space at the head of the bed to allow
room for unhindered motion. Ergonomic design of the trauma
bay has been shown to improve the process of e­mergency
i­ ntubation.13 Cervical spine instability is a c­onsideration in
most trauma victims; cervical injuries occur in 1.5% to 3%
of all major trauma cases, and up to 50% of cervical ­fractures
may be unstable.14
Exclusion of cervical spine instability requires at least
a cooperative patient without distracting injuries and may
further require appropriate diagnostic studies (see later).
­ model,22 and live-patient23–25 evaluations generally show that
The ­traditional “sniffing position” (head extension plus neck
­flexion) is thus contraindicated, whereas the presence of a
rigid cervical collar and the maintenance of in-line cervical
­stabilization also contribute to the difficulty of intubation.15
Blood and other debris in the oropharynx can also make
fiberoptic ­
­ laryngoscopy difficult. If properly p ­erformed,
direct laryngoscopy with manual in-line stabilization is
unlikely to aggravate an ­existing cervical spine injury and
has been judged safe and appropriate for the majority of
trauma patients. Unfortunately, any manipulation of the air-
way, including mask ventilation, intubation, even placement
of a laryngeal mask airway (LMA), can cause cervical spine
motion.14 Cadaveric ­models of ­cervical injury demonstrated
significantly less movement with in-line s­tabilization than
with a cervical ­collar,16 and this ­technique has been judged safe
and appropriate for the m ­ ajority of trauma patients.17 Whereas
some advocate ­routine use of fiberoptic intubation for all
trauma patients with the potential for c­ ervical instability, this
approach is time and resource ­intensive, with no data showing
improved outcomes. Multiple initial options that are less likely
to exacerbate ­cervical ­instability (e.g., intubating LMA, light
wand) may also be c­ onsidered, given availability and provider
experience.
Preprocedural preparation should include the availability of
a device to facilitate intubation of an anterior larynx (e.g., Parker
Directional Stylet, “trigger tube,” gum elastic bougie), rescue
devices for failed intubation (e.g., LMA, Combitube, Cobra
Perilaryngeal Airway, King Laryngeal Tube), and an interdis-
ciplinary understanding of when c­ ervical ­protection should
be abandoned in favor of achieving a successful ­intubation.
The likelihood of an anterior larynx argues for the routine
use of a stylet in the endotracheal tube (ETT). A stethoscope
and ­capnometry should be available to c­ onfirm ­endotracheal
placement and adequacy of ventilation. Equipment should
also be on hand for emergent p ­ ercutaneous or surgical
­cricothyroidotomy in the worst-case scenario.
The American Society of Anesthesiologists (ASA) Difficult
Airway Management Algorithm has been adapted for trauma,
because “awakening” the patient who is hemorrhaging or
unable to maintain an airway is not appropriate.18 In a review
of 10 years’ experience with intubation on arrival to a busy
Level I trauma center, 6088 patients required i­ ntubation within
the first hour of care. All were supervised or done by attending
trauma anesthesiologists. Of these patients, 21 (0.3%) received
a surgical airway. Unanticipated difficult upper airway anat-
omy was the leading reason for surgical airway. All these
intubations were performed or attempted with direct laryn-
goscopy.19 The leading causes of the need for surgical ­airway
were difficult anatomy (11), foreign body (6), and injury to
head or neck (5).
Several small studies have investigated various types of
indirect/video laryngoscopes (GlideScope, Bullard, McGrath,
Airtraq, Pentax Airwayscope, Truview EVO2, Viewmax),
which provide a theoretic advantage in minimizing cervi-
cal spine motion during intubation. Simulation,20,21 cadaver
the Cormack-Lehane grade is improved,22,23 cervical spine
motion is reduced,24 and time to intubation is similar with
indirect laryngoscopy compared with direct l­aryngoscopy
(DL).20,22 However, a cinefluoroscopic study of 20 patients
 Chapter 17  Trauma and Acute Care 493

without cervical pathology, using manual in-line ­stabilization Although a standard-of-care in emergency intubations,
by an assistant, showed no decrease in movement of the ­cervical the efficacy of cricoid pressure has been questioned. In 1961,
spine with GlideScope versus DL.26 Recently, p­ rehospital dif- Sellick described CP as a method to reduce the risk of aspira-
ficult intubation management by experienced European anes- tion during the induction phase of anesthesia,29 and although
thetists improved with the GlideScope.25 widely used, its method of application, timing, and role in dif-
ficult airways are not standardized.30–32 For emergency airway
Induction/Intubation Considerations. A rapid-sequence
management, the risk of aspiration is thought to be higher
intubation (RSI) technique is recommended, with the use of
than in elective cases, ranging up to 22% in ED-performed
cricoid pressure (CP, Sellick maneuver) from induction of
RSI,33 and CP is a theoretic preventive maneuver. However,
anesthesia (or onset of apnea) until confirmation of ­correct
the amount of pressure needed and the optimal method of
ETT positioning. Although how consistently CP ­ prevents
application are unknown,34–36 and the pressure may displace
regurgitation and aspiration of gastric contents has been
rather than occlude the esophagus.37,38 Also, CP may make
q
­ uestioned,27 the technique is also beneficial in moving the
both mask ventilation39,40 and laryngeal view33 more difficult,
larynx into a position of better visualization, the backward-
both of which can be improved by release of CP. In the United
upward-rightward pressure (BURP) technique, thus maxi-
Kingdom, where anesthetists work as prehospital physicians, a
mizing the laryngoscopic view of the vocal cords. If active
prospective study of CP for RSI in the field reported that of 402
vomiting (vs. passive regurgitation) begins while CP is being
intubations, CP was released in 22 patients to improve laryn-
held, the c­ ricoid cartilage should be released to minimize the
geal view, bimanual manipulation was used in 25 ­intubations,
risk of spontaneous esophageal rupture (Boerhaave's syn-
and BURP was applied in 14 intubations; 98.8% of patients
drome). Suction and positioning should be employed (e.g.,
were intubated on the first or second attempt.41 Two patients,
turning patient en masse if on spine board) to minimize the
who had prolonged bag-mask ventilation and d ­ ifficult intu-
risk of pulmonary aspiration.
bations, regurgitated after release of CP. This illustrates a
With adequate dosing of induction/intubation agents and
larger unanswered question: are trauma patients at risk for
suction immediately available to the intubator, aspiration is
­aspiration simply because they have a full stomach, or is it
unlikely during direct airway visualization. Specific manipula-
caused by often-inadequate induction doses of ­medications
tion techniques may optimize visualization of the glottic open-
(from hemodynamic instability) and challenging airways
ing, whereas other techniques may worsen the view. A study
with c­ ervical spine immobilization, blood/vomitus, or facial
of 104 emergency medicine physicians performing 1530 sets
­injuries? Many suggest using CP for RSI, with release of CP if
of laryngoscopy on fresh cadavers suggested that the percent-
the mask ­ventilation or visualization becomes difficult.
age of glottic opening using a validated scoring scale improved
more with bimanual laryngoscopy than with CP, BURP, or no Induction/Intubation Medications. Advantages and disad-
manipulation.28 vantages of various induction drugs are shown in Table 17-2.

TABLE 17-2  n  Medications Used During Emergency Airway Management

Medication Class Comments*

Sodium thiopental Sedative Fast, inexpensive, negative inotrope and vasodilator

Etomidate Sedative Fast, expensive, fewer cardiovascular effects, may cause transient myoclonus

Propofol Sedative Fast, expensive, easily titrated, negative inotrope and vasodilator

Ketamine Sedative Fast, inexpensive, positive inotrope; may cause “bad dreams” or dysphoric reactions

Lidocaine Sedative/ Blunts airway reactivity; negative inotrope

analgesic

Midazolam Sedative Expensive, slower onset; negative inotrope and vasodilator; may cause retrograde amnesia

Fentanyl Analgesic Blunts airway reactivity; does not produce amnesia

Morphine Analgesic Slower onset and longer half-life than fentanyl; may cause histamine release; has euphoric effect

Succinylcholine Paralytic Most rapid onset; produces fasciculations; will cause potassium release in vulnerable patients
(burns, spinal cord injury >48 hours)

Vecuronium Paralytic Slower onset and longer duration; no hemodynamic side effects

Rocuronium Paralytic Intermediate onset and duration, but less predictable than vecuronium; no hemodynamic side
effects

*Note that any sedative or analgesic medication will reduce the endogenous catechol response and may precipitate hemodynamic instability.
 494 ANESTHESIA AND UNCOMMON DISEASES
Although agents that lack a negative inotropic effect (e.g.,
­ketamine, etomidate) are more likely to preserve cardiovascu-
lar function in the euvolemic patient, any induction drug—and
even the change to PPV alone—can precipitate hemodynamic
instability in the patient in shock. This is because the hypovo-
lemic patient is relying on a high serum level of catecholamines
to support the blood pressure. Some degree of catecholamine
depletion should be assumed in the trauma patient.42 Many
sedative or analgesic agents may depress sympathetic tone,
impair the adrenal response to hemorrhage, “unmask” hypo-
volemia, and cause profound hypotension. Internal hem-
orrhage may not be readily apparent at induction, and vital
signs are at best a crude indicator of volume status; therefore
care should be taken with any anesthetic agent. Such situa-
tions demand the use of smaller-than-normal doses, carefully
titrated to the patient's response.
Although etomidate may seem to be the ideal agent for
use in trauma patients because it maintains hemodynamic
s­ tability,43 reported complications related to etomidate induc-
tion in trauma patients may preclude its use. Occult adrenal
insufficiency has been noted in up to 60% of severely injured
patients and is associated with persistent systemic inflamma-
tion, a hyperdynamic cardiovascular state, and vasopressor-
dependent shock.44 In a retrospective study of ICU patients at
a Level I trauma ­center, 137 patients had undergone cosyntro-
pin stimulation testing; there was no difference in age, gender,
race, injury severity or mechanism, rates of sepsis/septic shock,
mechanical v­ entilation, or mortality. Patients who had received
etomidate were more likely to have adrenal insufficiency, as
defined by “nonresponders” to cosyntropin.45 A more recent
study analyzed 94 patients who had received etomidate for pre-
hospital intubation. Again, with no differences between those
who did or did not receive etomidate, its use was associated
with a higher incidence of acute respiratory distress syndrome
(ARDS) and multiple-organ failure, thought to be caused by
etomidate's effect on the ­inflammatory system (inhibition of
11β-hydroxylase).46 A  larger, randomized prospective trial of
etomidate (234 patients) v­ ersus ketamine (235) for RSI did not
assess mortality; the primary endpoint was the maximum score
of the sequential organ failure assessment (SOFA) during the first
3 days in the ICU.47 The mean maximum SOFA score between
the two groups did not differ significantly, but the p
­ ercentage of
patients with adrenal insufficiency was ­significantly higher in
the e­ tomidate than in the ketamine group.
Succinylcholine is the standard paralytic agent for RSI and
is recommended in the absence of obvious ­contraindications
(pre-existing neuromuscular disease, known or s­uspected
hyperkalemia; burn, spinal cord deficit, or massive mus-
cle trauma occurring more than 24 hours previously; recent
prolonged bed-bound status; known history of malignant
­ geal detector device (EDD). Inspection by repeat DL may also
hyperthermia). Rocuronium or vecuronium can be used in
place of succinylcholine and will provide similar intubating
conditions and almost the same speed of onset, at the cost of
greatly ­prolonged paralysis thereafter.48
The administration of positive-pressure breaths by BVM
during RSI is controversial. In trauma cases in which RSI is
undertaken in a reasonably cooperative, maximally preoxy-
genated patient, PPV can often be completely avoided, to min-
imize gastric distention and increased likelihood of aspiration.
In the emergent, desaturating patient, or when preoxygenation
is limited or impossible, BVM ventilation throughout RSI may
be considered. No data support or refute this ­practice, and
the clinician must use best judgment in obtaining an airway.
Preoxygenation may be difficult if the patient is combative
or if anatomic positioning is suboptimal, and even transient
hypoxemia may be dangerous to the patient with TBI or hem-
orrhagic shock.
With trained providers, RSI of the trauma patient has been
reported to be successful on the first attempt more than 90%
of the time.19,40,41,49 In the remaining cases, knowledge of the
local difficult airway algorithm becomes essential. Providers
vary in their skills, institutions vary in available equipment,
and time pressures of an emergent intubation makes creative
thought difficult. The adage that “no one gets smarter in an
emergency” is particularly apropos in dealing with the air-
way of a trauma patient. It is therefore incumbent on every
­anesthesiologist to plan for the steps to follow if a given intu-
bation proves c­hallenging. Some “difficult airway” carts
include complex equipment, which is associated with com-
plications,50 and alternative devices are used less frequently.51
Small sets of more frequently used equipment are more helpful
in ­emergency situations.52
Every anesthesiologist should be familiar with the ASA
Difficult Airway Management Algorithm,53 modified for
trauma,18 which should be followed in most cases. The
­algorithm for emergent intubations is considerably simpler,
because awakening the patient usually is not a viable option.
Successful intubation by whatever route should ideally be
confirmed by multiple methods, including the detection of
carbon dioxide (CO2) in exhaled breaths. In areas where intu-
bation and mechanical ventilation are common, such as the
ED trauma bay or ICU, continuous-waveform capnography
is highly recommended. For other areas, a disposable CO2
­capnometer should be part of the emergency intubation setup.
Exhalation of CO2 is possible only in patients with a perfus-
ing rhythm; thus, patients with no cardiac output may ­produce
no exhaled CO2. The lack of positive capnometry despite a
properly placed ETT may be the first indication in the field
or remote setting that cardiac arrest has occurred. Even with
cardiopulmonary resuscitation in progress, the patient may
still produce little or no detectable CO2. In these patients,
­successful intubation should have been confirmed by initial
DL examination, with auscultation confirming bilateral breath
sounds, the absence of gastric sounds, the presence of equal
chest rise, and misting in the tube, or by the use of an esopha-
be considered, as opposed to improperly pulling a correctly
placed ETT.
After confirmation of successful intubation, the anesthesi-
ologist in some trauma centers is responsible for assessment
of hemodynamic stability after induction, initial ventilator
settings, vascular access, and ongoing sedation and analgesia.
 Chapter 17  Trauma and Acute Care 495

Patient awareness during intubation and mechanical venti-

lation is a significant problem in trauma cases, particularly
when hypotension limits the amount of induction or sedation
agent, and paralytic agents have been used to facilitate diag-
nostic studies or minor procedures. Ketamine, scopolamine,
or small amounts of a benzodiazepine may be considered in
patients at particular risk for awareness. Awareness moni-
tors, such as the Bi-Spectral Index, may be considered in such
cases, although at present these do not constitute the standard
of care and should not interfere with the application of defini-
tive care that will allow adequate levels of sedation. Even if not
directly involved in this phase of care, the anesthesiologist can
contribute substantially to the prevention and recognition of
this problem, as well as to the education of other hospital staff.
Airway and breathing are the first priorities in trauma care,
followed closely by assessment of the circulation—the ABCs.5
The anesthesiologist may share responsibility for hemody-
namic management in the ED with other members of the
trauma team, but in the OR this becomes their primary task.
In the ED the anesthesiologist should be ready to take pri-
mary responsibility for the ABCs if this critical task is being
neglected.

Damage Control and Fluid Resuscitation
Pathophysiology. Trauma causes disruption of blood ves-
sels of all sizes, and hemorrhage, whether frank and focused or
insidious and diffuse, is a hallmark of trauma. Although low-
pressure bleeding can be managed expectantly or with sim-
ple techniques, in other trauma patients, active intervention is
required to prevent hypovolemia, hypotension, and exsangui-
nation. Although control of hemorrhage is paramount and may
be easy to achieve in some injuries, airway management must
remain the priority, and practitioners need to avoid d ­ istraction
in completing the ABCs (Fig. 17-2). Uncontrolled, life-threatening
and noncompressible ­hemorrhage can occur from venous
bleeding in “open book” ­pelvic fractures and in some severe
liver injuries (Figs.  17-3 and 17-4). Life-threatening hemor-
rhage occurs into one of five “compartments,” summarized in
Table 17-3.7 Although not a complete list, patients with any of
the injuries in Box 17-3 should be considered at high risk of
FIGURE 17-2  Penetrating extremity injury with potential for life-
threatening hemorrhage.
death. Early diagnosis and control of hemorrhage are essential,
but equally important are nonsurgical hemorrhage control
and ongoing resuscitation, which may be underappreciated.
Shock is the term used to describe the complex pathophysi-
ology that arises from inadequate tissue perfusion (Box 17-4).
Shock was first described in trauma patients, in whom hemor-
rhage is a common cause.54 Trauma patients may exhibit shock
caused by an aberration in any or all components of cardiovas-
cular physiology: preload (mechanical impairment of blood
flow, as in tension pneumothorax or cardiac tamponade), con-
tractility (cardiac dysfunction, as in blunt myocardial injury
or secondary to severe TBI, ingestion of toxins, or ­anesthetic
overdose), and afterload (spinal cord injury, m ­ edications).
Affecting preload, hemorrhage is considered to be the source

FIGURE 17-3  A, “Open book”

pelvic fracture with disruption
of multiple venous plexuses.
B, External pelvic compression
with a “binder” (a sheet may
also be used) to reapproximate
bone edges and stop
hemorrhage.

A B
 496 ANESTHESIA AND UNCOMMON DISEASES

BOX 17-4   n  SYMPTOMS OF SHOCK

Patient Appearance
Pallor
Diaphoresis
Prolonged capillary refill
Poor skin turgor
Mental status
Agitation, then progressive obtundation
Thirst

Vital Signs
Hypotension (automated devices may be inaccurate)
Narrowed pulse pressure
Tachycardia
Tachypnea
Diminished or absent pulse oximeter signal

Laboratory Signs
FIGURE 17-4  Severe liver laceration. Metabolic acidosis
Elevated serum osmolarity
Elevated serum lactate
Decreased hematocrit (takes time to develop)
TABLE 17-3  n Sites of Exsanguinating Hemorrhage: Coagulopathy
Diagnostic and Therapeutic Options

Diagnostic Therapeutic
Compartment Mechanism Options of shock in all trauma patients until it is definitively ruled out.
Much of the ATLS curriculum is devoted to this important
Chest Auscultation Tube thoracostomy
Chest radiography Exploratory diagnostic and therapeutic process.5
Computed thoracotomy Hemorrhage reduces circulating blood volume, ­leading to
tomography decreased preload and reduced cardiac output. Vasoconstriction
Abdomen FAST Nonsurgical
and increased inotropy mediated by the sympathetic ­nervous
Computed management system allow for continued blood flow to vital organs in
tomography Angiographic the presence of blood loss as severe as 40 mL/kg, the ­cutoff
embolization between a class III and class IV hemorrhage per ATLS guide-
Exploratory lines, or about 2 L of the 5 L of total blood volume in a 70-kg
laparotomy
­previously healthy patient. Acute blood loss in excess of this
Retroperitoneum Computed Pelvic stabilization amount causes a critical reduction of perfusion to the heart
tomography Angiographic and brain, ­manifesting as coma, pulseless electrical a­ ctivity,
Angiography embolization
and death. Lesser blood loss may also be lethal, p ­ articularly
Thigh or thighs Physical Fracture reduction in elderly patients or those with medical comorbidities,
examination Fracture fixation because reduced ­perfusion leads to anaerobic metabolism
Radiography Vascular and ­accumulation of lactic acid and other toxins. Individual
Angiography exploration
cells react to ischemia by hibernation (reduction of all non-
“The street” Physical Direct pressure essential ­ activities), a­poptosis (programmed cell death),
(outside the examination Surgical closure or outright necrosis, ­ depending on the organ system in
body) Paramedic report
­question.55 Many ischemic cells, ­especially gut and muscle
FAST, Focused assessment by sonography for trauma. cells, react to i­schemia by absorption of e­ xtracellular fluid56;
this loss of ­potential ­circulating volume can be e­ xacerbated
by ­overaggressive or repetitive ­“running of the bowel” by
the ­surgeon, which also causes edema and dysfunction of
BOX 17-3   n INJURIES ASSOCIATED WITH LIFE-
THREATENING HEMORRHAGE the ­luminal wall. The end result of this t­issue edema is both
locally and ­ systemically ­ disruptive, by ­ clogging capillary
Traumatic aortic injury pathways ­(no-reflow ­phenomenon) and further ­hampering
Inferior vena cava (IVC) injury
autoresuscitation ­
­ (reclamation of ­ interstitial volume into
Femoral or iliac artery injuries
High-grade pelvic fractures (“open book”) vascular spaces). Ischemic cells also release inflammatory
­
Severe pulmonary contusions/lacerations mediators, triggering a chemical cascade that perpetuates the
Amputation pathophysiology of shock long after ­adequate circulation is
restored.57
 Chapter 17  Trauma and Acute Care 497

The “dose” of shock absorbed by the body, a summa-

TABLE 17-4  n Goals for Fluid Resuscitation during
tion of the depth of hypoperfusion and its duration, largely Active Hemorrhage
­determines the patient's clinical outcome, ranging from a mild
inflammatory response to organ system failure to death. The Parameter Goals
typical young male trauma patient has an enormous com-
Total fluids Adequate to prevent worsening of shock
pensatory reserve and may achieve normal pulse and blood
(increasing lactate or base deficit)
pressure while still significantly fluid depleted and highly
vasoconstricted. This phenomenon, known as the occult Vital signs Systolic blood pressure: 80-100 mm Hg
­hypoperfusion syndrome, is associated with a high incidence of Heart rate <120 beats/min
Pulse oximeter functioning
organ system failure if not recognized and corrected.58
Isotonic crystalloid infusion increases circulating volume Blood content Hematocrit 20%-30%; higher if risk
and preload, producing an immediate increase in cardiac factors for ischemic coronary disease
Normal prothrombin and partial
­output and blood pressure. Volume therapy is a double-edged
thromboplastin time
sword, however, as increased BP before adequate surgical and Platelet count >50,000/mm3
medical hemostasis is achieved can lead to increased bleeding Normal serum ionized calcium
from open vessels and rebleeding from previously h ­ emostatic
Temperature Normal core temperature
injuries (“popping the clot”), in part caused by decreased
blood viscosity and relaxation of compensatory vasonstric- Anesthetic depth Fluid therapy to allow appropriate
tion.59 Further, aggressive crystalloid infusion dilutes red anesthetic and analgesic depth
blood cell (RBC) mass and clotting factor concentration, pos- Overly aggressive resuscitation must be weighed against the risk of
sibly resulting in decreased O2 delivery at the tissue level and exacerbating hemorrhage.
an increase in blood loss, respectively. Unless properly heated,
such infusions may also lead to hypothermia, which should be
catheter) and by immediate and appropriately repeated mea-
cautiously guarded against using fluid warmers and forced-air
surements of arterial blood gases (ABGs), complete blood
warmers. Studies of uncontrolled hemorrhagic shock in rats,60
chemistry, clotting function, and serum lactate determina-
swine,61 sheep,62 and dogs63 have all demonstrated improved
tion. Toxicology screening and electrocardiography may be
survival when initial fluid therapy is titrated to a lower-than-
useful in discovering and addressing underlying reasons for
normal systolic BP (70-80 mm Hg). This finding is supported
suboptimal response to resuscitation. Patients who arrive to
by two human trials.64,65
the hospital with signs of coagulopathy on admission (­ elevated
Dilution of RBC mass is inevitable during early resuscita-
activated partial thromboplastin time) have likely developed
tion, because losses to hemorrhage are compounded by intra-
the “acute coagulopathy of trauma” and are at increased
vascular recruitment of extracellular fluid and exogenous
m
­ ortality risk.67,68
crystalloid administration, the phenomenon of autotransfu-
Response to fluid therapy will provide important diag-
sion. A hematocrit measured soon after hemorrhagic trauma
nostic information. Most patients in shock will demonstrate
may show little change, as whole blood is being lost and the
an improvement in vital signs after bolus fluid administra-
RBC percentage in the remaining volume does not change.
tion. In “responders,” those who have achieved spontaneous
Thus, a stable hematocrit in the face of ongoing loss is mean-
hemostasis (i.e., those with lung injury or peripheral orthope-
ingless information. The longer hemorrhage and resuscita-
dic injuries), the improvement in vital signs will be sustained.
tion persist, the more the hematocrit will fall. Loss of RBCs
“Transient responders,” those with ongoing hemorrhage (e.g.,
leads to decreased blood viscosity, allowing for a compensa-
abdominal visceral trauma, pelvic fracture) will show initial
tory increase in blood flow but a decrease in O2 content, and
improvement in vital signs that decays over about a half hour
tissue O2 delivery begins to decrease. Fluid resuscitation after
and are in need of urgent diagnostic studies and therapeutic
massive hemorrhage will result in extensive hemodilution
procedures. “Nonresponders,” those who do not respond to
and coagulopathy; this hemodilution affects procoagulants
an initial fluid bolus, either have a nonhemorrhagic source of
as well as anticoagulant, profibrinolytic, and antifibrinolytic
shock (e.g., obstruction to venous return to heart, spinal cord
­components of the coagulation cascade.66 Factor replacement
injury, cardiac disease) or are bleeding rapidly.
early in resuscitation, with plasma, platelets, and occasionally
The initial choice of crystalloid likely does not matter; it is
cryoprecipitate, may mitigate a severe coagulopathy.
critical, however, to understand the risks and benefits of each
Evaluation. The diagnostic characteristics of hemorrhagic type of fluid infused and, in life-threatening hemorrhage, to
shock and goals for resuscitation are listed in Box  17-4 and begin blood transfusion early. Hemorrhage control depends
Table 17-4. Control of bleeding is the overarching priority in on 13 factors in the coagulation cascade, none of which is
treatment, and nothing must interfere with the indicated diag- contained in crystalloid, packed red blood cells (PRBCs) or
nostic or therapeutic procedures shown in Table 17-3. Relevant in cell-saver blood. Dilutional resuscitation of hemorrhagic
patient physiology is assessed by continuous m ­ easurement of shock with colloid (e.g., hetastarch) or crystalloid reduces the
vital signs (facilitated by early placement of arterial p
­ ressure concentration of coagulation factors in the circulating blood
 498 ANESTHESIA AND UNCOMMON DISEASES
volume and impairs hemostasis.69 Resuscitation with normal
saline results in hyperchloremic acidosis that may be associ-
ated with systemic vasodilation, increased extravascular lung
water, and coagulopathy.70Ringer's lactate became the ­standard
of care for fluid resuscitation in the 1960s in an effort to replete
bicarbonate in patients with severe dehydration.71 Ringer's
lactate has recently been found to be p ­ roinflammatory and
to activate neutrophils, which are primary effector cells in
reperfusion injury, particularly in the formulations that
contain the d-lactate isomer (it is not oxidized by l-lactate
dehydrogenase, and therefore accumulates, and activates
neutrophils).71Plasmalyte is a “balanced physiologic” solution
that contains sodium, potassium, chloride, acetate, gluconate,
and magnesium, but not calcium, and is therefore compati-
ble with blood infusions. Small studies in animals have shown
increased mortality with Plasmalyte resuscitation, possibly
caused by the peripheral vascular resistance (PVR) effects of
magnesium72; no large resuscitation studies have been done.
Although there is no “optimal” crystalloid, these solutions
are still the fluids of choice for initial resuscitation in most
patients following hemorrhage. The anesthesiologist must
understand, however, that large volumes of replacement with
crystalloid result in distribution throughout the entire extra-
cellular compartment, resulting in massive fluid overload and
edema, with complications such as acute respiratory failure,
hepatic failure, renal failure, sepsis, and most recently, abdom-
inal compartment syndrome.69 Despite multiple randomized
controlled trials (RCTs) comparing albumin and colloids to
crystalloids, no strong data show that colloids are associ-
ated with improved survival in trauma or burn patients.73
Multiple studies of hypertonic saline solutions (3%, 5%, 7.5%)
for trauma resuscitation have been encouraging, although an
RCT of 7.5% saline, 7.5% saline/6% dextran, and 0.9% saline
(Resuscitation Outcomes Consortium) failed to show a differ-
ence in 28-day survival.
Because the civilian community has not yet adopted a
limited-fluid resuscitation strategy as has the military, and
because clinical trials have shown no significant benefit with
hypertonic fluids, standard use of these fluids cannot be rec-
ommended at this time.74 The recognition that use of fluid
replacement in severe injuries that was as near to whole
blood as possible (i.e., blood, plasma, and platelets in a 1:1:1
ratio), resulted in increased survival and decreased complica-
tions.75–77 This concept of “damage control resuscitation” has
recently become standard of care.
Preparation. Resuscitation of the actively hemorrhaging
patient requires large-bore, high-flow intravenous access, pref-
erably through at least two separate catheters. Warmed IV flu-
ids are highly recommended, especially early in resuscitation.
Commercial fluid-warming technology is highly effective and
should be used as frequently (or more so) in the trauma bay
as in the OR. Rapid infusion systems can warm and deliver
large volumes quickly and may be lifesaving in the patient
with rapid and uncontrolled hemorrhage. However, resuscita-
tion with a rapid-infusion system targeted to a normal blood
pressure, prior to hemorrhage control in trauma patients, is
associated with an increase in mortality.78
The ability to rapidly administer uncrossmatched type
O blood may be lifesaving. Many trauma center blood banks
and EDs maintain a supply for this purpose. Crossmatched
blood, plasma, and platelets should be requested at the earliest
moment that a massive transfusion is anticipated. Additional
personnel, from both the anesthesia and the nursing staff,
should be mobilized early to address the multiple needs of
emergency surgery and resuscitation.
High-level trauma centers will maintain a designated trauma
OR that is kept warmed and ready with drugs, IV fluids, and
rapid-infusion devices. As opposed to elective operative cases
where the surgery begins after anesthesia has instituted appro-
priate access and monitoring, the primary goal in treating a
patient with exsanguination is hemorrhage control; therefore
it may be necessary for anesthesia access and monitoring to be
obtained concurrently with surgical intervention.
Intraoperative Considerations. Resuscitation must be
carefully choreographed with diagnostic and therapeutic
procedures such that tissue perfusion is optimized without
unnecessarily large increases in blood pressure that can exac-
erbate uncontrolled hemorrhage. Recent understanding of
the potential for rebleeding and dilution has led to a change
away from the traditional ATLS approach of rapid crystalloid
infusion to one of deliberate, controlled fluid administration,
titrated to specific physiologic end points (see Box 17-4).
Replacement of RBCs is essential to limiting the severity
and duration of shock after hemorrhage. PRBCs should be
administered early in the resuscitative process, using uncross-
matched type O units if necessary. Adverse reaction to this
therapy is extremely unlikely: more than 100,000 units of
uncrossmatched blood were administered during the Vietnam
War without a single documented case of fatal transfusion
reaction, compared with the nine cases that occurred in the
600,000 crossmatched transfusions.79 Immediate transfusion
of type O blood is sufficiently safe and beneficial that it should
be considered for any patient presenting in extremis from
hemorrhagic shock. The most appropriate target hematocrit
for resuscitation must be individualized on the basis of age,
specific injury pattern, pre-existing disease, and the potential
for further hemorrhage.
Coagulopathy resulting from acute consumption of coagu-
lation factors is likely in any patient losing more than a sin-
gle blood volume (~5 L in 70-kg adult) or receiving more than
10 units of RBCs80 (Fig. 17-5). Because coagulopathy is more
easily prevented than treated, early administration of plasma
to any patient who has lost or will lose this amount of blood
is highly recommended. Timely initiation of a massive trans-
fusion protocol is associated with improved survival and
reduced transfusions.81,82 This was first described in military
resuscitation,83 but it has since also become a standard of care
at civilian trauma centers.76 This has come to be known as a
“1:1:1” resuscitation, suggesting that 1 unit of plasma should
be transfused per each RBC unit, and that platelets should be

FIGURE 17-5  Patient in angiography for traumatic hemorrhage
who has developed a dilutional coagulopathy after massive fluid
resuscitation, hypothermia, and acidosis.
administered similarly (remembering that a “pack” of platelets
is pooled from multiple donors and may represent 4-6 “units”).
Early activation of a massive transfusion protocol is asso-
ciated with improved patient survival.45 Plasma should be
ordered from the blood bank for any patient presenting emer-
gently to the OR with symptoms of acute hemorrhagic shock.
A ratio of 1:1 replacement of RBCs and plasma is appropri-
ate for any patient who has lost or is likely to lose more than
1 blood volume, although this should be guided by clinical
assessment and, time permitting, judicious laboratory evalu-
ation. Although concurrent plasma factor replacement with
ongoing blood infusion will promote clot formation, factor
levels (V, VII, VIII, protein S, and von Willebrand) decrease
with storage, so each patient's response will be variable and
may depend on the age of the blood products.84 Platelet count
usually remains adequate longer than coagulation factors, and
platelet therapy is therefore required less often than plasma.
Transfused platelets have a very short functional life span in
the circulation and pose both a significant immune stimulus
and an infective risk. However, factor replacement and platelet
therapy should not be delayed while awaiting laboratory values
in patients with exsanguinating hemorrhage. A multicenter
validation of a score to predict which patients will need a mas-
sive transfusion suggests that penetrating trauma, ED systolic
BP less than 90 mm Hg, heart rate greater than 120 beats/min,
and positive FAST score (focused abdominal sonography for
trauma) are indicators of severe hemorrhage.45
Chapter 17  Trauma and Acute Care 499
Coagulation factor concentrates and cryoprecipitate may
not offer a benefit beyond that of plasma infusion in the hem-
orrhaging trauma patient, unless fluid overload is a significant
risk, as in the coagulopathic elderly patient, or the patient is
known to have a specific factor deficiency. In exsanguinating
patients, however, fibrinogen replacement (with cryoprecip-
itate) may enhance clot stability,85 because fibrinogen is the
first coagulation factor to become critically low in patients
with major hemorrhage.86 Anecdotal reports after the early
use of activated recombinant factor VII (rFVIIa) describe
rapid resolution of traumatic coagulopathy after administra-
tion of 20 to 100 units.87 However, the large CONTROL trial,
which randomized patients who had bled 4 to 8 RBC units
to rFVIIa or to placebo, did not show a difference in 30-day
mortality.88 Patients who received rFVIIa had fewer units of
transfused blood overall, and with no increase in thrombotic
complications compared with placebo, it seems safe to use
when indicated.
Electrolyte abnormalities are common during resuscita-
tion from hemorrhage. Hyperosmolarity may result from
alcohol ingestion, dehydration, hypovolemia, or administra-
tion of normal saline (NS). Mild hyperglycemia secondary to
high circulating catecholamine levels is expected. Neither of
these conditions mandates specific treatment during resusci-
tation, because both will resolve with restoration of adequate
intravascular volume. Hyperchloremic metabolic acidosis is
a significant risk for overresuscitation, especially with mildly
hypertonic solutions such as NS,89 and can be managed with
the titrated addition of hypotonic fluids.
Hypocalcemia arises from chelation of circulating calcium
by the citrate or adenosine additives found in banked blood
products. IV administration of calcium is indicated in patients
with low serum Ca++ levels and should be considered for empiric
administration in the case of massive transfusion, p ­ articularly
in the presence of hemodynamic i­ nstability. Serum bicarbonate
levels will be lower than ­normal in the hemorrhaging patient as
a result of increased lactic acidosis and impaired renal blood
flow. Some recommend administration of ­bicarbonate ­solutions
to increase systemic pH in ­acidotic patients, to enhance the
functioning of important protein systems, including coagula-
tion and catecholamine receptors.90 Bicarbonate also supports
cardiac ­contractility and can be ­useful in cardiopulmonary
­collapse.91 The ­clinical ­utility of bicarbonate ­therapy, however,
has never been proved. Vasopressin ­(antidiuretic hormone) is
emerging as an important advance in the treatment of a ­variety
of shock states. Plasma levels of vasopressin increase within
a few minutes of circulatory arrest and also rise in response
to hemorrhage, in which endogenous vasopressin release is
an important ­vasoconstrictor mechanism. Vasopressin does
not depend on pH for its activity,92 so it would therefore
offer a ­theoretic advantage over other ­vasoactive agents, but
there are no large, prospective human trials. Adequate fluid
­resuscitation remains the primary ­therapy for restoration of
normal ­acid-base status.
Early resuscitation has evolved toward less aggressive fluid
administration. Late resuscitation is characterized by the
 500 ANESTHESIA AND UNCOMMON DISEASES
need to completely restore and support perfusion, usually in
the ICU. To do so requires the practitioner to look beyond
the vital signs for a more direct measure of tissue perfusion.
The speed with which serum lactate level normalizes after
shock is strongly associated with the risk of death from organ
system failure.93 End points of resuscitation should focus on
organ-specific signs of recovery of function: improved lung
function, cardiac contractility, and vasomotor tone; clear-
ance of toxins by the liver and kidney; and absence of infec-
tious complications, common after severe traumatic injury.
Although the overall mortality from multiple trauma has
declined in the past decade, there has been no ­significant
decrease in ­ mortality from sepsis after severe trauma.
Risk factors for posttraumatic sepsis are male gender, age,
­pre-existing m ­ edical conditions, Glasgow Coma Scale (GCS)
score of 8 or less, high injury severity score (ISS), number of
­injuries, n
­ umber of RBC units transfused, number of surgical
­procedures, and laparotomy.94
SPECIFIC CONDITIONS
Traumatic Brain Injury
Traumatic brain injury causes at least half of all deaths from
trauma.95 As with hemorrhagic shock, the pathophysiology
of TBI consists of both the primary injury, in which tissue is
disrupted by mechanical force, and a secondary physiologic
response. Because minimizing secondary injury is critical
to outcome, the anesthesiologist plays an important role in
­managing these patients in both the OR and the ICU.
Pathophysiology. Traumatic brain injury is classified as
mild, moderate, or severe, depending on the GCS score on
admission. Mild TBI (GCS score, 13-15) is the most common.
Although mild TBI does not usually necessitate intensive
treatment, patients may be significantly debilitated by post-
concussive symptoms, including headaches, sleep and mem-
ory disturbances, and mood swings.96 Progression of mild
TBI is rare but may be catastrophic. Research, case reports,
and media coverage of U.S. soldiers returning from the Iraq
and Afghanistan wars have highlighted the long-term and
­sometimes violent aftereffects of mild TBI that were previ-
ously underrecognized: depression, mood changes, aggressive
­behavior, depression, and memory loss.97,98
The most frequently proposed cellular mechanism in mild
TBI is diffuse axonal injury (DAI), associated with ­alterations
in many physiologic processes. There is an alteration in
­proteostasis; proteopathy is often evident at the histopatho-
logic level. Here, the pathways of idiopathic and ­posttraumatic
neurodegeneration apparently overlap, since identical protein
­aggregates accumulate in both conditions. As early as 2 hours
after severe TBI, increased levels of soluble amyloid-β (Aβ)
peptide and deposition of amyloid plaques are evident in
brains of 30% of survivors, regardless of their age. An acute,
single-incident TBI is also found in the history of 20% to 30%
of patients with Alzheimer's disease or parkinsonism, but in
only 8% to 10% of control subjects.
A broader military probe in 2010 found that up to half of
soldiers with posttraumatic stress disorder (PTSD) or depres-
sion after mild TBI while deployed reported misuse of a­ lcohol
or aggressive behaviors (punching, fighting) following their
return to society.98 Rates of depression and PTSD were higher
at 12 months than at 3 months after deployment. Many soldiers
do not seek help, but a new U.S. Army program Re-Engineering
Systems of Primary Care Treatment in the Military (RESPECT-
MIL) for returning soldiers, families, support systems, and the
public seeks to decrease the stigma traditionally associated
with difficulties with reintegration into society.
The U.S. National Football League, along with college
and high school football associations, has also begun a more
­cautious approach to the management of players with a “con-
cussion.” Chronic traumatic encephalopathy (CTE), a condi-
tion typically seen in retired or aging athletes, was recently
reported in a college football player who committed suicide.99
The diagnosis was unique in two ways: he was the first active
college athlete to be found with the disease, and unlike other
known victims of CTE, he was never diagnosed with a concus-
sion. However, this player had been a lineman and a linebacker,
positions that typically involve multiple hits to the head d
­ uring
every game and practice, with estimates of approximately 1000
hits per season or more. CTE is traditionally associated with
neurobehavioral disorders and bizarre behavior and is also
called dementia pugilistica, or boxer's dementia. Career box-
ers sustaining repeated blows to the head and concussions
may develop the syndrome. CTE is likely caused by large
­accumulations of tau proteins in the brain that kill cells in the
regions responsible for mood, emotion, and ­executive func-
tioning. Tau proteins are also found in the brains of patients
with Alzheimer's disease and dementia.
Players with mild TBI may be evaluated in the trauma bay
and discharged to home, with no need for anesthesia contact.
However, recognizing the potential long-term c­ onsequences
can be helpful if they present to the OR for other cases,
such as fracture fixation. A systematic review of “brain con-
cussion” management identified 4319 articles; when the
search term “mild TBI” was used, 2509 articles were identi-
fied, and this decreased to 39 articles with “return to play” as
k­ eywords.100 Although only few studies address this topic, the
Vienna Statement, Prague Statement, American Academy of
Neurology, U.S. Team Physician Consensus Statement, and
U.S. National Athletic Trainers Association Position Statement
all agree on the following points:
n There should be a period of rest, aerobic exercise, and drills
before players with mild TBI return to play (each ~24 hours),
in addition to evidence of normal cognitive f­unction, and
no recurrence of symptoms with exertion.
n There is an age-dependent difference in recovery of func-
tion; highschool athletes take an average of 30 days to
recover normal cognitive function, college athletes 7 to
10 days, and professional athletes only 3 to 5 days.
Moderate TBI (GCS 9-12) is more likely to be associated
with intracranial lesions that require surgical evacuation.

These patients have a higher potential for deterioration and are
more susceptible to secondary insult if not carefully managed.
Severe TBI (GCS ≤8) is a highly lethal condition, often asso-
ciated with intraparenchymal or intraventricular hemorrhage
or evidence of DAI on cranial CT. Magnetic resonance imag-
ing (MRI) is more sensitive than CT in the detection of trau-
matic brain lesions, especially in nonhemorrhagic DAI.97,101 A
patient who has a negative brain CT with a poor neurologic
status should be assumed to have DAI, especially without con-
founding factors such as intoxication or drugs. Patients with
severe TBI are usually unable to maintain airway patency
and may have diminished or absent respiratory drive, with
inability to protect the airway from aspiration. Most patients
presenting to the OR will have severe TBI, with elevation of
intracranial pressure (ICP) caused by hemorrhage (epidural,
subdural, or intraparenchymal), edema, or both. Failure to
promptly relieve elevated ICP will lead to herniation of brain
tissue, loss of brain blood flow, and death. The surgical goal
is resolving increased ICP and controlling any active hemor-
rhage. Even brief periods of hypotension or hypoxemia can
affect outcomes in head injury.98,102 An investigation of the
impact on outcome of hypotension (systolic BP <90 mm Hg)
and hypoxia (Pao2 ≤60 mm Hg or apnea or cyanosis in the
field) revealed that these were independently associated with
significant increases in morbidity and mortality from severe
head injury. Hypotension was profoundly detrimental, occur-
ring in 34.6% of these patients and associated with a 150%
increase in mortality.
Evaluation. Along with imaging studies, the neurologic
examination is of critical importance in the preoperative
assessment of the TBI patient. Recovery from TBI is a grad-
ual process. The sedative effects of anesthetic medications may
be exaggerated, and the trauma patient will seldom improve
immediately at the conclusion of cranial decompression. It
is important to monitor for deterioration in the neurologic
examination so that critical serial imaging studies and appro-
priate ICU management can commence as soon as possible.
More controversial is the timing of noncranial surgery in
the patient with TBI. Transient hypotension or hypoxemia
associated with orthopedic surgery may lead to worsening
of neurologic injury, whereas delay in repair of fractures may
increase the risk of pulmonary complications and sepsis.99,103
Although no definitive prospective study has been conducted,
recent retrospective work suggests that early surgery with
strict attention to hemodynamic goals does not necessarily
worsen TBI.100,104
The anesthesia provider has the responsibility for ensuring
adequate O2 delivery to the injured brain and the p
­ enumbra, in
an effort to prevent any further damage. Current Brain Trauma
Foundation guidelines recommend a cerebral ­ perfusion
­pressure (CPP) of 50 to 70 mm Hg; targeting a higher mean
arterial pressure (MAP) is associated with a higher ­incidence
of ARDS and mortality.101,105
Preoperative Preparation. Early intubation of the TBI
patient may be required because of combative or agitated
Chapter 17  Trauma and Acute Care 501
behavior, the need for diagnostic studies before reaching the
OR, and the potentially catastrophic consequences of respira-
tory depression or pulmonary aspiration. In fact, most patients
with moderate or severe TBI will present to the OR having been
intubated in the field or ED. There is no ­consensus on whether
patients with severe TBI should be intubated in the field or
in the ED on hospital arrival; studies show i­mprovement with
each management strategy.106–108 Where intubation occurs
likely depends more on the ability of ­prehospital providers
to manage an airway acutely, and more importantly, their
­training in RSI and access to emergency ­airway drugs.
Arterial pressure monitoring is required for any intra-
cranial procedure, because the dramatic BP swings that can
occur throughout such cases need to be closely monitored and
limited to the extent possible. Large-bore IV access is neces-
sary because blood loss from the open scalp or from the brain
parenchyma can become excessive, particularly in patients with
severe TBI and early onset of coagulopathy. Other m ­ edications
likely beneficial include induction or ­maintenance agents such
as thiopental, antiepileptics such as phenytoin (Dilantin) or
levetiracetam (Keppra), diuretics such as furosemide (Lasix)
or mannitol, and hypertonic saline (HTS). Patients with severe
TBI should receive a 7-day course of seizure prophylaxis with
either phenytoin or levetiracetam.102 If not administered in the
ED, the loading dose needs to be given in the OR. Although
many clinicians still use mannitol as their osmotic diuretic of
choice to decrease ICP, increasing evidence shows that HTS
solutions are more effective. A meta-analysis of RCTs found
that HTS is more effective than mannitol for the treatment of
elevated ICP.109 HTS can also be effective in lowering ICP after
failure of standard mannitol therapy.110,111 In addition to effects
of volume expansion, improved cardiac output, improved cere-
brospinal fluid (CSF) absorption, and immunomodulation,112
HTS may be superior to mannitol with respect to brain oxy-
genation and cerebral hemodynamics.110 It is always ­helpful to
know what therapies a patient has received in the ED or ICU
before coming to the OR.
Intraoperative Management. Patients with mild TBI pose
few additional anesthetic risks but are more susceptible to the
effects of sedative medication. Benzodiazepines should be
used judiciously throughout the perioperative period because
they can easily complicate the neurologic examination. The
anesthesiologist should strive to have the patient's sensorium
as clear as possible as rapidly as possible after any anesthetic.
Any change from the patient's preoperative mental status not
attributable to anesthetic drugs is an indication for immediate
repeat head CT and neurosurgical reassessment.
The care of patients with moderate TBI consists of serial
assessment of neurologic function, with repeat CT at regu-
lar intervals. If close monitoring is not possible, owing to the
need for general anesthesia or sedating medications, then
­continuous invasive measurement of CPP is indicated.113 An
ICP monitor is recommended in any patient with moderate
or severe TBI undergoing noncranial surgery likely to last
longer than 2 hours. Patients with severe TBI are particularly
 502 ANESTHESIA AND UNCOMMON DISEASES
challenging. Early, rapid focus on restoring ­systemic homeo-
stasis and maximizing perfusion to the injured brain will
produce best possible outcomes. Again, hypoxemia (Pao2
­ from the cranium, lowering ICP and improving CPP as long
<60 mm Hg) or hypotension (systolic BP <90 mm Hg) in
patients with severe TBI is associated with a significant
increase in ­mortality.102 Management requires a highly skilled
facility, close ­cooperation among providers, and a stepwise
implementation of therapies, as shown in Figure 17-6.
Aggressive restoration of intravascular volume is ­indicated
to maintain intracranial perfusion, especially if associated
pulmonary injuries necessitate the use of high mean air-
­ ful for control of elevated ICP but may make serial examina-
way pressures to support oxygenation. Hyperventilation,
­previously a mainstay in TBI management for its ability to
lower ICP through reduction of intracranial blood flow, is no
longer appropriate unless the patient shows signs of immi-
nent brainstem herniation, because this reduction of flow puts
ischemic brain tissue at further risk for necrosis or apopto-
sis. Hyperventilation is indicated only for patients who pres-
ent with strong lateralizing signs en route to CT and emergent
decompressive surgery.102
A systolic BP of 90 mm Hg should be maintained in patients
with severe TBI, with MAP of 50 to 70 mm Hg until invasive
ICP monitoring can be placed. Previous guidelines suggested
maintenance of CPP at a minimum of 70 mm Hg at all times;
increasing MAP to greater than 70 mm Hg may not improve
outcome, particularly in patients in whom autoregulation is
lost.102 Contrary to past practice, the patient with severe TBI
should be maintained in a euvolemic state. Fluid resuscitation
is the mainstay of therapy, followed by vasoactive infusions as
needed. Controversy surrounds the appropriate “transfusion
trigger” in patients with severe TBI, and whether these patients
should be treated as other critically ill patients in whom a
hemoglobin (Hb) concentration of 7 g/dL is a proven t­rigger.
Many neurosurgeons prefer an Hb level closer to 10 g/dL
in severe TBI patients, but the most recent data suggest that
blood transfusion itself, rather than the actual Hb value, is
associated with a worse long-term functional outcome.114
Several studies investigating the association of anemia with
outcome in patients with severe TBI have used Hb of 10 g/dL
to define “anemia,” although a few studies used 8 g/dL and one
used 9 g/dL.115 Thus the appropriate trigger for these patients
is unclear, and monitoring of cerebral oxygenation may be a
more appropriate end point.
If surgery is indicated, special care should be taken with
the ventriculostomy drain; both failure of drainage and exces-
sive loss of CSF can occur during transport. Familiarity with
advanced tissue oxygenation monitors, such as those mea-
suring brain tissue oxygen delivery (Pbro2) and oxygen
consumption (the jugular bulb) (Sjvo2) levels can also be
­beneficial. There is an association of poor outcomes with low
Pbro2 (<15 mm Hg), but it is unclear if higher Pbro2 l­ evels
­correlate with improved outcomes. Until there is consensus,
it is ­recommended to maintain Pbro2 above 20 mm Hg by
decreasing O2 demand of the brain (decrease ICP, administer
­analgesia, treat hyperthermia) or by increasing O2 supply to
the brain (increase cardiac output, transfuse RBCs).102
Positional therapy is used in almost every patient with severe
TBI. Elevation of the head facilitates venous and CSF drainage
as the patient is euvolemic. Pulmonary v­ entilation/perfusion
(V/Q) matching may also improve in this ­position, f­ acilitating
maintenance of cerebral O2 delivery. The patient should be
transported to the OR in this position and ­maintained with
the head up during surgery if possible.
Even in patients with severe TBI, analgesics are indicated
for pain arising from coexisting injuries. Sedatives are use-
tion difficult. Propofol is popular because it offers the most
rapid return of neurologic function when discontinued, but
the ­clinician must use this drug cautiously. Large doses of
­propofol sustained over days to weeks have recently been
associated with the development of lethal rhabdomyolysis,
the propofol infusion syndrome.116 This syndrome is more
­common, and should be suspected, in younger patients, those
with severe neurologic injuries, and those who are ­receiving
exogenous vasoactive infusions. The use of sedatives to
­
decrease ICP frequently mandates the use of vasoactive drugs
to maintain MAP. Invasive hemodynamic monitoring with
a central venous or pulmonary artery (PA) catheter, along
with f­requent assessment of lactate, base deficit, c­ ardiac out-
put, systemic vascular resistance (SVR), and central or mixed
venous ­oxygen ­saturation (Svo2) may be necessary to main-
tain appropriate intravascular volume in the presence of
the ­confounding parameters of ongoing shock physiology,
­pharmacologic agents, and mechanical ventilation.
Osmotic diuretic agents are common first-line agents for
severe TBI. Mannitol decreases ICP by drawing edema fluid
out of brain tissue and into the circulation. Mannitol may
also have a secondary benefit as a scavenger of free radicals
and other harmful inflammatory compounds. Hypertonic
saline has a similar osmotic effect on the brain, aids in the
repletion of circulating volume, and may also act as a benefi-
cial i­mmunologic agent. Use of mannitol or HTS will lead to
increased diuresis, necessitating greater attention to adequate
volume replacement so that euvolemia can be maintained. Use
of osmotic agents to reduce elevated ICP is usually titrated to a
serum osmolarity of about 310 to 320 mOsm/L.
Invasive physiologic monitoring, positional therapy,
­sedation, and osmotic diuresis apply to most patients with
severe TBI,113 but the next tier of therapy is reserved for the
subset with intractable ICP elevation. A small percentage may
respond to barbiturate coma, which not only lowers cerebral
metabolic rate but also decreases excitatory neurotransmit-
ters.117 Management of barbiturate coma necessitates ­rigorous
attention to intravascular volume, usually requiring a PA
­catheter and the use of vasoactive and inotropic agents to
maintain CPP.
Decompressive craniectomy is gaining increasing accep-
tance in the management of intractable ICP elevation.
Relieving pressure by removal of a piece of cranium and
­closure with a dural patch may improve outcomes in patients
who might not otherwise survive.118 Randomized studies for
 Chapter 17  Trauma and Acute Care 503

Establish airway, breathing, and circulation

Ventilate to maintain PaCO2 of 35 mm Hg
Provide supplemental O2 to keep PaO2 of
90–120 mm Hg or Spo2  95%
Maintain normothermia
Elevate head of bed to optimize CPP and minimize ICP
Reduce unnecessary noxious stimuli

Maintain systolic BP  90 mm Hg
Insert intraparenchymal or IVC
with transducer leveled at the
ICP monitor
phlebostatic axis
Utilize attached protocol to
manage hemodynamic status
Maintain CPP  65 mm Hg
Keep Hct 30%–33%
Maintain serum sodium
140–145 mg/dL
Intracranial hypertension? No
Obtain bedside lower extremity
duplex Doppler ultrasound  20 mm Hg
24 hours after admission and
weekly thereafter. Yes

Administer sedation (see algorithm)

Consider repeating a brain CT scan

Carefully
Intracranial hypertension? No remove
 20 mm Hg treatment
for ICP
Yes

Insert IVC and drain CSF

Consider repeating a brain CT scan

Intracranial hypertension? No
 20 mm Hg

Hyperventilation to PaCO2 of 30–35 mm Hg

Consider repeating a brain CT scan

Intracranial hypertension? No
 20 mm Hg

Yes

Mannitol 0.25–1.0 g/kg and/or hypertonic saline

(3% or 7.5% [50% chloride and 50% acetate])
Maintain serum Osmo  320 mOsm/L and
keep patient euvolemic
Consider repeating a brain CT scan

Intracranial hypertension? No Carefully

 20 mm Hg remove
treatment
Yes for ICP

Consider repeating brain CT scan

Other second-tier therapies

Decompressive High dose Hyperventilation to PaCO2

craniectomy barbiturate therapy  30 mm Hg
Monitoring Sjvo2, AvjDO2, PbrO2
and/or CBF recommended

FIGURE 17-6  Critical pathway for treatment of cerebral perfusion pressure (CPP). For patients with severe traumatic brain injury.
BP, Blood pressure; Hct, hematocrit; ICP, intracranial pressure; IVC, intravenous catheter; CT, computed tomography; CSF, cerebrospinal
fluid; CBF, cerebral blood flow; Pbro2, brain tissue oxygen delivery; Sjvo2, oxygen consumption (jugular venous bulb); Avjdo2, arteriojugular
venous difference of oxygen.
 504 ANESTHESIA AND UNCOMMON DISEASES
decompression therapy after TBI have required years of sub-
ject r­ecruitment, and although some show decreased ICP,
mechanical v­ entilation, and ICU stay, long-term outcome (at
6 months) is not improved.119 Craniectomy will likely remain
the procedure of choice for mass lesions, but for diffuse injury,
it is still not known which patients will and will not benefit
from decompression. Decompressive laparotomy may also be
indicated in patients with severe TBI if coexisting injuries or
vigorous ­ volume infusion have increased intra-abdominal
compartment pressure to greater than 20 mm Hg,120 a level
likely to have adverse effects on intrathoracic, inspiratory, and
intracranial pressures.
Although vigorous avoidance of fever is an undisputed rec-
ommendation, deliberate hypothermia to reduce the cerebral
metabolic rate remains controversial121 and is not currently
recommended. Corticosteroid therapy for severe TBI has not
proved beneficial and is now contraindicated because of its
high potential for deleterious side effects.102
More recently, the clinical picture of “sympathetic storm”
(also known as “brain storming”) has been described. Typically
seen in younger patients with more severe TBI, but ­possible at
all ages, “storming” is caused by massive catecholamine release.
This was initially recognized in patients with ­nontraumatic
subarachnoid hemorrhage (SAH),122 but storming has since
been appreciated in patients with TBI. Patients with severe
TBI manifest a hyperadrenergic state with adrenal release of
­catecholamines and clinically as tachycardia, hypertension,
tachypnea, mydriasis, and diaphoresis. They may have a greater
than sevenfold increase in norepinephrine, epinephrine, and
metabolites. Most pronounced after the first week of injury,
treatment of storming in patients with TBI c­ onsists of organ
system support and may require extreme ­measures, including
extracorporeal circulation.123,124 TBI should not be considered
to be a contraindication to extracorporeal m ­ odalities, as long
as exquisite attention is paid to the risks of bleeding and local
anticoagulation of the circuit.125,126
A less aggressive treatment available in all hospitals is the use
of beta-adrenergic blockade to decrease the sympathetic out-
flow and to mitigate symptoms. A retrospective review stud-
ied trauma patients with an abbreviated injury score (AIS) of 3
or greater who received β-blockade over a 14-month period.45
“Beta-blocker exposure” was defined as having received
β-blockers for 2 or more days. Of the 420 study patients, the
174 who received β-blocker therapy had a slightly higher
injury severity, with predicted survival of 59.1% and actual
survival of 94.9%; patients who did not receive β-blockers
had predicted survival of 70.3% and actual survival of 80.2%.
Therefore the patients who received β-blockers, despite their
severe injuries, had 5.1% mortality, versus 10.8% mortality in
those who did not receive β-blockers. Randomized prospec-
tive trials are needed to further elucidate this treatment.
Multiple-organ failure associated with neurologic injury
is increasingly recognized as a sequela of the ­initial insult.
Neuroinflammation may be an important ­ mediator of
secondary injury; patients with TBI have elevated CSF
­ mechanics, and the inability to adequately clear secretions.
­cytokine levels, with systemic delivery of these cytokines.
These inflammatory mediators probably play a large part in
the development of nonneurologic organ dysfunction. Of 209
consecutive ­multiple-trauma patients with severe TBI who
required more than 48 hours of intensive care management,
89% developed dysfunction of at least one nonneurologic
organ system. Respiratory dysfunction was most common
(81%), followed by cardiovascular (52%). Although seen in
smaller percentages of patients, hematologic (36%), hepatic
(8%), and renal (7%) dysfunction were also present.127 More
importantly, hospital mortality in this study was associated
with organ system failures: 26% for patients without nonneu-
rologic organ system failure, 40% for those with one organ
system failure, 47% for two failures, and 100% in the small
proportion of patients with three or more nonneurologic
organ failures.127
Spinal cord injury (SCI) is also associated with multior-
gan failure. In a retrospective review over 15 months, of 1028
patients admitted with SCI, 40 were identified with isolated
injury and ICU stay longer than 24 hours (AIS >3, with other
organs excluded). “Organ failure,” defined as failure in at least
one organ system, occurred in 75% of patients by multiple-
organ dysfunction score (MODS) criteria and 85% of patients
by sequential organ failure assessment (SOFA) scoring.128
There was an inverse correlation between the American Spinal
Injury Association (ASIA) score, which defines the motor and
sensory level of injury, and MODS/SOFA scores. Patients with
more severe (higher level or complete) SCI may therefore
­benefit from the specialized care of traumatic SCI units and
rehabilitation centers.
Spinal Cord Injury
Pathophysiology. Spinal cord injury (SCI) with complete
or partial neurologic deficit occurs in approximately 8000
Americans each year.129 High-energy falls or motor vehicle
crashes (MVCs) cause the majority of serious SCIs. Incomplete
deficits, sometimes referred to as “stingers,” typically resolve
within hours to days. Complete deficits imply a total disrup-
tion of the spinal cord and are much less likely to improve over
time. Cervical spine injuries causing quadriplegia are accom-
panied by significant hypotension as a result of inappropriate
vasodilation and loss of cardiac inotropy (neurogenic shock).
Autonomous functioning of the lower cord will return over
days to weeks, with restoration of autonomic innervation and
vascular tone, but without sensory or motor transmission.
Patterns of spinal cord fracture are described in Table  17-5
(see also Orthopedic Injuries later).
Evaluation. Early intubation is almost universally required
for patients with cervical spine fracture and quadriplegia,
because diaphragmatic function will cease in patients with
a deficit above C4. Patients with deficits ranging from C4
to C7 are likely to require early intubation due to the loss of
chest wall innervation, paradoxical and inefficient respiratory
A  retrospective review over 2 years of patients with cervical
 Chapter 17  Trauma and Acute Care 505

TABLE 17-5  n  Types of Spinal Cord Fracture

Type Description

Upper cervical spine Usually fatal; considered to be unstable in survivors; Jefferson, hangman's, and odontoid fractures
(occiput to C2)

Lower cervical spine Flexion with axial loading produces vertebral body compression fractures with possible displacement of
(C3 to T1) fragments; often with ligamentous injury; involvement with posterior elements can cause
unilateral or bilateral jumped facets

Thoracic spine (T2-T10) Flexion-extension injuries most common; with axial loading can produce burst fracture;
displacement of fragments into canal frequently associated with complete cord injury secondary
to smaller canal

Lumbar spine (T11-L1) Classified by mechanism: compression fracture with flexion, burst fracture with axial loading, transverse
process fracture, flexion-distraction injury, shear injury

Lower lumbar and sacral Uncommon injuries; can occur with hyperflexion and axial loading; longitudinal sacral fracture may have
spine sacral spine radiculopathy, whereas horizontal fracture associated with injury to cauda equina

Ligamentous injury without Plain radiographs with no evidence of bony injury do not preclude ligamentous injury; may be unstable
bony injury without bony injury and produce subsequent neurologic injury

SCI and neurologic deficit identified 119 patients, 45 with
complete SCI; 12 (27%) had C1 to C4 deficits, 19 (42%) had
C5, and 14 (31%) had C6 and below.130 Of 37 survivors, 92%
were intubated, 81% progressed to tracheostomy, and 51%
were on mechanical ventilation at discharge. All patients with
complete injuries at C5 and above required tracheostomy, and
71% of survivors were ventilated at discharge. However, only
35% of patients with incomplete SCI required intubation.
Atelectasis will develop quickly as a result of supine position-
ing and lack of diaphragmatic and intercostal muscle function,
leading to rapid, progressive desaturation. Recurrent pneumo-
nia is a common complication that may often require trache-
ostomy in half of all patients with complete deficits at the C5
to C7 level. Patients with complete motor deficits at C5 and
above (ASIA “A” classification) will likely require intubation and
­tracheostomy before hospital discharge,131 and early, controlled
intubation in the trauma bay or OR should be performed.
Preoperative Preparation. The urgency of surgical stabili-
zation of the spine is determined by the anatomic and neuro-
logic presentation. A patient with a partial deficit and visible
spinal canal impingement on imaging studies is considered an
emergency because of the potential for regaining neurologic
function after decompression. Patients with either no deficit
or complete deficit may require surgical stabilization to facili-
tate mobilization, but are less urgent cases. Surgery is required
more often for cervical lesions, whereas supportive bracing of
the torso is more common for thoracic and lumbar fractures.
Determining cervical spine stability can be complicated
and time-consuming, and many trauma patients who present
to the ED with a rigid cervical collar still in place may main-
tain it for some time until cervical spine clearance. Protocols
to rule out instability of the cervical spine are controversial
and often institution specific and may include plain films,
CT, flexion-extension radiography, MRI, and examination
by orthopedic or neurosurgical specialists; this process often
takes days to complete.132 Obtunded patients with gross move-
ment of all extremities may be cleared by CT scan.133 Insistence
by the anesthesiologist on definitive clearance of cervical spine
injury before proceeding with urgent or semiurgent surgery is
not reasonable, possibly exposing the patient to the risk of pul-
monary complications posed by leaving underlying orthope-
dic injuries unaddressed. For lower-risk cervical spine injuries
and for patients who are uncooperative or hemodynamically
unstable, the preferred approach is RSI with maintenance of
manual in-line axial stabilization throughout the procedure.
The safety record of this approach is impressive.14
Intraoperative Management. For the cooperative patient
with a known or probable injury (existing deficit, suspi-
cious radiographs, or substantial neck pain), maintaining
the patient in a rigid collar, cervical traction, or halo brace
while performing an awake fiberoptic intubation is both safe
and common practice. When awake intubation is elected, the
nasal route is usually easier; as after serial dilation of the nos-
tril, a nasal tube may be inserted to the level of the orophar-
ynx, even before fiberscopic visualization is attempted, and
will likely be in optimal position to find the trachea fiber-
optically. Oral intubation is more challenging technically
because of the greater pharyngeal anesthesia requirement and
the need to negotiate not only the tongue but also the more
severe angle between the oral cavity and the trachea. It is bet-
ter if the patient remains intubated postoperatively because
this reduces risk of sinusitis.134 However, blind nasal or d ­ igital
­intubation, t­ransillumination with the light wand, use of an
intubating LMA (e.g., Fastrach) or Bullard laryngoscope,
video laryngoscope (e.g., Glidescope), and other systems for
indirect ­laryngoscopy are acceptable per clinical preference.
As long as tracheal intubation is obtained with the least possi-
ble motion of the cervical spine, while preserving the ability to
 506 ANESTHESIA AND UNCOMMON DISEASES
assess neurologic function after intubation and patient posi-
tioning, the goals of this procedure will have been achieved;
anesthetizing clinicians should therefore use their preferred
technique.
Hemodynamic instability may complicate urgent and emer-
gent spinal surgery. Hypotension from neurogenic shock is
characterized by an inappropriate bradycardia due to loss
of cardiac accelerator function and unopposed parasympa-
thetic tone. However, this situation can still be difficult to dis-
tinguish from hypotension caused by acute hemorrhage, and
a trial of fluid administration is still indicated, subject to the
end points of resuscitation listed earlier. Once hemorrhage has
been controlled or ruled out, some support exists for mainte-
nance of an elevated MAP (>85 mm Hg) for 7 days after SCI,
although this approach is highly controversial.135 Fluid admin-
istration will expand the vascular volume and counter the
effects of i­nappropriate vasodilation, but volume loading may
­exacerbate myocardial dysfunction (from SCI, blunt trauma, or
­pre-existing cardiac disease). Any patient with a poor response
to initial volume loading, particularly the elderly patient, should
be considered for PA catheterization or ­echocardiographic
examination to guide subsequent resuscitation.
Almost all patients with a persistent deficit after blunt SCI
will be treated with high doses of methylprednisolone in the
days after surgery.136 Although this therapy is controversial
and the expected benefit is slight, no other alternatives are
presently available. Improved sensory and motor function can
be demonstrated if methylprednisolone therapy is initiated
within 3 hours after injury. Less benefit is achieved if initi-
ated 3 to 8 hours after injury (after return of full nerve root
level or minor improvement in sensation). There is no b ­ enefit,
and a potential for an increase in complications (infection,
­pneumonia), if initiated after 8 hours.137,138
If initiated, corticosteroid infusions should be continued
during surgical interventions, and the clinician should be
wary of the development of corticosteroid-related side effects,
including hyperglycemia, adrenocortical insufficiency, gastric
ulceration, and occult infections.
Autonomic hyperreflexia develops in 85% of patients with
a complete injury above T5, resulting from the loss of inhibi-
tory control of vascular reflexes.139 This condition mandates
general or regional anesthesia for any subsequent surgery in
a quadriplegic or high-paraplegic patient, even if the planned
procedure is in an insensate region.
Ocular Trauma
Ocular trauma, both penetrating and nonpenetrating, is
an important cause of visual loss and disability, with up to
90,000 injuries per year in the United States resulting in
some degree of visual impairment.140 Many patients with
severe ocular i­njuries have concomitant head and neck
trauma that may delay recognition and complete evaluation
of these problems. With current diagnostic methods, surgi-
cal techniques, and rehabilitation, vision can be salvaged in
many patients.
Pathophysiology. Types of ocular trauma are listed in
Box 17-5. Severe blunt injury to the globe and orbit can cause
damage to all of the ocular tissue. Force directed against the
globe pushes it back into the orbit, resulting in compression,
stretching, and disruption of the softer tissues lining the eye.
The thin, bony medial wall and floor of the orbit are prone
to translation away from the orbit, ­producing the “blow-
out” ­fracture. Such fractures typically do not require emer-
gent ­surgery unless there is an open globe or there is actual
or impending visual loss. With penetrating injuries of the
eye, closure of the laceration is the primary surgical goal
because of concerns about infection and loss of intraocular
­contents, ­particularly from the posterior segment. Prognosis
for p
­ enetrating eye injuries is related to many factors, includ-
ing initial visual acuity, type and extent of injury, presence of
retinal detachment, and presence of foreign bodies.
Evaluation. Preoperative documentation of visual func-
tion and degree of visual loss is important and may affect sub-
sequent decisions and timing of surgery. The examination
should be as complete as practical, but any examination that
risks further injury to the globe should be avoided. Because
many ocular injuries are accompanied by head and neck
trauma, a thorough examination, including imaging, should
evaluate both intraocular and periocular structures. CT may
also show whether a patient has sustained an intracranial
injury, such as subdural hemorrhage. Although CT provides
a helpful adjunct in penetrating ocular trauma, it may not be
sensitive enough to be the sole means of evaluating a potential
open-globe injury.
BOX 17-5   n  TYPES OF OCULAR TRAUMA
Periocular
Ecchymosis
Lid laceration
Orbital
Facial fracture
Retrobulbar hemorrhage
Traumatic optic neuropathy
Superficial Ocular
Corneal abrasion
Foreign body
Chemical injury
Thermal injury
Infection
Closed Globe
Iritis
Iris injury
Retinal damage
Traumatic cataract
Subchoroidal hemorrhage
Lens subluxation
Open Globe
Globe rupture
Laceration
Penetrating foreign body
 Chapter 17  Trauma and Acute Care 507

Preoperative Preparation. Once a known or suspected structures of the eye and orbit and a low risk for extrusion
globe injury has been identified, it becomes important to of intraocular contents, regional anesthesia or local anesthe-
avoid significant increases in intraocular pressure (IOP), as sia with sedation may be adequate. Given patient positioning
may occur during coughing, bucking, straining, or a Valsalva (head draped and airway inaccessible), the risk of overseda-
maneuver. This may require the judicious use of seda- tion and aspiration must be considered. General anesthesia is
tives, narcotics, and antiemetics in the preoperative period. indicated for severe lacerating injuries, pediatric patients, or
Additionally, the open globe should be protected with a shield, uncooperative patients (anxiety, intoxication), providing an
and because a penetrating injury may be infected with not immobile eye while allowing for maximal control of f­actors
only skin flora but also Pseudomonas, Bacillus, and anaerobic affecting IOP. During use of any face mask, particular care
species, broad-spectrum antibiotics (e.g., cephalosporin and must be taken not to apply direct ­pressure to the globe.
aminoglycoside) should be considered as well. Optimal timing Choices of muscle relaxants in open-globe injuries have
for surgical interventions is based on concomitant injuries, proved controversial. Succinylcholine, which can cause
coexisting disease (including pre-existing eye conditions), and contraction of extraocular muscles and choroidal conges-
­
surgical factors (Table 17-6). Many open-globe injuries occur tion, has been shown to produce slight, transient increases
in children, and specific pediatric considerations should not in IOP during a standard induction. When given without
be neglected in their management.141 IV or inhalational anesthetics, the IOP rise can be as high as
18 mm Hg.142 Typically, however, IOP increase is 2 to 5 mm
Intraoperative Considerations. Management objectives of
Hg with appropriate induction.143 A review of succinylcho-
the open globe include (1) overall patient safety, (2) avoidance
line use in ­open-globe injuries cited only anecdotal associated
of elevated IOP, (3) provision of a stable operative field, (4)
v­ itreous loss.144 Further, despite a lack of RCTs, several case
avoidance of external ocular pressure, and (5) minimization
series and animal studies have failed to demonstrate extru-
of bleeding. With most trauma patients, a full stomach must
sion of contents after succinylcholine use, if defasciculating
be assumed, making RSI the technique of choice. As long as a
pretreatment with a nondepolarizing muscle blocker was first
deep level of anesthesia is provided before laryngoscopy, intu-
employed.145,146 Thus, provided a small dose of a nondepolariz-
bation, and any resultant IOP rise, any IV agent except ket-
ing muscle relaxant precedes it to blunt the expected increase
amine is acceptable. General anesthesia is safe, effective, and
in IOP, the use of succinylcholine should be dictated by the
used most often in the repair of penetrating eye injuries; how-
need for rapid onset and termination of muscle relaxation,
ever, in the cooperative patient with injury limited to external
rather than by any concerns about loss of ocular contents.
The use of IV ­lidocaine, β-blockers, and short-acting narcot-
ics 3 to 5 minutes before induction may similarly be useful to
TABLE 17-6  n Timing of Intervention in Various Forms blunt the increase in heart rate, BP, and IOP associated with
of Ocular Trauma
­laryngoscopy and intubation.147,148
Timing Condition After induction and intubation, deep anesthesia with a
­combination of narcotics, inhalational agents, and m ­ uscle relax-
Absolute emergency Chemical injury (alkali > acid) ants will reduce extraocular pressure and ­choroidal congestion
Threat of gas gangrene by eliminating coughing, straining, or m ­ ovement. Although
Orbital abscess
Expulsive choroidal hemorrhage
occurring infrequently during repair of eye ­lacerations, the
extruding intraocular tissues oculocardiac reflex (severe bradycardia or a­ systole) may occur
through open wound during manipulation of the globe. Whereas successful place-
Vision loss because of expanding ment of a retrobulbar block will abolish or prevent this reflex,
orbital hemorrhage it should not be used with a potential open-globe injury. If
Urgent Endophthalmitis possible, maintenance of a head-up position will facilitate
High-risk intraocular foreign body venous drainage.
Within 24 hours Open wounds requiring surgical
As with induction and intubation, an increase in IOP is
closure also possible during emergence and extubation. Although less
Intraocular foreign body ­concern exists about loss of intraocular contents than before
globe repair, the associated straining, emesis, coughing, and
Within a few days Thick, submacular hemorrhage
(24-72 hours agitation may increase the risk of bleeding and adversely
preferred) affect surgical outcome. Placing an orogastric tube, suctioning
­gastric contents, and giving a promotility agent can increase
Within 2 weeks Intraocular foreign body
Secondary reconstruction if retina is
the safety of deep extubation but cannot completely obviate
detached the aspiration risk associated with this t­ echnique. Whether or
Media opacity in the amblyopic age not an awake extubation is p ­ ursued, appropriate antiemetic
group therapy is indicated along with ­narcotics for pain manage-
Modified from Kuhn F: Strategic thinking in eye trauma management, ment. Postoperative shivering should also be avoided and can
Ophthalmol Clin North Am 15:171-177, 2002. be treated with small doses of ­meperidine or propofol.
 508 ANESTHESIA AND UNCOMMON DISEASES

Complex Facial Injuries greater is the severity of the resultant fracture. With gunshot
wounds, damage severity is directly related to the velocity of
Although often gruesome in appearance and frequently dis-
the projectile. Fortunately, the structure of the midfacial skel-
tracting to practitioners who should remained focused on the
eton provides some buttressing and protection for the brain,
ABCDE priorities of the primary survey, severe maxillofacial
while the thinner, laminar bones on the periphery serve as
trauma is only life threatening if there is significant involve-
“crumple zones,” allowing for dispersal of force, which reduces
ment of the airway or severe concomitant hemorrhage. The
energy transmission to more vital structures.153,154
face and head are exposed to a broad range of physical trauma
The face can be divided into three anatomic regions. The lower
(Box 17-6). An estimated 3 million patients require hospital
third consists of the mandible, the ­temporomandibular joint
treatment for facial injuries every year from MVCs alone.149
(TMJ), and the coronoid process. The middle third ­comprises
Beyond airway and bleeding problems, severe ocular, nasal,
the maxilla, nasal bones, orbits, and zygomatic arch. The upper
jaw, and cosmetic deformities are potential consequences. The
third contains the frontal bone, frontal sinuses, frontozygomatic
anesthesiologist must be not only aware of all injuries but also
process, and nasoethmoidal ­complex. Table  17-7 summarizes
familiar with typical treatment plans to ensure appropriate
signs, symptoms, and long-term c­ omplications associated with
emergent management and optimize surgical correction.
facial fractures in these areas. Along with soft tissue injuries, this
Pathophysiology. The type and severity of facial injury are provides a framework for classification of facial injuries.
determined by the mechanism of injury; the extent, direction, Soft tissue injuries range from minor to severe, i­ncluding
and duration of force; and the characteristics of the impacted contusions, abrasions, punctures, lacerations, avulsion flaps,
facial structures. Significant bony disruption may be masked
by only modest soft tissue injury; similarly, dramatic soft tis-
sue swelling may occur without any fractures. Each of the
major mechanisms of injury produces distinctive patterns of TABLE 17-7  n  Types of Facial Fractures
injury and mandates a search for likely associated trauma.
Long-Term
Massive blunt trauma typically presents with more obvious Type Signs and Symptoms Complications
effects on the facial skeleton than on soft tissue. In cases of
assault or sports-related blunt trauma, edema and hematoma Nasal Pain, obstruction, Malunion,
may be the only soft tissue findings, while significant facial crepitus, swelling, obstruction
epistaxis
fractures lie underneath. Patients involved in MVCs pre-
senting with significant facial trauma should be presumed to Naso-orbital, Pain, obstruction, Malunion,
have both TBI and cervical injury150 until proved otherwise. ethmoid crepitus, swelling, telecanthus
Penetrating trauma from close range (e.g., shotgun, rifle, high- epistaxis
velocity projectile), may result in massive soft tissue loss and Frontal sinus Pain, epistaxis Mucopyocele
facial destruction. Burns can result in progressive cutaneous
Zygomatic arch Lateral pain, trismus, Unstable,
and mucosal edema, which can lead to sudden airway com- asymmetry, lateral recurrent
promise. Early intubation, before swelling produces an airway depression depression
emergency, is often the best approach in dealing with impend-
Zygoma Numb cheek and/or Asymmetry,
ing airway compromise (see Chapter 18).
lip, visual change, entrapment,
The force vectors applied to facial structures determines swelling entrapment, enophthalmos
fracture location. Given that lower forces are required to frac- scleral hemorrhage, associated
ture the thinner nasal bones—zygoma, frontal sinus, and man- epistaxis, step-off, globe injury
dibular ramus—compared with other facial bones, these are enophthalmos,
the most common sites of injury.151,152 As expected with blunt Orbital blowout scleral hemorrhage, Entrapment,
trauma, the greater the energy transferred on impact, the epistaxis, step-off, enophthalmos
enophthalmos,

Le Fort Malocclusion, trismus, Malocclusion,

BOX 17-6   n  MAJOR CAUSES OF FACIAL INJURIES numbness, visual malunion,
changes, massive dental loss,
Vehicle crash: motorized and nonmotorized swelling, epistaxis, asymmetry,
Pedestrian accident scleral hemorrhage lacrimal
Industrial accident midface mobility obstruction
Violence
Blunt force such as fist or club Mandible Lower lip numbness, Malocclusion,
Penetrating such as knife or gunshot trismus, pain referred malunion,
Sports to ear, crepitus, osteomyelitis,
Falls malocclusion, ankylosis, dental
Thermal injury open bite loss, nerve injury
Chemical injury Modified from Darian VB: Maxillofacial trauma. In Trunkey DD, Lewis FR, editors:
Current therapy of trauma, ed 4, St Louis, 1999, Mosby.

and frank tissue loss. Early management usually ­ consists
of debridement, conversion of unfavorable wounds to
favorable wounds (with acceptable cosmetic appearance),
­ way obstruction can occur with facial trauma, necessitating
and ­meticulous closure. Careful examination and multidis-
ciplinary management may be required for injuries involving
important structures, such as the facial nerve, parotid gland,
and lacrimal apparatus. Lacerations in the vicinity of the zygo-
matic arch may include injury to the frontal branch of the
facial nerve. Large hematomas, particularly those involving
the nasal septum and auricular cartilage, may require drain-
age to prevent infection, necrosis of underlying cartilaginous
structures, and subsequent cosmetic deformity.155
Mandibular fractures are the second most common form
of facial fracture after fractures of the nasal bones. More than
50% of mandible fractures are composed of two or more frac-
ture locations, so additional fracture sites should be highly
suspected whenever the mandible is evaluated.155 The strong
jaw musculature attached to the mandible tends to displace
fracture fragments laterally, leading to asymmetry, maloc-
clusion, and even airway compromise. Midface fractures may
affect the nasal, maxillary, orbital, and zygomatic arch struc-
tures. Again, the nasal bones are the most frequently injured
facial bones. Disruption of the nasal septum may result in
local airway obstruction as well as significant hemorrhage that
can complicate global airway management.
The classic midface fractures as described by Rene Le Fort
in 1902 are the Le Fort I (horizontal dentoalveolar separation),
Le Fort II (pyramidal or triangular separation of maxilla and
zygoma with a central fragment consisting of maxillary alveo-
lus, medial orbital wall, and nose), and Le Fort III (complete
dislocation of facial and cranial skeletons running parallel to
skull base and involving ethmoid bones and cribriform plate,
allowing a compromised anterior cranial fossa). The presence
of clear rhinorrhea may constitute CSF and should raise sus-
picion of a cribriform plate or basilar skull fracture; however,
absence of this rhinorrhea does not rule out these injuries.
Although useful in describing a midface fracture, these classic
patterns rarely are identified in isolation. Le Fort fractures are
rarely bilateral, may be seen in combination with other facial
fractures, and are obscured by soft tissue injury.
Zygomatic arch fractures are caused by blows to the lat-
eral aspect of the midface. Trismus may result from masseter
muscle hematoma or direct mechanical impingement of arch
fragments on the coronoid process of the mandible. Fractures
of the zygoma and orbital walls may allow entrapment of the
periorbital soft tissue and extraocular muscles. Direct globe
trauma may also occur, although obscured by the edema of
surrounding tissues. Fractures of the upper skull include fron-
tal sinus and frontal bone fractures. Concomitant nasoeth-
moidal, supraorbital, zygomatic, and cranial base fractures
are common and may involve the anterior cranial fossa. Thus,
particular attention must be paid to assessing for frontal lobe
contusion, CSF rhinorrhea, and pneumocephalus.
Evaluation. Because facial trauma may only be a small por-
tion in the constellation of injuries in a trauma patient, ini-
tial evaluation should focus on identification and treatment
Chapter 17  Trauma and Acute Care 509
of life-threatening problems and complete assessment of
more emergent injuries. Upper and occasionally lower air-
a detailed evaluation of the airway and careful, continuous
monitoring for impending compromise. Patients with multiple
mandibular fractures or combined maxillary, mandibular, and
nasal fractures are more likely to obstruct early. Mandibular
fractures disrupt the support structure of the tongue and the
floor of the mouth, permitting posterior displacement and
easy airway compromise. Obstruction of the nasopharynx
may occur with some midface fractures. Although mouth
breathing will still be possible in these patients, impaired con-
sciousness can contribute to obstruction. Alternatively, swell-
ing of the tongue, pharynx, palate, or floor of the mouth from
trauma or burns may allow progressive occlusion.
Diagnosis of facial injuries is typically accomplished by his-
tory, physical examination, and radiographic analysis. Careful
observation for abnormalities in soft tissue f­ ullness, facial sym-
metry, gross skeletal shape, eye movements, and alterations in
muscle tone should be documented precisely. Palpation may
reveal pain, crepitus, numbness, and deformity. Malocclusion
is an important sign of ­maxillofacial ­fracture. Any limitation
of or pain with mouth opening should be ascertained, and
mechanical causes versus pain or spasm should be differen-
tiated. Anesthetics and muscle relaxants can relieve spasm or
trismus, but inappropriate use in the patient with mechani-
cal obstruction may lead to airway loss and even inability to
perform direct laryngoscopy. Finally, loose or missing teeth,
tongue mobility, and source of ­hemorrhage should be noted.
Blunt trauma causing facial injury should raise suspicion
for concomitant cervical spine and closed-head injury.150,151
Extreme care should be taken in the airway management
of patients such that SCI is avoided. Radiographic analysis,
including plain films and CT, are essential in evaluating the
extent of facial injuries. Imaging studies also provide imme-
diate information on associated intracranial and cervical
injuries, and their judicious use can efficiently inform both
anesthetic and surgical management.
Preoperative Preparation. The majority of penetrat-
ing facial injuries will require urgent exploration. However,
the timing of surgical repair of blunt facial injuries depends
on associated injuries, extent of soft tissue damage, edema,
and overall patient condition. Definitive repair is sometimes
undertaken shortly after the injury, particularly if associated
injuries require surgical intervention. However, definitive
repair of many facial fractures can be delayed 7 to 10 days until
edema subsides, provided that soft tissue injuries are treated
and intermaxillary fixation is applied, if necessary.
Airway management in the patient with significant facial
trauma is the principal task of the anesthesiologist dur-
ing the preoperative phase. This management depends on
the ­significance of airway compromise, state of conscious-
ness, etiology and type of injuries sustained, identifiable or
known ­premorbid conditions, and need for medical or sur-
gical intervention. Partial airway obstruction is common for
the reasons described previously, and placement of an oral or
 510 ANESTHESIA AND UNCOMMON DISEASES

nasal airway may alleviate the problem. A nasal airway is less e­ vidence is insufficient to conclude that rates of ­reintubation
likely to ­stimulate gagging if airway reflexes are present, but it are reduced. In adults, corticosteroids do not appear to reduce
should not be used when a nasal or basilar skull fracture may the need for reintubation. Unobstructed venous drainage
be ­present.156 Stable patients with severely distorted airway of the head should be ensured, both through positioning
­anatomy may be best managed with an elective tracheostomy, and nonconstrictive bandaging. If intermaxillary fixation is
with or without first securing the airway by other means. applied, wire cutters should be immediately available at the
Preoperative preparation for emergent facial surgery bedside in the event of airway obstruction or hemorrhage.
should proceed as with any other traumatized patient, ensur-
ing a­dequate respiration and circulation while maintain-
Penetrating Trauma
ing cervical spine immobilization. When surgical repair is
delayed, every attempt should be made in the interim to clear While fortunately rare in most hospitals, knife and gunshot
the ­cervical spine of injury in order to facilitate subsequent air- wounds cause up to 30% of all admissions to busy urban trauma
way ­management, increase patient comfort, and decrease both centers. Penetrating injuries can affect all organ systems, but
sedation need and potential for skin breakdown. Judicious considerations for the anesthetic care of penetrating trauma
use of sedatives and analgesics may ameliorate muscle spasms victims are not substantially different than for the victims of
associated with TMJ fractures. blunt trauma. “Scene safety” is not solely a prehospital con-
cept; some hidden weapons may accompany patients into the
Intraoperative Considerations. Mask ventilation can be noto-
ED, and gang violence has been known to extend into hospital
riously difficult and even self-defeating in facial trauma patients.
wards. Initial patient assessment should establish the trajectory
Given the disruption of bony structures that support the perioral
and energy transmission of the injury, to indicate the organ sys-
tissues, achieving airway opening and adequate mask seal can
tems at risk. Gunshot wounds, particularly from high-velocity
be difficult. Improper technique may exert excessive pressure on
weapons such as assault rifles, may cause significant concussive
fracture sites or may extend the cervical spine. In stable patients
and cavitation damage to organs in the proximity of the bul-
with an injury-compromised airway, an awake intubation may
let path, even in the absence of direct penetration. Narcotic or
be the safest management choice. To optimize surgical access,
alcohol intoxication may mask pain, whereas youthful physiol-
procedures involving the lower face and mandible are best man-
ogy and cocaine use encourage underestimation of blood loss.
aged with a nasal intubation, if this approach is not contraindi-
Patients who are hemodynamically unstable after penetra­ting
cated. Likewise, patients undergoing procedures on the upper
trauma should be taken immediately to the OR for e­ xploration;
face and midface should receive oral intubation (optimally with
the only exceptions are those with limited ­thoracic penetration
oral right-angle ETT, or RAE) or a surgical airway.
who respond satisfactorily to tube thoracostomy. “Damage
Submental intubation (SI) has been proposed as an alterna-
control” principles will focus on stopping ­hemorrhage as soon
tive to nasoendotracheal intubation when oral endotracheal
as possible, completing resuscitation in the ICU, and then
intubation is contraindicated. In patients who require intuba-
returning to the OR for definitive reconstruction after 24 to
tion for maxillofacial reconstruction, SI is an alternative to a
48 hours of stability.
traditional tracheostomy.157 SI avoids the dangers of nasoen-
Stable patients will receive diagnostic testing with plain
dotracheal intubation in patients with midfacial fractures and
radiographs, CT, and ultrasound. The proportion of hemo-
avoids complications related to tracheostomy. The technique
dynamically stable, penetrating-trauma patients requiring
is easy to perform with coordination between the anesthe-
exploratory surgery has decreased in recent years because
sia and surgical teams. The risks and benefits of approaching
of the increasing capability of modalities such as CT and
the airway with alternative blind techniques, either orally or
­angiography to exclude surgical injury. Exploration of neck
nasally, must be weighed and tempered by the anesthesiolo-
wounds, the diagnostic pericardial window, and e­ xploratory
gist's experience. Choice of anesthetic technique should take
laparotomy for flank wounds are increasingly uncommon.
into account that facial reconstructions are often long, compli-
However, noninvasive technology is not sufficiently sensitive
cated cases that have intermittent intervals of intense stimula-
as yet to exclude diaphragm or bowel penetration ­reliably, and a
tion, that may require the ability to monitor nerve function,
penetrating wound suspected to have violated the p ­ eritoneum
and that may involve significant blood loss. Surgeons will
remains a strong indication for urgent ­exploratory laparotomy.
require unencumbered access to the face and neck and may
request controlled hypotension at times.
Postsurgical edema may further affect airway patency, and Traumatic Aortic Injury
patients should be awake with intact reflexes before extuba-
tion. In cases of soft tissue edema, IV dexamethasone (4-8 mg) Pathophysiology. Any high-velocity blunt trauma resulting
has been traditionally administered, but no data support this in sudden acceleration or deceleration of the torso may result
practice. A Cochrane review of RCTs in patients who received in a catastrophic injury to the aorta. Shear vectors exert tre-
steroids before extubation showed a trend toward a reduced mendous force at the aortic isthmus, where the relatively free-
incidence of reintubation in neonates receiving prophylactic floating heart and aortic arch are tethered to the descending
dexamethasone before extubation.158 In children, ­prophylactic thoracic aorta by the ligamentum arteriosum. The spectrum
dexamethasone reduces postextubation stridor, but the of anatomic injury ranges from “cracking” of the intima, with

creation of a small intravascular flap, to complete transection.
Many patients with complete resection are found dead at the
scene of injury, but survival to hospital admission does occur
because of the tamponading effect of the surrounding pleura
and pericardium. Patients with aortic trauma have a high risk
of rupture, loss of this tamponade effect, and exsanguination
during the hours immediately after injury. The natural history
of small intimal flaps is unknown, although some patients
form pseudoaneurysms that may become symptomatic years
after the initial injury.159 Patients with underlying atheroscle-
rotic disease are at particular risk of proximal or distal dissec-
tion of the aorta arising from the site of injury.
Evaluation. Timely diagnosis of aortic injury requires a
high degree of suspicion in any patient who has suffered a
high-speed frontal- or lateral-impact motor vehicle collision
(particularly when no airbag deployed), any pedestrian struck
by a motor vehicle, any motorcyclist, and any patient who
has fallen more than 10 feet. Symptoms of aortic injury are
nonspecific, consisting mainly of a thoracic back pain often
described as “tearing.” Blood pressure is usually labile, with
exaggerated peaks and troughs in response to painful stimu-
lation, hemorrhage from other injuries, and sedating medica-
tions. Common coexisting injuries include fractured ribs or
sternum, left hemothorax, humeral fracture, splenic rupture,
and left-sided femur or acetabular fracture, although none of
these is a highly sensitive marker for aortic trauma.
Chest radiography is warranted and sensitive but usually
not specific. If the aortic contour is normal and well visual-
ized, the chance of aortic injury is small, but a confident inter-
pretation of the anteroposterior chest radiograph is possible
in less than 50% of patients at risk. Visible disruption of the
aortic contour or other unusual shadowing of the mediasti-
num may be caused by injury to small vessels near the aorta
and is a strong indication for further diagnostic assessment.
The traditional “gold standard” was contrast aortography, but
advanced chest CT has improved resolution and accuracy,
making it the new standard in large centers with experienced
radiographers.160 Transesophageal echocardiography (TEE) is
highly sensitive and specific and is an appropriate diagnostic
approach when an experienced operator is available.
Preoperative Preparation. Transfer of the patient to a
trauma center with experience in aortic surgery is highly desir-
able if it can be effected expeditiously. Preoperative β-blocker
therapy is indicated to reduce shear-force stresses on the prox-
imal aorta. Large-bore IV access, right radial artery pressure
monitoring, and central venous and PA catheterization, or
TEE, are strongly indicated.161
Intraoperative Management. Surgical or angiographic
treatment of an aortic injury is indicated in any patient who
can tolerate the procedure. Angiographic vascular stenting
is playing an increasingly important role in recent years.162
Whatever the method, aortic surgery should be approached
on an urgent basis, following only emergent procedures such
as damage control laparotomy or evacuation of intracranial
Chapter 17  Trauma and Acute Care 511
hemorrhage. Intraoperative management of the open surgical
approach necessitates a double-lumen tube to allow adequate
exposure from a left-sided thoracotomy. Partial cardiac bypass
is often used to support systemic perfusion.163
Stent graft has resulted in major advances in the treat-
ment of trauma patients with blunt traumatic aortic injury
and has become the preferred method of treatment at many
trauma centers. A recent review of the role of stent grafts in
management showed that thoracic endovascular aortic repair
(TEVAR) repair of aortic injury offers a survival advantage and
reduction in major morbidity, including paraplegia, compared
with open surgery.164 However, endovascular procedures in
trauma patients require a sophisticated multidisciplinary and
experienced team approach.
The intraoperative double-lumen tube should be changed
under controlled conditions to a single-lumen tube at the
­earliest practical time, before admission to the ICU if possible,
because of basic unfamiliarity with and uncommon use of this
device and the resulting complications.
Orthopedic Injuries
Orthopedic trauma produces life- and limb-threatening mus-
culoskeletal injuries, including hemorrhage from open wounds
and open or closed fractures, infection from open fractures,
limb loss from vascular damage and compartment syndrome,
and loss of function from spinal or peripheral nerve injuries.
The management of these patients presents many challenges
for the anesthesiologist. Musculoskeletal injuries comprise the
most common indication for operative management in most
trauma centers. Because many procedures might be optimally
managed under regional anesthesia, familiarity with such
techniques is essential.
In addition to a familiarity with an array of regional a­ nesthetic
procedures, skill with fiberoptic intubation, ­hypotensive tech-
niques, hemodilution, intraoperative autotransfusion for
­minimizing intraoperative blood loss, and invasive hemody-
namic and evoked potential monitoring may be needed. The
duration of many procedures, particularly of those i­nvolving
multiple extremity injuries, necessitates attention to body
positioning, maintenance of normothermia, fluid balance,
tourniquet times, and preservation of peripheral blood flow,
especially in reimplantation procedures.
Pathophysiology. For more than two decades, trauma man-
agement of the multiply injured patient has de-emphasized
early stabilization of long-bone, spinal, pelvic, and a­ cetabular
fractures in order to decrease morbidity, pulmonary complica-
tions, and length of hospital stay.165,166 In one study, only 2% of
patients with femoral shaft fractures ­stabilized within the first
24 hours of injury had pulmonary complications, versus 38%
of patients in whom fracture stabilization was delayed for more
than 48 hours.167 Thus the treatment and anesthetic manage-
ment of orthopedic trauma necessitates surgical intervention.
Classification of orthopedic injuries considers the mech-
anism and site of injury, the type of fracture, soft t­issue
involvement, angulation, presence of vascular or nerve
 512 ANESTHESIA AND UNCOMMON DISEASES
TABLE 17-8  n  Classification of Open-Fracture Wounds
Type Description
I Clean wound less than 1 cm long
II Laceration greater than 1 cm without extensive
soft tissue damage, skin flaps, or avulsions
IIIA Extensive soft tissue lacerations or flaps with
adequate soft tissue coverage of bone; result
of high-energy trauma
IIIB Extensive soft tissue loss with periosteal
stripping and bony exposure; usually
contaminated
IIIC Arterial injury requiring repair regardless of size of
soft tissue wound
impairment, and whether the fracture is open or closed. The
anticipated rate and severity of fracture-related complica-
tions (e.g., amputation, infection, nonunion) and prognosis
are related to the classification of open fractures (Table 17-8).
The mechanism of injury for a given site can aid in the pre-
diction of ­potential complications that might affect or alter
the anesthetic plan. For example, approximate blood loss
from fracture hemorrhage varies from 500 mL with a closed
tibia fracture to life-threatening hemorrhage (several liters)
with a pelvic fracture.
Extremity injuries include fractures, dislocations, and/or
soft tissue damage. Knowledge of anatomy and the mecha-
nism of injury help in predicting associated nerve and vascu-
lar injuries. For example, displaced intracapsular femoral neck
fractures carry a high risk of avascular necrosis of the femoral
head, whereas posterior dislocation of the knee carries a high
risk of popliteal vessel injury.
The presence of pelvic fractures implies the application of
substantial force and may therefore be associated with sig-
nificant morbidity and mortality from direct pelvic trauma
combined with other injuries. Such fractures are classified
as having anteroposterior (AP) compression, lateral com-
pression, or vertical shear patterns. Noting the mechanism
of injury is essential because the relative risk of hemorrhage
from internal iliac artery or posterior pelvic venous plexus
disruption is increased with AP compression and vertical
shear injuries.167 Early stabilization of these fractures with
external compression or fixation, with or without angiogra-
phy and selective embolization, may be lifesaving, especially
if other life-threatening injuries must be addressed immedi-
ately. In addition to significant hemorrhage, other direct inju-
ries include nerve injury, rectal or vaginal laceration, bladder
rupture, and urethral injury. The presence of the latter two will
require urologic intervention, possibly complicating intraop-
erative and postoperative fluid management.
Trauma to the spinal column is a common injury and fre-
quently associated with neurologic dysfunction. The level of
injury is most often cervical (55%), with 30% thoracic and
15% lumbar.168 The most basic classification of spinal cord
injuries assesses for complete or partial loss of function at a
given level. A complete injury implies total loss of sensory and
motor function lasting for more than 48 hours in areas inner-
vated more than two levels below the level of bony injury.169
Late injury may still occur if stability has been compromised.
The mechanism and site of an injury may produce typical
fracture patterns and will frequently determine the need for
surgical stabilization (see Table  17-5). Chapter  8 provides a
more complete discussion of spinal cord injury.
Evaluation. Initial attention must necessarily focus on the
adequacy of the patient's airway, quality of ventilation, and
status of perfusion. Once these concerns have been addressed,
subsequent evaluation should focus on the identification
and treatment of associated injuries. In the multiply injured
patient, this requires prioritization of the injuries and coordi-
nation of care throughout the surgical and anesthetic teams.
Many orthopedic injuries require emergent intervention to
effect limb salvage, hemorrhage control, nerve repair, or infec-
tion prevention.
Although not always possible, a thorough history and phys-
ical examination can be vital. Time of the injury is important;
many orthopedic surgeons choose to address all open frac-
tures within 6 hours of the initial trauma. Further, a history
inconsistent with the extent of injury, particularly in at-risk
groups, may suggest a pathologic fracture or abuse. After the
initial assessment, secondary examination should document
a thorough neurologic assessment, including function and
sensation in injured extremities. This may be of particular
importance if regional anesthesia is considered, because pre-
existing postoperative deficits may be incorrectly attributed to
the regional technique. Distal perfusion should also be docu-
mented by palpation or Doppler assessment of distal pulses.
Capillary refill alone is inadequate clinical evidence of intact
perfusion and does not exclude compartment syndrome or
vascular injury.
Regional anesthetic techniques (epidural or nerve block)
may place the patient at risk for a missed diagnosis of com-
partment syndrome. Close monitoring and a high degree of
suspicion for compartment syndrome are always indicated in
these patients, but there is minimal to no evidence (class 3 case
reports) to suggest that regional anesthesia masks extremity
compartment syndrome.170,171
Preoperative Preparation. The initial management of
orthopedic trauma is not substantially different from that of
any other injured patient. Airway and ventilatory manage-
ment remain the highest priorities. Early definitive manage-
ment in patients with multiple extremity fractures, serious
pelvic injury, and high spine injuries with deficit should be
considered. The evaluation process will often include mul-
tiple evaluations and treatments in remote locations, such as
the radiology suite, CT, and angiography, where there may
not be suitable provisions for emergent airway management.
Early intubation, often before the clearance of the cervical
spine, is frequently needed to allow for reduction of fractures

or dislocation. Continuous vigilance of the adequacy of ven-
tilation and oxygenation must be maintained throughout the
evaluation process. Maintaining adequate circulation becomes
the next highest priority. Intravenous access should be estab-
lished with large-bore peripheral catheters if possible, but
extremities with known injuries should be avoided. Use of cen-
tral venous lines may be necessary, although femoral or lower
extremity cutdowns should be avoided in suspected pelvic or
lower extremity injuries, respectively, because of the potential
for venous injury and exacerbation of pre-existing blood loss.
In addition, it is important to anticipate the need for blood
products171 and to be prepared for massive blood transfusion
if indicated.
INTRAOPERATIVE CONSIDERATIONS
Choice of anesthetic technique will depend on m ­ ultiple ­factors,
including hemodynamic stability, associated ­injuries, ability
to cooperate with the anesthetic plan, coexisting ­disease, and
patient preference. Patients present along a c­ ontinuum of injury
severity, and thus no anesthetic ­technique is clearly superior
for all patients. Presentations range from minor injuries man-
aged with local anesthetic infiltration, to injuries amenable to
peripheral nerve or subarachnoid block, to those requiring
general anesthesia and invasive ­monitoring. Typically, general
anesthesia is the technique of choice for nonfasted patients
with m ­ ultiple injuries. While regional a­ nesthesia may seem
attractive because it interferes less with the patient's cardio-
pulmonary function and avoids airway manipulation, patients
with serious trauma often require definitive airway control
and mechanical ventilation because of concomitant injuries
and may not cooperate during ­placement of a block or lie still
during ­prolonged surgery. Further, ­neuraxial ­blockade
can interfere with sympathetically-mediated hemorrhage
compen­sation, leading to increased blood loss and refractory
shock. Thus, regional anesthesia is most useful for isolated
limb trauma (e.g., infraclavicular block for hand ­fracture,
lumbar plexus block for hip pinning in elderly ­ cardiac
patient).
Some specific considerations for the intraoperative man-
agement of patients with orthopedic trauma are positioning,
temperature management, use of tourniquets, potential for fat
embolism, and development of deep vein thrombosis (DVT).
Optimal outcomes for unstable, multiply injured patients are
frequently achieved if all injuries can be corrected at the initial
surgery. The blunt-trauma victim with m ­ ultiple fractures bene-
fits from early fixation, which will reduce ­ongoing ­hemorrhage
and intravascular release of bone ­marrow, decrease postoper-
ative complications of immobilization, o ­ bviate the need for
multiple return OR visits, and facilitate early extubation.165,172
During prolonged surgery, the anesthesiologist must closely
monitor blood loss, hematocrit, coagulation abnormalities,
electrolytes, fluid balance, and adequacy of oxygenation and
ventilation.
Positioning. Many orthopedic surgical procedures require
a nonsupine position. Ventilation should not be compromised,
Chapter 17  Trauma and Acute Care 513
and proper positioning should allow for adequate diaphrag-
matic excursion and thoracic expansion without excessive air-
way pressures. All extremities should be placed in positions
of comfort, preventing torsion, traction, or compression of
neurovascular bundles, particularly the brachial plexus at the
axilla and the ulnar nerve at the olecranon groove. All pressure
points should be padded, especially where nerves are placed in
a dependent position. The eyes, ears, nose, breasts, and geni-
talia should be protected when the patient is lateral or prone.
Temperature. Hypothermia contributes to CNS depres-
sion, cardiac irritability, coagulopathy, shivering, increased
O2 consumption, suboptimal wound healing, and altered liver
and kidney function. Thus, hypothermia can severely affect
outcomes in trauma patients, particularly those with multi-
ple extremity injuries. Many patients entering a trauma cen-
ter already have a low body temperature from environmental
exposure. Further exposure to cold ambulance and hospital
environments, evaporative heat loss from the respiratory tract,
infusion of cold fluids, and loss of heat production secondary
to shock or anesthetic-mediated sympathectomy can produce
further significant drops in core temperature and even reduce
the effectiveness of warming efforts.
With recent and appropriate emphasis on early fracture
stabilization and definitive repair, patients with multiple
extremity fractures will have long operations, large fluid vol-
ume requirements, and significant amounts of surface area
exposed to ambient temperatures. It is critical that all skin
surfaces not in the surgical field be covered to reduce convec-
tive and radiant heat loss, and forced-air warming should be
used where possible. Humidification of inspired gases through
the use of heat-moisture exchange units reduces evaporative
pulmonary heat loss. The combination of active surface heat-
ing and moisturization of inspired gases can produce optimal
active warming of the patient. Only appropriately warmed IV
fluids should be used; that is, the temperature of the infusate
should be known, and methods such as microwaving fluids to
unknown temperatures can be harmful to the patient. In situ-
ations where large volumes of fluid or blood will be needed,
heat exchangers capable of rapidly infusing fluids that have
been warmed to 37° C are ideal.
Tourniquet Problems. Tourniquets are increasingly applied
in the prehospital setting, particularly in the military environ-
ment, and are frequently used in extremity surgery to reduce
blood loss and improve surgical visualization. When used for
long durations or at extreme pressures, tourniquets can cause
injury to underlying nerves, muscles, and blood vessels and
may produce systemic effects as well. Effects can be seen at
initial inflation, during prolonged inflation, and on deflation.
Exsanguination of an injured limb with an Esmarch bandage
and inflation of the tourniquet typically produce only small
increases in central venous and arterial pressures. The appli-
cation of bilateral lower extremity cuffs, however, may result
in a significant elevation of central venous pressure.166 Patients
under general anesthesia may develop systemic ­hypertension
45 to 60 minutes after inflation.173 The mechanism for this
 514 ANESTHESIA AND UNCOMMON DISEASES

elevated BP is not clearly understood and does not always of the femur to external fixation. PA catheter monitoring or
respond to increasing anesthetic depth. Tourniquet deflation TEE may be necessary to optimize hemodynamics and main-
and reperfusion of the ischemic limb may be associated with tain intravascular volume. The possibility of acute right-sided
significant decreases in central venous and arterial pressures. heart failure resulting from elevated PA pressure requires
The sudden reduction in PVR, the increase in volume of the ­careful avoidance of volume overload. Also, the early use
intravascular space compared with a relatively fixed circulat- of corticosteroids has been advocated after treatment of fat
ing volume, and the circulatory effects of ischemic m ­ etabolites embolism syndrome.182–185
most likely account for these changes.174 Finally, awake patients
Deep Vein Thrombosis. Deep venous thrombosis is a
undergoing regional anesthesia may complain of tourniquet
c­ommon complication of orthopedic trauma, and ­resultant
pain despite an otherwise adequate block. Use of small doses
pulmonary embolism is a major contributor to p ­ ostoperative
of IV narcotics or transient deflation (10-15 minutes) may
mortality. The incidence of DVT varies by site and type of
mitigate this hemodynamic lability or patient discomfort.
operative procedure (Table  17-9). Thromboses can form
Recommended pressure levels are 100 mm Hg above s­ ystolic
­during periods of venous stasis at any point in the ­perioperative
pressure for thigh cuffs and 50 mm Hg above ­systolic pressure
period. Prevention is critical and should begin as soon as
for upper extremity cuffs.175 Duration of cuff ­inflation should
practical after a nonambulatory patient presents for care,
­
generally not exceed 120 minutes.176,177 As previously ­mentioned,
should be instituted in the OR if not already in place, and
preoperative vascular and neurologic ­ function should be
should ­continue into the postoperative period.186
­accurately documented whenever p ­ ossible, because regional
Mechanical prophylaxis methods such as intermittent
anesthetic techniques may be blamed for ­postoperative ­deficits
pneumatic compression devices and foot pumps speed venous
actually caused by tourniquet injury.
flow in the extremity, increase the volume of blood returned
to the heart, and induce endothelial changes that decrease
Fat Embolism Syndrome. Some lung dysfunction occurs
the risk of thromboembolic phenomena. These measures
in almost all patients with long-bone fractures, ranging from
have no effect on the coagulation system and thus should be
minor laboratory abnormalities to life-threatening fat embo-
used in all patients undergoing orthopedic procedures, unless
lism syndrome. A lack of universally accepted diagnostic cri-
contraindicated by injury. Sequential compression devices
­
teria combined with varying levels of pre-existing pulmonary
work through the mechanical effect of decreasing venous
and cardiovascular comorbidities account for the ­ varying
­stasis, and subsequently the rate of DVT, as well as a ­fibrinolytic
reported incidence of fat embolism. Most studies suggest clini-
effect from decreased plasminogen activator inhibitor-1 levels.
cally significant fat embolism syndrome occurs in 3% to 10% of
However, the Seventh ACCP Conference on Antithrombotic
patients, although the presence of multiple long-bone fractures
and Thrombolytic Therapy noted that “no mechanical pro-
is associated with the higher incidence. Patients with coexist-
phylaxis option has been shown to reduce the risk of death
ing lung injury are at additional risk of fat embolism.178 Signs
or PE.”187
include hypoxia, tachycardia, mental status changes, and pete-
Epidural and spinal anesthesia have been shown to reduce
chiae on the upper portions of the body, ­including the ­axillae,
DVT rates after total-knee replacement by 20% and after
upper arms and shoulders, chest, neck, and ­conjunctivae. Fat
total-hip replacement by approximately 40%.188 Although
embolism syndrome should be suspected whenever the alve-
postoperative epidural analgesia does not appear to provide
olar-arterial oxygen gradient deteriorates, especially in con-
additional benefit in reducing DVT rates,189 it may still be
junction with decrements of pulmonary compliance and CNS
beneficial by allowing earlier mobilization and ambulation.
function. CNS changes will manifest after general ­anesthesia
For postoperative thrombosis, there is good evidence for an
as a failure to emerge after surgery. If central hemodynamic
monitoring is available, PA pressure will be elevated, often
accompanied by decreases in cardiac index. Early surgical
­correction of fractures and minimization of trauma to the TABLE 17-9  n Incidence of Deep Vein Thrombosis
bone marrow may lessen the incidence or ­severity of embo- by Site or Procedure
lism, whereas excessive reaming of the medullary canal can Surgery/Fracture Site Rate of DVT
contribute to perioperative morbidity and severity of the fat
embolism syndrome.179 Knee arthroscopy 3%
Diagnosis of fat embolism syndrome in the OR is largely Total hip replacement 30%-50%
based on clinical presentation and ruling out other treat-
able causes of hypoxemia. Fat globules in the urine are not Total knee replacement 40%-60%
­diagnostic, but lung infiltrates on chest radiography c­ onfirm Tibial plateau 43%
the presence of lung injury and the need for appropriate
Femoral shaft 40%
v­ entilatory management.180,181
Treatment is limited to early recognition, O2 ­administration, Tibial shaft 22%
and judicious fluid management. Alteration of the orthope- Distal tibia 13%
dic procedure may be indicated, such as converting “rodding”

association between impaired fibrinolytic activity measured
either ­preoperatively or postoperatively and increased risk of
postoperative thrombosis. Whether this association is causal
or coincidental is unclear.190 Current guidelines suggest that
a low-molecular-weight heparin (LMWH) such as enoxapa-
rin provides the best prophylaxis for venous thromboembo-
lism in the high-risk trauma patient.191 Once started, LMWH
should be withheld for 12 hours before surgery, if possible,
and restarted a minimum of 3 hours after surgery. Recent
guidelines for neuraxial anesthesia in the patient undergo-
ing thromboprophylaxis detail the timing of the anesthetic
­procedure and the v­ arious thromboprophylactics.192 In high-
risk patients or those in whom postoperative prophylaxis is
contraindicated, vena cava filters may be placed periopera-
tively, although this is controversial.
Near-Drowning
As experts in airway management and pulmonary sup-
port, anesthesiologists are consulted in the care of victims of
asphyxia secondary to near-drowning. Prompt intubation and
restoration of normal oxygen saturation is crucial. Subsequent
management is symptomatic, consisting of frequent assess-
ment of ABGs and iterative weaning of mechanical ventilation
to achieve adequate recruitment of collapsed lung units with
the lowest possible airway pressures. Of all human reflexes,
those causing laryngoconstriction are among the strongest,
and many near-drowning victims do not aspirate significant
amounts of water at all. Patients after near-drowning may
manifest with hyponatremia or hypernatremia.193 Those with
evidence of aspiration likely suffered more profound lev-
els of hypoxia as well. Significant pulmonary aspiration not
only removes surfactant from the lungs but also contaminates
the alveoli, leading to significant acute lung injury and fluid
­volume loss into the pulmonary interstitium. Ventilatory sup-
port may be required for days after the acute event. Return
of normal pulmonary function is likely in most patients, and
long-term outcomes therefore depend predominantly on the
patient's neurologic injury secondary to the initial period of
hypoxia.
Smoke Inhalation and Carbon Monoxide
Poisoning
Pathophysiology. Patients exposed to fire or resulting toxic
gases may be hypoxic from three mechanisms: (1) thermal
injury to the upper airway, with edema and stricture of the lar-
ynx; (2) particulate inhalation and subsequent bronchocon-
striction; and (3) carboxyhemoglobin formation secondary
to carbon monoxide (CO) poisoning. CO binds hemoglobin
with an affinity approximately 250 times greater than oxy-
gen, leading to decreased O2-carrying capacity and delivery
with resultant hypoxia and acidosis at the tissue level. Pulse
­oximetry will not accurately reflect tissue O2 delivery because
such oximeters cannot discriminate the spectral signature of
carboxyhemoglobin from that of oxyhemoglobin. Early ABG
Chapter 17  Trauma and Acute Care 515
sampling, with specific co-oximetric measurement of the
­fraction of carboxyhemoglobin, is therefore essential.194
Evaluation. Although soot staining of oral mucosa
is c­ommon, patients with visible burns of the soft palate
­(erythema or blistering) should be promptly intubated, as
should any patient with laryngeal edema, indicated by stri-
dor or progressive change in voice. Hypoxia may present as
agitation or lethargy, and therefore any burn or CO-poisoned
patient with an altered mental status should be intubated and
mechanically ventilated until diagnostic studies are complete.
For less symptomatic patients, humidified oxygen and nebu-
lized bronchodilator therapy will contribute to clearance of
soot particles from the airways and resolution of edema.
Perioperative Management. Initial management consists
of strict adherence to the ABCs of trauma. The CO-poisoned
patient should receive high O2 concentrations, which will
competitively displace CO from Hb. At Fio2 of 1.0, the half-life
of carboxyhemoglobin is approximately 90 minutes. Patients
without neurologic symptoms generally respond well to face
mask administration alone. For neurologically impaired
patients or those with special risk factors (pregnancy, extremes
of age, significant comorbidity) intubation will ensure the
highest possible Fio2 and an adequate ventilatory rate, while
increasing mean airway pressures and optimally oxygenat-
ing unbound Hb. Hyperbaric oxygen therapy is indicated for
severe CO poisoning cases and will significantly shorten the
half-life of carboxyhemoglobin.195 Life-threatening ARDS
from CO poisoning may be successfully treated with extracor-
poreal support, allowing the lungs to recover from the initial
injury.196
The Pregnant Trauma Patient
Trauma in pregnancy poses unique problems for the anesthe-
siologist and resuscitation team. The significant alterations
in physiologic demand associated with pregnancy will com-
plicate the evaluation, treatment, and management of these
patients. Trauma is the leading cause of maternal death in the
United States, with 3 to 4 per 1000 pregnancies requiring hos-
pital admission for trauma.197 A high index of suspicion for
abuse should be maintained in this population. Even minor
trauma poses significant risk to the fetus and requires extra
vigilance during routine cases. The primary focus of resuscita-
tion and early management is the mother; there can be no fetal
survival without maternal survival. Stabilization of the moth-
er's condition typically takes priority over fetal concerns, with
the possible exception during the third trimester, when in rare
cases, the maternal prognosis is poor and immediate cesarean
section may save the fetus. (See also Chapter 19.)
Pathophysiology. The physiologic changes of pregnancy
alter the normal responses to traumatic injury. Table  17-10
summarizes the significant changes seen in the pregnant
patient and their implications on trauma care. Maternal
plasma volume expands by 40% to 50% by the end of the first
 516 ANESTHESIA AND UNCOMMON DISEASES
TABLE 17-10  n  Physiologic Changes of Pregnancy
Organ System Change
Cardiovascular Decreased peripheral vascular resistance
Increased cardiac output
Increased heart rate
Aortocaval compression
Hematopoietic Increased plasma volume
Hypercoagulable state
Increased leukocyte count
Respiratory Increased minute ventilation
Decreased residual capacity
Elevated diaphragm
Gastrointestinal Decreased motility
Decreased lower esophageal sphincter tone
Renal Increased filtration rate
Dilated collection system
Musculoskeletal Pelvic ligament laxity
Increased venous volume
trimester and peaks by 30 to 34 weeks’ gestation. RBC mass
expands to a lesser degree, resulting in dilutional a­nemia
(“physiologic anemia of pregnancy”), often with a normal
Hb of 10.5 to 12.9 mg/dL. As a result of this intravascular
volume expansion, mild to moderate blood loss associated
with traumatic injury may appear to be well tolerated by the
mother. However, further alterations in uteroplacental circu-
lation caused by compensatory mechanisms may have a sig-
nificant adverse impact on the fetus.198 Other alterations that
may impact management include changes to baseline BP and
cardiac output. By 28 weeks, normal maternal BP decreases
by 15% to 20% because of PVR reduction. At the same time,
cardiac output increases by 35% to 50% above baseline, with
a 17% increase in heart rate, a moderate increase in stroke
­volume, and a functional 20% to 30% arteriovenous shunt
produced by the low-resistance placental circulation.199
A further hemodynamic effect that may have an untoward
impact on the pregnant trauma patient is hypotension result-
ing from compression of the inferior vena cava (IVC) by the
gravid uterus. By 24 weeks, the uterus is large enough to pro-
duce mechanical compression of the IVC when the patient is
in a supine position. In the case of significant hemorrhage or
cardiac arrest, hemodynamic instability from IVC compres-
sion may become an acute problem, manifesting as a 25%
reduction of effective cardiac output. MVCs account for more
than 50% of all trauma during pregnancy, with 82% of fetal
deaths occurring during these crashes. With life-threatening
trauma, fetal loss is 50%.200 Supine positioning of the severely
traumatized pregnant patient should be avoided whenever
possible, particularly during the third trimester. This can be
accomplished by using the left lateral decubitus position, or
when injury prevents the patient from being placed on the
side, by means of a right hip wedge, by manual displacement
Implications
Reduced baseline blood pressure
Resting tachycardia
Supine hypotension
Dilutional anemia
Thromboembolism
Respiratory alkalosis
Abnormal chest radiograph
Aspiration
Aspiration
Hydroureter, hydronephrosis
Widened pubic symphysis
Bleeding with fractures
of the uterus laterally, or by lateral tilt of the backboard, bed,
or OR table.
Significant yet predictable respiratory changes of ­pregnancy
should also be anticipated. Minute ventilation is increased
by almost 50%, secondary to both an increase in respiratory
rate and tidal volume, resulting in a compensated respiratory
alkalosis with a reduction in buffering capacity. A “normal”
ABG value in a pregnant patient should therefore prompt
immediate evaluation of respiratory function. Functional
­residual ­capacity is reduced by 15% to 20% at term, whereas
O2 ­ consumption is significantly elevated, resulting in an
­impressive predisposition toward precipitous desaturation.
The circulatory changes associated with pregnancy cause
global capillary engorgement of respiratory tract mucosa,
­producing edema in the nasopharynx, oropharynx, larynx,
and trachea. Manipulation of this friable tissue requires extra
care; further injury might worsen the underlying edema and
predispose to airway obstruction. Endotracheal intubation
should incorporate smaller ETTs than might normally be used
in the nonpregnant patient (6.0-0.0 mm) given the probability
of moderate supraglottic edema. GI motility can be affected
by pregnancy, and the risk of gastric reflux is increased in the
gravid patient. While motility alterations are most prominent
during labor, a decrease in lower esophageal sphincter tone
and an increased gastric acid secretion suggest that the risk of
aspiration is increased in any pregnant patient near term.201
Renal changes include an increase in both renal blood
flow and creatinine clearance. A mild physiologic hydrone-
phrosis should be borne in mind when evaluating the patient
with abdominal or pelvic trauma. Coagulation parameters
are altered by an estrogen-induced increase in clotting f­actor
function, placing women at increased risk for thromboem-
bolic disease in the setting of venous stasis or vessel wall injury.

Fibrinogen is likewise increased by 50%, such that a “normal”
level in a term pregnant patient (300 mg/dL) may suggest a
consumptive process. A moderate leukocytosis is normal
and, in isolation, does necessarily imply an ­inflammatory or
i­ nfective process.
In addition to understanding the impact of maternal
­physiology on trauma management, the anesthesiologist must
also consider the effects on the fetus, which will depend on
gestational age, type and severity of trauma, and the extent of
disruption of uterine function. Fetal survival requires uninter-
rupted uterine perfusion and O2 delivery. Autoregulation is lack-
ing in the uterine circulation, and therefore uterine blood flow is
directly related to maternal BP. As the mother approaches hypo-
volemic shock, further maternal vasoconstriction will increas-
ingly compromise uterine perfusion. In frank maternal shock,
the chance of fetal survival is severely decreased.
Fetal bradycardia or tachycardia, decreased baseline fetal
heart rate (FHR) variability, absent normal FHR accelera-
tions, and repetitive decelerations suggest that oxygenation
and perfusion have been compromised. Direct or indirect
uterine trauma can injure the myometrium, possibly leading
to ­uterine contractions and even the induction of premature
labor. When maternal injuries are not lethal, placental abrup-
tion is the most common cause of fetal demise.202 As a­ bruption
can occur even with low energy impacts, all patients with
moderate blunt trauma should undergo FHR monitoring and
close observation.197,203
The Kleihauer-Betke test is used to detect the presence and
degree of fetal-to-maternal hemorrhage after trauma. This can
be used to predict fetal anemia (life-threatening hemorrhage) in
utero. If feto-maternal hemorrhage occurs in an Rh-negative
mother, prophylactic Rho(D) immune globulin (RhoGAM)
should be given to protect against isoimmunization result-
ing from the transfer of fetal hemoglobin to the maternal
circulation.204
Evaluation. Preoperative anesthetic evaluation of the
injured pregnant patient should involve immediate and close
consultation with an obstetrician or maternal-fetal special-
ist, with the primary goal of stabilizing the mother's condi-
tion. During the primary survey, treatment priorities remain
the same as for the nonpregnant patient. However, given the
increased likelihood of aspiration and rapid desaturation,
as well as the propensity toward fetal distress as a result of
maternal hypoxia, endotracheal intubation may be consid-
ered early. This must be balanced against the likelihood of an
edematous, friable, difficult airway, particularly in the later
stages of ­pregnancy. Although tachypnea is a normal finding
in the physiology of pregnancy, any life-threatening causes of
­respiratory compromise should be sought. The baseline heart
rate elevation of 10 to 15 beats/min can make estimation of
volume status difficult. While assessment of central and
peripheral pulses, capillary refill, skin color and t­emperature,
and mental status are still useful tools in the pregnant patient,
significant hypovolemia can be present despite ­
­ minimal
changes in these markers.
Chapter 17  Trauma and Acute Care 517
After initiation of lifesaving measures, the secondary
s­ urvey of the stable pregnant patient will include fetal assess-
ment. If possible, the pregnancy history should consider the
estimated gestational age, the prenatal care, and any compli-
cations (e.g., diabetes, hypertension). Estimated gestational
age and viability should be determined quickly because the
presence of a viable fetus (typically 24 weeks’ gestation) may
allow for early caesarean section. If the mother cannot provide
a history, palpation of the uterine fundus at 3 to 4 cm above
the umbilicus typically correlates with a viable gestational age.
Cardiotocographic monitoring (CTM) should begin as early
as possible. Fetal bradycardia is a sensitive indicator of poor
maternal perfusion and may be the first measurable change
secondary to significant maternal hypovolemia. CTM moni-
toring of uterine irritability and contractions can be useful in
detecting placental abruption.205,206 The American College of
Obstetricians and Gynecologists (ACOG) recommends that
any pregnant trauma patient beyond 22 to 24 weeks’ gesta-
tion undergo fetal monitoring for a minimum of 24 hours.206
If the patient presents with ruptured membranes, bleeding,
fetal arrhythmias or FHR decelerations, or more than four
­contractions per hour, the patient should be admitted with
continuous fetal monitoring for at least 24 hours, with further
management as the clinical scenario requires.
Laboratory evaluation should include hemoglobin/hema-
tocrit, type and crossmatch, coagulation parameters, lactate
determination, ABG analysis, and urinalysis. Interpretation
of the results should consider pregnancy-related changes to
normal values. Physiologic anemia may be confused with ane-
mia caused by hemorrhage, and a normal fibrinogen level in
the nonpregnant patient may be an early indicator of dissemi-
nated intravascular coagulation (DIC) in the pregnant patient
because of placental abruption. Additionally, given the higher
minute ventilation associated with pregnancy, a normal or
e­ levated Paco2 level may suggest pending respiratory failure.
Use of lactate levels as a marker of resuscitation is not affected
by the pregnant state.
Preoperative Preparation. Careful optimization of the
gravid trauma patient's perioperative volume status will help
maintain fetal perfusion. As in all trauma cases, large-bore
IV access is required. When large volumes of crystalloid are
­necessary, normal saline may lead to maternal and fetal hyper-
chloremic acidosis. Coagulation defects should be addressed
before surgery when possible, with pregnancy-related changes
such as elevated fibrinogen levels kept in mind. Prophylactic
reduction of gastric pH and volume will help to decrease the
risk of maternal morbidity and mortality from aspiration of
gastric contents on anesthesia induction.
Intraoperative Considerations. The anesthetic technique
chosen in the traumatized pregnant patient will be determined
by the urgency and location of the procedure, the presence of
concomitant injuries and pre-existing conditions, and mater-
nal preference. When feasible, regional anesthesia offers some
advantages to general anesthesia, including the maintenance
of airway reflexes and the avoidance of airway manipulation,
 518 ANESTHESIA AND UNCOMMON DISEASES
although no direct evidence shows a reduction in mortality.
Any possible limitation of dosages of systemically distributed
medications will reduce fetal exposure and should be sought
whenever possible.
General anesthesia is still necessary for many pregnant
trauma patients. Preoxygenation before anesthetic induction
should be accomplished for more than 3 minutes with 100%
O2 in an attempt to avoid the rapid onset of hypoxia seen with
apnea in these patients.207 This is usually accomplished through
RSI because of the increased risk of aspiration. Left uterine
displacement must be continued throughout the induction
and operative periods to maintain venous return and adequate
preload to the heart. Invasive hemodynamic monitoring may
be dictated by maternal conditions. Maternal Paco2 should be
kept at 33 to 36 mm Hg, since further degrees of hyperven-
tilation may be detrimental to fetal perfusion. Intraoperative
fetal CTM can supplement other available information regard-
ing maternal perfusion, although the need for operative access
may limit its use. CTM should be continued postoperatively to
monitor for premature labor.
Concerns about the effects of anesthetic agents on the
growth and development of the fetus should be considered.
A review of pharmacologic considerations and potential tera-
togenicity is provided in Chapter 19. Agents and techniques
that have historically-proven safety profiles should be used in
the care of the pregnant trauma patient whenever possible.
Geriatric Trauma
Trauma outcomes in elderly patients are dramatically worse
than those of the general population, with significantly
higher in-hospital morbidity and mortality rates after identi-
cal anatomic injuries.208 Persons age 75 years and older have
the highest injury death rates. Reasons for this difference
include a decreased basal metabolic rate, limited cardiopul-
monary reserve, atherosclerotic disease, impaired wound
healing, and increased susceptibility to sepsis. Pre-existing
neurologic impairment, including psychiatric disease, is com-
mon in the elderly trauma patient. For many elderly patients,
a traumatic event heralds the end of independent living and
the requirement for chronic nursing care or assisted living.
Statewide systems-level factors may also determine the qual-
ity of care that elders receive. In a 10-year retrospective review
of 430,081 patients admitted to California acute care hospitals
for trauma-related diagnoses, 27% were older than 65 years.
After adjusting for demographic, clinical, and system factors,
compared with trauma patients age 18 to 25 years, the odds of
admission to a trauma center decreased with increasing age.209
Although multiple clinical and demographic factors have
demonstrated an association with outcome following trauma in
geriatric patients,210 the ability of any specific factor to predict
an unacceptable outcome for any individual geriatric trauma
patient is quite limited. An initial course of aggressive therapy
seems warranted in all geriatric trauma patients, regardless
of age or injury severity, with the possible ­exception of those
patients who arrive in a moribund condition. Geriatric trauma
patients who do not respond to aggressive resuscitative efforts
in a timely manner are likely to have poor outcomes, even with
continued aggressive treatment. For g­ eriatric trauma patients
who do respond favorably to aggressive resuscitative efforts,
the prognosis, not only for survival but also for return to their
preinjury level of function, is quite good.211
Close attention to detail is required to achieve optimal
anesthetic results. This may include perioperative modalities
such as continuous insulin infusion and perioperative beta-
adrenergic blockade. Surgical procedures required by elderly
trauma patients are the same as for younger adults, but the
optimal timing of surgery may be more challenging. Bed-
bound elderly patients have a predictable, progressive loss of
pulmonary function to atelectasis and possibly pneumonia,
even in the presence of attentive nursing care; thus, delaying
surgery in an effort to improve ventilation or pursue diagnostic
studies may be counterproductive. Similarly, urgent repair of
long-bone fractures and open wounds should take precedence
over additional specialty consultation and risk stratification
studies (e.g., stress cardiac imaging), particularly when these
studies are unlikely to change management. Some patients
with pronounced myocardial ischemia or ­dysrhythmia may
­benefit from angioplasty or electrophysiologic intervention
before intervention, but most will benefit more from prompt
surgical correction of the traumatic injury.103
In the absence of confirmation to the contrary, the anesthe-
siologist should assume pre-existing heart disease in patients
with an unclear or unknown cardiac risk. All medications,
including induction agents, should be selected for efficacy as
well as ability to maintain cardiovascular stability and must
be carefully titrated to patient response. Elderly patients can
suffer prolonged sedation and disorientation after IV anxioly-
sis, frequently necessitating postoperative mechanical ventila-
tion. Invasive pressure monitoring and laboratory assessment
of perfusion should be considered whenever traumatic or
surgical blood loss is deemed more than “minimal.” PA
­
­catheterization and direct assessment of myocardial perfor-
mance and fluid volume status may be beneficial,210 although
this technique may be time-consuming or even hazardous. If
available, TEE and newer, noninvasive technologies may be
more appropriate. (See also Chapter 20.)
PREHOSPITAL ANESTHETIC CARE
The role of the U.S. anesthesiologist may at times extend beyond
the medical facility to include the prehospital environment, as
is standard in many European countries. Many large trauma
centers have established relationships with local e­mergency
medical service (EMS) providers to form field-response “go
teams” capable of extending lifesaving or limb-saving ­medical
support to disaster situations.212 Physician involvement in
­prehospital management of trauma is g­enerally limited to
consultation and occasional scene response in North America,
whereas the military and many other countries may push
this capability much closer to the point of injury. Physician
involvement is limited to consultation and occasional scene

response in North America, although Israel, Germany, France,
and other countries have mobile ICUs staffed by anesthesiolo-
gists and other physicians.213 Better outcomes have been dem-
onstrated in patients with head injury or blunt trauma when
a prehospital physician is present.214,215 Military medical teams
also use the prehospital physician for point-of-injury and
interfacility transport and resuscitation.216,217 The future role
of the prehospital physician has been discussed.218
Service on a “go team” assumes many training require-
ments for the unique conditions found in medical disaster
response. Training with an established anesthetic plan for
austere environments is helpful.219 An effective approach to
such challenges is to break the response down to recogniz-
able tasks (Box 17-7). Although involved physicians will likely
not be responsible for most, familiarity with these tasks will
make their integration into the team much more effective and
will establish a framework that optimizes their unique skills.
Individuals assigned to a “go team” must be facile in hazardous
materials, personal protective equipment (PPE), scene control,
forensics, public health, decontamination, rescue equipment,
helicopter medical evacuation, and basic emergency medicine.
The most common scenario for civilian “go team” response
is entrapment after an MVC or building collapse. Although
field amputation is rarely required for safe extrication, flexibil-
ity and familiarity with alternative airway techniques, adverse
positioning, nonstandard vascular access, and total intrave-
nous anesthesia (TIVA) are essential for such cases. The “go
team” may also have the ability to administer blood products
as well as higher degrees of sedation than might otherwise be
possible under most EMS protocols.220
ACUTE CARE ANESTHESIOLOGY
The U.S. Institute of Medicine has reported on hospital-
based emergency care as “at the breaking point.”221 U.S.
­hospitals report 39.4 million emergency department ­visits
for injury annually, and a 14.3% hospital admission rate; 7.3
million of those injured require operative intervention.222
Anesthesiologists care for these injured patients in the ED or
in the OR. Just as the needs of injured patients fueled the field
BOX 17-7   n  DISASTER RESPONSE TASKS
Scene Assessment
n Scene description
n Scene safety
n Patient conditions
Incident Management
n Command and control
n Communications
Victim Care
n Search and rescue
n Primary assessment and triage
n Transport
n Definitive care
Chapter 17  Trauma and Acute Care 519
of trauma surgery two decades ago, so have the needs of the
emergency general surgery patient driven the development of
a systematic approach to care,223 leading to a proposal for the
development of the Acute Care Surgery Fellowship.224
Increasing numbers of in-house acute care surgeons
and competition for OR time have led to more nonemer-
gent general surgery procedures at night, when there are
fewer ­ faculty, residents, nurses, and support staff avail-
able. Recently, ­performing nonemergent cases at night has
been proposed as a safe solution for daytime overcrowding
of ORs.225 A recent report of operative experience at a ter-
tiary academic, Level I trauma center documented that more
than 50% of ­surgical procedures are not elective cases: 40%
are urgent operations, 11% emergency procedures, and 8%
trauma-related ­procedures.226 Patients with intra-abdominal
sepsis, soft tissue infection, acute abdominal pathology, and
acute hemorrhage are more likely to require urgent or emer-
gent evaluation and operative intervention, with subsequent
ICU admission.227
As with trauma, patients presenting to the OR for emer-
gency surgery often do not have a thorough preoperative
assessment of baseline cardiac, respiratory, or renal physiol-
ogy. As ASA “E” class would suggest, these patients may be
at greater risk for adverse outcomes. Using the ACS National
Surgical Quality Improvement Program (NSQIP) data from
2005 to 2008, Ingraham et  al.228 compared the risk factors
and 30-day outcomes associated with a range of emergency
and elective general surgery cases. Of 473,619 procedures,
14.2% (67,445) were for emergency general surgery (EGS)
cases (appendectomy, colectomy/colostomy, cholecystectomy,
hernia repair, small intestine resection, anorectal abscess
­drainage). Although the EGS patients tended to be younger
(49.5 ±20.2 vs. 53.9 ±16.4 years), they were assigned a higher
ASA class and had a lower baseline functional status and more
comorbidities. The “overall morbidity,” defined as surgical site
infection, wound dehiscence, cerebrovascular event, cardiac
arrest, myocardial infarction, bleeding, pulmonary embo-
lism, ventilator dependence, renal failure, or sepsis, in EGS
patients was 19.8%, versus 8.8% in the elective surgery patients
(p <0.001), and mortality was 5.8% versus 0.8% (p <0.0001).
It is not known to what degree the skills of the anesthesiolo-
gist caring for these patients impacts outcome, through such
interventions as glucose control, timely administration of
­
antibiotics, β-blocker therapy, fluid and blood administration,
and intraoperative ventilator management.
The American College of Graduate Medical Education
(ACGME) currently requires that anesthesiology residents
complete only 20 trauma/emergency cases of patients with
“life-threatening” injuries during their training. Subspecialty
rotations in thoracic, neurosurgery, orthopedics, vascular, and
cardiac blocks ensure a broad exposure to the pathophysiol-
ogy and anesthetic requirements of managing these patients,
but the majority of these are scheduled cases.
Resuscitation strategies have advanced rapidly over the
past several years. Anesthesia and resuscitation for elective
surgical cases differs from anesthesia and resuscitation for
 520 ANESTHESIA AND UNCOMMON DISEASES
emergency cases, due to the common presence of shock.229
Contrary to elective cases, where large-volume blood loss
and fluid shifts are anticipated, bleeding or infection in EGS
patients often results in substantial total body fluid deficit at
presentation to the OR. Fluid administration, massive trans-
fusion protocols, prevention of coagulopathy, hypotensive
resuscitation, “damage control” surgery, advanced ventila-
tor modalities, and use of ultrasonography as a rapid, non-
invasive diagnostic tool have led to improved outcomes and
decreased mortality in patients after trauma and emergency
surgery.230–238
Recently there has been a call for restructuring anesthesi-
ology training, to include subspecialty focus in critical care or
pain medicine during the CA-3 year. The goal is to “develop
the aspects of our practice that are likely to assume a greater
prominence in the healthcare system of the future.”239 Another
proposal is to have anesthesiology trainees complete an addi-
tional, mandatory 2 years of training after the PG-3 year, pos-
sibly creating programs in hospital medicine and emergency
medicine in combination with anesthesiology. An additional
focus of research, in nurturing the clinician-scientist, should
establish our specialty as a leader in “best practices” in post-
graduate education and clinical expertise.240
Anesthesiologists possess the basic skill sets that would natu-
rally lead to advance practice in these fields. The acute care anes-
thesiologist would be equally functional, and capable, at a tertiary
care Level I trauma center in the Western world, the far-forward
combat environment, or a disaster in an austere developing nation.
CONCLUSION
The practices of trauma and acute care anesthesiology require
training and knowledge acquisition from all disciplines of
anesthetic practice. The cases often require emergent inter-
ventions and advanced techniques of management, and coor-
dination of care among multiple surgical specialties may be
needed. The trauma/acute care anesthesiologist is facile in the
emergency department, operating room, intensive care unit,
in transport, in the pain clinic, and in the military setting.
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 C H A P T E R
18
Burns
SANJAY M. BHANANKER, MD, FRCA  n
BRUCE F. CULLEN, MD  n

n Surgical burn patients are susceptible to hypothermia due

Pathophysiology to evaporative heat loss from exposed skin burn surface
Cardiovascular Effects
and donor areas.
Metabolic Changes
n Topical epinephrine, tourniquets, and a staged procedure
Hematologic Effects
reduce blood loss during tangential burn excision.
Renal Function
n Burn patients rapidly become tolerant to opiates.
Pharmacologic Effects
Perioperative analgesic needs can be high and are often
Inhalation Injury
underestimated.
Carbon Monoxide and Cyanide Poisoning
n Adjuncts to opiate analgesia include acetaminophen, ket-
Preoperative Preparation amine, nerve blocks, and tumescent analgesia.
Fluid Resuscitation
n A hyperkalemic response to succinylcholine can occur
Fasting Requirements
2 days to 6 months after thermal injury from proliferation of
Surgical Considerations acetylcholine receptors. During this period, patients become
Excision and Grafting
resistant to nondepolarizing neuromuscular blockers.
Anesthetic Considerations Perioperative management of patients with severe burn inju-
Airway Management
ries presents significant challenges to the anesthesiologist. An
Analgesia
estimated 1.25 million patients with burn injuries are treated
Ventilation
each year in the United States, up to 100,000 of whom require
Regional Anesthesia
hospitalization. More than 6500 patients succumb to their
Monitoring
thermal injuries.1 A better understanding of the pathophysi-
Blood Loss and Transfusion Requirements
ology of burn injuries, coupled with advances in burn resus-
Pediatric Issues citation, critical care, and surgical practice, has resulted in
Procedural Sedation
improved survival in severely burned patients over the past
Conclusion three decades.2–5 In 2001 the American Burn Association
(ABA) developed evidence-based guidelines for the manage-
ment of acute burn injury.6
Modern care for the severely burned patient can be divided
KEY POINTS
into four overlapping phases: (1) initial evaluation and resus-
n The morbidity and mortality associated with burns vary citation, (2) initial excision and biologic closure, (3) definitive
with total area burned, depth of burn, presence of inhala- wound closure, and (4) rehabilitation and reconstruction.7 The
tion injury, and coexisting diseases. anesthesiologist's services may be called on for airway man-
n Adequate fluid resuscitation, appropriate analgesia, and agement, intravenous access, and fluid resuscitation, in addi-
early excision of wounds are vital to improve the outcome tion to providing sedation and analgesia in the acute phase.
in burn patients. Administration of analgesia and sedation for wound care and
n Understanding the pathophysiologic changes associated provision of anesthesia for excision and grafting are even more
with major thermal injury, particularly the hypermeta- challenging tasks. Reconstructive surgery poses special chal-
bolic response, is essential for perioperative care of burn lenges because of the development of contractures, making
patients. airway management and positioning difficult.

526
 Chapter 18 Burns 527

PATHOPHYSIOLOGY TABLE 18-1  n  Classification of Burn Depth

The primary determinants of severity of burn injury are the
Classification Burn Depth Outcome
size and depth of the burn. However, patient age, body part
burned, presence of pre-existing disease, and associated non- Superficial (first Epidermis only Heal
burn injuries have an important impact on the outcome.3–5 degree) spontaneously
The size of the burn is usually estimated in adults by using the
Partial thickness Epidermis and
“rule of nines” and expressed as percentage of total body sur- (second degree) dermis
face area (TBSA)8,9 (Fig. 18-1). The burn depth is classified as
superficial, partial thickness, and full thickness (Table 18-1). Full thickness
First-degree (superficial) burns affect only the epidermis and Third degree Destruction of Wound excision
are characterized by erythema and edema of the burned epidermis and and grafting
areas without blistering or desquamation. Superficial burns dermis necessary
are treated with daily dressing and wound care until epithe- Fourth degree Fascia, muscle, Complete excision
lialization occurs. Second-degree (partial-thickness) burns bone burned required;
involve the epidermis and a portion of the dermis. In most functional
cases, ­partial-thickness wounds can be expected to heal spon- limitation likely
taneously in 1 to 4 weeks, although surgical treatment may be
necessary for extensive or deep second-degree burns. Pain is
characteristic of partial-thickness burns. Third-degree (full- cytokines,14 tumor necrosis factor alpha (TNF-α),15 endo-
thickness) burns extend entirely through both the epidermis toxin,16–18 oxygen-derived free radicals,19–21 nitric oxide,22 and
and dermis and will not heal spontaneously.10 complement.23,24
Severe burn injury results in release of circulating media-
tors that evoke a physiologic response, the systemic inflam- Cardiovascular Effects
matory response syndrome (SIRS), throughout the body11
(Fig. 18-2). These mediators include histamine,12 serotonin,13 There is an increase in capillary permeability and “third
spacing” of fluid in tissues surrounding the burn. Interstitial
edema and organ dysfunction in distant organs result from
combination of the vasoactive mediators and hypoprotein-
9% emia in severe burns.25,26 Increased capillary permeability is
seen in the burned tissue for more than 72 hours and in the

Minor Burns Major Burns

9%

Local mediators Systemic mediators

Histamine Cytokines, interleukins, TNF
9% 9% Prostaglandins Endotoxin
9% Bradykinin Nitric oxide
Serotonin Complement
Substance P O2-derived free radicals
1%

18% 18%
Systemic response

Contributing factors Immune suppression


Catecholamines Hypermetabolism

Glucagon, cortisol Protein catabolism

Skin barrier Sepsis

Multiorgan dysfunction/failure

FIGURE 18-1  Total body surface area (TBSA) in burn estimation. FIGURE 18-2  Pathophysiology of burns. Local and systemic
“Rule of nines” is used to estimate the percentage of BSA injured in mediators of major and minor burns, with systemic response. TNF,
burn patients. Tumor necrosis factor.
 528 ANESTHESIA AND UNCOMMON DISEASES
nonburned tissue for up to 24 hours.27 TNF-α, O2-derived free
radicals, and endothelin-1 exert a negative inotropic effect and
reduce cardiac output acutely. The cardiovascular response to
both endogenous and exogenous catecholamines is attenu-
ated because of decreased adrenergic receptor affinity and
decreased production of second messengers. Systemic vascu-
lar resistance (SVR) increases in the initial postburn period.
Later, in the hypermetabolic phase, cardiac output is increased
and SVR is reduced.
Metabolic Changes
Circulating levels of catecholamines are increased up to 10-fold
after severe burn injury.28,29 Along with wound-released medi-
ators, hormones, and bacterial products from the gut and
wound, this results in SIRS, manifested as hyperdynamic
circulation and large increases in basal energy expenditure
(hypermetabolic response).7,27,29 Glucagon and cortisol secre-
tion increases with postinjury insulin resistance, resulting in
use of amino acids to fuel production, leading to muscle wast-
ing and nitrogen imbalance.25 The supraphysiologic thermo-
genesis is associated with resetting of the core temperature to
higher levels, proportional to the size of the burned areas.30,31
Damaged skin is no longer able to retain heat and water, and
the vasomotor thermoregulatory responses are impaired; large
evaporative losses ensue.31,32 Loss of barrier function of skin
and blunting of immune response increase susceptibility to
infection and bacterial overgrowth within the eschar.26,31,33,34
Adequate pain control, alleviation of anxiety, maintenance of
a thermoneutral environment, and treatment of infection are
important steps in limiting catecholamine secretion and thus
hypermetabolism.
Hematologic Effects
Hematologic and coagulation factor changes after burn injury
depend on the magnitude of burn injury and time from
injury. Hematocrit is typically maintained early in the post-
burn period but drops during the weeks of care as erythrocyte
half-life is reduced.27,35 Platelet count diminishes with forma-
tion of microaggregates in the skin and smoke-damaged lung,
although this is rarely a clinical problem. Both thrombotic and
fibrinolytic mechanisms are activated after major burns.35,36
Clinically, hypercoagulability may be a problem in late post-
burn injury period, and patients should receive thromboem-
bolism prophylaxis.
Renal Function
The incidence of acute renal failure in burn patients ranges
from 0.5% to 38%, depending on the severity of burns.37,38
In the early postburn period, renal blood flow is reduced
as a result of hypovolemia and decreased cardiac output. In
addition, increased levels of catecholamines, angiotensin,
vasopressin, and aldosterone contribute to renal vasocon-
striction.39 Myoglobinuria and sepsis can also aggravate renal
dysfunction. Despite an increase in the renal blood flow dur-
ing the hypermetabolic phase of burn injury, tubular function
and creatinine clearance may be reduced and renal function
variable.
Pharmacologic Effects
Burn injury also affects the pharmacodynamic and phar-
macokinetic properties of many drugs. A decreased level of
serum albumin in these patients leads to increased free frac-
tion of acidic drugs such as thiopental or diazepam, whereas
an increased level of α-acid glycoprotein results in decreased
free fraction of basic drugs (with pKa >8) such as lidocaine
or propranolol.31 Renal and hepatic function may be impaired
in patients with large burns, in turn impairing the elimina-
tion of some drugs, whereas increases in renal blood flow and
glomerular filtration rate in the hyperdynamic phase of burns
may enhance renal drug excretion. Some drugs, such as genta-
micin, may be lost through the open wounds.40 The response
to muscle relaxants (other than mivacurium) is altered
because of proliferation of acetylcholine receptors away from
the synaptic cleft of the neuromuscular junction (see later dis-
cussion). Pharmacokinetics of morphine are unchanged after
burn injury.41 Although lorazepam has an increased volume of
distribution, increased clearance, and a reduced half-life,42 the
elimination half-life of diazepam is significantly prolonged in
burn patients.43
Inhalation Injury
Most airway inhalation injuries are caused by inhalation of
smoke. A history of closed-space exposure to hot gases, steam,
or smoke; singed nasal vibrissae; carbonaceous sputum; and
elevated levels of carboxyhemoglobin or cyanide suggest
the clinical diagnosis.6,26 Inhalation injury is a predictor of
increased morbidity and mortality in burn victims.44–46
UPPER AIRWAY INJURY
Direct thermal injury to the subglottic airway is rare, unless
superheated air or steam is inhaled. The severity of inhala-
tion injury depends on the fuels burned, intensity of combus-
tion, duration of exposure, and confinement. Unless steam
is involved, heat injury to the airway is supraglottic, causing
swelling of the posterior pharynx and supraglottic regions,
leading to potential upper airway obstruction. The natural his-
tory of upper airway inhalation injury is edema formation that
narrows the airway over the initial 12 to 48 hours. Early tra-
cheal intubation is recommended in patients who present with
stridor, wheeze, or voice changes. Burns to the face and neck
can result in tight eschar formation, making airway manage-
ment difficult when combined with pharyngeal edema.
LOWER AIRWAY INJURY (SMOKE INHALATION INJURY)
Lower airway or pulmonary parenchymal damage results
from inhalation of the chemical constituents of smoke, usually
becoming apparent 24 to 72 hours after the injury. Findings

include dyspnea, rales, rhonchi, and wheezing. Gas-phase
constituents of smoke include carbon monoxide (CO), cya-
nide, hydrochloric acid, aldehyde gases, and oxidants. These
gases can cause direct damage to mucociliary function and
bronchial vessel permeability, as well as produce broncho-
spasm, alveolar destruction, and pulmonary edema. Small
airway occlusion results from endobronchial sloughing and
resultant debris, whereas alveolar, interstitial, and chest wall
edema may cause intrapulmonary shunting and reduction in
compliance.26,47 The risk of pulmonary infection and baro-
trauma is also increased. The clinical picture is identical to
that of acute respiratory distress syndrome (ARDS). Delayed
ARDS (6-10 days after burn) may also develop in the absence
of inhalation injury in burn victims.48 Bronchoscopy reveals
carbonaceous endobronchial debris and/or mucosal ulcer-
ation.49,50 The usefulness of serial chest radiographs or radio-
isotope scanning with xenon or technetium for diagnosis and
predicting prognosis is questionable.6,51,52
Meticulous pulmonary toilet is the cornerstone of early care.
Tracheal secretions are often extremely viscous and may con-
tain carbonaceous particles and pieces of mucous membrane.
Carbon Monoxide and Cyanide Poisoning
Carbon monoxide has a high affinity for hemoglobin
(250 times more than for O2) and can interfere with O2 deliv-
ery to the tissues at higher concentrations. Administration of
100% O2 reduces the half-life of carboxyhemoglobin from 21⁄2
hours to 40 minutes and facilitates the elimination of CO.53
Hyperbaric oxygen therapy has limited indications because
of the logistical challenges presented by transport of patients
with concomitant burns to such chambers.54,55 Cyanide causes
tissue hypoxia by uncoupling oxidative phosphorylation in
mitochondria. Treatment with sodium nitrite, sodium thio-
sulfate, hydroxocobalamin, or dicobalt edetate should be con-
sidered for cyanide poisoning in patients with unexplained
severe metabolic acidosis associated with elevated central
venous O2 (therefore patients are clinically not cyanotic), nor-
mal arterial O2 content, and low carboxyhemoglobin.56
Signs such as hyperthermia, tachycardia, leukocytosis, and
tachypnea cannot be used to diagnose sepsis in burn victims.
Other identifiers, such as thrombocytopenia,57 enteral feeding
intolerance,58 and hyperglycemia, have been used instead.
PREOPERATIVE PREPARATION
The preoperative evaluation of burn patients should take into
account the continuum of pathophysiologic changes caused
by burns. Patient age, percentage of TBSA burned, depth
of burns, time after injury, sites and extent of planned exci-
sion and donor areas, presence of infection, other injuries
(especially inhalation injury), and the presence and extent of
comorbidities should all be assessed.
Careful airway assessment uses the standard bedside tests.
Mallampati class; thyromental distance; head, neck, and jaw
mobility; presence of facial or airway burns (or edema); and
Chapter 18 Burns 529
contractures of face and neck are used to plan the periopera-
tive airway management technique. The patient at risk for air-
way complications should have a difficult airway cart available
containing various-sized endotracheal tubes, Eschmann sty-
let, laryngeal mask airways (LMAs), Fastrach LMA, fiberoptic
bronchoscope, and fiberoptic stylets.
Fluid Resuscitation
The widely quoted Baxter (Parkland) formula for initial fluid
resuscitation of burn victims is 4 mL of Ringer's lactate per
kilogram of body weight per %TBSA burned, one half to
be given during the first 8 hours after injury and the rest in
the next 16 hours.59 Hypertonic saline may be useful in early
shock,60,61 and colloids are most effective when used in the
12- to 24-hour period of resuscitation.6,62 It is widely believed
that the Parkland formula underestimates resuscitation vol-
umes, particularly when concomitant smoke inhalation is
present.59,63 Repeated bedside observations and clinical evalua-
tions are useful to judge the adequacy of resuscitation. Normal
mentation, stable vital signs, and urine output of 30 to 50 mL/
hr can be used as end points,6 whereas use of core-­periphery
temperature gradient may be unreliable.64 However, several
studies have shown advantages to invasive hemodynamic
monitoring (with pulmonary artery catheter) in adults with
serious burns who do not respond as expected to fluid resusci-
tation.65,66 Serial lactate levels,67 monitoring the base deficit,68,69
and optimization of intrathoracic blood volume (ITBV)70 are
also useful guides to successful resuscitation (Box 18-1).
Fasting Requirements
Metabolic complications in burn patients are directly related
to extent of burn. Thermal injury leads to hypermetabolism
and protein hypercatabolic state. Early postpyloric enteral
feeding, which can be continued in the perioperative period,
is recommended by the ABA evidence-based guidelines.6
Early institution of enteral feeding in these patients decreases
infections and sepsis,71 improves wound healing and nitrogen
BOX 18-1   n CRITICAL QUESTIONS TO ASK BURN
PATIENT AND PHYSICIAN
What was the mechanism of injury for the burns? Body surface area
burned? Depth of burns?
Was closed-space confinement involved?
Did patient have black sputum?
What is elapsed time since injury?
Has adequacy of resuscitation been maintained?
What is the extent of the planned excision? Location of burn areas to
be excised and donor areas?
Has surgical position been determined? Need for intraoperative
change of position?
Are pain scores available? What is the patient's 24-hour analgesic
requirement?
Any associated injuries?
Any coexisting diseases?
 530 ANESTHESIA AND UNCOMMON DISEASES
balance,72,73 and reduces stress ulceration and duration of hos-
pitalization.74,75 Gastric emptying may not be delayed in burn
patients,76 and gastric acid production may actually be reduced
in the early postburn period.77 The safety and advantages of
perioperative enteral feedings have been reported.78 At the
authors’ institution, enteral feedings are continued throughout
the perioperative period in patients who come to the operat-
ing room intubated. In nonintubated patients, shorter fasting
times, typically 2 to 4 hours, may be acceptable.27,79
SURGICAL CONSIDERATIONS
Burn patients could present for five types of surgical proce-
dures: (1) decompression procedures such as escharotomy or
laparotomy, (2) excision and biologic closure of burn wounds,
(3) definitive closure procedures, (4) burn reconstructive pro-
cedures, and (5) general supportive procedures such as gas-
trostomy or line placement.80
Excision and Grafting
The need and timing for surgery is determined primar-
ily by the size of the burn injury. The objective is to identify,
excise, and achieve biologic closure of all full-thickness burns.
The advantages of early excision and grafting (1-5 days after
burn injury) include reduction in incidence of septic epi-
sodes, reduced hospital stay, and increased survival rates.81–86
Extensive burns may need staged excision to limit the physi-
ologic insult of one massive surgery and to allow autologous
skin grafts to be available. Excision and grafting involves tan-
gential excision of the second-degree burn wound, in which
the eschar is shaved off from the burn until a plane of via-
ble tissue is reached, followed by covering the excised wound
with a split-thickness skin graft, allogeneic skin from cadavers,
or skin substitutes (e.g., Integra).87 Excision of third-degree
burns requires fascial excision, in which the overlying burned
skin and subcutaneous fat are excised down to muscle fascia.
Box 18-2 summarizes the required equipment in preparation
for excision and grafting.
ANESTHETIC CONSIDERATIONS
General anesthesia, with the combination of an opioid, mus-
cle relaxant, and a volatile agent, is the most widely used
technique for burn excision and grafting.27 Succinylcholine
BOX 18-2   n KEY PREPARATIONS FOR BURN EXCISION
AND GRAFTING
“Difficult airway” cart; umbilical tape, dental floss, wire for suturing
tube
Operating room warmed to 28° to 32° C; fluid warmer, radiant heat
warmer
Availability of blood products
Adequate intravenous access; consider invasive monitoring
administration to patients more than 24 hours after burn
injury is unsafe because of the risk of hyperkalemic ventric-
ular dysrhythmias.88 The time frame during which succinyl-
choline must be avoided after a burn begins 48 hours after the
event.89 Patients who have been bedridden because of severity
of illness or concomitant disease or injury, or those receiv-
ing prolonged muscle relaxant therapy to facilitate mechan-
ical ventilation, may be particularly vulnerable.90 The exact
period of risk is unknown, although 6 months can be consid-
ered the absolute minimum91; acetylcholine receptors prolif-
erate and spread throughout the skeletal muscle membrane
under the burn and at sites distant from the burn injury.92
The upregulation of acetylcholine receptors, along with
altered protein binding, especially to α1-glycoprotein, makes
patients with thermal injury resistant to the action of non-
depolarizing muscle relaxants.93–95 In these patients, larger
doses of nondepolarizing muscle relaxants may be required
to achieve a given degree of neuromuscular blockade; onset
of paralysis may take longer, and duration of paralysis may be
shorter. The resistance is usually seen in patients with greater
than 30% TBSA burns; it develops after the first week follow-
ing injury and peaks at 5 to 6 weeks.94,96 Mivacurium may be
immune to this resistance, possibly because of its decreased
metabolism from depressed pseudocholinesterase activity in
burn patients.97,98
Airway Management
Airway management in burn patients can be challenging. Mask
ventilation may be a problem with facial burns. Successful use
of an LMA for burn surgery has been reported.99,100 However,
major procedures in critically ill patients, with frequent intra-
operative changes in patient position, are best done with
endotracheal intubation. Awake fiberoptic intubation may
be indicated if difficulties with intubation and ventilation are
identified preoperatively. Inhalation induction, maintenance
of spontaneous respirations, and intubation with fiberoptic
guidance or Fastrach LMA may be advocated in uncoopera-
tive patients.
Location of burns and donor skin sites indicate the need for
special positioning, for repositioning the patient during oper-
ation, or both. Fixing the endotracheal tube (ETT) for prone
positioning in the presence of facial burns is best achieved by
wiring it to the teeth or stitching it to the nares.101 We typically
use dental floss to tie the tube to the teeth or tie the tube to an
oronasal loop of rubber catheter. A combination of prolonged
prone positioning and relatively high fluid volume adminis-
tration may cause significant airway swelling. It is best to wait
until an air leak is present around the ETT before tracheal
extubation, because this indicates resolution of edema, espe-
cially in older children.102,103 If there is still no air leak and the
patient is deemed ready for tracheal extubation, direct laryn-
goscopy may be necessary to determine the extent of residual
edema. Once extubated, the patient should be closely moni-
tored for progressive airway obstruction during the subse-
quent 24 to 48 hours.

Edema, scarring, or contractures may narrow the mouth
opening and limit the neck movements, depending on the age
of the burns. Surgical release of neck contractures to facilitate
intubation has been described in both elective and emergency
settings.104,105
Analgesia
Severe pain is an inevitable consequence of a major burn
injury, and perioperative analgesic requirements are fre-
quently underestimated.106,107 Anxiety and depression are com-
mon components in a major burn and can further decrease
the pain threshold. Perioperative pain management should be
based on an understanding of the types of burn pain (acute
or procedure-related pain vs. background or baseline pain),
frequent patient assessment by an acute pain service team,
and the development of protocols to address problems such as
breakthrough pain.
High-dose opioids are needed to manage pain associated
with burn procedures, and morphine is currently the most
widely used drug.108 The pharmacokinetics of morphine are
similar in burn patients and control subjects.41 Providing ade-
quate analgesia with morphine reduces the risk of posttrau-
matic stress syndrome.109 Most burn patients rapidly develop
tolerance to opioids. With individual variation in response to
morphine, “titration to effect” and frequent reassessment are
especially important.
Fentanyl is also a useful analgesic perioperatively.
Continuous infusion of fentanyl in the preoperative period
may induce a rapid tolerance in burn patients.110
Methadone has the advantage of N-methyl-d-aspartate
(NMDA) receptor antagonist activity, which helps in pre-
venting the development of central sensitization, secondary
hyperalgesia, and neuropathic pain.10 In addition, the long
duration of action helps in achieving postoperative analge-
sia and it can be administered orally in the postoperative
period.
Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce
pain perception and modify the systemic inflammatory
response through inhibition of cyclo-oxygenase. The inci-
dence of gastric ulceration, increased operative blood loss,
and exacerbation of asthma is reduced with the use of selective
COX-2 inhibitors. However, potential for renal tubular dys-
function does exist. These drugs have not yet been systemati-
cally evaluated in burn patients.
Acetaminophen is a useful adjunctive analgesic in combi-
nation with opioids. Its antipyretic action is particularly use-
ful in burn patients. Doses of 15 mg/kg can be given orally or
rectally every 6 hours to a maximum of 4 g/day. Liver function
tests and acetaminophen levels should be checked weekly in
patients receiving long-term therapy.
Tumescent local anesthesia with a maximal dose of 7 mg/kg
of lidocaine has been shown to be safe and the sole poten-
tially effective locoregional anesthetic technique for the sur-
gical treatment of pediatric burns.111 Postoperative pain from
split-skin donor sites is often more intense than the pain at
Chapter 18 Burns 531
the grafted site. Addition of bupivacaine or lidocaine to the
“Pitkin solution” (subcutaneous crystalloid injection) can pro-
vide analgesia for pain originating from the donor areas.112,113
A continuous fascia iliaca compartment block can also be used
to reduce the pain at the thigh donor site.114 Intravenous lido-
caine (1 mg/kg) has provided significant postoperative analge-
sia for up to 3 days.115
Ventilation
Mechanical ventilation is necessary for patients with
­respiratory complications, inhalation injury, or large burns.
Hypermetabolic state after burn injury increases the carbon
dioxide production, and these patients need higher minute
ventilation to maintain normocapnia. In patients with acute
lung injury who need high levels of positive end-expiratory
pressure (PEEP >15 cm H2O) or peak inspiratory pressure
(PIP >50 cm H2O) to maintain gas exchange, use of sophis-
ticated intensive care ventilator and anesthesia maintenance
using total intravenous anesthesia technique (TIVA) may be
warranted.
Regional Anesthesia
Regional anesthesia alone or in combination with general
anesthesia can be used in patients with small burns or for
reconstructive procedures. For procedures on lower extremi-
ties, lumbar epidural or caudal catheters can be used to pro-
vide intraoperative and postoperative analgesia. The greatest
limitation to the use of regional techniques is the extent of
surgical field; most patients with major burns have a wide
distribution of injuries and need skin harvesting from areas
too large to be blocked by a regional technique. The pres-
ence of a coagulopathy or systemic or local infection may
also contraindicate regional anesthetic techniques in these
patients.
Monitoring
Monitoring for burn surgery should be based on knowledge
of the patient's medical condition and the extent of surgery.
Standard electrocardiographic electrodes may not adhere to
burned surfaces. Needle electrodes or alligator clips attached
to skin staples may be effective alternatives. If skin sites for
pulse oximetry monitoring are limited, the ear, nose, tongue,
or penis can be used with standard probes.116 The alternative is
to use reflectance pulse oximetry.
Arterial line placement allows repeated blood sampling for
estimation of arterial blood gas tensions, hematocrit, electro-
lytes, lactate, and coagulation profiles, in addition to continu-
ous blood pressure monitoring. The decision to use invasive
monitoring such as a central venous or pulmonary artery
catheter should be based on coexisting medical conditions
or burn-related complications. Core temperature (bladder
or esophageal), urine output, and degree of neuromuscular
blockade should be routinely monitored.
 532 ANESTHESIA AND UNCOMMON DISEASES
Hypothermia is a common complication of excision and
grafting and often delays extubation. Body temperature is
best maintained by a thermoneutral environment (room tem-
perature of 28°-32° C) with the additional use of an over-bed
warming shield and warming of intravenous fluids.85 Dry-air
warmers used directly over the burn wound can cause tissue
desiccation. Forced-air warming devices are less effective in
these patients because of the significant area of burned and
donor skin sites that must remain exposed. Use of “space blan-
kets” (aluminum foil coverings on nonexposed areas), plastic
sheets over the head and face, heat and moisture exchangers
in the breathing system, and low fresh-gas flow with circle
absorber can also help to reduce the heat loss.31
Blood Loss and Transfusion Requirements
Burn excision can result in massive and sudden blood loss117
that increases with delay to primary burn excision, with a
peak at 5 to 12 days after burn injury.118,119 Other factors that
correlate with increased blood loss include older age, male
gender, and larger body size; area of full-thickness (third-
degree) burn; high wound bacteria counts (derived from
quantitative tissue cultures); total wound area excised; and
operative time.118 A mean blood loss of 2.6% to 3.4% of a
patient's blood volume for each %TBSA excised has been
reported.120,121
Several techniques have been used to reduce blood loss
during primary burn excision. Intraoperative tourniquet
use on burned extremities reduces overall blood loss.122–124
Postexcision compression dressings and topical epinephrine
have been used to reduce blood loss during excision and graft-
ing procedures. Application of bandages soaked in 1:10,000
epinephrine after excision of burned skin and/or use of
thrombin spray, fibrin sealant, or platelet gel is effective in pro-
ducing a bloodless surface for placement of skin grafts.85,125,126
Extremely high levels of catecholamines in the blood have
been measured after the use of this technique. Sinus tachycar-
dia and hypertension are common, and thus heart rate and
blood pressure cannot be used to reliably titrate anesthetic or
analgesic agents. Serious dysrhythmias are fortunately rare
(See Box 18-2).127,128
Subcutaneous crystalloid is injected in generous amounts
using pressure-bags and Pitkin syringes (tumescent tech-
nique) to facilitate donor skin harvesting and reduce blood
loss. Epinephrine and local anesthetics such as bupivacaine or
lidocaine may be added to this therapy.112,126,129,130 Quantifying
blood loss is typically difficult in burn patients,121 and transfu-
sion is best guided by serial hematocrit estimations. Adequate
venous access is a prerequisite to burn excision and grafting
procedures. At least two intravenous access routes should be
established (peripheral or central), and these lines should be
sutured securely to prevent accidental dislodgment while posi-
tioning. Blood products should be readily available before exci-
sion begins. Femoral venous catheters placed through burned
skin have been shown to be safe,131 although this issue has
been questioned.132 The decision to transfuse blood products
should be individualized by carefully weighing the risks of
transfusion, including immunosuppression, versus the ben-
efits of correcting anemia in the setting of hypermetabolism
and increased oxygen demands. If blood loss is excessive, it is
prudent to rule out coagulation abnormalities. Burn patients
have a consumption coagulopathy that, combined with hemo-
dilution during surgery, results in a clinically significant defi-
ciency of coagulation factors II, VII, and X, despite reactive
elevation of coagulation factor VIII and fibrinogen.133 Platelets
or coagulation factors may need to be replaced, guided by the
coagulation profile.
Although infrequently used in current clinical practice,
intraoperative blood salvage in excisional burn surgery, using
a cell saver, has been shown to recover more than 40% of shed
red blood cells with acceptable levels of bacterial contamina-
tion and inflammatory mediators.134,135
PEDIATRIC ISSUES
Almost one third of burn admissions and burn deaths occur
in children younger than 15 years. Burns are second only to
motor vehicle crashes as the leading cause of death in children
older than 1 year. Flame burns account for about a third of
pediatric burns, are often more severe, and frequently involve
concomitant inhalation injury. Children younger than 2 years
have high surface area/body mass ratios, extremely thin skin,
and minimal physiologic reserves, causing higher morbidity
and mortality than in the older groups. The possibility of child
abuse must always be considered in children.
The disproportionate ratio of head-to-body size makes
the rule of nines (to estimate TBSA) not applicable in small
children. Lund-Browder or Berkow charts divide TBSA
into smaller units and make age-appropriate corrections9,26
(Table  18-2). When calculating fluid resuscitation volumes,
allowances should be made for daily maintenance fluids in
infants and toddlers. Adequate resuscitation is reflected by
normal mentation, stable vital signs, and urine output of 1
to 2 mL/kg/hr. Infants should be monitored for signs of fluid
overload and hyponatremia or hypernatremia, because their
immature kidneys may not be able to handle excessive fluid
and electrolyte load. Blood glucose levels should be moni-
tored and glucose-containing solutions added, as necessary, in
infants.
In children requiring high inspiratory pressures during
mechanical ventilation, a cuffed ETT is a better choice. The
small internal diameter of pediatric airway and ETTs increases
the risk of obstruction by the thick secretions or edema, espe-
cially in the presence of inhalation injury. Frequent suction-
ing helps in clearing the mucus and debris from the tracheal
tree, and a high index of suspicion should be maintained for
plugging of the tracheal tube. A substantial portion of subcu-
taneous crystalloid fluid injected for tumescent technique to
harvest skin graft may be absorbed into the circulation and
may cause hypervolemia in small children. Thermal mainte-
nance is critical in young children, especially those with burns
of more than 10% TBSA.4,5
 Chapter 18 Burns 533

TABLE 18-2  n  Berkow Chart for Estimating TBSA Burned (%) in Various Age Groups

Area 1 Yr 1-4 Yr 5-9 Yr 10-14 Yr 15 Yr Adult

Head 19 17 13 11 9 7

Neck 2 2 2 2 2 2

Anterior trunk 13 13 13 13 13 13

Posterior trunk 13 13 13 13 13 13

Right buttock 2.5 2.5 2.5 2.5 2.5 2.5

Left buttock 2.5 2.5 2.5 2.5 2.5 2.5

Genitalia 1 1 1 1 1 1

Right upper arm 4 4 4 4 4 4

Left upper arm 4 4 4 4 4 4

Right lower arm 3 3 3 3 3 3

Left lower arm 3 3 3 3 3 3

Right hand 2.5 2.5 2.5 2.5 2.5 2.5

Left hand 2.5 2.5 2.5 2.5 2.5 2.5

Right thigh 5.5 6.5 8 8.5 9 9.5

Left thigh 5.5 6.5 8 8.5 9 9.5

Right leg 5 5 5.5 6 6.5 7

Left leg 5 5 5.5 6 6.5 7

Right foot 3.5 3.5 3.5 3.5 3.5 3.5

Left foot 3.5 3.5 3.5 3.5 3.5 3.5

total 100 100 100 100 100 100

TBSA, Total body surface area, in percentages (%); Yr, year(s), age.

Procedural Sedation
Procedures such as dressing changes, wound care, and physi-
cal therapy frequently require sedation and analgesia in pedi-
atric burn patients. These procedures are often performed
on a daily basis on the burn ward, making involvement of an
anesthesiologist impractical.
Nurse-administered opioids (intravenous, oral, or trans-
mucosal), alone or in combination with benzodiazepine
anxiolysis, is the typical regimen. However, when wound
care procedures are extensive, particularly in children, more
potent anesthetic agents may be of benefit. Patient monitor-
ing must be appropriate to the level of sedation, as required
by The Joint Commission (formerly Joint Commission on the
Accreditation of Healthcare Organizations) and described by
the American Society of Anesthesiologists (ASA) guidelines
for sedation monitoring.
Oral transmucosal fentanyl citrate lozenges have been
shown to be safe and effective for pediatric burn wound care.136
The starting dose for fentanyl lozenges is 10 μg/kg. Peak effect
occurs after 20 to 30 minutes. About 25% of the total dose is
systemically available after buccal absorption. The remaining
75% is swallowed and is slowly absorbed from the gastroin-
testinal tract. Up to a third of this (25% of total dose) avoids
hepatic first-pass metabolism and is systemically available.137
Ketamine offers the advantage of stable hemodynamics
and analgesia and has been used extensively as the primary
agent for both general anesthesia and analgesia for burn dress-
ing changes.138–140 Nitrous oxide (N2O) with oxygen has been
used effectively for analgesia during burn wound dressing
changes.140,141 However, scavenging of the gas when adminis-
tered outside of an operating room is problematic. Combining
N2O with opioids may induce a state of general anesthesia with
profound respiratory depression. The efficacy of general anes-
thesia administered by an anesthesiologist for procedures on a
burn intensive care unit has been well documented.142
Analgesics such as acetaminophen can be used for
their opioid-sparing effect and are combined with gener-
ous administration of oral opioids.106,143 NSAIDs have anti-
platelet effects and may not be appropriate for patients who
require extensive excision and grafting procedures. In addi-
tion, burn patients can also manifest the nephrotoxic effects
of NSAIDs. Music therapy,144 hypnotherapy,145–147 massage,
 534 ANESTHESIA AND UNCOMMON DISEASES
cognitive-behavioral techniques,106 and more recently, virtual
reality techniques148–150 have been successfully used to reduce
pain during debridement and wound care.
CONCLUSION
Patients with severe burn injury are a challenge for the anes-
thesiologist. Recent advances in burn care and burn surgery
have led to an improved survival of these patients. Early exci-
sion and grafting is becoming a standard practice. Effective
anesthetic management of these patients requires knowledge
of the continuum of pathophysiologic changes, proper plan-
ning, and a team effort.
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Chapter 18 Burns 535
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 536 ANESTHESIA AND UNCOMMON DISEASES
100. Karam R, Ibrahim G, Tohme H, et al: Severe neck burns and laryngeal
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104. Kreulen M, Mackie DP, Kreis RW, et al: Surgical release for intubation
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105. Waymack JP, Law E, Park R, et al: Acute upper airway obstruction in the
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112. Beausang E, Orr D, Shah M, et al: Subcutaneous adrenaline infiltration
in paediatric burn surgery, Br J Plast Surg 52:480–481, 1999.
113. Jellish WS, Gamelli RL, Furry PA, et al: Effect of topical local anesthetic
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114. Cuignet O, Pirson J, Boughrouph J, et  al: The efficacy of continuous
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116. Cote CJ, Daniels AL, Connolly M, et  al: Tongue oximetry in children
with extensive thermal injury: comparison with peripheral oximetry,
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117. Brown RA, Grobbelaar AO, Barker S, et al: A formula to calculate blood
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 C H
Pregnancy and Obstetric Complications
Physiologic Changes of Pregnancy
Nonobstetric Surgery
Maternal Safety
Fetal Safety
Laparoscopic Surgery
In Vitro Fertilization
Obstetric Anesthesia for Uncommon Conditions
Morbid Obesity
Amniotic Fluid Embolism
Pre-Eclampsia and Eclampsia
HELLP Syndrome
Pulmonary Edema in Pre-Eclampsia
Abnormal Placentation and Massive Hemorrhage
Peripartum Cardiomyopathy
Cardiac Arrest and Cardiopulmonary Resuscitation
Conditions Complicating Regional Anesthesia
Regional Anesthesia and Anticoagulation
Local Anesthetic Allergy
Latex Allergy
Conclusion
KEY POINTS
n Airway changes throughout pregnancy worsen during
labor and delivery as a result of mucosal edema.
n Anesthetic agents are not teratogenic; however, inhala-
tion anesthetics and many intravenous agents may trigger
developmental apoptosis and other neurologic insults that
could impact cognitive development.
n Amniotic fluid embolism is associated with coagula-
tion abnormalities as well as hypoxia and cardiovascular
collapse.
n HELLP (hemolysis, elevated liver enzymes, low platelets)
is a more severe form of pre-eclampsia. Administration
A P T E R
19
DAVID L. HEPNER, MD  n
BHAVANI SHANKAR KODALI, MD  n
SCOTT SEGAL, MD, MHCM  n
of regional anesthesia depends on the platelet count
(­consider at ≥70,000), provided no other coagulation
abnormalities exist.
n Placenta accreta describes any abnormally firm adherence
to the myometrium, especially in those with a history of
placenta previa and previous cesarean section. Prompt hys-
terectomy is the treatment of choice. Epidural anesthesia
can be considered, with a low threshold to convert to gen-
eral anesthesia.
n Less restrictive ACOG guidelines in 2010 emphasize patient
autonomy; trial of labor after cesarean is most safely under-
taken in a facility with appropriate staff but may occur at a
smaller facility after risk/benefit analysis.
n Transfusion of 1 unit FFP for 1 unit RBC is reasonable
because many units of plasma are needed for coagulation
factor and fibrinogen replacement during postpartum
bleeding with disseminated intravascular coagulation.
A postpartum hemorrhage algorithm facilitates the trans-
fusion of blood products and communication with obste-
tricians and hematologists.
n Peripartum cardiomyopathy is an idiopathic dilated car-
diomyopathy occurring antepartum or immediately
postpartum. Patients who recover ventricular function
promptly have a better prognosis; subsequent pregnancy
is risky. Continuous spinal or spinal-epidural analgesia is
recommended.
n Cardiopulmonary resuscitation is largely unmodified from
that in nonpregnant patients, but effective uterine displace-
ment is essential. Emergency cesarean delivery should be
initiated promptly (delivery within 5 minutes) for the ben-
efit of both the fetus, even if of periviable gestational age,
and the mother.
n Knowledge of pharmacokinetics and pharmacodynam-
ics of common anticoagulants used during pregnancy is
essential to avoid neuraxial techniques when significant
anticoagulant effect may still be present. Guidelines should
complement this knowledge.
537
 538 ANESTHESIA AND UNCOMMON DISEASES

One study in a well-defined, continuously screened female

TABLE 19-1  n  Physiologic Changes of Pregnancy
population between 18 and 44 years of age found a preg-
nancy rate of more than 10% per year.1 The anesthetic RESPIRATORY SYSTEM
care of pregnant women is common; 1% to 2% of preg- Minute ventilation ↑ 50%
nant women undergo nonobstetric surgery.2,3 Even unrec-
Functional residual capacity ↑ 20%
ognized pregnancy in outpatients occurs in about 1 in 300
women.4 The challenge to the anesthesiologist in caring Oxygen consumption ↑ 20%
for the obstetric patient centers on the physiologic changes Carbon dioxide production ↑ 20%
of pregnancy and the interactions with anesthetic drugs
and techniques. In addition, the urgency of care is often Apneic desaturation Faster
intensified by the presence of a viable fetus. This chap- Paco2 32 mm Hg
ter explores some of the more unusual clinical challenges,
Paco2 − Petco2 −1 to 0.75 mm Hg
both in obstetric anesthesia and analgesia, as well as in the
anesthetic care of the pregnant patient undergoing nonob- CARDIOVASCULAR SYSTEM
stetric procedures. Cardiac output ↑ 50%

Stroke volume ↑ 25%

PHYSIOLOGIC CHANGES OF PREGNANCY Heart rate ↑ 25%
Administration of safe anesthesia for any pregnant woman Systemic vascular resistance No change
necessitates a clear understanding of the physiologic changes
Blood pressure No change at term gestation
associated with pregnancy. Several changes have direct bearing
on anesthetic management of obstetric patients (Table 19-1).5,6 GASTROINTESTINAL SYSTEM
Airway effects in pregnancy could pose intubation difficulties; Barrier pressure ↓
metabolic and respiratory changes may expeditiously cause
Gastric emptying time No change
hypoxemia during apnea; gastrointestinal effects predispose
the parturient to regurgitation and aspiration; the growing Renal system:
uterus puts pressure on the aorta and inferior vena cava; and   Plasma creatinine ↓
mechanical, hormonal, and biochemical factors can increase BRAIN
the spread of intrathecal and epidural local anesthetics in Minimal alveolar concentration ↓
pregnancy. Recent evidence suggests that airway changes are
METABOLIC
not limited to the duration of pregnancy and can continue
Free drug availability ↑
during labor and delivery.7,8
The implications of these physiologic changes on the coex- Plasma cholinesterase activity ↓
isting disease, or vice versa, must be evaluated in every pregnant
woman presenting with a coexisting disease or a complica-
tion of pregnancy. A coexisting disease, such as a cardiovascu-
lar lesion or a pulmonary condition, can translate physiologic considerations are maternal safety, fetal physiologic well-
changes into a clinically critical state, thereby contributing to being, avoidance of teratogenicity, and prevention of preterm
an increasing morbidity and mortality. In addition, pharma- labor (Box 19-1).
cokinetic and pharmacodynamic profiles are altered in preg-
nancy, and drug administration must be titrated carefully to
Maternal Safety
the desired effect. With the increase in blood volume there is a
greater volume of distribution; the low albumin and increased Maternal safety requires understanding of the altered physiol-
α-glycoprotein can also alter the free drug concentrations. ogy of pregnancy. The most important changes affecting the
Issues of fetal well-being, such as maintenance of uteroplacen- anesthetic management of these patients are the respiratory,
tal blood flow and oxygenation, prevention of fetal asphyxia, gastrointestinal (GI), and cardiovascular systems. Although
avoidance of teratogenic drugs, and prevention of preterm considerable controversy surrounds the physiology of gas-
labor, are essential to consider when taking care of the pregnant tric emptying and gastric acid production, pregnant patients
patient. Maintenance of uteroplacental blood flow is essential beyond the late second trimester should be considered at ele-
to fetal well-being. vated risk of aspiration. The cardiovascular changes of greatest
interest are the expansion of blood volume (but normal central
venous pressure [CVP] and pulmonary capillary wedge pres-
NONOBSTETRIC SURGERY
sure [PCWP]), elevated cardiac output, physiologic anemia of
The anesthetic management of pregnant patients undergo- pregnancy, and aortocaval compression. Respiratory changes
ing nonobstetric procedures has been extensively reviewed affecting anesthetic management include the increased fragil-
in major textbooks of obstetric anesthesiology. The principal ity of the mucosa, upper airway edema, more difficult mask
 Chapter 19  Pregnancy and Obstetric Complications 539
BOX 19-1   n GENERAL CONSIDERATIONS FOR
NONOBSTETRIC SURGERY IN PREGNANCY
Maternal Safety
Respiratory System
Fragility of nasal mucosa
Upper airway edema
Increased risk of difficult intubation
Increased risk of desaturation
Gastrointestinal System
Increased risk aspiration (increased intragastric pressure and
decreased lower esophageal sphincter tone)
Cardiovascular System
Expansion of blood volume (normal filling pressures)
Elevated cardiac output
Physiologic anemia of pregnancy
Fetal Safety
Direct Effects of Anesthesia
Maternal hypoxia and hypotension leading to fetal acidosis
Avoid uteroplacental vasoconstrictors (vasopressin, ketamine, high
systemic local anesthetic concentrations)
Teratogenicity of Drugs
No specific link to any anesthetic drug
Caution with nitrous oxide
Inhalation anesthetics may cause “behavioral teratogenicity”
(behavioral abnormalities without structural defects)
Avoidance of Preterm Labor
ventilation, a 10-fold increased risk of difficult intubation,
functional residual capacity (FRC) and oxygen (O2) consump-
tion changes that predispose to desaturation during apnea,
and chronic respiratory alkalosis.6
In addition, general anesthesia in pregnant patients must
consider the altered response to anesthetic drugs. Minimal
alveolar concentration decreases in pregnancy, well before
endorphins increase during labor.9 Indeed, increased sensi-
tivity to intravenous (IV) and inhalation anesthetics occurs
during the first trimester. There is increased sensitivity to suc-
cinylcholine,10 and patients receiving magnesium sulfate for
preterm labor or pre-eclampsia are more sensitive to nonde-
polarizing neuromuscular blocking drugs as well.11 Decreased
protein binding caused by lower concentrations of plasma
proteins, as well as increased volume of distribution from
increased blood volume and weight (fat) gain, makes pharma-
cokinetics of various drugs complex.6 The responses to many
anesthetic drugs, particularly those employed in some of the
unusual situations described in this chapter, are unknown.
Caution is therefore mandatory when any anesthetic agent is
used in the pregnant patient.
Fetal Safety
The fetus is potentially at risk by three mechanisms: direct
effects of anesthetic agents and techniques on fetal cardio-
respiratory homeostasis, teratogenic effects of maternally
administered drugs, and induction of preterm labor. Maternal
hypoxia and hypotension can adversely affect the fetus.
Modest hypoxia is well tolerated by the fetus because of the
high concentration of fetal hemoglobin and its affinity for O2.
More severe hypoxia is associated with fetal desaturation and
asphyxia. Conversely, hyperoxia does not adversely affect the
fetus, because of high placental shunt flow and inability of
high maternal oxygen partial pressure (Po2) to increase mater-
nal O2 content significantly. High maternal O2 concentrations
may be given whenever indicated for maternal well-being.12
Conversely, the fetus poorly tolerates maternal hypoten-
sion if it is severe or prolonged.13 Uteroplacental blood flow
is highly dependent on maternal systemic blood p ­ ressure
(SBP), and decreases in SBP lead to fetal asphyxia. During
nonobstetric surgery, causes of maternal ­ hypotension
may include hypovolemia, deep general anesthesia, high
spinal or epidural anesthesia, aortocaval compression,
­
­hemorrhage, positive-pressure hyperventilation, and sys-
temic ­hypotensive drugs. However, good fetal outcomes
have been reported after moderate deliberate hypotension
during neurosurgery.14 Uteroplacental blood flow may also
be impaired by systemic agents that produce uterine arterial
vasoconstriction or significantly increase myometrial tone.15
Drugs that may cause these effects include large doses of
alpha-adrenergic agonists, vasopressin, ketamine, and high
doses of local anesthetics. In contrast to classic animal stud-
ies, however, maternal administration of moderate-dose
phenylephrine during cesarean delivery has been associ-
ated with normal fetal blood gases.16 Minimal data exist on
the choice of vasopressor during nonobstetric surgery, and
authorities recommend choosing the drug most appropriate
for ­maternal safety.17
Teratogenicity of maternally administered drugs has been
extensively reviewed elsewhere, and the reader is referred to
these sources for more information. To date, no anesthetic
agent has been definitively shown to induce congenital abnor-
malities in the developing fetus. However, associations between
anesthetics and anomalies or abortion are strong enough to
dictate prudent use. Importantly, many drugs found to be ter-
atogenic in earlier animal or uncontrolled human epidemio-
logic studies have proved safe when using more sophisticated
methodology. This includes all common opioids, benzodiaz-
epines, barbiturates, and local anesthetics.18,19
Inhalation anesthetics present a more complex picture. In
animals, prolonged exposure to more than 50% nitrous oxide
(N2O) induces fetal resorption and skeletal or visceral anoma-
lies, depending on the timing of exposure.20–22 However, the
etiology is complicated and not completely understood. N2O
impairs 1-carbon metabolism through its action on vitamin
B12.23 This cannot explain all its effects, however, because sup-
plementation with folinic acid or methionine (which should
bypass many of the effects of inhibition of methionine synthase
on DNA synthesis and methylation reactions) only partially
reverses N2O effects on the developing fetus.24,25 Furthermore,
coadministration of isoflurane or halothane blocks many N2O
effects, implicating α-adrenergic uterine vasoconstriction in
N2O pathophysiology of.26 Human epidemiologic studies of
 540 ANESTHESIA AND UNCOMMON DISEASES
healthy women exposed to N2O in the workplace have yielded
conflicting results. Positive studies show only a slight increase
in spontaneous abortion that may be explained by confound-
ing variables.27,28 Large epidemiologic investigations confirm
slight increases in early pregnancy loss and low birth weight
but have yielded inconclusive or negative results regarding
congenital anomalies. It is impossible to separate the effect
of anesthesia from that of the surgical procedure or underly-
ing disease process requiring surgery in human epidemiologic
studies.3
A more ominous and insidious effect of inhalation anesthet-
ics has been termed behavioral teratogenicity. The term refers
to behavioral abnormalities occurring in the absence of obvi-
ous structural defects. Even relatively brief intrauterine or early
postnatal exposure to halogenated anesthetics, γ-aminobutyric
acid (GABA) agonists, or N-methyl-d-aspartate (NMDA)
antagonists in rodents has resulted in persistent defects in
memory and learning (maze solving).29,30 Studies in cell cul-
ture and pathologic investigation of neonatal brains of rodents
exposed in utero to isoflurane show widespread apoptosis and,
specifically, defects in hippocampal synaptic function, effects
that may explain the behavioral phenomena.29 These results
have yet to be confirmed in humans, although some epide-
miologic evidence has demonstrated worrisome increases in
cognitive dysfunction in infants and young children exposed
to anesthetics,31 although thus far not to fetuses exposed dur-
ing cesarean delivery.32 Until more definitive data on in utero
exposure of fetuses to anesthetic agents are available, these
results suggest caution in casually exposing the pregnant
woman to these agents.
Preterm labor is associated with surgery in pregnancy.
Although halogenated anesthetics inhibit uterine contrac-
tions, this effect is short lived and does not protect against
preterm labor. Intra-abdominal procedures and those occur-
ring during the third trimester are the most likely to be asso-
ciated with preterm labor. It is not clear from epidemiologic
studies whether the surgery itself, or the underlying condition
prompting it, is responsible.33 There is no evidence that any
anesthetic technique either increases or decreases the chance
of preterm labor. However, tocolytic therapy with magne-
sium, cyclo-oxygenase inhibitors, calcium channel blockers,
or beta-adrenergic agonists can have important anesthetic
implications.
Laparoscopic Surgery
Occasionally, pregnancy can be complicated by acute intra-
abdominal pathology, requiring surgical intervention.
Laparoscopic surgery is generally preferred to conventional
open procedures, and therefore the anesthesiologist must
be familiar with the physiologic implications and anesthetic
management of pregnant women requiring laparoscopic pro-
cedures. Laparoscopic procedures have become more popu-
lar than open procedures because of decreased morbidity
and convalescence.34 Although pregnancy was considered
a contraindication to the procedure less than 15 years ago,35
laparoscopic cholecystectomy has become the most frequently
performed laparoscopic procedure during pregnancy.36 Other
types of laparoscopic surgeries performed safely during preg-
nancy include appendectomy, ovarian cystectomy,37 man-
agement of adnexal torsion,38 diagnostic laparoscopies for
abdominal pain,39 splenectomy,40 heterotopic pregnancies,41
and adrenal pheochromocytoma.42
PNEUMOPERITONEUM
When faced with providing anesthesia for the pregnant patient
undergoing laparoscopic surgery, the anesthesiologist must
focus not only on maternal/fetal issues and prevention of pre-
term labor, but also on patient positioning during surgery and
the physiologic and mechanical effects of the carbon dioxide
(CO2) pneumoperitoneum. During laparoscopy, pneumoperi-
toneum can cause cardiovascular and respiratory alterations
in nonpregnant patients, which become accentuated in the
parturient. Adding pneumoperitoneum to an enlarged uterus
further limits diaphragm expansion and is associated with an
increase in peak airway pressure, decrease in FRC, increased
ventilation/perfusion (V/Q) mismatching, increased alveolar-
arterial O2 gradient, decreased thoracic cavity compliance,
and increased pleural pressure.43 Pneumoperitoneum and
Trendelenburg positioning moves the carina cephalad, which
can convert a low-lying tracheal tube to an endobronchial
position. The Trendelenburg position increases intrathoracic
pressure and accentuates all the respiratory-related physio-
logic changes.
The combination of pregnancy and CO2 pneumoperito-
neum predisposes the parturient to hypercapnia and hypox-
emia. Insufflation of CO2 results in CO2 absorption across the
peritoneum and into the maternal bloodstream. Elimination
depends on an increase in minute ventilation; however,
mechanical hyperventilation can reduce uteroplacental perfu-
sion, probably because of decreased venous return.44 Although
end-tidal CO2 concentration (ETco2, Petco2) correlates well
with arterial CO2 tension (Paco2) in healthy patients, these are
poor guides to Paco2 in sicker patients. Any increase in mater-
nal Paco2 or decrease in Pao2 can affect fetal well-being.43
The cardiovascular changes associated with CO2 insufflation
include reduction in cardiac index and venous return, which
can be exacerbated by reverse Trendelenburg positioning.45
The observed increase in intracardiac filling pressures is prob-
ably secondary to an increase in intrathoracic pressure. The
combination of reverse Trendelenburg position, general anes-
thesia, and peritoneal insufflation can decrease the cardiac
index (CI) by as much as 50%.46
The hemodynamic effects of aortocaval compression by
the gravid uterus could further accentuate the hemodynamic
effects of pneumoperitoneum and reverse Trendelenburg posi-
tioning, resulting in significant hypotension.43,47 Steinbrook
and Bhavani-Shankar47 studied the cardiac output changes
in four pregnant patients (17-24 weeks' gestation) undergo-
ing laparoscopic surgery using thoracic bioimpedance cardi-
ography.47 IV ephedrine (10 mg) was given if SBP decreased
by more than 20% with respect to baseline. The authors noted
 Chapter 19  Pregnancy and Obstetric Complications 541
a 27% decrease in CI after 5 minutes of CO2 insufflation. CI
remained 21% below baseline after 15 minutes of insuffla-
tion. The authors' aggressive management of blood pressure
during anesthesia (treating any decrease in BP approaching
20% of baseline measurements with IV ephedrine to mini-
mize decreases in uterine blood flow) may have resulted in
the somewhat smaller CI reduction during CO2 insufflation
in their pregnant patients (27%) compared with 30% to 50%
in nonpregnant subjects in most studies. Mean arterial pres-
sure (MAP) and systemic vascular resistance (SVR) increased
in these study subjects during CO2 insufflation, which is simi-
lar to that generally observed in nonpregnant subjects during
laparoscopic surgery.
MONITORING
With the large number of physiologic changes associated
with pregnancy, as well as the cardiovascular and pulmonary
changes induced by laparoscopic surgery, optimal periopera-
tive monitoring is unclear. The main debate is whether peri-
operative monitoring of arterial blood gases (ABGs) and fetal
and uterine activity is necessary in parturients undergoing lap-
aroscopic surgery. The Society of American Gastrointestinal
Endoscopic Surgeons (SAGES) published guidelines for lapa-
roscopic surgery during pregnancy that include perioperative
monitoring of ABGs, as well as perioperative fetal and uter-
ine monitoring,48 as echoed by other authorities.39,49–51 Amos
et  al.39 reported four fetal deaths in seven pregnant women
who underwent laparoscopic cholecystectomy or appendec-
tomy. During the same period, no fetal deaths occurred in
patients who underwent pelvic surgeries by laparotomy. Even
though no ABG data were collected, fetal demise could have
resulted from prolonged respiratory acidosis, despite main-
taining ETco2 in the physiologic range (low to mid-30s mm
Hg). These concerns stem from previous studies indicating
that elevation in maternal Paco2 could impair fetal CO2 excre-
tion across the placenta and could exacerbate fetal acidosis.
Other risk factors were present for fetal loss in this series, how-
ever, including perforated appendix and pancreatitis.
Steinbrook et  al.43 reported a case series of 10 pregnant
women, gestational age 9 to 30 weeks, undergoing laparo-
scopic cholecystectomy; ABGs or perioperative fetal and
uterine activity were not monitored. The patients underwent
general anesthesia with controlled ventilation, with ETco2
maintained at 32 to 36 mm Hg. Fetal heart rate (FHR) and
uterine activity were assessed preoperatively and immediately
postoperatively. All patients had an uneventful recovery and
did not need postoperative tocolysis, and no adverse maternal
or fetal outcomes were noted. Seven patients were followed to
delivery and had normal infants. The authors concluded that
standard monitors recommended by the American Society of
Anesthesiologists (ASA) are sufficient for the safety and well-
being of the parturient and the fetus.
Based on a series of 45 laparoscopic cholecystectomies
and 22 laparoscopic appendectomies performed during all
three trimesters, Affleck et  al.52 supported the use of nonin-
vasive monitors and maintenance of the ETco2 within the
physiologic range. They also recommended preoperative
and postoperative FHR and uterine activity monitoring and
no prophylactic tocolysis. No fetal loss or uterine injuries or
spontaneous abortions occurred. There was no significant dif-
ference in preterm delivery rate, Apgar scores, or birth weights
between the open and laparoscopic surgery groups. As in pre-
vious reports, the operative groups (both open and laparo-
scopic appendectomies and cholecystectomies) had a slightly
higher rate of preterm labor compared with the general popu-
lation. Furthermore, multiple case reports have reported suc-
cessful outcomes with noninvasive monitoring.53,54
Bhavani-Shankar et al.55 prospectively evaluated the Paco2-
ETco2 difference in eight parturients undergoing laparoscopic
cholecystectomy with CO2 pneumoperitoneum. The intra-
abdominal pressures were maintained at about 15  mm  Hg.
These women underwent surgery with general anesthesia
during the second and third trimester. After adjusting minute
ventilation to maintain the ETco2 at 32 mm Hg, ABGs (alpha-
stat method) were measured at fixed surgical phases: before
insufflation, during insufflation, after insufflation, and after
completion of surgery. The authors found no significant dif-
ferences in either mean Paco2-ETco2 gradient or Paco2 and
pH during the various phases of laparoscopy. During the sur-
gical phase the maximal Paco2-ETco2 difference detected was
3.1 mm Hg (range, 1.1-3.1). It appears that ETco2 correlates
well with arterial CO2, and adjusting ventilation to maintain
ETco2 also maintains optimal maternal Paco2. These results
do not support the need for ABG monitoring during laparos-
copy in pregnant patients.
Laparoscopic procedures have been performed safely
during all trimesters of pregnancy. However, some authors
advocate reserving semielective, nonobstetric surgery dur-
ing pregnancy only during the second trimester. During this
period, organogenesis is complete, and spontaneous abortions
are less common than in the first trimester. Furthermore, pro-
cedures during the third trimester have been associated with
more preterm labor and potential difficulty in visualization
with an enlarged uterus.36,38,56
ANESTHETIC TECHNIQUE
Table 19-2 summarizes recommended anesthetic and surgical
interventions for laparoscopy during pregnancy.57
In Vitro Fertilization
Infertility is defined as one year of frequent unprotected sex
without achieving a pregnancy and is not an irreversible
state. Infertility is becoming more common with the trend for
advanced maternal age before conception.58,59 The progno-
sis for infertility caused by major causes and tubal and male
factors has improved significantly with the introduction of
assisted reproductive technologies (ARTs).60 ART involves the
handling and manipulation of the oocyte and spermatozoa
to achieve a successful pregnancy. In vitro fertilization (IVF),
the most common form of ART introduced in 1978,61 has
increased greatly, with a North American review reporting
 542 ANESTHESIA AND UNCOMMON DISEASES

outcome of IVF, such as stimulation protocol, embryo factor,

TABLE 19-2  n Suggested Anesthetic Plan for
Laparoscopic Surgery during Pregnancy
physician supervising the cycle, and patient selection.64,65 As
such, close scrutiny of other factors that may affect outcome,
Anesthetic including medications and techniques used to provide anes-
Consideration Intervention/Drug thesia, would be expected.66
In vitro fertilization produces a variable amount of pain
Premedication Sodium citrate, 30 mL orally;
metoclopramide, 10 mg
that many practitioners consider a significant disadvan-
intravenously tage.67 Abdominal pain levels have been correlated with
body mass index (BMI), number of follicles, and duration
of technique and may vary between patients. Although the
Induction Rapid-sequence induction
most widely used method for pain relief (95% of U.S. cen-
Ventilatory adjustments Keep end-tidal Pco2 between 32 and ters),68,69 conscious sedation is rarely effective in prevent-
34 mm Hg ing ovarian puncture pain. Lack of coverage for IVF by
Maintenance of Desflurane, fentanyl, oxygen most insurance companies70 and a concern for a decreased
anesthesia in air, and muscle relaxants pregnancy rate with anesthetic agents may account for
(e.g., vecuronium) the decreased use of general and regional techniques for
Positioning Left or right uterine displacement; IVF.62 However, state laws requiring that insurance compa-
gradual change to reverse nies provide partial or complete coverage for IVF,70 as well
Trendelenburg as similar embryo implantation and pregnancy rates with
Fetal heart rate 16 weeks, preoperative and the use of local anesthetics and short-acting general anes-
monitoring immediate postoperative period thetic agents,62 are likely to increase the use of general and
regional anesthesia. Therefore, it is important to understand
Insufflation technique Open trocar technique
the implications of anesthetic techniques on IVF as well as
Tocolysis Terbutaline, 0.25 mg the implications of ARTs on regional and general anesthesia
subcutaneously, if needed (Tables 19-3 and 19-4).
Hypotension Increments of ephedrine
ANESTHETIC ISSUES
Postoperative period Left or right uterine displacement,
Transvaginal ultrasound–guided oocyte retrieval (TUGOR)
oxygen supplements, fetal heart
monitoring averages 10 to 20 minutes and can be performed with the
patient under conscious sedation, paracervical block, neur-
Data from Bhavani-Shankar K, Steinbrook RA: Anesthetic considerations for axial blockade, or general anesthesia. Therefore, short-­acting
minimally invasive surgery. In Brooks DC, editor: Current review of minimally
invasive surgery, ed 2, Philadelphia, 1998, Current Medicine, p 29. agents are desired to minimize recovery time. Monitored anes-
thesia care and conscious sedation rely on adequate local anes-
thesia. However, they are inadequate to anesthetize the ovary.
over 88,077 ART cycles since its inception.62,63 The majority Patient discomfort, motion caused by pain, and a deep level
of these cycles (63,639) consisted of IVF, with a delivery rate of sedation leading to airway obstruction are serious risks.
per retrieval of 29.8%.63 Overall, there was an increase of 7.5% In addition, significant discomfort may leave patients with
and 0.4% for cycles and deliveries per retrieval, respectively. bad memories and may discourage future attempts at IVF.
However, the high cost and the 70% failure rate have led repro- Therefore, we prefer to use neuraxial techniques or intrave-
ductive endocrinologists to analyze factors that may affect the nous general anesthesia (IVGA).

TABLE 19-3  n Different Types of Assisted Reproductive Technologies

Tugor Gift Zift/prost/tet

Average duration 10-20 minutes 60-90 minutes Two different procedures: embryo retrieval (10-20
minutes) followed by transfer (30-60 minutes)
24-48 hours after fertilization

Embryo transfer Fertilized oocyte on Unfertilized oocyte transferred Fertilized oocyte transferred 24-48 hours after
day 3 or 5 shortly after retrieval retrieval

Anesthetic options Multiple; general or Mainly general because of Two different anesthetics: intravenous general or short-
spinal preferred need for laparoscopy acting spinal preferred for embryo retrieval; general
anesthetic preferred for laparoscopy for transfer

TUGOR, Transvaginal ultrasound-guided oocyte retrieval; GIFT, gamete intrafallopian transfer; ZIFT, zygote intrafallopian transfer; PROST, pronuclear stage tubal
transfer; TET, tubal embryo transfer.
 Chapter 19  Pregnancy and Obstetric Complications 543

TABLE 19-4  n  Anesthetic Options for Assisted Reproductive Technologies

General Anesthesia Neuraxial Blockade Paracervical Block Conscious Sedation

Benefits Fast induction and emergence Able to avoid intravenous Fast induction and emergence without the need for
agents if so desired anesthesia personal.

Drawbacks Conflicting results on effects of Longer induction and Ovaries are not Relies on adequate
different agents on embryo recovery times anesthetized; operator local anesthesia
implantation and pregnancy rates dependent; lidocaine that is difficult to
appears in follicular fluid achieve

A target-controlled propofol infusion delivered by non-
anesthesiologists in the United Kingdom, initiated and super-
vised by a consultant anesthesiologist, required considerable
medical input, especially in the early stages, to ensure the safe
provision of care.71 Incremental alfentanil was used for anal-
gesia. The successful use of propofol and alfentanil by patient-
controlled pump was previously reported in IV sedation for
egg retrieval.72 The main concern with propofol is distin-
guishing among conscious sedation, monitored anesthesia care
(MAC), and general anesthesia. An anesthesiologist or nurse
anesthetist under the supervision of the reproductive endo-
crinologist or anesthesiologist should be present at all times
with the use of MAC. Therefore, it is essential to maintain
verbal contact with patients during the use of conscious seda-
tion. Even though propofol has been used by emergency med-
icine physicians and gastroenterologists in the United States
for conscious sedation and by nonphysician providers in the
United Kingdom, no data describe propofol use by nurses
under reproductive endocrinologist supervision in the United
States. Therefore, we discourage the practice of propofol use
by nonanesthesia providers for egg retrieval.
Embryo transfer (ET) is a simple procedure that occurs on
day 3 or 5 after TUGOR, relies on a fertilized oocyte, and rarely
requires any anesthetic involvement. After speculum insertion
into the vagina and examination of the cervix, a flexible cath-
eter loaded with embryos and culture medium is advanced
past the cervical os and injected into the uterus. Conscious
sedation or MAC may be necessary in cases of significant dis-
comfort with speculum insertion, or when there is difficulty
advancing the flexible catheter past the cervical opening.
Gamete intrafallopian transfer (GIFT) is an alternative to
IVF-ET that was more common before improved embryo
culture techniques and successful pregnancies with IVF-ET.
After hormone stimulation and TUGOR, unfertilized oocytes
are mixed with sperm and transferred shortly after retrieval
into the fallopian tube. Laparoscopy performed under gen-
eral anesthesia is preferred so as to have direct visualization
of the flexible catheter and fallopian tubes in GIFT. Although
spinal anesthesia is rarely used for laparoscopic procedures
because of concerns of shoulder discomfort and difficulty
breathing with CO2, one report highlights the safety of spi-
nal anesthesia for laparoscopic oocyte retrieval.73 Another
technique is performed with a minilaparoscopic approach,
reducing intraperitoneal pressure and CO2 and obviating
the need for general anesthesia.74 Pregnancy rates are similar
between IVF-ET and GIFT; therefore the less invasive IVF-ET
is more often performed. GIFT allows for the oocyte fertiliza-
tion in vivo and may be acceptable for couples with religious
beliefs that preclude IVF. Other transfer options include zygote
intrafallopian transfer (ZIFT), pronuclear stage tubal transfer
(PROST), and tubal embryo transfer (TET). Although fertiliza-
tion is confirmed before embryo transfer, all these techniques
require TUGOR to aspirate the follicular fluid and laparoscop-
ically guided transfer into the fallopian tube 24 to 48 hours
after fertilization. Similar pregnancy rates and the need for
two procedures and anesthetics have led to a marked decline
in the performance of these techniques.
In earlier reports of IVF when it was significantly longer,
general endotracheal anesthesia was used with a combination
of inhalation agents, with or without N2O. General endotra-
cheal anesthesia is now rarely used, except in cases of lapa-
roscopic oocyte retrieval or when dictated by the patient's
condition. Concern about the use of N2O originated from
earlier reports suggesting that it had a teratogenic effect and
caused fetal death in rats when used during organogenesis.75
In addition, lower DNA and RNA content and morphologic
abnormalities were demonstrated in the embryos of pregnant
rats exposed to N2O during organogenesis.76,77 This potential
teratogenicity has been attributed in part to the inactivation
of methionine synthase. Short exposures to clinical concen-
trations of N2O, isoflurane, and halothane had no deleterious
effect on IVF and early embryonic growth up to the morula
stage in the mouse.78 Despite the deleterious effect of N2O
in some rat studies, no significant differences between rates
of fertilization or pregnancy were demonstrated in humans
undergoing laparoscopic oocyte retrieval and isoflurane/N2O
or isoflurane/air general anesthesia.79 Inhaled agents have
not been shown to possess a teratogenic or embryo effect.80
Furthermore, halothane can protect against N2O-induced ter-
atogenicity and spontaneous abortions in rats.26 In addition,
higher pregnancy rates have been demonstrated in women
undergoing laparoscopic PROST under isoflurane/N2O com-
pared with propofol/N2O anesthesia.81
Propofol is an ideal induction and maintenance agent
because of its short-acting half-life and antiemetic proper-
ties. However, early reports demonstrated that propofol dif-
fuses into follicular fluid, with greater levels observed with
higher doses.82,83 Even though follicular fluid concentrations
 544 ANESTHESIA AND UNCOMMON DISEASES
are higher in the last follicle than the first follicle, no differ-
ences were found in the ratio of mature to immature follicles
or in fertilization, cleavage, or embryo cell number.83 In addi-
tion, a report on the use of propofol for IVGA for TUGOR of
donor oocytes demonstrated a lack of negative effect on the
oocyte, as evaluated by cumulative embryo scores and rates
of implantation and pregnancy.84 Use of propofol (with N2O)
for transfer of fertilized embryos resulted in fewer pregnan-
cies compared with an isoflurane, N2O-based anesthesia.81
However, higher maternal serum concentrations were needed
in this study to provide anesthesia for laparoscopic PROST
compared with the use of propofol for IVF-ET procedures.85
Another study on mouse oocytes found that high levels of pro-
pofol in the follicular fluid may affect pregnancy rates.86 The
use of thiopental and thiamylal for laparoscopic egg retrieval
has also been associated with accumulation in follicular fluid87;
a comparison of thiopental and propofol used for laparoscopic
GIFT demonstrated similar pregnancy rates.88 A case-control
study comparing propofol IVGA to paracervical block showed
no difference in fertilization rates, embryo cleavage character-
istics, or pregnancy rates between the two groups.89 Neither
group received premedication; both groups received 0.5 mg
of alfentanil at anesthesia induction, and the propofol group
received a full induction dose (2 mg/kg), followed by a contin-
uous infusion without additional anesthetic. The results of this
study are compelling because an IVGA group was compared
to a local anesthetic group without premedication. In addi-
tion, no studies demonstrate a teratogenic effect of propofol.
Overall, although it may appear in follicular fluid when used
for IVGA for brief IVF procedures, data support that propofol
has no adverse effect on pregnancy rates.
Fentanyl, alfentanil, and midazolam, when used as premed-
ications before TUGOR, reach low intrafollicular levels and
have no effect on rates of implantation or pregnancy.90,91 The
absolute concentration of intrafollicular levels is extremely
low compared with plasma levels.91,92 Alfentanil had the low-
est follicular fluid/plasma ratio (1:40) compared with mid-
azolam (1:20) and fentanyl (1:10).91 Remifentanil, a relatively
new analgesic agent, has a fast onset and a very short recovery,
suitable for IVF procedures. A comparison of propofol/fen-
tanyl anesthesia to a midazolam/remifentanil technique found
a decreased need for manual ventilation and a faster recovery
of function in the latter group. More patients in the propofol/
fentanyl group experienced intraoperative awareness and did
not enjoy the anesthetic, but time to discharge did not vary.93
Other studies have compared a propofol-based anesthetic with
a sedative combination of ketamine and midazolam without
demonstrating a difference in the recovery profile, embryo
transfers, or pregnancy rates.94 Of note, there are sparse data
on the safety of ketamine or remifentanil on ART.
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as
IV ketorolac, would be ideal for the acute visceral pain dur-
ing and after TUGOR. However, there is reluctance to use
them because prostaglandins (PGE2, PGF2α, PGI2) in the
embryo and endometrium are important for implantation.95,96
Prostaglandin H synthase, also known as cyclo-oxygenase
(COX), is an essential enzyme in prostaglandin synthesis and
primarily localized in the endometrial epithelium.97 Despite
these concerns, no animal or human data demonstrate any
changes produced by COX inhibitors on the embryo or on
implantation rates. Furthermore, implantation does not occur
until 3 to 5 days after egg retrieval. Some UK centers rou-
tinely use NSAIDs without any known effects on endometrial
lining or implantation rates.98 We prefer to use NSAIDs for
egg donors or for patients with pain refractory to significant
doses of opioids until further data are available. Future studies
should help to clarify some of these concerns.
Nausea and vomiting are the most common complications
of general anesthesia but is reduced with the use of propo-
fol, low doses of opioids, and the avoidance of inhaled anes-
thetic agents. We prefer to avoid metoclopramide in patients
undergoing IVF; the risk of affecting embryo implanta-
tion and a successful pregnancy is greater than its benefit in
patients not at significant risk for acid aspiration syndrome.
Metoclopramide, a dopamine receptor antagonist, causes ele-
vated prolactin levels that may be associated with inhibition of
pulsatile gonadotropin-releasing hormone (GnRH) secretion,
a hypoestrogenic state, and ovulatory dysfunction.99 Although
not helpful for gastric motility, ondansetron use for the treat-
ment or prevention of nausea and vomiting is not contrain-
dicated during IVF. Serotonergic agents, unlike serotonin
(5-HT3) receptor antagonists such as ondansetron, may also
increase prolactin levels. We prefer to use a neuraxial tech-
nique for patients at increased risk for postoperative nausea
and vomiting or acid aspiration syndrome.
During TUGOR, a transvaginal approach is used to punc-
ture the ovary and aspirate the follicular fluid. Both sym-
pathetic and parasympathetic nerves supply the ovaries.
Although most of the sympathetic nerves are derived from the
ovarian plexus that accompanies the ovarian vessels, a minor-
ity are derived from the plexus that surrounds the ovarian
branch of the uterine artery.100 Acute visceral pain is often dif-
fuse in distribution, vague in location of origin, and referred to
remote areas of the body.101 Paracervical block (PCB) has been
utilized with and without conscious sedation for TUGOR
to improve pain relief.68,102,103 PCB anesthetizes the vaginal
mucosa, uterosacral ligaments, and peritoneal membrane over
the pouch of Douglas.102 Although the ovaries are not anes-
thetized, their pain sensitivity is the lowest compared with the
rest of the internal female genital organs.101 PCB with 150 mg
of lidocaine reduced abdominal pain by one half compared
with placebo.102 The linear visual analog pain score (VAPS;
0-100 mm) decreased from 43.7 to 21.2 mm when evaluated
4 hours after TUGOR.102 Another study demonstrated no dif-
ference in VAPS when 50 mg of lidocaine was compared with
100 and 150 mg for PCB.103 Assessing VAPS immediately after
the procedure found median abdominal pain levels of 30 to
32 mm. Although small concentrations of lidocaine in the fol-
licular fluid can have adverse effects in mouse oocyte fertiliza-
tion and embryo development,102,104 these levels do not affect
embryo implantation or pregnancy rates.105 PCB alone is not
sufficient to provide complete analgesia because of its 10%
 Chapter 19  Pregnancy and Obstetric Complications 545
to 15% failure rate and lack of interference with afferent sen-
sory fibers originating from the ovarian plexus. This finding is
reflected in the 2.5 times higher vaginal and abdominal pain
levels with PCB alone versus PCB with the addition of con-
scious sedation.68
Neuraxial techniques have also been used for TUGOR and
are more likely to anesthetize the ovary, vaginal mucosa, and
peritoneal membrane. A thoracic dermatomal level of the
tenth thoracic vertebra (T10) or higher is needed to anesthe-
tize the ovaries. Spinal anesthesia is more likely to be beneficial
because of its increased reliability and fast onset. It requires
minimal to no conscious sedation and can be tailored to mini-
mize high sensory levels and motor blockade. The optimal spi-
nal anesthetic should allow adequate surgical anesthesia with
minimal side effects, a fast onset, a short recovery time, and a
similar rate of successful pregnancies as with other anesthetic
techniques. Earlier reports described the use of 60 mg of 5%
lidocaine for spinal anesthesia,106 but long recovery times and
the finding of transient neurologic symptoms caused some
concerns. In an effort to decrease recovery times and keep
patients comfortable, Martin et  al.107 decreased the dose to
45 mg of lidocaine and evaluated the benefit of adding 10 μg
of fentanyl to the spinal anesthetic. A comparison of these
studies demonstrated decreased time to ambulate, void, and
discharge in the lower-dose lidocaine group.106,107 The addi-
tion of fentanyl to the lidocaine resulted in improved analgesia
during the procedure and, postoperatively, a decreased opioid
consumption and no change in side effects or ability to ambu-
late, void, or be discharged. The addition of increased amounts
of fentanyl to the spinal technique and surgical improvements
leading to shorter egg retrieval led to a further decrease in the
dose of lidocaine to 30 mg.
Although we have had a good success with the subarach-
noid use of 30 mg of lidocaine combined with 25 μg of fen-
tanyl, controversy about lidocaine and transient neurologic
symptoms led to the evaluation of bupivacaine as an alterna-
tive. However, a comparison of 30 mg of lidocaine with equi-
potent doses of bupivacaine (3.75 mg) demonstrated a longer
time to micturition and recovery with bupivacaine.108 Of note,
patients undergoing IVF procedures demonstrate decreased
serum albumin and α1-acid glycoprotein levels during supra-
physiologic estrogen states at oocyte retrieval. This may lead to
an increased free fraction of highly protein-bound drugs such
as bupivacaine.109 However, this may only be significant when
using larger doses of bupivacaine during epidural anesthe-
sia, which is rarely used during IVF. At our institution, spinal
anesthesia even with low doses of local anesthetic and opioid
is associated with longer times to voiding and discharge com-
pared with IVGA. This finding and short surgical time led us to
use IVGA as our standard anesthetic for TUGOR. Spinal anes-
thesia with 30 mg of lidocaine and 25 μg of fentanyl is used at
the patient's request, in those with significant gastroesophageal
reflux disease (GERD) or morbid obesity, when the patient has
eaten and the oocytes must be retrieved before spontaneous
ovulation occurs, and when indicated because of severe side
effects to IVGA, such as postoperative nausea and vomiting.
Male factor infertility is the most common form of infertil-
ity.110 New variations of IVF include direct sperm harvesting
and a single sperm injection into the cytoplasm of the oocyte,
called intracytoplasmic sperm injection (ICSI). ICSI has greatly
increased pregnancy rates in patients with male factor infer-
tility caused by low sperm counts and is often combined with
direct sperm aspiration from the epididymis or testicular
biopsy. Earlier reports described a more invasive, microepi-
didymal sperm aspiration (MESA) with open surgical aspira-
tion of the scrotum. Recent work has pioneered less invasive
techniques, such as percutaneous epididymal sperm aspiration
(PESA) and testicular epididymal sperm aspiration (TESA).
These two techniques have been done under local anesthesia
of the superior and inferior spermatic nerves and the genital
branch of the genitofemoral nerve, without premedication.111
We prefer to use spinal anesthesia or IVGA for these proce-
dures to minimize patient discomfort and movement.
ANESTHETIC ISSUES
In  vitro fertilization consists of different stages, including
suppression therapy, stimulation therapy, trigger or ovula-
tion therapy, egg retrieval, fertilization, postovulation therapy
with progesterone, and embryo transfer. Therapy with leup-
rolide acetate (Lupron), a GnRH agonist, causes suppression
of gonadotropins (follicle-stimulating hormone and luteiniz-
ing hormone) and results in a lack of production of estrogen
and progesterone. Stimulation therapy is conducted with FSH-
and LH-containing human menopausal gonadotropin (hMG)
and causes ovarian follicle growth. Human chorionic gonado-
tropin (hCG) causes ovulation to occur within 36 hours, and
TUGOR is performed at this time. Supplemental progesterone
is given after embryo transfer.
Stimulation therapy with gonadotropins (e.g., hMG or FSH
preparations) may lead to very high estrogen levels and ovar-
ian hyperstimulation.112 High estrogen levels place patients
at risk for thromboembolic phenomena. In its more severe
form, ovarian hyperstimulation syndrome (OHSS) may lead
to increased vascular permeability with leaky capillaries and
findings such as weight gain, intravascular volume depletion,
ascites, pleural effusions, electrolyte changes, and renal dys-
function. These patients usually experience a state of fibri-
nolysis, with higher fibrinogen, plasmin/α2-antiplasmin,
thrombin/antithrombin complexes, and d-dimer levels than
women with lower estrogen levels.113–115 In addition, tissue fac-
tor increases with high estrogen levels and is a powerful trig-
ger of the extrinsic pathway of the coagulation cascade.115,116
Treatment is usually supportive, with intravascular volume
expansion, analgesics, bed rest, and thrombosis prophylaxis.
More invasive methods, such as paracentesis and thoracente-
sis, are more helpful for relief of symptoms, such as abdomi-
nal pain and shortness of breath. Conscious sedation is often
required for these procedures and should take into account
the increased sensitivity to medications caused by intravas-
cular volume contraction. Caution should be used if regional
anesthetic techniques are a consideration for these patients,
because of the potential for anticoagulation.
 546 ANESTHESIA AND UNCOMMON DISEASES
The retrieval of oocytes from the follicles is not considered an
elective procedure; failure to retrieve them may lead to sponta-
neous ovulation and a wasted cycle. In addition, failure to empty
the follicles may lead to OHSS with all its known complications.
Our preference is to perform TUGOR under spinal anesthesia
with minimal sedation in patients who did not follow preopera-
tive fasting guidelines. Aspiration prophylaxis is recommended
with sodium citrate and metoclopramide, despite the concerns
for increased prolactin levels with metoclopramide.
Although the rate of success continues to increase with
ARTs, a significant number of cycles still do not result in a live
birth. Therefore, close scrutiny is expected of variables that
may affect oocyte retrieval or embryo transfer. It is essential
to understand the impact of different anesthetic techniques
and medications on IVF and carefully study any data that
links these factors with implantation or pregnancy rates. The
anesthetic may have an impact on ART, and vice versa.
OBSTETRIC ANESTHESIA FOR UNCOMMON
CONDITIONS
Morbid Obesity
A weight greater than 300 pounds (135 kg) in a gravida at term
is considered morbid obesity.117 Pregnancy in obese patients
may have four important implications.118 First, some of the
physiologic changes associated with pregnancy (e.g., increased
blood volume and cardiac output, reduced FRC) may further
exacerbate deleterious effects produced by pathophysiologic
alterations of obesity. Second, obese patients are prone to
acquire pregnancy-related diseases and complications (e.g.,
pre-eclampsia, gestational diabetes). Third, an increased inci-
dence of obstetric and perinatal complications is associated
with morbid obesity. Finally, a combination of these three fac-
tors may lead to the fourth implication: an unfavorable out-
come of pregnancy.
Obese women should be strongly encouraged to lose weight
before conceiving. This will decrease obstetric and perinatal
morbidity and mortality. Careful systemic evaluation should
be performed at the first opportunity during pregnancy in
morbidly obese women to determine the systemic pathophysi-
ologic alterations of obesity. This includes the degree of respi-
ratory impairment resulting in hypoxia, with consequences
such as pulmonary hypertension, right ventricular (RV) hyper-
trophy, and RV impairment. The left ventricle undergoes
eccentric hypertrophy as a result of increased cardiac output,
hypertension, and blood volume. The end result is a biventric-
ular hypertrophy. A bedside method to determine the degree
of hypoxemia is to measure the decrease in O2 saturation on
assuming the supine position from an erect posture. If hypoxia
occurs in the supine position, further evaluation should be per-
formed to determine the RV functional changes.118 Pregnancy
in morbidly obese women can exaggerate sleep apnea, resulting
in pulmonary hypertension during pregnancy.119
Increased BMI, increased prepregnancy weight, and
excessive maternal weight gain increase the risk of cesarean
section.120 Abnormal presentations, fetal macrosomia, and
prolonged labor are predisposing factors associated with
increased incidence of cesarean delivery among obese women.
Evidence suggests that obese patients are at increased risk for
abnormal labor.121,122 Although not statistically significant, the
incidence of cesarean delivery for failure to progress was much
higher in the morbidly obese than the control group.
There is high incidence of umbilical arterial pH less than
7.1 among obese women, regardless of whether they had a
trial of labor or elective cesarean delivery.123 A significantly
higher incidence of Apgar score less than 5 at 1 minute or less
than 7 at 5 minutes, of birth weight greater than 4500 g or
less than 2500 g, of intrauterine growth retardation (IUGR),
and of neonatal intensive care unit (NICU) admission is
found in infants born to obese versus nonobese parturients.124
Congenital anomalies in infants seems to be associated with
gravid obesity in the mothers; these infants are at a greater
risk for developing neural tube defects and other congenital
malformations.125
ANESTHETIC MANAGEMENT
An anesthesiologist should assess the patient at about 28
weeks' gestation to determine the effect of pregnancy on vari-
ous systems (Box 19-2). A multidisciplinary approach should
be instituted, depending on the systemic findings. Careful
evaluation of airway should be performed, and the anesthetic
plan should be formulated well in advance and communicated
to the patient as well as the obstetrician. Regional anesthesia
is most appropriate for labor and delivery. Early initiation of
epidural anesthesia is recommended, to provide ample time
to negate difficulties encountered during epidural placements.
Continuous spinal anesthesia is a reasonable alternative.
These two techniques provide satisfactory analgesia and anes-
thesia as needed for cesarean delivery, urgent or otherwise.
More recently, ultrasound is being used to increase the success
of regional anesthesia in morbidly obese pregnant women.126
If general anesthesia is contemplated, an assistant is advan-
tageous, and airway backup equipment should be available.
Difficult intubation should be anticipated, and a contingency
backup plan should be initiated as needed. Great care must be
exercised in appropriately positioning morbidly obese preg-
nant women for cesarean delivery. Hypoxia may occur in the
BOX 19-2   n ANESTHETIC CONSIDERATIONS IN
PREGNANT WOMEN WITH MORBID OBESITY
Perform a preanesthetic evaluation during pregnancy.
Assess airway.
Evaluate associated cardiorespiratory abnormalities of obesity.
Perform early epidural placement to ensure a good working catheter.
Consider continuous spinal technique if epidural anesthesia is
unsuccessful and airway is anticipated to be difficult.
Place several folded bedsheets stepwise from back to occiput, to
attain a good intubating position.
Know that a large pannus may cause hemodynamic instability after
induction of regional anesthesia.
 Chapter 19  Pregnancy and Obstetric Complications 547
supine position, which may require elevation of the back rest
of the operating table. Retraction of the pannus to facilitate
surgery can result in exaggerated supine hypotensive syndrome
of pregnancy, which can result in cardiac arrest. A multidisci-
plinary approach is the key to a successful outcome of preg-
nancy in morbidly obese women.
Amniotic Fluid Embolism
Amniotic fluid embolism is one of the most intriguing com-
plications of pregnancy. Its diagnosis is difficult and uncertain
at times, its pathophysiology is debatable, its treatment is diffi-
cult and often inadequate and nonspecific, and morbidity and
mortality are high. Amniotic fluid or amniotic debris enters
the maternal circulation more often than perceived. However,
only a few develop full-blown amniotic fluid embolism and
what initiates the chain of events remains unclear.
The mortality of amniotic fluid embolism continues to be
high for patients who are symptomatic, at 61% to 86%.127,128
The classic description of amniotic fluid embolism is pro-
found and unexpected shock, followed by cardiovascular col-
lapse and death in most patients.129 The syndrome was thought
most likely in multiparous women who had an unusually
strong or rapid labor.130 The use of uterine stimulants, meco-
nium staining of the amniotic fluid, or the presence of a large
or dead fetus was also believed to increase the risk. However,
a number of exceptions exist to this classic description. There
are several case reports of amniotic fluid emboli occurring
during cesarean delivery and therapeutic abortion, as well
as occasional cases in the late postpartum period or rarely
in nonlaboring patients.131–134 Other cases have been associ-
ated with abdominal trauma, ruptured uterus, or intrapartum
amnioinfusion.135,136
Amniotic fluid may be trapped in the uterine veins dur-
ing contraction of the uterus at delivery, then released into the
circulation later, during normal postpartum uterine involu-
tion.137 This explains cases of amniotic fluid embolism occur-
ring in the late postpartum period. Delayed presentation could
also result from the initial onset being transient or subclinical
and going unrecognized. This in turn could account for the
delayed or atypical presentation reported in the literature.
CLINICAL PRESENTATION
Cardiorespiratory collapse was present in most patients with
amniotic fluid embolism, as seen in the Morgan series.127
However, the presenting symptom in 51% of patients was
respiratory distress. In the remainder, the first indication of a
problem was hypotension in 27%, a coagulopathy in 12%, and
seizures in 10%. On the other hand, Clark et al.128 found that, of
those women presenting before delivery, 30% had seizures or
seizurelike activity, whereas 27% complained of dyspnea. Fetal
bradycardia (17%) and hypotension (13%) were the next most
common presenting features. Of the 13 patients who devel-
oped symptoms after delivery, seven (54%) presented with
an isolated coagulopathy manifested by postpartum hemor-
rhage. Several additional case reports have suggested that the
BOX 19-3   n CONSIDERATIONS IN AMNIOTIC FLUID
EMBOLISM
Cardiorespiratory collapse may be the first sign of amniotic fluid
embolism.
The patient occasionally presents with hypotension, seizures,
dyspnea, and isolated coagulopathy.
Coagulopathy is an invariable accompaniment of amniotic fluid embolism.
Presence of squamous cells and other fetal debris (mucin, vernix,
lanugo) coated with leukocytes in the maternal circulation is the
hallmark of amniotic fluid embolism.
Initial pulmonary hypertension, hypoxia, left ventricular failure, and
coagulopathy are the primary events in amniotic fluid embolism.
Management is basically symptomatic and directed toward the
maintenance of oxygenation, circulatory support, and correction of
coagulopathy.
presentation of amniotic fluid embolus can vary with regard
to timing, presenting symptoms, and subsequent course.136
Therefore the differential diagnosis must be considered care-
fully while maintaining a high index of suspicion for amniotic
fluid embolism (Box 19-3).
ETIOLOGY
Intact fetal membranes isolate amniotic fluid from the mater-
nal circulation. After delivery, uterine vessels on the raw sur-
face of the endometrium become exposed to amniotic fluid.
Normally, uterine contractions are effective in collapsing
these veins. Therefore, in addition to ruptured membranes,
for amniotic fluid embolism to occur there must be a pres-
sure gradient favoring the entry of amniotic fluid from the
uterus into the maternal circulation.127 Although the placen-
tal implantation site is one potential portal of entry, particu-
larly with partial separation of the placenta, this is otherwise
unlikely if the uterus remains well contracted. On the other
hand, small tears in the lower uterine segment and endocervix
are common during labor and delivery and are now thought
to be the most likely entry points.127,131 In support of this con-
cept, Bastien et al.138 reported a case of amniotic fluid embolus
where postmortem examination revealed marked plugging of
both the cervical vasculature and the lungs by various amni-
otic fluid elements.
The misconception that amniotic fluid routinely enters
the maternal circulation at delivery arose from the belief that
the presence of squamous cells in the pulmonary vasculature
signaled amniotic fluid entry into the maternal circulation.
Studies now show that squamous cells can appear in the pul-
monary blood of heterogeneous populations of both pregnant
and nonpregnant patients who have undergone pulmonary
artery (PA) catheterization.139,140 The presence of squamous
cells is thought to have resulted from contamination by either
exogenous sources during specimen preparation or epithelial
cells derived from the entry site of the PA catheter.139 Because
it is difficult to differentiate adult from fetal epithelial cells,
the isolated finding of squamous cells in the pulmonary cir-
culation of pregnant patients without amniotic fluid embolus
 548 ANESTHESIA AND UNCOMMON DISEASES
is most likely a contaminant and not indicative of maternal
exposure to amniotic fluid. Furthermore, although squamous
cells may be present in both groups (clinical evidence with and
without amniotic fluid embolus), only the patients with amni-
otic fluid embolism had evidence of other fetal debris, such as
mucin, vernix, and lanugo. In these patients, squamous cells
and other granular debris were frequently coated with leu-
kocytes, suggesting a maternal reaction to foreign material.
Where other occasional unidentifiable debris was detected,
the material present in the patients who did not have an amni-
otic fluid embolism was “clearly different” from that seen in
the sample.140
Additional confusion centers on the importance of tropho-
blastic embolization to the maternal lung. Trophoblastic cells
are normally free floating in the intervillous space and there-
fore have direct access to the maternal circulation.127 Thus
their presence in the maternal peripheral or central vascular
circulation is neither surprising nor indicative of an amniotic
fluid embolism. Further evidence that amniotic fluid does not
normally enter the maternal circulation can be found from
autopsies of parturients who died of various complications of
pregnancy. A comparison of lung specimens from 20 toxemic
patients with an equal number who had clinical evidence of
amniotic fluid embolus, using a specific stain for acid muco-
polysaccharide, confirmed the presence of mucin in the lung
secretions from all the amniotic fluid embolism patients; no
section from the toxemic patients stained positive.141
In summary, the presence of squamous or trophoblas-
tic cells in the maternal pulmonary vasculature must not be
equated with the entry of amniotic fluid into the maternal cir-
culation. No evidence suggests or supports that amniotic fluid
embolism is a common physiologic event.
PATHOPHYSIOLOGY
Once the amniotic fluid enters the maternal circulation, a
number of physiologic changes occur that contribute to the
syndrome observed. The pathophysiology is multifactorial,
and the clinical presentation will depend on the predominant
physiologic aberration.
HEMODYNAMIC CHANGES
Animal models have suggested that severe pulmonary hyper-
tension was the major pathophysiologic change with amni-
otic fluid embolism.142 This was believed to result from either
critical obstruction of the pulmonary vessels by embolic mate-
rial or pulmonary vasospasm secondary to the response of
the pulmonary vasculature to fetal debris, resulting in acute
asphyxiation, cor pulmonale, and in turn sudden death or
severe neurologic injury.131,142 However, human hemodynamic
data do not support sustained periods of pulmonary hyperten-
sion.143,144 In fact, left ventricular (LV) failure seems to be the
pathognomonic feature in humans.136
Clark142 reviewed the available hemodynamic data from the
published cases of amniotic fluid embolus in humans and found
only mild to moderate increases in PA pressure, whereas all
patients had evidence of severe LV dysfunction. Calculation of
pulmonary vascular resistance further revealed that, with one
exception, all were either normal or in a range that was reflec-
tive of isolated LV failure. In an attempt to reconcile clinical
and animal experimental findings, Clark proposed a biphasic
model to explain the hemodynamic abnormalities that occur
with amniotic fluid embolus, suggesting that acute pulmo-
nary hypertension and vasospasm might be the initial hemo-
dynamic response. The resulting right-sided heart failure and
accompanying hypoxia could account for the cases of sudden
death or severe neurologic impairment. Those patients who
survive the initial phase of pulmonary hypertension, which is
transient, proceed to the next stage of LV failure. Mechanisms
that contribute to the later phase of LV failure include hypoxia,
leftward shift of interventricular septum secondary to right-
sided heart failure (resulting in a decrease in cardiac out-
put, leading to impaired coronary artery perfusion), and the
direct myocardial depressant effect of amniotic fluid itself.
Endothelin, which is in amniotic fluid in abundance, has been
cited as the cause of LV failure.145
Other humoral factors, including proteolytic enzymes,
histamine, serotonin, prostaglandins, and leukotrienes, may
contribute to the hemodynamic changes and consumptive
coagulopathy associated with amniotic fluid embolism.136
Because of the clinical resemblance to sepsis and anaphylaxis,
Clark et  al.128 suggested that the syndrome of amniotic fluid
embolism is caused by anaphylactoid reaction to amniotic
fluid and named the syndrome “anaphylactoid syndrome of
pregnancy.” Antigenic potential can vary in individuals and
therefore can lead to different grades of the syndrome. For
example, women carrying a male fetus are more likely to be
affected. Similarly, fluid containing thick meconium may be
more toxic than clear amniotic fluid. Human data have shown
that, although most patients dying of amniotic fluid emboli
have had clear amniotic fluid, there is a shorter time from the
initial presentation to cardiac arrest and an increased risk of
neurologic damage or death in the presence of meconium or
a dead fetus. Further indirect evidence for an immunologic
basis is the occurrence of fatal amniotic fluid emboli during
first-trimester abortions. This suggests that under the right
circumstances, maternal exposure to even small amounts of
amniotic fluid can initiate the syndrome.128 Confirming the
theory of “anaphylactoid reaction” to amniotic fluid requires
further research using tryptase markers.
COAGULOPATHY
Consumptive coagulopathy is often associated with amni-
otic fluid embolism. In Morgan's review,127 12% of patients
presented with a bleeding diathesis, with subsequent devel-
opment of a bleeding diathesis in an additional 37%. More
recent reviews, however, found an even higher incidence.
Clark et  al.128 reported that 83% of the cases in the national
registry had either clinical or laboratory evidence of consump-
tive coagulopathy. The remaining 17% died before the clotting
status could be assessed by either clinical or laboratory tech-
nique. Similarly, in 15 cases of fatal amniotic fluid embolism
associated with induced abortion, two patients presented with
 Chapter 19  Pregnancy and Obstetric Complications 549
coagulopathy, and an additional 75% of initial survivors went
on to develop disseminated intravascular coagulation (DIC).146
It now appears that amniotic fluid embolism is almost always
associated with some form of DIC, with or without clinically
significant bleeding. Isolated DIC causing maternal hemor-
rhage may be the first indication of the problem in a small
number of patients.147,148 The current laboratory evidence also
supports that amniotic fluid embolus is associated with coag-
ulation changes. Harnett et al.149 studied the effect of varying
concentrations of amniotic fluid (10-60 μL added to 330 μL
of whole blood) on thromboelastographic variables and found
that amniotic fluid is procoagulant even with a 10-μL study
sample.149
The etiology of the coagulopathy remains somewhat
obscure; investigations have yielded inconclusive and con-
tradictory results. Although amniotic fluid contains activated
coagulation factors II, VII, and X, their concentrations are
well below those found in maternal serum at term.150 On the
other hand, amniotic fluid has been shown to have a direct,
factor X–activating property and thromboplastin-like effect;
both increase with gestational age. The thromboplastin-like
effect is likely caused by substantial quantities of tissue fac-
tor in amniotic fluid. Potential sources include sloughed fetal
skin and epithelial cells derived from the fetal respiratory,
GI, and genitourinary tract mucosa. Tissue factor activates
the extrinsic pathway by binding with factor VII. This com-
plex in turn triggers clotting by activating factor X. Lockwood
et al.150 speculated that once clotting was triggered in the pul-
monary vasculature, local thrombin generation could then
cause vasoconstriction and microvascular thrombosis, as well
as secretion of vascular endothelin. This vasoactive peptide
can depress both myometrial and myocardial contractility
and may primarily or secondarily contribute to the hemody-
namic changes and uterine atony generally associated with
this syndrome.
DIAGNOSIS
There are no diagnostic criteria to confirm the presence of
amniotic fluid embolism. The differential diagnosis includes
air or thrombotic pulmonary emboli, septic shock, acute myo-
cardial infarction, cardiomyopathy, anaphylaxis, aspiration,
placental abruption, eclampsia, uterine rupture, transfusion
reaction, and local anesthetic toxicity.136 In the presence of
central venous access, blood from the pulmonary vasculature
should be collected using the method described by Masson.130
He suggested that to minimize the possibility of maternal or
exogenous contamination, a more representative sample of the
pulmonary microvasculature can be obtained if blood is drawn
from the distal lumen of a wedged pulmonary artery catheter.
After discarding the first 10 mL of blood, an additional 10 mL
is drawn, heparinized, and analyzed with Papanicolaou's
method.151 The presence of components of amniotic fluid,
including squamous cells and mucous strands, reinforces the
diagnosis. Although pulmonary vasculature preparations may
occasionally be contaminated by maternal squames, when
squamous cells are found in large numbers in such a sample,
it is clinically significant and strongly supportive of the diag-
nosis of amniotic fluid embolus. This is particularly true if the
squamous cells are coated with neutrophils or accompanied
by other fetal debris, such as mucin or hair. A more reliable
method of confirming the diagnosis might center on the iden-
tification of other amniotic fluid elements in the maternal pul-
monary vasculature, as opposed to squamous cells.140,152
Recent progress in the diagnosis of amniotic fluid embolus
has centered on the attempt to develop simple, noninvasive,
sensitive tests using peripheral maternal blood. Kobayashi
et al.153 studied maternal serum sialyl Tn antigen levels in four
women with clinical amniotic fluid embolism and compared
them to both pregnant and nonpregnant controls. Sialyl, a
mucin-type glycoprotein that originates in fetal and adult
intestinal and respiratory tracts, is present in both meconium
and clear amniotic fluid. Using a sensitive antimucin anti-
body, TKH-2, the authors found no difference in the serum
levels of pregnant patients throughout gestation or in the early
postpartum period compared with healthy nonpregnant con-
trols. However, the antigen levels were elevated in the amni-
otic fluid embolism group.153 Nonetheless, this test appears
promising, although it needs further evaluation. Study of a
second marker of diagnosis that involves the measurement of
zinc coproporphyrin, a characteristic meconium component,
found plasma concentrations were higher in patients with
amniotic fluid embolus.154
MANAGEMENT
The management of the pregnant patient with amniotic fluid
embolism is basically symptomatic and directed toward the
maintenance of oxygenation, circulatory support, and cor-
rection of coagulopathy. Depending on the circumstances, a
full cardiopulmonary resuscitation (CPR) protocol may be
required. If the fetus is sufficiently mature and is undelivered
at the time of cardiac arrest, cesarean delivery should be insti-
tuted as soon as possible.
Treatment of hemodynamic instability includes optimi-
zation of preload with rapid volume infusion. Direct-acting
vasopressors may be required in restoring aortic perfusion
pressure in the initial stages. Once this is attained, other
inotropes such as dopamine and dobutamine can be added
to improve myocardial function. When clinically feasible,
PA catheterization can be instituted to help guide therapy.
Diuretics may be required to mobilize pulmonary edema
fluid. Treatment of the coagulopathy associated with amniotic
fluid embolus involves blood component therapy. Amniotic
fluid embolism is associated frequently with massive hem-
orrhage, requiring replacement with packed red blood cells
(PRBCs). O-negative or group-specific blood can be used if
crossmatched blood is unavailable. Plasma and platelets are
given to replace the clotting factors. Ongoing therapy is gener-
ally guided by the clinical condition of the patient and labora-
tory evidence of coagulopathy.
Although cryoprecipitate is not first-line therapy for
treating coagulopathy, it may be useful in circumstances in
which fibrinogen is low and volume overload is a concern.
 550 ANESTHESIA AND UNCOMMON DISEASES
Cryoprecipitate was also found useful in a patient with severe
acute respiratory distress syndrome (ARDS) secondary to
amniotic fluid embolus.155 After administration of cryopre-
cipitate, the patient's cardiopulmonary and hematologic sta-
tus improved dramatically, suggesting that cryoprecipitate
may be useful when conventional medical therapy appears
unsuccessful in maintaining blood pressure, oxygenation, and
hemostasis. The recommendation was based on similar treat-
ment protocols for severely ill patients with multiple trauma,
burns, and postoperative sepsis. These patients are believed to
have impaired clearance of circulating microaggregates and
immune complexes by the reticuloendothelial system, leading
to cardiopulmonary insufficiency and DIC. Cryoprecipitate is
rich in opsonic α2 surface-binding glycoprotein, also known
as fibronectin, which facilitates the reticuloendothelial sys-
tem in the filtration of antigenic and toxic particulate mat-
ter. Depleted levels of this glycoprotein have been reported in
severely ill patients, with marked improvement in the clinical
status after repletion of fibronectin levels.155
Isolated reports exist for other modalities of treatment for
amniotic fluid embolism. In one patient, a serine protein-
ase inhibitor, FOY, was used to treat associated DIC.156 Nitric
oxide and aerosolized prostacyclin have been used to treat
refractory hypoxemia.157,158 Clark et  al.128 suggested the use
of high-dose corticosteroids and epinephrine as useful thera-
peutic adjuvants, in light of the similarities of amniotic fluid
embolism to anaphylaxis. In management of coagulopathy
of amniotic fluid embolism, Leighton et al.159 recently deter-
mined that patients receiving recombinant factor VIIa had sig-
nificantly worse outcomes than cohorts who did not receive
rVIIa, thus recommending that rVIIa be used in patients only
when the hemorrhage cannot be stopped by massive blood
component replacement.159 Recent evidence from clinical
case reports also suggests that institution of cardiopulmo-
nary bypass (CPB) may improve the outcome of patients with
severe amniotic fluid embolism. Use of transesophageal echo-
cardiography (TEE) during circulatory collapse confirmed the
presence of intracardiac embolus, leading to CPB and emer-
gent thrombectomy.160,161
Pre-Eclampsia and Eclampsia
Pre-eclampsia complicates 6% to 8% of all pregnancies. Other
conditions (eclampsia, HELPP, pulmonary edema) are not as
common but may coexist with pre-eclampsia and contribute
to significant morbidity and mortality in pregnant women.
Eclampsia is a life-threatening emergency that occurs sud-
denly, most often in the third trimester near term. In approxi-
mately 60% of pre-eclamptic patients, convulsions and coma
precede delivery. Most postpartum cases occur during the first 24
hours, but seizures attributed to eclampsia have been reported as
late as 22 days after delivery. Approximately 50% of all patients have
evidence of severe pre-eclampsia. In the remaining half, the clas-
sic triad of pre-eclampsia (hypertension, proteinuria, and edema)
may be absent or mildly abnormal.162 Incidence of eclampsia
varies widely in the literature (1:100 to 1:3448 pregnancies).
Eclampsia remains a significant complication of pregnancy
in the United States. In a study of 399 consecutive women with
eclampsia, the mortality rate was 1%, and antepartum onset
carried the greatest risk, especially before 32 weeks' gestation.
Postpartum eclampsia, however, was more likely to be associ-
ated with neurologic deficits.163 Eclampsia remains a common
condition and a leading cause of maternal and perinatal mortal-
ity in developing countries.164 Major maternal complications can
follow, including placental abruption, HELLP syndrome, DIC,
neurologic deficits, pulmonary aspiration, pulmonary edema,
cardiopulmonary arrest, and acute renal failure (ARF).163
Headache, visual disturbances, and epigastric or right upper
quadrant (RUQ) pain are consistent with severe pre-­eclampsia
and may forewarn of impending eclampsia. Seizures have an
abrupt onset, typically beginning as facial twitching and fol-
lowed by a tonic phase that persists for 15 to 20 seconds. This
progresses to a generalized clonic phase characterized by
apnea, which lasts approximately 1 minute. Breathing resumes
with a long stertorous inspiration, and the patient enters a
postictal state, with a variable period of coma. Pulmonary
aspiration of gastric contents may complicate a seizure. The
number of seizures varies from 1 or 2 to as many as 100 in
severe, untreated cases. The causes of eclampsia are poorly
understood. It is generally believed that cerebral vasospasm
and ischemia result in eclampsia. However, cerebral edema,
hemorrhage, and hypertensive encephalopathy have also been
implicated in its pathogenesis.165,166
Until proved otherwise, the occurrence of seizures dur-
ing pregnancy should be considered eclampsia. Conditions
simulating eclampsia should be considered (e.g., encephali-
tis, epilepsy, meningitis, cerebral tumor, and cerebrovascu-
lar accident) only after ruling out eclampsia167 (Box  19-4).
Computed tomography (CT) may be normal or may show evi-
dence of cerebral edema, infarction, or hemorrhage. Bleeding
occurs more frequently in elderly gravidas with pre-existing
BOX 19-4   n  CONSIDERATIONS IN ECLAMPSIA
Eclampsia can occur during the antepartum, intrapartum, and
postpartum periods.
Headache, visual disturbances, and epigastric or right upper quadrant
pain may be symptoms of impending eclampsia.
Seizures have an abrupt onset, beginning as facial twitching, followed
by a tonic phase and clonic phase.
The CT scan may be normal or may show evidence of cerebral
edema, infarction, or hemorrhage.
Management involves maintenance of airway, oxygenation, and
ventilation.
Propofol, midazolam, and succinylcholine may be required to facilitate
oxygenation and ventilation.
Magnesium sulfate is the preferred drug for the definitive treatment
of seizures.
Eclamptic patients should undergo expeditious delivery.
Regional anesthesia to facilitate labor and delivery can be considered
in patients who are seizure free, conscious, and rational in behavior,
with no evidence of increased intracranial pressure and absence of
coagulopathy.
 Chapter 19  Pregnancy and Obstetric Complications 551
hypertension and may result in death or permanent disability.
Other neurologic abnormalities include temporary blindness,
retinal detachment, postpartum psychosis, and other transient
neurologic deficits.151 The electroencephalogram (EEG) is also
abnormal, showing focal or diffuse slowing, as well as focal or
generalized epileptiform activity.166
Posterior reversible encephalopathy syndrome (PRES) has
been associated with pre-eclampsia and eclampsia. This neu-
rotoxic state is accompanied by a unique brain imaging pat-
tern. The mechanism behind the developing vasogenic edema
and CT or magnetic resonance imaging (MRI) appearance of
PRES is not known. Two theories have historically been pro-
posed: severe hypertension leads to failed autoregulation, with
subsequent hyperperfusion, endothelial injury, and vasogenic
edema; or vasoconstriction and hypoperfusion lead to brain
ischemia and subsequent vasogenic edema.168
MANAGEMENT OF ECLAMPSIA
Supplemental oxygen should be delivered immediately during
seizure. A soft nasopharyngeal airway may facilitate oxygen-
ation during seizure. Ventilation may be assisted once seizures
end. Simultaneously, precautions should be observed to mini-
mize chances of gastric aspiration. Midazolam in incremental
doses up to 20 mg may be necessary, either to suppress sei-
zures or to facilitate further treatment in a combative patient.
Occasionally, propofol and succinylcholine may be required
to facilitate oxygenation and ventilation. Immediate monitor-
ing should include pulse oximetry, electrocardiogram (ECG),
and blood pressure (BP) recordings. Left uterine displacement
should be maintained throughout the resuscitative effort and
until delivery of the infant.
Magnesium sulfate is the preferred drug for the definitive
treatment of seizures. After an immediate loading dose of 4 to
6 g infused intravenously (IV) over 20 to 30 minutes, a mainte-
nance dose of 1 to 2 g/hr is initiated, assuming that the patient
has adequate urine output. Hourly monitoring of urine output,
regular evaluation of deep tendon reflexes, and observation of
respiratory rate should be implemented to guard against mag-
nesium toxicity.
Unless otherwise contraindicated, eclamptic patients
should undergo expeditious delivery. The common indica-
tions for cesarean delivery include fetal distress, placental
abruption, prematurity with an unfavorable cervix, persistent
seizures, and persistent postictal agitation.
Regional anesthesia to facilitate labor and delivery can be
considered in patients who are seizure free, conscious, and
rational in behavior, with no evidence of increased intracra-
nial pressure (ICP) and absence of coagulopathy. Moodley
et al.169 found no difference in maternal and neonatal outcomes
when comparing epidural anesthesia with general anesthe-
sia for cesarean delivery in conscious women with eclampsia.
Unconscious or obtunded patients, or those with evidence of
increased ICP, should have general anesthesia in line with neu-
rosurgical anesthesia recommendations. Hyperventilation can
be initiated soon after the delivery of the infant to minimize
the effect of low Paco2 on the uterine arteries. The patient can
be extubated at the conclusion of surgery if awake and con-
scious. On the other hand, if general anesthesia was under-
taken in a woman who was not conscious initially, consider
leaving the patient intubated and transferring her to inten-
sive care for BP control and controlled weaning from assisted
ventilation while assessing neurologic recovery. Prolonged
unconsciousness should prompt further evaluation with CT.
Magnesium should be continued until BP normalizes and cen-
tral nervous system (CNS) hyperexcitability disappears.
HELLP Syndrome
The HELLP (hemolysis, elevated liver enzymes, and low plate-
lets) syndrome is believed to be a clinical state that may rep-
resent an advanced form of pre-eclampsia (Box 19-5). Based
on the platelet count, the HELLP syndrome is divided into
three classes. Class I patients have a platelet count of less than
50,000/mm3, class 2 is between 50,000 and 100,000/mm3, and
class 3 is more than 100,000/mm3.170 The etiology of HELLP
remains elusive. Its clinicopathologic manifestations result
from an unknown insult that leads to intravascular platelet
activation and microvascular endothelial damage.
Hemolysis, defined as the presence of microangiopathic
hemolytic anemia, is the highlight of the disorder. Sibai171
noted a lack of consensus regarding the diagnostic features of
HELLP syndrome and suggested these diagnostic criteria: (1)
hemolysis, defined by an abnormal peripheral blood smear
and an increased bilirubin level (1.2 mg/dL or greater); (2) ele-
vated liver enzymes, defined as an increased aspartate trans-
aminase (aminotransferase, AST) level of at least 70 U/L and a
lactate dehydrogenase (LDH) level greater than 600 U/L; and
(3) a low platelet count (<100,000/mm3). A diagnosis of full
HELLP syndrome is made only if all three criteria are present.
A diagnosis of partial HELLP syndrome is made if only one or
two criteria are present, and a diagnosis of severe pre-eclampsia
is made if none is present. Patients with full HELLP syndrome
are likely to have a higher incidence of stroke, cardiac arrest,
DIC, placental abruption, need for blood transfusion, pleural
effusion, ARF, and wound infections.172 Most cases of HELLP
syndrome occur preterm, but 20% may present postpar-
tum. Patients who develop HELLP postpartum have a higher
BOX 19-5   n  CONSIDERATIONS IN HELLP SYNDROME
Hemolysis, elevated liver enzymes, and low platelets characterize the
HELLP syndrome.
Classification is based on platelet count:
n Class I (<50,000/mm3)
n Class II (50,000-100,000/mm3)
n Class III (>100,000/mm3)
Etiology remains elusive.
Delivery represents the only definitive treatment and should be
undertaken immediately, with few exceptions.
Dexamethasone increases the number of platelets significantly.
 552 ANESTHESIA AND UNCOMMON DISEASES
incidence of pulmonary edema and ARF.173 A recent analy-
sis of placental pathology found no significant differences
between placentas obtained from patients with pre-eclampsia
or with HELLP, except for statistically more frequent retropla-
cental hematoma in the pre-eclampsia group than the HELLP
group.174
Studies show better maternal outcome with administration
of 10 mg of dexamethasone IV at 12-hour intervals until dis-
ease remission is noted.175 Dexamethasone is continued until
BP is 150/100 mm Hg or less, urine output is at least 30 mL/
hr for 2 consecutive hours without a fluid bolus or the use of
diuretics, platelet count is greater than 50,000/mm3, LDH level
begins to decline, and the patient appears clinically stable.
When these occur, IV dexamethasone is decreased to 5-mg
doses 12 hours apart.175
Compensated DIC may be present in all patients with the
HELLP syndrome.176 In addition, patients with this syndrome
may experience RUQ pain and neck pain, shoulder pain, or
relapsing hypotension caused by subcapsular hematoma and
intraparenchymal hemorrhage. Because abnormal liver func-
tion studies do not accurately reflect the presence of liver
hematoma and hemorrhage, this subset of patients, particu-
larly if associated with thrombocytopenia, should undergo
CT examination of the liver.177 An abnormal hepatic imaging
finding was noted in 77% of patients with a platelet count of
20,000/mm3 or less.
Delivery represents the only definitive treatment of the
HELLP syndrome and should be undertaken immediately,
with few exceptions. Conservative treatment that includes bed
rest, antithrombotic agents, and plasma volume expansion is
typically unsuccessful and often results in early maternal or
fetal deterioration. In the presence of prematurity, cortico-
steroids may be administered to accelerate lung maturity, fol-
lowed by delivery 48 hours later. Administration of high doses
of corticosteroids may increase platelet numbers to allow
placement of a regional anesthetic, especially if a latency of
24 hours is achieved before delivery.178
Pulmonary Edema in Pre-Eclampsia
Three percent of women with severe pre-eclampsia develop
pulmonary edema (PE)179 (Box 19-6). PE results from low col-
loid oncotic pressure, increased intravascular hydrostatic pres-
sure, and increased pulmonary capillary permeability.180 Many
PE cases develop 2 to 3 days postpartum, and thus patients
with pre-eclampsia must remain under careful surveillance
in the immediate postpartum period. The resolution of PE
requires management of the underlying cause (e.g., overhy-
dration, sepsis, cardiac failure). Echocardiography may be
required to exclude cardiogenic causes.181,182 The initial treat-
ment of PE includes supplemental oxygen, fluid restriction,
and administration of a diuretic. In a subset of patients, if no
resolution of PE is in sight, PA catheter placement may facili-
tate further management. This includes vasodilator therapy to
reduce preload or afterload and administration of dopamine
or dobutamine in women with evidence of LV failure. Colloid
BOX 19-6   n  PULMONARY EDEMA IN PRE-ECLAMPSIA
About 3% of women with severe pre-eclampsia develop pulmonary
edema.
Pulmonary edema results from low colloid oncotic pressure, increased
intravascular hydrostatic pressure, and increased pulmonary
capillary permeability.
Edema is likely to occur 2 to 3 days postpartum.
Treatment
n Management of underlying cause (overhydration, sepsis, cardiac
failure)
n Administration of supplemental oxygen and diuretic with fluid
restriction
n Pulmonary artery catheter placement may occasionally facilitate
further management (vasodilators, inotropes).
n Tracheal intubation and ventilation may be required in the
minority of cases where respiratory failure complicates refractory
pulmonary edema.
administration may prove beneficial if the colloid oncotic
pressure-PCWP gradient is lowered. In rare cases, tracheal
intubation and ventilation may be required if respiratory fail-
ure complicates refractory PE.183 ARDS can complicate severe
pre-eclampsia, especially if pulmonary capillary permeability
is increased.184
Abnormal Placentation and Massive Hemorrhage
Despite the overall decrease in maternal mortality, peripar-
tum hemorrhage is still a major cause of maternal morbidity
and mortality, accounting for about 10% of maternal deaths.185
Hemorrhage is one of the leading causes of maternal mortal-
ity in the United States and is the leading cause of maternal
death in developing countries. Many conditions predispose to
hemorrhage; abnormal placentation is one of the major causes
and may be increasing at the fastest rate. An understanding
of the risk factors, identification, and obstetric management
of abnormal placentation may prove lifesaving for the mother
and fetus, because unexpected hemorrhage often occurs with
little or no warning and may be massive. General or regional
anesthesia could be used for cesarean delivery (Table 19-5).
Unlike other places in the body where hemostasis depends
on vasospasm and blood clotting, hemostasis at the placental
site depends on myometrial contraction and retraction. At term,
approximately 600 mL/min of blood flows through the placental
site.186 As the placenta separates, the blood from the implantation
site may escape into the vagina immediately (Duncan mecha-
nism) or may be concealed behind the placenta and membranes
(Schultze mechanism) until the placenta is delivered.
PLACENTA ACCRETA
Adherent pieces of placenta prevent effective contraction of
the myometrium and may cause bleeding. Placenta accreta
describes any placental implantation in which there is abnor-
mally firm adherence to the myometrium of the uterine wall.
It is the result of deficient decidual development resulting in
implantation of the placenta into the myometrium without
 Chapter 19  Pregnancy and Obstetric Complications 553

Modern ultrasonographic techniques and MRI are providing

TABLE 19-5  n Anesthetic Considerations for Patients
with Abnormal Placentation
a more reliable diagnosis of adherent placenta.
The diagnosis should also be suspected during attempts at
General Anesthesia Regional Anesthesia manual removal of the placenta without success or with con-
tinued bleeding. Typical attempts at removal do not usually
Invasive Could be inserted Need for sedation succeed because a cleavage plane between the maternal pla-
monitors after induction when to minimize
patient unaware discomfort
cental surface and the uterine wall cannot be formed, and
continued traction on the umbilical cord may lead to uterine
Blood loss Controlled hypotension Sympathectomy inversion and life-threatening hemorrhage. Successful control
may help minimize likely to decrease
of the bleeding may be challenging; the bleeding is unlikely to
blood loss blood loss
respond to uterotonic agents or uterine massage because the
Comfort Patient is more Sedation likely will uterus is unable to contract with retained placental tissue.
comfortable in the be needed, and Once the level of suspicion is high, exploratory laparot-
setting of blood there should be
transfusions and a low threshold
omy should be performed in cases of a vaginal delivery. In
decreased blood for general both vaginal and cesarean deliveries, prompt hysterectomy is
pressure anesthesia the treatment of choice, because 85% of patients will require
a hysterectomy. In patients diagnosed with placenta accreta
Airway Protected Sedation, mental
status, and volume in whom attempts at removal of the placenta are stopped, the
resuscitation may maternal mortality is low (3%), with an average blood loss of
compromise airway approximately 3500 mL. There are several case reports of liga-
tion of hypogastric, uterine, and ovarian arteries. However,
all these techniques have a highly variable success rate, and
intervening decidua basalis. Whereas in placenta accreta the massive blood loss with potential maternal morbidity and
placental villi are attached to the myometrium, in placenta mortality is four times higher if conservative management is
increta the placental villi invade the myometrium, as opposed employed.
to placenta percreta, where the placental villi penetrate through Selective transcatheter embolization of the pelvic arteries
the myometrium. The abnormal adherence may involve all or is an alternative to more invasive procedures and has shown
a few of the cotyledons (total vs. partial placenta accreta). The promise as a technique to preserve the uterus and fertility.190
predominant histopathologic feature is the absence of decidua Embolization could be performed prophylactically when mas-
with direct attachment or invasion of the cotyledon into sive hemorrhage is suspected, to decrease the blood flow to
the myometrium. Decidua deficiency is also partly respon- the uterus, even when the plan is to perform a hysterectomy.
sible for placenta previa and may account for the high inci- Transcatheter embolization consists of the preoperative place-
dence of their coexistence.187 Other causes of placenta accreta ment of balloon catheters in the internal iliac arteries and is
include prior uterine surgery, infection, and trauma because performed in the interventional radiology suite. The bal-
of the adverse effects on the endometrium. Uterine trauma loons are inflated at the time that hemorrhage is expected and
may result from dilation and curettage (D&C), endometritis, should be deflated once hemostasis is achieved, to maximize
leiomyoma, Asherman's syndrome, or prior pregnancies. The blood flow to the lower extremities. The procedure could also
overall incidence of placenta accreta in the obstetric popula- be used as a treatment for unexpected massive hemorrhage
tion is 1:533,188 but is greatly increased in those with a history in a patient who wants to preserve fertility. When properly
of placenta previa (1:26), a previous cesarean section (1:10), or used, embolization appears to be safe and effective, is mini-
both.189 The greater the number of previous cesarean sections, mally invasive, and has often been beneficial in avoiding
the greater is the risk for placenta accreta. hysterectomy.
The incidence of placenta accreta ranges from 0.26% in an A low threshold should be used in performing a hyster-
unscarred uterus, 24% in the presence of placenta previa and ectomy once massive hemorrhage develops. If intraoperative
one prior cesarean section, to 67% with four or more prior bleeding persists after peripartum hysterectomy despite suture
cesarean deliveries and placenta previa. Placenta accreta has ligation or cautery, collagen-derived products with or without
overtaken uterine atony as the most common reason for a thrombin impregnation (Gelfoam, Surgicel, FloSeal) can be
postpartum hysterectomy. More recent data demonstrate that topically applied. This can be especially helpful where bleed-
the most important risk factors are age (odds ratio/OR 1.14), ing involves raw surfaces or is adjacent to areas of engorged
previous cesarean delivery (OR 8.62 if >2, not significant if vessels. In the event of DIC, whether dilutional or consump-
only 1), and placenta previa (OR 51.42). No increased inci- tive, pelvic packing may be required, with the patient (laparot-
dence of placenta accreta was found in patients with history omy closed or open) transferred to the ICU until the adequate
of D&C or abortion.188 A high index of suspicion should be replacement of blood and clotting factors with blood products
raised in the parturient with placenta previa or prior cesar- such as red blood cells, fresh-frozen plasma, cryoprecipitate,
ean section, especially with an anterior placenta, because the and platelets can be achieved. The packing would be removed
diagnosis of placenta accreta may be difficult by ultrasound. later once the patient is deemed stable.
 554 ANESTHESIA AND UNCOMMON DISEASES
Massive blood loss is common with placenta accreta. Even
though antepartum recognition and elective hysterectomy are
likely to decrease blood loss and morbidity, significant hemor-
rhage may result from the increased vascularity of the gravid
uterus. Two large-bore IV lines should be started, cross-
matched blood should be available, and consideration given
to invasive monitoring, including arterial and central venous
lines. A regional technique is permissible in a patient requir-
ing gravid hysterectomy, as long as no significant hemorrhage
has occurred and adequate volume resuscitation is main-
tained.191 The most challenging cases occur with the retention
of an adherent placenta after delivery of a neonate in a patient
without risk factors for placenta accreta, because sudden mas-
sive blood loss can happen with multiple attempts at manual
removal of the placenta. The anesthetic technique in this situa-
tion is different because major hemodynamic changes may be
present in the parturient. It is highly recommended to assess
the ability of the anesthesiologist to both manage the airway
and volume-resuscitate the patient simultaneously. We per-
form epidural anesthesia in parturients at high risk or with
known placenta accreta, but we ensure low likelihood of a dif-
ficult airway, adequate IV access, and low threshold to con-
vert to general anesthesia. If hypovolemia is suspected, general
anesthesia induction should be considered, to have earlier
control of the airway.192 Other reasons for conversion to gen-
eral anesthesia include generalized patient discomfort due to
prolonged surgery, difficult surgical conditions, and earlier
airway control before swelling results with massive fluid resus-
citation. We previously reported peripartum airway changes
during cesarean hysterectomy and fluid resuscitation that
gradually resolved over the next 2 days.193
UTERINE RUPTURE
Cesarean delivery is the most common surgery performed in
the United States, with the most common reason being elective
repeat cesarean section. The increased risks of bleeding, infec-
tion, thromboembolism, and cost with cesarean section led
to encouraging vaginal birth after a cesarean section (VBAC),
with an increase in VBAC rate from 6.6% in 1985 to 30.3%
in 1996. However, this rate has declined in the past decade
because major complications (uterine rupture, hysterectomy,
injury to uterine arteries, bladder, and ureter) and neonatal
mortality were reportedly higher in women attempting VBAC
compared with elective repeat cesarean sections.194,195 Uterine
rupture may occur at the site of a prior uterine scar, usually
a previous cesarean section scar. A classic cesarean scar goes
through uterine muscle and is more likely to dehisce than a
low transverse cesarean scar. It was always believed that the
risk of uterine rupture in patients attempting VBAC was less
than 1%. However, this rate may be as high as 1.5% with a
low transverse incision and higher with other types of inci-
sions. VBAC is allowed only in cases of a low transverse scar.
The American College of Obstetricians and Gynecologists
(ACOG) recommends that physicians caring for parturients
attempting VBAC should be immediately available to pro-
vide emergency care.196 Not only are these parturients at an
increased risk for uterine rupture, but its results may be life
threatening. The relative risk of uterine rupture is threefold
to fivefold with spontaneous labor and labor induced with-
out prostaglandins, but an astonishing 15-fold when there is
induction of labor with prostaglandins compared with elec-
tive repeat cesarean birth. The incidence of infant death was
increased 10-fold in the presence of uterine rupture.195 ACOG
discourages the use of prostaglandins for cervical ripening or
for the induction of labor in women attempting VBAC.197
The guidelines that restricted trial of labor after cesarean
(TOLAC) to a specific parturient population and only in
centers with staff immediately available to perform cesarean
delivery led to a decline in VBAC rate to 8.5% in 2006. As a
result, ACOG issued less restrictive VBAC guidelines in 2010
that emphasize patient autonomy.198 Women who have had
two previous cesarean births, with an unknown uterine scar
or with twin gestation, are now allowed to attempt TOLAC.
Although TOLAC is most safely undertaken in a facility with
staff immediately available to perform a cesarean section,
resources may not be available or the parturient may attempt a
TOLAC at a smaller facility after a thorough risk/benefit analy-
sis and a discussion with the obstetrician. A joint ASA-ACOG
statement leaves the definition of “immediately available per-
sonnel and facilities” to the discretion of the institution, based
on available resources and geographic location.199
Risk factors for rupture of the uterus include a tumultuous
labor, prolonged labor, infection, previous uterine manipula-
tions (D&C or evacuation), midforceps delivery, breech ver-
sion, and extraction and uterine trauma. Signs and symptoms
of uterine rupture include sudden abdominal pain, shock, vag-
inal bleeding, fetal distress, change of uterine contour, and loss
of a uterine contraction pattern. Some obstetric authorities
used to discourage epidural analgesia for VBAC because of the
concern of masking the abdominal pain. However, only a high
and dense epidural anesthetic such as used for cesarean sec-
tion would blunt the pain of uterine rupture. Regional anes-
thesia can be safely employed, and although it does not have
an effect on the success rate of a vaginal delivery, it is more
likely to encourage parturients to attempt TOLAC. It is best
to use dilute solutions of local anesthetic with opioids because
a sudden incidence of abdominal pain in an otherwise com-
fortable patient in labor (TOLAC) with epidural anesthesia
should suggest uterine rupture. Also, abdominal pain is one of
the least reliable signs of uterine rupture, because pain may be
minimal, particularly when a previous cesarean scar dehisces.
The best diagnostic signs for uterine rupture are changes in
contraction pattern, changes in configuration of the abdomen,
and fetal distress. Continuous FHR monitoring is paramount
for its early diagnosis. Rapid recognition and management are
necessary to prevent maternal and fetal death. Except in par-
tial rupture of a previous low transverse uterine scar, which
can be repaired under a spinal or epidural anesthetic, emer-
gency hysterectomy is usually needed. This is likely to require
rapid anesthesia induction, even in the presence of shock, to
allow control of the hemorrhage. Importantly, spontaneous
uterine rupture of an unscarred uterus, although much less
 Chapter 19  Pregnancy and Obstetric Complications 555
common (1:15,000) than rupture of a previous uterine scar,
is more serious and catastrophic. It results in high maternal
mortality (≥50%) and fetal mortality (up to 80%) with massive
blood loss, often exceeding 15 units in severe cases.
MANAGEMENT OF MASSIVE HEMORRHAGE
Adequate surgical hemostasis and careful fluid and blood
replacement are essential to achieve good hemodynamic con-
trol. Increases in maternal blood volume and coagulation
proteins compensate for the average blood loss, and parturi-
ents are often able to tolerate 1000 to 1500 mL of blood loss
without major hemodynamic changes.200 However, obstetric
hemorrhage can occur rapidly, especially when difficulties
in placental separation arise, because 600 to 700 mL of blood
flows through the placental intervillous spaces each minute.
DIC may occur with little or no warning, in part because of
the mixing of fetal and maternal blood and other cellular
products, and intensifies blood loss.201 Physiologic changes
of pregnancy may allow signs of significant hemorrhage to be
concealed until sudden hypotension and tachycardia occur.
Urine output, heart rate, and BP assessments are useful in esti-
mating the volume status. Aggressive volume replacement is
essential to maintain tissue perfusion and oxygenation. Early
consideration should be given to colloids and blood prod-
ucts, along with a request for assistance, a second large-bore
IV line, and rapid infusion equipment for transfusion. A type
and crossmatch for at least 2 to 4 units of PRBCs should be
considered when the potential for significant blood loss is
likely, such as in cases of placenta accreta. Uncrossmatched,
type O, Rh-negative blood is rarely necessary if sufficient pre-
cautions are taken to order blood products in advance, except
when massive hemorrhage is unexpected and occurs in a short
period.
Although the ASA Task Force on Perioperative Blood
Transfusion and Adjuvant Therapies recommends the trans-
fusion of PRBCs, platelets, and fibrinogen only after the care-
ful assessment of volume status, surgical conditions, and
laboratory monitoring,202 recent reports with trauma patients
support the transfusion of 1 unit fresh-frozen plasma (FFP)
for every 1 unit RBCs.203 We believe that it is reasonable to take
this approach with obstetric patients because the majority with
severe postpartum bleeding will be in DIC and will lack both
fibrinogen and clotting factors from both consumption and
blood loss. At the beginning of an emergency, the blood bank
should be able to supply 4 units of already-thawed plasma
immediately, plus additional plasma within 15 to 20 minutes.
PRBCs are available promptly, and it takes about 45 minutes
to have cryoprecipitate ready for transfusion. Four  units of
plasma contains about the same amount of fibrinogen as a
pool of 8 to 10 bags of cryoprecipitate in a much larger vol-
ume. We developed a postpartum hemorrhage (PPH) algo-
rithm together with our obstetric and blood bank colleagues
using a 1:1 FFP/RBC ratio for massive obstetric hemorrhage
(Figure 19-1). More products are ordered based on frequent
laboratory results (CBC, PT, PTT, fibrinogen), aiming for the
target values stated in the algorithm. Many units of plasma
will be needed for both coagulation factor and fibrinogen
replacement, so a 1:1 ratio would be reasonable to correct DIC
provided results are followed and product selection is modi-
fied accordingly. We decrease or stop the plasma transfusion
when the patient's coagulation values approach normal. In the
absence of significant hemorrhage, transfusion of blood com-
ponents is rarely necessary unless hemoglobin (Hb) concen-
tration is less than 6 g/dL, the international normalized ratio
(INR) is greater than 1.5, the platelet count is less than 50/mm3
or there is evidence of platelet dysfunction and microvascu-
lar bleeding, or the fibrinogen concentration is less than 80 to
100 mg/dL in the presence of microvascular bleeding.202
The administration of recombinant human factor VIIa can
be considered if intraoperative bleeding persists after peripar-
tum hysterectomy and blood product replacement. Release
from the blood bank at the Brigham and Women's Hospital
requires a hematology consult and approval. This can only
be done if the fibrinogen level is greater than 100 mg/dL, so
plasma transfusion and lab draws are essential.
Some modalities for blood conservation are especially help-
ful in parturients who are at high risk for hemorrhage, who
refuse blood products, and who are scheduled for a planned
procedure. These techniques include autologous donation
(parturient's own blood) before the scheduled procedure,
acute normovolemic hemodilution immediately before the
procedure (parturient's own blood is removed and replaced
with an equal proportion of crystalloid or colloid), and intra-
operative cell salvage. Although reinfusion of blood contain-
ing amniotic fluid is possible, intraoperative cell salvage has
been safely used with leukocyte depletion filtration to remove
amniotic fluid.204,205 These techniques are still in evolution,
especially in parturients, and future studies need to validate
their utility and safety.206,207 However, these blood conserva-
tion techniques should always be considered in patients who
refuse blood products.
In summary, retention of an adherent placenta and a rup-
tured uterus can present with little or no warning and should
be in the differential diagnosis of postpartum hemorrhage.
Massive blood loss is common, and the anesthesiologist should
be prepared to provide massive volume resuscitation. Regional
anesthesia can be safely and effectively used, but some situ-
ations warrant general endotracheal anesthesia. Therefore,
identification of risk factors, antepartum recognition of uter-
ine rupture, and early planning with multidisciplinary team-
work are important.
Peripartum Cardiomyopathy
Peripartum cardiomyopathy (PPCM) occurs rarely, with
an exact incidence that remains unknown. In part because
the definition of PPCM is disputed, and perhaps because of
reporting bias or epidemiologic differences in different areas
of the United States and in different countries, rates from 1:100
to 1:15,000 live births have been reported.208 The generally
accepted incidence in the United States is 1:3000 to 1:4000.209
There is variation by ethnicity, with twofold to threefold
 556 ANESTHESIA AND UNCOMMON DISEASES

Step 1

Obstetric anesthesia (OB) Blood bank

1. Call blood bank, state: 1. State: “We will tube 2 RBC units immediately
• “Obstetric emergency/need emergency release” and prepare a cooler.”
• Patient name (Emergency release if applicable)
• Medical record number
• Location
• Attending physician 2. Check sample status – advise OB

3. Tube 2 RBCs immediately

(Emergency release if applicable)

2. Send runner to blood bank (BB) for cooler 4. Prepare a cooler for runner:
6 RBC units
4 FFP units
3. Arrange RBC pickup at tube station

4. Draw CBC, PT/PTT, fibrinogen 5. Thaw 1 pool CRYO

• Call lab to make super-stat
6. Thaw 4 more FFP

5. Receive coolers. Call BB to order additional

products

Step 2

OB Blood bank

Before labs come back, transfuse: 1. Tube 1st CRYO pool as soon as prepared,
1. RBCs based on estimated blood loss (EBL) notify OB
2. 1 FFP unit for each RBC
3. 1 CRYO pool

After labs come back, transfuse: 2. Issue additional products as ordered

1. CRYO to fibrinogen > 100 mg/dL
If first fibrinogen level is
<100 mg/dL Order 2 more CRYO pools
100-200 mg/dL Order 1 more CRYO pool

2. RBCs to Hct > 21%

3. Single donor platelets (SDP) to platelet
count > 50,000/L
4. Plasma to PT/PTT < 1.5 times control

Recombinant activated factor VII (rFVIIa, NovoSeven) is not recommended as first-line therapy in
postpartum hemorrhage or disseminated intravascular coagulation (DIC). Can be considered as a late
intervention; please consult hematology fellow before ordering.
FIGURE 19-1  Postpartum hemorrhage (PPH) algorithm. RBC, Red blood cells; CBC, complete blood count; PT/PTT, prothrombin/
partial thromboplastin time; FFP, fresh-frozen plasma; CRYO, cryoprecipitate; Hct, hematocrit.

higher incidence in African Americans than Caucasians, and
a lower incidence in Hispanics.210
Although classically viewed as a nongenetic type of dilated
cardiomyopathy (DCM), several investigations now show
familial clustering of PPCM and an association with fami-
lies demonstrating genetic forms of DCM. PPCM is charac-
terized by onset of cardiac failure typically occurring late in
gestation or, most often, in the first few months postpartum.
However, a recent review of 23 cases of pregnancy-­associated
cardiomyopathy compared to 100 cases diagnosed in the
final month of gestation or postpartum found them to be
indistinguishable.211
The diagnosis is one of exclusion, because there are
no pathognomonic signs or definitive diagnostic tests.
Criteria used for establishing the diagnosis were formu-
lated by a National Institutes of Health (NIH) consensus
 Chapter 19  Pregnancy and Obstetric Complications 557
BOX 19-7  n DIAGNOSIS OF PERIPARTUM
CARDIOMYOPATHY
All the following must be present:
n Cardiac failure occurring in the last month of pregnancy, or within
5 months postpartum
n Absence of an identifiable cause for the cardiac failure
n Absence of heart disease before the last month of pregnancy
n Echocardiographic evidence of left ventricular (LV) systolic
dysfunction:
n LV ejection fraction <45% or
n Fractional shortening <30% or
n LV end-diastolic dimension >2.7 cm/m2
Data from Pearson GD, et al: JAMA 283:1183-1188, 2000.
panel209 (Box  19-7). The European Society of Cardiology
has recently embraced more liberal language regarding tim-
ing of onset.212
The differential diagnosis of PPCM includes many other
causes of the clinical signs, such as severe hypertension, dia-
stolic dysfunction, pulmonary or amniotic fluid embolism,
exacerbation of valvular heart disease, infection, and toxic/
metabolic disorders. A wide variety of “risk factors” have
been suggested, but because PPCM is so rare, few are widely
accepted or strongly associated. The strongest factors include
maternal age over 30, African American ethnicity (Hispanics
appear relatively less susceptible), and multiple gestation; less
clear factors include multiparity, family history, long-term
tocolysis, pre-eclampsia, cocaine abuse, malnutrition, and
infection.208 In Africa, some populations demonstrate a much
higher incidence of PPCM (1%), apparently associated with
peripartum and postpartum consumption of large salt loads
and high ambient temperature.213
The clinical presentation of PPCM is similar to other forms
of DCM, although many symptoms are common in normal
pregnancies, often delaying the diagnosis in antepartum pre-
sentations. Patients may complain of dyspnea, orthopnea,
cough or hemoptysis, generalized fatigue, and chest or abdom-
inal pain. Physical findings include peripheral edema, crackles
on pulmonary auscultation, jugular venous distention, a third
heart sound, and a mitral regurgitation murmur.214 ECG and
chest films show typical signs of cardiomyopathy, including
tachycardia, atrial ectopy, nonspecific ST-segment and T-wave
changes, cardiomegaly (LV hypertrophy, left atrial enlarge-
ment), and pulmonary edema. As noted earlier, echocardiog-
raphy shows signs of LV systolic dysfunction.
The pathophysiology of PPCM remains unknown. One
prevailing theory suggests that myocarditis of viral or auto-
immune origin is responsible for the LV failure. Some series
have found a high incidence (80%) of myocarditis on endo-
myocardial biopsy,215 but others found an incidence of less
than 10%, similar to age- and gender-matched controls with
idiopathic cardiomyopathy.216 Still others have found the inci-
dence of myocarditis to be greater in PPCM than in idiopathic
DCM (29% vs. 9%).217 The wide discrepancy in myocarditis
may be caused by differences in timing of biopsy and criteria
for diagnosis.208 Other hypothesized pathophysiologic mecha-
nisms include abnormal cytokines (e.g., tumor necrosis factor
alpha [TNF-α], interleukin-6, Fas/APO-1), abnormalities of
relaxin, selenium deficiency, and genetic factors. An exciting
recent hypothesis with immediate implications for possible
therapeutic interventions involves an abnormal cleavage prod-
uct of prolactin. Mice with an induced deficiency of a tran-
scription factor (STAT3) in myocytes develop PPCM thought
to arise from increased activity of cardiac cathepsin D, which
cleaves prolactin into an antiangiogenic and proapoptotic hor-
mone that leads to myocyte damage. Preliminary data from a
small human trial of bromocriptine, which inhibits prolactin
release from the pituitary, demonstrated better LV functional
recovery, reduced mortality, and better functional status at 6
months.218
Treatment of peripartum cardiomyopathy is largely sup-
portive and aimed at establishing normal hemodynamics,
avoiding further deterioration of cardiac function, and avoid-
ing complications of heart failure, such as thromboembolism.
In the minority of cases appearing antepartum, consideration
must be given to possible adverse effects on the fetus. Sodium
and water restriction and diuresis are initial steps. Digoxin has
improved symptoms and is safe in pregnant patients. Beta-
adrenergic blockade, especially with vasodilating antagonists
(e.g., carvedilol), improves hemodynamics and reduces mor-
tality in idiopathic DCM, although efficacy in PPCM has not
been conclusively demonstrated.209,219 The addition of pent-
oxifylline (which decreases TNF-α) to conventional therapy
with diuretics and β-blockers significantly improved outcome
in PPCM patients.220 Angiotensin-converting enzyme (ACE)
inhibitors are recommended in other DCMs but cause renal
toxicity in the fetus or breastfed newborn. Hydralazine is
the vasodilator of choice.209 Anticoagulation is generally rec-
ommended if the left ventricular ejection fraction (LVEF) is
greatly decreased. Heparin, low-molecular-weight heparin,
and warfarin have been used; warfarin is generally reserved
for postpartum patients because of teratogenic effects in early
pregnancy. However, use of warfarin in late pregnancy, when
PPCM occurs, has not been shown to be harmful. All types
of anticoagulants may be safely used in postpartum women,
including breastfeeding mothers, because none is secreted in
breast milk.209
Other therapies of possible efficacy include maneuvers
designed to ameliorate myocarditis, including immunosup-
pressive drugs such as prednisone and azathioprine221 or
intravenous immune globulin (IVIG).222 As noted earlier,
inhibition of prolactin is a promising experimental therapy.
Cardiac transplantation has been described, including the use
of left ventricular assist devices (LVAD) as bridges to trans-
plant.223 Because the course of LV recovery is variable but
often rapid, implantable cardioverter-defibrillators (ICDs)
are best reserved for patients with persistent poor LV func-
tion, and temporizing measures such as automatic external
defibrillators (AEDs) are used in high-risk patients early in
 558 ANESTHESIA AND UNCOMMON DISEASES
the course.210 Successful pregnancy after transplantation has
been reported.224 However, deterioration of LV function is
common in patients with incomplete recovery after the initial
presentation.
Prognosis is poor unless rapid normalization of LVEF
occurs (<6 months). Mortality ranges from 25% to 50% in
patients with PPCM, although more recent series indicate bet-
ter outcomes than historical series.209,225 Survivors whose ven-
tricular function returned to normal have reduced contractile
reserve and may still experience further deterioration with
subsequent pregnancies.226
Anesthetic management of an undelivered parturient with
initial or recurrent PPCM has been described, but only in iso-
lated case reports. In most patients, anesthesiologists have used
continuous spinal or combined spinal-epidural analgesia.227–231
Invasive monitoring with an arterial catheter and a central
venous or PA catheter has generally been recommended as
well.227–232 Active anticoagulation may contraindicate regional
anesthesia. One case report described general anesthesia with
target concentration–controlled propofol and remifentanil for
emergency cesarean section in a PPCM patient in active labor.233
Another described cesarean delivery with etomidate and suf-
entanil with good maternal and fetal outcomes.234 PPCM has
also first appeared during anesthetic management for cesarean
delivery, requiring intraoperative resuscitation.235,236 The hemo-
dynamic picture should guide the management of patients who
have recovered from a previous episode, although the limited
cardiac reserve in these patients should be considered.232
Cardiac Arrest and Cardiopulmonary
Resuscitation
Cardiac arrest occurs at an estimated rate of 1:20,000 to
1:30,000 late pregnancies.237,238 Unfortunately, maternal sur-
vival is rare, averaging just 7%.238 Causes of cardiac arrest
in pregnancy include hemorrhage, embolism (air, amniotic
fluid), complications of pre-eclampsia, PPCM, pre-existing
cardiac disease (e.g., coronary syndromes, valvular disease,
congenital defects, dysrhythmias), intracranial hemorrhage,
trauma, anaphylaxis, sepsis, local anesthetic toxicity, failed
airway management, and hemodynamic effects of spinal and
epidural anesthesia. Whereas the most common etiology
overall is hemorrhage, the most common conditions produc-
ing cardiac arrest in late pregnancy are embolism and hyper-
tension.239 As in any resuscitation situation, the fundamental
goals are establishment of an effective airway and circulation
(basic CPR), followed by electrical and pharmacologic steps
to restore spontaneous circulation. The care of the pregnant
patient in cardiac arrest must also include consideration of the
physiologic changes of pregnancy and the welfare of the fetus,
if of viable gestational age (Box 19-8).
BASIC LIFE SUPPORT
A fundamental principle in resuscitation of the arrested
pregnant patient is that the best way to care for both mother
and infant is to restore circulation to the mother.238 Thus,
BOX 19-8   n CARDIOPULMONARY RESUSCITATION
IN PREGNANT PATIENTS
Basic Life Support
No change in technique of chest compressions.
Noninvasive ventilation complicated by anatomic and physiologic
changes of pregnancy.
Early intubation recommended.
Left uterine displacement essential (folded clothing, linens, rescuer's
knees, Cardiff wedge).
Advanced Cardiac Life Support
No change in advanced cardiac life support (ACLS) protocols.
No change in defibrillation techniques or voltages.
Caution when using paddle electrodes on enlarged breasts to avoid
shocking rescuers.
Obstetric anesthesiologist is logical “code leader.”
Consider open-chest massage or cardiopulmonary bypass for
reversible conditions not responding to conventional ACLS.
Delivery of Infant
Delivery within 5 minutes enhances intact neonatal survival.
Delivery may improve success of maternal resuscitation.
Incision at 4 minutes of ACLS, with delivery at 5 minutes.
pregnant basic life support (CPR) is essentially nonpregnant
basic life support. Mouth-to-mouth, pocket mask, or bag/
mask ventilation should be established immediately, followed
as soon as possible by endotracheal intubation and ventila-
tion. Noninvasive ventilation is complicated by the higher
O2 consumption, reduced chest compliance, pressure on the
diaphragm by the enlarged uterus, enlarged breasts, obesity,
and potential regurgitation of gastric contents associated with
pregnancy.237 Successful use of the laryngeal mask airway in
the setting of failed airway in an obstetric emergency has been
described.240 Chest compressions should begin promptly, fol-
lowed by advanced cardiac life support (ACLS) techniques, as
the clinical situation dictates.
A vital aspect of CPR in pregnancy is the maintenance of
uterine displacement to facilitate venous return to the heart.
Any convenient soft object (blanket, towel, pillow, cloth-
ing) may be used as a wedge, placed under the patient's right
flank. Chest compressions have been found to be effective in
tilted patients up to 30 degrees, although less so than in supine
patients.237 However, CPR is more effective when the patient
is on a hard surface. For this reason, some suggest a purpose-
built device known as the Cardiff wedge that tilts the patient
on a rigid wooden structure with a lip on the dependent edge
to keep her from sliding off.241 A “human wedge” has also been
described in which the patient is tilted over the knees of a kneel-
ing person on the right side of the patient.242 A chair inverted
to rest on the seat and top of the back may also provide a firm,
tilted support for the pregnant patient in cardiac arrest.238
Current American Heart Association (AHA) guidelines sug-
gest first attempting chest compressions in the supine position
with manual displacement of the uterus to the left, followed by
use of a wedge device if ineffective. Such manual displacement
is as effective as tilting in nonarrest patients, and further, rescu-
ers frequently overestimate the degree of tilt achieved.238
 Chapter 19  Pregnancy and Obstetric Complications 559
ADVANCED CARDIAC LIFE SUPPORT
The AHA recommends that no changes from standard ACLS
protocols be implemented when caring for pregnant patients.
The reader is referred to standard texts to review such pro-
tocols.243 Unfortunately, studies indicate poor adherence
to such guidelines in simulated cardiac arrest during preg-
nancy, and many recommend team drills to practice such
infrequently used skills.244,245 In addition, special consider-
ations include theoretic concern regarding the appropriate
method for direct-current (DC) cardioversion. The enlarged
breasts in pregnant patients may make access to the apex of
the heart difficult, particularly when the patient is severely
wedged. Furthermore, the anatomic and physiologic changes
of pregnancy may, in theory, alter the electrical properties of
the chest. However, measurements in pregnant women show
normal impedance.246 Others recommend caution to ensure
that the left breast does not contact the hand of the person
administering the shock.237 There is no known risk to the fetus
of DC defibrillation or cardioversion. The AHA recommends
standard timing and energies for such maneuvers.238,243 Similar
recommendations apply to pharmacologic interventions,
including large doses of α-agonists (epinephrine) to support
the maternal circulation, even though these may theoretically
decrease uteroplacental blood flow.243
A logistical question concerns who should serve as the
“code leader” for resuscitative efforts in pregnant patients.
Although the availability of various personnel and local
­customs may dictate otherwise, we believe that a senior anes-
thesiologist is the most appropriate clinician to fill this role.
Anesthesiologists are skilled in airway management, IV access
techniques, and ACLS pharmacologic interventions. Other
personnel often present at cardiac arrest situations, including
internists and surgeons, may not appreciate the physiologic
changes of pregnancy and the impact on maternal resuscita-
tion as thoroughly as an obstetric anesthesiologist. Further,
the obstetrician should attend to the fetal status and make
preparations for possible emergency cesarean delivery.
DELIVERY OF THE INFANT
Significant controversy surrounds the decision on whether
and when to perform an emergency cesarean delivery during
cardiac arrest in pregnant patients. There are two reasons to
consider such a drastic intervention. First, there is substantial
evidence from retrospective reviews that fetal outcome greatly
improves with cesarean delivery when maternal resuscitative
efforts are not rapidly successful. In a review of 61 perimor-
tem cesarean sections performed in the 20th century through
the mid-1980s, Katz et al.247 reported 100% of the 42 infants
delivered within 5 minutes of maternal arrest survived with
no neurologic sequelae. As the interval from arrest to deliv-
ery lengthened, the chance of survival decreased and the
incidence of severe neurologic damage increased among sur-
vivors. When the interval exceeded 15 minutes, intact survival
was rare. Most authors continue to advocate early deliv-
ery of the viable infant when initial maternal resuscitation is
unsuccessful.248–253 Preparations for operation should begin
immediately, incision should occur at 4 minutes of arrest, and
delivery should be accomplished by 5 minutes.238,247 Follow-up
investigations by Katz et al.254 since their original recommen-
dation247 continue to support better outcomes for both fetus
and mother when cesarean delivery is initiated promptly.
Some evidence suggests that perimortem cesarean delivery
has increased with improved awareness of these recommen-
dations, although timing usually exceeds 5 minutes, and over-
all maternal and fetal outcomes remain poor.255
A second reason to consider emergency cesarean delivery
during CPR is to improve the maternal condition.238,249,252–254
This may be the case even when the fetus is previable, because
the mechanism of improvement may be both relief of aortoca-
val compression and removal of the low-resistance uteropla-
cental circulation. The AHA recommends cesarean delivery
even for very premature infants if the maternal condition does
not appear immediately reversible, so that some chance of fetal
survival is preserved and maternal resuscitation facilitated.238
ADDITIONAL INTERVENTIONS
Cardiopulmonary arrest during pregnancy is considered a
possible indication for attempting open-chest cardiac mas-
sage, although the AHA does not specifically endorse its use.238
When anatomic factors limit the success of closed-chest CPR,
or the etiology of the arrest (e.g., PE, penetrating chest or
abdominal trauma) indicates this approach, thoracotomy and
open-chest cardiac massage may be considered. Retrospective
data suggest invasive CPR is most likely to be successful when
initiated relatively early in the resuscitation sequence. Also,
CPB has been successfully employed in select clinical situa-
tions involving pregnant patients in cardiac arrest: hypother-
mia from massive transfusion,256 bupivacaine cardiotoxicity,257
and pulmonary embolism.250
POSTRESUSCITATION CONSIDERATIONS
Restoration of spontaneous circulation may be accompanied
by other problems, depending on the etiology of the arrest.
Therapeutic hypothermia has been described but is not spe-
cifically endorsed by the AHA.238 Liver rupture has been
reported after CPR in pregnant patients.258 Hemostasis during
cesarean section in the setting of cardiac arrest may initially
be straightforward, due to shunting of blood away from the
uterus, but subsequently cause further hemodynamic compro-
mise after resuscitation.239 Management of brain-dead moth-
ers with spontaneous circulation and undelivered infants has
also been reported.259
CONDITIONS COMPLICATING REGIONAL
ANESTHESIA
Regional Anesthesia and Anticoagulation
Pregnancy is a prothrombotic state with an increase in
most coagulation factors (except XI and XIII, which are
decreased) and a decrease in clot inhibitors such as protein S.
The hypercoagulable state of pregnancy is also characterized
 560 ANESTHESIA AND UNCOMMON DISEASES

by increased platelet hemostatic capacity, despite a decreased

TABLE 19-6  n Comparison of Unfractionated Heparin
platelet count. Fibrinogen increases by as much as 50%.100 and Low-Molecular-Weight Heparin
Prothrombin and the thrombin-antithrombin complex are
also elevated in normal pregnancies, whereas fibrinolysis Unfractionated Low-Molecular-
is diminished. This is demonstrated by elevated levels of Heparin Weight Heparin
plasminogen activator inhibitor 1 and 2.260 In addition, the
Molecular 3000 to 30,000 1000 to 10,000
increase in estrogen that accompanies pregnancy is a well- weight daltons daltons
known prothrombotic cause.261 The tendency toward exag-
gerated coagulation is worsened by anatomic factors, such Placental None None
passage
as the decrease of the blood flow in the lower extremities by
the gravid uterus, a condition worsened in the supine posi- Anti–factor Xa/ 1:1 Greater than 2:1
tion. Furthermore, the increased maternal vascular volume factor IIa ratio
and decreased ability to exercise lead to venous conges- Bioavailability About 30% Close to 100%
tion of the lower extremities and an impediment to venous
return. Maternal conditions such as preterm labor and pla- Half-life 1 to 2 hours 3 to 6 hours
centa previa may lead to prolonged periods of bed rest and Measurement of Activated plasma Anti–factor Xa
further predispose the patient to lower extremity venous activity thromboplastin activity
thrombosis. time
Hypercoagulable states are common in the general popula- Clearance Saturable cellular Renal
tion, with some reports demonstrating that 5% of whites are mechanism;
heterozygous for factor V Leiden, a point mutation of factor V dose dependent
that renders it resistant to activated protein C. Other, less com- Protamine Neutralizes Partial reversal
mon, but more severe hypercoagulable states include factor V response activity from reduced
Leiden homozygosity and deficiencies of protein S, protein binding
C, and antithrombin III.262 Many of the low-risk thrombo-
philias, such as heterozygosity for factor V Leiden, are silent
until pregnancy, when they may become manifest as a result anticoagulation may lead to an exaggerated anticoagulation in
of the imbalance between the prothrombotic and antithrom- the fetus. Nevertheless, warfarin continues to be the anticoag-
botic forces. Initial manifestations of prothrombotic condi- ulant of choice in parturients with prosthetic heart valves; no
tions during pregnancy may include the first presentation of data document the benefits of subcutaneous unfractionated
deep vein thrombosis, repeated missed abortions, and recur- heparin or LMWH in this patient population.270 Prosthetic
rent late fetal losses.263–265 Prophylactic anticoagulation may be heart valve thrombosis and maternal and fetal deaths have
indicated in some cases to prevent venous or placental throm- been reported with LMWH use.272,273
bosis, because improved placental blood flow is likely to lead Vitamin K is required for the formation of γ-carboxyglutamic
to better pregnancy outcomes. acid in the liver. The absence of this amino acid interferes with
Common anticoagulation options include warfarin, the synthesis of vitamin K–dependant factors (e.g., II, VII, IX,
unfractionated heparin, and low-molecular-weight heparin X). The prolongation of the prothrombin time (PT) is seen
(LMWH) (Table  19-6). Knowledge of the pharmacokinet- as early as 24 to 36 hours after the first warfarin dose, and it
ics and pharmacodynamics of these agents is essential for the usually reflects the absence of factor VII. Warfarin is usually
practitioner involved in the care of parturients, leading to a stopped 5 days before a regional anesthetic; it generally takes
better understanding of the implications on the obstetric and 4 days for INR to reach 1.5 in most patients. The INR should
anesthetic management. Current guidelines for regional anes- be measured before a neuraxial technique,266 with recom-
thesia and anticoagulation266,267 are better used to complement mended levels of 1.4 or less for single-shot spinal anesthesia
rather than to replace the understanding of the pharmacology and 1.2 or less for epidural anesthesia.267 Neuraxial catheters
of common anticoagulants during the puerperium. should be removed when the INR is less than 1.5.266

WARFARIN UNFRACTIONATED HEPARIN

Warfarin, a competitive inhibitor of vitamin K, is rarely used
during pregnancy because it readily crosses the placenta, is a
first-trimester teratogen, and may cause fetal intracranial hem-
orrhage during the third trimester.268–270 It is most important
to avoid warfarin during weeks 6 to 12, the period of organ-
ogenesis, and the last 2 weeks of pregnancy to diminish the
risk of warfarin embryopathy and bleeding in the mother and
infant.270,271 The fetus has a smaller concentration of vitamin
K–dependent factors, and therefore normal targeted maternal
Unfractionated heparin is a strongly acidic, anionic, sulfated
mucopolysaccharide with a high molecular weight (average
3000-30,000 daltons) that prevents placental passage and that
makes it, along with other forms of heparin discussed later, the
anticoagulant of choice during pregnancy.274,275 Unfractionated
heparin has a unique pentasaccharide sequence (only one
third of heparin molecules) that is responsible for the antico-
agulation properties by activating a conformational change in
antithrombin III (AT-III), leading to an accelerated interaction
 Chapter 19  Pregnancy and Obstetric Complications 561
between AT-III, thrombin (factor IIa), and factor Xa. Heparin
leads to a similar inhibition of factors IIa and X (1:1 ratio). In
addition, although to a lesser degree, unfractionated heparin
catalyzes the inactivation of factors IIa, IXa, Xa, XIa, and XII.
It also indirectly affects the thrombin-mediated activation of
factors V and VIII, the end result being a decrease in impor-
tant cofactors (Va and VIIIa) in the coagulation cascade.
Unfractionated heparin is cleared from the circulation rap-
idly, because high-molecular-weight species are cleared more
rapidly than low-molecular-weight species. It has a s­aturable
cellular mechanism of clearance through receptors on endo-
thelial cells and macrophages, with a rapid saturable mech-
anism at low doses, a combination of rapid saturable and
dose-dependent mechanisms at therapeutic doses, and a
much slower first-order mechanism through the kidneys that
is nonsaturable and dose independent with high doses. This
dose-dependent mechanism of clearance leads to nonlinear
pharmacodynamic properties that affect the intensity and
duration of action of unfractionated heparin, most noticeable
when high doses are used.276 In addition, the nonlinear phar-
macodynamic properties of unfractionated heparin lead to an
unpredictable bioavailability when injected subcutaneously, a
condition that is easily noticed when low-dose subcutaneous
(SC) injections are used. Its bioavailability ranges from 30%
with low doses to 100% with very high doses (>35,000 U).
Although very high doses of SC unfractionated heparin have
a bioavailability similar to IV injection, with peak levels at
3 hours (range, 2-4 hours) after injection, its duration of action
is much less predictable, reported as longer than 24 hours
after injection.277 Other causes of an exaggerated response to
unfractionated heparin include prolonged therapy and its use
in debilitated patients. The half-life of IV unfractionated hepa-
rin is also affected, although to a lesser degree, by its nonlinear
pharmacodynamic properties.
Knowledge of the pharmacodynamic properties of unfrac-
tionated heparin may be more important than laboratory tests.
The activated partial thromboplastin time (aPTT) response to
heparin during pregnancy is attenuated secondary to increased
levels of factor VIII and fibrinogen, despite significantly ele-
vated heparin levels.276,277 The use of small-dose (≤5000 U) SC
unfractionated heparin for prophylaxis does not usually pro-
long aPTT, and blood levels are not typically monitored. The
use of SC unfractionated heparin for more than 5  days may
lead to a decrease in the platelet count. However, the aPTT
may be a better predictor of unfractionated heparin levels,
compared with pharmacodynamic properties, when very
high SC doses are used. We recommend checking the aPTT
of a parturient receiving high-dose SC unfractionated heparin
on arrival at the labor floor and waiting for the result before
performing a neuraxial technique. The anticoagulant effect
of high doses, as reflected by the aPTT, may persist for up to
28 hours after the last injection. In addition, a platelet count
is recommended for any parturient who received unfraction-
ated heparin for more than 4 days. It is important to realize
that parturients at risk for deep vein or placental thrombo-
sis are maintained on some form of heparin for most of the
pregnancy. High doses of unfractionated heparin may be used
throughout the pregnancy or, more frequently, after 36 weeks'
gestation at the time when LMWH is discontinued.
The American Society of Regional Anesthesia (ASRA)
developed guidelines for the performance of neuraxial tech-
niques in the anticoagulated patient in 1996, and these guide-
lines were updated in 2003 and 2010.266 ASRA based these
guidelines on the available scientific information, but in some
cases this information may be sparse. In addition, guidelines
are recommendations and not standards or absolute require-
ments. They are based not only on scientific information
but also on synthesis of expert opinion and clinical feasibil-
ity data. Variances from recommendations may be acceptable
based on the physician's judgment, and specific outcomes can-
not be guaranteed by following these recommendations.266,267
Moreover, clinical and scientific information and evolving
clinical practices may modify these guidelines with time.
The ASRA guidelines for the anesthetic management of
the patient receiving unfractionated heparin state that per-
formance of a neuraxial technique should proceed for at least
1  hour before systemic IV anticoagulation with unfraction-
ated heparin. Systemic IV anticoagulation with unfractionated
heparin should be discontinued 2 to 4 hours before a neur-
axial technique or epidural catheter manipulation (includ-
ing removal).266 In addition, the coagulation status should be
evaluated with aPTT, which must normalize before epidural
catheter insertion or removal. Despite the limited risk for epi-
dural hematoma formation when SC unfractionated heparin
is combined with neuraxial techniques, we prefer to perform
this technique either longer than 4 hours after injection of
SC heparin (half-life, 2-4 hours) or before its administration
(≥1-hour interval). However, ASRA states that there does not
appear to be an increased risk with neuraxial block in the pres-
ence of SC unfractionated heparin unless higher-than-average
doses (>10,000 daily or >twice daily) are used. Administration
to small or weak patients may result in a prolongation of the
aPTT. The addition of other medications (e.g., NSAIDs, aspi-
rin, oral anticoagulants) and other forms of heparin that affect
the coagulation cascade may increase the risk of epidural
hematoma when SC unfractionated heparin is used concomi-
tantly with a neuraxial technique.
LOW-MOLECULAR-WEIGHT HEPARIN
Low-molecular-weight heparin (1000-10,000 daltons) does
not cross the placenta,278 is formed by controlled depolymer-
ization of unfractionated heparin, and has the same penta-
saccharide sequence (potentiates action of antithrombin).
Overall, however, LMWH has a lower number of chains with
greater than 18 saccharide units (one half to one fourth of
LMWH fragments), providing a greater anti–factor Xa/anti–
factor IIa ratio.277,279 The 18 saccharide units are required for
the inhibition of factor IIa but not factor Xa. Different LMWHs
have different anti–factor Xa/factor IIa activity (e.g., 2.7:1 for
enoxaparin vs. 2.1:1 for dalteparin) but have equivalent antico-
agulation on clinical practice.279,280 Exogenous protamine com-
pletely reverses the anti–factor IIa activity of LMWH but only
 562 ANESTHESIA AND UNCOMMON DISEASES
60% of the anti–factor Xa activity, because of reduced binding
to its components. There are few trials comparing LMWHs
with functional or structural heterogeneity, although there is a
report from the orthopedic population, where enoxaparin was
similar to tinzaparin for deep vein thrombosis prophylaxis.280
Enoxaparin is discussed here because it is the most widely
used LMWH in the United States and the one most often cited
in the literature.
Low-molecular-weight heparin has a lower binding to pro-
teins and endothelial cells and dose-independent clearance
compared with unfractionated heparin. The end result is a
renal excretion that is dosage independent, a pharmacody-
namic effect that is proportional to the dose used and more
predictable, and a better bioavailability at low doses. In addi-
tion, LMWH has a similar bioavailability after SC and IV injec-
tion and is less immunogenic. Its dosage is adapted to body
weight, and there is a risk of accumulation with obesity and
renal failure.280 The half-life of LMWH is 3 to 6 hours after SC
injection, is independent of the dose, and is longer than that
of unfractionated heparin. LMWH has peak activity in 3  to
4 hours and low interpatient variability because of its more
predictable dose response; its once-daily or twice-daily dosage
is convenient for a parturient. LMWH has significant anti–
factor Xa levels 12 hours after injection because of its longer
half-life. It is controversial whether blood testing with an anti–
factor Xa assay is helpful in monitoring response to LMWH
or helpful before performing neuraxial techniques in the par-
turient anticoagulated with LMWH (see later). Despite their
similar efficacy, LMWH is replacing unfractionated heparin
when prophylactic anticoagulation is needed in a parturient
because of LMWH's improved bioavailability, longer half-life,
more predictable dose response with greater activity against
factor Xa, and lower incidence of bleeding complications.281
The safety and efficacy of LMWH in pregnancy is sup-
ported by a review of 624 high-risk parturients with a prior
incidence of thrombosis receiving enoxaparin prophy-
laxis.282,283 The congenital anomaly rate was 2.5%, (no greater
than in general population), with 1.1% fetal mortality unre-
lated to enoxaparin. There was only one enoxaparin-related
hemorrhage and a 1.3% incidence of recurrent maternal
venous thrombotic events (low for this high-risk popula-
tion). The study's conclusion, supported by an ACOG com-
mittee opinion,283 is that LMWH is safe and efficacious for
the prevention of thrombosis in high-risk parturients. Typical
prophylactic doses of LMWH during pregnancy are 40 mg
subcutaneously (1 mg is equivalent to 100 units) of enoxa-
parin once daily, or 30 mg subcutaneously twice daily. These
dosages are used in parturients with a remote history of
thrombosis but without a thrombophilia, low-risk thrombo-
philia, recurrent pregnancy loss, or a history of fetal demise.
Prophylactic doses are usually discontinued at 36 weeks' ges-
tation and changed to SC unfractionated heparin. High-dose
therapy typically ranges from 1 to 1.5 mg/kg of SC enoxapa-
rin twice daily and is indicated for the management of acute
thrombosis, remote history of thrombosis and presence of
antiphospholipid antibodies, or a high-risk thrombophilia.
High-dose therapy is usually continued until 24 hours before
induction of labor or a planned cesarean section.
Low-molecular-weight heparin does not usually influ-
ence the aPTT but has an effect on anti–factor Xa values. An
­anti–factor Xa chromogenic assay measures the activity against
factor Xa but not that against factor IIa.284 Although minimal
anticoagulation is equivalent to values below 0.2 U/mL, pro-
phylactic levels of 0.1 to 0.2 U/mL may suffice.285 It is not
usually measured for prophylactic doses because of the pre-
dictable dose response of LMWH. It may be prudent to check
assay values in patients with obesity, low body weight, or renal
failure, because LMWH has renal elimination and is affected
by changes in body weight.284,285 Monitoring anti–factor Xa
levels while using high doses of LMWH during pregnancy
is recommended because of increases in glomerular filtra-
tion rate, clotting factor concentration, weight, and volume
of distribution.286 Testing may also be useful with prolonged
therapy and in parturients at high risk of bleeding or throm-
bosis.285 Whether this assay confers any improved efficacy and
safety has not been confirmed, and interassay variability is an
issue.287 Further investigation is needed on this topic.
The peak activity of LMWH is already reduced by the end of
the first trimester, further reduced by the beginning of the third
trimester, and returns to normal postpartum.286 Overall, there
is a volume expansion as a term pregnancy approaches, leading
to subtherapeutic levels. Occasionally, LMWH is changed to IV
unfractionated heparin in high-risk patients and then discon-
tinued 4 to 6 hours before delivery. This may create a problem
if the patient requires a surgical procedure or placement of a
regional anesthetic, because a combination of both agents may
result in an unpredictable anti–factor Xa and aPTT response.
EPIDURAL HEMATOMA
Epidural hematoma is the most feared complication of neur-
axial techniques and is much more likely in the patient with
an inherited clotting abnormality or with use of anticoagu-
lants. Although a review found 61 cases over an 88-year period
(1906–1994),288 in 2003 a U.S. Food and Drug Administration
(FDA) MedWatch found 60 cases over a 9-year period associ-
ated with the use of neuraxial anesthesia and LMWH ther-
apy.289 There was one case of an epidural hematoma in a
parturient receiving LMWH. The timing of LMWH admin-
istration, removal of the epidural catheter, and development
of the hematoma are unclear, and the patient had a temporary
lower extremity motor weakness that resolved spontaneously
without surgical intervention.
The 1994 review had only five cases in parturients (8.2%
of cases),288 results that support the pregnancy-associated pro-
thrombotic state and its associated resistance to anticoagu-
lation. These factors counteract the epidural venous plexus
engorgement during pregnancy, with an increased incidence
of intravascular epidural catheters. An analysis of the obstet-
ric cases demonstrates that the majority occurred when the
anticoagulant dosing was close to the placement of a neurax-
ial technique or when patients were taking other medications
that alter coagulation.
 Chapter 19  Pregnancy and Obstetric Complications 563
In addition, a UK review found no cases of epidural hema-
toma in more than 9000 epidurals placed in parturients who
were taking aspirin as possible prophylactic treatment for pre-
eclampsia. Although not found beneficial for the prevention
of pre-eclampsia, aspirin was not associated with a signifi-
cant increase in placental hemorrhages or in bleeding during
preparation for epidural anesthesia.290 Of note, the decreased
incidence of epidural hematoma during pregnancy should
not modify the recommendations regarding the use of neur-
axial techniques in parturients with clotting abnormalities or
in those being anticoagulated. In addition, it has been docu-
mented that epidural catheter placement is as important as its
removal, because both situations could lead to epidural hema-
toma in the anticoagulated patient.288
Epidural hematoma is a rare complication of neuraxial
techniques, with an incidence ranging from 1:220,000 after
spinal anesthesia to 1:150,000 after epidural anesthesia.288 It is
more common in the presence of LMWH, with an incidence
as high as 1:3000 after a continuous epidural catheter and
1:40,000 after a spinal anesthetic.279 It is important to use very
low concentrations of local anesthetic to detect any change
in the patient's neurologic state. In addition, close follow-up
of the neurologic status is essential after the removal of an
epidural catheter. Clinical symptoms of epidural hematoma
include radicular back pain, bowel or bladder dysfunction,
and sensory or motor deficits.291,292 Interestingly, and counter
to common wisdom, severe radicular back pain is rarely the
presenting symptom. MRI is the best diagnostic test for a sus-
pected epidural hematoma, and early decompressive laminec-
tomy is the treatment of choice.
The ASRA guidelines were developed in part because of
the increased incidence of epidural hematoma associated
with the use of LMWH and neuraxial techniques.266 These
guidelines recommend discontinuing prophylactic doses of
LMWH at least 10 to 12 hours before a regional technique,
and a single-dose spinal anesthetic is the preferred technique.
Therapeutic doses should be discontinued at least 24 hours
before a regional technique, and LMWH should not be started
until 2 hours after epidural catheter removal. The presence of
blood at the time of epidural catheter placement may increase
the risk of bleeding into the epidural space and necessitates
a delay of 24 hours before LMWH administration. Although
epidural catheters are not usually kept for postoperative pain
management in parturients, in part because of the excellent
and prolonged analgesia with neuraxial morphine, it is impor-
tant to be careful when these catheters are kept in place in par-
turients who require LMWH prophylaxis or therapy. Catheter
management depends on total daily dose, timing of the first
postoperative dose, and dosing schedule.266 Epidural catheters
can be safely continued while using prophylactic single daily
dosing, as long as the LMWH is not started before 6 to 8 hours
postoperatively, the second postoperative dose is no sooner
than 24 hrs after the first dose, and the catheter is removed
10 to 12 hours after the last LMWH dose. Epidural catheters
should be removed in parturients receiving twice-daily dos-
ing before initiation of thromboprophylaxis because of its
association with an increased risk of epidural hematoma. The
first dose of LMWH should not be given earlier than 24 hours
postoperatively and not until 2 hours have elapsed since cath-
eter removal.
The ASRA does not recommend the use of the anti–­factor
Xa assay because this level is not predictive of bleeding risk.266
However, anti–factor Xa activity of LMWH is affected by
body weight, renal dysfunction, pregnancy, and prolonged
therapy.285,293 Therefore the dosage during pregnancy should
take all these factors into account. We do not routinely check
this assay in parturients because no data support the safety of
neuraxial techniques with lower levels. We encourage more
senior anesthesiologists to perform the block, and we prefer to
use midline neuraxial techniques to minimize the risk of intra-
vascular epidural catheters.
OTHER AGENTS: FONDAPARINUX
Newer anticoagulants are being compared to traditional anti-
coagulants, such as unfractionated heparin, and are being
used with an increased frequency, in part because of their sim-
ilar safety profile and ease of administration.
Fondaparinux is a synthetic pentasaccharide that gained
FDA approval in 2001. It selectively binds to antithrombin,
inducing a conformational change that significantly increases
the anti–factor Xa activity without inhibition of factor IIa.294–
296
Fondaparinux does not cross-react with antibodies against
heparin–platelet factor 4 complexes and therefore is unlikely
to lead to thrombocytopenia. It has a long half-life of about
18 hours, which may be prolonged with renal failure, a per-
tinent fact for regional anesthesia. It takes at least 4 days to
eliminate this agent completely from the circulation, and
regional anesthesia should be avoided during this period.
Fondaparinux is administered 2 hours after an atraumatic,
single spinal needle pass or epidural catheter removal.266
Indications for fondaparinux thromboprophylaxis d ­ uring
pregnancy include allergic reactions to LMWH and deep
vein thrombosis during LMWH therapy. Prophylactic doses
range from 2.5 to 5 mg and therapeutic doses from 7.5 to
10 mg.294,295
ANTIPLATELET MEDICATIONS
Maternal age has increased with the use of ARTs, and some
parturients may present with more comorbidities, including
coronary artery disease. Therefore, antiplatelet agents now
warrant discussion here. Aspirin (acetylsalicylic acid, ASA)
and NSAIDs produce an acetylation of COX, leading to an
inhibition of platelet aggregation. This inhibition lasts 1 to
3  days for NSAIDs and up to 7 to 10 days for ASA, which
produces a permanent defect in platelet aggregation. Several
reports have documented the use of neuraxial techniques in
the presence of antiplatelet medications without any untow-
ard effects, as mentioned earlier.290 Current recommendations
state that use of neuraxial techniques in pregnant patients
taking antiplatelet medications alone does not represent an
increased risk for epidural hematoma.240 Antiplatelet drugs
may augment the effect of other anticoagulants, however, and
 564 ANESTHESIA AND UNCOMMON DISEASES
therefore caution should be exercised when considering a
neuraxial technique on patients receiving more than one med-
ication that affects coagulation.266,267
Ticlopidine (Ticlid) and clopidogrel (Plavix) belong to a newer
class of antiplatelet agents, the thienopyridines. These medi-
cations cause selective inhibition of adenosine ­diphosphate–
mediated platelet activation.266,267 They bind irreversibly
to platelets and inhibit platelet adhesion, aggregation, and
secretion. These medications are frequently used in patients
with coronary stents. Clopidogrel has a potency that is 40 to
100 times greater than ticlopidine. Oral administration results
in peak plasma levels after 2 hours. Clopidogrel's effect on
platelet function lasts 5 days, versus ticlopidine's effect of 10 to
15  days. Although ASRA recommends discontinuation of
ticlopidine for 14 days and clopidogrel for 7 days before neur-
axial blockade,266 Nordic guidelines recommend discontinua-
tion of no less than 5 days before central neuraxial blockade.267
Platelet GP IIb/IIIa inhibitors block the final common
pathway to platelet aggregation. Time to normal platelet
aggregation ranges from 8 hours for eptifibatide and tirofiban
to 24 to 48 hours for abciximab. Neuraxial techniques should
be avoided until platelet function has recovered.266
Other medications interfere with primary or secondary
hemostasis, but data are incomplete and guidelines lacking or
limited. Examples include direct thrombin inhibitors (hiru-
dins and argatroban), synthetic Xa inhibitors (danaparoid),
oral Xa inhibitors (rivaroxaban and apixiban), oral direct
thrombin inhibitors (dabigatran) and thienopyridines (prasu-
grel). Knowledge of the pharmacokinetics and pharmacody-
namics of these drugs is the best guide for the use of neuraxial
techniques in patients taking these medications.
SUMMARY
It is important to use appropriate neuraxial techniques, to
avoid multiple anticoagulants, and to exercise caution in
proper parturient selection. The decision to perform neuraxial
anesthesia should utilize a risk/benefit analysis. Low concen-
tration local anesthetic techniques should be used to facili-
tate lower extremity neurologic assessment during neuraxial
anesthesia and analgesia. It is important to remember that
epidural hematomas have been reported at epidural catheter
withdrawal in patients with altered coagulation, and there-
fore neurologic examination should be continued for a time
after catheter removal. Soft, flexible catheters are preferred for
an epidural technique because they have a lower incidence of
venous cannulation. Appropriate use of neuraxial techniques,
proper patient selection, timing of a regional technique in
­relation to an anticoagulant, avoidance of multiple medica-
tions that alter the coagulation cascade, and use of less trau-
matic techniques (e.g., subarachnoid) are likely to decrease the
incidence of bleeding complications. In addition, the use of
opioid and dilute solutions of local anesthetic and thorough
neurologic checks may assist in the early diagnosis of an epi-
dural hematoma. Symptoms to look for include severe back
pain that is often radiating, leg weakness or sensory changes
unrelated to the block, and bladder or bowel changes.
Early emergency decompressive laminectomy, ideally
within 12 hours, is the treatment of choice for an epidural
hematoma. Recent UK data demonstrate that adherence to
these precautions has reduced the risk of epidural hematoma
to an acceptable level.297
Knowledge of the pharmacokinetics and pharmacody-
namics of common anticoagulants used during pregnancy
is essential to avoid neuraxial techniques when a significant
anticoagulant effect may still be present. In addition, under-
standing the mechanism of action, side effect profile, and half-
life of newer anticoagulants is important. Guidelines should
not be used as a substitute but rather as a complement to this
knowledge.
Local Anesthetic Allergy
A true immunoglobulin E (IgE)–mediated anaphylactic reac-
tion to an anesthetic agent, although often life threatening,
is rare in the patient under anesthesia. The incidence varies
between 1:3500 and 1:20,000, with neuromuscular blocking
drugs and latex being the most common offending agents.
A review of allergic reactions during anesthesia in France dur-
ing a 2-year period found no cases of local anesthetic allergy.298
Local anesthetics belong to the ester or amide type. Whereas
ester local anesthetics are metabolized to p-­aminobenzoic acid
(PABA), amide local anesthetics are metabolized in the liver to
a variety of compounds. Methylparaben is a preservative that
may be present in amide or ester local anesthetics and can have
some cross-reactivity with PABA. An IgE-mediated reaction
to a local anesthetic, most likely caused by the PABA metabo-
lite from esters or methylparaben, accounts for less than 1% of
all reactions to local anesthetics.299 Almost all cases of ques-
tionable allergic reactions to local anesthetics result from a
vasovagal episode, systemic injection of local anesthetic with
CNS manifestations, or intravascular injection of epinephrine,
with its associated cardiovascular manifestations. Further,
most allergic reactions to local anesthetics are caused by a type
IV delayed hypersensitivity reaction that presents as a contact
dermatitis.299
Cross-reactivity to other local anesthetics should be con-
sidered when a true IgE-mediated reaction to an amide or
ester group local anesthetic is suspected or confirmed by prior
testing. Skin tests should then be conducted, not only for the
suspected agent but also for other local anesthetics, including
agents of both types, to identify a safe alternative.300 There is
even a report of an IgE-mediated reaction to ropivacaine in
a patient with a history of an anaphylactic reaction to other
amide local anesthetics, including lidocaine, bupivacaine, and
mepivacaine. This patient tolerated procaine, an ester local
anesthetic, well. Skin tests are conducted by intradermally
injecting small quantities of local anesthetic and watching for
a wheal and flare response. A positive response should be fol-
lowed by a skin prick test and then SC injection, because the
results are equivocal in many cases.301 The Chandler method-
ology for provocative skin testing302 can be performed over
a 1- to 2-hour period by a trained allergist incrementally
 Chapter 19  Pregnancy and Obstetric Complications 565
performing SC injections of a local anesthetic while observ-
ing the patient closely on a monitored unit for any signs of an
allergic reaction.
The history of a local anesthetic allergy in an obstetric
patient is more complicated, because skin testing is not rec-
ommended during pregnancy unless the results obtained will
lead to a significant implication for treatment.303 Regional
anesthesia is much safer in parturients compared with general
anesthesia,304 and regional analgesia is by far the most effec-
tive means of analgesia during labor and delivery. Although
the best time to conduct skin testing is before pregnancy,
some believe provocative challenge skin testing can be con-
ducted during pregnancy to rule out a true local anesthetic
allergy.305,306 The timing of the testing during pregnancy is also
controversial, because an allergic reaction caused by skin test-
ing before fetal viability may lead to untoward effects on the
fetus. Other risks include the possibility of fetal sensitization,
and it remains unclear whether a response to skin testing is
modified by pregnancy.
Therefore, in the event that testing has not been performed
during pregnancy, a thorough history should be conducted
first to rule out other causes of an adverse local anesthetic
reaction. In addition, it is important to elicit a family history
because genetic linkage has been postulated.307 Other options
for anesthesia and analgesia should be considered, and a thor-
ough informed consent process with the patient is strongly
recommended while conducting a risk/benefit analysis. The
risks of skin testing during pregnancy should also be dis-
cussed with the patient, in collaboration with an allergist and
the obstetrician. If skin testing is planned, the timing should
be close to the date of delivery to maximize fetal well-being.
Most cases of reactions to local anesthetics are not aller-
gic and should not preclude their use. However, even though
a life-threatening anaphylactic reaction to a preservative-
free local anesthetic is uncommon, it has been reported and
should be taken seriously and followed closely if confirmed or
strongly suspected (Box 19-9).
Latex Allergy
More recently, anaphylaxis has been reported to occur imme-
diately after latex exposure. This trend is likely correlated to
the higher level of sensitization to latex in high-risk patients.
BOX 19-9   n DIFFERENTIAL DIAGNOSIS OF LOCAL
ANESTHETIC ALLERGY
Vasovagal episode
Systemic local anesthetic injection
n Central nervous system reaction
Systemic epinephrine
n Cardiac toxicity
Type IV cell-mediated reaction
n Contact dermatitis
Type I cell-mediated reaction
n Anaphylaxis
Obstetric and gynecologic examinations and latex condom use
sensitize women to latex.308 For this reason, patients undergo-
ing obstetric and gynecologic procedures account for almost
50% of latex-mediated reactions.309 Oxytocin-induced uter-
ine contractions may cause the release of latex particles in the
uterus into the systemic circulation.
High-risk groups for latex allergy include those with occu-
pational exposure to latex (e.g., health care workers), atopic
individuals, spina bifida patients, patients with multiple sur-
geries (e.g., genitourinary abnormalities), and people allergic
to tropical fruits (e.g., bananas, avocados, papaya, kiwi, pears).
These fruits contain proteins that cross-react with latex,
resulting in the latex-fruit syndrome. Latex-mediated reactions
include irritant contact dermatitis, type IV cell-mediated reac-
tions (allergic contact dermatitis), and type I IgE-mediated
hypersensitivity reactions (anaphylaxis).
Anaphylaxis during pregnancy is managed medically the
same as in nonpregnant patients with a few modifications.
The first step in the treatment of an anaphylactic reaction con-
sists of the withdrawal of the likely causative drug and early
use of epinephrine.310 Epinephrine interrupts the effects of the
preformed mediators and prevents more mediator release.
Epinephrine is considered the drug of choice in the treatment
of anaphylaxis during pregnancy; no alternative more com-
pletely treats the physiologic manifestations of anaphylaxis.
Some concern surrounds the use of epinephrine during preg-
nancy because of its potential to reduce uterine blood flow, a
result of its effect on uterine vascular resistance through its
α-mediated blood vessel vasoconstriction in the placenta.308
However, only when given in excessive doses does epinephrine
decrease uteroplacental blood flow. Appropriate epinephrine
dosage—a starting dose of 0.1 to 0.2 μg/kg in the treatment
of mild to moderate hypotension, titrated to response—will
increase SVR, cardiac output, and uteroplacental perfusion.
Doses of 0.1 to 0.5 mg IV are used in the presence of cardio-
vascular collapse.
The best position for the parturient is left uterine dis-
placement, avoiding the supine, sitting, or standing position,
because such positioning alone can precipitate cardiac arrest
from aortocaval compression, with resultant supine hypoten-
sive syndrome or massive vasodilation.311
Other important steps in the treatment of anaphylaxis
include airway support with 100% oxygen to compensate for
the increased O2 consumption, and IV crystalloid replace-
ment (2-4 L) to compensate for the peripheral vasodilation.
Bronchospasm may be initially treated with bronchodilators
(nebulized albuterol, ipratropium bromide). When cardiovas-
cular collapse and bronchospasm occur together, epineph-
rine remains the first-line therapy to correct cardiovascular
homeostasis and treat hypotension and bronchospasm at the
same time. The epinephrine total dosage requirement may be
correlated with the severity of the reaction.
Even though anaphylaxis is uncommon during pregnancy,
it is important to recognize it rapidly and treat it effectively;
the maternal hypoxia and hypotension that can result from
anaphylaxis may be catastrophic to both mother and fetus.
 566 ANESTHESIA AND UNCOMMON DISEASES
Prevention is the most important part of management to
decrease the incidence of anaphylaxis. Patients who experi-
ence anaphylaxis during pregnancy should have a follow-up
assessment from an allergy/immunology specialist to confirm
the trigger for anaphylaxis and prevent recurrence.
CONCLUSION
Pregnancy is a common and nonpathologic condition.
However, the altered physiology of pregnancy complicates
the anesthetic care of even healthy pregnant patients. When
unusual conditions of pregnancy further alter the physiologic
state, the anesthesiologist faces additional challenges. Basic
principles of management of the pregnant patient are sum-
marized in this chapter, along with various diseases that may
complicate pregnancy and select conditions specific to preg-
nant patients.
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 C H
The Geriatric Patient
Huntington's Chorea (Huntington's Disease)
Amyloidosis
Idiopathic Pulmonary Fibrosis
Polycythemia Vera
Essential Thrombocythemia
Myeloid Metaplasia with Myelofibrosis
Polymyalgia Rheumatica
Goodpasture's Syndrome
Male Breast Cancer
Primary Hepatic Lymphoma
Creutzfeldt-Jakob Disease
KEY POINTS
n Patients with Huntington's disease are at higher risk of
pulmonary aspiration, altered anesthetic pharmacology,
and worsening generalized tonic spasms. Rapid-sequence
induction with cricoid pressure is recommended for
­general anesthesia.
n Autonomic dysfunction from amyloidosis has dramatic
perioperative ramifications. Administering ­ anesthetics
to patients with amyloidotic polyneuropathy risks sig-
nificant hypotension; depolarizing muscle relaxants are
controversial.
n In patients with idiopathic pulmonary fibrosis, anesthetic
evaluation focuses on degree of disease progression and
available pulmonary reserve.
n Uncontrolled polycythemia vera is associated with
a high risk of perioperative bleeding and postopera-
tive thrombosis, requiring aggressive disease control
preoperatively.
n Elderly patients with essential thrombocytosis are at high
risk for thrombotic and hemorrhagic complications.
Perioperative management of the patient with essential
thrombocythemia focuses on whether to normalize the
platelet count.
A P T E R
20
STEVEN J. SCHWARTZ, MD  n
FREDERICK E. SIEBER, MD  n
n Perioperative considerations in myeloid metaplasia with
myelofibrosis include careful platelet count monitoring and
attention to hemorrhagic complications.
n In patients with polymyalgia rheumatica, preoperative
­history and physical examination focus on the airway and
symptoms related to systems affected by rheumatoid arthri-
tis (neurologic, pulmonary, cardiovascular). Advanced
planning is anticipated for identified or potentially difficult
intubation.
n In Goodpasture's syndrome, patients at risk for perioper-
ative renal failure have pre-existing renal insufficiency or
diabetes or require contrast procedures. ­Dialysis-dependent
patients require careful coordination of dialysis and ­elective
surgery.
n Preoperative evaluation of male patients with breast can-
cer is similar to that of female breast cancer patients and
should focus on the heart, lungs, and neurologic and hema-
tologic systems.
n In patients with primary hepatic lymphoma, degree of
hepatic dysfunction and infection risk must be determined
preoperatively.
n In patients with suspected Creutzfeldt-Jakob disease, any
tissue or body fluid is potentially infectious, and precau-
tions should be taken to prevent transmission.
Elderly surgical patients are subject to many of the same rare
diseases seen in younger populations. The focus in this c­ hapter
is on several uncommon diseases that are more unique to aged
individuals.
HUNTINGTON'S CHOREA (HUNTINGTON'S
DISEASE)
Huntington's chorea is a rare, autosomal dominant, inher-
ited degenerative disorder of the nervous system with an inci-
dence of 5 to 10 per 100,000 population. It is characterized
by the clinical hallmarks of progressive chorea and dementia.
573
 574 ANESTHESIA AND UNCOMMON DISEASES
The onset is usually in the fourth or fifth decade of life, but
there is a wide range in age at onset, from childhood to late
life (>75 years). Symptoms appear to worsen progressively
with age.
Pathophysiology. Huntington's disease is an a­utosomal
dominant disorder with complete penetrance. The H ­ unting­ton's
disease gene, IT15, is located on chromosome 4p, contains
CAG-trinucleotide repeats, and codes for a protein called
huntingtin. The protein is found in neurons throughout the
brain; its normal function is unknown. Transgenic mice with
an expanded CAG repeat in the Huntington's disease gene
develop a progressive movement disorder. It is a basal ganglia
disease; caudate and putamen are the regions most severely
affected. The most significant neuropathologic change is a
preferential loss of medium-spiny neurons in the neostriatum.
Neurochemically, there is a marked decrease of γ-aminobutyric
acid (GABA) and its synthetic enzyme glutamic acid decar-
boxylase throughout the basal ganglia, as well as reductions
of other neurotransmitters (e.g., substance P, enkephalin). The
movement disorder is slowly progressive and may eventually
become disabling.
Diagnosis and Differential. The DNA-repeat expansion
forms the basis of a diagnostic blood test for the disease gene.
Patients having 38 or more CAG repeats in the Huntington's
disease gene have inherited the disease mutation and will
eventually develop symptoms if they live to an advanced age.
Each of their children has a 50% risk of also inheriting the
abnormal gene; a larger number of repeats is associated with
an earlier age at onset. Huntington's can also be diagnosed by
caudate atrophy on magnetic resonance imaging (MRI) in the
context of an appropriate clinical history.
Differential diagnosis of Huntington's disease includes
other choreas, hepatocerebral degeneration, schizophrenia
with tardive dyskinesia, Parkinson's disease, Alzheimer's dis-
ease, and other primary dementias and drug reactions.
Preoperative Preparation. Even though memory in
patients with Huntington's chorea is frequently not impaired
until late in the disease course, attention, judgment, aware-
ness, and executive functions may be seriously deficient
at an early stage. Depression, apathy, social withdrawal,
­irritability, ­fidgeting, and intermittent disinhibition are com-
mon. Delusions and obsessive-compulsive behavior may
occur. These signs, along with poor articulation of speech,
make preoperative evaluation and obtaining consent arduous
tasks. Characteristic choreoathetoid movements, along with
­frequent, irregular, sudden jerks and movements of any of the
limbs or trunk, make physical examination, as well as regional
anesthesia, difficult to perform.
Cachexia and frailty may be observed in the elderly
Huntington's patient. Pharyngeal muscle involvement leads
to dysphagia and makes these patients susceptible to pulmo-
nary aspiration.1 Before elective surgery, it is important to rule
out ongoing aspiration pneumonitis or pneumonia by careful
physical examination and chest radiography.
There is no specific treatment to stop progression of
Huntington's disease, but the patient's movements and
behavioral changes may partially respond to phenothiazines,
haloperidol, benzodiazepines, or olanzapine. Selective sero-
tonin reuptake inhibitors (SSRIs) may help with associated
depression.
ANESTHETIC CONSIDERATIONS
Major concerns in anesthetic management of Huntington's
disease are potential difficult airway, sleep apnea, risk of aspi-
ration, and altered reactions to various drugs. A ­difficult
airway may result from a rigid, stiff, unstable posture with
­hyperextension of the neck. Sleep apnea may also be present.
It is controversial whether the pharmacology of a­nesthetic
agents is altered in Huntington's disease. Authors have
reported a decrease in plasma cholinesterase activity and a
prolonged effect of succinylcholine.2 In addition, patients may
have an exaggerated response to sodium thiopental3 or mid-
azolam.4 On the other hand, both thiopental5 and succinyl-
choline5,6 have been used safely in Huntington patients. Other
agents used safely include propofol7 and sevoflurane.5 The
safety profile and pharmacokinetics of the nondepolarizing
muscle relaxants mivacurium and rocuronium are similar to
those in patients without Huntington's disease.5,8,9
It is generally recommended that rapid-sequence or
modified rapid-sequence induction with cricoid pressure
be used for induction of general anesthesia in Huntington
patients. Others suggest a total intravenous anesthesia (TIVA)
­technique to reduce the risk of postoperative shivering related
to inhalational agents and thus avoid initiating generalized
tonic spasms.
AMYLOIDOSIS
Amyloidosis results from the deposition of insoluble, f­ ibrillar
proteins (amyloid), mainly in the extracellular spaces of organs
and tissues in amounts sufficient to impair normal func-
tion. Amyloid fibrils can be deposited locally or may involve
­virtually every organ system of the body. Symptoms and signs
depend on the organs and tissues involved.
Pathophysiology. The cause of amyloid production and its
deposition in tissues is unknown. All amyloid fibrils share an
identical secondary structure, the β-pleated sheet conforma-
tion. The polypeptide backbone of these protein precursors
assumes similar fibrillar morphology that renders them resis-
tant to proteolysis. The amyloidoses have been classified into
many subtypes,10 based on the amyloid protein involved. The
name of the amyloidosis subtype uses the capital letter A as
the first letter of designation and is followed by the protein
­designation. Three major types of amyloid and several less
common forms have been defined biochemically.
Whether an amyloidosis is systemic or localized (organ
limited) depends on the biochemical structure of the amy-
loid protein. Systemic amyloidoses include biochemically
distinct forms that are neoplastic, inflammatory, genetic, or
 Chapter 20  The Geriatric Patient 575

iatrogenic, whereas localized or organ-limited amyloidoses
are associated with aging and diabetes and occur in ­isolated
organs, often endocrine, without evidence of ­ systemic
involvement. Despite their biochemical differences, the var-
ious amyloidoses have similar pathophysiologic features
(Table 20-1).
The three major systemic clinical forms currently recog-
nized are primary or idiopathic amyloidosis (AL), secondary
amyloidosis (AA), and hereditary amyloidosis (Table  20-2).
The most common form of systemic amyloidosis seen in cur-
rent clinical practice is AL (light-chain amyloidosis, primary
idiopathic amyloidosis, or associated with multiple myeloma).
A fourth type of systemic amyloidosis is seen only in patients
with long-standing dialysis.
Diagnosis and Differential. Symptoms and signs of amy-
loidosis vary depending on the involved systems and organs.
The nephritic syndrome is the most striking early manifesta-
tion. The renal lesion is usually not reversible and p
­ rogressively
leads to azotemia and death.
Regardless of etiology, the clinical diagnosis of amyloidosis
is usually not made until the disease is far advanced, because
of its nonspecific symptoms and signs. The diagnosis is made
by identification of amyloid fibrils in biopsy or n
­ ecropsy ­tissue
sections using Congo red stain. A unique protein (member of
the pentraxin family of proteins) called AP (or serum AP)
is universally associated with all forms of amyloid and forms
the basis of a diagnostic test. Once amyloidosis is diagnosed,
it can be further classified by genomic DNA, protein, and
immunohistochemical studies; the r­elationship of immu-
­
noglobulin-related amyloid to multiple myeloma should be
confirmed by electrophoretic and i­mmunoelectrophoretic
studies.
Preoperative Preparation and Treatment. A comprehen-
sive survey of all systems should be performed, focusing on
the most frequently involved organs. Careful evaluation for
systemic involvement of amyloidosis or associated disease is
important, even in apparently isolated tumorous amyloidosis
(Table 20-3).

TABLE 20-1  n  Amyloidosis: Multisystem Involvement and Clinical Features

Involvement Manifestations

Nervous system
Polyneuropathy Sensory loss, carpal tunnel syndrome, myopathy, myelopathy, vitreous opacities
Autonomic neuropathy Postural hypotension, inability to sweat, sphincter incompetence
Respiratory system
Upper respiratory tract Localized tumor can be found in respiratory tracts and lungs
Nasal sinuses, larynx, and trachea Tracheobronchial lesions, or diffuse alveolar deposits
Tongue Macroglossia
Lower respiratory tract and lung parenchyma Accumulation of amyloid, which block the ducts; may resemble a neoplasm
Cardiovascular system
Conduction system Arrhythmia, heart block
Endocardium and valves Valvular diseases
Myocardium Cardiomyopathy: dilated, restrictive, and obstructive forms; congestive heart failure
Pericardium Pericarditis
Gastrointestinal system
Liver Hepatomegaly, abnormal liver function, portal hypertension
Gastrointestinal tract Unexplained GI disease, malabsorption; unexplained diarrhea or constipation; obstruction,
ulceration, and protein loss; esophageal motility disorders

Kidney Nephrotic syndrome, proteinuria, renal failure; renal tubular acidosis or renal vein
thrombosis
Spleen Spleen enlargement; not associated with leukopenia or anemia
Musculoskeletal system Pseudomyopathy; cystic bone lesions
Endocrine system
Thyroid gland Hypothyroidism; full-blown myxedema (almost invariably accompanies medullary
carcinoma of thyroid)
Adrenal gland Type II diabetes
Pituitary gland, pancreas Other endocrine abnormalities
Skin Lichen amyloidosis; papules; plaques; ecchymoses
Hematologic system Fibrinogenopenia, including fibrinolysis
Endothelial damage Selective deficiency of clotting factors (factor X)
Clotting abnormalities, abnormal bleeding time
Other Rheumatoid arthritis; chronic inflammation and infection
 576 ANESTHESIA AND UNCOMMON DISEASES
TABLE 20-2  n  Major Systemic Amyloidosis: Clinical Features and Diagnosis
Primary (AL)*
Organs typically Localized amyloid tumors may be
involved found in respiratory tract.
Vascular system, especially heart
Other organs: tongue, thyroid gland,
heart, lung, liver, intestinal tract,
spleen, kidney, skin
Associated Multiple myeloma
diseases
Diagnosis Monoclonal immunoglobulin in urine
or serum plus any of following:
macroglossia, cardiomyopathy,
hepatomegaly, malabsorption or
unexplained diarrhea or
constipation, unexplained nephrotic
syndrome, carpal tunnel syndrome,
or peripheral neuropathy
*or Idiopathic.
†or Secondary, acquired, reactive.
TABLE 20-3  n Amyloidosis: Preoperative Assessment
and Workup
System Assessment
Nervous Peripheral neuropathy: document
pre-existing peripheral neurologic
symptoms
Autonomic neuropathy: orthostatic blood
pressure, etc.
Airway Macroglossia
Pulmonary Diffuse dysfunction: pulmonary function
studies
Cardiac Arrhythmia, cardiomyopathy, and
valvular involvement: cardiac function
echocardiogram and electrocardiogram
Gastrointestinal Esophageal motility abnormality,
intestinal obstruction
Liver Liver function studies
Kidney Abnormal renal function: electrolytes,
renal function studies
Hematology Enlarged spleen; check CBC: RBCs,
platelets, coagulation coagulopathy,
and factor deficiency
Endocrine Pancreatic or adrenal gland involvement;
thyroid function test to rule out
hypothyroidism
Secondary (AA)† Hereditary
Spleen, liver, kidney, adrenal glands, Peripheral sensory and motor
lymph nodes; vascular involvement neuropathy, often autonomic
No organ spared, but significant neuropathy
involvement of the heart is rare Carpal tunnel syndrome
Vitreous abnormalities
Cardiovascular and renal amyloid
Infection (tuberculosis, bronchiectasis,
osteomyelitis, leprosy)
Inflammation (rheumatoid arthritis,
granulomatous ileitis)
Familial Mediterranean fever
Tumors such as Hodgkin's disease
Chronic infection (osteomyelitis, Family history of neuropathy
tuberculosis), chronic plus any of following: early
inflammation (rheumatoid arthritis, sensorimotor dissociation,
granulomatous ileitis) plus any vitreous opacities,
of following: hepatomegaly, cardiovascular disease,
unexplained GI disease, or GI disease, autonomic
proteinuria neuropathy, or renal disease
Treatment of localized amyloid tumors is surgical exci-
sion. However, no effective treatment exists for systemic amy-
loidosis. Currently, care is generally supportive, and therapy
is directed at reducing production of and promoting lysis of
amyloid fibrils. Hemodialysis and immunosuppressive ther-
apy may be useful. Current treatment of primary amyloidosis
includes a program of prednisone/melphalan or prednisone/
melphalan/colchicine. Liver transplantation, kidney trans-
plantation, and stem cell transplants have yielded promising
results. In certain familial amyloidoses, genetic counseling is
an important aspect of treatment.
Ultimately, some people with amyloidosis continue to
deteriorate. The major causes of death are heart disease and
renal failure. Sudden death is common, presumably caused by
arrhythmias.
ANESTHETIC CONSIDERATIONS
Localized amyloid deposition has been reported at ­various
sites. Amyloid in the tongue can cause macroglossia to a degree
requiring glossectomy.11 In addition, amyloid macroglossia
may be associated with coexisting hypothyroidism.12 Laryngeal
amyloidosis is fragile and carries the risk of ­spontaneous
massive hemorrhage, even without m
­ ­ anipulation.13 The
­airway tumor should be assessed by noninvasive ­imaging, such
as computed tomography (CT) or MRI. Before i­ntubation,
­preparations should be made for both difficult airway and
massive hemorrhage.
A smaller endotracheal tube (ETT) may be ­considered. In
addition, direct laryngoscopy monitored by a fiberscope-video

system, rather than blind insertion of the ETT through vocal
cords over a fiberoptic bronchoscope,14 has been advocated.
It is controversial whether depolarizing muscle relaxants
should be administered to patients with amyloidosis, especially
those with cardiac involvement. Patients with familial amyloid
polyneuropathy have a high incidence of cardiac arrhythmias
during anesthesia. Exaggerated elevations in potassium con-
centration may occur after succinylcholine administration and
may be a contributing factor.15 However, Viana et al.16 reported
that the average increase in plasma potassium concentrations
after succinylcholine administration in patients with familial
amyloid polyneuropathy was similar to the increase observed
in a normal population. However, they could not exclude that
a dangerous rise in serum potassium concentration might not
occur in a certain percentage of patients with familial amy-
loid after administration of succinylcholine. This may also be
true in patients with amyloidosis who also have long-standing
polyneuropathy.17 Thus, it may be prudent to avoid admin-
istration of depolarizing muscle relaxants in patients with
amyloidosis, especially in the presence of coexisting polyneu-
ropathy or cardiac disease.
Autonomic dysfunction secondary to ­ amyloidosis has
dramatic perioperative ramifications.17 In particular, the
­ patients.
administration of anesthetic drugs to patients with ­amyloidotic
polyneuropathy presents a risk of significant hypotension (even
use of ketamine does not prevent hypotension). Patients with
decreased preload are especially sensitive. In addition, hypo-
tension is frequent even in patients with adequate p ­ reload
as a result of low systemic vascular resistance. Given these
­observations, the anesthesiologist should consider using inva-
sive blood pressure monitoring and preparation of a vasocon-
strictor infusion for effective anesthetic management of these
patients.
IDIOPATHIC PULMONARY FIBROSIS
The pathophysiology of idiopathic pulmonary fibrosis (IPF)
is not currently understood. IPF may represent a model of
chronic dysregulated repair and lung remodeling, resulting
from an epithelial/endothelial insult and persistent inflam-
matory cell activation.18 The initial injury event remains
undefined. However, evidence suggests that viral infections
or environmental factors may provide mediating events.
Interestingly, a majority of patients with IPF have a smoking
history.
Symptoms associated with IPF include breathlessness,
fatigue, weight loss, and a chronic dry cough. On physical
examination, dry “Velcro” crackles may be heard throughout
the lung fields. Cyanosis and clubbing may also be observed.
As the disease progresses, signs of pulmonary hypertension
and right-sided heart failure (loud S2 heart sound, right ven-
tricular heave, or pedal edema) may be present.
A chest radiograph may show interstitial infiltrates in
the lung bases. CT is more sensitive than a chest radiograph
for detecting disease early. Typically, CT shows a pattern of
patchy white lines in the lower lungs. In areas of more severe
Chapter 20  The Geriatric Patient 577
involvement, the thick scarring often creates a honeycomb
appearance. Pulmonary function studies show a restrictive
pattern. Arterial blood gas (ABG) analysis may show hypox-
emia with minimal exercise and, as the disease progresses,
even at rest. However, the definitive test to confirm diagnosis
of IPF is lung biopsy.
The diagnosis of idiopathic pulmonary fibrosis should be
reserved for patients with a specific type of fibrosing inter-
stitial pneumonia known as usual interstitial pneumonia.
Foremost in the differential diagnosis is to distinguish usual
interstitial pneumonia from other idiopathic interstitial pneu-
monias. This distinction is made on a pathologic basis.19
Numerous other disease processes may lead to IPF and
should be ruled out as diagnoses (Box  20-1). Fibroses may
occur as a result of occupational or environmental exposure
to toxic substances, lung infection, drug exposure, connective
tissue disease, and sarcoidosis.
Idiopathic pulmonary fibrosis may be associated with
respiratory failure and chronic hypoxemia in the later stages.
Polycythemia also occurs in this context. Cor pulmonale
should be specifically sought in evaluation of these patients.
Incidence of bronchogenic carcinoma is increased in IPF
BOX 20-1   n  IDIOPATHIC PULMONARY FIBROSIS
Symptoms: Breathlessness; dry cough; weight loss; fatigue
Physical findings: Change in shape of fingers and toenails (clubbing);
cyanosis (late stages of disease); dry “Velcro” crackles throughout
lung fields on auscultation
Differential Diagnosis
Pathologic distinction from other types of fibrosing interstitial
pneumonia:
n Desquamative interstitial pneumonia (respiratory bronchitis,
interstitial lung disease)
n Acute interstitial pneumonia
n Nonspecific interstitial pneumonia
n Cryptogenic organizing pneumonia (bronchiolitis obliterans,
organizing pneumonia)
Pulmonary fibrosis resulting from occupational or environmental
exposure: asbestosis, silicosis, farmer's lung, bird breeder's lung;
exposure to metal dust, bacteria, fumes, animals, other dusts, or
gases
Fibrosis resulting from infection: tuberculosis; pneumococci;
Pneumocystis jiroveci (P. carinii); bacterial, fungal, viral pneumonia
Drug exposure: bleomycin
Connective tissue disease: rheumatoid arthritis, systemic sclerosis
Sarcoidosis
Comorbidities: Respiratory failure, chronic hypoxemia, cor pulmonale,
polycythemia, increased incidence of lung cancer
Critical Questions
n Is the patient approaching end-stage disease?
n Is there a history of respiratory failure?
n Is there a need for home oxygen?
n Are there any signs and symptoms of chronic hypoxemia?
n Is there any evidence of cor pulmonale?
Chronic medications: Corticosteroids, cyclophosphamide (Cytoxan),
oxygen, colchicine
 578 ANESTHESIA AND UNCOMMON DISEASES
The critical questions to ask the patient and family
­ hysician should focus on determining how advanced the
p BOX 20-2   n  POLYCYTHEMIA VERA
­disease has become and how much pulmonary reserve is
present (see Box 20-1). In appropriate patients, the clinician
should assess for the long-term complications of corticoste-
roid administration.
At present, the therapeutic options available to treat patients
with IPF are limited (see Box 20-1). Many patients receive cor-
ticosteroids or immunosuppressants despite no studies clearly
documenting their efficacy. Many patients require home
oxygen.
ANESTHETIC CONSIDERATIONS
Typical surgical procedures where the anesthesiolo-
gist may encounter idiopathic pulmonary fibrosis include
open or ­ thoracoscopic lung biopsy and lung transplan-
tation. In these procedures, one-lung ventilation is often
required. Therefore, the major anesthetic consideration is
the inability to tolerate one-lung ventilation secondary to
hypoxemia or the ­generation of high airway pressures.20 In
addition, hypercapnia may occur in these patients during
one-lung ventilation.21 An arterial catheter is indicated when
­anesthetizing these patients, because frequent ABG studies
may be required. In addition, central venous access should
be strongly considered.
These patients may generate large negative intrathoracic
pressures during spontaneous ventilation. Therefore, special
care must be taken to prevent air emboli during placement
of the central line. Access to inhaled nitric oxide should be
available for patients with cor pulmonale.22 In patients with
­limited pulmonary reserve, regional or local anesthesia should
be ­considered if the surgical procedure permits.
POLYCYTHEMIA VERA
Polycythemia vera is a clonal stem cell disorder in which all
three myeloid components are involved. Erythrocytosis is
the foremost expression of the disease. Studies suggest that
impaired signaling of hematopoietic growth factors may be
an underlying pathophysiologic mechanism of polycythemia
vera.23,24
Patients with polycythemia vera are prone to both throm-
botic and hemorrhagic events. The mechanisms underlying
thrombotic complications may be related to the increased
red blood cell (RBC) mass.24 An elevated hematocrit (Hct)
increases both blood viscosity and RBC aggregation, inducing
a hypercoagulable state.23 Hemorrhagic events are associated
with elevations in absolute platelet count. Defects in platelet
function have been reported in polycythemia vera. In addi-
tion, an acquired von Willebrand's disease occurs with elevated
platelet counts in myeloproliferative syndromes. This acquired
von Willebrand's disease is characterized by decreased large
von Willebrand multimers and increased cleavage products.24
Polycythemia can evoke both general symptoms and
those secondary to underlying thrombotic or hemorrhagic
pathologic processes. General symptoms include bone pain
Symptoms
General: Headaches, tinnitus, fatigue, shortness of breath, pruritus
(aquagenic), tingling or burning of hands and feet, visual changes,
bone pain, weight loss, night sweats, vertigo
Thrombotic: Cerebrovascular accident (stroke), myocardial infarction,
angina, intermittent claudication
Hemorrhagic: Bleeding diathesis, GI bleeding, unusual bleeding from
minor cuts, epistaxis
Physical findings: Splenomegaly (later stages), hepatomegaly, retinal
vein engorgement, ruddy complexion, hypertension
Differential Diagnosis
Is there an underlying decrease in tissue oxygenation secondary
to lung disease, high altitude, intracardiac shunt, hypoventilation
syndromes, abnormal hemoglobin, smoking, or carbon monoxide
poisoning?
Is there aberrant erythropoietin production secondary to tumors
(brain, liver, uterus) or cysts (especially renal)?
Has hemoconcentration occurred secondary to diuretics, burns,
diarrhea, or stress?
Comorbid Conditions
Hemorrhagic: gastric ulcer, epistaxis
Thrombotic: Budd-Chiari syndrome; cerebral, coronary, mesenteric, or
pulmonary thrombosis
Other: gout
Critical Questions
n Does the patient undergo phlebotomy?
n Is
the patient on myelosuppressive therapy?
n What are the most recent hematocrit and platelet counts?
n What are the results of the most recent coagulation studies?
Chronic medications: Cytoreductive drugs, including 32P; alkylating
agents (chlorambucil, busulfan), hydroxyurea, interferon-α,
paroxetine, aspirin
Anesthetic Management
Ensure adequate access and availability of blood products, including
platelets.
Use of regional techniques is controversial.
and tingling or burning of the hands and feet (Box 20-2). In
addition, exposure to warm water may provoke an intense
pruritus. Patients may initially present with ischemic or
­
thrombotic ­vascular symptoms, including stroke, intermittent
claudication, or angina. Signs of a bleeding diathesis can also
be ­present, such as epistaxis or gastrointestinal (GI) bleeding.
On physical examination a ruddy complexion or pleth-
ora may be noted. Polycythemia vera is also associated with
hypertension. Patients may complain of visual changes, and
retinal vein engorgement may be noted. Hepatomegaly and
splenomegaly occur late in the course of the disease.
Alternative conditions that should be considered when
presented with a polycythemic patient include any underlying
mechanism that decreases blood oxygenation. Aberrant eryth-
ropoietin production may cause polycythemia. Polycythemia
may also result from hemoconcentration. The comorbidities
observed with polycythemia vera may be of a hemorrhagic or
thrombotic nature (Box 20-2). In addition, gout often occurs
in these patients.

Preoperative Preparation. Before surgery, it is important to
ascertain how the elevated RBC mass has been treated, if at all.
Phlebotomy is an effective remedy for the hypercoagulability
observed with polycythemia vera. A recommended therapeu-
tic end point is Hct less than 42% in women and 45% in men.25
Optimally, Hct should be normalized 2 to 4 months before
elective surgery. Patients older than 60 years or with a previous
thrombotic episode are defined as “high risk.” These individu-
als may also receive cytoreductive treatment in an attempt to
aggressively treat the disease. Perioperative risk of thrombotic
or hemorrhagic events is influenced by how aggressively the
polycythemia has been treated. Thus, it is important to obtain
a history of the platelet counts and Hct values to determine
past treatment of the disease. Coagulation studies, including
bleeding time, should be obtained before surgery.
Cytoreductive agents are administered in high-risk patients.
Aspirin is often used as adjunctive therapy, even in low-risk
individuals. Patients with severe pruritus may be treated with
interferon-α or paroxetine (see Box 20-2).
ANESTHETIC CONSIDERATIONS
Uncontrolled polycythemia vera is associated with a high
risk of perioperative bleeding and postoperative thrombosis.
Control of the disease before surgery will reduce the incidence
of these complications.
It is important to ensure adequate vascular access in case
bleeding occurs. In addition, the ready availability of platelet
transfusion should be ensured in larger blood loss cases. At
present there is insufficient evidence to determine whether
antiplatelet drugs are contraindicated during the periopera-
tive management of the polycythemic patient.
The use of regional versus general anesthesia is controver-
sial. Both techniques have been used successfully in patients
with polycythemia vera. Studies suggest a lower incidence
of deep vein thrombosis with regional techniques. However,
this moderate effect must be weighed against the risk of
­epidural or subarachnoid hemorrhage in a patient who may
be ­predisposed toward bleeding events.
ESSENTIAL THROMBOCYTHEMIA
The World Health Organization (WHO) has defined essential
thrombocythemia as a sustained platelet count of greater than
600,000 cells/mm3 with a bone marrow biopsy showing mainly
proliferation of the megakaryocytic lineage. In addition,
patients must show no evidence of polycythemia vera, chronic
myeloid leukemia, idiopathic myelofibrosis, ­myelodysplastic
syndrome, or reactive thrombocytosis.26
The principal feature of essential thrombocythemia is an
increase in megakaryocytes and platelets. Disease patho-
genesis more than likely involves alterations in the signaling
­pathways that regulate thrombopoiesis.
The principal pathophysiologic features of essential thrombo-
cytosis are thrombosis and hemorrhage. Thrombosis may involve
the microcirculation or large-vessel ­occlusions, ­predominantly
of the arteries. The incidence rate is approximately 8% per
Chapter 20  The Geriatric Patient 579
patient-year in untreated patients.27 Hemorrhagic complications
only occur with very high platelet counts and are ­secondary to
abnormal platelet function.
Symptoms of essential thrombocythemia are associated
with vasomotor changes in the cerebral and peripheral circu-
lation, including headache, transient ischemic attacks (TIAs),
or migraines (Box  20-3). The principal clinical features of
essential thrombocythemia are thrombosis affecting the arte-
rial more frequently than venous circulation and hemor-
rhage. Major arterial thrombosis may include both stroke and
peripheral arterial occlusion. The most common presentation
of bleeding involves the GI tract, although bleeding may occur
from the skin, gums, and nose.
Patients may present with splenomegaly and hepatomegaly
secondary to extramedullary hematopoiesis. In the peripheral
circulation, acrocyanosis and erythromelalgia are common
complaints. Erythromelalgia is characterized by burning pain
and erythema of the digits, especially of the lower extremity.
Of note, the pain associated with essential thrombocytopenia
increases with heat and improves with cold. Likewise, ­pruritus
may occur in the extremities when exposed to warmth but
improves with colder temperatures.
BOX 20-3   n  ESSENTIAL THROMBOCYTHEMIA
Signs: Splenomegaly; digital pain that increases with heat, improves
with cold; sweating, pruritus, low-grade fever, hepatomegaly;
bleeding from skin, gums, or nose
Symptoms
Vasomotor symptoms of cerebral circulation: Headache, dizziness,
visual disturbances, TIAs, migraines
Vasomotor symptoms of peripheral circulation: Paresthesias,
acrocyanosis, erythromelalgia
Thrombotic symptoms: Venous thrombotic events, superficial
thrombophlebitis, deep vein thrombosis, portal or splenic venous
thrombosis, major arterial thrombosis, including stroke
Hemorrhagic symptoms: Bleeding diathesis, especially GI bleeding
Differential Diagnosis
Clonal thrombocytosis: Associated with other chronic
myeloproliferative disorders
Reactive thrombocytosis: Acute bleeding, hemolysis, iron deficiency
anemia, acute and chronic inflammatory conditions (e.g., arthritis,
stress, surgery), osteoporosis, metastatic cancer, severe trauma,
splenectomy, medication
Critical Questions
n Does patient have a history of previous thrombosis? Platelet
count? Obesity? Smoking? Age?
n Any evidence of ongoing bleeding?
n How has the platelet count been managed?
Chronic medications: Cytoreductive drugs, including hydroxyurea,
anagrelide, interferon-α, or 32P; low-dose aspirin
Anesthetic Management
Platelet counts should be normalized before surgery.
Consider plateletpheresis in emergency situations to achieve a rapid
decrease in platelet count.
Administer cytoreductive therapy to decrease platelet count before
surgery.
 580 ANESTHESIA AND UNCOMMON DISEASES
In particular, two differential diagnoses should be consid-
ered when encountering a patient with essential thrombocyto-
sis (see Box 20-3). First, essential thrombocytosis may represent
part of a continuum of the myeloproliferative disorders. Over
the course of time patients with essential thrombocytosis may
develop myelofibrosis, myelodysplastic syndrome, or acute
myelocytic leukemia. In addition, both polycythemia vera and
myelofibrosis may present as thrombocytosis. Second, reactive
thrombocytosis must be ruled out. Numerous conditions, both
acute and chronic, may produce thrombocytosis.
The comorbidities of interest to the anesthesiologist that
occur with essential thrombocytosis are associated with the
complications of hemorrhage and thrombosis.
The clinician must first assess a patient's risk of throm-
bosis (Box 20-3). Studies show that the primary risk factors
for a thrombotic event are history of previous thrombosis
and age. Other, less significant risk factors include a history
of smoking and obesity. Retrospective studies show that the
­incidence of thrombotic events per year is 1.7%, 6.3%, and
15.1%, at younger than 40 years, 40 to 60 years, and older
than 60 years, respectively.28 In addition, the incidence rate
of thrombosis has been reported at 31.4% and 3.4% per year
in patients with and without a history of previous throm-
bosis. The absolute platelet count cannot provide a defini-
tive assessment of t­ hrombotic risk. Thrombotic events have
been reported with platelet counts in the range of 400,000 to
600,000/mm3.29 Although the platelet count does not neces-
sarily predict the risk of thrombosis, evidence suggests that
controlling the platelet count does decrease the incidence
of thrombosis. Prospective studies comparing long-term
risk of thrombosis in patients treated with myelosuppres-
sive ­therapy versus those without found incidence rates of
8% versus 1.5% per patient-year in untreated and treated
patients, respectively.27 Thus, the degree of controlling the
platelet count assumes importance in assessing thrombotic
risk. The main risk factor for ­hemorrhage is a platelet count
greater than 1.5 million/mm3.25
Treatment of essential thrombocytosis consists of chronic
myelosuppressive therapy to manage the platelet count in
high-risk individuals. Antiplatelet drugs may also be included
in the regimen. Low-dose aspirin has been shown to be effica-
cious in managing both erythromelalgia and TIAs associated
with essential thrombocytosis.30
ANESTHETIC CONSIDERATIONS
The most important issue in perioperative management of
the patient with essential thrombocythemia is whether to
normalize the platelet count before surgery. No clear guide-
lines exist as to which patients should be aggressively nor-
malized preoperatively, and consultation with a hematologist
should be pursued. However, elderly patients with consistently
­elevated platelet counts and a history of prior thrombosis
­represent a high-risk group requiring aggressive management.
Elective surgical patients may have adequate time to undergo
­cytoreductive therapy preoperatively. In the case of urgent or
­emergency surgery, plateletpheresis may be considered.
MYELOID METAPLASIA WITH
MYELOFIBROSIS
The intrinsic characteristics of this metaplasia include both
myeloproliferation and myelofibrosis. It is currently hypoth-
esized that dysregulated Janus kinase (JAK) signaling may be
an underlying etiology for myelofibrosis.
Myeloid metaplasia with myelofibrosis may present in a
variety of ways. Constitutional symptoms may relate to the
catabolic aspects of this disease and include cachexia, fatigue,
weight loss, low-grade fever, and night sweats (Box  20-4).
Extramedullary hematopoiesis may evoke a constellation of
symptoms and signs. The most common presenting ­feature
is hypersplenism. Extramedullary hematopoiesis may also
occur in other organ systems such that lymphadenopathy,
acute cardiac tamponade, hematuria, papular skin nodes,
­pleural ­effusion, pulmonary hypertension, and spinal cord
­compression may be observed. Of note, patients with pulmo-
nary hypertension have a poor prognosis.
From 50% to 75% of patients are anemic at diagnosis,
whereas the white blood cell (WBC) count and platelet count
initially may be either increased or decreased. An early find-
ing on peripheral blood smear, myelophthisis, is characterized
by teardrop-shaped RBCs, immature granulocytes, and nucle-
ated RBCs. Several disorders are also associated with myelo-
phthisis and possible myelofibrosis (Box 20-4). Therefore, the
­differential diagnosis must include other malignancies, such
as chronic myeloid leukemia, myelodysplastic syndrome,
­metastatic cancer, lymphoma, Hodgkin's disease, and plasma
BOX 20-4   n MYELOID METAPLASIA WITH
MYELOFIBROSIS
History: Constitutional symptoms, including weight loss, night
sweats, and low-grade fever
Physical findings: Splenomegaly, anemia, pallor, petechiae and
ecchymosis, gout
Findings related to extramedullary hematopoiesis: Acute cardiac
tamponade, hematuria, lymphadenopathy, papular skin nodes,
pleural effusion, spinal cord compression
Laboratory findings: Anemia, WBC count increased or decreased,
platelet count increased or decreased, myelophthisis
Differential Diagnosis
Malignancies that may display bone marrow fibrosis
Essential thrombocythemia
Granulomatous involvement of bone marrow (e.g., histoplasmosis,
tuberculosis)
Associated Conditions
Portal hypertension
Splenic infarction
Complications related to extramedullary hematopoiesis
Anesthetic Management
Obtain CBC and platelet count.
Consider cytoreductive therapy in patients without significant
thrombocytopenia.
Bleeding may require platelet transfusion or cryoprecipitate.
Obtain DIC panel.

cell dyscrasia. Granulomatous involvement of the bone ­marrow
may cause myelofibrosis. Thus, tuberculosis and histoplasmo-
sis must also be entertained as possible diagnoses. In patients
presenting with elevated platelet counts and minimal myelofi-
brosis, it may be difficult to exclude the diagnosis of essential
thrombocythemia.
The conditions commonly associated with myelofibrosis
and myeloid metaplasia result from the underlying pathophys-
iology. Portal hypertension may result from either increased
portal flow secondary to splenomegaly or thrombotic obstruc-
tion of small hepatic veins.
ANESTHETIC CONSIDERATIONS
The greatest experience in perioperative management of
myelofibrosis and myeloid metaplasia has occurred with sple-
nectomy. Indications for splenectomy include splenomegaly
refractory to chemotherapy, portal hypertension, or progres-
sive anemia. Morbidity and mortality after this procedure
have been reported at 30.5% and 9%, respectively.31 Significant
perioperative complications after splenectomy include hemor-
rhage (14.8%), infection (8.5%), and thrombosis (7.5%). The
primary cause of death includes hemorrhage (4.5%), infection
(2.7%), and thrombosis (1.3%). The only preoperative variable
that correlates with increased hemorrhage or thrombosis is a
platelet count of less than 100,000/mm3.
With this experience in mind, the critical information
and interventions before surgery would include a complete
blood cell count (CBC) and platelet count. In patients without
thrombocytopenia, prophylactic cytoreductive therapy should
be considered to reduce the risk of perioperative thrombosis.
Adequate blood products should be available before ­surgery,
including access to platelets and cryoprecipitate. Occult
­disseminated intravascular coagulation (DIC) has been asso-
ciated with perioperative bleeding, so a preoperative DIC
panel should be performed. Splenectomy should be postponed
in patients with d-dimer levels greater than 0.5 μg/mL.31
POLYMYALGIA RHEUMATICA
Patients with polymyalgia rheumatica are classically older
than 50 years (90% older than 60), and most are Caucasian.32
It is a syndrome characterized by pain and morning stiffness
in the neck, shoulder girdle, and pelvic girdle, with consti-
tutional symptoms such as malaise and fatigue (Fig.  20-1).
Typically the erythrocyte sedimentation rate (ESR) is higher
than 50 and frequently higher than 80 mm/hr. Polymyalgia
rheumatica can occur as a separate entity or in association
with temporal arthritis. Patients who have polymyalgia rheu-
matica dramatically improve with low doses of prednisone
(10-15 mg/day). Once symptoms have resolved and ESR has
normalized, the dose of prednisone is tapered slowly while
the patient is closely monitored for recurrence of symptoms
or increased ESR.
A wide variety of conditions can mimic polymyalgia rheu-
matica.33 When present, distal-limb symptoms may initially
make it difficult to differentiate polymyalgia rheumatica from
Chapter 20  The Geriatric Patient 581
FIGURE 20-1  Untreated hands of patient with polymyalgia
rheumatica.
rheumatoid arthritis (RA) or similar syndromes. Pronounced
symmetric involvement of peripheral joints, seropositivity
for rheumatoid factor, and joint erosions and extra-­articular
manifestations clearly differentiate RA from polymyalgia
­rheumatica. In elderly patients, systemic lupus erythemato-
sus may present as polymyalgia rheumatica.34 The ­presence
of pleuritis or pericarditis (common in late-onset SLE),
­leukopenia or thrombocytopenia, and antinuclear antibodies
should raise the clinical suspicion of SLE. The predominant
­proximal muscular weakness demonstrated with movement,
rather than pain and an increase in muscular enzyme levels,
differentiate polymyositis from polymyalgia rheumatica.35 The
­presence of peripheral enthesitis, dactylitis, anterior uveitis,
and ­radiologic evidence of sacroiliitis differentiate late-onset
spondyloarthropathy from polymyalgia rheumatica.36
ANESTHETIC CONSIDERATIONS
The preoperative history and physical examination should
focus on symptoms related to the many organ systems
affected by RA, in particular the airway and neurologic, pul-
monary, and cardiovascular systems. A careful history may
elicit ­neurologic deficits, neck and upper extremity pain,
and a crunching sound with neck movement. Patients with
neurologic deficits or symptoms of long-standing, severely
deforming disease, or those scheduled to undergo proce-
dures requiring manipulation of the cervical spine or special
positioning (e.g., turning prone), require anteroposterior and
lateral cervical radiographs with special flexion, extension,
and open-mouth odontoid views.37 Significant ­abnormalities
(anterior atlas-dens interval >9 mm or p ­ osterior interval
<14 mm) may benefit from consultation with a ­neurologist
or neurosurgeon. However, the duration, severity, or symp-
toms of the disease do not correlate with cervical spine
subluxation.
Preoperative documentation of deformities and neurologic
deficits is important to establish baseline level of function. For
patients with significant hoarseness, referral to an otolaryn-
gologist to assess mobility of the vocal cords and the degree of
cricoarytenoid arthritis may be of benefit.38 Acute or worsen-
ing pulmonary symptoms may trigger a need for additional
 582 ANESTHESIA AND UNCOMMON DISEASES
pulmonary workup. Muffled heart sounds, pericardial rubs,
and an enlarged heart detected by examination or on a chest
radiograph together with low voltage on an electrocardiogram
(ECG) suggest a pericardial effusion, which can be further
evaluated.
Advanced planning for the management of identified
or potentially difficult intubation should be anticipated and
­discussion of regional anesthetic options undertaken in appro-
priate clinical circumstances. Continuation of steroids and
chronic pain medications is optimal, but drugs with antiplate-
let effects are often discontinued, and immunosuppressants
may need to be temporarily stopped to allow normalization
of blood counts. Patients with complex regimens and severe
disease are best managed in concert with a rheumatologist or
primary physician.
GOODPASTURE'S SYNDROME
Goodpasture's syndrome, or anti–glomerular basement
­membrane (anti-GBM) antibody nephritis, is a rare autoim-
mune disease characterized by formation of anti-GBM anti-
bodies and, in 60% of patients, antibodies to pulmonary
alveolar basement membranes.39 Confirmatory ­ diagnosis
involves the finding of circulating anti-GBM antibodies and,
on immunofluorescent imaging of renal biopsy samples,
severe crescentic glomerulonephritis with linear deposition of
immunoglobulin G on GBMs (Fig. 20-2).
In elderly patients, Goodpasture's syndrome is chiefly
found in women and may not present with overt pulmo-
nary hemorrhage. With extensive crescents, the prognosis
for recovery is poor without aggressive therapy. Treatment
consists of oral cyclophosphamide (in reduced dosage), oral
and intravenous (IV) glucocorticoids, and aggressive plasma
exchange. Circulating antibody levels decrease quickly but
FIGURE 20-2  Nephron in patient with Goodpasture's syndrome
(anti-GBM antibody nephritis).
renal recovery depends on the extent of damage at the time
treatment is begun.39 Dialysis-dependent patients with serum
creatinine of more than 7 mg/dL have only a 10% chance of
recovery. If life-threatening pulmonary hemorrhage is also
present, plasma exchange may be lifesaving.
ANESTHETIC CONSIDERATIONS
Patients with Goodpasture's syndrome at risk for periopera-
tive renal failure include those with pre-existing renal insuf-
ficiency (the single strongest predictor) or diabetes, especially
in combination, and those undergoing procedures with the
administration of contrast medium. If all three conditions
are present, the risk of renal failure may be as high as 12%
to 50%. Preoperative identification of at-risk patients alters
management, such as hydration, administration of sodium
bicarbonate, change in type of contrast medium, and avoid-
ance of hypovolemia. Many clinical trials have failed to
include ­sufficient numbers of elderly persons, making it dif-
ficult to translate therapeutic recommendations. In addition,
the risks of aggressive treatment of glomerular disease may
be enhanced in older patients, which is crucial in therapeutic
decision making.
Drugs with particular implications for anesthesia and
surgery are the low-molecular-weight heparins (LMWHs)
because there is no easy method of monitoring their anti-
coagulation effects. All the LMWHs available in the United
States are cleared by the kidneys and are not removed during
dialysis. Therefore, LMWH may have a prolonged duration
of action in patients with chronic kidney disease, possibly
increasing the risk of bleeding with neuraxial anesthesia.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclo-
oxygenase (COX-2) inhibitors interfere with autoregulation
of renal perfusion and should be avoided or discontinued in
patients with or at risk for renal insufficiency. Cyclosporine
and aminoglycoside antibiotics can cause renal insufficiency.
Angiotensin-converting enzyme (ACE) inhibitors and alpha-
receptor blockers (ARBs) prevent deterioration in patients
with diabetes or renal insufficiency but may worsen function
during hypoperfusion states.
In patients on dialysis, coordinating the scheduling of dial-
ysis and elective surgery is an important aspect of preopera-
tive care. Preoperative renal replacement therapy (dialysis)
schedules should be determined, with scheduling of surgery
ideally within 24 hours after dialysis. In elective cases, dialysis
is best performed within 24 hours of surgery but not immedi-
ately before, because of acute volume depletion and electrolyte
alterations. Dialysis should be performed to correct volume
overload, hyperkalemia, and acidosis.
MALE BREAST CANCER
The incidence of male breast carcinoma in the United States
is 1 per 100,000, almost 150 to 200 times less common than
female breast cancer. The median age of male breast cancer
patients varies between 63 years39 and 70 years. Because of its
infrequent nature and presentation in elderly patients, who

often exhibit typical senile gynecomastia, delays in diagno-
sis by physicians (and delayed recognition of symptoms by
patients) are common.40,41 This is one factor accounting for the
percentage of patients with positive axillary nodes on diagno-
sis (50%) and metastatic disease (80%).
Klinefelter's syndrome is the only known risk factor for
male breast cancer. Presentation is usually with a lump or
retraction of the skin or nipple. Male breast cancers are usu-
ally eccentric masses, whereas gynecomastia is almost always
central. Infiltration of the skin or nipple occurs much earlier
in male breast cancer because of the smaller breast volume.
Mammography is valuable in determining whether breast
enlargement is caused by gynecomastia or breast cancer. When
in doubt, fine-needle aspiration should be performed to estab-
lish a definitive diagnosis. The histology and prognosis for each
tumor stage are similar to those for female breast cancer.
ANESTHETIC CONSIDERATIONS
Preoperative evaluation of male breast cancer patients is simi-
lar to that of female breast cancer patients and should focus
on the heart, lungs, and neurologic and hematologic systems.
Previous head and neck irradiation may cause carotid artery
disease, hypothyroidism, or difficulty with airway manage-
ment.42 Mediastinal, chest wall, or left breast irradiation can
cause pericarditis, conduction abnormalities, cardiomyopa-
thy, valvular abnormalities, and premature coronary artery
disease, even without traditional risk factors.43 Preoperative
neuroimaging, if available, should be reviewed for evidence of
metastasis.
Breast tumors often metastasize to bone and liver. Bone
lesions can result in hypercalcemia or pancytopenia. Lung
metastases can compromise pulmonary function. Paraneoplastic
syndromes can complicate almost any malignancy and may
be associated with hypercalcemia, inappropriate secretion of
antidiuretic hormone, Lambert-Eaton or Cushing's syndromes,
and neuropathy.
PRIMARY HEPATIC LYMPHOMA
The primary hepatic form is a rare presentation of lymphoma
that mainly affects middle-age or older men. The major-
ity of primary hepatic lymphomas are diffuse, large-B-cell
FIGURE 20-3  Computed tomography scan (left) and pathologic specimen (right) of patient with primary hepatic lymphoma.
Chapter 20  The Geriatric Patient 583
lymphomas, and as many as 40% of patients with primary
hepatic lymphoma have an underlying immunologic abnor-
mality, including immunodeficiency caused by human immu-
nodeficiency virus (HIV). Primary hepatic lymphoma has
also been associated with infection with hepatitis B or hepati-
tis C virus and long-standing chronic inflammation caused by
tuberculosis.44–46 Primary hepatic lymphoma is treated similar
to lymphoma at other sites, if the diagnosis can be made before
a liver resection (Fig. 20-3).
ANESTHETIC CONSIDERATIONS
Important issues to explore include the cause and degree of
hepatic dysfunction. The presence of encephalopathy, coag-
ulopathy, ascites, volume overload, and infection risk needs
to be determined preoperatively. New-onset or worsening
encephalopathy is frequently caused by an acute insult such as
infection, GI bleeding, hypovolemia, or sedatives. It is impor-
tant to determine reversible factors and treat accordingly; lact-
ulose is first-line therapy.
Coagulopathy can be a result of vitamin K deficiency caused
by an inability to secrete bile (cholestatic disorders), ­deficiency
of coagulation factors because of loss of s­ynthetic function
as a result of cirrhosis, or thrombocytopenia ­secondary to
splenomegaly and portal hypertension. Therapy to correct
­
coagulopathy is directed at the cause. Vitamin K, fresh-­frozen
plasma (FFP), or platelets are used to correct deficiencies.
Vitamin K, 1 to 5 mg orally or subcutaneously daily for 1 to
3 days, may correct a prolonged prothrombin time (PT) and
carries minimal risk. However, the coagulopathy in patients
with synthetic failure will probably not correct with such mea-
sures, and performing a type and screen will prepare the patient
for platelet and FFP transfusions, with the goal of achieving
a platelet count higher than 50,000/mm3 and ­international
­normalized ratio (INR) less than 1.5, respectively.
Reduction of ascites preoperatively may decrease the
risk of wound dehiscence and improve pulmonary func-
tion. Sodium restriction (in diet and IV solutions), diuretics
(especially spironolactone, which inhibits aldosterone), and
even paracentesis are useful. If paracentesis is ­performed, it
is important to analyze the fluid for infection. Correction
of anemia is controversial but may limit renal dysfunc-
tion. Lactulose, 30 mL orally every 6 hours for 3 days before
 584 ANESTHESIA AND UNCOMMON DISEASES
surgery, with the last dose given within 12 hours of surgery,
or oral bile salts with IV hydration beginning the night before
surgery, may reduce perioperative progression of renal dis-
ease in patients at risk.47
CREUTZFELDT-JAKOB DISEASE
Creutzfeldt-Jakob disease (CJD) is a rare illness that may be
acquired by infection and secondarily transmitted. The most
common form (sporadic CJD) affects only approximately 1 to
2 per 1 million population per year, most of whom are mid-
dle aged or elderly. CJD is a spongiform encephalopathy, clas-
sified as a prion disease.48 A limited number of other prion
diseases are known; kuru is linked to cannibalism in Papua,
New Guinea, and Gerstmann-Sträussler-Scheinker syndrome
is usually inherited. Other diseases of this type have been doc-
umented in animals.49
All these prion diseases are widespread degenerative
­diseases of the central nervous system with long incubation
periods. Once symptoms occur, there is a rapid progression to
death, typically in 6 months. Patients with sporadic CJD have
dementia of rapid onset, cerebellar dysfunction with ataxia,
increased tone, and sometimes myoclonus. Cortical blind-
ness may occur, as well as rapid deterioration with epileptic
seizures. Diagnosis of CJD is usually made clinically and con-
firmed by brain biopsy. Treatment is symptomatic because no
satisfactory therapy is yet available.
The infective agent can only be isolated from the brain,
spinal cord, and other tissues. Iatrogenic transmission of
­ 19. Gross TJ, Hunninghake GW: Idiopathic pulmonary fibrosis, N Engl J Med
­prions can occur in neurosurgical procedures, corneal grafts,
and with growth hormone injections obtained from cadaveric
pituitaries.50 Currently the risk of transmitting prions causing
CJD is unknown. It was found in the lymphoreticular system
in 1999 during a tonsillar biopsy.
ANESTHETIC CONSIDERATIONS
Any tissue or body fluid should be considered potentially
infectious. Accidental transmission has occurred by con-
taminated instruments as well as a contaminated dural graft.
Particular care should be taken during any brain biopsy in
patients with undiagnosed dementia. If CJD is suspected,
biopsy may not be advisable. The anesthesiologist should be
gowned and gloved and masked appropriately with water-
proof garments.51 All equipment should be disposable and
incinerated if possible.
Anesthetic management may be complicated by autonomic
dysfunction in patients with Creutzfeldt-Jakob disease.
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 C H A P T E R
21
The Pediatric Patient
DOREEN SOLIMAN, MD  n
FRANKLYN P. CLADIS, MD  n
PETER J. DAVIS, MD, FAAP  n

increased by hypoxemia acidosis, hypothermia, and stress;

Neonatal and Pediatric Physiology inability to lower PVR in fetal circulation will not allow
Cardiac Physiology
extrauterine neonatal survival.
Respiratory Physiology
n Congenital laryngeal webs are glottic, extending to subglot-
Temperature Regulation
tic area, with vocal cord dysfunction from mild hoarseness
Renal Physiology
to aphonia. Treatment of anterior webs includes incision
Pain and Perioperative Stress Response
and dilation; subglottic involvement requires division of
Nervous System Anomalies: Meningomyelocele web and cricoid plate with cartilage grafting.
Otolaryngologic Anomalies n Choanal atresia may be unilateral or bilateral. Patients
Congenital Laryngeal Webs and Atresia
­present with apneic episodes and cyclic cyanosis ­exacerbated
Choanal Atresia
by feeding and improved by crying.
Cystic Hygroma
n Mediastinal masses are classified by location (anterior,
Craniofacial Anomalies middle, and posterior), which frequently affects symptoms;
Clefts: Treacher Collins Syndrome
compression of the large airways and great vessels can
Craniosynostosis
result in cardiovascular and respiratory compromise.
Hypoplasia
n Patients with anterior mediastinal masses presenting for
Surgical Correction
diagnostic biopsies or central venous catheter insertion
Mediastinal Masses under general anesthesia are at risk for cardiovascular and
Congenital Malformations of Lung respiratory collapse.
Bronchogenic and Pulmonary Cysts
n Initial management of neonates with lung anomalies
Congenital Cystic Adenomatous Malformation
focuses on fluid and electrolyte resuscitation, temperature
Pulmonary Sequestration
homeostasis, and protection of eviscerated organs.
Congenital Lobar Emphysema
n In meningomyelocele, excessive preoperative and intraop-
Congenital Diaphragmatic Hernia
erative third-space fluid losses means hypovolemia should
Tracheoesophageal Fistula
be avoided by meticulous attention to fluid management.
Abdominal Wall Defects n Radiant heat loss in neonatal and pediatric patients should
Omphalocele and Gastroschisis
be aggressively addressed by the use of warming devices
Prune-Belly Syndrome
and increasing the ambient room temperature.
Bladder and Cloacal Exstrophy
n In patients with abdominal wall defects, reduction of i­ ntestinal
Cardiovascular Disease: Williams’ Syndrome contents can increase intra-abdominal pressure and compro-
Dermatologic Disease: Epidermolysis Bullosa mise blood flow to other organs and the ­inferior vena cava.
Monitoring of gastric airway pressure and central venous
pressure is recommended.
KEY POINTS
n Survival of the neonate depends on pulmonary vascular For neonates to survive in the extrauterine environment,
resistance transitioning from a high to a low state. PVR is a series of adaptations must occur. These adaptations, or
586

physiologic transitions, have profound implications, are inter-
dependent on each other, and include: (1) conversion of the
cardiovascular circulation from a parallel circulation to one
in series; (2) establishment of a functional residual capacity
and maintenance of an air exchange; (3) regulation of fluid
and electrolytes in the presence of an immature kidney and
the absence of a placenta; and (4) temperature homeostasis in
an organism easily overwhelmed by its environment. All these
physiologic or transitional tasks can be further compromised
by the presence of surgical or medical diseases. The transition
from neonate to infant is characterized by maturation of all
its organ systems and occurs over weeks to months. However,
the relative immaturity of these organ systems in infants,
­compared with adults, creates challenges for the anesthesiolo-
gist. To understand how best to approach uncommon diseases
of the infant, a basic understanding of normal physiology is
required.
NEONATAL AND PEDIATRIC PHYSIOLOGY
Cardiac Physiology
The transition from fetal to neonatal circulation is charac-
terized by a change from parallel circulation (cardiac output
contributes to both pulmonary and systemic perfusion, simul-
taneously allowing mixing of oxygenated and deoxygenated
blood) to one that occurs in series (cardiac output contrib-
utes to either pulmonary or systemic perfusion with minimal
admixture). High pulmonary vascular resistance (PVR) and
relatively low systemic vascular resistance (SVR) also char-
acterize fetal circulation. In utero, oxygenated blood from
the placenta is transported to the fetus via the umbilical vein
(Fig.  21-1). Blood from the gastrointestinal (GI) tract com-
bines with the umbilical vein to become the ductus venosus,
which drains into the inferior vena cava (IVC). Blood from
the IVC enters the right atrium and preferentially crosses the
foramen ovale to the left atrium and left ventricle, thereby pro-
viding slightly more oxygenated blood for c­ erebral circulation.
The superior vena cava (SVC) drains into the right atrium and
is pumped primarily to the systemic circulation via the ductus
arteriosus. Less than 10% of c­ ombined ventricular output con-
tributes to pulmonary flow.1 A series of events occur at birth
that change fetal (parallel) circulation into ­neonatal circula-
tion (series).
During delivery, PVR decreases and SVR increases, allow-
ing for a significant increase in pulmonary blood flow. The
increase in SVR occurs secondary to separation from the pla-
centa. The decrease in PVR occurs for several reasons. With the
onset of lung ventilation, there is a decrease in the mechanical
compression of the alveoli and an increase in ­oxygen tension
(Po2).2,3 At birth, the mechanical distention of the alveoli cou-
pled with the increased Po2 results in a ­precipitous decrease
in PVR. The changes in PVR are mediated by b ­ iochemical
factors, including nitric oxide and prostaglandin. In the new-
born period, the pulmonary vessels exhibit a highly reactive
tone. Maintenance of an elevated PVR is lethal to the ­neonate.
Pulmonary vasoconstriction with right-to-left shunting in
Chapter 21  The Pediatric Patient 587
response to hypoxia, hypercarbia, sepsis, and acidosis can
cause severe hypoxemia and death.
With a decrease in PVR, pulmonary blood flow and venous
return to the left atrium increase. The increase in left atrial
pressure and flow closes the foramen ovale. Over the next
few months of life, PVR decreases even further. Hypoxemia
and acidosis are two important factors that affect PVR. An
increase in PVR can lead to right-to-left shunting across the
foramen ovale and ductus arteriosus. This persistence of an
elevated PVR can lead to further hypoxemia and tissue acido-
sis. Thus, hypoxemia and acidosis can lead to a vicious cycle
of increased PVR, increased right-to-left shunting, increased
hypoxemia, increased tissue acidosis, and further increase in
PVR and shunting.
The neonatal myocardium is immature and continues its
development after birth. Many functional differences between
the neonatal and adult myocardium are directly related to the
immaturity of the neonatal tissue components.4 At ­delivery
and extending into the neonatal period, fewer contractile
elements and less elastin are present in the newborn's myo-
cardium, resulting in a decreased contractile capacity and
decreased ventricular compliance, respectively. Fetal myocar-
dium has limited ability to generate the equivalent contrac-
tile force as the adult myocardium throughout the entire range
of the length-tension curve. The consequence is a reduced
capacity to adapt to increases in preload or afterload.5,6 This
does not mean the stroke volume is fixed. Echocardiographic
­evidence indicates that the immature heart, while limited,
is able to increase stroke volume.7 Because of this immatu-
rity, the neonatal heart has a diminished capacity to handle
­significant volume loads and more easily develops ventricular
­overload and failure.
Respiratory Physiology
A significant difference between neonatal and adult respi-
ration is oxygen consumption. Neonatal O2 consumption
is two to three times greater than that of the adult (5-8 vs.
2-3 mL/kg/min).8 This contributes to the rapid O2 desat-
uration observed in infants during periods of apnea or
hypoventilation.
The neonatal/infant lung is less compliant than the adult
lung. The immature lung in the pediatric patient is charac-
terized by small, poorly developed alveoli with thickened
walls and decreased elastin. The amount of elastin in the
lung ­continues to increase until late adolescence.9 Before and
after late adolescence, pulmonary elastin is decreased. Elastin
­provides elasticity to the lung, without which there is air-
way collapse. Because they have less elastin, infants and older
adults are prone to alveolar collapse.9,10 The closing capacity,
the lung volume at which there is airway collapse, occurs at
a larger lung volume in the very young and the very old pop-
ulations (Fig.  21-2). In the infant, airway closure can occur
before end exhalation, resulting in atelectasis and right-to-left
transpulmonary shunting. In contrast to the pediatric lung,
the pediatric chest wall is more compliant than the adult chest
 588 ANESTHESIA AND UNCOMMON DISEASES

To head

To arm To arm

Aorta
Superior vena cava
Ductus
arteriosus
Pulmonary artery
Left
Foramen ovale atrium
Right atrium
Right lung Left lung
Right ventricle

Hepatic vein
Left ventricle
Ductus venosus
FIGURE 21-1  Course of fetal circulation in
late gestation. Note the selective blood flow Liver
patterns across the foramen ovale and the Inferior vena cava
ductus arteriosus. (From Greeley WJ, Steven JM,
Nicolson SC: Anesthesia for pediatric cardiac Renal arteries & veins
surgery. In Miller RD, editor: Miller's anesthesia,
ed 6, Philadelphia, 2005, Churchill Livingstone, Umbilical vein
p 2007.) Portal vein Aorta

Umbilical
Umbilicus arteries

Hypogastric arteries

Umbilical cord
To left leg
Placenta Arterial blood
Bladder Venous blood
Mixed arterial-
venous blood

wall, because of the increased amount of cartilage in pediatric
ribs. This increased chest wall compliance may help contribute
to airway collapse because negative intrathoracic pressure can
result in chest wall collapse.
Temperature Regulation
Neonates and infants are at increased risk of thermoregulatory
instability because they are more prone to heat loss and they
have a decreased ability to produce heat. They are at increased
risk of heat loss because of their large surface area/volume
ratio.11 They also have decreased ability to restrict heat loss
secondary to limited vasoconstriction compared with adults.12
The primary method of heat production in the neonate and
infant consists of nonshivering ­thermogenesis, which compen-
sates poorly for heat loss. Nonshivering thermogenesis occurs
primarily in brown fat, which may be decreased in premature
neonates. This mechanism can also be inhibited by inhalational
agents.13,14 Nonshivering thermogenesis is mediated by norepi-
nephrine, a potent pulmonary vasoconstrictor. Consequently,
cold stresses can cause elevations to PVR and provide a mech-
anism for right-to-left shunting. Shivering thermogenesis
assumes a less significant role in infants. Temperature stability
can be ensured by using ­neonatal ­warming lights, forced warm
air blankets, intravenous fluid warmers (if large amounts of
fluids or blood products are given) increasing the ambient
temperature of the operating room and keeping the infant
covered.
 Chapter 21  The Pediatric Patient 589

L
1
0.8
0.6
0.4 FIGURE 21-2  Closing capacity in
relation to age. The difference between
0.2 functional residual capacity (FRC) and
0 closing capacity is charted against age.
Note that closing capacity is greater than
0.2 FRC in children younger than 5 years and
0.4 adults older than 45. (From Mansell A,
Bryan C, Levison H: J Appl Physiol 33:
0.6
771-774, 1972.)
0.8

1
5 10 15 20 24 28 32 36 40 44 48 52 56 60
Age in years

Renal Physiology mature adult. In neonates, thresholds of response to mechani-

In the first few days of life, a major physiologic priority of
the neonate is to lose weight as a result of a reduction in
extracellular body water. This physiologic weight loss usu-
ally is a ­function of an isotonic contraction of body fluids.
Perturbations of this process can affect infant morbidity and
mortality. The neonatal kidney develops its full complement
of nephrons by 36 weeks’ gestation. The glomerular filtration
rate is lower in the neonate (~25% of adult value) and achieves
adult values within the first few years of life. Tubular function
in the neonate is also limited; consequently, a ­glomerular/
tubular imbalance is present in the first few years of life
as well.
Neonates have limited capacity to concentrate their urine.
When challenged, term infants can concentrate to 800 mOsm/
kg of plasma water, whereas preterm infants can concentrate to
600 mOsm/kg of plasma water. Neonates have diminished end-
organ responsiveness to vasopressin, whereas fluid-challenged
term infants and premature infants can dilute their urine to 50
and 70 mOsm/kg of plasma water, respectively. Thus, excessive
fluid restriction and overhydration can result in dehydration
and intravascular volume overload. Renal sodium losses are
inversely related to gestational age and d
­ isease states (hypoxia,
respiratory distress, acute tubular necrosis, and hyperbilirubi-
nemia can exacerbate these losses).
Pain and Perioperative Stress Response
Pain and stress can induce significant physiologic and behav-
ioral consequences. Newborns and infants are capable of
mounting a hormonal response to the stress of their illness.15,16
A better understanding of the causes, mechanisms, and treat-
ment of pain during development has provided clinicians with
a wide array of techniques to manage procedural and postop-
erative pain safely.17–19
The nervous system at birth displays h ­ ypersensitivity to
­sensory stimuli compared with the nervous system of the
cal and thermal stimulation are reduced, and further sensi-
tization can occur with sustained or repetitive stimulation,
which is different from the mature nervous system.20 Structural
and functional changes in the peripheral and central ner-
vous systems that take place in the postnatal period involve
­alterations in expression, distribution, and function of recep-
tors, ion ­channels, and neurotransmittors.21 These changes
can ­profoundly affect the character of nociceptive responses
at different stages of development. Perinatal brain plasticity
is affected by this sensitization and increases the vulnerability
of the neonatal brain to early adverse experiences, leading to
abnormal neurologic development and behavior.22,23
A multimodal approach to pediatric pain management
is necessary and may involve pharmacologic and nonphar-
macologic methods.24 The use of nonopioid analgesics
(­acetaminophen, nonsteroidal anti-inflammatory drugs),
­opioids, local anesthetics, and regional techniques provides a
balanced ­analgesic approach to pain management.
NERVOUS SYSTEM ANOMALIES:
MENINGOMYELOCELE
Meningomyelocele (MMC) is a defect of neural tube devel-
opment occurring around the fourth week of gestation. The
incidence of MMC is 0.5 to 1 per 1000 live births. The etiology
is multifactorial but may occur secondary to folate deficiency,
exposure to toxins (valproic acid, carbamazepine), and genetic
disorders (trisomy 13 and 18). MMC is the most common
neural tube defect and is characterized by lack of development
of the layers that naturally cover and protect the spinal cord,
resulting in protrusion of the meninges through the bony
defect overlying the cord. The sac created by the protruding
meninges may (MMC) or may not (meningocele) contain
nerve tissue (Fig.  21-3, A). The defect may occur anywhere
along the spinal cord, but the lumbosacral region is the most
common site. Defects at the thoracic and cervical region occur
rarely. MMC results in neurologic injury below the level of the
 590 ANESTHESIA AND UNCOMMON DISEASES
A ANESTHETIC CONSIDERATIONS
B Induction. Anesthesia can be induced with intravenous (IV)
FIGURE 21-3  Nervous system anomalies. A, Lumbosacral
myelomeningocele in newborn; skin appears dysplastic. B, MR
image of patient with Chiari II malformation. Note the upward
herniation of the cerebellum (arrowhead); curved arrow indicates
downward herniation of brainstem through foramen magnum; thin
arrow marks foramen magnum. (A, courtesy Stephanie Greene, MD.)
lesion. The neurologic injuries can include paraplegia, ­urinary
and fecal incontinence, and sexual dysfunction; ­ however,
there is considerable clinical variation.
Associated Anomalies. The most common associated
­eurologic anomaly is the Arnold-Chiari (Chiari type II)
n
malformation, characterized by downward herniation of
­cerebellar vermis and fourth ventricle. Infants with Chiari II
malformations can present with clinical evidence of brainstem
compression, resulting in a weak cry, poor swallowing, poor
feeding, aspiration, apnea, and opisthotonus (Fig.  21-3, B).
Older ­children may present with neurologic symptoms involv-
ing the upper extremity. Hydrocephalus can occur in as many
as 85% of patients with lumbar MMC. The etiology of the
hydrocephalus is not clear but may occur secondary to ana-
tomic ­abnormalities associated with the Chiari malformation
or abnormal cerebrospinal fluid (CSF) absorption.25
Other associated anomalies include clubfoot, Klippel-Feil
syndrome, hydronephrosis, exstrophy of the bladder, and
­congenital heart defects.
Pathophysiology. Most children with MMC survive into
early adulthood.26 About 30% of the deaths in the first two
decades of life are secondary to respiratory complications,
largely attributable to hydrocephalus and Arnold-Chiari
malformation.27 In the first few weeks of life, infants with
MMC require immediate repair to prevent infection, further
­neurologic injury, and dehydration.
Infants with MMC present to the operating room (OR) for
primary repair of their MMC. Later in life, they present for
ventriculoperitoneal shunt (VPS), VPS revisions, tethered
­
cord repair, and posterior spine fusion.
The anesthetic management of the infant with MMC begins
with a complete preoperative assessment. Infants with Chiari
type II malformations may be at risk for apnea and aspiration.
Preoperative echocardiography and renal ultrasound may be
part of the evaluation to rule out congenital heart defects and
hydronephrosis. Examination of the neck may reveal decreased
range of motion secondary to Arnold-Chiari malformation or
Klippel-Feil sequence. An assessment of the patient's volume
status is important, given the risk of significant intraoperative
third-space losses from the open-skin defect. Laboratory data
can be tailored to the infant's needs but should include at least
a blood glucose check. Bleeding can occur secondary to tissue
dissection. Hemoglobin and hematocrit values and type and
screen may be performed preoperatively (Table 21-1).
induction agents or a standard inhalational agent. Standard IV
induction agents include atropine, sodium pentothal, or pro-
pofol and a neuromuscular blocking agent. Succinylcholine
has been administered to patients with MMC with no reported
increase in serum potassium level.28 Airway management may
be more challenging in the infant with MMC because of asso-
ciated neck pathology (Chiari malformation, Klippel-Feil
­syndrome), positioning, and increased association with short
trachea.29 Positioning during airway management and laryn-
goscopy is critical to avoid pressure and subsequent injury to
the neural placode. The infant can be induced and intubated
on the side or supine, provided there is appropriate support to
the back to protect the neural elements. Towels can be rolled
and used to support the infant when supine. The neural cord
defect can also be placed in a small, donut-shaped gel head
ring to allow the infant to be supine without putting pressure
on the neural elements. The trachea may be short in infants
with MMC.29 Attention must be paid to identifying the carina
and properly positioning the endotracheal tube to prevent
endobronchial intubation.
Maintenance. Anesthesia can be maintained with an inha-
lational agent. Remifentanil may be advantageous given its
rapid clearance, short terminal half-life, and nonaccumulating
properties.30 Subsequent use of intraoperative ­neuromuscular
blockers is not recommended because nerve stimulation by
the neurosurgeons is sometimes performed to identify n ­ eural
tissue. The open-skin defect can occupy a large portion of

TABLE 21-1  n  Meningomyelocele and Occipital/Nasal Encephalocele: Anesthetic Considerations
Pathology Associated Anomalies
Meningocele Chiari type II malformation
Apnea
Meningomyelocele Hydrocephalus: VPS
Congenital cardiac defects
Genitourinary
Klippel-Feil syndrome
Occipital encephalocele As above
Nasal encephalocele As above
VPS, Ventriculoperitoneal shunt.
surface area and can result in significant third-space fluid
losses. These infants are also at risk for hypothermia because
of the relatively large area of exposed skin and may require
resuscitation with room-temperature fluids. Maintaining a
warm room and using a full-access, forced-warm-air blanket
can reduce this risk. Because the patient is positioned prone
for the primary closure, the face, eyes, and extremities must be
appropriately padded and protected.
Regional Anesthesia. Spinal anesthesia has been reported
for the primary repair of lumbosacral MMCs. Infants with
thoracic lesions were excluded. The initial introduction of
intrathecal local anesthetic was by the anesthesiologist. The
dural puncture was performed at the most caudad region of
the defect, with a hyperbaric mixture of tetracaine. The block
was supplemented by the neurosurgeons, if needed, and
a pacifier along with IV midazolam was provided for those
infants who remained unsettled after supplementation. Of
14 infants ­successfully anesthetized and surgically corrected,
seven required supplementation of local anesthetic, two had
postoperative apnea, and no new neurologic events were
­
noted immediately after surgery.31
Latex Precautions. Latex sensitization is increased in chil-
dren with myelodysplasia. Pittman et  al.32 studied the prev-
alence of latex specific immunoglobulin E (IgE) in children
with MMC and found that 47% had antibodies against latex,
compared with 15% of the chronically ill control group and
3.8% of the medical control group.32 Using epicutaneous skin
testing, Shah et al.33 demonstrated latex s­ ensitization in 44%
of children and adolescents with MMC; 21% of these children
Chapter 21  The Pediatric Patient 591
Anesthetic Issues
Preoperative labs: blood glucose, hemoglobin, type and screen
Preoperative labs: blood glucose, hemoglobin, type and screen, renal
ultrasound, echocardiogram
Airway management: possible decreased neck extension from Chiari II and
Klippel-Feil (rare), intubation may be lateral decubitus to protect neural
elements
Hypothermia risk: full-access heating blanket, neonatal warming lights
Latex precautions
Postoperative apnea
Preoperative labs: blood glucose, hemoglobin, type and screen
Airway management: head positioning for mask ventilation and intubation may
be more difficult secondary to location of neural elements
Preoperative labs: blood glucose, hemoglobin, type and screen
Airway management: may be difficult to mask-ventilate because of nasal defect
Craniotomy: consider arterial catheter
Positioning: may be positioned head up or sitting; consider central venous
catheter
Postoperative ventilation: may be required due to airway edema or blood in
upper airway
had a history of clinical latex allergy. Age and n ­ umber of
­surgical procedures were significantly correlated with latex
sensitization. Patients with latex allergies often have ­additional
­allergies, most often secondary to repeated antibiotic e­ xposure,
but reports of sensitization to opioids and n ­ euromuscular
blockers have been reported.34
Postoperative Considerations. Infants with meningo-
myelocele may be at increased risk of postoperative apnea.
Extubation after primary repair of the defect may take place in
hemodynamically stable infants who are awake and can main-
tain their airway. Infants should recover in a monitored setting
with respiratory and cardiac monitors.
Fetal Surgery. Prenatal intervention had been proposed,
initially in an attempt to improve neurologic and urologic
function. Earlier animal studies suggested an improvement in
postnatal function. In a randomized trial comparing ­prenatal
surgery before 26  weeks with standard postnatal repair,
­prenatal surgery reduced the need for shunting and improved
motor outcome at 30 months, but prenatal surgery was associ-
ated with an increased risk of premature delivery and uterine
dehiscence.35
OTOLARYNGOLOGIC ANOMALIES
Congenital Laryngeal Webs and Atresia
Congenital laryngeal webs are uncommon and have an esti-
mated incidence of 1 in 10,000 births. Most laryngeal webs
are glottic with extension into the subglottic area. The laryn-
geal web is a result of a failure to recanalize the laryngeal inlet
 592 ANESTHESIA AND UNCOMMON DISEASES

at about 10 weeks’ gestation. The symptoms vary accord-

ing to the location of the web and the degree of involvement
(Fig. 21-4 and Box 21-1). Symptoms are related to vocal cord
dysfunction ranging from mild hoarseness to aphonia. Most
webs involve the anterior glottis and are generally thin and
associated with mild hoarseness and minimal airway obstruc-
tion. With laryngoscopy the vocal folds are visible. Subglottic
webs are infrequent, and supraglottic webs are rare. Complete
congenital laryngeal atresia is incompatible with life unless an
emergency tracheotomy is carried out in the delivery room.
Complete congenital atresia is associated with tracheal and
esophageal anomalies36 (Fig.  21-5). Signs and symptoms of
infants with congenital laryngeal webs include disorders of
phonation, stridor, and airway obstruction; Box  21-2 lists
­disorders mimicking these laryngeal web symptoms.
Thin anterior webs and laryngeal webs in the glottic area
may require incision and dilation. If the web involves the

FIGURE 21-5  Laryngeal atresia. (Courtesy Charles Bluestone, MD.)

BOX 21-2   n DISORDERS THAT MIMIC LARYNGEAL

WEBS

Laryngomalacia
Congenital subglottic stenosis
Laryngeal and laryngotracheoesophageal clefts
Vascular anomalies (hemangiomas)
Vocal cord paralysis

subglottic larynx, the anterior cricoid plate is usually abnor-

FIGURE 21-4  Congenital laryngeal web. Medium-sized, thicker,
anterior glottic web. (Courtesy Charles Bluestone, MD.)
mal. In these patients, treatment requires an external approach
with division of the web and the cricoid plate and the use of
cartilage grafting. Fibrosis and scarring of the vocal cords tend
to occur with the laryngotracheal reconstruction ­techniques.
Recently, the combination of minimally invasive endoscopic
approaches with carbon dioxide (CO2) laser scar t­ransection,
mitomycin C application, and antiproliferation agents
­effectively reduced scar tissue.37

BOX 21-1   n CONGENITAL LARYNGEAL WEBS: ANESTHETIC MANAGEMENT

CLINICAL MANIFESTATIONS
Phonatory abnormalities
High-pitched or absent cry occurs with glottic anomalies.
Muffled cry is characteristic of supraglottic obstruction.
Stridor
Severe airway obstruction
Increased work of breathing (retractions)
Tachypnea, apnea, and cyanosis
Data from Gerber ME, Holinger LD: Congenital laryngeal anomalies.
In Bluestone CD et al, editors: Pediatric otolaryngology, ed 4, vol 2,
Philadelphia, 2003, Saunders-Elsevier.
A systematic approach to airway evaluation is essential for
laryngeal webs. Flexible fiberoptic nasopharyngolaryngos-
copy and rigid laryngoscopy and bronchoscopy are needed
to fully assess the airway. Because anesthetic agents can affect
vocal cord motion, flexible fiberoptic nasopharyngolaryn-
goscopy is used to assess vocal cord mobility with the patient
awake or lightly sedated.
An experienced endoscopist and anesthesiologist should pro-
vide the care for these infants, in an OR fully equipped for man-
aging pediatric airway emergencies. Surgeon-­anesthesiologist
communication is crucial.38 IV access can be established
after general anesthesia induction using inhalational agents.
 Chapter 21  The Pediatric Patient 593

Frontonasal process
BOX 21-3   n PATIENTS WITH LARYNGEAL WEB:
ANESTHETIC MANAGEMENT
Eye
Experienced anesthesiologist and ear, nose, and throat surgeon
Operating room equipped with airway emergency equipment
Careful communication with the surgeon and anesthesiologist Maxillary
Fasting protocols observed except for emergencies prominence
Anticholinergics: glycopyrrolate, 5 to 10 μg/kg, or atropine, 10 μg/kg
Topical anesthesia with lidocaine 1%
Dexamethasone, 0.5 to 1 mg/kg Nasal pit
Postoperative care: humidified oxygen therapy placode

Nasal pit
Sevoflurane or halothane can be used, although sevoflurane
has been associated with fewer side effects.39 Anticholinergic
agents are recommended for rigid bronchoscopy to decrease Mandibular prominence
secretions and minimize the risk of ­ bradycardia. Topical A
anesthesia of the vocal cords and the trachea is used as
­
an adjunct. Lidocaine 1% has a short duration of action Lateral nasal process Medial nasal process
(10 minutes).40
Total intravenous anesthesia (TIVA), including remifent-
anil and propofol, can be used for maintenance of anesthesia.41
The choice of spontaneous or controlled ventilation depends
on the severity of airway obstruction.42 Spontaneous ventila-
tion is probably the ventilation mode of choice in patients with
severe airway compromise. IV dexamethasone, 0.5 to 1 mg/kg,
should be administered to treat potential airway edema. In
cases of severe stenosis, cricotracheal resection requires post-
operative nasotracheal intubation and mechanical ventilation
for 5 to 14 days. This postoperative care requires the use of seda-
tion, neuromuscular blockade, and intensive care ­monitoring
to avoid accidental endotracheal extubation. Prolonged use of
neuromuscular blockade can result in residual muscle weak-
ness, which may compromise or delay planned extubation43
(Box 21-3).

Choanal Atresia
Choanal atresia occurs in approximately 1 in 7000 live births.
About 90% of the atresias are bony, and 10% are membranous.
Abnormal embryogenesis of neuroectodermal cell lines may
explain choanal atresia. The primitive face develops from five
facial prominences (Fig. 21-6). The frontonasal prominence is
responsible for nasal development from weeks 3 to 10 of gesta-
tion. Migrating neural crest cells form the nasal (or olfactory)
placode, a convex thickening on the frontonasal prominence.
The primitive nasal pit is formed from a central depression in
these placodes. Mesenchymal proliferation around the nasal
placode allows horseshoe-shaped medial and lateral promi-
nences to develop and fuse to form the nostril. The nasal pits
grow backward.44
Choanal atresia is thought to result from the persistence
of bucconasal and buccopharyngeal membranes or an insuf-
ficient excavation of the nasal pits. Postnasal cavity outlet
obstruction is more common. Half of patients with choanal
atresia have other congenital anomalies.45 Choanal atresia may
be partial or one of a constellation of congenital abnormalities
B
FIGURE 21-6  Facial embryogenesis. A, Five facial
prominences: frontonasal process, paired mandibular processes,
and paired maxillary processes. B, Fusion of medial and lateral
nasal processes. (From Losee JE, Kirschner RE, Whitaker LA,
Bartlett SP: Plast Reconstr Surg 113:676-689, 2004.)
known as the CHARGE association (coloboma, heart disease,
atresia [choanal], retarded growth, genital abnormalities, ear
deformity). Choanal atresia can be unilateral or bilateral.
Because neonates are obligate nose breathers, bilateral c­ hoanal
atresia frequently presents as immediate onset of respira-
tory distress. Obstruction of the nasal cavity can present with
apneic episodes and “cyclic” cyanosis, which are exacerbated
by feeding and improved with crying.46
 594 ANESTHESIA AND UNCOMMON DISEASES
The initial presentation of the newborn with bilateral
c­ hoanal atresia is the immediate onset of respiratory d ­ istress.
The relationship between the neonatal tongue and the p ­ alate
perpetuates this obstruction. The use of an oral airway or
McGovern nipple (modified nipple with enlarged perfora-
tions at tip) acts as an alternative, temporary airway. Unilateral
choanal atresia is usually asymptomatic, except for unilateral
mucoid discharges.
Diagnosis. Inability to pass a 6-Fr catheter through the
nasal cavity to more than 32 mm, coupled with an endoscopic
examination, verifies the suspected diagnosis. Axial computed
tomography (CT) remains the study of choice to delineate the
type of atresia and aid with operative planning (­transpalatal
vs. transnasal approach). Adequate preparation of the patient
before scanning by aspirating secretions and the use of
­decongestant drops helps ensure the best-quality radiographic
result. Box 21-4 lists associated craniofacial syndromes.
Treatment. About 90% of patients with choanal atresia
have bony involvement, whereas in 10% the obstruction is
membranous. For bilateral choanal atresia, surgical ­correction
occurs in the neonatal period and involves a transnasal
BOX 21-4   n CHOANAL ATRESIA: CRANIOFACIAL
ASSOCIATIONS
CHARGE association: Coloboma, heart defects, atresia of choanae,
retarded CNS growth or development, GU abnormalities, ear
anomalies/deafness
Apert's syndrome (acrocephalosyndactyly, type I): Craniosynostosis,
syndactylism, difficult airway
Fraser's syndrome (cryptophthalmos syndrome): Laryngeal/tracheal
stenosis, congenital heart disease, GU anomalies, renal agenesis/
hypoplasia
Data from Papay FA, McCarthy VP, Eliachar I, et al: Laryngotracheal
anomalies in children with craniofacial syndromes, J Craniofac Surg
13:351-364, 2002.
CNS, Central nervous system; GU, genitourinary.
FIGURE 21-7  Choanal atresia.
A, Choanal atresia in neonate.
Atresia plate on the right side has
just been perforated. B, The situation
after opening in atresia plate has
been enlarged. (Courtesy Charles
Bluestone, MD.)
A B
correction using CO2 or neodymium:yttrium-aluminum-­
garnet (Nd:YAG) lasers. The nasal passage is stented open
for 3 to 5 weeks to improve airway patency. The surgical tech-
nique generally involves an endoscopic approach in which a
­vertical mucosal incision is made in the posterior bony sep-
tum and a perforation created in the atresia plate (Fig. 21-7).
This ­perforation is then amenable to serial dilation.47
A transpalatal approach has also been used for bony and
bilateral atresia. However, the disadvantages of the transpala-
tal approach are long operative time and large blood loss.
Additionally, malocclusion occurs in 50% of patients, and
­oronasal fistulas can occur. In patients with unilateral c­ hoanal
atresia, surgery is usually performed at any time during
­childhood; the approach can be transnasal or transpalatal.48
ANESTHETIC CONSIDERATIONS
Anesthetic concerns for infants undergoing choanal sur-
gery involve age-appropriate concerns as well as manage-
ment of a difficult airway. In addition, for infants having the
CHARGE association, any underlying cardiac issue must
be addressed. The airway is secured with an oral RAE tube
after an i­nhalational or IV induction. The anesthetic agent
is titrated to allow the patient to be extubated as awake as
­possible with airway reflexes intact. However, if the procedure
has been lengthy, airway edema is present, or hemodynamic
­instability is p
­ resent, the patient should remain intubated until
these issues have been resolved.
Cystic Hygroma
Cystic hygroma is a congenital lymphatic malformation caused
by dysplasia of lymphatics, but it may also result from hamar-
toma or true neoplasm. The lesion is uncommon, occurring in
1 in 12,000 live births. Clinically, a cystic hygroma occurs most
often (60%-70%) in the neck (Fig. 21-8). Typically, the neck
mass develops in the posterior triangle. If it develops higher in
the neck (suprahyoid), it can occupy the anterior ­triangle and
may be associated with intraoral lesions. S­ uprahyoid lymphan-
giomas are more likely to involve the mouth and cause feeding
 Chapter 21  The Pediatric Patient 595

s­ ignificant. Maintenance of body temperature can be achieved

with warming lights, fluid warmers, and forced-warm-air
blankets. Surgical resection may involve manipulation of
the vagal nerve, which can result in bradycardia. Evaluation
at the end of surgery will determine the feasibility of early
extubation. Infants with difficult intubation, significant fluid
shifts, or hemodynamic instability should remain intubated
and undergo recovery in the intensive care unit (ICU). Vocal
cord dysfunction can result from nerve injury from the sur-
gical d ­ issection and should be considered if acute airway
­obstruction occurs after extubation.
Management of prenatally diagnosed cystic hygromas may
involve delivery through the ex utero intrapartum ­treatment
(EXIT) procedure. During EXIT the head and torso of the
fetus are delivered and the airway is secured while uteroplacen-
tal support is maintained.51,52 Intubation can be achieved with
direct laryngoscopy. If the anatomy makes this i­mpossible,
FIGURE 21-8  Neonate with large neck mass consistent with
cystic hygroma. (From Zitelli BJ, Davis HW: Atlas of pediatric rigid bronchoscopy or tracheostomy can be ­ performed
physical diagnosis, ed 4, St Louis, 2002, Mosby, p 560.) (Fig. 21-9). Tracheostomy may be difficult if the mass reposi-
tions or covers the trachea.

problems and airway obstruction.49 Infection or h ­ emorrhage

CRANIOFACIAL ANOMALIES
into the cyst can also cause acute airway compromise. About
20% of cystic hygromas occur below the c­ lavicles in the axillae Craniofacial anomalies are characterized by congenital
or the mediastinum. Mediastinal extension can cause respi- or acquired deformities of the cranial and facial skeleton.
ratory symptoms. Usually, cystic hygromas are ­ diagnosed Craniofacial anomalies, although rare, make up a considerably
at birth; however, many are diagnosed during ­ prenatal diverse group of defects. The incidence of all of the anoma-
ultrasound. lies may be difficult to determine because they include only
those defects that are well defined. An estimated 1200 persons
ANESTHETIC MANAGEMENT per year are born with these defects. In the past 25 years the
During the preoperative evaluation, infants with feeding surgical repairs have advanced significantly and now include
difficulties should be suspected of having intraoral lesions. the surgical expertise from multiple fields. These special-
Those with respiratory symptoms or coughing should be ties include plastic surgery, neurosurgery, oral maxillofacial
evaluated for mediastinal involvement with a chest radio-
graph or CT. Delay in the evaluation should be minimized
because the lesions can grow rapidly. The primary anes-
thetic concern during induction is airway management.
Inhalational induction can be performed, but difficulty
with both ventilation and intubation has been described.50
A nasopharyngeal airway may help open the airway and
restore ventilation. If ­preoperative ­examination suggests dif-
ficulty with both ventilation and intubation, consideration
should be given to p ­ erforming an awake or a sedated fiber-
optic nasal intubation. Other options include sedated place-
ment of a laryngeal mask airway (LMA) with subsequent
fiberoptic intubation, blind nasotracheal intubation, or a
sedated tracheostomy.
The surgical resection of a cystic hygroma can be associ-
ated with significant blood loss. Intraoperative management
should focus on maintaining normovolemia and normother-
mia. Intravascular access with two large IV catheters and an
arterial catheter may be required to manage the resuscita-
tion. Central venous access from the neck or chest may not
be possible depending on the location of the lymphangioma. FIGURE 21-9  Rigid bronchoscopy performed during the EXIT
Femoral venous cannulation should be considered as an procedure on neonate with cystic hygroma. (Courtesy Laura
alternative. Fluid shifts and third-space fluid losses may be Myers, MD.)
 596 ANESTHESIA AND UNCOMMON DISEASES
s­ urgery, otorhinolaryngology, dentistry, orthodontics, speech
pathology, genetics, and anesthesiology. The goal of surgical
intervention is to restore both form and function.
The classification of craniofacial anomalies is difficult
because of their variability, rarity, and degree of severity, as
well as the lack of understanding about the etiology and patho-
genesis. The Committee on Nomenclature and Classification
of Craniofacial Anomalies of the American Cleft Palate
Association has proposed the following classification: (1)
clefts, (2) synostosis, (3) hypoplasia, (4) hyperplasia, and (5)
unclassified.53
Clefts: Treacher Collins Syndrome
Craniofacial clefts involve a defect of the underlying cranial
and/or facial skeleton. This group of deformities has been
best classified by Tessier, who uses the orbit as the center of
the defect from which the clefts radiate like the spokes of a
wheel (Fig. 21-10). Cleft lip and palate are the more commonly
­recognized examples of craniofacial clefts.
Treacher Collins syndrome, also known as the incomplete
form of mandibulofacial dysostosis, is an example of a cra-
niofacial cleft that involves clefts 6, 7, and 8. Treacher Collins
syndrome was first described in 1846 by Thompson and was
further elaborated by Treacher Collins. This is a rare syn-
drome of facial clefting and is transmitted in an autosomal
dominant pattern. The syndrome is ­characterized by poorly
developed supraorbital ridges, aplastic/hypoplastic zygomas,
ear deformities, cleft palate (in one third), and m ­ andibular
and midface hypoplasia (Fig.  21-11). From birth, issues of
airway adequacy take priority. The hypoplastic maxillae
FIGURE 21-10 Tessier
classification of rare craniofacial
clefts. Using orbit as center of
reference, clefts are oriented
4 13 11
like spokes of wheel, with those
caudad to the orbit considered
facial and those cephalad
considered cranial. For descriptive
purposes, clefts involving two
regions are designated by two
numbers (e.g., 4, 10), the sum of 0 1
which is typically 14. Bony clefts
(B) are usually reflected in soft
tissue (A). (From Whitaker LA,
Bartlett SP: Craniofacial anomalies.
In Jurkiewicz J, Krizek T, Mathes S,
Ariyan S, editors: Plastic surgery:
principles and practice, St Louis,
1990, Mosby, p 109.)
A B
and mandible along with choanal atresia and ­glossoptosis
all contribute to varying degrees of airway obstruction.
Tracheostomy may be required during infancy for those at
highest risk of obstructive sleep apnea and sudden infant
death syndrome (SIDS).54 Aside from cleft lip and palate
repair, the timing of major reconstruction typically occurs
during childhood or adolescence when the cranio-orbital-
zygomatic bony development is almost complete. Infants and
children with Treacher Collins syndrome can have congenital
cardiac defects.
ANESTHETIC CONSIDERATIONS
Anesthetic concerns specific to this syndrome primar-
ily involve the airway. Infants and children with Treacher
Collins syndrome may be difficult or impossible to mask-
ventilate or intubate, and this airway difficulty may increase
with age.55 Several techniques have successfully managed the
airway safely in these infants. The LMA has successfully ven-
tilated a newborn with Treacher Collins syndrome for an
extended time.56 Direct laryngoscopy, regardless of the blade
used, may be difficult. The Bullard laryngoscope has been
used successfully.57 The LMA has also been used to assist in
the intubation of these children.58,59 The glidescope has also
been successfully used in Treacher Collins patients.60 Given
the potential for difficult mask ventilation and intubation,
this population may be best managed with a sedated fiberop-
tic intubation or a sedated tracheostomy. Another c­ oncern
for the anesthesiologist is protecting the patient's eyes.
Because of the maxillary and zygomatic hypoplasia, prone
positioning may increase the risk of orbital compression and
perioperative blindness.
14 13 12
0 12
12
11 10
10 3 4
1 3 4 9 9
8
8
2 3
3 6 7 4 6 7
5
4
5 0
7
12 3
30

A B
Craniosynostosis
Craniosynostosis is defined as a premature closure of one or
more of the cranial sutures. This results in abnormalities in
the size and shape of the calvarium, cranial base, and orbits
and constitutes a diverse group of deformities. The craniosyn-
ostoses not only affect cosmetic appearance but also can affect
brain growth, intracranial pressure (ICP), and vision, result-
ing in developmental delay, increased ICP, and visual loss. The
synostoses are classified based on head shape, not the involved
suture (Fig. 21-12).
Craniosynostosis can occur alone (simple) or as a major
component of a syndrome (complex or syndromic). Six
syndromes are associated with craniosynostosis: Apert's,
Pfeiffer's, Saethre-Chotzen, Carpenter's, Meunke's, and
Crouzon's. Table  21-2 lists the various syndromes and their
­associated anomalies and anesthetic concerns. Four of the five
Chapter 21  The Pediatric Patient 597
FIGURE 21-11  Child with
Treacher Collins syndrome. (From
Losee JE, Bartlett SP: Treacher
Collins syndrome. In Lin KY, Ogle
RC, Jane JA, editors: Craniofacial
surgery: science and surgical
technique, Philadelphia, 2001,
Saunders.)
are categorized as acrocephalosyndactylies because they involve
deformities of the head (cephalo) and extremities (syndactyly).
Crouzon's disease does not have musculoskeletal anomalies
as part of the syndrome. Infants and children with synosto-
sis present to the OR for cranial vault remodeling to reduce
ICP, prevent brain injury, and enhance ­appearance. Repair of
syndromic craniosynostosis may be more ­complicated and
appears to be associated with increased blood loss. The etiol-
ogy of the increased bleeding is unclear but may be related to
the length of surgery.61
Apert's syndrome is an acrocephalosyndactyly with an
autosomal dominant pattern of inheritance. The etiology is a
mutation within the fibroblast growth factor receptor-2 gene
(FGFR2).62 The characteristic features of Apert's ­syndrome
include turribrachycephaly (high steep flat forehead and
occiput), midface hypoplasia, and orbital hypertelorism
 598 ANESTHESIA AND UNCOMMON DISEASES

A B

C D
FIGURE 21-12 Craniosynostosis. Typical patterns of associated craniofacial morphology: A, Turribrachycephaly; B, plagiocephaly;
C, trigonocephaly; D, scaphocephaly. (From Whitaker LA, Bartlett SP: Craniofacial anomalies. In Jurkiewicz J, Krizek T, Mathes S, Ariyan S,
editors: Plastic surgery: principles and practice, St Louis, 1990, Mosby, p 119.)

(Fig. 21-13). Cleft palate occurs in approximately 30% of Apert's
patients. Choanal atresia and occasionally tracheal stenosis are
reported and can cause airway obstruction. Congenital car-
diac disease is one of the more common associated visceral
anomalies, occurring in approximately 10%. Genitourinary
(GU) anomalies (hydronephrosis, ­cryptorchidism) also occur
in 10% of patients with Apert's syndrome.63 Severe ­synostosis
can result in increased ICP and, if uncorrected, developmen-
tal delay. Syndactyly of the hands and feet often present as
the fusion of digits 2 to 4, which can make IV access difficult.
Cervical spine fusion has been reported in Apert's patients
and may make endotracheal intubation even more challeng-
ing if there is decreased neck mobility.64 Many ­children with
Apert's syndrome have been intubated uneventfully. However,
suboptimal laryngoscopic views secondary to abnormal
­
­anatomy may require flexible fiberoptic intubation. The LMA
may also be a reasonable adjunct in patients ­difficult to ven-
tilate or intubate, although to date there are no reported
cases of its use in infants or ­children with Apert's syndrome.
The clinical features and the anesthetic ­ implications of
Apert’ syndrome and the other a­ crocephalosyndactylies are
­outlined in Table  21-2. Unlike Apert's syndrome, the other
acrocephalosyndactylies are not typically associated with
­difficult airways. However, midface hypoplasia is common in
these infants and may cause significant upper airway obstruc-
tion intraoperatively and postoperatively.65
Crouzon's disease, also known as craniofacial dysosto-
sis, is also part of the syndromic craniosynostoses. These
infants present with craniofacial anomalies without visceral
or extremity involvement. The anomalies can result in signifi-
cant airway obstruction that may require early tracheostomy.
Crouzon's disease results from a mutation in FGFR2, the same
gene that causes Apert's syndrome. Table  21-2 outlines the
main clinical features and anesthetic issues. During infancy
these patients may present to the OR for tracheostomy and
cranial vault remodeling.
Hypoplasia
Hypoplasia of the craniofacial skeleton is a category of
­craniofacial anomalies characterized by hypoplasia or ­atrophy
of a portion of the craniofacial soft tissue and skeleton. Pierre
Robin sequence and hemifacial microsomia (including
Goldenhar's syndrome) are examples of these anomalies.

TABLE 21-2  n  Anesthetic Considerations with Craniofacial Syndromes
Affected Suture(s) Clinical Features
APERT'S SYNDROME
Coronal HEENT: turribrachycephaly, midface hypoplasia,
orbital hypertelorism, cleft palate in 30%,
occasional choanal atresia and tracheal stenosis,
airway obstruction
Cardiac: congenital heart disease occurs in 10%;
may include ventricular septal defect, pulmonary
stenosis
Genitourinary: hydronephrosis in 3%, cryptorchidism
in 4.5%
Musculoskeletal: syndactyly of hands/feet; fusion of
digits 2 to 4, fusion of cervical vertebrae
Neurologic: mental retardation common; elevated ICP
possible
Dermatologic: acne vulgaris common
PFEIFFER'S SYNDROME
Coronal and HEENT: tower skull, midface hypoplasia, orbital
occasionally sagittal hypertelorism, proptosis; choanal atresia
uncommon
Pulmonary: obstructive sleep apnea
Cardiac: may have cardiac defects
Musculoskeletal: usually mild syndactyly involving
broad thumbs and great toes; rarely, ankylosis of
elbow; fusion of cervical vertebrae reported
Neurologic: generally normal but mild developmental
delay can occur; may have increased ICP
SAETHRE-CHOTZEN SYNDROME
Coronal and others HEENT: brachycephaly, maxillary hypoplasia, orbital
hypertelorism, beaked nose, occasional cleft
palate
Genitourinary: renal anomalies and cryptorchidism
Musculoskeletal: short stature, mild syndactyly;
cervical fusion possible
Neurologic: mild developmental delay; rare
increased ICP
CARPENTER'S SYNDROME
Coronal and others HEENT: tower skull, down-thrust eyes, orbital
hypertelorism, low-set ears, small mandible
Cardiac: cardiac defects common (ventricular/atrial
septal defects)
Genitourinary: hypogonadism
Musculoskeletal: syndactyly of hands and feet
Neurologic: developmental delay common but
variable; may have increased ICP
Other: obesity
CROUZON'S SYNDROME
Coronal, lambdoid, HEENT: frontal bossing, tower skull, midface
others hypoplasia, beaked nose, hypertelorism, ocular
proptosis; airway obstruction can occur
Neurologic: occasional mild developmental delay;
may have increased ICP
HEENT, Head, eyes, ears, nose, and throat; ICP, intracranial pressure; IV, intravenous.
Chapter 21  The Pediatric Patient 599
Anesthetic Issues
Preoperative labs: hematocrit, type/screen
Airway management: may be difficult mask ventilation
because of midface hypoplasia, choanal atresia,
and tracheal stenosis; may be difficult intubation
secondary to facial anomalies and decreased neck
mobility
Cardiac: emphasis on balancing pulmonary and
systemic blood flow; de-air IV lines; endocarditis
prophylaxis
Musculoskeletal: cervical fusion may decrease neck
extension; syndactyly may make vascular access
difficult
Neurologic: caution with premedication if elevated ICP
Preoperative labs: hematocrit, type/screen
Airway management: no reported cases of difficult
intubation; airway obstruction may occur
intraoperatively or postoperatively
Cardiac: emphasis on balancing pulmonary and
systemic blood flow; de-air IV lines; endocarditis
prophylaxis
Musculoskeletal: cervical fusion may decrease neck
extension; syndactyly may make vascular access
difficult
Neurologic: caution with premedication if elevated
ICP; eyes require protection if ocular proptosis
present
Preoperative labs: hematocrit, type/screen
Airway management: no reported cases of difficulty
with ventilation or intubation
Musculoskeletal: cervical fusion may decrease neck
extension; syndactyly may make vascular access
difficult
Neurologic: caution with premedication if elevated ICP
Preoperative labs: hematocrit, type/screen
Airway management: small mandible may make
intubation difficult; obesity may make ventilation
difficult
Musculoskeletal: syndactyly may make IV access
difficult
Neurologic: caution with premedication if elevated ICP
Preoperative labs: hematocrit, type/screen
Airway management: may be a difficult intubation;
may have airway obstruction during awake or sleep
states; caution with premedication
Neurologic: caution with premedication if elevated ICP;
eyes require protection if ocular proptosis present
 600 ANESTHESIA AND UNCOMMON DISEASES
FIGURE 21-13  Child with Apert's syndrome. (From Buchman SR,
Muraszko KM: Syndromic craniosynostosis. In Lin KY, Ogle RC, Jane JA,
editors: Craniofacial surgery: science and surgical technique,
Philadelphia, 2001, Saunders.)
Pierre Robin sequence is characterized by retrognathia,
glossoptosis (tongue falling to the back of the throat), and
airway obstruction and probably occurs secondary to a fixed
fetal position in utero that inhibits mandibular growth.
Management of this sequence depends on the severity of
respiratory distress and airway obstruction. Infants with
mild obstruction and minimal respiratory distress who can
continue to feed may require only prone positioning or no
intervention. For more severe respiratory distress, the tongue
can be surgically attached to the lower lip (tongue-lip adhe-
sion) to decrease airway obstruction and allow the mandible
to grow.
Airway management in the infant with Pierre Robin
sequence can be challenging because of difficulty with mask
ventilation and intubation. The LMA has been success-
fully used to ventilate and to assist in the intubation of these
patients.66,67 Nasal intubation with the flexible fiberoptic scope
has also been described.68 In infants who present with sig-
nificant difficulty with ventilation or intubation, aside from
oropharyngeal and oronasal airways, a suture (0-silk) can be
placed at the base of the tongue to displace the tongue anteri-
orly to assist with ventilation or intubation.
Hemifacial microsomia is characterized by unilateral or
asymmetric development of the facial bones and muscles and
frequently involves the ear. This manifests as hypoplasia of the
malar-maxillary-mandibular region and usually involves the
temporomandibular joint. The defect occurs from an anom-
aly of the first and second branchial arches and is believed
to be secondary to a fetal vascular accident. Goldenhar's
syndrome is a subset of hemifacial microsomia and is com-
posed of hemifacial microsomia, epibulbar dermoid, and rib
or ­vertebral anomalies. The vertebral pathology can involve
the cervical vertebrae and can significantly reduce range of
motion. Other associated anomalies of hemifacial microso-
mia include cardiac (ventricular septal defect, tetralogy of
Fallot, coarctation), renal, and neurologic (hydrocephalus)
defects. Patients with hemifacial microsomia can have signif-
icant upper airway obstruction and obstructive sleep apnea.
Airway management is a major concern in hemifa-
cial microsomic patients. Mask ventilation may be difficult
because of the facial asymmetry. Intubation is more chal-
lenging because of micrognathia, asymmetric mandibular
hypoplasia, and potentially from decreased cervical range
of motion. This difficulty may decrease with age but may
increase after surgical reconstruction. Successful ventilation
and intubation of an infant with Goldenhar's syndrome has
been reported with an LMA and flexible fiberoptic scope.69
Successful intubation has also been described with the
­glidescope in this population.69,70
Surgical Correction
Craniofacial anomalies are surgically corrected to improve
form and function and to minimize disability. Airway
obstruction, increased ICP, developmental delay, and
visual loss are some of the pathologic processes that may be
­corrected or prevented with appropriate surgical ­intervention.
Procedures to correct these deformities include strip
­craniectomy ­(endoscopic or open), cranial vault remodel-
ing, ­frontal-orbital advancement, midface advancement (Le
Fort I, Le Fort III, monoblock advancement), and distraction
­osteogenesis. Craniectomy, remodeling, and advancement are
surgical approaches to correct craniosynostosis. The goal is to
release the synostotic sutures and open up the cranium to
allow brain growth and development. The endoscopic strip
craniectomy involves less blood loss but because of premature
refusion, is usually reserved for patients with sagittal synos-
tosis. The surgical approach for the open strip craniectomy,
cranial vault remodeling, and frontal-orbital advancement is
through a bicoronal incision. Subperiosteal dissection allows
access to the upper facial skeleton for surgical manipulation
(Fig. 21-14). These procedures are performed during the first
year of life. Blood loss can be significant, and preparations to
ensure patient safety include adequate IV access and availabil-
ity of blood products.
Mandibular advancement procedures are frequently per-
formed to correct appearance, malocclusion, and airway obstruc-
tion. These can be performed with distraction o ­ steogenesis and
during infancy.
Distraction osteogenesis was developed to elongate bone by
creating a bone cut (osteotomy) and distracting the two ends.
first used by orthopedic surgeons but not for craniofacial
­surgery until 1992, McCarthy et  al.71 described ­distraction
osteogenesis to lengthen the human mandible. This tech-
nique has now been used in many children to distract the
mandible and midface, used to correct appearance and upper
airway obstruction (Fig. 21-15). Airway obstruction has been
­corrected using distraction osteogenesis in infants as young
as 14 weeks.72
 Chapter 21  The Pediatric Patient 601

FIGURE 21-14  Bicoronal incision (A) with extensive

subperiosteal dissection (B) provides access for
surgical manipulation of upper facial skeleton. (From
Whitaker LA, Bartlett SP: Craniofacial anomalies. In
Jurkiewicz J, Krizek T, Mathes S, Ariyan S, editors:
Plastic surgery: principles and practice, St Louis,
1990, Mosby, p 107.)

A B

associated with some of the syndromes (e.g., Treacher Collins,

Apert's, Pfeiffer's, Carpenter's, hemifacial microsomia). Some of
these infants and children may have increased ICP, manifesting
as headaches, vomiting, and somnolence.
A thorough airway examination may be difficult to per-
form on an infant. Features that may predict difficulty with
mask ventilation include midface hypoplasia and enlarged
tongues. In addition, a small mandibular space, decreased
jaw opening and translocation, and decreased neck flex-
ion and extension predict difficult intubation. Identifying
a heart murmur may uncover an underlying congenital car-
diac defect. In infants with syndactyly, identifying potential
IV and arterial access sites is critical. For reconstructions that
involve ­significant blood loss, a preoperative hematocrit and
type and crossmatch should be performed. Former premature
infants and infants younger than 1 month should have their
glucose ­level monitored. Premedication can be performed for
most ­children older than 1 year but is rarely necessary in those
younger than 10 months. Children with evidence of airway
obstruction or acutely elevated ICP should not receive a pre-
medicant. Endocarditis prophylaxis is not typically required
in patients with congenital heart disease having craniofacial
FIGURE 21-15  Mandibular distractor in infant with Pierre Robin
surgery.
sequence. (Courtesy Joseph E. Losee.) Airway management in these patients may be very
­challenging. As previously stated, the difficulty may present
during attempts at ventilation, intubation, or both. Although
ANESTHETIC MANAGEMENT difficult airways are not common, the incidence is higher in
The anesthetic management of infants with craniofacial anoma- patients with congenital syndromes and in those with previ-
lies begins with a complete preoperative evaluation. The history ous reconstruction. Many techniques have been successfully
should define the anomaly and identify if there is an associated described in infants (e.g., Bullard laryngoscope, LMA, flexi-
syndrome. Infants and children with syndromes may have more ble fiberoptic scope, glidescope, retrograde intubation).57,68,73
difficult airways, other organ involvement, and more compli- A combination of techniques may be required to secure the
cated surgical repair with more bleeding. Associated anomalies airway. For example, the LMA has been used to facilitate the
that can present a challenge to the anesthesiologist include facial passage of the fiberoptic scope and endotracheal tube (ETT).58
and airway features that make mask ventilation and intubation Some infants with craniofacial anomalies require tracheos-
difficult. Airway pathology can also cause obstruction, and tomy because of significant upper airway obstruction.65,74
some of these children have obstructive sleep apnea. History Adequate preparation entails having all the necessary equip-
of fatigue or sweating with feedings, cyanosis, and syncope ment available and experienced personnel, perhaps also with a
suggests an underlying cardiac anomaly. Cardiac pathology is pediatric otorhinolaryngologist immediately available.
 602 ANESTHESIA AND UNCOMMON DISEASES
Several intraoperative considerations exist when man-
aging the anesthetic for craniofacial repairs. Often these
­procedures are long and expose infants to the risks of hypo-
volemia, hypothermia, blood loss, and venous air emboli. The
craniofacial procedures performed during the first year of
life include ­cranial vault remodeling, fronto-orbital advance-
ment, strip craniectomy, and distraction osteogenesis. The
cranial-based procedures can involve significant blood loss
because of the duration of the procedure and also because
of complications such as entering the sagittal sinus. In some
centers 90% to 100% of the infants undergoing these proce-
dures will require a blood transfusion.75 However, some cen-
ters have significantly reduced blood transfusions through
a perioperative blood conservation program, including cell
salvage and preoperative epogen.76 Even the endoscopic strip
craniectomy, which is typically performed to correct s­ agittal
synostosis and results in less blood loss, can still produce
significant hemorrhage. Infants are particularly at risk of
being exposed to transfusions because they can present to
the OR at the nadir of their physiologic anemia (2-3 months).
Preparation for these procedures requires a baseline hema-
tocrit and a type and crossmatch. Adequate IV access needs
to be obtained for resuscitation. In an infant, at least two
large-bore (22- to 18-gauge) peripheral IV catheters should
provide adequate access. Arterial pressure monitoring is rec-
ommended for beat-to-beat analysis of blood pressure and
intravascular volume status, as well as for arterial blood gas
(ABG) monitoring.
Techniques to minimize blood loss have been proposed and
include preoperative recombinant erythropoietin, acute nor-
movolemic hemodilution, induced hypotension, electrocautery,
aprotinin, and use of a cell saver. Preoperatively, recombinant
erythropoietin may decrease the transfusion requirements in
infants having craniosynostosis repair.76 The reported dose
of erythropoietin is 300 to 600 units/kg subcutaneously one
to three times weekly, along with oral iron supplementation.
Erythropoietin is started 3 weeks before surgery. A prospective
study of once-weekly dosing decreased the incidence of transfu-
sion in infants having craniosynostosis repair from 93% to 57%.61
Antifibrinolytics can reduce the transfusion requirements in
infants having cranial vault reconstructions. Two p ­ rospective
blinded studies demonstrated a reduction in allogeneic blood
exposure in infants having craniofacial surgery for craniosynos-
tosis.77,78 A 50-mg/kg loading dose of tranexamic acid was fol-
lowed by 5 mg/kg/hr.
In the past, the use of cell saver has been reported as being
impractical for small pediatric patients because of the size of
the receptacle.79 Recently, the cell-saver reservoirs are available
in sizes as small as 55 mL. This technology may reduce the rate
of autogenous blood transfusion in infants having craniofa-
cial surgery. In a prospective analysis evaluating the use of cell
saver with a 55-mL pediatric bowl in patients pretreated with
erythropoietin, only 30% of those infants having cranial vault
remodeling required allogeneic blood.80
Venous air embolism (VAE) is a potential complication of
craniofacial and neurosurgical procedures. It can present as
hemodynamic instability and can result in death. VAE can
occur frequently in pediatric patients having cranial-based
procedures. A prospective study using a precordial Doppler
detected VAE in 82% of infants and children having cranio-
synostosis repair; 31% developed hypotension secondary to
VAE, but none developed cardiovascular collapse.81 This is
higher than the previously reported incidence of 66%.82 Infants
may be at increased risk of VAE because they can hemor-
rhage significantly during cranial vault remodeling, resulting
in low central venous pressure (CVP). In addition, the rela-
tively large size of the infant head may raise the surgical site
above the level of the heart, thereby increasing the pressure
gradient for air entrainment. Some advocate the placement of
central venous catheters to monitor the CVP trend and mini-
mize the risk of air embolism. However, no data suggest that
CVP monitoring decreases the risk of VAE. Management of
VAE begins with preventing hypovolemic states by provid-
ing adequate volume resuscitation and using a precordial
Doppler for early d ­ etection of VAE. Lowering the head of the
bed, flooding the surgical field with saline, applying bone wax,
­discontinuing nitrous oxide, and providing inotropic support
are all ­measures used to manage VAE acutely.
Craniofacial procedures can last several hours.
Complications resulting from long surgical procedures include
skin breakdown, neuropathic injury, and hypothermia.
Attention must be paid to the initial setup to ensure adequate
positioning and padding to minimize these ­intraoperative
injuries. Infants having cranial vault remodeling may be posi-
tioned prone, and attention to protecting the face and eyes is
important. Patients with syndromes that alter the ­architecture
of the midface may present a challenge when placed prone
because adequately protecting the face and eyes may be more
difficult; Figure 21-16 shows an example of the initial setup.
The infant is placed on a full access Bair hugger to minimize
hypothermia, and the surgical site (head) is then isolated from
the body using plastic drapes. This not only minimizes con-
vective and radiant heat losses, but also prevents conduc-
tive heat loss to a wet bed from irrigation and blood. Blood
­products should be warmed through a fluid warmer before
administration (except for platelets).
Postoperative Management. The postoperative manage-
ment of infants having craniofacial surgery depends on coexist-
ing morbidities and the procedure performed. Infants who have
had distractors placed may have a more difficult airway after
extubation because of location of the device. Mask v­ entilation
can be difficult with mandibular distractors. Airway equip-
ment, including appropriately sized LMAs, should be available
after extubation. External maxillary distractors are not typi-
cally placed in infants. However, their use in older children
can make access to the airway more challenging, and person-
nel and equipment to remove part of the device are impor-
tant in the OR.83 Infants having cranial vault remodeling and
frontal-orbital advancement can e­ xperience ­significant blood
loss intraoperatively. Providing these patients are ­adequately
resuscitated and are hemodynamically stable, they can often

be extubated in the OR. Infants with difficult airway, signifi-
cant airway obstruction, or who have experienced intraopera-
tive complications may benefit from delayed extubation in the
ICU/OR after their condition has stabilized. Ongoing blood
loss is common after major c­ raniofacial surgery, and infants
may require repeat transfusions in the immediate postoper-
ative setting. Other complications include cerebral edema,84
visual changes,85 CSF leak,86 infection,87 ­electrolyte abnormali-
ties (hyponatremia),84,88 metabolic acidosis, and transfusion
reactions.
MEDIASTINAL MASSES
Mediastinal masses in infants and children present a diagnos-
tic and therapeutic dilemma to the medical team caring for
them. Careful communication between the oncologists, pedi-
atric surgeons, anesthesiologists, radiologists, and intensivists
is important for a favorable outcome. An understanding of
the pathology, clinical presentation, diagnosis, imaging, and
treatment is instrumental in the efficient and safe care of these
­children with mediastinal masses.
Anatomic Considerations. A classification of mediastinal
masses based on location is presented in Table 21-3. The ante-
rior mediastinum is the zone posterior to the sternum, anterior
to the pericardium, superior to the diaphragm, and inferior
to the plane through the sternomanubrial junction. Anterior
mediastinal masses are common in children. The most com-
mon anterior mediastinal masses are teratomas, thymomas,
Chapter 21  The Pediatric Patient 603
FIGURE 21-16 Operating
room setup for posterior
cranial vault remodeling.
Note application of forced-
warm-air plastic sheets to
isolate the head from the body.
This creates a barrier to fluids
(blood, prep solution, irrigation).
Special attention to avoid ocular
pressure is essential. (Courtesy
Joseph E. Losee.)
and lymphomas (Hodgkin's and non-Hodgkin's lymphoma).
They account for approximately 40% of the tumors. The ­middle
mediastinum is defined by the pericardium and o ­ rigins of the
great vessels. The posterior mediastinum is o ­ utlined by the peri-
cardium and great vessels anteriorly, the v­ ertebral ­column pos-
teriorly, and the parietal pleurae laterally. Generally, ­neurogenic
tumors occur in the posterior mediastinum, of which neuro-
blastoma is the most common.89
Pathology. Anterior mediastinal masses have been reported
mostly in older children, but there are several cases reported
in infants.90–92 Most masses in children younger than 2 years
are benign. Malignant masses are more frequently found in
older children and are mainly lymphomas, Hodgkin's and
non-Hodgkin's, as well as neurogenic tumors.93,94 Masses of
the mediastinum surround the large airways, heart, and great
vessels. Compression of the airways and great vessels can
result in respiratory and cardiovascular symptoms.
Clinical Presentation. The signs and symptoms depend
on the size and location of the mediastinal mass and on the
extent of compression of the tracheobronchial tree and the
cardiovascular system.95 Symptoms related to compression
of the tracheobronchial tree include cough, dyspnea, and
orthopnea. The symptoms are generally exacerbated when the
child is in the supine position. Signs of respiratory compro-
mise include stridor, cyanosis, wheezing, and decreased breath
sounds. Compression of the cardiovascular system manifests
as fatigue, headaches, fainting spells, and orthopnea and may
cause SVC obstruction or SVC syndrome: edema of the head
 604 ANESTHESIA AND UNCOMMON DISEASES

TABLE 21-3  n Mediastinal Tumors: Benign vs. TABLE 21-4  n Clinical Findings in Patients with
Malignant by Location Mediastinal Masses

Benign Malignant Physical

History Examination Laboratory
ANTERIOR MEDIASTINUM
Thymoma Thymic carcinoma AIRWAY
Thymic cyst Thyroid carcinoma Cough Decreased breath Chest radiograph
Thymolipoma Seminoma Cyanosis sounds (posteroanterior
Thymic hyperplasia Mixed germ cell Dyspnea Wheezing and lateral to
Thyroid Lymphoma Orthopnea Stridor look for tracheal
Cystic hygroma Thymic carcinoid Cyanosis deviation or
Parathyroid adenoma compression)
Foramen of Morgagni hernia Flow-volume loops,
supine and sitting
MIDDLE MEDIASTINUM
Benign adenopathy Lymphoma CARDIOVASCULAR
Cysts Metastases Fatigue Neck or facial Chest radiographic
Esophageal masses Esophageal cancer Faintness edema changes
Hiatal hernia Thyroid carcinoma Headache Jugular distention in cardiac
Cardiovascular structures Shortness of Papilledema silhouette
Lipomatosis breath and Blood pressure Echocardiogram
Cardiovascular structures orthopnea changes or done supine and
Cardiophrenic fat pad Cough changes in pallor sitting
Foramen of Morgagni hernia with postural
Ectopic thyroid changes
Pulsus paradoxus
POSTERIOR MEDIASTINUM
Neurofibroma Neuroblastoma Data from Pulleritz J, Holzman RS: Can Anaesth Soc J 36:681-688, 1989.
Schwannoma
Foramen of Bochdalek hernia believed to be at highest risk of perioperative ­complications.
Meningocele Anesthesia was safely provided to all the patients, and the t­ issue
Data from Yoneda KY, Louie S, Shelton DK: Curr Opin Pulm Med 7:226-233, 2001. sample was still adequate to make a diagnosis.99 Limiting the
duration of treatment or shielding an area of the tumor from
the radiation may improve the chances of a tissue diagnosis.
and neck; distended neck veins and collateral veins on the chest However, empiric therapy can alter the tissue and should be
wall; plethora; cyanosis of the face, neck, and arms; ­proptosis; considered as a last resort.
and Horner's syndrome.96 Symptoms of cerebral edema from
Preanesthetic Evaluation. Many mediastinal tumors are
venous hypertension can occur with SVC obstruction and
asymptomatic and are first noted on routine chest radiogra-
include headaches, syncope, and lethargy (Table 21-4).
phy. In some studies, only 30% of children with Hodgkin's
Diagnosis. Procurement of tissue for diagnosis of medias- disease demonstrated symptoms.100 Chest CT with iodin-
tinal masses can be achieved by several methods. Fine-needle ated contrast is the study of choice to determine the ­location
aspiration biopsy can be performed by experienced interven- and extent of compression of adjacent structures in the
tional radiologists, but carries a 15% inconclusive result.97 This chest. Magnetic resonance imaging (MRI) is superior to CT
requires surgical biopsy to ascertain the diagnosis. Surgical for imaging nerve plexus and blood vessels. MRI is useful
approaches depend on the location of the mass. The clinician when iodinated contrast is contraindicated or in the diagno-
should always consider collecting tissue from a remote loca- sis of thyroid masses.101 When cardiovascular structures are
tion, such as a cervical lymph node or pleural fluid, under involved, ­echocardiography, contrast medium–enhanced CT,
local anesthesia. If these sites cannot be used, a tissue sample or cardiac MRI is essential. Echocardiography may provide
must be collected from the mediastinum. dynamic information regarding ventricular compression and
Anterior mediastinotomy (Chamberlain procedure), in ­performance. Pulmonary function tests (PFTs) in the supine
which the second or third interspace is incised for exposure, and sitting positions are important in determining the extent
allows access to the anterior mediastinal, right paratracheal, of airway compromise. The supine position tends to exacer-
and aortopulmonary areas.97,98 Mediastinoscopy and thora- bate the respiratory compromise. Intrathoracic obstruction
coscopy with video assistance have become widely accepted causes distortion of the maximal expiratory flow rate, whereas
for the diagnosis and management of mediastinal disease. If extrathoracic obstruction causes distortion of the inspiratory
local anesthetic techniques are not possible and the patient flow rate. An equal reduction of both inspiratory and expi-
is ­considered at high anesthetic risk, empiric therapy with ratory flow rates is affected by fixed lesions. In patients with
irradiation or corticosteroids may be considered. A  brief
­ mediastinal masses, PFTs reveal both an obstructive and a
­preoperative course of radiation has been described in patients restrictive impairment102 (Fig. 21-17).

Presentation
4 4
Predicted
3 3
Flow, liters/second
Flow, liters/second
2 Sitting 2 reduction in maximum flows
Supine
1 1
0 0
0 1 2 0
Volume, liters
The essential component of the preanesthetic evaluation is
to identify those patients at highest risk of perioperative respi-
ratory and cardiovascular complications. One study suggests
that the narrowing of the trachea and bronchi to less than 50%
predicted on CT indicates an increase in anesthetic risk.103 In
another study, all children with anterior mediastinal masses
who demonstrated tracheal cross-sectional areas greater than
50% predicted or a peak expiratory flow rate greater than 50%
predicted underwent uneventful general anesthesia.102 The
only symptom that appears to correlate with a cross-sectional
area of the airway is orthopnea. In the previous study, no
patients with a cross-sectional area of the airway greater than
50% demonstrated orthopnea; and in several cases, ­orthopnea
was the only symptom that consistently preceded respira-
tory collapse on induction of anesthesia.92,103,104 In adults it
appears that those with cardiorespiratory signs and symp-
toms, both obstructive and restrictive abnormalities on PFTs,
and those with tracheal compression greater than 50% are at
greatest risk of having life-threatening, early p ­ ostoperative
complications.105
ANESTHETIC MANAGEMENT
Several reports have described the risk of life-threatening
airway obstruction and cardiovascular collapse during gen-
eral anesthesia in patients with mediastinal masses.92,104,106
These catastrophic outcomes occur because of the physiologic
changes during general anesthesia. During general anesthesia,
lung volume is reduced from loss of inspiratory muscle tone,
as well as from loss of the tethering effect of the expanded lung
on the airway. The normal transpleural pressure gradient that
distends the airway during inspiration is diminished, and this
further compromises the airway caliber. During spontaneous
ventilation, the diaphragm moves caudad. While the patient is
paralyzed with neuromuscular blocking agents, the ­diaphragm
shifts cephalad at the end of expiration.107 This change further
compromises the airway. The size of the infant may magnify
the physiologic consequences of anterior mediastinal masses.
Chapter 21  The Pediatric Patient 605
Post chemotherapy
Predicted
FIGURE 21-17 Expiratory
flow-volume loops in 8-year-
Sitting
old patient with anterior
mediastinal mass. Note the
that improves after 4 days
of chemotherapy. (From
Supine Shamberger RC et al: J Pediatr
Surg 26:138-142, 1991.)
1 2
Volume, liters
The increased cartilaginous component of the ribs increases
the compliance of the thoracic wall, making it less likely to
support the weight of a tumor. Also, a reduction in an already-
small airway will significantly increase airway r­esistance
(Poiseuille equation demonstrates that resistance of laminar
flow in a tube is inversely proportional to fourth power of
radius).
Laminar gas flow through a narrow airway is best main-
tained with spontaneous ventilation.107 Positive-pressure
­ventilation (PPV) and airway obstruction disrupt ­laminar
flow and increase the resistance to gas flow in the airways. An
inspired mixture of helium and oxygen decreases resistance to
gas flow through the airways because of helium's lower ­density
compared with oxygen.108 During turbulent flow, the p ­ ressure
gradient required to produce a given gas flow becomes
directly proportional to the density of the gas. Also, helium's
lower density increases the likelihood of ­laminar flow, thus
reducing resistance further. Heliox (­helium-oxygen) has been
described in a 3-year-old patient with a large, symptomatic
anterior mediastinal mass who underwent g­ eneral ­anesthesia
with LMA.109
For patients undergoing diagnostic procedures or catheter
placement, an effort should be made to perform the procedure
under local anesthesia with sedation. General anesthesia can
be performed safely; however, there needs to be a high index
of suspicion for respiratory and cardiovascular complications.
The induction of anesthesia can be achieved with either IV
or inhalational techniques. The emphasis should be on main-
taining spontaneous ventilation. Airway management with
mask, LMA, and ETT has been described.109,110 Reinforced
armor tubes have also been described to help maintain air-
way patency, and rigid bronchoscopy may become n ­ ecessary
should complete airway collapse occur.90,91,111 In older c­ hildren
who require intubation but are clinically too tenuous for gen-
eral anesthesia, a fiberoptic intubation can be accomplished
with sedation and topical anesthesia of the airway. The
Chamberlain approach has been performed under sedation
 606 ANESTHESIA AND UNCOMMON DISEASES
FIGURE 21-18 Algorithm
for anesthetic management
in child with anterior
mediastinal mass. CBC,
Complete blood count; CPB,
cardiopulmonary bypass; CT, Airway and/or cardiovascular
computed tomography; CXR, obstruction (e.g., stridor /or
chest radiograph; LP, lumbar
puncture; PICU, pediatric
intensive care unit; SVC,
Biopsy under local
superior vena cava. (Data from anesthesia, tracheostomy,
Hammer GB: Pediatr Anesth 14: CPB available
95-97, 2004.)
BOX 21-5   n PATIENTS WITH MEDIASTINAL MASSES:
ANESTHETIC MANAGEMENT
Evaluate with computed tomography, echocardiography, pulmonary
function studies, and chest radiography.
Attain intravenous (IV) access in the lower extremity if superior vena
cava syndrome is present.
Prepare to change position lateral or prone.
Maintain spontaneous ventilation.
Have rigid bronchoscope available.
Have cardiopulmonary bypass on standby.
with local anesthetic infiltration in children and should be
considered for those at greatest risk of complications. In
patients with respiratory compromise, IV access should be
secured before the start of anesthesia, and in patients with
SVC syndrome, IV access should be secured in the lower
extremities. Because the supine position during induction
of anesthesia may ­compromise an already-tenuous airway,
patients with mediastinal masses should be positioned in a
semisitting ­position. If severe ­airway ­obstruction develops,
the patient should be placed in the prone or lateral p ­ osition.
Patients thought to be at greatest risk of ­ cardiovascular
c­ollapse should be considered preoperatively for cardiopul-
monary bypass (Fig. 21-18 and Box 21-5).
CONGENITAL MALFORMATIONS OF LUNG
Bronchogenic and Pulmonary Cysts
Bronchogenic cysts occur from abnormal budding of bron-
chial tissue. The cysts may occur anywhere from the medi-
astinum to the periphery, depending on when they separate
during embryogenesis. They can be classified as mediastinal
(central) or pulmonary (peripheral). Mediastinal cysts are
more common and are usually located in the paratracheal and
Undiagnosed mediastinal mass
Consults: pediatrics, hematology/oncology, anesthesiology, PICU,
radiation oncology, pediatric surgery
Nondiagnostic: CBC, LP, bone marrow
aspiration/biopsy
Perform: CT flow-volume loops if feasible
No airway or cardiovascular
obstruction (e.g., no stridor or
SVC syndrome) SVC syndrome)
Biopsy under local
anesthesia not feasible
Biopsy
Local anesthesia with
Radiation therapy sedation
or
General anesthesia
BOX 21-6   n PATIENTS WITH BRONCHOGENIC CYSTS:
ANESTHETIC MANAGEMENT
Preoperative Evaluation
History: May have respiratory symptoms, cough, fever, and recurrent
lung infections.
Chest radiography/computed tomography
Evaluate location and size of cyst.
Evaluate for cardiac compression.
Laboratory studies: Hematocrit, type/screen, oxygen saturation
Anesthetic Considerations
If fluid-filled cyst, consider single-lung ventilation.
Avoid nitrous oxide.
paraesophageal area, with the majority occurring between the
trachea and the esophagus. The majority of pulmonary cysts
occur in the lower lobes. Bronchogenic cysts may be filled with
air or mucoid or serous fluid.112,113 Although unlikely, they may
communicate with the tracheobronchial tree. Most patients
are asymptomatic, but if present, symptoms are related to air-
way, respiratory, and cardiovascular compromise from cyst
enlargement or infection. Infection may present as chronic
cough, fever, and recurrent pneumonia.114 Diagnosis is made
with chest radiography and chest CT. The m ­ anagement of
symptomatic patients is surgical resection (Box 21-6).
ANESTHETIC MANAGEMENT
Concerns regarding the anesthetic management include respi-
ratory compromise secondary to cyst expansion from PPV
and/or nitrous oxide (N2O) and spillage of cyst contents into
the airway. A review of the anesthetic management of 24 cases
of bronchogenic cysts indicated that these complications do
not occur as often as previously thought. All the patients in
this case series received muscle relaxation and PPV intra-
operatively, and no problems were encountered. There were

three reports of excessive tracheal secretions, possibly related
to drainage of fluid-filled cysts. Repeated suctioning was
required, but no airway compromise was reported. The use
of one-lung ventilation was not described.109 Spillage of cyst
fluid in the airway with transient oxygen desaturation has been
reported after induction of anesthesia. Lung isolation was also
not employed in this case.115 During the anesthetic manage-
ment of bronchogenic cysts, lung isolation techniques may be
advantageous, particularly with the manipulation of fluid-filled
cysts. Although PPV and N2O appear to be reasonably well tol-
erated, the degree of associated risk is unclear.
Congenital Cystic Adenomatous Malformation
Congenital cystic adenomatoid malformation (CCAM) occurs
secondary to an abnormal overgrowth of terminal bronchioles
with a lack of mature alveoli, bronchial glands, and cartilage.116
They are rare and occur at an estimated incidence of 1:25,000
to 1:35,000 live births.117 These cysts communicate with the
tracheobronchial tree. CCAMs may be made up of a solid mass
or a cystic structure that may consist of a single large domi-
nant cyst or multiple cysts. Stocker classified CCAMs into
three groups based on size and the histology of the cyst lining.
Associated anomalies include renal agenesis and d ­ ysgenesis
and prune-belly syndrome. Clinical signs and symptoms at
presentation depend largely on the size of the mass. The cystic
lesions communicate with the tracheobronchial tree and may
B A, Plain film; B, CT scan;
C
Chapter 21  The Pediatric Patient 607
have a ball-valve effect, becoming distended secondary to gas
trapping. In utero compromise with anasarca and ascites may
occur if the lesion is large enough to impair fetal circulation.
Compression of surrounding structures can result in lung
hypoplasia. Neonates and infants may present with significant
respiratory distress, requiring immediate resection. Patients
presenting after the neonatal period often develop recurrent
pulmonary infections localized to one lobe.118 Diagnosis is
made by clinical symptoms, chest radiography, and chest CT
(Fig. 21-19). In-utero diagnosis is made during prenatal ultra-
sound. Definitive treatment is surgical removal of the affected
lobe (Box 21-7).
ANESTHETIC MANAGEMENT
Communication of the CCAM with the tracheobronchial
tree potentially increases the anesthetic risk. PPV and N2O
may expand the lesion and cause cardiovascular and respi-
ratory compromise. Spillage of cyst contents during anesthe-
sia and ETT obstruction has also been reported.115 Induction
of anesthesia by an inhalational anesthetic with spontaneous
ventilation may be preferential, but maintaining spontaneous
ventilation during thoracotomy or thoracoscopy is difficult
and not feasible. Lung isolation may be ideal because it not
only minimizes the risk of cyst overinflation during PPV but
also minimizes the risk of exposure to cyst contents should
it rupture. Lung isolation in neonates and infants can be
achieved either with purposeful main stem intubation of the
FIGURE 21-19 Microcystic
adenomatoid malformation.
C, surgical specimen. (From
Zitelli BJ, Davis HW: Atlas of
pediatric physical diagnosis, ed
4, St Louis, 2002, Mosby, p 565.)
 608 ANESTHESIA AND UNCOMMON DISEASES
BOX 21-7   n CONGENITAL CYSTIC ADENOMATOUS
MALFORMATION (CCAM): ANESTHETIC
MANAGEMENT
Preoperative Evaluation
History: Symptoms depend on size of mass, respiratory distress (may
be severe), and recurrent lung infection
Chest radiography/computed tomography: Evaluate location and size
of CCAM
Laboratory studies: Hematocrit, type/screen, oxygen saturation
Associated Anomalies
Renal agenesis or dysgenesis
Prune-belly syndrome
Anesthetic Considerations
Spillage of CCAM contents can occur into airway; consider single-lung
ventilation
CCAM can expand; consider avoiding nitrous oxide; consider
single-lung ventilation
right or left bronchus or with placement of a 5-Fr bronchial
blocker. The advantage of the bronchial blocker is that it may
allow better protection from drainage of cyst contents into the
contralateral lung. However, neither option for lung isolation
allows suctioning, oxygenation, or continuous positive airway
pressure (CPAP) to the isolated lung.
Standard surgical exposure is through a thoracotomy.
However, the development of smaller equipment has allowed
this procedure to occur less invasively using a thorascopic
approach. The potential advantages include less pain and
faster recovery, with potentially shorter hospital stays. Lung
isolation may facilitate the surgeon's exposure, and some
centers routinely employ this technique. The CCAM has
also been removed while the fetus is on uteroplacental sup-
port during the EXIT procedure. Prenatal diagnosis provides
accurate prognostic information for appropriate management
and parent counseling. Antenatal fetal intervention is recom-
mended in hydropic fetuses of less than 32 weeks’ gestation.
Early delivery should be considered in fetuses after 32 weeks
using EXIT.119
Pulmonary Sequestration
Pulmonary sequestration is characterized by a segment of
lung tissue that is ectopic and serves no ventilatory func-
tion. It has its own vascular supply, however, typically ­arising
from the thoracic or abdominal aorta.120 Venous drainage
has been reported through the pulmonary, azygous, or por-
tal vein. Unlike the cystic malformations of the lung, seques-
trations have no tracheobronchial communications and are
not at risk of spillage of contents or expansion. The two types
of pulmonary sequestrations are intralobar and extralobar.
The intralobar or intrapulmonary sequestration is located
within a lobe and has no distinct pleural covering. Extralobar
­sequestrations have their own pleural covering and in 50% of
cases are ­associated with other congenital anomalies, includ-
ing communication with the GI tract, duplication of the colon
FIGURE 21-20  Pulmonary sequestration. Chest radiograph
demonstrating scimitar syndrome in child with pulmonary
sequestration. (From Zitelli BJ, Davis HW: Atlas of pediatric physical
diagnosis, ed 4, St Louis, 2002, Mosby, p 134.)
and ileum, cervical vertebral anomalies, pulmonary hypo-
plasia, diaphragmatic defects, and bronchial atresia of right
upper lobe with anomalous pulmonary venous drainage.
Sequestration with anomalous pulmonary venous drainage
has the characteristic appearance of a wedge shape along the
right heart border, resembling a scimitar on chest radiogra-
phy120 (Fig. 21-20).
Clinically, these two types of sequestrations present dif-
ferently. Often, intralobar sequestrations are asymptomatic
and may not present until later childhood or adolescence.121
Extralobar sequestrations usually present before age 2 years.
Symptoms include cough, pneumonia, and failure to thrive.
Plain radiographs will identify sequestrations but are unable
to distinguish intralobar from extralobar sequestrations.
Angiography provides definitive diagnosis and identifies
the arterial supply and venous drainage. MRI and ­magnetic
resonance angiography (MRA) may provide high-definition
images and may replace the need for standard angiography.122
Surgical resection is the treatment of choice for symptom-
atic sequestration. Asymptomatic patients may also benefit
from resection to prevent the occurrence of infection. Because
of its separate pleural covering, removal of extralobar seques-
trations can be performed without sacrificing surrounding
lung tissue. However, lobectomy is usually required to resect
intralobar sequestrations because of the intimate relationship
with normal lung.123
Congenital Lobar Emphysema
Congenital lobar emphysema is characterized by overinflation
of a pulmonary lobe secondary to in utero bronchial ball-valve
obstruction. The bronchial obstruction may occur because of
intrinsic or extrinsic compression. Defects of the bronchial
wall cause the intrinsic obstruction. This defect usually occurs
in the upper lobes and is caused by a deficiency in the quan-
tity or quality of the cartilage in the bronchial wall.124 Extrinsic
compression is usually from cardiac or vascular abnormalities.
 Chapter 21  The Pediatric Patient 609

BOX 21-8   n CONGENITAL LOBAR EMPHYSEMA:

ANESTHETIC MANAGEMENT

Preoperative Evaluation
Signs/symptoms: Respiratory distress, cyanosis
Computed tomography: Rule out vascular rings and slings,
intrathoracic masses
Chest radiography: Evaluate size and location of emphysematous lobe
Laboratory studies: Hematocrit, type/screen, oxygen saturation

Associated Anomalies
Cardiac: Congenital heart disease (15%)

Differential Diagnosis
Tension pneumothorax
Bronchial obstruction: foreign body, mucus plug

Anesthetic Considerations
Maintain spontaneous ventilation; consider lung isolation
Avoid nitrous oxide

These abnormalities may include tetralogy of Fallot, patent

ductus arteriosus, and vascular rings or slings. Other causes of
extrinsic obstruction include intrathoracic masses (teratoma),
enlarged lymph nodes, and bronchogenic cysts. Congenital
cardiac deformities occur in approximately 15% of patients
with congenital lobar emphysema125 (Box 21-8).
Most cases of congenital lobar emphysema are diagnosed
by 6 months of age, with 33% diagnosed at birth and 50%
diagnosed by 1 month.126 Respiratory distress and cyanosis are
the most common presenting symptoms. Chest radiography
reveals a large, emphysematous lobe with ipsilateral atelecta-
sis. These findings may be misinterpreted as a tension pneu-
mothorax.127 The differential diagnosis also includes bronchial
obstruction from a foreign body or mucus plug. Accurate
diagnosis is important because surgical management of a for-
eign body or mucus plug would be bronchoscopy, not thoracic
surgery.
ANESTHETIC MANAGEMENT
Definitive treatment for congenital lobar emphysema is lobec-
tomy and is usually performed in patients with hypoxemia
(Pao2 <50 mm Hg), despite supplemental O2.126 Rarely, cases
have resolved spontaneously.128 The primary concern during
anesthetic management is that PPV may expand the emphy-
sematous lobe and cause respiratory and cardiovascular col-
lapse. Maintaining spontaneous ventilation when feasible and
employing lung isolation techniques may minimize this risk.
N2O is also contraindicated because of the risk of expansion of
the emphysematous lobe.
Congenital Diaphragmatic Hernia
Congenital diaphragmatic hernia (CDH) is characterized by a
defect in the diaphragm that allows the herniation of abdomi-
nal contents into the thoracic cavity. The defect occurs on the
left in about 85% of cases, and the most common form is the
herniation through a left posterolateral defect or foramen of
FIGURE 21-21  Congenital diaphragmatic hernia. Postmortem
view shows obliteration of the left pleural cavity and severe
compression of the right heart and lung. (From Zitelli BJ, Davis HW:
Atlas of pediatric physical diagnosis, ed 4, St Louis, 2002, Mosby,
p 563.)
Bochdalek (Fig. 21-21). Herniation through the anterior fora-
men of Morgagni occurs in only 2%. The incidence of CDH
is approximately 1 in 3000 to 5000 births. A typical chest
­radiographic finding is bowel contents herniation into the left
thorax (Fig. 21-22).
The severity of disease correlates with the timing of the
diagnosis, the size of the defect, and the associated anomalies.
The relationship between observed to expected (o/e) lung-
to-head circumference ratio (LHR) and lung-to-body weight
ratio (LBWR) has been used antenally to assess mortality and
prediction of pulmonary hypoplasia.129 These measurements
correlated well in left-sided CDH. In fetuses with LHR less
than 1 or LHR o/e less than 25%, with the liver in the tho-
rax, survival is less than 20%. In utero treatment improved
survival from 20% to 50%.130 Diagnosis before 25 weeks’ ges-
tation and large defects (LHR <1 and liver herniation into
thorax) correlate with increased mortality.129,130 Associated
anomalies can occur in as many as 40% to 50% of CDH
patients.131 The most common of these involve the central
nervous system (CNS) and the cardiac system. Congenital
cardiac defects may include ­ventricular outflow tract obstruc-
tions ­(hypoplastic left heart syndrome, tetralogy, coarctation)
as well as atrial and ­ventricular septal defects.132 GU, GI, and
chromosomal abnormalities also occur in 23%, 17%, and 10%,
respectively133,134 (Box  21-9). Failure of the pleuroperitoneal
 610 ANESTHESIA AND UNCOMMON DISEASES

Other entities may mimic CDH, including a large CCAM

near the diaphragm. Abdominal ultrasound or a CT can help
determine the integrity of the diaphragm. Diaphragmatic
eventration may result from birth trauma or anterior horn cell
neuropathy (Werdnig-Hoffman disease) and can be ­diagnosed
by demonstrating paradoxical diaphragmatic excursion on
ultrasonography or fluoroscopy.136
Medical Management. The goal of medical management
consists primarily of maintaining adequate oxygenation
and ventilation, but most important, it is to avoid ­iatrogenic
­barotrauma from mechanical ventilation (Box 21-10). At deliv-
ery, the patient should be endotracheally intubated. An effort
should be made to minimize bag-mask ventilation before intu-
bation to reduce the risk of gastric expansion. Immediately
after intubation, the gut should be decompressed and vascular
access obtained. The umbilical vein and artery may be used,
or a right radial arterial catheter (for preductal ABG analy-
sis) and a central venous catheter may be placed. Preductal
and postductal oxygenation should be measured to assess the
degree of right-to-left shunting, a surrogate marker of pulmo-
nary hypertension. Shunting through the ductus arteriosus
is suggested if the preductal Pao2 is 15 to 20 mm Hg higher
than the postductal Pao2. Shunting at the level of the foramen
ovale will decrease the predicted value of the preductal Pao2
FIGURE 21-22  Chest radiograph of congenital diaphragmatic and will not produce a gradient compared with the postductal
hernia. (From Zitelli BJ, Davis HW: Atlas of pediatric physical Pao2. Preductal arterial oxygen saturation (Sao2) also reflects
diagnosis, ed 4, St Louis, 2002, Mosby, p 563.) cerebral oxygenation. The ventilatory strategy should achieve
a preductal Sao2 greater than 85%, while maintaining a Paco2
of 45 to 55 mm Hg and a pH greater than 7.3, with peak inspi-
BOX 21-9   n CONGENITAL DIAPHRAGMATIC HERNIA: ratory pressure (PIP) of 25 cm H2O or less.137 Neonates who
ASSOCIATED ANOMALIES require PIP greater than 25 cm H2O for ­adequate oxygenation
Central nervous system: Meningomyelocele, hydrocephalus may need to be ventilated with high-frequency oscillatory
Congenital heart disease: Atrial and ventricular septal defects, ventilation (HFOV) to minimize the risk of ventilator-associ-
coarctation, tetralogy of Fallot ated barotrauma.
Gastrointestinal: Malrotation, atresia
Wung et al.138 first proposed permissive hypercarbia in 1985
Genitourinary: Hypospadias
for infants with persistent fetal circulation. Many centers have
adopted this strategy for neonates with CDH.138 Hypercarbia
Data from David TJ, Illingworth CA: J Med Genet 13:253, 1976.

BOX 21-10   n CONGENITAL DIAPHRAGMATIC HERNIA:

membrane to fuse allows the abdominal contents to enter MEDICAL MANAGEMENT
the thoracic cavity during the 10th week of gestation. This Airway
in utero compression prevents lung development and causes Endotracheal intubation
alveolar and vascular hypoplasia. The degree of pulmonary
Breathing
hypoplasia depends on the size of the defect and the dura- Decompress stomach
tion of the compression. Typically, both lungs are involved, Ventilation goal: positive inspiratory pressure <25 cm H2O, preductal
even though the defect is unilateral. A controversial theory Sao2 >85%, Paco2 = 45 to 55 mm Hg
regarding the embryology of CDH states that the initial defect pH >7.3
Consider high-frequency oscillatory ventilation if unable to oxygenate
is primary pulmonary hypoplasia with secondary diaphrag-
with pressures <25 cm H2O
matic defect.135 Regardless of the etiology, the result is alveo-
lar and vascular ­hypoplasia. Medial thickening occurs in the Circulation
Cardiac echocardiography to:
preacinar and intra-acinar arterioles, causing an increase in Exclude congenital heart disease
pulmonary vascular ­resistance, which ultimately contributes Assess right ventricular function
to persistent ­pulmonary hypertension. Pulmonary hyperten- Assess pulmonary hypertension
sion is a ­significant determinant of ­mortality in ­neonates with Assess right-to-left shunting at ductal level
CDH.

and ductal shunting may be tolerated by the neonate with
CDH, provided there is adequate right-sided heart function
(evaluated with echocardiography) and adequate systemic
perfusion, as demonstrated by normal lactate levels, mixed
venous saturation greater than 70%, and the absence of a met-
abolic acidosis. Patients with evidence of persistent pulmo-
nary hypertension with elevated right ventricular pressures, or
preductal Sao2 less than 85%, may require a trial of inhaled
nitric oxide (iNO). Although there may be a response to iNO
in neonates with CDH, no clear data show that this impacts
survival.139 Neonates with right ventricular dysfunction and
low systemic pressures may require IV fluids and inotropic
support. Predictors of outcome during the initial resuscitation
are inexact. The inability to achieve a preductal Pao2 greater
than 100 mm Hg predicted 100% mortality in one study.140
Apgar scores and birth weight have also been described to pre-
dict mortality in neonates with CDH.141
The benefit of extracorporeal membrane oxygenation
(ECMO) on the morbidity and mortality of CDH is contro-
versial. Some centers reported significant improvement in
survival with the introduction of ECMO.142 However, some
centers have experienced the same survival statistics without
the use of ECMO.143 Also, significant morbidity is associated
with ECMO. Anticoagulation with heparin to prevent clot for-
mation in the ECMO circuit and platelet activation and con-
sumption increase the risk of bleeding. Bleeding may cause
significant morbidity if this occurs in the CNS, and bleed-
ing may complicate attempts at surgical correction while on
ECMO. Inclusion criteria for ECMO include gestational age
after 34 weeks, weight greater than 2 kg, presence of revers-
ible disease, and predicted mortality of greater than 80%.
Neonates with an oxygenation index (OI = Fio2 × mean air-
way pressure × 100/Pao2) greater than 40 to 50 may represent
those at ­greatest risk (>80%) of mortality. Intraventricular
hemorrhage more than grade II or those with another life-
threatening c­ongenital anomaly should be excluded from
ECMO.144 ECMO is considered in neonates with progressive
hypoxia, hypercarbia, and persistent pulmonary hyperten-
sion who have failed other attempts at medical correction,
including iNO, inotropic support, or opening the ductus with
prostaglandin E1.137 A review indicates a possible short-term
benefit with ECMO, but no long-term benefit because of the
­associated morbidity.145
Surgical Management. In the past, CDH was thought to
represent a neonatal emergency requiring immediate surgical
decompression of the thorax. Postoperatively, patients experi-
enced a “honeymoon” period of brief improved oxygenation.
This was soon followed by worsening hypoxia secondary to
increased PVR and increased right-to-left shunting.146 The
poor outcomes with immediate repair raised the question of
whether these patients should be stabilized preoperatively
before surgical repair. No clear data support delayed repair
over early surgical intervention. A prospective randomized
trial evaluated the importance of timing on survival and inci-
dence of ECMO between early (6 hours) versus late (96 hours)
Chapter 21  The Pediatric Patient 611
surgery and found no difference between the groups.147
A Cochrane review again found no clear advantage with
delayed surgical repair after medical stabilization.148
Most often the surgical approach is through a subcos-
tal incision. The majority of the repairs take place through a
left-sided incision. After the abdominal contents are removed
from the thoracic cavity, the bowel is eviscerated from the
abdominal cavity to expose the defect. The diaphragmatic
defect may be closed primarily or with a Gore-Tex patch.
After the abdominal contents are replaced, there may be a
significant e­levation in abdominal pressure with surgical
­
wound ­closure.146 A silo may be required to gradually reintro-
duce the abdominal contents.
Fetal surgery for CDH was initiated after animal mod-
els demonstrated a reversal of lung hypoplasia when dia-
phragmatic hernias were corrected in utero.149 Fetal repair
in humans was first described in 1990.150 Overall success of
the open fetal approach was limited by maternal morbid-
ity, which included premature rupture of membranes and
preterm labor. Fetal intervention was only considered for
those fetuses at highest risk of mortality. Research during
the late 1970s introduced the concept of tracheal o ­ cclusion
to reverse the lung pathophysiology from diaphragmatic
herniation. This concept resulted in a fetal strategy in
­
humans to occlude the trachea temporarily in utero until
birth, “plug the lung until it grows” (PLUG).151–153 However,
this strategy and variations of this strategy have not dem-
onstrated any survival advantage over standard postnatal
­medical management.154
ANESTHETIC MANAGEMENT
Preoperative assessment of the neonate with CDH should
begin with an evaluation of the degree of respiratory com-
promise and pulmonary hypertension. Attention to the type
of ventilatory support and associated ABG values is impor-
tant. Consideration should be given to using the newborn
ICU ventilator or HFOV if there is concern about achieving
adequate ventilation. Cardiovascular evaluation should focus
on identifying any congenital heart defects and the degree
of right-to-left shunting, pulmonary hypertension, and right
ventricular performance. Severe pulmonary hypertension
can result in severe hypoxia, decreased cardiac output, and
metabolic acidosis. This information can be provided from
­echocardiography and preductal and postductal ABG analy-
sis. Associated ­neurologic findings include MMC and hydro-
cephalus. Premature neonates are at risk for development
of ­intraventricular hemorrhage, which excludes them from
ECMO because of the anticoagulation. Head ultrasound is
routinely performed in this population, before ECMO can-
nulation. Hematologic issues require maintaining adequate
hemoglobin (~ 12 mg/dL) and checking for vitamin K admin-
istration at birth. Some patients may be receiving diuretics. An
electrolyte panel should be performed to evaluate for hypoka-
lemia. The ­neonate will already have a nasogastric or ­orogastric
tube in place. If not, this should be placed to decompress the
stomach.
 612 ANESTHESIA AND UNCOMMON DISEASES
Intraoperative management consists of first ensuring
a­ dequate room temperature and using either warming lights
or a forced-warm-air blanket to maintain normothermia.
Induction of anesthesia has been described using both IV and
inhalation techniques. Given the risk of aspiration and the
resulting injury to already-immature lungs, a rapid-sequence
intubation may be preferred after the gastric tube is suctioned
and the neonate is preoxygenated. If any barrier to safe intuba-
tion exists, such as a difficult airway, an awake intubation may
be safest. Mask PPV should be minimized to prevent gaseous
distention of the stomach.
In addition to the standard monitors, a preductal arterial
catheter should be placed, but an umbilical artery catheter
may also be used. Both preductal and postductal pulse oxim-
eters should be placed, and a precordial stethoscope on the
contralateral chest can be used to identify a pneumothorax.
If central venous access is attempted, consideration should be
given to avoid the internal jugular veins, because these may be
future cannulation sites for ECMO.
The hallmark of medical management of CDH patients
is to minimize the risk of iatrogenic ventilatory injury. Peak
pressures should not exceed 25 to 30 cm H2O. An opioid-
based anesthetic has been described and may minimize
the surgical stress and PVR lability.155 Muscle relaxation
is ­ typically employed to facilitate surgical exposure and
­abdominal closure. N2O is not used because of the risk of
bowel ­distention. This could impair ventilation while the
bowel is in the thoracic cavity and may impede abdomi-
nal closure once the abdominal contents are replaced in
the abdominal cavity. N2O can also exacerbate the onset of
a pneumothorax. Contralateral p ­ neumothorax is a poten-
tial intraoperative complication and needs to be considered
if there is an acute clinical deterioration. Pulmonary hyper-
tension can be ­managed by maintaining a normal pH, Pao2,
and Paco2 and minimizing hypothermia and surgical stress.
Sodium ­bicarbonate may need to be administered to treat aci-
dosis or to alkalinize the blood and treat pulmonary hyper-
tension. If used p ­ reoperatively, iNO should be continued in
the OR.
Epidural analgesia has been described in the anesthetic
management of neonates with CDH. This option for intra-
operative and postoperative management may be best suited
for those with smaller defects, who likely will not require
­prolonged ventilation or anticoagulation for ECMO.156
Despite the advances in the medical and surgical care of
fetuses and neonates with CDH, the mortality still remains
significant. Delayed surgery, HFOV, iNO, ECMO, and feto-
scopic surgery have not significantly improved the overall
mortality. An outcome study reported a mortality of 62% that
did not vary statistically despite the introduction of ECMO,
iNO, surfactant, and delayed surgery.149 The concept of “per-
missive hypercarbia and gentle ventilation” may have had the
most significant impact on survival in neonates with CDH.
Some centers have observed an improvement in survival from
50% to 75% up to 90% with the introduction of this ventilation
strategy137,157 (Box 21-11).
BOX 21-11   n CONGENITAL DIAPHRAGMATIC HERNIA:
ANESTHETIC MANAGEMENT
Preoperative Evaluation
Place oral or nasogastric tube
Evaluate severity of pulmonary hypoplasia and pulmonary
hypertension
What ventilation requirements exist?
Preductal saturation <85%?
Right ventricular strain on echocardiography?
Echocardiography: Evaluate right ventricular function, right-to-left
shunting, and pulmonary hypertension
Chest radiography: Evaluate size of hernia
Laboratory studies
ABG analysis, hematocrit, type/screen, preductal/postductal Sao2
Vitamin K given? Hypokalemia from diuretics?
Anesthetic Considerations
Monitoring: Arterial catheter, preductal/postductal pulse oximeter,
precordial on contralateral chest
Avoid nitrous oxide
Decompress stomach
Use endotracheal intubation
Ventilation goals:
Positive inspiratory pressure <25 cm H2O
Preductal Sao2 >85%
Paco2 of 45-55 mm Hg
pH > 7.3
Maintain normothermia
Administer bicarbonate to maintain normal pH
Continue inhalational nitric oxide if used preoperatively
Administer IV dextrose solution
Opioid-based anesthetic; consider epidural analgesia
Consider contralateral pneumothorax if clinical deterioration occurs
Tracheoesophageal Fistula
Tracheoesophageal fistula (TEF) is a generalized term for a
condition characterized by esophageal atresia with or with-
out a communication (fistula) between the esophagus and the
trachea. The several anatomic variations cannot be described
by one definition. Esophageal atresia is the most common
esophageal anomaly, occurring in approximately 1 in 2000
to 1 in 5000 live births. Prematurity and polyhydramnios
are associated with TEF. The inability to swallow amniotic
fluid in utero results in polyhydramnios. Associated anom-
alies occur in 30% to 50% of cases. Mortality varies from
5% to 60%. More recent analysis indicates a survival rate of
approximately 95%.158 Morbidity and mortality are increased
in infants with severe coexisting congenital anomalies and
prematurity. Cardiac and pulmonary anomalies appear most
significant, with children who have severe congenital cardiac
anomalies and respiratory ­complications requiring mechani-
cal ­ventilation at highest risk.
Classification. The classification system of Gross159 ­outlines
A to F types of esophageal atresia with and without fistula, as
follows (Fig. 21-23):
A—Esophageal atresia without fistula
B—Esophageal atresia with communication of the upper
esophageal segment to the trachea

A B C D
FIGURE 21-23  Gross's classification of esophageal atresia. A, without fistula; B, with proximal fistula; C, with distal fistula;
D, with proximal and distal fistula; E, tracheoesophageal fistula without atresia; F, esophageal stenosis. (From Ulma G, Geiduschek JM,
Zimmerman AA, Morray JP: Anesthesia for thoracic surgery. In Gregory GA, editor: Pediatric anesthesia, ed 4, Philadelphia, 2002, Churchill
Livingstone, p 440.)
C—Esophageal atresia with communication of the lower
esophageal segment to the trachea
D—Esophageal atresia with both upper and lower esophageal
segments communicating with the trachea
E—No esophageal atresia but TEF
F—Esophageal stenosis without fistula
Type C is the most common, occurring in approximately
85% of TEFs.
Infants with esophageal atresia are unable to manage their
oral secretions and present with excessive oral and nasal sali-
vation, choking, coughing, and regurgitation with first feed-
ing. The tracheoesophageal communication results in gastric
dilation and aspiration of gastric contents. Pneumonia (of the
right upper lung) and pneumonitis can occur, as well as respi-
ratory compromise from gastric dilation. These patients can
present with cyanosis and apnea. Tracheomalacia can also
occur, resulting in a barking cough.160
Associated Anomalies. Associated anomalies occur in
30% to 50% of patients with TEF. A common association is
the VATER complex161; however, this mnemonic omits car-
diac anomalies. A more appropriate complex name would be
VACTERL, as follows:
V—Vertebral anomalies
A—Anal atresia
C—Cardiovascular anomalies
T—Tracheoesophageal fistula
E—Esophageal atresia
R—Renal (kidney) and/or radial anomalies
L—Limb defects
Diagnosis of TEF is based on clinical signs and symptoms.
The inability to pass an orogastric catheter into the stomach
and a chest radiograph showing the catheter in the proximal
esophageal pouch confirm the diagnosis. Gastric air may or
may not be present, depending on the anatomy of the lesion.
Surgical Management. Surgical management consists of
identifying and ligating the TEF and then anastomosing the
Chapter 21  The Pediatric Patient 613
E F
atretic esophagus. If the gap between the esophageal segments
is large enough to prevent a primary anastomosis, a staged
repair is performed. This may consist of interposing a segment
of colon or upward movement of the stomach.162
The primary goal in the preoperative period is to pre-
vent pulmonary complications. These infants should be kept
NPO. Prone or lateral positioning with the head of the bed at
30 degrees may reduce the risk of aspiration. A nasoesopha-
geal catheter should be attached to suction. Pneumonia should
be treated and a gastrostomy to vent the stomach only con-
sidered in the infant with immature lungs or respiratory dis-
tress syndrome. Intubation is avoided, if possible, to minimize
­gastric distention. Metabolic acidosis should be treated before
surgical repair. Associated anomalies need to be identified and
evaluated (echocardiography, abdominal ultrasound, radio-
graphs of spine and extremities). These infants may already
have central IV access for total parenteral nutrition. Routine
preoperative blood studies should include hemoglobin, type
and crossmatch, and glucose determination.
ANESTHETIC MANAGEMENT
The principal issues that dictate anesthetic management of the
patient with TEF include the risk of aspiration, negative effects
of PPV before ligation of the fistula, management of associated
anomalies (e.g., prematurity), and surgical technique (thora-
cotomy) (Box  21-12). Standard monitoring includes electro-
cardiography, pulse oximetry, noninvasive blood ­ pressure,
temperature, and capnography. An arterial catheter may be
beneficial in the infant with significant p­ ulmonary disease or
cardiac disease. An esophageal ­stethoscope placed over the left
chest will facilitate the detection of ETT migration into the
right main stem bronchus. Positioning for definitive surgical
repair requires left lateral positioning for a right thoracotomy.
Aspiration and gastric distention with respiratory embar-
rassment are the initial concerns during induction of
­anesthesia. In medically unstable infants, a gastrostomy may
be required before induction to relieve gastric distention, and
an awake intubation may be considered. In patients who are
stable, an IV or mask induction can be performed. PPV should
 614 ANESTHESIA AND UNCOMMON DISEASES
BOX 21-12   n TRACHEOESOPHAGEAL FISTULA:
ANESTHETIC MANAGEMENT
Signs/symptoms: Respiratory distress, coughing, choking, unable to
pass oral catheter into stomach; pneumonia, pneumonitis
Radiographs of spine and upper extremities: Evaluate vertebral and
radial anomalies
Chest radiography: Radiopaque oral catheter in proximal esophagus;
gastric gas pattern
Echocardiography: Evaluate cardiac defects
Imaging studies: Renal ultrasound
Laboratory studies: Hematocrit, type/screen, oxygen saturation,
glucose
Associated Anomalies
VACTER association:
Vertebral anomalies
Anal atresia
Cardiac defects
Tracheoesophageal fistula
Radial/renal anomalies
Anesthetic Considerations
Preoperative management: Oral esophageal suctioning, maintain NPO,
gastrostomy tube for respiratory distress syndrome or immature
lungs; may require endotracheal intubation; treat metabolic
acidosis
Monitoring: Arterial catheter
Induction: Maintain spontaneous ventilation until fistula is isolated
(main stem intubation, bronchial blocker)
Complications
Obstruction of endotracheal tube from secretions, purulent drainage,
blood, or mechanical bend
Atelectasis
be minimized to small tidal volumes or spontaneous ventila-
tion maintained, if possible. Presence of a g­ astrostomy may
slow mask inductions, requiring transient partial clamping of
the tube. ETT positioning is important to ­minimize ­gastric
distention. Usually the fistula inserts along the ­ posterior
aspect of the trachea just above the carina. Proper ­positioning
can be achieved by purposefully placing the ETT into the
right main stem bronchus and then slowly withdrawing until
breath sounds are just heard at the left axillae. Placement can
also be confirmed with a fiberoptic bronchoscope. Other
options for minimizing gastric distention include placement
of a balloon-tipped catheter (Fogarty, 2-3 Fr) into the fistula,
either from above (through trachea, next to ETT) or from
below through gastrostomy (5 Fr). The Fogarty catheter can
be placed from above during bronchoscopy by the surgeon to
evaluate the location of the fistula and other anatomic anom-
alies.163 Occasionally, massive gastric distention can result in
respiratory compromise and cardiovascular collapse, requir-
ing an emergency gastrostomy. The risk of gastric distention
increases with the size of the fistula. Muscle relaxation has
been described successfully in the anesthetic management
of TEF in patients with smaller fistulas.164 Large fistulas or
those located near the carina may benefit from isolation with
a Fogarty catheter.
Once the fistula is isolated, muscle relaxation and
c­ontrolled ventilation can be used. Common problems are
hypoxemia secondary to right main stem intubation, ETT
obstruction from secretions, drainage from lung infections,
and bleeding. In addition, kinking of the bronchus or even the
­trachea by surgical manipulation can occur, as well as atelecta-
sis of the retracted lung during surgical exposure. Recruitment
maneuvers to re-expand the lungs may be necessary to
­
improve intraoperative oxygenation. A forced-air heating
blanket is used to prevent hypothermia. IV dextrose solution
is provided to prevent hypoglycemia. Extubation at the end of
surgery may minimize manipulation of the anastomosis from
the ETT, but respiratory distress syndrome or pneumonias
may require ­prolonged intubation. IV opioids are effective
for intraoperative and postoperative pain management, but
regional anesthesia is advantageous to avoid opioids and the
risk of postoperative respiratory depression. If no significant
vertebral anomalies exist, a caudal catheter can be placed and
threaded to the thoracic region. The catheter's position can be
confirmed by injecting low-ionic-strength contrast medium
(e.g., 0.5-mL Omnipaque 180).165
Postoperative Considerations. Postoperative concerns
include the management of an orogastric tube that will be
marked to the level of the esophageal anastomosis. There
should be no suctioning beyond this point, to prevent disrup-
tion of the anastomosis. Also, head extension can put tension
on the anastomosis and should be minimized.
Postoperative complications include anastomotic leak,
­tracheomalacia or bronchomalacia, stricture, pneumonia, and
pneumothorax.166 Complications can also result from under-
lying medical conditions and cause significant morbidity and
mortality. All patients who have undergone TEF repair are con-
sidered to have esophageal dysmotility and ­gastroesophageal
reflux.
ABDOMINAL WALL DEFECTS
Omphalocele, gastroschisis, and bladder and cloacal
exstrophy are forms of congenital abdominal wall defects.
Congenital abdominal wall defects present a peculiar chal-
lenge to neonatologists, surgeons, and anesthesiologists. The
optimal management of neonates with anterior wall defects
depends on the careful prenatal assessment of these patients,
as well as the experience and knowledge of the defect's
­natural history. A multidisciplinary approach can improve
neonatal outcome.
Omphalocele and Gastroschisis
Gastroschisis and omphalocele are congenital defects of the
anterior abdominal wall that differ in many aspects. The
diagnostic distribution between the two entities is important
because of the associated abnormalities. Omphaloceles have a
much higher incidence of associated a­ bnormalities (Fig. 21-24).
Omphaloceles have associated cardiac, neurologic, GU, skel-
etal, or chromosomal abnormalities in two thirds of patients.
 Chapter 21  The Pediatric Patient 615

A B
FIGURE 21-24 Omphalocele. A, Infant with an omphalocele. Note how abdominal wall contents are enclosed in a sac-like structure
that is related to the umbilical cord. B, Newborn with large omphalocele, sac intact. Umbilical cord is seen emerging from mass. The
major problem will be replacing the viscera in the small abdominal cavity. (A from Keljo DJ, Gariepy CE: Anatomy, histology, embryology,
and developmental anomalies of the small and large intestine. In Feldman M, Friedman LS, Sleisenger MH, editors: Sleisenger & Fordtran's
gastrointestinal and liver disease, ed 7, Philadelphia, 2002, Saunders, p 1651; B from Brett C, Davis PJ: Anesthesia for general surgery.
In Davis PJ, Cladis FP, Motoyama EK, editors: Smith's anesthesia for infants and children, ed 8, Philadelphia, Saunders-Elsevier, 2011, p 564.)

TABLE 21-5  n  Comparison of Gastroschisis and Omphalocele

Gastroschisis Omphalocele

Incidence 1:10,000 1:4000-7000

Intact umbilical cord and evisceration of bowel Herniation of bowel and liver through umbilical wall
through defect in abdominal wall to the right covered by membranes unless ruptured liver and
of the cord other organs

Sac No membrane covering (sac absent) Present

Associated organs No

Associated anomalies Intestinal atresia, 25% Chromosomal anomalies

Cryptorchidism, 31% Trisomy 18, 13, 15, and 21
Beckwith-Wiedemann syndrome
Pentalogy of Cantrell
Prune-belly syndrome

Maternal age <25 years Older

Smoking/alcohol use Yes No

Teratogens Acetaminophen, aspirin, pseudoephedrine use No

in pregnancy: Yes

Congenital heart disease 12% 24%

Prematurity 40%-67% 10%-23%

In addition, GI anomalies are common. Prematurity occurs in
60% of patients with abdominal wall defects (Table 21-5).
Anatomy and Embryology. These defects are thought to
result from an imbalance between cell proliferation and apop-
tosis (cell death). Apoptosis in the region of the umbilical ring
results in relative growth delay in that region, whereas rapid
development of the foregut causes herniation of the bowel
through the umbilical stalk.
In gastroschisis, the abdominal wall forms in a dysplas-
tic manner because of decreased cell deposition or vascular
abnormality. This results in the formation of a thin area in the
abdominal wall to the right of the umbilicus. This area ruptures
from increased intra-abdominal pressure. Also, gastroschisis
may represent rupture of an umbilical cord hernia at the weak-
est point of the hernia sac, the site where the right umbilical
vein involutes. Patients with omphalocele present with a cen-
tral defect of the umbilical lining, and the abdominal contents
are contained within a sac.167
Clinical Management. Prognosis for the infant with gas-
troschisis is determined by the condition of exteriorized
bowel. Elective cesarean section, especially for gastroschisis,
was advocated to prevent bowel trauma. However, analysis
of data on mode of delivery concluded that cesarean section
had no distinct advantage over vaginal delivery on neonatal
outcome.167 Bowel damage has been attributed to exposure to
amniotic fluid and constriction at the abdominal wall defect.
 616 ANESTHESIA AND UNCOMMON DISEASES

Preterm delivery may be advisable for patients with increasing plasma and tissue esterases and has an ultrashort duration of
bowel distention. The risk of prematurity should be weighed action, can be an ideal anesthetic agent for neonates. Muscle
against the potential advantage of preterm delivery to salvage relaxants should be used to help facilitate abdominal closure.
the bowel. In patients in whom primary closure cannot be achieved,
postoperative ventilation may be necessary. During abdomi-
Surgical Repair and Anesthesia Induction. Initial manage­
nal closure, monitoring of the patient's airway pressure and
ment for neonates with abdominal wall defects is focused on
blood pressure helps to determine whether a primary repair
newborn resuscitation, fluid and electrolyte maintenance,
or staged repair is necessary. In addition, CVP monitoring
temperature homeostasis, and protection of the e­viscerated
can also be used to detect caval compression and increased
organs. After the infant is stabilized, which includes
­intra-abdominal pressure.
administration of broad-spectrum antibiotics, protection
­
Postoperative management is a function of the surgi-
of the ­eviscerated organs with wrapped fluids, impermeable
cal procedure and any associated congenital abnormality. In
­dressings, and IV hydration, the neonate is brought to the OR
infants with large intraoperative fluid requirements or those
for either a ­primary closure or a staged repair.
with suspected elevated intra-abdominal pressure, mechanical
Anesthesia is induced with IV agents and the patient's
ventilation should continue until diuresis has occurred or the
trachea intubated. The major intraoperative concerns are
increased intra-abdominal pressure resolves.
fluid requirements, temperature regulation, cardiovascular
­stability, and increased intra-abdominal pressure. Large third-
space losses may be associated with anterior wall defects, Prune-Belly Syndrome
both ­ preoperatively and intraoperatively. Hypothermia is
Prune-belly syndrome (PBS, triad syndrome, Eagle-Barrett
a ­ frequent complication and is multifactorial; the infant's
syndrome, abdominal muscular deficiency) presents with a lax,
­ongoing fluid requirements, increased evaporative water loss,
wrinkled abdominal wall.170 PBS is a specific constellation of
and increased radiant heat loss are major contributing factors.
anomalies that involve an abdominal wall deficient in muscular
Cardiovascular instability can result from both the ongoing
tissue, dilated urinary tracts, bilateral cryptorchidism, pulmo-
water and heat losses and the instability associated with the
nary hypoplasia from in utero impaired drainage of the bladder
normal changes in the transition from fetal to adult-type cir-
and oligohydramnios, GI abnormalities, and ­orthopedic (mus-
culation. In addition, cardiovascular compromise can result
culoskeletal) disorders (­congenital hip dislocation, s­coliosis,
from the increase in intra-abdominal pressure that occurs
pectus excavatum, clubfoot, congenital ­muscular torticollis,
with the reduction of the eviscerated organs. The surgical
renal osteodystrophy).171 The pathogenesis of PBS arises from
approach to treatment involves decompressing the intestines,
the effects of intrauterine urethral obstruction associated
nasogastric suction, and anorectal irrigation.
with oligohydramnios.172 Oligohydramnios ­produces limited
The goal of surgical management is reduction of abdomi-
intrauterine space, leading to fetal compression and resultant
nal contents and the approximation of the fascial edges and
deformities.
skin coverage. Primary closure is attempted if abdominal pres-
Patients with PBS vary widely in clinical presentation. They
sure does not impair ventilation, venous return, cardiac out-
can have significant respiratory compromise secondary to pul-
put, or perfusion to the gut, kidneys, and lower extremities.
monary hypoplasia and a decreased ability to cough. Patients
Because the reduction of the intestinal contents can create a
may also develop restrictive lung disease secondary to the
high increased intra-abdominal pressure, compromise to the
absence of abdominal musculature.173 Because of these defects,
organs, as well as IVC blood return compromise, can occur.
they may have recurrent respiratory tract infections and may
Monitoring of gastric pressure, bladder pressure, and CVP has
be more prone to postoperative respiratory complications.174,175
been advocated.168,169 If primary repair is not feasible, a staged
In severe forms, death occurs in the neonatal period. Some
repair with a silo is placed. A prosthetic silo is sutured to the
PBS patients may have no pulmonary hypoplasia except sig-
fascial edges of the defect, and in days to weeks the abdominal
nificant renal involvement and failure to thrive. Other patients
contents are reduced back into the abdomen. At completion,
may have an abnormally appearing urinary tract but normal
the silo is removed and the ventral hernia or abdominal wall
renal function. Anesthetic management is determined by the
defect repaired.
patient's underlying pulmonary and renal status.
In the postoperative period the major concerns are n­ utrition,
In PBS patients with impaired renal function, s­ election of
sepsis, and intestinal obstruction.
anesthetic agents is important. Although renal insufficiency
has no effect on the choice of inhaled anesthetic agents, renal
ANESTHETIC MANAGEMENT insufficiency can alter a patient's response to muscle relaxants
Anesthetic management of patients with abdominal wall and IV opioids. The kidneys have a minor role in the elimination
defects involves the use of IV and/or inhalational anesthetic of most opioids. Fentanyl has been administered to anephric
agents. Increased intra-abdominal pressure can result in patients without untoward effects. Alfentanil kinetics vary in
reduced drug clearance; consequently, infusions of fentanyl patients with renal failure.176 Morphine kinetics are unchanged
and sufentanil can lead to drug accumulation and prolonged in patients with renal ­failure; however, its ­metabolites, mor-
drug effect. Remifentanil, an opioid that is metabolized by phine-3-glucuronide and morphine-6-glucuronide, are
 Chapter 21  The Pediatric Patient 617

significantly prolonged. Because the 6-glucuronide is phar-

macologically active, it can lead to respiratory depression.
Meperidine is mainly ­metabolized by the liver, but its ­principal
metabolite, normeperidine, is ­ pharmacologically active,
causes CNS excitability (­tremors, myoclonus, seizures), and is
excreted by the kidney. The elimination half-life is double in
patients with renal failure. Although renal excretion of meper-
idine plays a minor role in adults, patients with renal disease
had higher plasma concentration, longer elimination half-life,
decreased protein b ­ inding, and large volume of distribution in
one study.177
Neuromuscular blocking agents are generally excreted in
the urine and bile. In patients with renal failure, the sensitivity
of the neuromuscular junction does not appear to be affected.
Atracurium and cisatracurium, which undergo Hoffman
­elimination and enzymatic hydrolysis, are not affected by
patients with renal disease. Vecuronium and rocuronium
clearance can be prolonged in patients with renal failure. In
patients with renal failure and low levels of plasma pseudo-
cholinesterase, mivacurium administration may result in a
prolonged effect. Pancuronium elimination, half-life, and
duration of action are also prolonged in patients with renal
disease.
The depolarizing drug succinylcholine is relatively con- FIGURE 21-25  Cloacal exstrophy. Infraumbilical omphalocele
traindicated in patients with renal failure. Because serum with exstrophy of the bladder, in which bladder is separated into
potassium level increases in patients after succinylcholine halves by exposed intestine. Both proximal and distal loops
have prolapsed, producing “elephant trunk” appearance. (From
administration, acute life-threatening hyperkalemia can occur
Barksdale EM Jr: Surgery. In Zitelli BJ, Davis HW: Atlas of pediatric
in patients with an elevated serum potassium concentration. physical diagnosis, ed 4, St Louis, 2002, Mosby, p 601.)
The use of sevoflurane in patients with renal failure does not
appear harmful. Sevoflurane is metabolized in vivo to inorganic
fluoride and hexafluoroisopropanol, whereas in vitro, sevoflu- bladder wall.183 Classic exstrophy is characterized by wide
rane is degraded by soda lime or Baralyme to compound A. pubic separation and an exposed bladder.
Both IV fluoride levels and compound A have been associ- Cloacal exstrophy involves the urinary and GI tracts. OEIS
ated with nephrotoxicity.178 However, nephrotoxicity does not refers to the association of bladder exstrophy with omphalo-
appear to occur in humans.179 Reasons for this lack of nephro- cele, exstrophy of the bladder, imperforate anus, and spinal
toxicity may be related to sevoflurane's low solubility, its rapid defects such as myelomeningocele.184 Diastasis of the pubis
elimination, and the small amount of ­intrarenal metabolism and absence of the genitalia are frequent findings in patients
that sevoflurane undergoes.180 Although ­ pre-existing renal with cloacal exstrophy, neural tube defects are present in 50%
insufficiency is a risk factor for postoperative renal dysfunc- of infants, and congenital short bowel syndromes occur in
tion, neither high-flow nor low-flow sevoflurane anesthesia in 20%185,186 (Fig. 21-25).
patients with pre-existing renal disease appears to alter renal
Diagnosis. Prenatal sonographic diagnosis reveals absence
function compared with isoflurane.181,182
of the bladder as well as associated GU anomalies.187 Cloacal
exstrophy has been identified through associated neural tube
Bladder and Cloacal Exstrophy
defects, omphalocele, or splaying of the pubic rami. Prenatal
Bladder exstrophy and cloacal exstrophy are rare but devas- diagnosis of bladder or cloacal exstrophy should be fol-
tating anomalies. Bladder exstrophy is a developmental defect lowed by a careful search for other chromosomal and struc-
seen in 1 in 40,000 live births, whereas cloacal exstrophy is tural anomalies. Parental counseling by a multidisciplinary
found in about 1 in 200,000 births. team should address issues of continence and possible gender
reassignment.
Embryology. Bladder exstrophy is a defect of the caudal
fold of the anterior abdominal wall. It results from persis- Treatment. Reconstruction involves several procedures,
tence of the cloacal membrane, preventing cephalad migra- including urologic and orthopedic surgeries. A three-stage
tion of the mesoderm to the midline during development. approach is often used to repair the exstrophy complex.
When the cloacal membrane eventually degenerates, it leaves The first procedure is performed in the neonatal period and
behind a midline defect. A small defect may cause epispadias involves bladder closure, pubic symphysis approximation,
alone, whereas a large defect leads to exposure of the posterior and abdominal wall closure. The second-stage procedure later
 618 ANESTHESIA AND UNCOMMON DISEASES
in infancy involves epispadias repair. The final procedure
involves bladder neck reconstruction and is generally per-
formed at the age when toilet training is begun.188 Osteotomies
are performed to allow approximation of the pubic symphysis
to facilitate midline repair. This is followed by pelvic stabiliza-
tion with traction and external fixation or with plate fixation.
ANESTHETIC CONSIDERATIONS
Bladder and cloacal exstrophy repair need to be addressed at
birth. The newborn will undergo the initial repair, and anesthetic
considerations for the care of the newborn should be observed
(Box 21-13). Regional anesthesia can be used for intraopera-
tive and postoperative pain management with a s­ingle-shot
caudal with injection of local anesthetic (­bupivacaine 0.125%
or ropivacaine 0.1%) with Duramorph (20 μg/kg). A catheter
threaded to the lumbar level is another option for continuous
epidural analgesia. A combined ­general and regional technique
allows for the use of fewer inhalational agents and early extu-
bation of the neonate. With the use of epidural narcotics, the
­neonate needs to undergo recovery in a monitored environ-
ment. Spina bifida associated with cloacal exstrophy may be a
contraindication for regional techniques.189 Latex precautions
should be observed in this patient population because 75% of
children with bladder ­exstrophy are ­sensitized to natural rub-
ber latex and develop a latex allergy.190,191
CARDIOVASCULAR DISEASE: WILLIAMS’
SYNDROME
Williams’ syndrome (WS) is a rare, complex neurodevelopmen-
tal disorder caused by the deletion of 26 genes, including the
elastin gene on the long arm of chromosome 7,192–194 and first
described in 1961.195 The incidence of WS is 1 in 7500 to 1 in
20,000 births. Patients have distinct facial features, characteristic
behavioral and neurodevelopmental traits, supravalvular aortic
stenosis, and idiopathic neonatal hypercalcemia. Facial dysmor-
phism is characteristic and may not be ­recognized in the neona-
tal period. Children are described as having elfin facies, which
includes periorbital fullness, strabismus, epicanthic folds, and
flat nasal bridge. Hypotonia with joint laxity occurs frequently
and is more prevalent in adolescents than in younger patients.
Chiari type I malformation has also been reported in some
WS patients.196 Patients tend to be sociable and are described
BOX 21-13   n BLADDER/CLOACAL EXSTROPHY:
ANESTHETIC CONSIDERATIONS
Neonatal Care
Prevention of heat loss: fluid warmers, forced-warm-air blankets
Glucose management: check blood glucose level
Fluid management for third-space losses
Maternal Care
Evaluation of other associated congenital anomalies
Regional anesthesia
Latex precautions
as having a “cocktail party” personality. Despite their o ­ utgoing
personalities, however, they tend to be socially isolated, and
attention deficit and anxiety disorders are common.197
Cardiovascular diseases account for the majority of early
mortality in WS patients and is attributed to the elastin gene
haploinsufficiency.193 The disorder is an elastin ­arteriopathy
that involves medium-sized and large vessels. In elastin
­arteriopathies the smooth muscle cells in WS patients produce
15% of the elastin of normal cells. Thus the arterial media of
these affected vessels contain hypertrophied smooth mus-
cle cells, increased collagen, and decreased elastin. The loss
of elastin in the arterial wall allows for the proliferation of
smooth muscle cells and subsequent development of intimal
narrowing. In addition to involvement of the aorta, the renal,
mesenteric cerebral, and coronary arteries are also involved.
The major cardiac component of Williams’ syndrome
involves supravalvar aortic stenosis (SVAS) and is a result of the
elastin arteriopathy. The natural course of SVAS is the develop-
ment of left ventricular (LV) hypertrophy, systemic hyperten-
sion, and diastolic dysfunction. With loss of aortic distensibility,
pulse pressure widens, LV afterload increases, and coronary
blood flow during diastole decreases. Coronary blood flow is fre-
quently compromised due to adhesion of the right or left aortic
leaflet edge to the wall of the aorta (at the sinotubular junction)
restricting coronary blood flow into the sinus of Valsalva). Elastin
arteriopathy involves the coronary ostia and arteries, further
compromising myocardial blood supply.196,197 Pulmonary artery
(PA) involvement also occurs with SVAS in 40% of patients. The
natural history of central PA stenosis is less severe than in ­aortic
disease. The incidence of sudden death in WS patients is 25-fold
to 100-fold higher than in age-matched controls.198,199 Patients
with SVAS undergoing anesthesia for diagnostic or surgical pro-
cedures are at increased risk of cardiac arrest and sudden death.
A review of arrests and death in association with sedation and
anesthesia noted that myocardial ischemia occurred in most WS
patients, leading to sudden, rapid deterioration with bradycardia
and hypotension.198 These patients were refractory to aggressive
resuscitative measures.200,201
Preoperative Evaluation. A baseline electrocardiogram
may reveal ventricular hypertrophy and dysrhythmias in the
WS patient. Echocardiography can be used to assess the degree
of outflow tract gradients and any wall motion abnormalities
but will not detect impaired ostial or distal coronary artery
blood flow.202 Cardiac catheterization is the “gold standard” to
evaluate coronary anatomy as well as aortic leaflet tethering.
Reports of cardiac arrest during catheterization procedures,
however, indicate a significant associated risk. Although CT
and cardiac MRI are potentially noninvasive alternatives to
more invasive cardiac catheterization,203,204 their use as a gold
standard has not been verified.
ANESTHETIC MANAGEMENT
Recommendations for the patient with Williams’ syndrome
include performing diagnostic and surgical procedures in
­cardiac and noncardiac centers with the appropriate experience
 Chapter 21  The Pediatric Patient 619

and capabilities,198 including availability of ECMO.205 Further,
maintenance of an adequate preload is important for coronary
perfusion, and preoperative liberalization of clear liquids as
well as adequate hydration before and shortly after induction
is essential.
Tachycardia carries a significant risk of decreasing diastolic
coronary perfusion time, so judicious use of drugs such as
atropine and glycopyrrolate is recommended. Maintenance of
sinus rhythm and rapid treatment of supraventricular tachy-
cardia are important. For some rhythms, cardioversion even
in the absence of hypotension may be preferred to a treatment
involving pharmacologic conversion. Maintaining SVR is also
important. Thus, anesthetic agents (e.g., inhalants, propofol)
that affect both SVR and contractility in a dose-dependent
manner should be used with caution. Increases in PVR should
be avoided (atelectasis, hypoxia, hypercarbia). Measures to
decrease PVR should be used, including ventilator parameters
using low mean airway pressures.
Treatment of outflow tract obstruction is a surgical as well
as a catheter-based intervention. Coronary revascularization
and aortic root reconstruction techniques are used to relieve
coronary ostial stenosis and SVAS, respectively, in patients
with Williams’ syndrome.206
DERMATOLOGIC DISEASE: EPIDERMOLYSIS
BULLOSA
Epidermolysis bullosa (EB) constitutes a heterogeneous group
of inherited genodermatoses. It is characterized by trauma-
induced blistering and erosion of the skin and mucous mem-
branes.207 EB is caused by genetic mutations in 1 of 13 different
genes encoding structural proteins that provide adhesion
between the epidermis and dermis. EB is classified into four
major types: simplex, junctional, dystrophic, and Kindler's
syndrome. The area of blistering and tissue separation deter-
mines the type of EB208 (Fig. 21-26). The simplex, ­junctional,
and dystrophic types of EB are characterized by tissue sepa-
ration within the epidermis, at the dermoepidermal junction
and the dermis. In Kindler's syndrome, cleavage occurs at
multiple levels of the dermoepidermal junction.

Basal cell
Tonofilament (keratin 5/14)
Hemidesmosomes
Lamina lucida
Anchoring fibril (type VII collagen) Lamina densa
Type I and type III collagen

Abnormal Abnormal Abnormal

tonofilaments hemidesmosomes anchoring fibrils

Intraepidermal blisters Blisters in the Subepidermal blisters

(epidermolysis) lamina lucida (dermolysis)
Epidermolysis bullosa Junctional epidermolysis Dystrophic epidermolysis
simplex (EBS) bullosa (JEB) bullosa (DEB)
FIGURE 21-26  Skin layers and epidermolysis bullosa. Skin consists of the epidermis (basal keratinocytes), the dermis, and the dermal-
epidermal basement membrane zone (BMZ) separating these two compartments. The basal keratinocytes contain the desmosomes
and hemidesmosomes; plectin, keratin, and integrin proteins are recognized in the epidermis. The cutaneous BMZ consists of the
lamina lucida and lamina densa layers; laminin protein and type IV collagen are found in the BMZ. The innermost papillary dermis
contains the anchoring filaments and anchoring plaque as well as type VII collagen. Bottom panels show pathophysiology in three
forms of epidermolysis bullosa (simplex, junctional, dystrophic). (From Shinkuma S, McMillan JR, Shimizu H: Ultrastructure and molecular
pathogenesis of epidermolysis bullosa, Clin Dermatol 29:412-419, 2011; modified from McMillan J, Akiyama M, Shimizu H: Epidermal
basement membrane zone components: ultrastructural distribution and molecular interactions, J Dermatol Sci 31:169-177, 2003.)
 620 ANESTHESIA AND UNCOMMON DISEASES
Epidermolysis Bullosa Simplex. Intraepidermal blister-
ing typically occurs in EB simplex (EBS). Onset is shortly after
birth. The localized form of EBS can manifest in late childhood
or early adulthood. Dominantly inherited EBS is caused by
mutations in the basal keratinocytes (keratin 5 and 14 genes).207
Recessively inherited EBS is caused by mutations in the ­plectin
gene and is associated with muscular dystrophy, the onset of
which tends to occur in the latter part of the first decade of
life. Cutaneous manifestations of EBS, including scarring, nail
dystrophy, and milia (firm white papules resembling cysts and
pustules), are less severe than with other types of EB.
Junctional Epidermolysis Bullosa. Junctional EB (JEB)
subtypes have an autosomal recessive inheritance. JEB is pres-
ent at birth. The severe Herlitz type occurs in 20% of JEB
patients and involves the skin, upper airway, esophagus (stric-
tures), external eye, and GU system (Fig.  21-27). The more
common, non-Herlitz type of JEB is less severe.
Recessive Dystrophic Epidermolysis Bullosa. The recessive
dystrophic form of EB (RDEB) is more aggressive than the
dominant dystrophic EB. The most severe subtype, severe gen-
eralized RDEB is a multiorgan condition characterized by skin
scarring, corneal blisters and scarring, esophageal strictures,
FIGURE 21-27  Epidermolysis bullosa. Severe Herlitz type of
junctional epidermolysis bullosa (JEB) involving the skin. (From
Fine JD: Orphanet J Rare Dis 5:12, 2010.)
FIGURE 21-28 Severe
generalized RDEB. A, Complete
mutilating deformities of hands
in young adult with severe
generalized recessive dystrophic
epidermolysis bullosa (RDEB).
B, Partial “mitten deformity”
of hand in child with severe
generalized RDEB. (From Fine JD:
Orphanet J Rare Dis 5:12, 2010.)
A B
anemia, and debilitating hand and foot deformities (mitten
deformities; Fig. 21-28).209 Dilated cardiomyopathy has been
associated with RDEB.
Kindler's Syndrome. Kindler's syndrome is inherited in
an autosomal recessive manner. It involves several skin layers
and is typically characterized by acral blistering in infancy and
childhood, progressive poikiloderma, skin atrophy, abnormal
photosensitivity, and gingival fragility.209
Clinical Presentation. Cutaneous manifestations of EB
include blister formation and scarring. Lesions occur in the
oropharyngeal, laryngeal, tracheal, and bronchial mucosa.
Although uncommon, laryngeal involvement is accompanied
by severe morbidity and mortality. Lesions include supraglot-
tic obstruction and arytenoid scarring leading to immobility
of the vocal cords. Severe intraoral blistering results in micro-
stomia and reduced extension of the tongue (ankyloglossia).
When the esophageal mucosa is affected, it can lead to stric-
tures, difficulty feeding, and malnutrition. Anemia is common
in EB patients because of frequent trauma and malnutrition.
Patients with severe generalized RDEB have a 4.5% risk of
developing a severe dilated cardiomyopathy by age 20 years.210
The cause of the cardiomyopathy is unknown but is probably
related to iron overload, carnitine and selenium deficiency,
chronic anemia, and chronic viral infections. Aggressive squa-
mous cell carcinoma may arise in the second decade of life in
patients with severe RDEB and JEB.
Diagnosis. Initial diagnosis of EB is based on the clini-
cal manifestations as well as the family history. Skin biopsy
from a fresh blister should be obtained to classify the disease.
­DNA-based diagnosis is accurate for prenatal and genetic
counseling.
Treatment. At present, no definitive treatment exists for EB.
Gene therapy and bone marrow stem cell therapy have been
developed to treat RDEB by restoring the bridging fibrils.211
ANESTHETIC MANAGEMENT
Preoperative Evaluation.  Patients with EB present for
a variety of procedures, including esophageal dilation, oral
rehabilitation, gastrostomy tube insertion, hand/foot surgery,
 Chapter 21  The Pediatric Patient 621

BOX 21-14   n EPIDERMOLYSIS BULLOSA: ANESTHETIC

MANAGEMENT

Preoperative Evaluation
Potentially difficult airway
Cardiomyopathy
Anemia
Nutritional status
GI problems: strictures, aspiration
Scarring of skin and extremities
Multidisciplinary approach to management

Anesthetic Considerations
Careful padding (e.g., egg crate)
Avoidance of skin trauma
Careful positioning
Nonadhesive ECG monitoring
Clip pulse oximetry
Fiberoptic intubation for difficult airway
Petroleum jelly gauze under face mask FIGURE 21-29  Use of paraffin-coated gauze over the chin and
Use of special tape and lubricants nose of the child with epidermolysis bullosa can prevent trauma
Suturing of catheters by the anesthesiologist's hand or the mask.
Ultrasound for regional anesthesia and IV access

management; petroleum jelly gauze around the shaft can min-

and whirlpool debridement.212 A multidisciplinary approach
is ­recommended for perioperative care of EB patients; the
­primary care physician can provide valuable input (Box 21-14).
Airway Evaluation. Scarring and ankylosis can result in
poor mouth opening and can pose a problem for conven-
tional direct laryngoscopy. Cardiac evaluation in patients
with specific types of EB is recommended. Anemia and the
need for transfusion should be addressed preoperatively.
Premedication is recommended to avoid anxiety and further
skin trauma. Careful OR preparation is important; moni-
toring devices should avoid contact points that will abrade
the skin. Pulse oximeter probes should be the clip-on style
rather than an adhesive type. Electrocardiographic (ECG)
electrodes are placed over the skin and covered with petro-
leum jelly gauze to allow for direct contact. Alternatively,
needle electrodes can be used. Silicone-based gauze and tape
(e.g., Mepiform, Mepitel, Mepitac) and bandages should be
used to prevent friction and work well for these patients.213,214
Equipment such as ­laryngoscopes, ETTs, and nasogastric
tubes should be well lubricated with water-soluble and petro-
leum jelly lubricants. Friction and trauma should be avoided,
with careful attention to positioning and padding; patients
with contractures may be especially challenging. IV access
can be difficult because of scarring and contractures. The
use of ultrasound can facilitate venous and arterial access.
Catheters can be sutured in place.
Airway Management. Mask ventilation must be accom-
plished by avoiding trauma and friction by the anesthesia
mask (Fig.  21-29). Direct laryngoscopy is generally uncom-
plicated in infants with EB. In older children and adolescents,
however, scarring and ankylosis can create airway manage-
ment challenges, and fiberoptic bronchoscopy for intubation
may be needed. The LMA has been successfully used in airway
imize trauma to the lips and mouth. Cuff pressure needs to be
low to maintain the shape of the LMA and avoid trauma to the
airway. ETTs are secured in a manner that avoids damage to
the skin and lips (e.g., Koban tape); a surgical face mask can
be placed on the back of the head with the straps holding the
tube. Selecting smaller ETT size and careful inflation of the
cuff can minimize the risk of postoperative croup and airway
edema.
The perioperative use of steroids is recommended. The
choice of anesthetic agents generally depends on the EB
patient's underlying comorbid disease.
Regional Anesthesia. Neuraxial and peripheral nerve
blocks have been described for perioperative pain manage-
ment. Ultrasound-guided axillary plexus block has been used
in a child with dystrophic EB215 (see Box 21-14).
Pain Management. Chronic pain is a major sequela of epi-
dermolysis bullosa. Skin and mucous membrane lesions in
the GI tract, joints, and bones are the source of pain. Patients
are unable to swallow, which precludes the use of oral analge-
sics. The absorption of oral or medication delivered through
gastric feeding tubes is not reliable. Different modalities of
pain management can be combined to help alleviate pain and
improve the EB patient's quality of life. Pharmacologic tech-
niques include the use of opiates, acetaminophen, ­tricyclic
antidepressants, nonsteroidal anti-inflammatory drugs,
and anxiolytics. Psychological support includes meditation,
­biofeedback, and relaxation and has been successfully used in
older children.216
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I ND E X
γ-Aminobutyric acid (GABA), 193 Adrenal medulla
anesthetic considerations for, 425–426, 425b
A endocrine system and, 424–426
α-Synuclein, 257–258 pheochromocytoma as, 424–426
ABCDE priority approach, 489 Adrenocortical hormone deficiency
Abciximab, 361–362, 564 glucocorticoid deficiency as, 422–423
Abdominal compartment syndrome, 239 mineralocorticoid deficiency as, 423
Abdominal surgery, 383 Adrenocortical hormone, excessive, 421–422
Abdominal wall defect Adult Gaucher's disease, 180–181
omphalocele and gastroschisis as, 614–616 Adult onset myotonic dystrophy, 303
prune-belly syndrome as, 616–617 Afterload, 495–496
Abscess, appendiceal, 388 Airway
Accelerated hypertension, 230 management of
Achondroplasia burn patients and, 530–531
differential diagnosis for, 320, 321b evaluation of, 491–492, 491b
intraoperative considerations for, 321–322, 321b induction/intubation considerations
pathophysiology of, 320–322, 320t for, 493
preoperative preparation for, 320–321, 321b induction/intubation medications
summary for, 322 and, 493–495, 493t
Acquired immunodeficiency syndrome (AIDS), pathophysiology of, 491–495, 491b
9–10, 10b preparation for, 492–493
Acrocephalosyndactyly, 597 trauma patient and, 490–495
Acromegaly obesity and
ear, nose, throat and, 22–23 considerations for, 218–220
hyperpituitarism and, 417 maintenance of, 219–220
surgery and anesthetic concerns for, 22–23, 22b Airway injury, lower, 528–529
ACTH stimulation test, 423 Airway injury, upper, 528
Acute blood loss, 355–356 Alagille's syndrome, 175–176
treatment for, 356 Alanine transaminase, 169t, 170
Acute coinfection, hepatitis D and, 173 Albumin, 169
Acute inflammatory polyneuropathy. See Alcohol withdrawal syndrome, 462
Guillain-Barré syndrome Alcoholic cardiomyopathy, 37
Acute kidney injury syndrome, 236 Aldolase deficiency type XII, 307
Acute leukemia, 357–358 Alfentanil, 544
Acute renal failure. See Kidney disease, chronic Alimentary hypoglycemia, 426
Acute respiratory distress syndrome (ARDS), Alkaline phosphatase (ALP), 170
147b, 152–153, 153t Allergic granulomatosis. See Churg-Strauss
Acyl-coenzyme A dehydrogenase deficiency, 310 syndrome
Addison's disease, 414. See also Primary adrenal Allergy, latex, 565–566
insufficiency Allergy, local anesthetic, 564–565, 565b
Adenoma, 421–422 Allicin, 479
ADHD. See Attention-deficit/hyperactivity Alpha fetoprotein, 166–167
disorder (ADHD) Alpha1-antitrypsin deficiency, 176
Adipose tissue, subcutaneous, 216 ALS. See Amyotrophic lateral sclerosis
Adjusted body weight, 220–221 ALS-plus, 274
Adrenal cortex Amebic liver abscess, 386–387
adrenocortical hormone deficiency and, anesthesia considerations for, 387
422–423 Amide local anesthetic, 564
excessive adrenocortical hormones and, 421–422 Aminotransferase. See Transaminase
perioperative stress/corticoid supplementation Amiodarone, 412
and, 423 Ammonia, 168
physiology of, 419–421 Amniotic fluid embolism
clinical presentation of, 547, 547b
coagulopathy and, 548–549
Page numbers followed by f indicate figure; diagnosis of, 549
t, tables; b, boxes. etiology of, 547–548
Amniotic fluid embolism (Continued)
hemodynamic changes of, 548
management of, 549–550
obstetric anesthesia and, 547–550
pathophysiology of, 548
Amyloidosis
geriatric patient and, 574–577
anesthetic considerations for, 576–577
diagnosis and differential for, 575
pathophysiology of, 574–577, 575t
preoperative preparation and treatment
of, 575–576, 576t
valvular aortic stenosis and, 56
Amyotrophic lateral sclerosis (ALS)
anesthetic considerations for, 275
motor neuron diseases and, 273–275
pathophysiology and incidence of, 274–275
pharmacologic therapy for, 274–275
symptom management and palliation
for, 274
Analgesia, burns and, 531
Analgesia, postoperative, 203
Anderson's disease. See Branching enzyme
deficiency type IV
Androgen, 421
Anemia
anesthetic considerations for HIV and, 382
hematologic diseases and, 350–355, 351b,
351t
hemolytic anemia as, 353–355
iron deficiency anemia as, 352
megaloblastic anemia as, 353
thalassemia as, 352–353
treatment of, 352
Anesthesia
acute care and, 519–520
agents of
congenital heart disease hemodynamics
and, 82–85, 82b
dexmedetomidine and, 84
ketamine and, 84
opioids/benzodiazepines and, 83
pharmacokinetics/intracardiac shunts
and, 84–85
propofol and, 83–84
volatile anesthetics as, 82–83
local techniques of, 435
mitochondrial function and, 435–436, 435b
obesity and emergence from, 221
obstetrics and, 546–559
regional techniques of
burn management and, 531
complicating conditions of
anticoagulation and, 559–564, 560t
latex allergy and, 565–566
local anesthetic allergy and, 564–565
627
 628 Index
Anesthesia care, monitored, 543
Anesthetic care, prehospital, 518–519
Angle-closure glaucoma, 5–6
Aniridia, types I and II, 2
Ankylosing spondylitis, 154–155, 155b
Anomalous pulmonary venous return, 102–104,
102b
Anterior mediastinum, 603
Anterior pituitary disease
anesthetic considerations for, 417
hyperpituitarism and, 417
hypopituitarism and, 415–417
Anthrax, 391–392
anesthetic considerations for, 392, 393t
Anti-GBM antibody disease, 226–227
Antibiotic
sepsis source unknown and, 377
septic shock treatment and, 370b, 377
Antibody-induced hemolysis, 355
autoimmune hemolytic anemia, 355
Anticoagulation, 559–564
summary for, 564
Antidepressant, 449t, 450t
pharmacologic therapy and, 448–451
Antidepressant, second-generation, 451
Antidiuretic hormone, 419, 419b
Antifibrinolytics, 602
Antiphospholipid syndrome, 151–152
Antiplatelet medication, 563–564
Antithrombin III deficiency, 363
treatment for, 363
Antithrombotic drug therapy, 361–362
Anxiety disorder
anesthetic considerations for, 457
generalized anxiety disorder as, 454–455
obsessive-compulsive disorder as, 455–456
panic attacks as, 457
posttraumatic stress disorder as, 456–457
psychiatric disorders and, 454–457, 455t
social phobia as, 455
Aorta
coarctation of, 87f, 88f, 104–106, 105b, 105f,
106f
traumatic injury to
evaluation of, 511
intraoperative management for, 511
pathophysiology of, 510–511
preoperative preparation for, 511
Aortic insufficiency, 61, 61t, 125–126
Aortic stenosis, 107–108, 107f, 108b
Aortic stenosis, supravalvular, 618
Aortocaval compression, 540–541
Aortopulmonary window, 94
Apert's syndrome, 597–598, 599t, 600f
Apoptosis, 168, 436, 496
Arnold-Chiari malformation, 282–285, 282t, 590.
See also Chiari I malformation
Arrhythmogenic right ventricular
cardiomyopathy/dysplasia, 32
anesthetic considerations for, 32
Arterial switch operation, 116–117
Arteriohepatic dysplasia. See Alagille's syndrome
Arthritic disease
ankylosing spondylitis as, 154–155
kyphosis/scoliosis as, 155–156
upper airway and respiratory problems and,
154–156
Ascites, 189–190 Bispectral index scale, 465
Ascorbic acid. See Vitamin C Black pepper, 481
Aspartate transaminase, 169t, 170 Bladder exstrophy
Assisted reproductive technologies, 541–542 anesthetic considerations for, 618, 618b
Atrial septal defect, 94–96, 95f, 96b diagnosis of, 617
Atrial switch operation, 116, 116f embryology of, 617–618
Atrioventricular canal (AVC), 86f, 97–99, 98b, 98f treatment of, 617–618
Atropine, 396 Bland-White-Garland syndrome, 47, 48
Attention-deficit/hyperactivity disorder Bleomycin toxicity, 156–157, 157b
(ADHD), 465–466, 466t Blepharospasm, 266
Autoimmune hemolytic anemia, 355 Bloch-Sulzberger syndrome. See Incontinentia
treatment for, 355 pigmenti
Autologous donation, 555 Bloodstream infection, catheter-related, 377
Autonomic dysfunction, 255 Bone disease
AVC. See Atrioventricular canal (AVC) differential diagnosis for, 336
intraoperative management of, 336–337
B osteomalacia as, 335–336
Backward-upward-rightward pressure (BURP) osteopetrosis as, 336
technique, 493 osteoporosis as, 335–337
Ballooning degeneration, 168 preoperative preparation for, 336, 336b
Barbiturate, 435 summary for, 337
Barbiturate coma, 502 Boswellia, 476t, 482
Bardet-Biedl syndrome, 416–417 Botulinum, 397, 397t
Bartter's syndrome, 228–229 anesthetic considerations for, 397
Basal ganglia/cerebellar disorder Boxer's dementia, 500
dystonia as, 265–267 Branching enzyme deficiency type IV, 305
Huntington's disease as, 264–265 Bronchiolitis obliterans organizing pneumonia
Parkinson's disease as, 260–264 (BOOP), 146, 147b
Sydenham's chorea as, 265 Bronchitis, 51
Basal septal hypertrophy, 30 Bronchogenic cyst, 606–607, 606b
Bax protein, 436 anesthetic management of, 606–607
Beck's triad, 131 Bronchopulmonary dysplasia, 127–128
Becker's muscular dystrophy, 299 Bronchopulmonary lavage, 149–150
Behavioral teratogenicity, 540 Brugada's syndrome, 33
Behçet's disease Bubonic plague, 394
differential diagnosis/clinical manifestations Bullous pemphigoid, 339
of, 322–323 Bunina bodies, 274
intraoperative considerations for, 322–323, 323f Bupivacaine, 545
preoperative preparation for, 322, 322b Burn excision and grafting, 530, 530b
skin and bone diseases and, 322–323, 322b Burns
summary for, 323, 323b anesthetic considerations for, 530–532
Benign cardiac tumor, 44 conclusion for, 534
Benzodiazepine, 83, 83f introduction to, 526
Beriberi, 222t pathophysiology of, 527–529, 527f, 527t
Bernard-Soulier syndrome. See Thrombasthenia carbon monoxide/cyanide poisoning
syndrome and, 529
Biliary atresia, 187–188 cardiovascular effects of, 527–528
Biliary atresia splenic malformation, 187–188 hematologic effects of, 528
Biliary cirrhosis, 187–188 inhalation injury and, 528–529
Biliary tract, anesthetic procedures for, 202 metabolic changes and, 528
Bilirubin, 169 pharmacologic effects of, 528
metabolism of, 167–168 renal function and, 528
Biologic toxin pediatric issues for, 532–534
botulinum as, 397 preoperative preparation for, 529–530
ricin as, 396–397 surgical considerations for, 530
sarin as, 396 blood loss/transfusion requirements for,
Biologic weapon 530b, 532
biologic toxins as, 396–397 monitoring of, 531–532
infectious agents as, 391–395, 392t
Bipolar disorder C
anesthetic considerations for, 454 Capsicum annuum, 476t, 481
comorbidities and, 452 Carbohydrate metabolism, 165, 166f
electroconvulsive therapy and, 453–454 Carbon monoxide poisoning
lithium and, 453 burns and, 529
mood disorders and, 452–454 evaluation of, 515
prevalence of, 452–453 pathophysiology of, 515
risk factors for, 452 preoperative evaluation of, 515

Carcinoid syndrome, 278
Carcinoid tumor, 45
Cardiac arrest, 558–559. See also
Cardiopulmonary resuscitation
Cardiac disease
cardiac tumors as, 44–45
cardiomyopathies as, 29–44
conclusion for, 67
ischemic heart disease as, 45–49
patient with transplanted heart and, 66–67
pericarditis, effusion, tamponade as, 52–56,
131–132
pulmonary hypertension/cor pulmonale as,
49–52, 126–130
uncommon causes of valvular lesions and,
56–66
Cardiac lesion
anomalous pulmonary venous return as,
102–104
aortopulmonary window as, 94
atrial septal defect as, 94–96
atrioventricular canal as, 97–99
coronary artery anomalies as, 124–125
double-outlet right ventricle as, 99–100
hypertrophic cardiomyopathy as, 109–110
left-sided obstructive lesions as, 104–110
left-to-right shunt lesions as, 91–92
patent ductus arteriosus as, 92–94
regurgitant valvular lesions as, 125–126
right-sided obstructive lesions as, 110–118
single ventricle as, 118–124
truncus arteriosus as, 100–102
vascular rings as, 126
ventricular septal defect as, 96–97
Cardiac tumor
anesthetic considerations for, 45, 45f
benign cardiac tumors as, 44
cardiac diseases and, 43–44, 44t
malignant cardiac tumors as, 44–45
manifestation of extracardiac tumors as, 45
metastatic cardiac tumors as, 45
Cardiomyopathy
arrhythmogenic right ventricular
cardiomyopathy/dysplasia as, 32
conduction system disease as, 32–33
dilated cardiomyopathy as, 34–41, 130–131
general classification of, 29, 29f, 30b
hypertrophic cardiomyopathy as, 30–32
ion channelopathy as, 33–34
left ventricular noncompaction as, 32
miscellaneous cardiopathies as, 43
restrictive cardiomyopathies as, 41–42
secondary cardiopathies as, 43–44
Cardiopulmonary resuscitation, 558–559, 558b
additional interventions and, 559
advanced cardiac life support and, 559
basic life support and, 558
delivery of the infant and, 559
postresuscitation considerations for, 559
Cardiovascular system
anesthetic considerations for HIV and, 382
burns and, 527–528
effects of liver disease on, 189
Carnitine deficiency, 309–310
Carnitine palmitoyltransferase deficiency, 310
Carrier state, 370
Caspases, 436
Cataract, 3, 3b
Catecholamine, 424
Catecholaminergic polymorphic ventricular
tachycardia, 34
Catheter, central venous/pulmonary artery, 375,
375f, 376f
Cayenne pepper. See Capsicum annuum
Cell saver, 602
Cellulitis, 378
Central core myopathy, 311
Centrilobular necrosis, 168
Cerebellar disorder. See Basal ganglia/cerebellar
disorder
Cerebellar dysfunction, 258
Cerebral tetany, 408
Cervical dystonia, 266
Cervical spine disorder of childhood, 285–287
Chagas' disease, 37
Charcot-Marie-Tooth disease. See Hereditary
motor and sensory neuropathy, primary
CHARGE association, 593
Catecholamine, 424
Chiari I malformation
anesthetic considerations for
general anesthesia for, 284
labor and delivery anesthesia for, 284
Arnold-Chiari malformations and, 282–284,
283t
preoperative evaluation for, 283–284
Chiari II malformation
anesthetic considerations for, 285
Arnold-Chiari malformations and, 284–285,
285t
nervous system anomalies and, 590, 590f
preoperative evaluation for, 284–285
elective procedures for, 285
emergency procedures for, 285
Child-Turcotte-Pugh cirrhosis classification,
195t, 199
Choanal atresia
anesthetic considerations for, 594
diagnosis of, 594, 594b
otolaryngologic anomalies and, 593–594,
593f
treatment of, 594, 594f
Cholecalciferol, 403
Cholestasis, benign postoperative, 206
Cholesterol, 166
Cholinergic crises, 315
Chorioretinal coloboma, 2–3
Chromophobe adenoma, 416
Chronic glomerulonephritis, 227
Chronic liver injury, 186
Chronic lung disease, 11
Chronic renal failure. See Kidney injury, acute
Chronic tubulointerstitial nephropathy, 228
Churg-Strauss syndrome, 140b, 142, 142b
Chvostek sign, 406
Cirrhosis
anesthetic management for, 198–199
cellular responses to injured liver and, 168
perioperative risk assessment for, 195
Cirrhosis, hepatic, 169b
Cirrhotic cardiomyopathy, 189
CJD. See Creutzfeldt-Jacob disease
Cleft, craniofacial, 596, 596f. See also Treacher
Collins Syndrome
INDEX 629
Cloacal exstrophy
anesthetic considerations for, 618, 618b
diagnosis of, 617
embryology of, 617–618, 617f
treatment of, 617–618
Clopidogrel, 359, 362, 362f, 564
Closed-angle glaucoma, 5–6, 5t
Closing capacity, 587–588
Clostridial myonecrosis, 389–390
Cloves, 480–481
Coagulation, impaired, 362–363
Coagulopathy, 548–549
Cobalt, 474
Cocaine abuse, 48
Coenzyme Q deficiency, 308f, 309
Cogan's syndrome, 61
Cognitive disorder
delirium after surgery as, 462
dementia as, 464
other disorders as, 464–465
Coloboma, 2–3
Complete deficit spinal cord injury, 504
Complex IV deficiency, 308f, 309
Conduction system disease
Lenègre's disease as, 31
Wolff-Parkinson-White syndrome as, 31
Congenital heart disease (CHD)
anesthetic agents/hemodynamic effects and,
82–85
conclusion for, 133
general principles of, 76–81
classification of, 76, 76t
hemodynamic management of, 79–81
pathophysiology of, 77–79, 77f, 79f
ventilatory management, 81
introduction to, 75–76
other cardiac disease and, 126–132
pacemakers/defibrillators and, 132
post-cardiac transplant patient and, 132–133
preanesthetic assessment/planning for, 85–91
airway/ventilation management for, 88
anesthetic techniques for, 88
history/physical examination for, 85, 86f,
87f, 88f, 89t
infective endocarditis prophylaxis for,
88–90
patients at greatest anesthetic risk and,
90–91, 91b
postoperative care plan/disposition for, 88
premedication/monitoring for, 85–88
specific cardiac lesions and, 91–126
w/single functional ventricle, 128
w/two ventricles and large left-to-right
shunt, 127
Congenital hypomyelinating neuropathy, 253
Congenital insensitivity to pain w/anhidrosis, 255
pathophysiology and diagnosis of, 257
Congenital pulmonary alveolar proteinosis, 149
Conjugated bilirubin, 169
Conn's syndrome. See Hyperaldosteronism,
primary
Constrictive pericarditis, 52–55, 54t
anesthetic considerations for, 55
Continuous renal replacement therapy, 242
Contractility, 495–496
Contrast dye nephropathy, 240
Convection, 241
 630 Index
Cor pulmonale
bronchitis and, 51
pulmonary hypertension and, 50–51
types of, 50
Cor pulmonale, chronic, 50
Cor triatriatum, 86f, 109
Cori-Forbes disease. See Debranching enzyme
deficiency type III
Cortisol, 420
Corneal pathology, 3, 3b
Coronary arterial circulation, 48
Coronary arteriovenous fistula, 48
Coronary artery anomaly, 124–125, 124f
Coronary artery arteritis, infectious, 48
Coronary artery disease (CAD)
hypothyroid patients and, 414
physiology of, 46–47, 46f, 47b
Coronary artery dissection, 48
Coronary artery spasm, 47–48
Coronary sinus atrial septal defect, 94
Corticoid supplementation, 423
Cortisol, 420
Craniectomy, decompressive, 502–504
Craniectomy, suboccipital, 283
Craniofacial anomaly
anesthetic management of, 601–603, 603f
postoperative management of, 602–603
clefts and, 596
craniosynostosis and, 597–598
hypoplasia and, 598–600
pediatric patient and, 595–603
surgical correction and, 600–603, 601f
Craniofacial dysostosis. See Crouzon's disease
Craniosynostosis, 597–598, 598f, 599t
Creatinine, 237
Crescentic glomerulonephritis, immune
complex, 227
Crescents, 226–227
Creutzfeldt-Jacob disease (CJD)
anesthetic considerations for, 385–386, 584
geriatric patient and, 584
prions and, 385
Crouzon's disease, 598, 599t
Cryptogenic cirrhosis, 168
Cushing's syndrome. See Glucocorticoid, excessive
Cutaneous anthrax, 392
Cutaneous porphyria, 181
Cyanide poisoning, 529
Cystic adenomatous malformation, congenital,
607–608, 607f, 608b
anesthetic management of, 607–608
Cystic fibrosis
anesthetic management of, 145, 145b
genetically caused liver disease and, 176–177
obstructive disease and, 144–145, 144t
Cystic fibrosis transmembrane regulator, 144
Cystic hygroma
anesthetic management for, 20–21, 20b, 595
ear, nose, throat and, 20–21, 20f
otolaryngologic anomalies and, 594–595, 595f
Cytochrome c, 436
Cytomegalovirus retinitis, 10
D Drug therapy, antithrombotic, 361–362
Damage control approach (to trauma), 490
Darier's sign, 329–330
de Morsier's syndrome. See Septo-optic dysplasia
Debranching enzyme deficiency type III, 305 Duchenne's muscular dystrophy, 297–298,
Deep hypothermic circulatory arrest, 93 299t, 300t
Deep tendon reflex, 298 Dwarfism, 320–322
Deep vein thrombosis (DVT), 218, 514–515, 514t Dysautonomic crisis, 255
Deep-brain stimulator, 264 Dysmyelinating disease, 267
Defective immunity, 173 Dysthymia, 451
Defibrillator, 132, 132b Dysthymic disorder, 451–452
Degeneration, liver injury and, 168 Dystonia
Dejerine-Sottas syndrome, 253 anesthetic considerations for, 263b, 266–267
Delirium after surgery, 462, 463f basal ganglia/cerebellar disorders and, 263b
Delta agent. See Hepatitis D virus etiology of, 266
Delusional disorder, 460–461 pathophysiology of, 266
Dementia, 460t, 464 treatment of, 266
Dementia pugilistica, 500 Dystonic reaction, acute, 459
Demyelinating disorder, 267 Dystrophic epidermolysis bullosa, 323
Denervated heart, 66 Dystrophic myotonia, 302
Depression, major
characteristics of, 447 E
mood disorders and, 447–451 Ear, nose, throat (ENT)
pharmacologic therapy for, 448–451 acromegaly and, 22–23
risk factors of, 447 considerations for, 15–24
Depressive mood disorder, 447 cystic hygroma and, 20–21
Dermatomyositis, 316 Ludwig's angina and, 23–24
Desflurane, 83, 221 recurrent respiratory papillomatosis and, 17–20
Desmopressin, 418 sleep apnea and, 15–17
Detoxification, 167 Wegener's granulomatosis and, 21–22
Devil's claw, 476t, 482 Eaton-Lambert myasthenic syndrome, 315–316
Dexmedetomidine, 84 Ebstein's anomaly, 110–111, 110f, 111b
Dextrotransposition of the great arteries, 86f, Echinacea, 476t, 477–478
115–117, 116b, 116f Echinococcal disease of lung, 158b, 159
Diabetes insipidus, 418b, 419 Eclampsia
Diabetes mellitus obstetric anesthesia and, 550–551, 550b
acute complications of, 428–429 management of, 551
pancreas and, 218, 428–430, 428f pregnancy-associated liver disease and, 188
renal involvement in, 230 Ectopia lentis, 4, 4b, 4f
Diabetic nephropathy, 230 Edema factor, 391
Diagnostic and Statistical Manual of Mental Eisenmenger's syndrome, 50, 97–98, 128, 129f
Disorders, 4th ed. (DSM-IV), 447 Elastase, 176
Dialysis disequilibrium syndrome, 242 Elastin, 587–588
Difficult Airway Management Algorithm Elastin arteriopathy, 618
(American Society of Anesthesiologists), 492 Electroconvulsive therapy, 453–454
Diffuse axonal injury, 500 Electroretinography, 12–13
Diffuse idiopathic skeletal hyperostosis, 336 Elfin facies, 618
Diffusion, 241, 241f Embryo transfer, 543
DiGeorge syndrome, 408 Emergent-urgent-nonurgent trauma case,
Dilated cardiomyopathy (DCM) 490, 490t
anesthetic considerations for, 40–41 Emery-Dreifuss muscular dystrophy, 301–302
cardiac disease and, 130–131, 131b Emphysema, congenital lobar, 608–609, 609b
cardiomyopathies and, 34–41 anesthetic management of, 609
inflammatory cardiomyopathy as, 34–37 Encephalopathy, 437
noninflammatory dilated cardiomyopathy End-stage renal disease (ESRD), 226
as, 37 Endocrine system, diseases of
pathophysiology of, 37–40, 40f adrenal cortex and, 419–423
Dilated cardiomyopathy, noninflammatory, 37, 38t adrenal medulla and, 424–426
Diphtheritic myocarditis, 35–37 pancreas and, 426–430
Distraction osteogenesis, 600, 601f parathyroid glands and, 402–408
Diverticular abscess, 388 pituitary gland and, 415–419
Dobutamine, 377 thyroid gland and, 408–415
Dopa-responsive dystonia, 266 Endoscopic strip craniectomy, 600
Dopamine, 376–377 Endothelin, 548
Double aortic arch, 126 Endotoxin, 371
Double-outlet right ventricle, 99–100, 99b Enzyme deficiency anemia
Doxacurium, 245 glucose-6-phosphate dehydrogenase deficiency
as, 355
Drug-eluting stent, 362 pyruvate kinase deficiency as, 355
DSM-IV. See Diagnostic and Statistical Manual of Eosinophilic pneumonia, chronic, 147–148, 147b
Mental Disorders, 4th ed. (DSM-IV) Ephedra, 478–479
 Index 631
Ephedrine, 478–479
Epidermolysis bullosa. See also Epidermolysis
bullosa, pediatric
diagnosis for, 323–324
intraoperative care for, 324
preoperative preparation for, 324, 324b
skin and bone diseases and, 323–324, 323t
summary for, 324, 324b
Epidermolysis bullosa simplex, 323, 620–621
Epidermolysis bullosa, pediatric
anesthetic management of, 620–621
airway evaluation of, 621
airway management of, 621, 621f
pain management for, 621
preoperative evaluation of, 620–621, 621b
regional anesthesia for, 621
clinical presentation of, 620
diagnosis of, 620
epidermolysis bullosa simplex and, 620–621
introduction to, 619–621, 619f
junctional epidermolysis bullosa and, 620
Kindler's syndrome as, 620
recessive dystrophic epidermolysis bullosa
and, 620
treatment of, 620
Epidermolysis bullosa, recessive dystrophic, 620
Epiglottitis, 390–391, 391t
anesthetic considerations for, 390–391
Epinephrine, 377, 565
Eptifibatide, 361–362, 564
Erythema multiforme
anesthetic management of, 326
pathophysiology/clinical manifestations of,
325–326, 325t
preoperative preparation for, 326, 326b
skin and bone diseases and, 325–326
summary for, 326
Erythema nodosum
differential diagnosis for, 326–327
intraoperative considerations for, 327, 327b
pathophysiology/clinical manifestations of,
326–327, 327b
preoperative preparation for, 327
summary for, 327
Erythema nodosum migrans, 326–327
Erythropoietic porphyria, 181
Esophageal atresia, 612
Esophageal varices, 198
Essential thrombocytosis, 579b, 580
Ester local anesthetic, 564
Etomidate, 84, 245
bipolar disorder and, 454
mitochondrial function and, 435
Eugenol, 480–481
Euthyroid, 411
Ex utero intrapartum treatment (EXIT), 595,
595f
Excision. See Burn excision and grafting
Extracardiac tumor, 45
Extracorpuscular hemolytic anemia, 353
Extrahepatic cholestasis, 206
Extralobar sequestration, 608
Extrinsic biliary obstruction, 187
Eye disease
corneal pathology and systemic diseases of, 3
general considerations for, 2–6, 2b
glaucoma and systemic diseases of, 4–6
Eye disease (Continued)
lens pathology and systemic diseases of, 3
retinal complications of systemic disease
and, 6
specific considerations for
acquired immunodeficiency syndrome as,
9–10
eye trauma as, 13–15
Graves' disease as, 7–8
hemoglobinopathies as, 8–9
homocystinuria as, 8
incontinentia pigmenti as, 12
Marfan's syndrome as, 6–7
retinitis pigmentosa as, 12–13
retinopathy of prematurity as, 10–12
Eye trauma, 13–15
anesthetic management for, 14–15, 14b
Eye, ear, nose, throat disease
conclusion for, 24
ear, nose, throat considerations and, 15–24
general eye disease considerations and, 2–6
specific eye disease considerations and, 6–15
F Galactokinase deficiency, 177
Fabry's disease. See also Periarteritis nodosa
clinical manifestations of, 327–328, 327b
diagnosis for, 328
intraoperative considerations for, 328, 328b
pathophysiology of, 327–328
preoperative considerations for, 328, 328b
summary for, 328
Facial injury, complex
evaluation of, 509
intraoperative considerations for, 510
pathophysiology of, 508–510, 508t
preoperative preparation for, 509–510
trauma and, 508–510, 508b
Facial-oral herpes, 329
Facioscapulohumeral dystrophy, 299
Factor V Leiden mutation, 363
treatment for, 363
Familial amyloid polyneuropathy, 577
Familial dysautonomia, 255–256, 256b
anesthetic considerations for, 254b, 256–257
Familial isolated pituitary adenoma, 415, 415t
Fanconi's syndrome, 229
Fascial excision, 530
Fasting requirement, burns and, 529–530
Fat embolism syndrome, 514
Fatty acid metabolism disorder
acyl-coenzyme A dehydrogenase deficiency
as, 310
carnitine deficiency and, 309–310
carnitine palmitoyltransferase deficiency as,
310
muscle diseases and, 298f, 309–310, 310f
Fatty acids, 165
Fatty liver of pregnancy, acute, 189
Fentanyl
burn patients and, 531
in vitro fertilization and, 544
opioids/benzodiazepines and, 83
Fentanyl citrate, 533
Fetal safety, 539–540
Feverfew, 476t, 478
Fibroma, 44
Fibromuscular dysplasia, 231
Fibrosis, hepatic, 163f, 168
First-degree burn, 527
Flail arm syndrome, 273–274
Flail leg syndrome, 273–274
Fluid management, 203
Fluid resuscitation. See also Trauma damage
control/fluid resuscitation
burns and, 529, 529b
Foamy degeneration, 168
Focal necrosis, 168
Folate, 475
Folic acid, 473t, 475
deficiency of, 353
Fondaparinux, 563
Fontan completion, 123, 123b
Frataxin gene, 275
Free fatty acids, 165
Friedreich's ataxia, 275
anesthetic considerations for, 275–276
Fulminant hepatic failure. See Liver failure, acute
Fundus coloboma, 2–3
G
Galactosemia, 177
key points for, 177
Gamete intrafallopian transfer, 543
Gamma-glutamyl transpeptidase, 170
Gangrenous myositis, spontaneous, 389–390
Garlic, 479
Gas gangrene. See Clostridial myonecrosis
Gastroesophageal reflux disease (GERD), 218
Gastrointestinal anthrax, 392
Gastroschisis
abdominal wall defects and, 614–616, 615t
anatomy and embryology of, 615–616
anesthetic management of, 616
clinical management of, 615–616
surgical repair/anesthesia induction for, 616
Gaucher's disease, 180–181
GBM. See Glomerular basement membrane
(GBM)
General anesthesia, intravenous, 542
General anxiety disorder, 454–455
Genital herpes, 329
Geriatric patient
amyloidosis and, 574–577
Creutzfeldt-Jakob disease and, 584
essential thrombocythemia and, 579–580
Goodpasture's syndrome and, 582
Huntington's chorea and, 573–574
idiopathic pulmonary fibrosis and, 577–578
liver injury in, 187
male breast cancer and, 582–583
myeloid metaplasia w/ myelofibrosis and,
580–581
polycythemia vera and, 578–579
polymyalgia rheumatica and, 581–582
primary hepatic lymphoma and, 583–584
trauma and, 518
Gestational diabetes, 428
Geste antagoniste, 266
Ginger, 476t, 477b, 479
Ginkgo biloba, 476t, 479–480
Ginseng, 476t, 480
Ginsenosides, 480
Gitelman's syndrome, 229
 632 Index
Glanzmann's thrombasthenia, 359–360
treatment of, 360
Glaucoma, 4–6, 5b
Glomerular basement membrane (GBM), 226–227
Glomerular disease
glomerulonephritis as, 226–227
nephrotic syndrome as, 227–228
Glomerulonephritis, 226–227
Glomerulonephritis, acute, 226
Glucocorticoid, 416f, 420, 420t
Glucocorticoid deficiency, 422–423, 422t, 423b
Glucocorticoid, excessive, 421–422, 422t
Gluconeogenesis, 165
Glucose-6-phosphate dehydrogenase deficiency,
355
Glycogen storage disease, 177, 178t
Glycogen storage myopathy
aldolase deficiency as, 307
debranching enzyme deficiency type III as, 305
debranching enzyme deficiency type IV as, 305
metabolic myopathies and, 304–307, 306f
muscle lactate dehydrogenase deficiency as, 307
muscle phosphofructokinase deficiency as, 306
myophosphorylase deficiency as, 305–306
phosphoglycerate kinase deficiency as, 307
phosphoglycerate mutase deficiency as, 307
phosphorylase B kinase deficiency as, 306–307
Glycogenolysis, 165
Glycogenosis type I, 307
Glycogenosis type II, 307–308
Goal-directed resuscitation, 374, 374f
Goldenhar's syndrome, 600
Goodpasture's syndrome, 147b, 148–149, 148b
geriatric patient and, 582, 582f
anesthetic considerations for, 582
Grafting. See Burn excision and grafting
Granulomatosis with polyangiitis, 227
Graves' disease, 7–8
anesthetic management for, 7–8, 8b
Great arteries, congenitally corrected
transposition of, 117–118, 117f, 118b, 118f
Great arteries, dextrotransposition of, 116f
Guillain-Barré syndrome, 272t
anesthetic considerations for, 272–273, 273b
H Hepatic resection, anesthetic management
Hallermann-Streiff syndrome. See mandibulo-
oculofacial dyscephaly
Halothane, 82, 186, 197–198
Halothane hepatitis, 186
Hashimoto's disease, 413
Heart transplant
anesthetic considerations for, 66–67
denervated heart and, 66
immunosuppressive therapy and, 66
patients with, 66–67
post-cardiac patient of, 132–133, 133b
Heat shock protein, 435–436
HELLP syndrome, 188
obstetric anesthesia and, 551–552, 551b
Helminthic myocarditis, 37
Hematologic disease
acute blood loss/hemorrhagic shock as, 355–356
anemia and, 350–355
conclusion for, 365
diseases of leukocytes as, 356–358
diseases of thrombocytes as, 358–365
Hematologic effect, burns and, 528
Hematoma, epidural, 562–563
Hematuria, asymptomatic, 226
Heme, 167–168
Heme synthesis, 181
Hemochromatosis, hereditary, 178–179, 179b
Hemodynamic management
arrhythmias and, 79–81, 80t, 81t, 82t
congenital heart disease and, 80t
Hemoglobin, 351
Hemoglobin concentration, 351
Hemoglobinopathy, 8–9, 354. See also Sickle cell
disease
Hemolysis, 551–552
Hemolytic anemia
anemias and, 353–355
antibody-induced hemolysis as, 355
enzyme deficiency anemia as, 354–355
hemoglobinopathies as, 354
renal anemia as, 355
spherocytosis as, 353–354
traumatic hemolysis as, 355
treatment for, 353
Hemophilia A, 362
Hemophilia B, 363
Hemorrhage, massive, 552–555
management of, 555, 556f
Hemorrhagic shock, 355–356
Hemostasis, 243
Henoch-Schönlein purpura, 226
Heparin, low-molecular-weight, 561–562
Heparin, unfractionated, 560–561
Hepatic anatomy, normal, 163–164, 163f, 165f
key points for, 164
Hepatic encephalopathy, 193, 193b, 194f
Hepatic function
carbohydrate metabolism and, 165
detoxification/transformation and, 167
lipid metabolism/transport and, 165–166
protein synthesis and, 166–167
Hepatic infarction, 188
Hepatic lobule, 163–164, 164f
Hepatic lymphoma, primary, 583–584, 583f
anesthetic considerations for, 583–584
Hepatic porphyria, 181
of, 202–203
Hepatic rupture, 188
Hepatic steatosis, 166
Hepatic venous pressure gradient, 190
Hepatitis, 168
Hepatitis A virus, 171–172
Hepatitis B virus
transmissible infections and, 379–380, 380f
anesthetic considerations for, 380, 380b,
381t
viral hepatitis and, 172–173
Hepatitis C virus
transmissible infections and, 380
anesthetic considerations for, 380, 380b
viral hepatitis and, 173–174
Hepatitis D virus, 173
Hepatitis E virus, 174
Hepatitis G virus, 174
Hepatitis, acute, 195
anesthetic management of, 197–198
Hepatitis, chronic, 195
Hepatobiliary dysfunction
laboratory manifestations of
injured liver and, 168–170, 169t
key points for, 170
serum enzyme tests and
alkaline phosphatase and, 170
gamma-glutamyl transpeptidase and, 170
lactate dehydrogenase and, 170
transaminases and, 170
tests that reflect hepatic clearance and
ammonia as, 168
bilirubin as, 169
tests that reflect synthetic function and
albumin and, 169
prothrombin time and, 170
Hepatocellular necrosis, 205–206
Hepatolenticular degeneration. See Wilson's
disease
Hepatopulmonary syndrome, 192–193, 192t
Hepatorenal syndrome, 190–191
Hepatorenal syndrome type I and II, 191
Herbal remedy
anxiety attack and, 457
kava as, 457
saw palmetto, 475
supplements and, 475–482, 477b
Hereditary amyloidosis, 575, 576t
Hereditary dystonia, 266
Hereditary fructose intolerance, 177–178
Hereditary hemochromatosis, 178–179
Hereditary motor and sensory neuropathy,
primary
anesthetic considerations for, 254–255, 254b
hereditary peripheral neuropathies and,
252–255
pathophysiology and diagnosis for, 253–254,
254b
Hereditary sensory and autonomic neuropathy
congenital insensitivity to pain w/anhidrosis
and, 257
familial dysautonomia as, 255–256
hereditary peripheral neuropathies and,
255–257
Hernia, congenital diaphragmatic
anesthetic management of, 611–612, 612b
congenital malformations of the lung and,
609–612, 609f, 610b, 610f
lung hypoplasia and, 127–128
medical management of, 610–611, 610b
surgical management of, 611
Herpes simplex
diagnosis of, 329
intraoperative care for, 329
preoperative considerations for, 329, 329b
skin and bone diseases and, 328–329, 329b
summary for, 329
Herpetic whitlow, 329
Heteroplasmy, 434
Hibernation, 496
Hirsutism, 421
HIV. See Human immunodeficiency virus (HIV)
Hodgkin's disease, 356–357, 357t
Homocystinuria, 4f, 8, 8b, 48
Human immunodeficiency virus (HIV)
inflammatory myopathies and, 316–317
the heart and, 42–43
anesthetic considerations for, 35t, 43
 Index 633
Human immunodeficiency virus (HIV)
(Continued)
transmissible infections and, 380–384, 382b
anesthetic considerations for, 381–384, 383t
pregnancy and, 383–384
risk to anesthesiologist and, 380b, 384
surgery and, 383
Hunter's disease (syndrome), 180, 331
Hunter's glossitis, 353
Huntington's chorea. See Huntington's disease
Huntington's disease
anesthetic considerations for, 263b, 265
associated procedures for, 265
basal ganglia/cerebellar disorders and,
264–265
geriatric patient and, 573–574
anesthetic considerations for, 574
diagnosis and differential for, 574
pathophysiology of, 574
preoperative preparation for, 574
Hurler's syndrome, 180, 331
Hybrid palliation, 120
Hydatid cyst disease, 174–175
Hydatid disease
anesthetic considerations for, 388
intra-abdominal infections and, 387–388
surgery for, 387
Hydrocephalus, 284–285
Hyperaldosteronism, primary, 422
Hypercalcemia
clinical presentation of, 403–404
etiology of, 403–406, 404f
intraoperative/postoperative considerations
for, 405–406
management of, 404–405, 405b
preoperative considerations for, 405
Hypercarbia, permissive, 610–611
Hyperglycemia, preoperative management of,
429–430
Hyperglycemic hyperosmolar state, 429
Hyperinsulinism, 426–428
Hyperkalemia, 243
Hyperkalemic distal renal tubular acidosis type
IV, 229
Hyperkalemic periodic paralysis, 312–313
Hyperparathyroidism, primary, 402, 405–406
Hyperpituitarism
acromegaly and, 417
pituitary gland and, 417
prolactinomas and, 417
Hyperplasia, 421–422
Hyperreflexia, autonomic, 505t
Hypersplenism, 580
Hypertension, 230, 230f
Hyperthermia, malignant
anesthetic management of, 440–441
diagnosis of, 311–312, 311t
management of susceptible patients of, 312
muscle diseases and, 310–312
pathogenesis of, 310–312
treatment of, 312
Hyperthyroidism
amiodarone/thyroid function and, 412
elective surgery and, 411–412, 411b
thyroid gland and, 410–412, 411f
thyroid storm and, 412
thyrotoxicosis during pregnancy and, 412
Hypertrophic cardiomyopathy
anesthetic considerations for, 31–32, 31t
cardiac disease and, 30–32, 30t
cardiac lesions and, 109–110, 110b
Hypertrophic osteoarthropathy, 336
Hypoalbuminemia, 169
Hypoaldosteronism, 423
Hypocalcemia
clinical presentation of, 407–408
DiGeorge syndrome and, 408
etiology of, 406–408, 407f
hypoparathyroidism and, 408
intraoperative considerations for, 406
management of, 408, 408b
Hypoglycemia, 426–428, 427f
anesthetic considerations for, 427–428
Hypokalemic distal renal tubular acidosis
type I, 229
Hypokalemic periodic paralysis, 313
Hypoketotic hypoglycemia, 309
Hypomagnesemia, 406
Hyponatremia, 418–419
Hypophosphatemia, 406
Hypopituitarism, 415–417, 415t, 416f
Hypoplasia, 598–600
Hypoplasia, midface, 597–598
Hypoplastic left heart syndrome, 119–123, 120f,
121b, 121f
fontan completion and, 123
superior cavopulmonary anastomosis
and, 122
Hypothyroidism
coronary artery disease and, 414
surgery and, 414, 414b
thyroid gland and, 413–414, 413f
Hypotonia, 256
Hypoxemia, 614
I 272
Ideal body weight, 221
Idebenone, 275
Idiopathic pulmonary alveolar proteinosis
(PAP), 149
Idiopathic pulmonary hemosiderosis, 146–147,
147b, 148t
Idiopathic scoliosis, 155
Idiopathic ventricular fibrillation, 34
Idiosyncratic hepatotoxin, 186
Immunoglobulin A nephropathy, 226
Immunosuppressive therapy, 66
In vitro contracture test, 311
In vitro fertilization
anesthetic issues for, 542–546, 542t, 543t
nonobstetric surgery and, 541–546
Incomplete deficit spinal cord injury, 504
Incontinentia pigmenti, 12, 12b, 12f
Induction agent, 244–245
Infantile Gaucher's disease, 181
Infantile neuropathic NPD, 181
Infection, 370–371
Infection, transmissible
hepatitis B as, 379–380
hepatitis C as, 380
human immunodeficiency virus as,
380–384
prions as, 385–386
tuberculosis as, 384–385
Infectious disease
intra-abdominal infections and anesthesia
as, 386–388
introduction to, 370
key points for, 369–370
necrotizing soft tissue infection as, 388–391
sepsis and systemic inflammatory response
syndrome as, 370–379
transmissible infections and, 379–386
Infectious respiratory disease
echinococcal disease of lung as, 159
influenza A as, 157–159
severe acute respiratory syndrome as, 158–159
Infectiousness, 370
Infective endocarditis, 88–90, 90b, 90t
Infective myopathy
human immunodeficiency virus as, 316–317
muscle diseases and, 316–317
necrotizing myopathy as, 317
thyrotoxic myopathy as, 317
Infiltrative and interstitial disease
acute respiratory distress syndrome as,
152–153
bronchiolitis obliterans organizing pneumonia
as, 146
chronic eosinophilic pneumonia as, 147–148
Goodpasture's syndrome as, 148–149
idiopathic pulmonary fibrosis as, 152
idiopathic pulmonary hemosiderosis as,
146–147
lymphangioleiomyomatosis as, 154
pulmonary alveolar proteinosis as, 149–150
pulmonary histiocytosis X as, 153–154
sarcoidosis as, 150–151
systemic lupus erythematosus as, 151–152
Inflammatory cardiomyopathy, 35t
Inflammatory cascade, 372
Inflammatory demyelinating polyneuropathy,
Inflammatory myopathy
dermatomyositis as, 316
inclusion body myositis as, 316
overlap syndromes as, 316
polymyositis as, 316
Influenza A, 157–158, 158b, 158t
Informed consent, 446
Infracardiac TAPVR, 102
Inhalation agent
mitochondrial respiration and, 435
obesity and, 221
Inhalation injury, burns and
lower airway injury and, 528–529
upper airway injury and, 528
Inhalational anesthetic, 186
Inhalational anthrax, 392, 393t
Inlet-type ventricular septal defect, 96
Insulin resistance syndrome. See Metabolic
syndrome
Insulinoma, 426
Intensive care unit psychosis, 464
Intensive insulin therapy, 429–430
Intermittent hemodialysis, 241–242
Interrupted aortic arch, 107f
types A, B, C and, 106
Interstitial disease. See Infiltrative and interstitial
disease
Intoxicated patient trauma, 492
 634 Index
Intra-abdominal infection
amebic liver abscess as, 386–387
appendiceal abscess as, 388
diverticular abscess as, 388
hydatid disease as, 387–388
pyogenic liver abscess as, 386
splenic abscess as, 388
Intracytoplasmic sperm injection, 545
Intraepidermal acantholysis, 339
Intraepidermal autoimmune blistering
disease, 339
Intrahepatic cholestasis, 206
Intrahepatic cholestasis of pregnancy, 188
Intralobar sequestration, 608
Intraoperative cell salvage, 555
Intrinsic factor, 353
Intrinsic hepatotoxin, 186
Intubation technique, 19
obstructive sleep apnea and, 219
Ion channelopathy
anesthetic considerations for, 34
Brugada's syndrome as, 33
catecholaminergic polymorphic ventricular
tachycardia as, 34
idiopathic ventricular fibrillation as, 34
long QT syndrome as, 33
short QT syndrome as, 34
Iron deficiency anemia, 352, 352t
treatment of, 352
Ischemic heart disease
anesthetic considerations for, 49
cardiac disease and, 45–49
coronary artery disease physiology and, 46–47
uncommon causes of
cocaine abuse as, 48
congenital abnormalities of coronary
arterial circulation as, 48
coronary artery spasm as, 47–48
inflammatory causes of, 48
metabolic causes of, 48
Ischemic liver injury, 186–187
Islet cell tumor of pancreas, 426–428
Isoflurane, 82, 197–198, 221
Ito cells. See Stellate cells
J Laryngeal nerve injury, bilateral recurrent, 405–406
JAG1 gene, 175
Jet ventilation, 19
Junctional ectopic tachycardia (JET), 112
Junctional epidermolysis bullosa, 323, 620, 620f
Juvenile Gaucher's disease, 181
Juvenile myotonic dystrophy, 303
Juxtaglomerular cell hyperplasia. See Bartter's
syndrome
K Left coronary artery arising from pulmonary
Kahler's disease. See Multiple myeloma
Kallmann's syndrome, 416–417
Kava, 457, 480
Kawasaki's disease, 48
Kayser-Fleischer ring, 185
Ketamine
hemodynamic effects of anesthetic agents
and, 84
mitochondrial function and, 435
pediatric burns and, 533
induction agents and, 245
Ketoacidosis, 429
Kidney disease
anesthetic effects on renal function and, 246
hemodynamic management of, 243–244
induction and, 244–245
maintenance and postoperative period for, 246
muscle relaxants and, 245
pharmacologic choices for, 244–246, 245t
Kidney disease, chronic
clinical presentation of, 233–234, 233b, 233t
differential diagnosis for, 234, 234b
introduction to, 231–235, 231f
pathophysiology of, 232–234, 232t
preoperative evaluation and preparation for,
234–235, 236t
Kidney injury, acute
abdominal compartment syndrome and, 239
acute tubular necrosis as, 236–237
introduction to, 235–239, 236b, 237t
renal function tests and, 237–238
rhabdomyolysis and, 238–239
Kidney vascular disease, 231
Kidney, polycystic, 229–230
Kindler's syndrome, 620
King-Denborough syndrome, 311
Klippel-Feil syndrome
anesthetic considerations for, 286–287, 287b
neurologic diseases and, 285–287, 286t
preoperative evaluation for, 286–287
Korsakoff 's syndrome, 222t
Kupffer cells, 164
Kuru, 584
Kyphoscoliosis, 155
Kyphosis, 155–156, 155b
L Lipid storage disorder, 180–181
Lactate dehydrogenase, 170
Lactulose, 193
Laparoscopic surgery
anesthetic technique for, 541, 542t
during pregnancy, 540–541
monitoring of, 541
pneumoperitoneum and, 540–541
Laparotomy, decompressive, 502–504
Laryngeal amyloidosis, 576
Laryngeal webs and atresia, congenital, 591–593,
592b, 592f
anesthetic management of, 592–593, 593b
Laryngospasm, 459
Late onset myotonic dystrophy, 303
Latex-fruit syndrome, 565
Lean body weight, 220–221
Leber's hereditary optic neuropathy, 437
LeFort fracture, 509
artery, 48
Left coronary artery, anomalous, 124, 124f, 125b
Left ventricular noncompaction, 32
anesthetic considerations for, 32
Left ventricular outflow tract, 30
Lenègre's disease, 32–33
Lesion, left-sided obstructive
aortic stenosis as, 107–108
coarctation of the aorta as, 104–106
cor triatriatum as, 109
interrupted aortic arch as, 106
Lesion, left-sided obstructive (Continued)
mitral stenosis as, 108–109
Shone's complex as, 109
Lesion, left-to-right, 91–92, 91f, 92b
Lesion, right-sided obstructive
congenital heart disease and, 110–118
congenitally corrected transposition of the
great arteries and, 117–118
dextrotransposition of the great arteries and,
115–117
Ebstein's anomaly and, 110–111
pulmonary atresia w/intact ventricular septum
and, 113–114
pulmonary atresia w/ventricular septum
defect/major aortopulmonary collaterals
and, 114–115
pulmonary stenosis and, 112–113
tetralogy of Fallot and, 110–111
Lesioning, intentional, 260
Lethal factor, 391
Leukemia
acute leukemia as, 357–358
chronic myeloproliferative disease as, 358
diseases of leukocytes and, 357–358
Leukocyte, disease of
leukemias as, 357–358
lymphomas as, 356–357
myelodysplastic syndrome as, 358
Lewy bodies, 260
Liddle's syndrome, 229
Lidocaine, 531
in vitro fertilization and, 544–545
Limb compartment syndrome, 238–239
Limb-girdle muscular dystrophy, 299–301
Lipid metabolism, 165–166, 167f
Lipoma, cardiac, 44
Lipopolysaccharide, 371
Lithium, 453
Liver disease
anesthetic management of, 196–206
abnormal laboratory values and, 197, 197b
acute hepatitis and, 197–198, 198b
acute liver failure and, 199–201, 200b, 201b
biliary tract procedures and, 202, 202b
cirrhosis and, 196t, 198–199, 198b, 199b
hepatic resection, 202–203, 203b
introduction to, 196–206
liver transplantation and, 203
postoperative liver dysfunction and,
203–206
transjugular intrahepatic portosystemic
shunt and, 201
assessment of perioperative risk and, 193–195,
195t, 196f
conclusion for, 206–207
etiology of liver dysfunction and, 170–189
genetic causes of, 175–185
Alagille's syndrome as, 175–176
alpha1-antitrypsin deficiency as, 176
cystic fibrosis as, 176–177
galactosemia as, 177
glycogen storage diseases as, 177
hereditary fructose intolerance as, 177–178
hereditary hemochromatosis as, 178–179
hereditary tyrosinemia type 1 as, 179–180
lipid storage disorders as, 180–181
 Index 635
Liver disease (Continued)
lysosomal storage diseases as, 180
other lysosomal storage diseases as, 181
porphyria as, 181–184
hepatic function in health and, 165–168
injured liver and, 168–170
introduction to, 163
normal hepatic anatomy and, 163–164
systemic effects of, 189–193
Liver disease, drug induced, 185–186, 185t
Liver disease, pregnancy-associated
acute fatty liver of pregnancy as, 189
HELLP syndrome as, 188
hepatic infarction or rupture as, 188
intrahepatic cholestasis of pregnancy as, 188
introduction to, 188–189
key points for, 189
pre-eclampsia and eclampsia as, 188
Liver disease, systemic effects of
cardiovascular effects as, 189
hepatic encephalopathy as, 193
portal hypertension and ascites as, 189–190
pulmonary effects as, 192–193
renal effects as, 190–192
Liver dysfunction, etiology of
biliary cirrhosis as, 187–188
drug-associated and other liver disease as,
185–186
genetic causes of liver disease as, 175–185
hydatid cyst disease as, 174–175
ischemic liver injury as, 186–187
liver function in the geriatric patient as, 187
nonalcoholic steatohepatitis as, 175
pregnancy-associated liver disease as, 188–189
Liver dysfunction, postoperative, 203–206, 206t
Liver failure, acute
anesthetic management of, 199–201
Liver injury
cellular responses to, 168
laboratory manifestations of hepatobiliary
dysfunction, 168–170
Liver transplant, orthotopic, 203, 204b, 204t,
205b
Liver transplantation
orthotopic liver transplant and, 203, 204t
previously transplanted patient and, 203
Localized amyloidosis, 574–575
Long QT syndrome, 33
Low birth weight, 10
Ludwig's angina, 23–24, 23f, 24b
anesthetic concerns for, 24
Luft's disease, 309
Lung hypoplasia, 127–128
Lung injury, drug-induced
bleomycin toxicity as, 156–157
Lung, congenital malformations of
bronchogenic and pulmonary cysts as,
606–607
congenital cystic adenomatous malformation
as, 607–608
congenital diaphragmatic hernia as, 609–612
congenital lobar emphysema as, 608–609
pulmonary sequestration as, 608
tracheoesophageal fistula as, 612–614
Lusitropic support, 79
Luxation, 4
Lymphangioleiomyomatosis, 147b, 154
Lymphangioma, suprahyoid, 594–595
Lymphoma
diseases of leukocytes and
Hodgkin's disease as, 356–357
macroglobulinemia as, 357
multiple myeloma as, 357
non-Hodgkin's lymphoma as, 357
treatment of, 356
lymphomatoid granulomatosis and, 141
Lymphomatoid granulomatosis, 141–142, 141b
anesthetic management of, 140b, 141–142
Lysosomal storage disease
introduction to, 180
mannosidosis as, 181
mucopolysaccharidoses as, 180
Wolman's disease as, 181
M Metabolic myopathy
Ma huang, 478
Macroglobulinemia, 357
Macroglossia, 576
Macrovesicular steatosis, 168
Major aortopulmonary collateral, 114–115
Male breast cancer, 582–583
anesthetic considerations for, 583
Male factor infertility, 545
Malignant cardiac tumor, 44–45
Malignant hyperthermia, 254
Mandibular fracture, 509
Mandibulo-oculofacial dyscephaly, 3
Manic depression, 447
Manic-depressive disorder. See Bipolar disorder
Mannosidosis, 181
Marfan's syndrome, 4f, 6–7
anesthetic management for, 6–7, 7b
Mastocytosis
diagnosis of, 330–331
intraoperative considerations for, 330–331
preoperative considerations for, 330, 330b
skin and bone diseases and, 329–331, 330b,
330t
summary for, 331
Maternal safety, 538–539
McArdle's disease. See Myophosphorylase
deficiency type V
Mechanical biliary obstruction, 187
Mediastinal cyst, 606
Mediastinal mass
anatomic considerations for, 599t, 603–606
anesthetic management of, 605–606, 606b, 606f
clinical presentation of, 603–604, 604t
diagnosis of, 604
pathology of, 603
preanesthetic evaluation for, 604–605, 605f
Megaloblastic anemia, 353
treatment for, 353
Memantine, 464
Membranous glomerulopathy, 227
Meningococcemia, 378
Meningomyelocele
anesthetic considerations for, 590–591, 591t
fetal surgery and, 591
induction and, 590–591
latex precautions for, 591
maintenance of, 590–591
postoperative considerations for, 591
regional anesthesia and, 591
Meningomyelocele (Continued)
associated anomalies and, 590–591, 590f, 604t
Chiari II malformation and, 284
pathophysiology of, 590
pediatric nervous system anomalies and,
589–591, 590f
Mental disorder
characterization of, 445–446
epidemiology of, 445
preoperative evaluation for, 446–447
informed consent and, 446
patient history and, 446
unrecognized perioperative problems
and, 446–447
psychiatric disorders and, 445–447
Mental retardation, 465
Metabolic change, burns and, 528
glycogen storage myopathies as, 304–307
glycogenosis type I as, 307
glycogenosis type II as, 307–308
muscle diseases and, 304–308, 305f
myoglobinuria as, 307
Metabolic syndrome, 218
Metastatic cardiac tumor, 45
Methadone, 531
Methohexital, 454
Methysergide toxicity, 56
Metoclopramide, 544
Microcirculatory failure, 372
Microepididymal sperm aspiration, 545
Microscopic polyangiitis, 227
Microsomia, hemifacial, 600
Microvesicular steatosis, 168
Midazolam, 83
mitochondrial function and, 435
Middle mediastinum, 603
Midface fracture, 509
Mild traumatic brain injury, 500
Milrinone, 79
Mineralocorticoid, 420–421
deficiency of, 423
Mineralocorticoid, excessive, 422
Minerals
calcium as, 471–472
chromium as, 472
iron as, 472–473
magnesium as, 472
selenium as, 473
supplements and, 471–473, 471t
zinc as, 473
Minimal change disease, 227
Mitochondrial disease
anesthetic of, 440–441, 440b
background of, 434–435, 434f
conclusion of, 441
effects of anesthetics and, 435–436
inherited disorders w/adult onset and,
437–439, 438f
inherited disorders w/childhood onset and,
436–437, 437b, 438t
introduction to, 433
preoperative evaluation for, 439–440, 439b, 440b
Mitochondrial encephalomyelopathy, 437
Mitochondrial myopathy, 308, 308f
Mitochondrial neurogastrointestinal
encephalomyopathy, 437
 636 Index
Mitochondrion, 308
Mitral regurgitation, 62–63, 64t, 126, 126b, 126f
Mitral stenosis, 56–58, 58t, 108–109, 109b
Mixed TAPVR, 102
Model for end-stage liver disease (MELD), 195,
196t
Moderate traumatic brain injury, 500–501
Monoamine oxidase inhibitor, 450–451
anesthetic considerations for, 451
Mood disorder
bipolar disorders as, 452–454
dysthymic disorder as, 451–452
major depression as, 447–451
psychiatric disorders and, 447–454
Morphine, 531
Morquio's syndrome, 331
Motor neuron disease
amyotrophic lateral sclerosis as, 273–275
Friedreich's ataxia as, 275–276
neurologic diseases and, 273–276, 273b
spinal muscular atrophy as, 276
mtDNA depletion syndrome, 437
Mucocutaneous lymph node syndrome. See
Kawasaki's disease
Mucopolysaccharidosis
anesthetic considerations for, 288–289, 288b
differential diagnosis/clinical manifestations
of, 331–332, 331b
intraoperative management of, 332, 332b
lysosomal storage diseases and, 180
neurologic diseases and, 287–289, 287t
preoperative preparation for, 331–332, 332b
skin and bone diseases and, 331–332, 331t
summary for, 332
Multiorgan dysfunction syndrome
activated protein C and, 373
sepsis and, 373
Multiple endocrine neoplasia type I, 402
Multiple myeloma, 357
Multiple sclerosis (MS)
anesthetic considerations for, 268–270, 269b
myelin diseases and, 267–270, 267b
treatment for, 268
Multiple system atrophy, 259
anesthetic considerations for, 259, 259b
Muscle channelopathy
hyperkalemic periodic paralysis as, 312–313
hypokalemic periodic paralysis as, 313
Muscle disease
fatty acid metabolism disorders as, 309–310
infective and toxic myopathies as, 316–317
inflammatory myopathies as, 316
introduction to, 297
malignant hyperthermia as, 310–312
metabolic myopathies as, 304–308
mitochondrial myopathies as, 308
muscle channelopathies as, 312–313
muscular dystrophies as, 297–302
myasthenias as, 313–316
myotonia as, 302–304
oxidative phosphorylation disorders as,
308–309
pyruvate metabolism disorders as, 310
Muscle lactate dehydrogenase deficiency
type XI, 307
Muscle phosphofructokinase deficiency
type VII, 306
Muscle relaxant, 245
Muscular dystrophy
anesthetic considerations for, 301–302, 301b
diagnosis and differential for, 298–301
muscle disease and, 297–302, 298f
pathophysiology for, 297–298
Muscular ventricular septal defect, 96
Mutism, 464
Myasthenia
Eaton-Lambert myasthenic syndrome as,
315–316
muscle diseases and, 313–316, 313f
myasthenia gravis as, 314–315
Myasthenia gravis, 314b, 315–316
anesthetic considerations for, 315
Mycotic myocarditis, 37
Myelin, disease of
multiple sclerosis as, 267–270
neurologic diseases and, 263b, 267b
nitrous oxide-induced subacute combined
degeneration as, 270
Myelocytic leukemia, chronic, 358
Myelodysplastic syndrome, 358
Myeloid metaplasia w/ myelofibrosis, 580–581,
580b
anesthetic considerations for, 581
Myelomeningocele, 284–285
Myelophthisis, 580–581
Myeloproliferative disease, chronic, 358
Myocarditis, 130–131, 131b
Myoclonic epilepsy, 437
Myoclonus dystonia, 266
Myoglobinuria, 307
Myophosphorylase deficiency type V, 305–306
Myositis, inclusion body, 316
Myotonia
muscle diseases and, 302–304
myotonia congenita as, 304
myotonic dystrophy, 303–304
Myotonia congenita, 304
Myotonia fluctuans, 304
Myotonic dystrophy, 303–304, 303t
anesthetic considerations for, 303–304
Myotonic dystrophy, congenital, 303
Myxedema coma, 413
N syndrome, 437
Nasal placode, 593
Near-drowning, 515
Neck circumference, 218
Necrosis, 168, 496
Necrotizing fasciitis
anesthetic considerations for, 389
treatment for, 378
Necrotizing myopathy, 317
Necrotizing soft tissue infection
clostridial myonecrosis as, 389–390
epiglottitis as, 390–391
infectious diseases and, 388, 389b
necrotizing fasciitis as, 389
soft tissue infections of head and neck as, 390
Neoantigen, 186
Neonatal physiology. See Pediatric/neonatal
physiology
Nephritis, 228, 228t
Nephritis, acute interstitial, 228
Nephropathy, 228
Nephrotic syndrome, 227–228, 227b, 228b
Neuraxial technique, TUGOR and, 545
Neuroaxial anesthetic technique, 255
Neurodegenerative disorder w/autonomic failure
multiple system atrophy and, 259
neurologic diseases and, 257–260, 258t
pure autonomic failure and, 259–260
Neuroectodermal disorder
neurofibromatoses as, 277–279
neurologic diseases and, 276–282, 276t
Sturge-Weber syndrome as, 281–282
tuberous sclerosis as, 280–281
von Hippel-Lindau disease as, 279–280
Neurofibromatosis
anesthetic considerations for, 278–279, 279b
clinical manifestations of, 332–334, 333b
diagnosis of, 333, 333b
intraoperative considerations for, 333
neuroectodermal disorders and, 277–279, 277t
postoperative evaluation for
airway assessment and, 278
cardiovascular assessment and, 278
central nervous system assessment and, 278
other systems and, 278
pulmonary assessment and, 278
preoperative considerations for, 333, 333b
skin and bone diseases and, 332–334
summary for, 334
Neuroleptic malignant syndrome, 460
Neurologic disease
basal ganglia and cerebellar disorders as, 260–267
hereditary peripheral neuropathy as, 252–257
introduction to, 252
Klippel-Feil syndrome/cervical spine disorders
of childhood as, 285–287
motor neuron diseases as, 273–276
mucopolysaccharidoses as, 287–289
myelin diseases as, 267–270
neurodegenerative disorders w/autonomic
failure as, 257–260
neuroectodermal disorders as, 276–282
peripheral nerve disease and polyneuropathies
as, 270–273
posterior fossa anomalies and Arnold-Chiari
malformations as, 282–285
Neuropathy, ataxia, retinitis pigmentosa
Neurosurgery, 383
Neurotoxicity, anesthesia-induced, 436, 436f
Neutrophilic dermatosis, 322
NICE-SUGAR, 429–430
Niemann-Pick disease (NPD), 181
Nitrous oxide (N2O), 221
Non-Hodgkin's lymphoma, 357
Nonalcoholic steatohepatitis (NASH), 175, 175f
Nondepolarizing muscle relaxant, 254–255
Nondystrophic myotonia, 302
Nonintubation technique, 19
Nonneuronopathic Niemann-Pick disease, 181
Nonshivering thermogenesis, 588
Nonurgent trauma case, 490
Norepinephrine, 376
Normokalemic periodic paralysis, 313
Normovolemic hemodilution, acute, 555
NOTCH-2, 175
NPD. See Niemann-Pick disease (NPD)
Nutrition disorder, 221, 222t
 Index 637
O Outlet ventricular septal defect, 96
Obese, morbidly, 216
Obesity
airway considerations of, 218–220
cardiovascular effects of, 217
comorbidities of, 216–217, 217t
conclusion for, 223
gastrointestinal and metabolic effects of, 218
introduction to, 215–221
pathophysiology of, 216, 216t
pharmacologic issues of, 220–221, 220t
pregnancy and, 546–547
anesthetic management for, 542t, 546–547,
546b
respiratory effects of, 217
Obesity-hypoventilation syndrome, 216–217
Obsessive-compulsive disorder, 455–456
Obstructive hypertrophic cardiomyopathy, 30
Obstructive respiratory disease, cystic fibrosis as,
144–145
Occult hypoperfusion syndrome, 497
Occupational dystonia, 266
Octreotide, 45
Ocular trauma
evaluation of, 506
intraoperative considerations for, 507
pathophysiology of, 506–507, 506b
preoperative preparation for, 507, 507t
Oligohydramnios, 616
Oliguria, 235–236
Omphalocele
abdominal wall defects and, 614–616, 615f, 615t
anatomy and embryology of, 615–616
anesthetic management for, 616
surgical repair/anesthesia induction and, 616
Ondansetron, 544
Oocyte retrieval, transvaginal ultrasound-guided
(TUGOR), 542
Open strip craniectomy, 600
Open-angle glaucoma, 4, 5t
Opioid, 83, 83f
Optic nerve hypoplasia, 3
Orthopedic injury
evaluation of, 512
intraoperative considerations for, 513–515
deep vein thrombosis as, 514–515
fat embolism syndrome as, 514
positioning as, 513–515
temperature as, 513
tourniquet problem as, 513–514
pathophysiology of, 505t, 511–513, 512t
preoperative preparation for, 512–513
trauma and, 511–515
Osteogenesis imperfecta
clinical manifestations of, 334–335, 334b
diagnosis of, 334
intraoperative management of, 335
preoperative preparation for, 334–335, 334b
skin and bone diseases and, 334–335
summary for, 335
Osteomalacia, 335–336
Osteopetrosis, 336
Osteoporosis, 335–337
Otolaryngologic anomaly (pediatric)
choanal atresia as, 593–594
congenital laryngeal webs and atresia as, 587
cystic hygroma as, 594–595
Ovarian hyperstimulation syndrome, 545
Overlap syndromes, 316
Overnutrition, 218
Overresuscitation, 376
Oxidative phosphorylation disorder (OxPhos)
anesthetic considerations for, 309
co-enzyme Q deficiency as, 309
complex I deficiency as, 309
complex IV deficiency as, 309
Luft's disease as, 309
muscle diseases and, 308–309
P neonatal and pediatric physiology of, 587–589
Pacemaker, 132, 132b
Paget's disease of bone
diagnosis of, 337–338
intraoperative issues for, 338
pharmacologic therapy for, 337–338
preoperative preparation for, 338, 338b
skin and bone diseases and, 337–338, 338b
summary for, 338
Pancreas
anesthetic considerations for, 427–428
diabetes mellitus and, 428–430
hypoglycemia/hyperinsulinism and, 426–428
physiology of, 426
Pancuronium, 245
Panic attack, 457
Panniculitis
differential diagnosis for, 339
intraoperative considerations for, 339
preoperative considerations for, 339, 339b
skin and bone diseases and, 338–339
summary for, 339
Papilloma (papillary fibroelastoma), 44
Paracervical block, 544–545
Paraganglioma, 424
Parallel circulation, 587
Paramyotonia congenita, 312
Parathyroid glands
endocrine system and, 402–408, 402t
hypercalcemia and, 403–406
hypocalcemia and, 406–408
physiology of, 402–403, 403f
Parkinson's disease
anesthetic considerations for, 262–264, 263b
intraoperative management for, 263
postoperative concerns for, 263–264
preoperative concerns for, 262–264, 263b
preoperative evaluation for, 262–263
associated procedures for
anesthesia for deep-brain stimulator
placement and, 264
anesthesia for implantable deep-brain
stimulators and, 264
basal ganglia/cerebellar disorders and, 260–264
medical management of, 260, 261t
pathophysiology of, 260–262
surgical management of, 260–262
Parkinsonism, 258, 259
Partial anomalous pulmonary venous return
(PAPVR), 102
Partial atrioventricular canal, 97
Patent ductus arteriosus, 92–94, 92f
Paternal mtDNA, 434–435
Pathergy, 322–323
Patient history, 446
Pauci-immune RPGN, 227
Pediatric burn issues, 532–534, 533t
procedural sedation for, 533–534
Pediatric patient
abdominal wall defects and, 614–618
cardiovascular disease and, 618–619
congenital malformations of lung and,
606–614
craniofacial anomalies and, 595–603
dermatologic disease, 619–621
introduction to, 586–587
mediastinal masses and, 603–606
nervous system anomalies for, 589–591
otolaryngologic anomalies and, 591–595
Pediatric/neonatal physiology
cardiac physiology and, 587, 588f
pain and perioperative stress response for, 589
renal physiology and, 589
respiratory physiology and, 587–588, 589f
temperature regulation and, 588
Pellagra, 222t
Pelvic fracture, 512
Pemphigoid. See Pemphigus/pemphigoid
Pemphigus vulgaris, 339, 340f
Pemphigus/pemphigoid
intraoperative course for, 340
preoperative considerations for, 340, 340b
skin and bone diseases and, 339–340, 340f
summary for, 340
Percussion myotonia, 302–303
Periarteritis nodosa, 49
Pericardial effusion
anesthetic considerations for, 56
cardiac disease and, 131–132, 132b
cardiac diseases and, 54t, 55–56
Pericarditis, 52–56
Perimembranous ventricular septal defect, 96
Peripartum cardiomyopathy, 43, 555–558, 557b
Peripheral nerve disease, 270–273, 271b
Guillain-Barré syndrome as, 270–273
Peripheral neuropathy, hereditary
hereditary sensory/autonomic neuropathy
as, 255–257
neurologic diseases and, 253t, 287–289
primary hereditary motor/sensory
neuropathies as, 252–255
Periportal necrosis, 168
Peritoneal dialysis, 242
Pernicious anemia, 474
Phakomatosis, 276–277
Pharmacologic effect, burns and, 528
Phenylephrine, 377
Pheochromocytoma, 45, 424–426, 424t
Phosphoglycerate kinase deficiency type IX, 307
Phosphoglycerate mutase deficiency type X, 307
Phosphorylase B kinase deficiency type VIII,
306–307
Pickwickian syndrome. See Obesity-
hypoventilation syndrome
Pierre Robin sequence, 600
Pituitary gland
anterior pituitary disease and, 415–417
endocrine system and, 415–419, 415t
physiology of, 415, 416f
posterior pituitary disorders and, 417–419
 638 Index
Placenta accreta, 552–554
Placenta increta, 552–553
Placenta percreta, 552–553
Placenta previa, 552–553
Placentation, abnormal, 552–555, 553t
Plague, 394–395, 395t
anesthetic considerations for, 395
Plasmacytoma. See Multiple myeloma
Plasmalyte, 497–498
Platelet aggregometry, 365
Platelet function monitoring
platelet aggregometry as, 365
platelet function tests as, 364
dynamic tests and, 364
static tests and, 364
response to agonist stimulus as, 364–365
Platelet sequestration, 359
Pneumonia, community-acquired, 377
Pneumonia, usual interstitial, 577
Pneumonic plague, 394
Pneumothorax, 145
Point-of-care platelet function testing, 364
Polyarteritis nodosa, 48
Polycystic ovarian disease, 421
Polycythemia vera
anesthetic considerations for, 579
geriatric patient and, 578–579, 578b
preoperative preparation and, 579
Polydipsia, primary, 417–418
Polymyalgia rheumatica, 581–582, 581f
anesthetic considerations for, 581–582
Polymyositis, 316
Polysomnography, 17
Pompe's disease, 56. See also Glycogenosis type II
Porphyria, 181–184, 182f, 183t, 184t
key points for, 184
Porphyria, acute intermittent, 181–182
Portal hypertension, 189–190, 190b, 191f
anesthetic management of cirrhosis and, 198
Portopulmonary syndrome, 192t, 193
Positioning, orthopedic injury and, 513–515
Posterior fossa anomaly, 282t. See also Arnold-
Chiari malformation
Posterior mediastinum, 603
Posterior pituitary disorder
anesthetic considerations for, 419
diabetes insipidus as, 417–418
hypersecretion of vasopressin (SAIAIDH) as,
418–419
Posterior reversible encephalopathy
syndrome, 551
Postrenal acute kidney injury, 236
Poststreptococcal glomerulonephritis, 226
Posttraumatic stress disorder, 456–457
traumatic brain injury and, 500
Prader-Willi syndrome, 416–417
Pralidoxime, 396
Pre-eclampsia, 188, 550–551
Pregnancy
diabetes mellitus and, 428
HIV-seropositive women and, 383–384, 384t
obstetric complications and
anesthesia for uncommon conditions and,
546–559
conclusion for, 566
conditions complicating regional anesthesia,
559–566
Pregnancy (Continued)
nonobstetric surgery and, 538–546
physiologic changes of, 538, 538t
thyrotoxicosis during, 412
Pregnant trauma patient
evaluation of, 517
intraoperative considerations for, 517–518
pathophysiology of, 515–518, 516t
preoperative preparation for, 517
trauma and, 515–518
Preload, 495–496
Prerenal acute kidney, 236
Pressure work, 50
Primary adrenal insufficiency, 422
Primary amyloidosis, 575, 576t
Primary biliary cirrhosis (PBC), 187
Primary dystonia, 266
Primary lateral sclerosis, 273–274
Primary myocardial disease, 29
Primary progressive MS, 268
Primary pulmonary hypertension, 142–144,
142b, 143t
anesthetic management of, 140b, 143–144
Primum atrial septal defect, 94
Prion (Proteinaceous infective particle), 385–386
Progressive bulbar palsy, 273–274
Progressive cardiac conduction defect. See
Lenègre's disease
Progressive external ophthalmoplegia, autosomal
dominant, 439
Progressive muscular atrophy, 273–274
Progressive-relapsing MS subtype, 268
Prolactin, 415
Prolactinomas, 417
Propofol, 83–84
in vitro fertilization and, 543–544
mitochondrial function and, 435
Propofol infusion syndrome, 309, 502
Proteasomal system, 437–439
Protective antigen, 391
Protein C deficiency
treatment for, 363
Protein C, activated, 373
Protein S deficiency
treatment for, 363
Protein synthesis, 166–167
Prothrombin time (PT), 169t, 170
Proximal myotonic myopathy (PROMM), 303
Proximal renal tubular acidosis type II, 229
Prune-belly syndrome, 616–617
PS. See Pulmonary stenosis
Pseudohypertrophic muscular dystrophy. See
Duchenne's muscular dystrophy
Pseudohypoaldosteronism type I (PHA-1), 229
Pseudohypoparathyroidism, 407
Pseudosyndactyly of hands, 323–324
Psoriasis
diagnosis of, 340–341
intraoperative considerations for, 341
pathophysiology of, 340–341
preoperative preparation for, 341, 341f
summary for, 341
Psoriasis vulgaris, 340–341
Psychiatric and behavioral disorders
anxiety disorders as, 454–457
cognitive disorders as, 462–465
conclusion for, 466
Psychiatric and behavioral disorders (Continued)
developmental stages and, 465–466
introduction to, 444–445
mental disorders as, 445–447
mood disorders as, 447–454
nonaffective psychoses as, 457–461
substance-related disorders as, 461–462
Psychiatric problem, perioperative, 446–447
Psychosis, nonaffective
delusional disorder as, 460–461
schizophrenia as, 457–460
Pulmonary alveolar proteinosis, 147b, 149–150
Pulmonary arteriovenous (AV) fistulas, 139–140,
139b, 140b
Pulmonary atresia
w/intact ventricular septum (PA/IVS),
113–114, 113b, 113f
w/ventricular septal defect and major
aortopulmonary collaterals, 114–115,
114b, 114f, 115f
Pulmonary circulation disease
Churg-Strauss syndrome as, 142
lymphomatoid granulomatosis as, 141–142
primary pulmonary hypertension as, 142–144
pulmonary arteriovenous fistulas as, 139–140
Wegener's granulomatosis as, 140–141
Pulmonary cyst, 606–607
Pulmonary edema in pre-eclampsia, 552, 552b
Pulmonary fibrosis, idiopathic, 147b, 152, 152t,
577–578, 577b
anesthetic considerations for, 578
Pulmonary histiocytosis X (PHX), 147b,
153–154, 153t
Pulmonary hypertension (PHT), 49–52, 49b
anesthetic considerations for, 51–52, 53t
cardiac disease as, 126–130, 130b, 130f
of the newborn, 128
pathophysiology of, 50
secondary to left ventricular dysfunction, 128
Pulmonary hypertension, idiopathic, 128
Pulmonary Langerhans cell granulomatosis. See
Pulmonary histiocytosis X (PHX)
Pulmonary sequestration, 608, 608f
Pulmonary stenosis, 112–113
Pulmonary system
effects of liver disease on, 192–193, 192t
Pulmonary venous obstruction, 128
Pulmonic insufficiency, 63, 65t
Pulmonic stenosis, 59–61, 60t
Pure autonomic failure, 259–260
Pyelonephritis, 228
Pyoderma gangrenosum
diagnosis of, 342
intraoperative considerations for, 342
pathophysiology of, 341–342, 341b
preoperative considerations for, 342
summary for, 342
Pyogenic liver abscess, 386, 386b
Pyostomatitis vegetans, 341
Pyruvate kinase deficiency, 355
treatment of, 355
Pyruvate metabolism disorder, 310
R
Rapidly progressive glomerulonephritis (RPGN),
226–227
Rastelli type A, B, C, 97, 98f
 Index 639
Recessive dystrophic epidermolysis bullosa,
severe generalized, 620, 620f
Recombinant erythropoietin, 602
Regeneration, liver injury and, 168
Regurgitant valvular lesion
aortic insufficiency as, 61, 125–126
congenital heart disease and, 125–126, 126b
mitral regurgitation as, 62–63, 126
pulmonic insufficiency as, 63
tricuspid insufficiency as, 63
Relapsing-remitting MS subtype, 268
Remifentanil, 544
Renal anemia, 351t, 355
Renal artery stenosis, 231
Renal cystic disease, 229–230
Renal disease
intraoperative considerations for, 243–246
introduction to, 225
perioperative renal dysfunction and, 239–241
renal replacement therapy and, 241–242
renal transplantation and, 242–243
specific diseases of, 226–231
Renal dysfunction, preoperative
pathophysiology of, 239–241
renal disease and, 239–241
risk factors for, 231f, 240–241, 240t, 241b
Renal function test, 237–238, 238t
trauma and, 238
Renal replacement therapy (RRT), 241–242,
241b, 242f
Renal system
burns and, 528
effects of liver disease on, 190–192
key points for, 192
Renal transplantation, 242–243, 243t
anesthetic considerations for, 243
Renal tubular acidosis (RTA), 229
Respiratory disease
arthritic diseases w/upper airway problems
and, 154–156
conclusion for, 159
drug-induced lung injury and, 156–157
infectious diseases and, 157–159
infiltrative and interstitial disease and, 146–154
introduction to, 138
obstructive disease and, 144–145
pulmonary circulation diseases and, 139–144
Respiratory papillomatosis, recurrent, 18f
anesthetic management for, 18–19, 19t
ear, nose, throat considerations and, 17–20, 18b
summary of, 20
Restrictive cardiomyopathy, 41–42, 42t
anesthetic considerations for, 42
Resuscitation, immediate
immediate stabilization and, 374
re-establishing circulation and, 374–376
vasopressor therapy and, 376–377
Retina
systemic disease complications and, 6, 6b
Retinal, 474
Retinitis pigmentosa, 12–13
anesthetic concerns for, 13
Retinoid, 474
Retinol, 474
Retinopathy of prematurity (ROP), 10–12, 11b
anesthetic concerns for, 11–12, 11b
Rhabdomyolysis, 238–239, 239b
Rhabdomyoma, 44–45 Sevoflurane, 82, 221, 246
Rheumatic chorea. See Sydenham's chorea Shivering thermogenesis, 588
Ricin, 396–397 Shock, 495–496
RIFLE criteria, 236, 237t Shone's complex, 109
Riley-Day syndrome. See Familial dysautonomia Short QT syndrome, 34
Riluzole, 274–275 Shunt, intracardiac, 84–85
Ringer's lactate, 497–498 Shunt, pharmacokinetic, 84–85
Rocuronium, 245 SIADH. See Syndrome of inappropriate secretion
RV-dependent coronary circulation (RVDCC), 113 of AVP (SIADH)
Sickle cell anemia, 354
S treatment for, 354
SAIDH. See Syndrome of inappropriate secretion Sickle cell disease, 9, 9b
of AVP (SIADH) anesthetic concerns for, 9
Sarcoidosis, 150–151 renal involvement in, 230–231
Sarcoma, 44–45 Single functional ventricle, 118
Sarin, 396t, 397 Single ventricle (SV), 109–110, 119b, 119f
anesthetic considerations for, 396 Single-lung ventilation, 93
Scheie's disease, 180 Sinus venosus atrial septal defect, 94
Schizoaffective disorder, 458, 460–461 Skin and bone disorders
Schizophrenia introduction to, 320
anesthetic considerations for, 458–460, 460t Sleep apnea, obstructive, 15–17, 16b
neuroleptic malignant syndrome and, 460 anesthetic management of, 17
nonaffective psychoses and, 457–460, 458t, 459t obesity and, 218–219, 219b, 219f
Schizophreniform, 460–461 Sly's syndrome, 180
Scimitar syndrome, 103 Smallpox, 392–393
Sclerema neonatorum, 338–339 Smoke inhalation injury
Sclerosing cholangitis, primary, 187 burns and, 528–529
Scoliosis, 155–156, 155b evaluation of, 515
Second-degree burn, 527 pathophysiology of, 515
Secondary adrenal insufficiency, 423 preoperative management of, 515
Secondary amyloidosis, 575, 576t trauma and, 515
Secondary biliary cirrhosis, 187–188 Social phobia, 455, 455t
Secondary cardiomyopathy, 43–44 Soft tissue infection of head and neck
Secondary dystonia, 266 anesthetic considerations for, 390
Secondary myocardial disease, 29 Soft tissue injury, facial trauma and, 508–509
Secondary PAP, 149 Somatosensory evoked potential, 156
Secondary progressive MS, 268 Spasmodic dysphonia, 266
Secundum atrial septal defect, 94, 95–96 Sperm aspiration, percutaneous epididymal, 545
Selective serotonin reuptake inhibitor (SSRI), Spherocytosis, 353–354
448, 449t, 450t treatment of, 354
Selective transcatheter embolization, 553 Spinal cord injury
Sepsis evaluation of, 504–505
definition of, 370–371 intraoperative management for, 505–506
infectious disease and, 370–379, 370b, 371b, 371f pathophysiology of, 504–506, 505t
multiorgan dysfunction syndrome and, 373 preoperative preparation for, 505
pathophysiology of, 371–373, 372f Spinal muscular atrophy, 276
hemodynamic derangement in, 372–373, anesthetic considerations for, 276
372f, 373f Splenectomy, 383
inflammatory cascades and, 372 Splenic abscess, 388
treating the patient with septic shock and, Sporadic Creutzfeldt-Jacob disease, 584
374–379 St. John's wort, 475–477, 476t
Septic shock, treatment of Steatohepatitis, 195
sepsis and, 374–379, 374f Steatohepatitis, nonalcoholic, 175
stage 1: immediate resuscitation, 374–377 Steatosis, 168
stage 2: empiric therapy-antibiotics, 377–378 Stellate cells, 164
stage 3: source control, 378, 378f Stenotic valvular lesion
stage 4: prevention of complications, 378–379, mitral stenosis as, 56–58
379b pulmonic stenosis as, 59–61
Septo-optic dysplasia, 3 tricuspid stenosis as, 58–59
Septo-optic syndrome, 416–417 valvular aortic stenosis as, 56
Serotonin, 457 Stenting, 201
Series (neonatal) circulation, 587 Stevens-Johnson syndrome, 325–326, 326f
Serotonergic syndrome, 477 STOP-BANG questionnaire, 218–219, 219b
Serotonin, 457 Storming, 504
Severe acute respiratory syndrome (SARS), Stress cardiomyopathy, 43
158–159, 158b Stroke volume, reduced, 372
Severe TBI, 501 Sturge-Weber syndrome (SWS), 281–282
 640 Index
Subacute combined degeneration, nitrous oxide-
induced, 267–270
Subarterial ventricular septal defect, 96
Subepidermal autoimmune blistering disease, 339
Subluxation, 4
Substance-related disorders, 460–461, 461t
Subvalvular AS, 107
Subvalvular PS, 112–113
Succinylcholine, 245, 254
bipolar disorder and, 454
Superior cavopulmonary anastomosis, 122,
122b, 123f
Supine hypotensive syndrome of pregnancy,
546–547
Supplements
conclusion for, 482–483
herbals as, 475–482
minerals as, 471–473
vitamins as, 473–475
Supracardiac anomalous pulmonary venous
return, 102
Supravalvular stenosis, 107
Surgery, nonobstetric
anesthetic management of pregnancy patients
and, 538–546, 539b
fetal safety and, 539–540
in vitro fertilization and, 541–546
laparoscopic surgery and, 540–541
maternal safety and, 538–539
SVC syndrome, 603–604
Sydenham's chorea (SC), 265
anesthetic considerations for, 263b, 265
Syndesmophyte, 154–155
Syndrome of inappropriate secretion of AVP
(SIADH)
anesthetic considerations for, 419
posterior pituitary disorders and, 418–419,
419b
Syndrome X. See Metabolic syndrome
Synucleinopathy, 257–258
Syringomyelia, 283
System anterior motion (SAM), 30
Systemic amyloidosis, 574–575, 576t
Systemic disease
corneal pathology and, 3
glaucoma and, 4–6
lens pathology and, 3–4
renal involvement in
hypertension and diabetes as, 230
sickle cell disease as, 230–231
retinal complications and, 6
Systemic inflammatory response syndrome
(SIRS), 370–379, 371f. See also Sepsis
airway management and, 491
Systemic lupus erythematosus (SLE), 48
chronic glomerulonephritis and, 227
infiltrative/interstitial disease and, 147b,
151–152, 151t
Systolic anterior motion (SAM), 30
T physiology of, 409–410, 409f
Takayasu's disease, 48
Takotsubo cardiomyopathy. See Stress
cardiomyopathy
Tamponade, cardiac, 54t, 55f, 131–132, 132b
anesthetic considerations for, 56
Tangential excision, 530
TAPVR. See Total anomalous pulmonary venous
return (TAPVR)
Tardive dyskinesia, 459
Tauri's disease. See Muscle phosphofructokinase
deficiency type VII
TBI. See Traumatic brain injury
Temperature, orthopedic injury and, 513
Testicular epididymal sperm aspiration, 545
Tetany, 407
Tetralogy of Fallot (TOF), 111–112, 111b,
111f, 112f
Thalassemia, 352–353
treatment for, 353
Thiopental, 255
Third-degree burn, 527
Thoracic surgery, 383
Thrombasthenic syndrome
antithrombotic drug therapy and, 361–362
concomitant drugs and, 361
disease of thrombocytes and, 359–362, 359t
Glanzmann's thrombasthenia and, 359–360
von Willebrand's disease, 360–361
Thrombin receptor agonist peptide, 365
Thrombocyte, disease of
hematologic diseases and, 358–365
impaired coagulation as, 362–363
monitoring platelet function and, 364–365
thrombasthenic syndromes as, 359–362
thrombotic disorders as, 363–364
thrombocytopenia as, 358–359, 358t
Thrombocythemia, essential
anesthetic considerations for, 580
geriatric patient and, 579–580, 579b
Thrombocytopenia
diseases of thrombocytes and, 358–359, 358t
immune thrombocytopenic purpura and,
358–359
platelet sequestration and, 359
thrombotic thrombocytopenic purpura and, 359
Thrombocytopenia, heparin-induced, 363–364
treatment for, 364
Thrombocytopenic purpura, immune, 358–359
Thrombocytosis, 579
Thromboelastography, 364
Thromboembolic events
obesity and, 190
Thrombotic disorders
antithrombin III deficiency as, 363
factor V Leiden mutation as, 363
heparin-induced thrombocytopenia as,
363–364
protein C and S deficiency as, 363
Thrombotic thrombocytopenic purpura, 359
Thyroid carcinoma, 414
Thyroid function test, 410
Thyroid gland
anesthetic considerations for, 414
endocrine system and, 408–415, 409t
hyperthyroidism and, 410–412
hypothyroidism and, 413–414
thyroid nodules and carcinoma of, 414
Thyroid storm, 411–412
Thyroiditis, lymphocytic, 413
Thyrotoxic myopathy, 317
Thyrotoxicosis, 412
Thyroxine, 409
Ticlopidine, 362, 564
TIPS. See Transjugular intrahepatic
portosystemic shunt (TIPS)
Tirofiban, 361–362, 564
Tissue factor, 372
Torsades de pointes, 33
Total anomalous pulmonary venous return
(TAPVR), 102, 103f
Total body weight (TBW), 220–221
Total intravenous anesthesia, 335
Tourniquet problem, orthopedic injury and,
513–514
Toxic epidermal necrolysis, 325–326
Toxic liver disease, 186
Toxic myopathy, 316. See also Thyrotoxic
myopathy
Tracheoesophageal fistula
anesthetic management of, 613–614, 614b
postoperative considerations for, 614
associated anomalies of, 613
classifications of, 612–613, 613f
congenital malformations of the lungs and,
612–614
surgical management of, 613
Transaminase, 170
Transcapillary refill, 372
Transesophageal echocardiography (TEE), 31
Transformation, 167
Transitional atrioventricular canal, 97
Transjugular intrahepatic portosystemic shunt
(TIPS), 201, 201b
Trauma damage control/fluid resuscitation
evaluation of, 496b, 497–498, 497t
intraoperative considerations for, 496b,
498–500
pathophysiology of, 495–500, 495f, 496b,
496f, 496t
preparation for, 498
Trauma team organization, 489–490, 489f
Trauma, penetrating, 510
Trauma/acute care
acute care anesthesiology and, 519–520
basic considerations for, 489–500
airway management and, 490–495
damage control/fluid resuscitation and,
495–500
team organization/trauma priorities and,
489–490
conclusion for, 520
prehospital anesthetic care and, 518–519
specific conditions of, 500–518
Traumatic brain injury
evaluation of, 501
intraoperative management of, 501–504, 508b
pathophysiology of, 500–504
preoperative preparation for, 501
Traumatic encephalopathy, chronic, 500
Traumatic hemolysis, 355
Treacher Collins syndrome, 596, 597f
anesthetic considerations for, 596
Tri-iodothyronine, 409
Trial of labor after cesarean, 554
Tricuspid atresia, 123–124, 123f
Tricuspid insufficiency, 63, 65t
Tricuspid stenosis, 58–59, 59t
Tricyclic antidepressant, 448–450
Trousseau sign, 406
 Index 641

Truncus arteriosus, types I, II, III, 100–102, Valvular aortic stenosis, 56, 57t Vitamins (Continued)
100b, 101f Valvular lesion, uncommon causes of vitamin B12 and, 474
Trypanosomiasis. See Chagas' disease anesthetic considerations for, 63–66 vitamin C and, 474
Tubal embryo transfer, 543 regurgitant valvular lesion as, 61–63 vitamin D and, 474–475
Tubal transfer, pronuclear stage, 543 stenotic valvular lesions as, 56–61 vitamin E and, 475
Tuberculosis, 384–385 Variant Creutzfeldt-Jacob disease, 385 Volatile anesthetic, 82–83, 83f
anesthetic considerations for, 385, 385b Variceal bleeding, 190 Volume, 351
Tuberous sclerosis (TS) Vascular ring, 126, 127f Volume resuscitation, 374, 374f
anesthetic considerations for, 279b, 281 Vasomotor neuropathy, 373 Volume work, 50
neuroectodermal disorders and, 280–281 Vasoplegia, 372 von Gierke's disease. See Glycogenosis type I
preoperative evaluation for, 281 Vasopressin, 377 von Hippel-Lindau disease, 279–280, 279b, 280t
Tubular function disorder, 228–229 hypersecretion of, 418–419 von Recklinghausen's variant, 332
Tubular necrosis, acute (ATN), 236–237 Vasopressor therapy, 376–377 von Willebrand's disease
Tubulointerstitial disease Vecuronium, 83, 245 surgery and, 361
disorder of tubular function as, 228–229 Venous air embolism, 602 thrombasthenic syndromes and, 360–361, 360t
nephritis as, 228 Ventilation, burns and, 531 treatment for, 361
nephropathy as, 228 Ventilatory management, congenital heart VSD. See Ventricular septal defect
TUGOR. See Oocyte retrieval, transvaginal disease and, 81
ultrasound-guided (TUGOR) Ventricular septal defect (VSD), 86f, 96–97, W
Tularemia, 393–394 96b, 96f Waist circumference, 218
Tumescent local anesthesia, 531 Video-assisted thoracoscopy, 93 Waldenström's disease. See Macroglobulinemia
Tumor, sex hormone-secreting Viral hepatitis Warfarin, 560
adrenal glands and, 421 hepatitis A and, 171–172 Water deprivation test, 418
Turner's syndrome, 297–298 hepatitis B and, 172–173 Wegener's granulomatosis, 21–22, 21f. See also
Type I collagen, 334 hepatitis C and, 173–174 Granulomatosis with polyangiitis
Tyrosinemia type 1, hereditary (HT-1), 179–180 hepatitis D and, 173 anesthetic concerns for, 21–22, 22b
hepatitis E and, 174 pulmonary circulation diseases and, 140–141,
U hepatitis G and, 174 140b
Unconjugated bilirubin, 169 key points for, 173 Werdnig-Hoffmann disease, 273b
Undernutrition, 218 liver dysfunction and, 170–174, 171t Wernicke's encephalopathy, 222t
Unifocalization, 114 postoperative liver dysfunction and, 206 Whipple's triad, 427
Unilateral recurrent laryngeal nerve injury, Viral infection White willow bark, 481
405–406 inflammatory cardiomyopathy and, 37 Williams' syndrome
Unrestrictive ventricular septal defect, 96 Visual evoked potential, 13 anesthetic management of, 618–619
Urea, 237 Vitamin A, 474 pediatric patient and, 618–619
Uremic syndrome, 232–233 Vitamin B12, 473t, 474 preoperative evaluation for, 618–619
Urgent trauma case, 490 deficiency of, 353, 353b supravalvular aortic stenosis and, 108
Urosepsis, 378 Vitamin C, 474 Wilson's disease, 184–185
Urticaria pigmentosa, 329–330 Vitamin D, 474–475 Wolff-Parkinson-White syndrome, 33
Urticate, 329–330 Vitamin E, 475 anesthetic considerations for, 33
Uterine rupture, 554–555 Vitamin K, 170, 560 Wolman's disease, 181
Vitamins
V folate and, 475 Z
Vaginal birth after cesarean section, 554 supplements and, 473–475, 473t Zygomatic arch fracture, 509
Valvular PS, 113 vitamin A and, 474 Zygote intrafallopian transfer, 543