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ACCP Critical Care


Medicine
Board Review:
21st Edition
The American Board of Internal Medicine (ABIM) is not affiliated with, nor does it endorse,
preparatory examination review programs or other continuing medical education. The
content of the ACCP Critical Care Medicine Board Review: 21st Edition is developed
independently by the American College of Chest Physicians (ACCP), which has no
knowledge of or access to ABIM examination material.

The views expressed herein are those of the authors and do not necessarily reflect the
views of the ACCP. Use of trade names or names of commercial sources is for information
only and does not imply endorsement by the ACCP. The authors and the publisher
have exercised great care to ensure that drug dosages, formulas, and other information
presented in this book are accurate and in accord with the professional standards in
effect at the time of publication. However, readers are advised to always check the
manufacturers product information sheet packaged with the respective products to
be fully informed of changes in recommended dosages, contraindications, etc, before
prescribing or administering any drug.

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Copyright 2012 by the AMERICAN COLLEGE OF CHEST PHYSICIANS
Copyright not claimed on material authored by the US Government. All rights reserved.
No part of this book may be reproduced in any manner without permission of the publisher.

Published by the
American College of Chest Physicians
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ACCP Website: www.chestnet.org

Printed in the United States of America


First Printing
ISBN - 978-0-916609-97-9

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Contents
Chapter 1. Endocrine Emergencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Robert C. Hyzy, MD, FCCP

Chapter 2. Postoperative Crises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11


David L. Bowton, MD, FCCP, FCCM

Chapter 3. Mechanical Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21


Gregory A. Schmidt, MD, FCCP

Chapter 4. Hypertensive Emergencies and Urgencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35


R. Phillip Dellinger, MD, MSc, FCCP; and Jean-Sebastien Rachoin, MD

Chapter 5. Pregnancy and Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47


Mary E. Strek, MD, FCCP

Chapter 6. Venous Thromboembolic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63


R. Phillip Dellinger, MD, MSc, FCCP; and Wissam B. Abouzgheib, MD, FCCP

Chapter 7. Acute Coronary Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75


Phillip A. Horwitz, MD; and Hjalti Gudmundsson, MD

Chapter 8. Heart Failure and Cardiac Pulmonary Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91


Steven M. Hollenberg, MD, FCCP

Chapter 9. Acute and Chronic Liver Failure in the ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103


Jesse B. Hall, MD, FCCP

Chapter 10. Hemodynamic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111


John P. Kress, MD, FCCP

Chapter 11. Tachycardia and Bradycardia in the ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123


Frank Zimmerman, MD

Chapter 12. Infections in AIDS Patients and Other Immunocompromised Hosts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
George H. Karam, MD, FCCP

Chapter 13. Liberation From Mechanical Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163


John F. McConville, MD

Chapter 14. Trauma and Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169


Bennett P. deBoisblanc, MD, FCCP

Chapter 15. Airway Management, Sedation, and Paralytic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175


John P. Kress, MD, FCCP

Chapter 16. Acute Lung Injury/Acute Respiratory Distress Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187


Jesse B. Hall, MD, FCCP

Chapter 17. Coma and Delirium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197


John F. McConville, MD

Chapter 18. The Acute Abdomen, Pancreatitis, and the Abdominal Compartment Syndrome . . . . . . . . . . . . . . . . 201
Bennett P. deBoisblanc, MD, FCCP

Chapter 19. Hypothermia/Hyperthermia and Rhabdomyolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205


Janice L. Zimmerman, MD, FCCP

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Chapter 20. Ventilatory Crises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Gregory A. Schmidt, MD, FCCP

Chapter 21. Poisonings and Overdoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227


Janice L. Zimmerman, MD, FCCP

Chapter 22. Anemia and RBC Transfusion in the ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243


Karl W. Thomas, MD, FCCP

Chapter 23. Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259


John P. Kress, MD, FCCP

Chapter 24. Coagulopathies, Bleeding Disorders, and Blood Component Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
Karl W. Thomas, MD, FCCP

Chapter 25. Gastrointestinal Bleeding in the ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285


Nikhil R. Asher, MD; Kevin McGrath, MD; and Douglas B. White, MD, MAS

Chapter 26. Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293


Brian K. Gehlbach, MD

Chapter 27. Resuscitation: Cooling, Drugs, and Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299


Brian K. Gehlbach, MD

Chapter 28. Ethical Issues in Intensive Care Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305


Douglas B. White, MD, MAS

Chapter 29. Interpreting Clinical Research and Understanding Diagnostic Tests in Critical Care Medicine . . . 311
Douglas B. White, MD, MAS

Chapter 30. Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317


Brian K. Gehlbach, MD

Chapter 31. Approach to Acid-Base Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323


Harold M. Szerlip, MD, MS, FCCP

Chapter 32. Severe Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337


Michael S. Niederman, MD, MS, FCCP

Chapter 33. ICU Guidelines, Best Practices, and Standardization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357


Arthur P. Wheeler, MD, FCCP

Chapter 34. Status Epilepticus, Stroke, and Increased Inracranial Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Arthur P. Wheeler, MD, FCCP

Chapter 35. Derangements of Serum Potassium, Sodium, Calcium, Phosphate, and Magnesium . . . . . . . . . . . . 387
Stephen P. Kantrow, MD

Chapter 36. Antibiotic Therapy in Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403


Michael S. Niederman, MD, FCCP

Chapter 37. Transplant-Related Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419


Stephen P. Kantrow, MD

Chapter 38. Acute Kidney Injury in the ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435


Harold M. Szerlip, MD, MS, FCCP

Chapter 39. Nervous System Infections and Catheter Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447


George H. Karam, MD, FCCP

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Authors
Wissam B. Abouzgheib, MD, FCCP Phillip A. Horwitz, MD Jean-Sebastien Rachoin, MD
Director of Interventional Pulmonary Associate Professor of Internal Medicine Assistant Professor of Medicine
Program University of Iowa Carver College of Cooper Medical School of Rowan
Pulmonary and Critical Care Department Medicine University
Cooper University Hospital University of Iowa Department of Medicine, Division of
Camden, NJ Iowa City, IA Hospital Medicine
Cooper University Hospital
Nikhil R. Asher, MD Robert C. Hyzy, MD, FCCP Camden, NJ
Associate Professor
Clinical Fellow
Division of Pulmonary and Critical Care Gregory A. Schmidt, MD, FCCP
Department of Critical Care Medicine
Medicine Professor, Division of Pulmonary, Critical
University of Pittsburgh Medical Center
University of Michigan School of Medicine Care, and Occupational Medicine
Pittsburgh, PA
Ann Arbor, MI Department of Internal Medicine
David L. Bowton, MD, FCCP University of Iowa
Stephen P. Kantrow, MD Iowa City, IA
Professor and Head, Section on Critical Care
Associate Professor of Medicine
Department of Anesthesiology Section of Pulmonary and Critical Care Mary E. Strek, MD, FCCP
Wake Forest University School of Medicine Medicine Professor of Medicine
Winston-Salem, NC LSU Health Sciences Center Section of Pulmonary and Critical Care
New Orleans, LA The University of Chicago
Bennett P. deBoisblanc, MD, FCCP
Chicago, IL
Professor of Medicine and Physiology George H. Karam, MD, FCCP
Director, Critical Care Services Paula Garvey Manship Professor of Harold M. Szerlip, MD, MS, FCCP
Medical Center of Louisiana Medicine Professor and Vice-Chairman
New Orleans, LA Louisiana State University School of Department of Medicine, University of
Medicine Arizona College of Medicine
R. Phillip Dellinger, MD, MSc, FCCP New Orleans, LA Chief of Medical Service, UAMC-SC
Professor of Medicine Head, Department of Internal Medicine University of Arizona/UPHH Consortium
Cooper Medical College of Rowan Earl Long Medical Center Tucson, AZ
University Baton Rouge, LA
Vice Chief, Department of Medicine Karl W. Thomas, MD, FCCP
Head, Division of Critical Care John P. Kress, MD, FCCP Clinical Professor
Cooper University Hospital Associate Professor of Medicine Division of Pulmonary Diseases, Critical
Camden, NJ Section of Pulmonary and Critical Care Care, and Occupational Medicine
University of Chicago University of Iowa
Brian K. Gehlbach, MD Chicago, IL Iowa City, IA
Associate Professor
Division of Pulmonary, Critical Care, and John F. McConville, MD Arthur P. Wheeler, MD, FCCP
Occupational Medicine Assistant Professor of Medicine Professor of Medicine
Department of Internal Medicine Section of Pulmonary and Critical Care Division of Allergy, Pulmonary, and Critical
University of Iowa Medicine Care Medicine
Iowa City, IA Director, Internal Medicine Residency Vanderbilt University School of Medicine
Program Nashville, TN
Hjalti Gudmundsson, MD University of Chicago
Chicago, IL Douglas B. White, MD, MAS
Fellow, Interventional Cardiology
Associate Professor
Cardiovascular Division
Kevin McGrath, MD Director, Program on Ethics and Decision
University of Iowa Carver College of
Associate Professor of Medicine Making in Critical Illness
Medicine
Director, GI Endoscopy Lab Department of Critical Care Medicine
Iowa City, IA
University of Pittsburgh Medical Center University of Pittsburgh Medical Center
Jesse B. Hall, MD, FCCP Pittsburgh, PA Pittsburgh, PA
Professor of Medicine, Anesthesia, and Michael S. Niederman, MD, FCCP Frank Zimmerman, MD
Critical Care Chairman, Department of Medicine Assistant Professor of Pediatrics
The University of Chicago Winthrop University Hospital The University of Chicago Childrens
Pritzker School of Medicine Mineola, NY Hospital
Chicago, IL Professor of Medicine Chicago, IL
Vice Chairman, Department of Medicine
Steven M. Hollenberg, MD, FCCP Janice L. Zimmerman, MD, FCCP
SUNY at Stony Brook
Professor of Medicine Stony Brook, NY Professor of Clinical Medicine
Robert Wood Johnson Medical School Weill Cornell Medical College
University of Medicine and Dentistry of David Pitrak, MD Division Head, Critical Care
New Jersey Professor of Medicine Department of Medicine
Director, Coronary Care Unit Chief of Infectious Diseases Director, Medical ICU
Cooper University Hospital The University of Chicago The Methodist Hospital
Camden, NJ Chicago, IL Houston, TX

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DISCLOSURE OF AUTHORS CONFLICTS OF INTEREST
The American College of Chest Physicians (ACCP) remains strongly committed to providing the best available evidence-based clinical
information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our
committee members. It is not the intent of the ACCP to eliminate all situations of potential conflict of interest, but rather to enable those
who are working with the ACCP to recognize situations that may be subject to question by others. All disclosed conflicts of interest are
reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to
ensure that such situations are properly evaluated and, if necessary, resolved. The ACCP educational standards pertaining to conflict of
interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of
science. Through our review process, all ACCP CME activities are ensured of independent, objective, scientifically balanced information.
Disclosure of any or no relationships is made available for all educational activities.

The following authors of the ACCP Critical Care Medicine Board Review: 21st Edition have disclosed to the ACCP that a relationship does
exist with the respective company/organization as it relates to their presentation of material and should be communicated to the
participants of this educational activity:

Authors Relationship
Steven M. Hollenberg, MD, FCCP Speakers bureau: Novartis-Makers of Valsartan
Phillip A. Horwitz, MD Grant monies (from industry related sources): Industry supported
grants for clinical trials in Acute Coronary Syndrome subjects:
AstraZeneca, GlaxoSmithKline, Schering Plough, Roche
John P. Kress, MD, FCCP Grant monies (from industry related sources): Unrestricted research
grant from Hospira
Consultant fee, speaker bureau, advisory committee, etc: Hospira
speaker bureau
Michael S. Niederman, MD, FCCP Grant monies (from sources other than industry): Nektar to study
aerosolized amikacin in VAP therapy; Biomerieux to study
procalcitonin
Consultant fee, speakers bureau, advisory committee, etc: Pfizer,
Merck, Ortho-McNeil, Nektar, Novartis, Bayer
Product/procedure/technique that is considered research and is NOT
yet approved for any purpose: Aerosolized amikacin
Harold M. Szerlip, MD, MS, FCCP Grant monies (from industry related sources): Spectral Diagnostics
research grant CytoPherx research grant
Janice L. Zimmerman, MD, FCCP Product/procedure/technique that is considered research and is NOT
yet approved for any purpose: glucagon, insulin for beta-blocker and
calcium channel blocker overdose; lipid emulsion for overdose

The following authors of the ACCP Critical Care Medicine Board Review: 21st Edition have indicated to the ACCP that no potential
conflict of interest exists with any respective company/organization, and this should be communicated to the participants of this
educational activity:

Wissam B. Abouzgheib, MD, FCCP Jesse B. Hall, MD, FCCP Jean-Sebastien Rachoin, MD
Nikhil R. Asher, MD Robert C. Hyzy, MD, FCCP Gregory A. Schmidt, MD, FCCP
David L. Bowton, MD, FCCP Stephen P. Kantrow, MD Mary E. Strek, MD, FCCP
Bennett P. deBoisblanc, MD, FCCP George H. Karam, MD, FCCP Karl W. Thomas, MD, FCCP
R. Phillip Dellinger, MD, MS, FCCP John F. McConville, MD Arthur P. Wheeler, MD, FCCP
Brian K. Gehlbach, MD Kevin McGrath, MD Douglas B. White, MD, MAS
Hjalti Gudmundsson, MD Frank Zimmerman, MD

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Needs Assessment
Rely on the ACCP Critical Care Medicine Board Review 2012 to review the type of information you should know for the Critical Care
Subspecialty Board Examination of the American Board of Internal Medicine (ABIM). Designed as the best preparation for anyone taking
the exam, this comprehensive, exam-focused review will cover current critical care literature and management strategies for critically ill
patients.

The ABIM Critical Care Subspecialty Board Examination tests knowledge and clinical judgment in crucial areas of critical care medicine.
This premier course will review the information you should know for the exam. Course content mirrors the content of the exam, as
outlined by the ABIM, and includes the following topics:

Pulmonary disease 22.5%


Cardiovascular disorders 17.5%
Renal/endocrine/metabolism 15%
Infectious disease 12.5%
Neurologic disorders 7.5%
Surgical/trauma/transplantation 7.5%
Gastrointestinal disorders 5%
Hematologic/oncologic disorders 5%
Pharmacology/toxicology 5%
Research/administration/ethics 2.5%
Total 100%

Target Audience
* Physicians in critical care and pulmonary medicine
* Physicians in EDs
* Physicians in anesthesiology
* Physicians in surgery
* Advanced critical care nurse practitioners
* Advanced respiratory therapy practitioners
* Physician assistants
* Pharmacists

General Publications Disclaimer


The American College of Chest Physicians (ACCP) and its officers, regents, executive committee members, members, related entities,
employees, representatives and other agents (collectively, ACCP Parties) are not responsible in any capacity for, do not warrant and
expressly disclaim all liability for, any content whatsoever in any ACCP publication or other product (in any medium) and the use or
reliance on any such content, all such responsibility being solely that of the authors or the advertisers, as the case may be. By way of
example, without limiting the foregoing, this disclaimer of liability applies to the accuracy, completeness, effectiveness, quality,
appearance, ideas, or products, as the case may be, of or resulting from any statements, references, articles, positions, claimed diagnosis,
claimed possible treatments, services, or advertising, express or implied, contained in any ACCP publication or other product.
Furthermore, the content should not be considered medical advice and is not intended to replace consultation with a qualified medical
professional. Under no circumstances, including negligence, shall any of the ACCP Parties be liable for any DIRECT, INDIRECT,
INCIDENTAL, SPECIAL or CONSEQUENTIAL DAMAGES, or LOST PROFITS that result from any of the foregoing, regardless of legal
theory and whether or not claimant was advised of the possibility of such damages.

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Edition vii
ACCP Member Benefts
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Welcome to The CHEST Foundation
The CHEST Foundation is the philanthropic arm of the American College of Chest Physicians (ACCP)
with a mission to provide resources to advance the prevention and treatment of diseases of the
chest for ACCP members, their patients, and the public.

The CHEST Foundation focuses on four key program areas: Tobacco, Clinical Research, Critical
and End-of-Life Care, and Pro Bono and Humanitarian Service.

OneBreath The CHEST Foundation Awards


In 2010, The CHEST Foundation created the For more than 15 years, The CHEST Foundation has
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OneBreath brings together the three program


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and community. It serves as a unifying force for the
diferent medical specialties that form the ACCP
community. Together, ACCP members serve society
by helping people make the most of each breath.

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Chapter 1. Endocrine Emergencies
Robert C. Hyzy, MD, FCCP

Objectives: of ketoacid production and urinary excretion.


 Recognize the clinical presentations of endocrine emer- Hyperglycemia produces glycosuria and an
gencies involving the pancreas, thyroid, adrenal, and osmotic diuresis, resulting in extracellular fluid
pituitary glands.

volume depletion, which can be profound and
Learn the approach to laboratory testing necessary for
the diagnosis and management of these conditions in the result in hypotension. Many of the symptoms of
ICU. DKA result in large measure from this: polyuria,
 Understand the treatment for each endocrine emergency. polydipsia, tachycardia, and lethargy. The degree
of acidosis is the primary determinant of de-
Key words: adrenal failure; diabetes insipidus; diabetic pressed sensorium. In addition, other symptoms
ketoacidosis; hyperosmolar hyperglycemic state; hypogly-
such as nausea, vomiting, abdominal pain, and
cemia; myxedema coma; pheochromocytoma; thyroid storm
Kussmaul respirations with a characteristic fruity
Synopsis: breath may be present.
DKA is usually diagnosed in known diabetics
Many endocrine emergencies require admission to the ICU.
Although not necessarily common as a primary diagnosis who present to the emergency room with either
requiring ICU admission, many endocrine emergencies noncompliance or with a concomitant stressful
occur in the context of ongoing illness and comorbidities, illness, especially infection, which has resulted in
where the stress of intercurrent illness serves to exacerbate
progressively worsened glycemic control and the
and unmask the underlying condition. Hence, the practicing
intensivist needs not only to be able to diagnose and onset of ketogenesis. Occasionally, a patient,
manage these conditions as presenting diagnoses but also to usually an adolescent or young adult, will
recognize endocrine emergencies in the context of critical present with DKA as the initial presentation of
care more generally.
their diabetes. Other causes of ketoacidosis
include alcohol and starvation, which should be
in the differential diagnosis in patients without a
Diabetic Ketoacidosis known history of diabetes.
Besides elevations in serum glucose and the
Clinically significant hyperglycemic syndromes presence of ketones in serum in urine, laboratory
consist of diabetic ketoacidosis (DKA) and the abnormalities seen at presentation in DKA
hyperglycemic hyperosmotic state (HHS), fre- include: a low serum bicarbonate, elevated anion
quently also referred to as hyperosmotic nonke- gap, leukocytosis, hyperkalemia, elevated BUN
totic syndrome. The American Diabetes and creatinine (suggesting prerenal azotemia),
Association definitions for these conditions are and elevated amylase and lipase. Leukocytosis is
given in Table 1. Serum glucose level is usually proportionate to the degree of acidemia and can
below 800 mg/dL in DKA, whereas in HHS a confuse the clinical picture as regards the
glucose level in excess of 1,000 mg/dL is not presence of infection. Hyperkalemia, due to
uncommon. DKA is characterized by a syndrome extracellular osmotic shifting and insulin defi-
of hyperglycemia, ketonemia, and an anion gap ciency, is common despite a deficit in total body
metabolic acidosis, usually in excess of 20. potassium, largely from urinary losses. Serum
sodium is variable in DKA and reflects a balance
Anion gap serum sodium between osmotic dilution in the serum from
serum chloride
hyperglycemia and urinary losses due to osmotic
serum bicarbonate
diuresis. Pseudohyponatremia may be seen in
The degree of acidosis and magnitude of the patients with concomitant hyperlipidemia. Al-
increase in anion gap are contingent on the rate though pancreatitis is uncommon, patients with

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Table 1Diagnostic Criteria for Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar Syndrome (HHS)

DKA
Diagnostic Criteria
and Classification Mild Moderate Severe HHS

Plasma glucose, mg/dL .250 mg/dL .250 mg/dL .250 mg/dL .600 mg/dL
Arterial pH 7.257.30 7.00 to ,7.25 ,7.00 .7.30
Serum bicarbonate, mg/dL 1518 10 to ,15 ,10 .15
Urine ketone Positive Positive Positive Small
Serum ketone Positive Positive Positive Small
Effective serum osmolality Variable Variable Variable .320 mOsm/kg
Anion gap .10 .12 .12 ,12
Mental status Alert Alert/drowsy Stupor/coma Stupor/coma

Adapted from Kitabchi AE. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American
Diabetes Association. Diabetes Care. 2006;29(12):27392748.

elevations of amylase and lipase should have dextrose 5 in 0.45 NaCl, should be administered
pancreatitis ruled out. Arterial blood gas shows until the DKA has resolved. This serves to avoid
acidosis with a compensatory respiratory alkalo- hypoglycemia in the context of not as yet
sis and hypocapnia. Acidemia is usually present. resolved DKA and permits the continued ad-
Treatment of DKA is centered on expanding ministration of IV insulin. IV insulin should be
intravascular volume and is best performed utiliz- continued until ketogenesis has resolved, as
ing normal saline solution. As patients are usually reflected in normalization of the anion gap.
several liters down, there is little risk in adminis- The routine treatment of metabolic acidosis
tering normal saline solution in large quantity. with IV sodium bicarbonate has been largely
Regular insulin is administered as an IV bolus of abandoned, in recognition that vigorous volume
0.10 to 0.15 U/kg/h, followed by a continuous IV expansion alone is generally sufficient. Never-
infusion at 0.10 U/kg/h. Blood glucose should be theless, patients presenting with a pH ,7.00 can
lowered by about 50 mg/dL/h and assessed be considered for this if tissue perfusion is
hourly, with downward adjustments made in the compromised or life-threatening hyperkalemia
insulin drip as blood glucose lowers. Clinicians is present. The management of serum potassium
should recognize that fingerstick capillary blood levels in DKA requires careful attention, with
glucose measurements can be inaccurate in criti- frequent monitoring necessary. Despite initial
cally ill patients. Fingerstick glucose measurements hyperkalemia, with the administration of insulin
are lower than glucose measured from venous and the correction of metabolic acidosis, hypo-
blood in hypotensive patients but at other times kalemia develops and should be treated with IV
may be found to be higher than venous blood. potassium supplementation. Usually 20 to 30
Serum electrolytes should be assessed q2-4h. mEq/L is added to 0.45 saline solution, as the
IV fluid resuscitation aimed at expanding addition of potassium to normal saline solution
intravascular volume is essential, and several would result in the administration of hypertonic
liters may be required. Although hypernatremia fluids. Hypophosphatemia often develops dur-
is frequently present, normal saline solution ing treatment of DKA, but it seldom requires
should be administered IV until the intravascular supplementation, which should be administered
volume deficit is corrected, as normal saline only if clinically significant or severe (,1.0 mg/
solution is hypotonic relative to the patients dL).
serum and is more effective at expanding plasma Clinical resolution of DKA can be monitored
volume than the administration of hypotonic via venous pH and serum anion gap. Repeat
saline solution such as 0.45 NaCl. Once intravas- arterial blood gases are not required. After the
cular volume has been restored and the patients normalization of the anion gap has occurred, the
glucose has lowered to the 200 range, glucose patient should receive subcutaneous regular
and hypotonic saline solution, in the form of insulin. The administration of IV dextrose is

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stopped, and IV insulin is discontinued 30 min amount of volume resuscitation required:
later. These changes are best made once the Free water deficit (men) (Weight in kg 3 0.6)
patient has resumed oral nutrition, otherwise (Na/140 1)
ketogenesis may resume.
Cerebral edema can occur as a complication Free water deficit (women) (Weight in kg 3 0.5)
of DKA treatment in patients under 20 years of (Na/140 1)
age, but the risk is mitigated if rapid correction of
sodium and water deficits are avoided and The treatment of HHS involves the same man-
glucose is added to IV fluids once serum glucose agement principles as DKA: vigorous volume
level has dropped to the low 200 range. replacement and an IV insulin drip. The amount
of normal saline solution required to restore
Hyperosmolar Nonketotic extracellular fluid tends to be greater in HHS
Dehydration Syndrome than in DKA. Half normal saline solution is
administered once this has been achieved.
HHS, also often referred to as the hyperos-
molar nonketotic syndrome, occurs when hyper- Glucose Control in the ICU
glycemia occurs with little or no ketoacidosis.
HHS occurs in patients who are only partially Reports of significant benefit to patients with
insulin deficient, and hence HHS is more stress-induced hyperglycemia in the ICU treated
common among older, type 2 diabetics. While with IV insulin to achieve blood glucose levels
the usual symptoms of hyperglycemia such between 80 and 100 mg/dL were followed by
polyuria, polydipsia, dehydration, and tachycar- others that suggested that the risk of hypoglyce-
dia are present, an anion gap metabolic acidosis mia was significant, particularly among patients
from ketogenesis is not. The severity of hyper- with sepsis. The large Normoglycemia in Inten-
glycemia is often quite significant (.1,000 mg/ sive Care Evaluation and Survival Using Glucose
dL). The resultant hyperosmolality produces Algorithm Regulation (NICE-SUGAR) trial dem-
depression of the CNS, which, when severe, can onstrated an increase in 90-day mortality in
cause coma. HHS is contrasted with varying patients treated with this approach, sometimes
degrees of DKA in Table 1. called tight glycemic control, compared with a
Serum sodium is often low in HHS due to less aggressive approach. Only the subset of
osmotic shifting of water from the intracellular patients with trauma or those being treated with
compartment. That is, water enters the extracel- corticosteroids demonstrated a trend toward
lular compartment, following the gradient creat- benefit with tight control. However, it should be
ed by the osmotically active glucose molecules. recognized that the control group in NICE-
As serum glucose levels tend to be higher in HHS SUGAR had a mean glucose level around 140
than in DKA, this effect can be quite profound. In mg/dL; this suggests that, while practices have
addition, just as in DKA, plasma volume is changed over the last decade and tight control is
contracted at the same time, owing to osmotic not warranted, patients with stress-induced
diuresis from glucosuria. If, however, the glucos- hyperglycemia should still be treated with IV
uria effect predominates, hypernatremia may be insulin, albeit at a more modest target of less than
observed. In either circumstance, the serum 150 mg/dL.
sodium level is fictitiously altered by hypergly-
cemia. A common correction factor to determine Hypoglycemia
the actual serum sodium is:
Hypoglycemia (blood glucose level ,60 mg/
Na corrected Na measured [0.016 dL) is seldom a cause of admission to the ICU but
3 (Glucose in mg/dL 100)] is seen as a consequence of other conditions, the
ingestion of oral hypoglycemic agents or an
The corrected sodium is used to determine free overdose of long-acting insulin being exceptions.
water deficit, which can serve as a guide to the Common causes of hypoglycemia in the ICU

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include hepatic failure, renal failure, sepsis, Myxedema coma is often the result of
adrenal insufficiency, leukemia, lymphoma, tu- prolonged noncompliance with thyroid supple-
mors including hepatoma or pancreatic islet b- mentation in the face of absent thyroid function,
cell tumor, or additional drugs such as b-blockers such as following I131 ablation. Drugs that can
or pentamidine. Symptoms of hypoglycemia cause underlying hypothyroidism include amio-
include nervousness, tremulousness, tachycar- darone, propylthiouracil, lithium, and sulfon-
dia, and diaphoresis, all of which are triggered amides. Myxedema coma can be precipitated by
by a compensatory adrenergic response to the cold exposure, the concomitant administration of
hypoglycemia. If severe hypoglycemia is present, sedative drugs, especially opioids, or stress such
coma or seizures can ensue. as infection and myocardial infarction. Infection
When clinically suspected, hypoglycemia may be masked by an inability to mount a
should be promptly treated with an ampule of temperature spike. Myxedema has a significant
dextrose, containing 50 mL of 50% dextrose attributable mortality of almost 40%, particularly
solution, IV push. Blood glucose should be among elderly and septic patients or patients
monitored hourly via fingerstick measurements, with prolonged hypothermia, cardiac compro-
enabling a timely therapeutic response. A second mise, or coma.
ampule may be required within an hour of Once clinically suspected, a serum TSH, free
treatment. Patients should also receive a dextrose T4, and cortisol should be drawn. A cosyntropin
drip of either 5% or 10% solution, at a rate stimulation test should also be performed when-
appropriate to the clinical circumstances encoun-
ever possible. However, treatment of myxedema
tered.
coma should begin based on clinical suspicion and
Glucagon, hydrocortisone, or octreotide can
should not wait for laboratory confirmation. The
be administered if hypoglycemia is profound and
treatment of myxedema coma is IV administration
refractory to the above measures, but it is seldom
of thyroxine, starting with a loading dose of 300 lg
required.
of thyroxine followed by daily administration of
doses ranging from 50 to 100 lg. As unsuspected
Myxedema Coma
adrenal insufficiency is frequently also in evi-
dence, all patients with myxedema coma should
Myxedema coma is a severe form of hypothy-
be empirically treated for possible adrenal insuf-
roidism characterized by CNS depression and
hypothermia from a low basal metabolic rate. ficiency. This can be accomplished either through
Women are more commonly affected than men. the daily administration of hydrocortisone at a
The other manifestations common to less severe dose of 300 mg. Patients with myxedema coma are
hypothyroidism may also be present. These frequently intubated for airway protection or
include: lethargy, cold intolerance, delayed deep hypercapnia. Other supportive measures include
tendon reflexes, hypothermia, bradycardia, alope- the use of passive warming and supplemental
cia, dry, doughy skin, hoarseness, and hyper- nutrition.
glossia. A pericardial effusion may be present,
although significant cardiac compromise is un- Euthyroid Sick Syndrome
common. Laboratory abnormalities that are diag-
nostic include an elevated TSH and a low free T4. Patients who are critically ill frequently man-
In addition, several other laboratory abnormalities ifest abnormalities in thyroid function tests,
can occur. These include hyponatremia, hypercap- suggesting the possibility of hypothyroidism.
nia, a normocytic normochromic anemia, hyper- Owing to an increased conversion of T3 to reverse
lipidemia, hypoglycemia, and an elevation in T3, these patients demonstrate a low serum T3
creatine phosphokinase. Hyponatremia is due to level, a condition called euthyroid sick syndrome.
an impairment in free water excretion and can T4 levels may also be low, particularly in the
result in seizure activity. Hypoglycemia can occur setting of protracted critical illness, and the TSH
from hypothyroidism alone or may be due to level can also vary, being either slightly elevated or
concomitant adrenal insufficiency. decreased. Free T4 levels are normal, indicating

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the absence of clinical hypothyroidism. Hence, no exacerbating the problem by enhanced thyroid
thyroid supplementation is required. hormone production. Decreasing conversion of
T4 into T3 is accomplished through the admin-
Thyroid Storm istration of propylthiouracil, hydrocortisone, 100
mg q8h, and propranolol. Propranolol, 60 to 80
Thyroid storm is hyperthyroidism in the mg q4-6h, is also administered to block the
presence of significant cardiac or CNS manifes- hyperadrenergic manifestations of thyrotoxicosis
tations. These include cardiac dysrhythmias, and to control tachyarrhythmias. IV esmolol can
such as new onset atrial fibrillation, atrial flutter, be used instead of propranolol.
and supraventricular tachycardia, or CNS man- Other adjuncts to care of the patient with
ifestations, such as tremor, delirium, stupor, or thyroid storm include passive cooling if hyper-
even coma. The patient may be hypertensive and pyrexia is present. Acetaminophen is preferred,
tachycardic. Apathetic affect may also be present, as acetylsalicylate increases free thyroid hormone
particularly among the elderly. Other manifesta- in the serum through displacement on plasma
tions of hyperthyroidism may be present, such as proteins. Thyroidectomy may be required if a
exophthalmos, hyperreflexia, heat intolerance, patient develops life-threatening agranulocytosis
anxiety, nausea, vomiting, diarrhea, abdominal from propylthiouracil or methimazole. Finally, as
pain, and the presence of fine hair or pretibial with myxedema, the patient should be evaluated
edema. and treated for the possibility of concomitant
Graves disease, an autoimmune condition, is hypoadrenalism.
the most common cause of hyperthyroidism. Iodine therapy is discontinued and cortico-
Importantly, thyroid storm can be triggered by steroids may be tapered once hyperpyrexia, CNS,
physiologic stress in the setting of underlying and cardiac manifestations have resolved. Pa-
hyperthyroidism, which may have been unsus- tients with Graves disease should ultimately
pected until that time. These can include surgery, undergo thyroid ablation. This can be accom-
pregnancy, trauma, or significant acute illness of plished either surgically or with I131.
any kind.
As with myxedema, the diagnosis of thyroid Adrenal Crisis
storm is made clinically, with treatment under-
taken in anticipation of confirmatory laboratory Adrenal insufficiency can be seen in a variety
tests. Laboratory findings in hyperthyroidism of conditions and may be either primary, that is,
and thyroid storm include elevations in T3 and due to insufficient production of adrenocortico-
T4, with a low TSH. In an uncommon variant of tropic hormone, or secondary, usually resultant
thyroid storm called T3 thyrotoxicosis, T3 levels from underproduction of glucocorticoids and
are elevated but T4 levels remain normal. Less mineralocorticoids. Causes of primary adrenal
commonly, in central hyperthyroidism, TSH, T3, insufficiency include autoimmune, that is, Addi-
and T4 are all elevated. sons disease; bilateral adrenal hemorrhage;
Treatment of thyroid storm is multifaceted abrupt withdrawal of exogenously administered
and attempts to affect thyroid hormone produc- corticosteroids, TB; septic shock; meningococce-
tion, release, and peripheral conversion to the mia; metastatic malignancy; amyloidosis; and
physiologically more active T3 and to block the drugs such as etomidate and ketoconazole.
effect of thyroid hormone on the body. Thyroid Causes of secondary adrenal insufficiency in-
hormone synthesis is inhibited by administering clude pituitary tumors; craniopharyngioma; as a
either propylthiouracil, 200 mg q4h, or methima- postoperative complication; postpartum hypopi-
zole, 20 mg q4-6h. Iodine, either saturated tuitarism (Sheehans syndrome); infiltrative diseas-
solution potassium iodide or Lugol solution, is es such as hemochromatosis, sarcoidosis,
administered to block thyroid hormone release histiocytosis, or histoplasmosis; TB; or withdrawal
from the thyroid gland. Importantly, iodine must of exogenously administered corticosteroids. Pa-
only be administered after thyroid hormone tients with secondary adrenal insufficiency lack
synthesis has been blocked, in order to avoid hyperpigmentation, dehydration, and hyperkale-

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mia. Hypotension is less prominent, whereas cosyntropin stimulation test was found to be
hypoglycemia is more common than in primary unreliable when correlated with free cortisol levels.
adrenal insufficiency. In addition, contrary to earlier studies, a mortality
Adrenal crisis occurs in patients with adrenal benefit was not observed in the corticosteroid
insufficiency who have hypotension and volume group. Patients receiving corticosteroids were able
depletion from the absence of mineralocorticoids. to be weaned off vasopressor medications an
Like thyroid storm, adrenal crisis is often average of 2 days sooner than the placebo group
triggered by physiologic stress such as trauma, but also were found to have a threefold risk of
surgery, or acute medical illness. Clinically, subsequent sepsis while in the ICU. In contrast,
patients may manifest hypotension, nausea, meta-analyses suggest that a mortality benefit
vomiting, fatigue, anorexia, depression, and might be expected only among patients who are
amenorrhea and may lack hyperpigmentation at a high risk of death. Whether or not to administer
and/or vitiligo. Abdominal, flank, lower back, or corticosteroids to patients with vasopressor-depen-
chest pain are common in patients with bilateral dent shock remains an area of great controversy in
adrenal hemorrhage or infarction, the main risk critical care. The standard dose is hydrocortisone,
factors for which are anticoagulation and post- 50 mg IV q6h for 5 days. Concomitant mineralo-
operative state. Laboratory abnormalities can corticoid administration has also been advocated in
include hypoglycemia, hyponatremia, hyperka- this setting, but a beneficial effect may only occur if
lemia, and eosinophilia. given prophylactically.
In individuals who are not stressed, a total Adrenal crisis is treated with an initial dose of
cortisol level of .15 lg/dL is sufficient to rule out 200 mg of IV hydrocortisone followed by 100 mg
adrenal insufficiency. A level ,5 lg/dL consti- q6h. IV administration of normal saline solution is
tutes absolute adrenal insufficiency with 100% important to correct volume contraction. Hypo-
specificity but low sensitivity (36%). A cut-off level tonic fluids should not be administered, as they
of 10 lg/dL is 62% sensitive but only 77% specific. can worsen hyponatremia. Mineralocorticoid ad-
The appropriate response of the adrenal glands in ministration is not required in adrenal crisis, with
the setting of critical illness is unknown. Some the possible exception of patients with sepsis.
authors suggest that a level ,25 lg/dL may be
insufficient in critical illness such as sepsis. Pheochromocytoma
Cortisol is protein bound, and total cortisol levels
bear a variable relationship to free cortisol levels. A pheochromocytoma is a catecholamine-
Patients who are hypoproteinemic may have a secreting tumor of chromaffin cells; most common
normal total free cortisol level despite a seemingly in the adrenal glands, it may occur elsewhere in
insufficient total cortisol level. In patients who are the body. It is an uncommon cause of secondary
not septic, a cosyntropin stimulation test may be hypertension that may present in an accelerated
useful in order to determine whether adrenal form in the ICU. Symptoms, which are due to the
reserve is lacking and relative adrenal insufficien- release of catecholamines such as epinephrine,
cy is present. Thirty or 60 min after the adminis- norepinephrine, and/or dopamine, include tachy-
tration of 250 lg of cosyntropin, a form of synthetic cardia, palpitations, diaphoresis, headache, chest
adrenocorticotropic hormone, a rise in total pain, tremor, and flushing. The classic triad of
cortisol level ,9 lg/dL or an absolute level ,20 episodic headache, sweating, and tachycardia is
lg/dL may be indicative of relative adrenal seldom in evidence. Episodes of catecholamine
insufficiency. release and resultant symptoms tend to be
Dexamethasone, 10 mg may be administered episodic and seldom last more than a few hours
as a single dose while a cosyntropin stimulation at time. Other conditions resulting in increased
test is being performed as therapy for adrenal sympathetic activity can result in BP elevations
insufficiency so that the laboratory analysis is not suggestive of pheochromocytoma, including auto-
altered, as is the case with hydrocortisone. nomic dysfunction such as may be the case with
In a recent randomized, placebo-controlled trial spinal injury or Guillain-Barre syndrome; the use
of corticosteroids in septic patients, CORTICUS, the of sympathomimetic drugs such as cocaine,

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phencyclidine, or amphetamines; and the inges- nephrogenic DI. Symptoms are driven by the
tion of tyramine-containing foods in patients loss of free water and include polyuria, polydip-
taking monoamine oxidase inhibitors. sia, hypernatremia, volume contraction, and
The diagnosis, once suspected, is best con- hyperosmolality. Most ICU patients have intake
firmed by obtaining plasma levels of metaneph- medically determined and, as a result, cannot
rine and normetanephrine or 24-h urine levels of respond to an increased thirst drive, resulting in
metanephrines and catecholamines when the hypernatremia. Diagnosis is made by measuring
patient is stable and not critically ill, as the stress urine specific gravity, which reveals dilute urine.
of critical illness can produce misleading values In primary polydipsia a low plasma sodium
that may be false positives. The administration of concentration (,137 mEq/L) is seen with a low
tricyclic antidepressants can also result in falsely urine osmolality (,one-half the plasma osmolal-
elevated results. Subsequent to a chemical ity), whereas in DI a high-normal plasma sodium
diagnosis, imaging studies such as CT scan or concentration (.142 mEq/L, due to water loss) is
I123 -metaiodobenzylguanidine scan are per- seen. Urine osmolality should be less than the
formed to localize the tumor and determine plasma osmolality.
resectability. ADH is produced in the hypothalamus and
As with some other endocrinopathies, the released by the anterior pituitary gland. Causes
stress of surgery can precipitate a hypertensive of central DI include causes of panhypopituita-
crisis due to catecholamine release in these rism, such as Sheehans syndrome, anoxia,
patients. Patients with undiagnosed pheochro-
trauma, and tumors. In addition, infiltrative
mocytoma presenting with a hypertensive crisis
conditions including sarcoidosis and lymphoma
following surgery have a high mortality. Patients
as well as infectious diseases such as neurosyph-
with known pheochromocytoma who are sched-
ilis or tuberculosis can result in central DI.
uled to undergo surgery should receive preoper-
Nephrogenic DI occurs in the setting of adequate
ative management well in advance of surgery
AVP and is caused by disorders of the kidney
with an a-agent, such as phenoxybenzamine. b-
that involve damage to the collecting tubules,
Blocker administration is contraindicated unless
where AVP would ordinarily act to promote
prior a- blockade has been accomplished in order
water adsorption. Nephrogenic DI can be caused
to avoid unopposed a-tone. The calcium channel
by several drugs, including lithium, demeclocy-
blocker nicardipine can be a useful adjunct to
cline, amphotericin B, and antiretroviral drugs
management of these patients. Metyrosine, an
inhibitor of catecholamine synthesis, may also be such as tenofovir and indinavir. Hence, ADH
used. levels are elevated in nephrogenic DI but are
As opposed to patients with essential hyper- diminished or absent in central DI.
tension who have a hypertensive crisis, the drug Central DI can be clinically distinguished
of choice for a patient with pheochromocytoma from nephrogenic DI by administering the ADH
who develops a hypertensive crisis is phentol- analog desmopressin in conjunction with water
amine. This is administered intravenously in restriction: administration of 1 lg desmopressin
doses ranging from 2 to 5 mg every 5 min until subcutaneously will cause the urine osmolality to
the target BP is achieved. Sodium nitroprusside increase by at least 50% if there is complete DI on
and nicardipine may also be considered. a central basis. In partial central DI, the urine
osmolality will increase by 10% to 50%. In
Diabetes Insipidus (DI) nephrogenic DI, the urine osmolality will gener-
ally not increase after AVP administration. Water
DI is a condition in which water adsorption restriction is useful to determine if primary
by the collecting tubules of the kidney is polydipsia is present. With water restriction,
impaired, either from a lack of the antidiuretic patients with primary polydipsia will exhibit a
hormone (ADH) arginine vasopressin (AVP), as rise in urine osmolality, usually to above 500
in central DI, or due to the lack of responsiveness mOsm/kg, but will not respond to desmopressin
of the collecting tubules, as is the case in since endogenous release is intact.

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Treatment of central DI entails correcting the patients with severe sepsis. N Engl J Med. 2008;
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Free water deficit is calculated in the following
Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA.
manner:
Hyperglycemic crises in adult patients with diabetes: a
0:6 3 patient0 s weight in kg consensus statement from the American Diabetes
3 patient0 s sodium=140 1; Association. Diabetes Care. 2006;29(12):27392748.

where 0.6 3 weight equals estimated body water, Nyenwe EA, Razavi LN, Kitabchi AE, et al. Acidosis: the
and 140 is the desired sodium. This represents prime determinant of depressed sensorium in diabetic
ketoacidosis. Diabetes Care. 2010;33(8):18371839.
total body water for young males; for females
and elderly males multiply the weight in kg by Service FJ. Hypoglycemic disorders. N Engl J Med.
0.5. Because the urinary fluid losses in DI are 1995;332(17):11441152.
hypotonic, the IV fluid is also hypotonic. Patients The NICE-SUGAR Study Investigators. Intensive
who are hypotensive due to hypovolemia should versus conventional glucose control in critically ill
receive normal saline solution until intravascular patients. N Engl J Med. 2009;360(13):12831297.
volume has been replenished. Otherwise, hypo-
Umpierrez G, Freire AX. Abdominal pain in patients
tonic fluids may be administered. Careful mon-
with hyperglycemic crises. J Crit Care. 2002;17(1):6367.
itoring of intake and output as well as serial
electrolyte measurements are required to suc- Van den Berghe G, Wilmer A, Hermans G, et al.
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Management of nephrogenic DI is similar,
although desmopression is not administered. The Van den Berghe G, Wouters PJ, Bouillon R, et al.
discontinuation of any drugs that may be causing Outcome benefit of intensive insulin therapy in the
nephrogenic DI is an important component of critically ill: insulin dose versus glycemic control. Crit
management. A thiazide diuretic is administered Care Med. 2003;31(2):359366.
to induce mild extracellular fluid volume deple- White NH. Management of diabetic ketoacidosis. Rev
tion, which causes increased water reabsorption Endocr Metab Disord. 2003;4(4):343353.
at the proximal tubule. As a result, there is less
Wiener RS, Wiener DC, Larson RJ. Benefits and risks
water delivered to the distal nephron and,
of tight glucose control in critically ill adults: a meta-
therefore, less urine is produced.
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Nothing to Disclose
Thyroid Disease
The author has disclosed that no relation-
ships exist with any companies/organizations Bahn RS (chair), Burch HB, Cooper DS, et al.
whose products or services may be discussed in Hyperthyroidism and other causes of thyrotoxicosis:
this chapter. management guidelines of the American Thyroid
Association and American Association of Clinical
Suggested Reading Endocrinologists. Thyroid. 2011;21(6):593646.
Kwaku MP, Burman KD. Myxedema coma. J Intensive
DKA, HHS, and Glycemic Control Care Med. 2007;22(4):224231.
Langley RW, Burch HB. Perioperative management of
American Diabetes Association. Hyperglycemic crises the thyrotoxic patient. Endocrinol Metab Clin North Am.
in patients with diabetes mellitus. Diabetes Care. 2003; 2003;32(2):519534.
26(Suppl 1):S109S117. Ngo SY, Chew HC. When the storm passes unno-
Brunkhorst FM, Engel C, Bloos F, et al. Intensive ticeda case series of thyroid storm. Resuscitation.
insulin therapy and pentastarch resuscitation in 2007;73(3):485490.

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Rodrguez I, Fluiters E, Perez-Mendez LF, et al. Sprung CL, Annane D, Keh D, et al. Hydrocortisone
Factors associated with mortality of patients with therapy for patients with septic shock. N Engl J Med.
myxoedema coma: prospective study in 11 cases 2005;358(2):111124.
treated in a single institution. J Endocrinol. 2004; Zaloga G, Marik P. Diagnosis and treatment of adrenal
180(2):347350. insufficiency during septic shock. Crit Care Med. 2003;
Yamamoto T, Fukuyama J, Fujiyoshi A. Factors 31(8):22522253.
associated with mortality of myxedema coma: report
of eight cases and literature survey. Thyroid. 1999; Pheochromocytoma
9(12):11671174.
Baguet JP, Hammer L, Mazzuco TL, et al. Circum-
stances of discovery of phaeochromocytoma: a retro-
Adrenal Disorders
spective study of 41 consecutive patients. Eur J
Endocrinol. 2004;150(5):681.
Annane D, Bellissant E, Bollaert PE, et al. Corticoste-
roids in the treatment of severe sepsis and septic Guerrero MA, Schreinemakers JM, Vriens MR, et al.
shock in adults: a systematic review. JAMA. 2009; Clinical spectrum of pheochromocytoma. J Am Coll
301(22):23622375. Surg. 2009;209(6):727732.
Pacak K, Linehan WM, Eisenhofer G, et al. Recent
Erturk E, Jaffe CA, Barkan AL. Evaluation of the
advances in genetics, diagnosis, localization, and
integrity of the hypothalamic-pituitary-adrenal axis
treatment of pheochromocytoma. Ann Intern Med.
by insulin hypoglycemia test. J Clin Endocrinol Metab.
2001;134(4):315329.
1998;83(7):23502354.
Hamrahian AH, Oseni TS, Arafah BM. Measurements
Diabetes Insipidus
of serum free cortisol in critically ill patients. N Engl J
Med. 2004;350(16):16291638. Brewster UC, Hayslett JP. Diabetes insipidus in the
Hicks CW, Sweeney DA, Danner RL, et al. Efficacy of third trimester of pregnancy. Obstet Gynecol. 2005;
selective mineralocorticoid and glucocorticoid agonists 105(5 Pt 2):11731176.
in canine septic shock. Crit Care Med. 2012;40(1):199207. Mavrakis AN, Tritos NA. Diabetes insipidus with
Mohammad Z, Afessa B, Finkielman JD. The inci- deficient thirst: report of a patient and review of the
dence of relative adrenal insufficiency in patients with literature. Am J Kidney Dis. 2008;51(5):851859.
septic shock after the administration of etomidate. Crit Sands JM, Bichet DG. Nephrogenic diabetes insipidus.
Care. 2006;10(4):R105. Ann Intern Med. 2006;144(3):186194.

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Chapter 2. Postoperative Crises
David L. Bowton, MD, FCCP, FCCM

Objectives: noted in more than 20% of patients in a recent


 Differentiate between and describe the early and late observational study of over 1,000 patients.1 In
causes of postoperative fever. this discussion of postoperative fever, a temporal
 List common causes of postoperative hyponatremia in
classification will be used: immediately postop-
the neurosurgical patient and discuss management and
therapeutic options. erative, acute (within the first week), and
 Describe the common causes of hypotension following subacute (after the first week).
cardiac surgery and discuss their treatment options. Immediately postoperatively, malignant hy-
perthermia (MH) is the most serious, potentially
Key words: cardiac surgery; fever; hypotension; neurosur- fatal cause of fever and one requiring immediate
gery; postoperative complications
intervention. While MH is not strictly a postop-
Synopsis:
erative phenomenon, it usually requires manage-
ment and monitoring in the intensive care unit.
This short review will summarize the presentation and
management of selected postoperative complications, includ-
MH occurs in approximately 1 in 30,000 general
ing postoperative fever and shock after general surgery; anesthetics. It typically requires both a genetic
postoperative neurosurgical crises, including hyponatremia; predisposition and a triggering agent. Triggering
hypotension after cardiac surgery; and perioperative man- agents include all of the inhalational anesthetics
agement of antithrombotic therapy for cardiac stents. Malig-
nant hyperthermia is characterized by hypercarbia, fever, and and succinylcholine. Nitrous oxide (NO) and IV
metabolic acidosis intraoperatively but may continue or recur anesthetics are not triggers. While there is a
postoperatively. Treatment is the discontinuation of anesthetic genetic basis for MH and the inheritance pattern
agents and administration of dantrolene. Fever in the first 2 to
appears to be autosomal dominant in about 50%
3 days postoperatively is often due to surgical inflammation,
while after 48 to 72 h it is more likely infectious. While the of identified cases, a family history of MH is
initial management of hypotension postoperatively is usually elicited in fewer than 10% of MH patients.2 There
volume resuscitation, the consequences of volume resuscita- is a 2:1 male:female predominance and the
tion include abdominal compartment syndrome defined as a
bladder pressure .20 to 25 mm Hg and organ failure. Its
majority of patients present in adulthood (medi-
treatment is prompt recognition and surgical decompression. an age 22 years).2 Mutations in the ryanodine
Hyponatremia in the postoperative neurosurgical patient is receptors (RYR1) in the sarcoplasmic reticulum
usually due to the syndrome of inappropriate diuretic are far and away most commonly associated with
hormone secretion, but cerebral salt wasting must be in the
differential diagnosis. In the symptomatic patient, both are MH, though other mutations are known to be
treated with 3% saline solution. Hypotension after cardiotho- associated with MH, such as within the dihy-
racic surgery is most commonly due to vasoplegia but can dropyridine receptors (DHP) in the striated
represent myocardial dysfunction or cardiac tamponade.
muscle t-tubule membrane.
Atrial fibrillation after cardiac surgery is common and is
associated with prolonged length of stay. The unstable patient MH usually occurs within 90 min of induction
should be cardioverted, while more stable patients can be and presents with respiratory acidosis and rapidly
treated with calcium antagonists, amiodarone, or b-blockers. increasing temperature. Respiratory acidosis is
The perioperative management of antiplatelet therapy in
patients with cardiac stents is challenging. These patients
seen in more than 90% of patients and rapidly
should generally have dual antiplatelet therapy continued rising temperature in nearly two-thirds of pa-
throughout the perioperative period, with exceptions being tients. Metabolic acidosis, muscle rigidity, and
cardiac and intracranial surgery. elevations in creatine kinase (usually .10,000 IU/
L), while also observed commonly, are each
General reported in fewer than half of patients. The initial
treatment is to stop all inhalational anesthetics
Postoperative Fever (except NO), switch to an IV anesthetic agent, (eg
propofol), and immediately increase minute ven-
Postoperative fever is common. A tempera- tilation and FIO2. Pharmacologic therapy with
ture above 100.48F within 72 h of surgery was dantrolene is a cornerstone of therapy. Prior to

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the introduction of dantrolene, mortality was as remaining patients sustained superficial surgical
high as 60%, while the current mortality rate in site infections. Thus, the clinical examination can
the MH registry is 2%. Dantrolene is initiated as a suggest or confirm the cause of early postopera-
bolus of 2.5 mg/kg IV, then 1 mg/kg boluses are tive fever in a large percentage of patients. The
given until fever decreases, PaCO2 decreases, or causes of infectious fever that most commonly
muscle rigidity abates (up to a total dose of 10 required laboratory or radiographic investigation
mg/kg). It is continued at 1 mg/kg every 6 h for to ascertain were pneumonia, Clostridium difficile
48 h. Electrolytes, especially serum potassium, enterocolitis, and urinary tract infections. Surgical
and serum creatine kinase levels should be site infections often present after the first week
monitored. MH patients are predisposed to and frequently after the patient has been dis-
hyperkalemia due to potassium release from charged from hospital.
muscle contraction and rhabdomyolysis. The An unusual cause of fever after surgical
administration of calcium channel blockers should intervention is the postimplantation syndrome
be avoided as they can precipitate marked seen in 30% to 60% of patients after placement of
elevations in serum potassium. an aortic stent graft. It is characterized by fever
The patient and their family should receive and leukocytosis and perigraft air (within the
counseling regarding MH and consider under- native aorta and around the stent graft) on CT
going MH susceptibility testing. The patient scan, without demonstrable infection.4,5
should also wear a wristband alerting medical Atelectasis is often cited as a cause of
providers to their history of MH. postoperative fever. However, there are few data
In the first postoperative week, tissue injury to endorse this belief. A recent systematic
(without infection), dead bowel, anastomotic leak, review6 concluded that there was insufficient
and abscess should lead the differential diagnosis evidence to support an association between
of elevated temperature. Tissue injury releases atelectasis and postoperative fever or even that
fever-associated cytokines, including IL-6, IL-1, atelectasis caused fever.
TNF-a, and IFN-c.3 Their release is determined
both by the amount of tissue injury and by Postoperative Hypotension
genetically determined responses to tissue injury.
This cytokine release is transient and is the likely Hypotension in the immediate postoperative
etiology of the majority of postoperative fever period is common. In the patient with a major
within the first 72 h of surgery or trauma. In a intraabdominal catastrophe (eg, necrotic bowel,
recent prospective examination of more than anastomotic leak), this usually is due to hypo-
1,000 inpatients undergoing surgery,1 nearly volemia caused by large fluid shifts to the
25% developed a temperature .100.48 F within extravascular space and blood loss. The magni-
the first 72 h postoperatively. In most of these tude of hypovolemia is often underappreciated.
patients, there were no other signs or symptoms In this setting, volume resuscitation is the
of an infectious etiology and an evaluation for an cornerstone of therapy. The end points of
infectious etiology was performed in only 100 resuscitation remain a topic of controversy.
patients. In these 100 patients, an infection was While central venous pressure (CVP) goals are
identified in only 18 patients. There were no often stated, CVP correlates poorly with volume
parameters identified, including the maximal responsiveness, and its application to bedside
temperature and the degree of elevation of the management is uncertain.7 While some au-
WBC count, which differentiated between those thors8,9 suggest that supranormal values for
with an infection and those without infection. Of cardiac index and oxygen delivery are appropri-
the 18 patients with confirmed infection, the ate goals, the evidence is contradictory and
source was clinically evident (symptoms and generally not supportive of such targets.
findings on abdominal examination) in nine: Bleeding is a specific case of hypovolemia in
three with anastomotic leaks and one with an the immediate postoperative period. In the
accidental unrecognized enterotomy, all requiring setting of massive blood loss, balanced transfu-
return to the operating room. Four of the sion is now widely recommended based on data

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accumulated in the treatment of war-related Abdominal Compartment Syndrome
traumatic injury. Thus, in patients who are
massively bleeding and require more than 4 Abdominal compartment syndrome (ACS) is
units of packed red blood cells, a strategy of the syndrome of elevated intraabdominal pres-
using blood and plasma in ratios of 2:1 or 1:1 is sure in the setting of organ failure due to
now commonly employed.10 compression of abdominal structures. It was
Regional anesthesia, specifically epidural or originally described in patients following severe
spinal anesthesia, is a relatively common cause of abdominal trauma but is now increasingly
hypotension as a consequence of vasodilation recognized as potentially complicating any clin-
due to loss of sympathetic tone. It usually ical setting where accumulation of ascitic and
responds to decreasing the dosage of anesthetic interstitial fluid within the abdominal compart-
or narcotic and modest volume administration. ment occurs. Thus, in addition to primary intra-
Adrenal insufficiency is an uncommon cause of abdominal processes, medical or surgical
hypotension in the immediate postoperative patients following large-volume fluid resuscita-
period. Preoperative glucocorticoid therapy is a tion (as for septic shock) are also at risk for ACS.
major risk factor. Small doses of corticosteroids or Intraabdominal pressure is most often measured
steroid administration for a short period of time as intravesical pressure and is normally less than
are generally not risks; patients who receive less 12 mm Hg. Pressures above 12 mm Hg define
than 5 mg of prednisone daily or steroids for less intraabdominal hypertension, while pressures
than 2 weeks do not appear to be at increased above 20 mm Hg with organ dysfunction define
risk for adrenal insufficiency.11,12 While etomi- ACS.17 Commonly seen organ failures include
date suppresses 11b-hydroxylase for 24 to 72 h, renal failure due primarily to renal vein com-
thus reducing cortisol synthesis, it does not pression, pulmonary failure due to severe reduc-
appear to result in an increased need for cortisol tion of thoracic compliance, gut failure due to
replacement therapy.13 The diagnosis of adrenal reduced mesenteric and mucosal blood flow,
insufficiency in critically ill patients is difficult hypotension (cardiovascular failure) due to im-
because of variability in the cortisol assay and the paired venous return and ventricular filling,
response to ACTH stimulation.14,15 However, a hepatic failure due to reduced blood flow and
random serum cortisol level 10 lg/dL is highly consequent impaired lactate clearance, and CNS
predictive of adrenal insufficiency using the failure due to elevation of intracranial pressure
metyrapone stimulation test as the criterion resulting from impaired venous drainage. The
standard.14 definitive treatment of ACS is usually surgical
From 25 to 48 h postoperatively, the etiology decompression, though in the setting of large
of hypotension and fever is more often related to volumes of ascites, large-volume paracentesis
intraabdominal sepsis caused by abscess, necrot- (.1,500 mL) has been successfully employed.18
ic bowel, or an anastomotic leak. Patients usually Other measures to reduce intraabdominal vol-
present with fever, tachycardia, tachypnea, and ume or increase abdominal compliance, includ-
elevated WBC, along with abdominal pain or ing NG suction, sedation, and paralysis, may be
tenderness and abdominal distension. Elderly, employed as temporizing measures until defin-
chronically ill, or immunocompromised patients itive therapy can be undertaken.
may present atypically without one or more of
these findings. Abdominal CT scans, while often Postoperative Neurosurgic Crises
useful, may not be able to differentiate blood
from abscess or benign fluid collections. Reex- Altered Mental Status
ploration is often needed to ascertain the diag-
nosis and for appropriate treatment, but it is too A rapid decline in level of consciousness or new
often delayed.16 Clostridium difficile enterocolitis deficits on neurologic examination is almost always
has become an increasingly common cause of related to compromised brain blood flow, either
fever with diarrhea and should always be focal or global. These alterations can be due to
considered in the differential diagnosis. space-occupying lesions (edema, blood) compro-

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mising blood flow, hydrocephalus increasing in- patients with focal symptomatic brain ischemia
tracranial pressure (ICP) and reducing cerebral such as in the setting of vasospasm after
perfusion pressure (CPP), or a primary vascular subarachnoid hemorrhage, elevation of perfusion
process (thrombosis or vasospasm). Because acute pressure can be associated with improvement in
reductions in brain blood flow must be treated the neurologic deficits. A trial of therapeutic
promptly to minimize the volume of infarcted hypertension may be warranted in this setting,
tissue, acute alteration in mental status or function with systolic blood pressures above 200 mm Hg
is almost always an indication for emergent cranial sometimes required to achieve reversal of the
CT scan to evaluate treatment options. Epidural neurological deficit. This clearly must be bal-
hematomas, subdural hematomas, and large su- anced against the risk of adverse cardiac effects,
perficial intraparenchymal hemorrhages resulting and there are no prospective trials to guide
in acute compression are usually considered good decision making with respect to improving long-
candidates for operative treatment. Importantly, term outcomes or balancing risks and benefits.
hemorrhage within the posterior fossa, because of When the decline in mental status develops
the very limited room for expansion and the more gradually, over many hours or a day or
proximity of the brainstem, is a neurosurgical more, hypoventilation and hyponatremia are
emergency, and surgical evacuation of posterior prominent causes. Hypoventilation can be easily
fossa hemorrhages should routinely be consider- confirmed with blood gas analysis, followed by
ed.19,20 Acute hydrocephalus results from obstruc- appropriate steps to increase minute ventilation.
tion of the lateral, third, or fourth ventricles due to These include the initiation of noninvasive
tumor, edema, parenchymal hemorrhage, or intra- positive pressure ventilation in patients who are
ventricular blood. It occurs in over 20% of patients cooperative, reduction in dosage or careful
with subarachnoid hemorrhage. If a CTscan reveals reversal of sedative and/or narcotic medications,
acute hydrocephalus in the patient with an altered or intubation and mechanical ventilation.
level of consciousness, consideration should be
given to placement of an external ventricular drain, Hyponatremia
which permits both the measurement of ICP and
the drainage of CSF to reduce ICP. Hyponatremia frequently complicates neuro-
When cerebral edema is seen on the CT scan logical diseases. The most common cause is the
in the patient with an acute alteration in syndrome of inappropriate antidiuretic hormone
consciousness, ICP should generally be moni- secretion (SIADH), while cerebral salt wasting is
tored and consideration given to the initiation of much less common and is most often seen in
osmotherapy. Monitoring the ICP permits know- patients with subarachnoid hemorrhage (SAH).
ing and maintaining CPP. Generally, the CPP Both present with an inappropriately high urine
target is greater than 50 mm Hg, although as sodium concentration and urine osmolarity in
noted below, higher levels are sometimes re- the setting of a low serum sodium and low serum
quired in patients with acute brain ischemia due osmolarity. In SIADH, intravascular volume is
to cerebral vasospasm or thrombosis. ICP can be normal or high, while in cerebral salt wasting,
effectively lowered with mannitol or hypertonic intravascular volume is low. In patients with low
saline solution. Hypertonic saline solution is intravascular volume, a high urine sodium
available as 3%, 7.5%, and 23.4% concentrations. concentration helps to distinguish cerebral salt
A recent metaanalysis21 suggests that hypertonic wasting from volume depletion (which will
saline solution is probably more effective than result in low urinary sodium) but with elevated
mannitol, though mannitol remains first-line antidiuretic hormone (ADH) levels (appropriate
therapy in most ICUs. Corticosteroids are often ADH secretion) to minimize urinary volume loss
used in patients with cerebral edema due to and restore intravascular volume. The treatment
tumors or inflammation (vasogenic edema). of mild to moderate hyponatremia due to SIADH
Dexamethasone is most often used. There is no (serum sodium value greater than 120 mEq) is
role, however, for steroids in the treatment of usually fluid restriction. In patients with SAH,
cerebral edema due to trauma or stroke.22,23 In volume restriction is not usually employed for

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fear of causing hypovolemia and worsening DI immediately after and up to 5 days postop-
vasospasm or precipitating cerebral ischemia. In eratively due to suppression of ADH release
patients with SAH and symptomatic patients because of hypothalamic dysfunction, followed
with a serum sodium value less than 120 mEq, within 5 to 10 days by SIADH due to ADH
hypertonic saline solution is the mainstay of release from degenerating posterior pituitary,
therapy. Three percent saline solution is most followed by delayed or permanent DI due to
commonly used because in patients with SIADH, depletion of ADH. Early DI is seen in approxi-
0.9% saline solution will not usually raise the mately 40% of patients, delayed SIADH in 8%,
serum sodium concentration because of obligate and delayed or permanent DI in about 5%. Fewer
excretion of the administered sodium in the than 5% of patients undergoing transsphenoidal
inappropriately concentrated urine (urine osmo- hypophysectomy will manifest all components of
larity greater than serum osmolarity), resulting in the triphasic response. High urine output (often
a net increase in retention of free water. In 400800 mL/h) immediately following surgery
patients who are severely symptomatic (eg, must be differentiated from postoperative fluid
seizures), the goal is to raise the serum sodium diuresis or excretion of an osmotic load (radio-
level by 1 mEq/h for the first 2 to 4 h but by no graphic contrast or mannitol). A very low urine-
more than 10 mEq in the first 24 h; 100 mL of 3% specific gravity (,1.005) or low urine osmolarity
saline solution will raise the serum sodium (Na) (,200 mOsm/L) is highly suggestive that the
by 1.0 to 2 mEq. Too-rapid correction of high urine output is due to DI and that volume
hyponatremia is associated with central pontine status and serum sodium must be carefully
myelinolysis, or the more general osmotic demy- monitored to avoid the development of hypoten-
elination syndrome (describing extra-pontine sion due to volume loss and hypernatremia.
demyelination). The increase in serum Na can Normal saline solution is used to maintain
be approximated by the following formula: intravascular volume; using urine output to
Increase in serum Na gauge the amount required. Desmopressin ace-
tate can be used to reverse the DI, but care must
Infusate Na Serum Na
be used to avoid hyponatremia, which is com-
3 Liters infused=TBW 1
mon in this patient population in the postoper-
where TBW total body water (approximately ative period.24
0.5 3 lean body weight in women; 0.6 in men).
The role of vasopressin-2 receptor antagonists Airway Emergencies
(tolvaptan and conivaptan) remains uncertain
because of the paucity of evidence demonstrating Airway emergencies are an infrequent but
clinical benefit in critically ill patients and the highly morbid postoperative crisis. In a patient
inability to control the rate of rise of sodium. undergoing surgery in the neck (eg, anterior
cervical spine surgery or carotid endarterecto-
Diabetes Insipidus my), complaints of difficulty swallowing or
breathing or the presence of stridor should
Diabetes insipidus (DI) is characterized by prompt an immediate evaluation of the patient
excretion of large volumes of urine with low and consideration of airway compromise in the
specific gravity despite low intravascular volume differential diagnosis. In patients undergoing
and is due to decreased excretion of ADH, cervical spine surgery, 25% to 6% will develop
central DI or loss of effect of ADH, nephrogenic an airway complication, and one third or more of
DI. Central DI is observed in 10% to 60% of these will require reintubation.25 In patients
patients following transsphenoidal hypophysec- undergoing carotid endarterectomy (CEA), the
tomy. The range in incidence is largely a function reintubation rate is 1% to 2%.26 Hematoma is the
of tumor size, with resection of larger tumors cause of airway compromise in almost all
more often associated with DI. A triphasic patients following CEA, in contrast to edema
response following transsphenoidal hypophysec- and consequent airway narrowing and compres-
tomy has been described. This consists of early sion after anterior cervical spine surgery. Hemato-

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ma formation typically occurs within the first 6 h of bleeding is required in approximately 2.4% of
CEA, while airway compromise after anterior patients following CABG.28 Patients who require
cervical spine surgery occurs later but usually reoperation for bleeding have about four times
within the first 36 h. Following cervical spine the mortality rate of patients who do not require
surgery or CEA, it should be presumed that the reoperation (8% vs 2%), but whether this is due to
patient will have a difficult airway and that the reoperation or that many of the risk factors for
most skilled airway provider available should be bleeding are also risk factors for mortality is
present to assist with securing the airway. There is unclear. There are numerous risk factors for
no clear consensus regarding the relative merits of bleeding, the most important of which are age
fiber-optic intubation versus direct laryngoscopy to .70 years, reoperation (eg, prior CABG), renal
secure the airway, but both should be available with replacement therapy or elevated serum creati-
clinical circumstances and operator expertise dic- nine, emergency surgery, and the use of preoper-
tating the choice. While the need for an emergent ative adenosine diphosphate receptor inhibitors
surgical airway is rare, its very rarity should dictate (eg thienopyridines) or glycoprotein IIb/IIIa
that each hospital have a process in place to effect receptor antagonists. Bleeding is usually manifest-
this without delay when needed. ed by excess drainage from mediastinal and/or
pleural drains (. 200 mL/h). In the patient with
Postoperative Cardiothoracic Surgical excessive blood loss after CABG, reversible factors
Crises should be sought beginning with a prolonged
activated clotting time due to residual heparin
Hypotension effect, which should be treated with protamine
sulfate. Hypothermia inhibits coagulation, and the
Hypotension after cardiothoracic surgery is patient should be rewarmed if hypothermic.
common and can be due to vasodilation, blood Thrombocytopenia is common after cardiopulmo-
loss, cardiac tamponade, myocardial dysfunc- nary bypass (CPB) and, coupled with platelet
tion, or dysrhythmias. Vasodilation is the most dysfunction due to preoperative antiplatelet
common cause of hypotension and is seen agents, often argues for platelet transfusion in the
immediately postoperatively; it can persist for bleeding patient. Platelets are suspended in plas-
hours to days. The etiology of the vasodilation is ma, so platelet transfusions will provide some
multifactorial. A low preoperative ejection frac- clotting factors as well. Less commonly, prolonga-
tion is associated with relatively depressed levels tion of the aPTT or PT will suggest clotting factor
of arginine vasopressin and with postoperative depletion and the need for repletion with pro-
vasodilation. IL-1 is increased following cardio- thrombin complex concentrate. Recombinant factor
pulmonary bypass and, by generation of cyclic VII concentrate is usually avoided in this popula-
guanine monophosphate, is associated with tion because of the risk of precipitating bypass graft
vasodilation and hypotension. Use of ACE thrombosis. Inadequate surgical hemostasis is
inhibitors preoperatively is also associated with usually a diagnosis of exclusion, but chest drainage
depressed levels of arginine vasopressin and exceeding 400 mL/h that does not rapidly slow
hypotension. Treatment of hypotension, after should precipitate consideration of reoperation.
ensuring adequate intravascular volume reple- Patients who receive anticoagulants after CABG
tion, is vasopressor infusion, most commonly have a three-fold increased risk for bleeding,29 and
neosynephrine or norepinephrine. Recently, in recent ACCP guidelines suggest that DVT prophy-
light of the relative depression of arginine laxis in patients undergoing CABG with an
vasopressin levels, the use of vasopressin in uncomplicated postoperative course be limited to
low fixed doses (0.03 U/min) to restore vaso- pneumatic compression hose.30
pressin levels to more appropriate levels has
been suggested.27 Myocardial Dysfunction
Bleeding resulting in hypotension occurs in
approximately 5% of patients following coronary Myocardial dysfunction is another frequent
artery bypass grafting (CABG). Reoperation for cause of hypotension following cardiac surgery.

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It may be consequent to myocardial injury or vasopressor, often phenylephrine, or a balanced
edema consequent to cardiopulmonary bypass inotrope/vasopressor, such as epinephrine.
(CPB), cardiac tamponade with inadequate ven- Right ventricular dysfunction can cause left
tricular filling, left ventricular myocardial ische- ventricular dysfunction due to forward flow
mia, or right ventricular dysfunction due to failure with reduced left ventricular filling and
pulmonary hypertension or right ventricular by shifting of the ventricular septum toward the
ischemia. Postoperative cardiac tamponade may left ventricle, impairing both left ventricular
occur even with an open pericardium due to filling and optimally coordinated left ventricular
focal collection of blood and compression of contraction. Right ventricular dysfunction can be
cardiac chambers, most often the right atrium due to ischemia or acutely worsening pulmonary
and/or right ventricle. The risk of tamponade is hypertension. As with left ventricular ischemia,
increased by the use of anticoagulants in the maintenance of coronary perfusion pressure is
immediate perioperative period. While atypical important to maintain coronary blood flow to the
presentations are common, cardiac tamponade right ventricle. Milrinone can often reduce
should be suspected in the patient with tachy- pulmonary vascular resistance and improve right
cardia, a low cardiac index, and a high CVP. ventricular systolic function. If inotropes alone
Hypotension and elevated pulmonary artery are ineffective, pulmonary vasodilators, such as
occlusion pressure (equal to the CVP) are inhaled nitric oxide and inhaled epoprostenol,
frequently seen. If cardiac tamponade is suspect- may be useful to reduce right ventricular
ed, echocardiography should be performed to afterload and increase cardiac output. Inhaled
confirm the diagnosis. After median sternotomy, epoprostenol is less expensive than nitric oxide
it is often difficult to obtain good sonographic and has replaced nitric oxide for this indication
windows, and transesophageal echocardiogra- in many centers.
phy is usually needed to detect right atrial
compression as opposed to pericardial fluid Dysrhythmias
surrounding the heart, as might be seen with a
closed pericardium. Pericardial tamponade is Dysrhythmias are a frequent cause of hypo-
almost always an indication for reoperation to tension after cardiac surgery. Bradycardia due to
remove the compressing fluid. edema or damage of the cardiac conduction
Ischemic myocardial dysfunction can be due system or secondary to ischemia (eg, from nodal
to graft occlusion, coronary embolization, or arterial interruption) is common, and most
inadequate intraoperative myocardial protection. patients will have temporary epicardial pace-
Graft occlusion occurs in 5% to 10% of CABGs maker leads inserted intraoperatively. Following
and is more often due to graft kinking or other CPB, the stroke volume is often small and fixed,
technical problem (eg, occluding stitch) than to necessitating a more rapid heart rate to maintain
thrombosis or spasm. Correction of a correctable cardiac index. Thus it is common to pace these
mechanical cause of ischemia should be under- patients at heart rates of 95 to 100 beats/min if
taken when feasible. When not possible or the initial cardiac index is low. The bradycardia
unsuccessful, inotropic support is the mainstay and small stroke volume are most often transient
of therapy. Epinephrine and milrinone are the and the need for pacing resolves within 24 h.
current mainstays of inotropic support. Epineph- The most common tachyarrhythmia after
rine acts at b and a receptors, providing inotropy CABG or valve replacement surgery is atrial
(b1-receptor agonism) and support of blood fibrillation; it occurs in 25% to 35% of patients
pressure. Milrinone inhibits phosphodiesterase and is an independent predictor of prolonged
3 and results in both increased inotropy and hospital stay and increased costs.31 With the
reduced afterload through vasodilation. Conse- onset of atrial fibrillation, ventricular filling is
quently, its impact on blood pressure can be often inadequate because of both the loss of
difficult to predict (increased flow vs reduced coordinated atrial contraction and the shortening
resistance) but usually results in a fall in blood of the filling time. This can result in loss of
pressure and thus is usually used with a cardiac output and in hypotension. In patients

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who are hemodynamically unstable, D/C car- patients require continuous antiplatelet therapy
dioversion is the preferred treatment. However, after stent placement. However, antiplatelet
because patients are susceptible to recurrence therapy poses an increased risk for perioperative
and are predisposed to atrial fibrillation for bleeding, and thus the challenge of perioperative
several weeks following surgery, additional management of patients with intracoronary
treatment directed at rate control or rhythm stents is a common one. Stent thrombosis, while
control should be provided. No large prospective uncommon with appropriate patient manage-
trial has been performed to determine the ment, can be catastrophic. Case fatality rates of
relative merits of rate control vs rhythm control stent thrombosis in the perioperative period have
in postoperative atrial fibrillation, though a rate been reported to be 50% or greater.32 There are no
control approach has the merit of not exposing prospective trials of management strategies
the patient to the risks of class I or class III focused on the perioperative period; thus, rec-
antiarrhythmic drugs. Further, the noncardiac ommendations are based on evidence gleaned
adverse effects of amiodarone are significant and from studies of discontinuation of antiplatelet
in a patient without markedly impaired ventric- agents for various reasons. Discontinuation of
ular function, hypotension, or severe asthma, b- dual antiplatelet therapy within 6 weeks of
blockers are probably the treatment of choice. placement of a bare metal stent or 3 to 6 months
However, in patients who are hypotensive or of placement of a drug-eluting stent is associated
who have significantly depressed myocardial with an increased risk stent thrombosis. Con-
function, the administration of either b-blockers versely, dual antiplatelet therapy increases the
or nondihydropyridine calcium antagonists has a risk of perioperative bleeding and morbidity in
higher incidence of myocardial depression and patients undergoing CABG, but whether this
hypotension than amiodarone. increased risk of bleeding extends to patients
Because of the frequency of postoperative undergoing other types of surgery is not clearly
atrial fibrillation and its impact on cost and defined. A recent systematic review of published
length of stay, considerable attention has been studies examining the risk of discontinuation of
given to the prevention of atrial fibrillation. The antiplatelet agents and stent thrombosis 30 days
most effective prophylactic agents appear to be b- or more after placement of a drug-eluting stent
blockers and amiodarone, though magnesium found that the median time to ischemic event
and biatrial pacing have also been proposed.31 with cessation of thienopyridine or thienopyr-
There is insufficient evidence for definitive idine plus aspirin was 7 days, while if aspirin
recommendations; however, prophylactic b- was continued, the median time to event was 122
blockers and amiodarone appear to provide the days.33 On the basis of these and other data, the
greatest benefit. b-Blockers appear somewhat ninth edition of the ACCP Evidence-Based
more effective than amiodarone when begun Clinical Practice Guidelines recommends defer-
preoperatively but if begun postoperatively, b- ring surgery for 6 weeks following placement of
blockers and amiodarone appear equally, if a bare metal stent and at least 6 months following
incompletely, effective in reducing the incidence placement of a drug-eluting stent.32 In patients in
of atrial fibrillation. Discontinuation of b-blocker whom non-CABG or intracranial surgery cannot
therapy in patients receiving preoperative b- be deferred for these time periods, the current
blockers significantly increases the risk of post- recommendation is to continue dual antiplatelet
operative atrial fibrillation; thus, b-blockers therapy. In patients undergoing CABG within
should be continued in these patients whenever this early time frame, the recommendation is to
possible. discontinue clopidogrel or prasugrel 5 days
before CABG, continue aspirin through the
Surgery and Cardiac Stents perioperative period, and reload the thienopyr-
idine (eg, 300 mg clopidogrel) postoperatively.
Over 500,000 patients undergo percutaneous For urgent intracranial surgery, thienopyridines
coronary intervention with stent placement an- should probably be discontinued even earlier if
nually in the United States. Virtually all these feasible and aspirin discontinued prior to surgery

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18From: http://books.publications.chestnet.org/ on 07/19/2012 Chapter 2. Postoperative Crises (Bowton)
and restarted as early as possible postoperatively surgery: a prospective randomized trial. Arch
(depending on the specific surgery and perceived Surg. 2010;145(12):11931200.
bleeding risk). 10. Borgman MA, Spinella PC, Perkins JG, et al. The
ratio of blood products transfused affects mortal-
Nothing to Disclose ity in patients receiving massive transfusions at a
combat support hospital. J Trauma. 2007;63(4):
The author has disclosed that no relation- 805813.
ships exist with any companies/organizations 11. Yong SL, Marik P, Esposito M, Coulthard P.
whose products or services may be discussed in Supplemental perioperative steroids for surgical
this chapter. patients with adrenal insufficiency. Cochrane Da-
tabase Syst Rev. 2009;(4):CD005367.
References 12. Cooper MS, Stewart PM. Corticosteroid insuffi-
ciency in acutely ill patients. N Engl J Med. 2003;
1. Lesperance R, Lehman R, Lesperance K, Cronk D, 348(8):727734.
Martin M. Early postoperative fever and the 13. Payen JF, Dupuis C, Trouve-Buisson T, et al.
routine fever work-up: results of a prospective Corticosteroid after etomidate in critically ill
study. J Surg Res. 2011;171(1):245250. patients: a randomized controlled trial. Crit Care
2. Larach MG, Gronert GA, Allen GC, Brandom BW, Med. 2012;40(1):2935.
Lehman EB. Clinical presentation, treatment, and 14. Annane D, Maxime V, Ibrahim F, Alvarez JC, Abe
complications of malignant hyperthermia in E, Boudou P. Diagnosis of adrenal insufficiency in
North America from 1987 to 2006. Anesth Analg. severe sepsis and septic shock. Am J Respir Crit
2011;110(2):498507. Care Med. 2006;174(12):13191326.
3. Clarke DE, Kimelman J, Raffin TA. The evaluation 15. Cohen J, Ward G, Prins J, Jones M, Venkatesh B.
of fever in the intensive care unit. Chest. 1991; Variability of cortisol assays can confound the
100(1):213220. diagnosis of adrenal insufficiency in the critically
4. Arnaoutoglou E, Kouvelos G, Milionis H, et al. ill population. Intensive Care Med. 2006;32(11):
Post-implantation syndrome following endovas- 19011905.
cular abdominal aortic aneurysm repair: prelim- 16. Blot S, De Waele JJ. Critical issues in the clinical
inary data. Interact Cardiovasc Thorac Surg. 2011; management of complicated intra-abdominal in-
12(4):609614. fections. Drugs. 2005;65(12):16111620.
5. Velazquez OC, Carpenter JP, Baum RA, et al. 17. Cheatham ML, Malbrain ML, Kirkpatrick A, et al.
Perigraft air, fever, and leukocytosis after endo- Results from the International Conference of
vascular repair of abdominal aortic aneurysms. experts on intra-abdominal hypertension and
Am J Surg. 1999;178(3):185189. abdominal compartment syndrome. II. Recom-
6. Mavros MN, Velmahos GC, Falagas ME. Atelec- mendations. Intensive Care Med. 2007;33(6):
tasis as a cause of postoperative fever: where is 951962.
the clinical evidence? Chest. 2011;140(2):418424. 18. Cheatham ML, Safcsak K. Percutaneous catheter
7. Jain RK, Antonio BL, Bowton DL, Houle TT, decompression in the treatment of elevated intra-
Macgregor DA. Variability in central venous abdominal pressure. Chest. 2011;140(6):14281435.
pressure measurements and the potential impact 19. Naidech AM. Intracranial hemorrhage. Am J
on fluid management. Shock. 2010;33(3):253257. Respir Crit Care Med. 2011;184(9):9981006.
8. Jammer I, Ulvik A, Erichsen C, Lodemel O, 20. Lukovits TG, Goddeau RP Jr. Critical care of
Ostgaard G. Does central venous oxygen satura- patients with acute ischemic and hemorrhagic
tion-directed fluid therapy affect postoperative stroke: update on recent evidence and interna-
morbidity after colorectal surgery? A randomized tional guidelines. Chest. 2011;139(3):694700.
assessor-blinded controlled trial. Anesthesiology. 21. Kamel H, Navi B, Nakagawa K, Hemphill JC, Ko
2010;113(5):10721080. NU. Hypertonic saline versus mannitol for the
9. Futier E, Constantin JM, Petit A, et al. Conserva- treatment of elevated intracranial pressure: a
tive vs restrictive individualized goal-directed meta-analysis of randomized clinical trials. Crit
fluid replacement strategy in major abdominal Care Med. 2011;39(3):554559.

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Care Medicine Board Review:on21st
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Edition 19
22. Adams HP Jr., Del Zoppo G, Alberts MJ et al. use of a novel pressor agent. J Thorac Cardiovasc
Guidelines for the early management of adults Surg. 1998;116(6):973980.
with ischemic stroke. Stroke. 2007;38(5):16551711. 28. Mehta RH, Sheng S, OBrien SM, et al. Reopera-
23. CRASH Trial Collaborators. Final results of MRC tion for bleeding in patients undergoing coronary
CRASH, a randomised placebo-controlled trial of artery bypass surgery. Circ Cardiovasc Qual Out-
intravenous corticosteroids in adults with head comes. 2009;2(6):583590.
injuryoutcomes at 6 months. Lancet. 2005; 29. Jones HU, Muhlestein JB, Jones KW, et al. Early
365(9475):19571959. postoperative use of unfractionated heparin or
24. Hensen J, Henig A, Fahlbusch R, Meyer M, enoxaparin is associated with increased surgical
Boehnert M, Buchfelder M. Prevalence, predictors re-exploration for bleeding. Ann Thorac Surg. 2005;
and patterns of postoperative polyuria and 80(2):518522.
hyponatraemia in the immediate course after 30. Gould MK, Garcia DA, Wren SM, et al. Prevention
transsphenoidal surgery for pituitary adenomas. of VTE in nonorthopedic surgical patients. Chest.
Clin Endocrinol (Oxf ). 1999;50(4):431439. 2012;141(suppl 2):e227Se277S.
25. Sagi HC, Beutler W, Carroll E, Connolly PJ. 31. Mitchell LB. Canadian Cardiovascular Society
Airway complications associated with surgery atrial fibrillation guidelines 2010: prevention and
on the anterior cervical spine. Spine. 2002;27(9): treatment of atrial fibrillation following cardiac
949953. surgery. Can J Cardiol. 2011;27(1):9197.
26. Shakespeare WA, Lanier WL, Perkins WJ, Paster- 32. Douketis JD, Spyropoulos AC, Spencer FA, et al.
nak JJ. Airway management in patients who Perioperative management of antithrombotic ther-
develop neck hematomas after carotid endarter- apy. Chest. 2012;141(suppl 2):e326Se350S.
ectomy. Anesth Analg. 2010;110(2):588593. 33. Eisenberg MJ, Richard PR, Libersan D, Filion KB.
27. Argenziano M, Chen JM, Choudhri AF, et al. Safety of short-term discontinuation of antiplate-
Management of vasodilatory shock after cardiac let therapy in patients with drug-eluting stents.
surgery: identification of predisposing factors and Circulation. 2009;119(12):16341642.

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Chapter 3. Mechanical Ventilation
Gregory A. Schmidt, MD, FCCP

Objectives: desired (eg, to strengthen or improve the


 Review modes.
coordination of the respiratory muscles; to assess
 Examine physiology of ventilation. the ability of the patient to sustain the work of
 Discuss the types of respiratory failure. breathing; or to begin spontaneous ventilation). It
 Introduce key ventilation concepts. is important for the intensivist to be explicit
 Review equation of motion.

about whether the respiratory muscles should be
Discuss VILI and VIDD.
 Review autoPEEP. rested or exercised because the details of venti-
 Examine permissive hypercapnia. lation (mode, settings) usually follow logically
 Discuss the ventilator bundle. from this fundamental point. For example, in a
patient in profound shock, the ventilator should
Key words: acute lung injury; airway pressure release be set to fully take over the work of breathing (eg,
ventilation; ARDS; assist-control ventilation; autoPEEP; using volume assist-control) while the flow and
COPD; equation of motion; high-frequency oscillatory
ventilation; inverse ratio ventilation; lung-protective venti- pressure waveforms are examined to determine
lation; mechanical ventilation; noninvasive ventilation; whether this goal has been met.
permissive hypercapnia; pressure assist-control ventilation;
pressure control; pressure-regulated volume control; pres-
sure support; status asthmaticus; synchronized intermittent Using the Ventilator to Control
mandatory ventilation; tidal volume; ventilator bundle Oxygenation
ventilator-induced diaphragm dysfunction; ventilator-in-
duced lung injury; volume assist-control ventilation
The ventilator settings most concerned with
Synopsis: oxygenation are the fractional inspired oxygen
(FIO2) and positive end-expiratory pressure
This chapter offers an approach in which two aspects of
mechanical ventilation, oxygenation (largely determined by (PEEP). Generally, mode, tidal volume, rate,
FIO2 and positive end-expiratory pressure [PEEP]) and and other settings have only very modest effects
ventilation (depending mostly on mode, rate, and tidal on arterial partial pressure for oxygen (PaO2). For
volume or set inspiratory pressure) are considered separately.
example, in the ARDS Network tidal volume
Then the ventilator is used as a probe of the patients
respiratory system mechanical derangements, and ventilator trial, use of 6 vs 12 mL/kg predicted body weight
settings are tailored to the patients mechanical and gas was associated with a small but real decrement in
exchange abnormalities. Modes of ventilation are analyzed the ratio of PaO2 to FIO2 (P/F ratio 156 vs 178).1
and key ventilation concepts of ventilator-induced lung
injury; ventilator-induced diaphragm dysfunction; auto-
PEEP; permissive hypercapnia; and the ventilator bundle Oxygen
are covered.

Oxygen is clearly toxic in high concentration,


likely because of reactive oxygen species effects on
The fundamental purpose of mechanical ventila- many biological systems. The threshold for toxicity
tion is to assist in elimination of carbon dioxide is uncertain, especially in the injured lung. Gener-
and the uptake of adequate oxygen while the ally, FIO2 less than 0.6 is considered nontoxic while
patient is unable to do so or should not be higher fractions are avoided when possible. There
allowed to do so. Such patients fall into two main is some experimental evidence that the injured lung
groups: (1) those in whom full rest of the may be more resistant to oxygen-induced injury.
respiratory muscles is indicated (such as during Given the uncertainties in this area, most clinicians
shock; severe, acute pulmonary derangement; or strive to limit exposure to concentrations in excess
deep sedation or anesthesia), and (2) those in of 0.6 to less than 24 h, using PEEP, diuresis,
whom some degree of respiratory muscle use is positional maneuvers, or inhaled vasodilators.

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PEEP lung inflates, possibly signaling overdistention:
tidal volume or PEEP should be lowered.
Nearly 40 years ago, PEEP was linked to
protection against gross and histologic lung Mean Airway Pressure
injury.2 It has been postulated that PEEP limits
tidal recruitment and derecruitment, thereby In addition to FIO2 and PEEP, the mean
reducing lung inflammation.3,4 Yet PEEP may airway pressure affects recruitment and oxygen-
provoke deleterious effects so that choosing the ation. High-frequency oscillatory ventilation
appropriate level requires balancing benefits and (HFOV), inverse ratio ventilation (IRV), and
costs. One widely used approach is that devised airway pressure release ventilation (APRV) are
by the ARDS Network, in which PEEP and FIO2 various ways to raise mean airway pressure and,
combinations are chosen from a table to achieve thereby, oxygen partial pressures.
oxygenation goals.1 Three clinical trials ad-
dressed the potential role of higher levels of Using the Ventilator to Effect Carbon
PEEP than required for acceptable oxygenation. Dioxide Elimination
Although each failed to demonstrate that higher
PEEP enhances survival, all showed a trend in The arterial partial pressure for carbon
that direction (after adjustment for differences in dioxide (PaCO2) depends on total body carbon
baseline covariates),57 and meta-analyses have dioxide production and alveolar ventilation. The
shown this benefit to be statistically significant.8,9 ventilator can be used to set minute ventilation,
In patients with acute lung injury (ALI) and the sum of alveolar ventilation and dead space
ARDS, lung units collapse largely because of ventilation. Various ventilatory modes control
compressive forces, especially in dependent lung minute ventilation by delivering a tidal volume
zones. One would anticipate PEEP to be effective (directly, as in volume-preset modes, or indirect-
in keeping the lung open when it produces a ly, as in pressure-preset modes). Carbon dioxide
positive transpulmonary pressure. Surprisingly, is also eliminated during HFOV through various
when patients are managed according to the incompletely understood mechanisms.
ARDS Network low PEEP recommendations,
transpulmonary pressure is often negative, de- Modes of Mechanical Ventilation
spite PEEP.10 Raising PEEP to produce a positive
transpulmonary pressure raised oxygenation and Technologic innovations have provided a
compliance and produced a trend toward higher plethora of differing modes by which a patient
survival. Alternative approaches to indivualizing can be mechanically ventilated. Various modes
the level of PEEP include analyzing the pressure- have been developed with the hope of improving
volume curve for evidence of the inflation limb gas exchange, patient comfort, or speed of return
lower inflection point (Pflex), deflation limb to spontaneous ventilation. Aside from minor
upper Pflex, maximal compliance, true inflection subtleties, however, nearly all modes allow full
point of the deflation limb, the degree of rest of the patient, on the one hand, or substantial
hysteresis, or the stress index.11,12 Normally the exercise on the other. Thus, in the great majority
airway opening pressure rises linearly during of patients, choice of mode is mostly a matter of
constant flow, volume-controlled ventilation be- patient or physician preference. Noninvasive
cause respiratory system mechanical properties ventilation should be considered before intuba-
(compliance and resistance) do not vary much tion and ventilation in many patients who are
over the tidal range. If compliance increases hemodynamically stable and do not require an
during tidal inflation (suggesting that lung is artificial airway, especially those with acute-on-
being recruited), the pressure-time display will chronic respiratory failure, postoperative respi-
be convex upward (stress index ,1): more PEEP ratory failure, cardiogenic pulmonary edema, or
is likely to be helpful. If the pressure-time display acute respiratory failure complicating severe
is concave upward, compliance is falling as the immunosuppression.

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The equation of motion relates the pressure at which demonstrated a mortality reduction in the
the airway opening (Pao) to volumes, flows, low-VT group, used VACV and a VT of 6 mL/kg
respiratory system mechanics, and patient effort: predicted body weight.1 Pressure-preset modes
V could make such a lung-protection strategy
Pao VR VI Pmus easier to carry out by dispensing with the need
Crs
to repeatedly determine Pplat and periodically
Where V is volume above functional residual adjust the VT. During use of pressure-preset
capacity; Crs is static compliance of the respira- modes, the patient also has greater control over
tory system; V is inspiratory flow rate; R is inspiratory flow rate, and, therefore, potentially
inspiratory resistance; the V I term relates to increased comfort. Several features of pressure-
acceleration and inertia and is relevant only preset modes have raised concern that lung
during HFOV; and Pmus is the pressure pro- protection cannot be assured. Most importantly,
duced by patient muscular effort. a safe level of maximal alveolar pressure is not
During volume-preset ventilation (and as- known. Moreover, unless the patient is fully
suming a passive patient, where Pmus 0), the passive, the transpulmonary pressure cannot be
plateau airway pressure (Pplat) is determined by controlled using pressure-preset modes and is
the tidal volume (VT) and the static compliance of not even known. A final limitation is that
the respiratory system (Crs): pressure-preset modes do not allow ready
Pplat VT=Crs PEEP determination of the respiratory system mechan-
ical properties.
where PEEP also includes autoPEEP. In the following descriptions, each mode is
Conversely, in pressure-preset modes, a fixed first illustrated for a passive patient, such as
inspiratory pressure (Pinsp) is applied to the following muscle paralysis, then for the more
respiratory system, whatever the resulting VT. common situation in which the patient plays an
However, the VT is predictable (again, assuming active role in ventilation. On some ventilators, VT
a passive patient) when the Crs is known: can be selected by the physician or respiratory
VT Pinsp PEEP 3 Crs therapist, while on others a minute ventilation
and respiratory rate (f) are chosen, secondarily
assuming time for equilibration between Pinsp determining the VT. Similarly, on some machines
and alveolar pressure. Thus, a patient with static an inspiratory flow rate is selected while on
Crs of 50 mL/cm H2O ventilated on volume others flow depends on the ratio of inspiratory
assist-control ventilation (VACV) at a VT of 500 time (TI) to total respiratory cycle time and f, or
mL with no PEEP (or autoPEEP) will have a an inspiratory to expiratory (I:E) ratio and f.
Pplat of about 10 cm H2O while the same patient
ventilated on pressure assist-control ventilation Conventional Modes of Ventilation
(PACV) at 10 cm H2O will have a VT of about 500
mL. Thus, although physicians comfort level Volume Assist-Control Ventilation
with volume-preset and pressure-preset modes
may be very different, the modes can be similar Volume assist-control was found to be the
as they are tied to each other through the most commonly used mode in an international
patients Crs. survey of mechanical ventilation. Among its
A potential advantage of pressure-preset advantages are that it was the mode used in the
ventilation is greater physician control over the ARMA trial demonstrating reduced mortality in
Ppeak (since Ppeak Pinsp) and the peak alve- patients with ALI and ARDS and that respiratory
olar pressure, which could lessen the incidence of mechanics can be measured readily.
ventilator-induced lung injury. However, this Passive Patient: The set parameters of the
same reduction in volutrauma risk should be assist-control mode are the inspiratory flow rate,
attainable during volume-preset ventilation if a frequency (f), and VT. The ventilator delivers f
VT appropriate to the lung derangement is equal breaths per minute, each of VT volume. VT
chosen. Indeed, the ARDS Network ARMA trial, and flow determine the TI, TE, and the I:E ratio.

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Pplat is related to VT, the compliance of the work of breathing by lowering the mandatory
respiratory system, and PEEP, while the differ- breath f, but SIMV has been shown to prolong
ence between Ppeak and Pplat includes contri- weaning.13,14 Although this mode continues to be
butions from flow and inspiratory resistance. used widely, there is little rationale for it, and
Active Patient: The patient has the ability to SIMV is falling out of favor.
trigger extra breaths by exerting an inspiratory
effort exceeding the preset trigger sensitivity, PACV
each at the set VT and flow, and to thereby change
TI, TE, and I:E ratio, and to potentially create or In the passive patient, ventilation is deter-
increase autoPEEP. Typically, each patient will mined by f, the inspiratory pressure increment
display a preferred rate for a given VT and will (Pinsp PEEP), I:E ratio, and the time constant of
trigger all breaths when the controlled ventilator the patients respiratory system. In patients
frequency is set a few breaths/min below the without severe obstruction (ie, time constant not
patients rate; in this way, the control rate serves elevated) given a sufficiently long TI, there is
as an adequate support should the patient stop equilibration between the ventilator-determined
initiating breaths. When high inspiratory effort Pinsp and alveolar pressure (Palv) so that
continues during the ventilator-delivered breath, inspiratory flow ceases. In this situation, VT is
the patient may trigger a second, superimposed highly predictable, based on Pinsp ( Palv) and
(stacked) breath (rarely a third, as well). the mechanical properties of the respiratory
Patient effort can be increased (if the goal is to system (Crs). In the presence of severe obstruction
exercise the patient) by increasing the magnitude or if TI is too short to allow equilibration between
of the trigger or by lowering VT (which increases ventilator and alveoli, VT will fall below that
the rate of assisting). Lowering f at the same VT predicted based on Pinsp and Crs. It is typically
generally has no effect on work of breathing the case during PACV that alveolar and ventilator
when the patient is initiating all breaths. pressures do not equilibrate either at end-inspira-
tion or at end-expiration. Thus the maximal
Synchronized Intermittent Mandatory inspiratory alveolar pressure is generally less than
Ventilation the set inspiratory pressure on the ventilator and
the end-expiratory pressure exceeds the set
In the passive patient, SIMV cannot be expiratory pressure (ie, there is autoPEEP).
distinguished from controlled ventilation in the The active patient can trigger additional
ACV mode. Ventilation is determined by the breaths by reducing the airway opening pressure
mandatory f and VT. However, if the patient is (Pao) below the triggering threshold, raising the
not truly passive, he may perform respiratory I:E ratio. The inspiratory reduction in pleural
work during the mandatory breaths. More to the pressure combines with the ventilator Pinsp to
point of the SIMV mode, he can trigger addition- augment the transpulmonary pressure and the
al breaths by lowering the airway opening VT. This point leads many intensivists to be
pressure below the trigger threshold. If this skeptical regarding the ability of PACV to ensure
triggering effort comes in a brief, defined interval lung-protective tidal volumes in patients with
before the next mandatory breath is due, the ALI and ARDS. Because TI is generally set by the
ventilator will deliver the mandatory breath physician, care must be taken to discern the
ahead of schedule to synchronize with the patients neural TI (from the waveforms display)
patients inspiratory effort. If a breath is initiated and adjust the ventilator accordingly; otherwise,
outside of the synchronization window, VT, flow, additional sedation might be necessary.
and I:E ratio are determined by patient effort and
respiratory system mechanics, not by ventilator Pressure-Support Ventilation (PSV)
settings. The spontaneous breaths tend to be of
small volume and are highly variable from The patient must trigger the ventilator in
breath to breath. The SIMV mode has historically order to activate this mode, so pressure support
been used to gradually augment the patients is not applied to passive patients. Ventilation is

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determined by Pinsp, patient-determined f, ventilation (which PSV does not), this mode
patient effort, and the respiratory mechanics. combination may have value in occasional
Once a breath is triggered, the ventilator patients at high risk for abrupt deterioration in
attempts to maintain Pao at the physician- central drive.
determined Pinsp, using whatever flow is
necessary to achieve this. Eventually flow begins Dual-Control Modes
to fall as a result of either cessation of the
patients inspiratory effort or increasing elastic The sophisticated microprocessors included
recoil of the respiratory system as VT rises. The with modern ventilators allow remarkably com-
ventilator will maintain a constant Pinsp until plex modes of ventilation. These modes typically
inspiratory flow falls an arbitrary amount (eg, to try to meld the best features of volume-preset
25% of initial flow) or below an absolute flow and pressure-preset modes. Some cause a switch
rate. Because patients respiratory system time- of modes between breaths (eg, pressure-regulat-
constants vary widely (so that the time for flow ed volume control [PRVC]; volume support
to fall to 25% varies widely), many patients have [VSV]) or within a breath (eg, volume-assured
to work actively to turn off the inspiratory pressure support [VAPS]). In general, these
pressure, raising the work of breathing. Some modes are complex, and their effects may vary
ventilators allow the intensivist to adjust the greatly depending on the details of the patients
threshold for turning off the expiratory flow, effort. None has been shown to be safer or more
allowing the ventilator to be tailored to the useful than more conventional modes. The
respiratory mechanics. Especially in patients greatest problem with such newer modes is that
with exacerbations of COPD, a threshold well they are very complex, the algorithm describing
above 50% is often necessary to minimize this their function is not usually understood by
unintended expiratory work. During PSV, the practitioners, and they change during a breath,
work of breathing can be increased by lowering or from breath to breath, depending on patient
Pinsp or making the trigger less sensitive, and effort, sometimes in ways that can provoke
can inadvertently increase if respiratory system unanticipated effects.
mechanics change, despite no change in ventila-
tor settings. Respiratory system mechanical PRVC
parameters cannot be determined readily on this
mode because the ventilator and patient contri- This is a pressure-preset mode with a set TI
butions to VT and flow are not represented by (ie, it is time-cycled) in which the ventilator
Pao; accordingly, these important measurements compares the VT with a physician-set tidal
of Pplat, Ppeak Pplat, and autoPEEP are volume and automatically and gradually adjusts
measured during a brief, daily switch from PI of subsequent breaths to deliver the desired
PSV to volume-preset ventilation. A potential VT. A downside of PRVC is that as patient effort
advantage of PSV is improved patient comfort increases, the ventilator reduces support. Propo-
and, for patients with very high drive, reduced nents argue that this mode provides the benefits
work of breathing compared with volume-preset of pressure-preset modes while at the same time
modes. guaranteeing VT. Whether this guarantee makes
the mode better or worse for the patient is
Mixed Modes debated, but this is one way to provide a lung-
protective tidal volume using a pressure-preset
Some ventilators allow combinations of mode.
modes, most commonly SIMV plus PSV. There
is little reason to use such a hybrid mode, VSV
although some physicians use the SIMV as a
means to add sighs to PSV, an option not Volume support is a pressure-preset mode in
otherwise generally available. Because SIMV which PI is automatically varied to gradually
plus PSV guarantees some backup minute bring VT in line with the desired VT over several

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breaths, differing from PRVC in that TI is not set The first step is to seek signs of inspiratory
but, rather, depends on patient effort as in PSV. It effort in the pressure tracing. In volume-preset
is unknown whether this mode speeds or modes, the signs of persistent effort include the
impedes weaning. presence of triggering, concavity during inspira-
tion, and a variable peak airway opening pressure
VAPS (Ppeak). When the goal of ventilation is to rest the
respiratory muscles, ventilator adjustments, psy-
This mode begins as PSV but, if a desired VT chological measures, and pharmacologic sedation
is not met, the ventilator switches to VACV all may be effective. Ventilator strategies to reduce
within the same breath in order to guarantee VT. the patients work of breathing include increasing
As with many dual-control modes, the physician the minute ventilation to reduce PCO2 (although
delegates decision-making to the ventilator. this may run counter to other goals of ventilation,
Complex adjustments and their potentially det- especially in patients with ARDS or severe
rimental effects on the patient may come into obstruction), increasing the inspiratory flow rate,
play at any time of day or night, depending on and changing the mode to pressure-preset ventila-
changes in mechanical properties of the respira- tion (PSV or PACV). Therapeutic paralysis is
tory system or changes in the patients level of required to achieve ventilatory goals only occa-
consciousness, comfort, or neuromuscular com- sionally, but it is interesting that 48 h of cis-
petence. atracurium for the sickest patients with ARDS
(P/F , 150) reduces lung inflammation, overt
Choosing Mode and Settings barotrauma, and mortality.15
The next step is to determine whether the
If full rest of the respiratory muscles is patient has significant airflow obstruction. This
desired, it is incumbent on the physician to can be inferred by inserting a brief end-inspiratory
ensure that this is indeed achieved (although see pause, then determining the difference between
ventilator-induced diaphragm dysfunction be- Ppeak and plateau airway pressure (Pplat), as long
low). Although some patients are fully passive as a constant inspiratory flow (square wave) is
while being ventilated (those with deep sedation used. Alternatively, one can examine the expira-
or therapeutic paralysis, some forms of coma, tory flow waveform, seeking low flow and
metabolic alkalosis, sleep-disordered breathing), prolonged expiration, signs that are present
most patients will make active respiratory efforts, regardless of the mode of ventilation (VACV,
even on volume assist-control ventilation SIMV, PSV, PACV). Bronchodilator therapy can
(VACV), at times performing extraordinary be assessed by noting whether expiratory flow
amounts of work. Unintended patient effort can increases, the expiratory time (TE) shortens, or
be difficult to recognize but, aside from obvious there is a reduction in Ppeak, Pplat, or autoPEEP.
patient effort, may be signaled by an inspiratory Finally, one should ensure that the patient
fall in intrathoracic pressure (as noted on a and ventilator are synchronized, that is, that each
central venous or pulmonary artery pressure attempt by the patient to trigger the ventilator
tracing, or with an esophageal balloon) or by generates a breath. The most common situation
triggering of the ventilator. Recognizing patient in which the patient fails to trigger breaths occurs
effort has been greatly aided by the provision of in severe obstruction when autoPEEP is present.
real-time displays of flow and pressure wave- This is recognized at the bedside when the
forms. Using waveforms, it is easiest to gather patient makes obvious efforts that fail to produce
information regarding the patient-ventilator in- a breath. Using waveforms, these ineffective
teraction when patients are ventilated with a efforts cause a temporary slowing of expiratory
volume-preset mode [VACV or synchronized flow, sometimes halting it completely.
intermittent mandatory ventilation (SIMV)]. Still, Full rest of the respiratory muscles has an
some useful information can be gleaned from adverse consequence: active disuse atrophy,
waveforms during pressure-preset ventilation termed ventilator-induced diaphragm dysfunc-
(PSV and PACV). tion (VIDD). Within hours of full respiratory

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muscle rest, enhanced muscle proteolysis can be known whether APRV can deliver lung-protec-
detected and diaphragm muscle fibers atrophy.16 tive ventilation, so this mode is not a good choice
Active diaphragm contraction is able to reduce in patients with ALI or ARDS, although it is often
the risk of VIDD, suggesting that most patients selected as a rescue mode when oxygenation
should be ventilated in a way to preserve some cannot be maintained with usual therapy. Wheth-
active effort. VIDD can be sufficiently severe as to er this mode provides any benefit over modern
impede extubation as the patient recovers from low-VT ventilation remains to be shown.
critical illness.
PAV
Triggered Sensitivity
PAV is intended only for spontaneously
In the assist-control, SIMV, and pressure- breathing patients. The goal of this novel mode
support modes, the patient must lower the Pao is to attempt to normalize the relationship
below a preset threshold in order to trigger the between patient effort and the resulting ventila-
ventilator, or divert some flow from the ventilator tory consequences.17 The ventilator adjusts Pinsp
circuit (flow-triggering). There is no significant in proportion to patient effort both throughout
difference in the work required to trigger any given breath and from breath to breath. This
between pressure-triggered and flow-triggered allows the patient to modulate his breathing
settings. When autoPEEP is present the patient pattern and total ventilation. This is implemented
must lower Palv by the autoPEEP amount to by monitoring instantaneous flow and volume (V)
have any impact on Pao or divert flow. This can of gas from the ventilator to the patient and
dramatically increase the required effort for varying the Pinsp as follows:
breath initiation, a problem that cannot be solved Pinsp f1 3 V f2 3 flow
by adjusting the sensitivity or type of triggering.
where f1 and f2 are selectable functions of volume
Unconventional Ventilatory Modes (elastic assist) and flow (resistive assist), values for
which can be estimated from the patients respi-
IRV ratory mechanics. Potential advantages of this
method are greater patient comfort, lower Ppeak,
IRV is defined as a mode in which the I:E and enhancement of the patients reflex and
ratio is .1. Compared with conventional modes behavioral respiratory control mechanisms.
of ventilation, lung oxygen exchange is often
improved with IRV, owing to increased mean HFOV
alveolar pressure and volume consequent to the
longer time above functional residual capacity or Several modes of ventilation have in common
as a result of creation of autoPEEP. Delivering the use of VT smaller than the dead space
IRV using PACV and VACV generally requires volume. Gas exchange does not occur through
heavy sedation with or without muscle paralysis, convection as during conventional ventilation,
leading most practitioners to use APRV when but through bulk flow, Taylor diffusion, molecu-
selecting IRV. lar diffusion, nonconvective mixing, and possibly
other mechanisms. Theoretical benefits of HFOV
APRV include the possibility to keep the lung open
(recruited) while limiting overdistention, since
APRV consists of CPAP, which is intermit- tidal excursions are small. A substantial risk is
tently released to allow a brief expiratory that dynamic hyperinflation is the rule and
interval. Conceptually, this mode is pressure- alveolar pressure is greatly underestimated by
controlled IRV during which the patient is monitoring pressure at the airway opening.
allowed to initiate spontaneous breaths. An HFOV holds promise as the natural extension
advantage over IRV is that patients are more of lowering the VT as a means to prevent
comfortable, requiring less sedation. It is not volutrauma, and there is renewed interest in this

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old technique. In a controlled trial in patients PEEP with externally applied PEEP provides a
with ARDS, HFOV showed no advantage in means by which to lower the work of triggering.
terms of gas exchange or of short-term or long- The second common mechanism for PVA is
term mortality but did appear to be safe, at least failure of the ventilator to detect end inspiration
during the performance of a clinical trial.18 A because the patients subsiding effort is cloaked
nonsignificant trend toward a short-term mortal- by a mask leak. Most pressure-support ventila-
ity benefit for HFOV has been interpreted as a tors terminate inspiration when inspiratory flow
reason to pursue additional clinical studies. It is falls to a preset threshold, often at an arbitrary
worth mentioning, however, that the control arm low value of flow or at a fixed percent of the peak
ventilation strategy was not lung-protective, inspiratory flow. Mask leaks prevent the flow
potentially biasing the study in favor of HFOV. from falling to this threshold, so the ventilator
fails to switch off the inspiratory pressure even
Noninvasive Ventilation while the patient is making active expiratory
efforts. This serves to increase patient discomfort
Mechanical ventilation for acute respiratory and the work of breathing. Ventilators designed
failure carries a high morbidity and mortality for NIV are very leak tolerant as are some
caused, in part, by violation of the glottis by the newer ICU ventilators redesigned with NIV in
endotracheal tube. In patients with acute-on- mind. Using other methods for terminating
chronic respiratory failure, numerous studies inspiration, such as time-cycled pressure-support
have demonstrated that noninvasive ventilation or volume assist-control, can minimize this
(NIV) effectively relieves symptoms, improves problem.
gas exchange, reduces the work of breathing, Either conventional ICU ventilators or one of
lessens complications, shortens the ICU length of many portable bilevel pressure-targeted ventila-
stay, and improves survival.19,20 tors, initially designed for home ventilation, can
Nasal, oronasal, and full facial masks, as well be used. Limitations of portable pressure-target-
as full-head helmets, have been used successful- ed ventilators include the lack of waveform
ly. Nasal masks are especially difficult to use in displays, the inability to deliver a high FIO2
edentulous patients who are unable to control (greater than about 40%; some new machines
mouth leak. Careful attention to mask leaks and allow an FIO2 as high as 1.0), and the potential for
adjusting air flow and pressure-support levels rebreathing of exhaled gas. Whether volume-
are important considerations. Inflatable cuffs, preset ventilation (such as assist-control) or
nasal bridge protection, and the availability of a pressure-preset ventilation is superior for NIV
range of mask sizes to ensure proper fit can remains debated, but nearly all practitioners now
minimize mask complications. The author finds use pressure-support. Both modes have been
it useful to initiate ventilation by briefly holding used successfully, but direct comparisons be-
the mask (already connected to the ventilator) tween modes are few.
onto the patients face, rather than first strapping The author believes the following points will
the mask on and then initiating ventilatory minimize the chances that NIV will fail:
assistance. Sedative medications are occasionally
appropriate and can improve tolerance of NIV, 1. Develop an individual and institutional com-
but they carry some risk of respiratory depres- mitment to NIV.
sion and aspiration. 2. Select patients carefully, excluding those with
Patient-ventilator asynchrony (PVA) de- hemodynamic instability, inadequate airway
scribes a patients breathing efforts that are not protective reflexes, or little prospect of im-
coupled to machine output. During NIV, two provement within the next several days.
mechanisms of PVA are common. The first is 3. Have available a selection of masks to increase
failure of the patient to lower sufficiently the the probability of a good fit.
proximal airway pressure (mask pressure) be- 4. Use the pressure-support mode, beginning
cause of the presence of autoPEEP. As during with modest settings, such as PEEP 3 cm
invasive ventilation, counterbalancing the auto- H 2 O, PSV 3 8 cm H 2 O, and the most

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sensitive trigger, periodically removing the pressure (eg, hypovolemia, venodilating drugs,
mask to allow the patient to sense its effect. decreased sympathetic tone from sedating drugs,
5. Education, reassurance, and modest sedation neuromuscular disease) or a very high ventila-
(when required) may improve tolerance to the tion-related pleural pressure (eg, chest wall
mask and ventilator. restriction, large amounts of PEEP, or obstruction
6. Increase the PEEP to ease the work of causing autoPEEP). If hypotension occurs, intra-
triggering with a goal of (typically) 4 to 6 cm vascular volume should be rapidly expanded
H2O; raise the level of PSV until the patient is while steps are taken to lower the pleural
subjectively improved, the VT is sufficient, and pressure (smaller VT, less minute ventilation).
the rate begins to fall, with a goal of 10 to 15
cm H2O. Patients With Normal Respiratory Mechanics
7. Detect and correct mask leaks by reposition- and Gas Exchange
ing, achieving a better fit, changing the type of
mask, removing nasogastric tubes (gastric Patients with normal lung mechanics and gas
decompression is not recommended during exchange can require mechanical ventilation for
NIV), or adjusting the ventilator to reduce several reasons: (1) because of loss of central drive
peak airway pressure. to breathe (eg, drug overdose or structural injury
8. Pay particular attention in the first hour to to the brainstem); (2) because of neuromuscular
patient-ventilator synchrony, using waveform weakness (eg, high cervical cord injury, acute
displays as a guide. idiopathic myelitis, myasthenia gravis); (3) as an
adjunctive therapy in the treatment of shock; or (4)
to achieve hyperventilation (eg, in the treatment
Management of the Patients Initial of elevated intracranial pressure following head
Ventilator Settings trauma). In patients who do not have acute lung
injury, data are accumulating that using low tidal
Initial ventilator settings depend on the goals volumes (68 mL/kg of predicted body weight)
of ventilation (eg, full respiratory muscle rest vs reduces the risk of developing lung injury.21
partial exercise), the patients respiratory system Soon after the initiation of ventilation, airway
mechanics, and minute ventilation needs. Al- pressure and flow waveforms should be inspect-
though each critically ill patient presents myriad ed for evidence of patient-ventilator dyssyn-
challenges, it is possible to identify five subsets of chrony or undesired patient effort. If the goal of
ventilated patients: (1) the patient with normal ventilation is full rest, the patients drive can
lung mechanics and gas exchange; (2) the patient often be suppressed by increasing the inspiratory
with severe airflow obstruction; (3) the patient flow rate, frequency, or VT; of course, the latter
with acute-on-chronic respiratory failure; (4) the two changes may induce respiratory alkalemia. If
patient with acute hypoxemic respiratory failure, such adjustments do not diminish breathing
and (5) the patient with restrictive lung or chest effort (despite normal blood gases) to an unde-
wall disease. tectable level, sedation may be necessary. If this
In all patients, the initial FIO2 should usually does not abolish inspiratory efforts and full rest
be 0.5 to 1.0 to ensure adequate oxygenation is essential (as in shock), muscle paralysis should
although it can usually be lowered within be considered. A small amount of PEEP (57.5
minutes when guided by pulse oximetry and, cm H2O) is used to prevent atelectasis.
in the appropriate setting, applying PEEP. In the
first minutes following institution of mechanical Patients With Severe Airflow Obstruction
ventilation, the physician should remain alert for
several common problems. These include, most Severe obstruction is seen most commonly in
notably, airway malposition, aspiration, and patients with status asthmaticus but also rarely in
hypotension. Positive-pressure ventilation may those with inhalation injury or central airway
reduce venous return and so cardiac output, lesions, such as tumor or foreign body, that are
especially in patients with a low mean systemic not bypassed with the endotracheal tube. Some

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of these patients may benefit from NIV, but most Patients With Acute-on-Chronic Respiratory
will require invasive ventilation. These patients Failure
are usually extremely anxious and distressed.
Deep sedation should be provided in such Acute-on-chronic respiratory failure is a term
instances, supplemented in some patients by used to describe the exacerbations of chronic
therapeutic paralysis. These interventions help to ventilatory failure, often requiring ICU admis-
reduce oxygen consumption (and hence carbon sion, usually occurring in patients with COPD.
dioxide production) to lower airway pressures Unlike patients with status asthmaticus, patients
and to reduce the risk of self-extubation. in this population tend to have relatively smaller
Because the gas exchange abnormalities of increases in inspiratory resistance, their expira-
airflow obstruction are largely limited to ventila- tory flow limitation arising in equal amount from
tion-perfusion mismatch, an FIO2 of 0.5 suffices in loss of elastic recoil. As a consequence, in the
the vast majority of patients. The primary patient with COPD and minimally reversible
principle behind ventilation settings is to limit airway disease, peak airway pressures on the
minute ventilation to reduce the consequences of ventilator tend not to be extraordinarily high, yet
dynamic hyperinflation.22 An inspiratory flow of autoPEEP and its consequences are common. At
60 L/min is recommended, and higher flow rates the time of intubation, hypoperfusion is com-
do little to increase TE. For example, if the VT is mon, as manifested by tachycardia and relative
500, the respiratory rate is 15, and the flow is 60 hypotension, and typically responds to briefly
L/min, the TE is 3.5 s. Raising flow (dramatically) ceasing ventilation combined with fluid loading.
to 120 L/min increases the expiratory time to only Many such patients can be ventilated effec-
3.75 s, a trivial improvement. In contrast, a small tively with NIV as described above. For those
reduction in respiratory rate to 14/min increases who require intubation, the goals of rest and
the TE to 3.8 s. This example serves to emphasize appropriate hypoventilation can usually be
not only the relative lack of benefit of raising the achieved with initial ventilator settings of a VT
flow rate but also the importance of minimizing of 5 to 7 mL/kg and a respiratory rate of 20 to 24
minute ventilation when the goal is to reduce breaths/min, with a VACV mode set on minimal
autoPEEP. Some patients who remain agitated sensitivity. Because gas exchange abnormalities
during ACV can be made more comfortable by are primarily those of ventilation-perfusion mis-
using PSV (or PACV) with a total inspiratory match, supplemental oxygen in the range of an
pressure of around 30 cm H2O. Finally, if the FIO2 of 0.4 should achieve better than 90%
patient is triggering the ventilator, some PEEP saturation of arterial hemoglobin. Daily sponta-
should be added to reduce the work of trigger- neous breathing trials (SBT) help identify the
ing.23 Although this occasionally compounds the earliest opportunity to extubate. Also, there may
dynamic hyperinflation, potentially compromis- be advantage in extubating to NIV, even after
ing cardiac output, usually autoPEEP increases failing an SBT.
little as long as PEEP is not set higher than about
85% of the autoPEEP. The goals are (1) to Patients With Acute Hypoxemic Respiratory
minimize alveolar overdistention (Pplat , 30) Failure
and (2) to minimize dynamic hyperinflation
(autoPEEP , 15 cm H2O or end-inspiratory lung Acute hypoxemic respiratory failure is
volume , 20 mL/kg), a strategy that largely caused by alveolar filling with blood, pus, or
prevents barotrauma. Reducing minute ventila- edema, the end results of which are impaired
tion to achieve these goals generally causes the lung mechanics and gas exchange. The gas
PCO2 to rise above 40 mm Hg, often to 70 mm Hg exchange impairment results from intrapulmo-
or higher. Although this requires sedation, such nary shunt that is largely refractory to oxygen
permissive hypercapnia is tolerated quite well, therapy. In ARDS, the significantly reduced
except in patients with increased intracranial functional residual capacity arising from alveolar
pressure and perhaps in those with ventricular flooding and collapse leaves many fewer alveoli
dysfunction or critical pulmonary hypertension.24 to accept the VT, making the lung appear stiff and

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dramatically increasing the work of breathing. chest wall (including the abdomen), the large
The ARDS lung should be viewed as a small ventilation-induced rise in pleural pressure has
lung, however, rather than a stiff lung. In line the potential to compromise cardiac output. This
with this current conception of ARDS, it is now in turn will lower the mixed venous PO2 and, in
clearly established that excessive distention of the setting of ventilation/perfusion mismatch or
the ARDS lung compounds lung injury (ventila- shunt, the PaO2 as well. If the physician responds
tor-induced lung injury) and may induce sys- to this falling PaO2 by augmenting PEEP or
temic inflammation.1,25 Ventilatory strategies increasing the minute ventilation, further circu-
have evolved markedly in the past decade, latory compromise ensues. A potentially cata-
changing clinical practice and generating tre- strophic cycle of worsening gas exchange,
mendous excitement. increasing ventilator settings, and progressive
The goals of ventilation are to reduce shunt, shock is begun. This circumstance must be
avoid toxic concentrations of oxygen, and choose recognized because the treatment is to reduce
ventilator settings that do not amplify lung dead space (eg, by lowering minute ventilation
damage. The initial FIO2 should be 1.0 in view of or correcting hypovolemia).
the typically extreme hypoxemia. PEEP is indi-
cated in patients with diffuse lung lesions but may The Airway During Split-Lung
not be helpful in patients with focal infiltrates, Ventilation
such as lobar pneumonia. In patients with ARDS,
higher levels of PEEP than required for oxygen- The lungs may be separated for purposes of
ation may reduce the degree of recruitment- differential ventilation by two major means: (1)
derecruitment, potentially improving outcomes blocking the bronchus of a lobe or whole lung
as discussed above. Recruitment maneuvers have while ventilating with a standard endotracheal
generally applied a sustained inflation pressure tube, or (2) passing a double-lumen tube (DLT).
while the patient is therapeutically paralyzed. For A number of different devices have been used to
example, CPAP of 40 cmH2O for 40 s has often obstruct a bronchus, but experience is largest
been chosen. Although these maneuvers have with the Fogarty embolectomy catheter. DLTs
shown some ability to transiently raise the PO2, carry the advantages of allowing each lung to be
they have not been shown to change clinically ventilated, collapsed, re-expanded, or inspected
meaningful outcomes. The VT should be 6 mL/kg independently.
on ACV; a higher VT is associated with higher Split-lung ventilation is only rarely useful in
mortality. Potentially, PACV could be used as well, the critical care unit, but occasionally its benefits
but the parameters that ensure lung-protective are dramatic. Large bronchopleural fistulas se-
ventilation are not known. In either mode, the verely compromise ventilation and may not
respiratory rate should be set at 24 to 36/min. An respond to HFOV. A DLT will maintain ventila-
occasional consequence of lung-protective venti- tion of the healthy lung while facilitating closure
lation is hypercapnia. This approach of preferring of the bronchopleural fistula. During massive
hypercapnia to alveolar overdistention, termed hemoptysis, lung separation may be lifesaving by
permissive hypercapnia, is very well tolerated. minimizing blood aspiration, maintaining airway
patency, and tamponading the bleeding site
Patients With Restriction of the Lungs or while awaiting definitive therapy. Finally, pa-
Chest Wall tients with focal causes of acute hypoxemic
respiratory failure, such as lobar pneumonia or
A small VT (57 mL/kg) and rapid rate (18 acute total atelectasis, may benefit from differen-
24/min) are especially important to minimize the tial ventilation and application of PEEP.
hemodynamic consequences of positive-pressure
ventilation and to reduce the likelihood of Ventilator Bundle
barotrauma. The FIO2 is usually determined by
the degree of alveolar filling or collapse, if any. Ventilator-associated pneumonia (VAP) is
When the restrictive abnormality involves the costly, may contribute to mortality, and is often

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preventable. Several tactics have been shown to tory distress syndrome: a randomized controlled
reduce the risk of VAP and, when joined together, trial. JAMA. 2008;299(6):637645.
this group is called the ventilator bundle. The 8. Phoenix SI, Paravastu S, Columb M, Vincent JL,
components include elevation of the head of the Nirmalan M. Does a higher positive end expira-
bed to 308 or greater; daily sedative interruption; tory pressure decrease mortality in acute respira-
daily spontaneous breathing trials; deep venous tory distress syndrome? A systematic review and
thrombosis prophylaxis; and preventive measures meta-analysis. Anesthesiology. 2009;110(5):1098
to reduce the risk of GI hemorrhage. 1105.
9. Briel M, Meade M, Mercat A, et al. Higher vs
Nothing to Disclose lower positive end-expiratory pressure in patients
with acute lung injury and acute respiratory
The author has disclosed that no relation- distress syndrome: systematic review and meta-
ships exist with any companies/organizations analysis. JAMA. 2010;303(9):865873.
whose products or services may be discussed in 10. Talmor D, Sarge T, Malhotra A, et al. Mechanical
this chapter. ventilation guided by esophageal pressure in acute
lung injury. N Engl J Med. 2008;359(20):20952104.
References 11. Caramez MP, Kacmarek RM, Helmy M, et al. A
comparison of methods to identify open-lung
1. Ventilation with lower tidal volumes as compared PEEP. Intensive Care Med. 2009;35(4):740747.
with traditional tidal volumes for acute lung 12. Grasso S, Stripoli T, De Michele M, et al. ARDSnet
injury and the acute respiratory distress syn- ventilatory protocol and alveolar hyperinflation:
drome: the Acute Respiratory Distress Syndrome role of positive end-expiratory pressure. Am J
Network. N Engl J Med. 2000;342(18):13011308. Respir Crit Care Med. 2007;176(8):761767.
2. Webb HH, Tierney DF. Experimental pulmonary 13. Brochard L, Rauss A, Benito S, et al. Comparison
edema due to intermittent positive pressure of three methods of gradual withdrawal from
ventilation with high inflation pressures: protec- ventilatory support during weaning from me-
tion by positive end-expiratory pressure. Am Rev chanical ventilation. Am J Respir Crit Care Med.
Respir Dis. 1974;110(5):556565. 1994;150(4):896903.
3. Tremblay L, Valenza F, Ribeiro SP, Slutsky AS. 14. Esteban A, Ala I, Gordo F, et al. Extubation
Injurious ventilatory strategies increase cytokines outcome after spontaneous breathing trials with
and c-fos m-RNA expression in an isolated rat T-tube or pressure support ventilation. Am J Respir
lung model. J Clin Invest. 1997;99(5):944952. Crit Care Med. 1997;156(2 Pt 1):459465.
4. Dreyfuss D, Soler P, Basset G, Saumon G. High 15. Papazian L, Forel J-M, Gacouin A, et al. Neuro-
inflation pressure pulmonary edema: respective muscular blocker in early acute respiratory
effects of high airway pressure, high tidal volume, distress syndrome. N Engl J Med.
and positive end-expiratory pressure. Am Rev 2010;363(12):11071116.
Respir Dis. 1988;137(5):11591164. 16. Hussain SNA, Mofarrahi M, Sigala I, et al.
5. Brower RG, Lanken PN, MacIntyre N, et al. Higher Mechanical ventilation-induced diaphragm dis-
versus lower positive end-expiratory pressures in use in humans triggers autophagy. Am J Respir
patients with the acute respiratory distress syn- Crit Care Med. 2010;182(11):13771386.
drome. N Engl J Med. 2004;351(4):327336. 17. Younes M, Puddy A, Roberts D, et al. Proportional
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acute lung injury and acute respiratory distress 18. Derdak S, Mehta S, Stewart TE, et al. High-
syndrome: a randomized controlled trial. JAMA. frequency oscillatory ventilation for acute respi-
2008;299(6):646655. ratory distress syndrome in adults: a randomized,
7. Meade MO, Cook DJ, Guyatt GH, et al. Ventilation controlled trial. Am J Respir Crit Care Med.
strategy using low tidal volumes, recruitment 2002;166(6):801808.
maneuvers, and high positive end-expiratory 19. Brochard L, Mancebo J, Wysocki M, et al.
pressure for acute lung injury and acute respira- Noninvasive ventilation for acute exacerbations

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of chronic obstructive pulmonary disease. N Engl 23. Ranieri VM, Giuliani R, Cinnella G, et al.
J Med. 1995;333(13):817822. Physiologic effects of positive end-expiratory
20. Kramer N, Meyer TJ, Meharg J, Cece RD, Hill NS. pressure in patients with chronic obstructive
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Rev Respir Dis. 1993;147(1):513.
21. Gajic O, Dara SI, Mendez JL, et al. Ventilator-
24. Feihl F, Perret C. Permissive hypercapnia: how
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permissive should we be? Am J Respir Crit Care
lung injury at the onset of mechanical ventilation.
Med 1994;150(6 Pt 1):17221737.
Crit Care Med. 2004;32(9):18171824.
22. Tuxen DV, Lane S. The effects of ventilatory 25. Ranieri VM, Suter PM, Tortoella C, et al. Effects of
pattern on hyperinflation, airway pressures, and mechanical ventilation on inflammatory media-
circulation in mechanical ventilation of patients tors in patients with acute respiratory distress
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Dis. 1987;136(4):872879. 1999;282(1):5461.

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Notes

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Chapter 4. Hypertensive Emergencies and Urgencies
R. Phillip Dellinger, MD, MSc, FCCP; and Jean-Sebastien Rachoin, MD

Objectives: elevation in BP resulting in end-organ damage


 Be able to recognize a hypertensive emergency. with dire consequences.
 Have insight into characteristics of antihypertensive The nomenclature pertaining to hypertensive
medications that allow matching them to specific types crises has undergone many revisions and the
of hypertensive emergencies.
 Know toxicities and side effects of antihypertensive term malignant hypertension has been replaced
drugs. by two more explicit appellations, hypertensive
emergency and hypertensive urgency (based on
Key words: aortic dissection; hypertensive emergency; the presence or absence of end-organ damage).2
hypertensive encephalopathy; postoperative hypertension; Distinguishing between those two syndromes
stroke has substantial clinical implications and impacts
the goal of BP treatment as to both timing and
Synopsis:
mode of administration of medications.
A hypertensive emergency is defined as hypertension Hypertensive urgency is defined as an
associated with acute organ dysfunction. In the presence of
elevation of BP greater than 179/109 mm Hg.
a hypertensive emergency, the goal BP over the first hour
should be a reduction in mean arterial pressure no greater When accompanied with end-organ dysfunction,
than 20% to 25% (in consideration of the effects of BP it is called hypertensive emergency.2
lowering on the cerebrovascular blood flow autoregulation
curve, which is likely to be shifted to the right in these
patients). Exceptions to the 20% to 25% rule include
Frequency, Risk Factors, and Impact
unclipped or uncoiled aneurismal hemorrhage associated on Mortality
with hypertension and aortic dissection. There are many
drugs used to treat hypertensive emergencies. Intravenous The exact incidence of hypertensive emer-
nicardipine acts primarily as an arterial vasodilator and has a
quick onset of action but a slower offset. Clevidipine is a
gency is unclear, ranging from 1% to 15% in most
newer agent similar to nicardipine but with a quicker offset. studies.35 There does not seem to be any decline
Intravenous labetalol is a combined ab-blocker, and esmolol in its occurrence over the last 40 years.3 On the
is an IV b-blocker, both of potential utility. Sodium other hand, however, the mortality attributable to
nitroprusside has stood the test of time as a reliable agent
for effective treatment for hypertensive emergencies, al- hypertensive emergencies has steadily declined
though there should be some caution as to cyanide toxicity over the same time period from more than 70% to
when exceeding US Food and Drug Administration labeling less than 10% currently.6,7
instructions or in patients with renal insufficiency. Specific The most frequent risk factors for hyperten-
clinical situations that require special considerations for
therapy include hypertensive encephalopathy, acute aortic sive emergency include lack of access to a
dissection, acute ischemic stroke, and intracerebral/sub- primary care physician, poor compliance with
arachnoid hemorrhage. Treatment of catecholamine-induced medications, drug abuse, and obesity.8 Secondary
hypertension is best managed with benzodiazepines along causes of hypertension are not commonly seen
with nicardipine or verapamil. postoperative hypertension is
associated with wound hemorrhage and other complications. but can be considered in young nonobese
patients.

Pathogenesis
Definitions
Two parallel processes synergistically interact
Hypertension is one of the most common chronic and result in hypertensive emergency. The
medical conditions affecting almost one-third of primum mauvens seems to be the rapid elevation
adults in the United States.1 The course of this in BP from various mechanisms (eg, illicit drug
disease can be complicated by abrupt and severe use) that induces both volume contraction (from

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trigger a workup for a secondary cause (cause
other than essential hypertension).11
Once the clinical picture of the patient is
classified as emergency vs urgency, appropriate
therapy can be instituted.

Principles of Treatment of
Hypertensive Urgencies and
Emergencies
In normotensive patients, cerebral blood flow
is maintained constant despite variation in
Figure 1. Cerebral blood flow autoregulation. Reprinted systemic BP by changing the caliber of lumen
with permission from ACCP Critical Care Medicine Board or arterioles. This process of autoregulation can
Review. 20th ed. Northbrook, IL: American College of Chest be sustained between 50 and 150 mm Hg for
Physicians; 2009.
normal patients. Beyond the upper limit, the
increased BP overcomes the protective abilities of
pressure natriuresis) with subsequent generation
vessels that vasodilate, leading to brain hyper-
of vasoconstrictive substances and endothelial
perfusion, cerebral edema, and hypertensive
damage with free oxygen species formation and
encephalopathy.12
thrombotic microangiopathy.
In chronic hypertensive patients, the same
autoregulation curve is shifted to the right, and
Identification of End-Organ Damage brain blood perfusion occurs at higher pres-
sure.13 Additionally, the curve can become a
A complete history, thorough physical exam-
straight line in patients with acute CNS events
ination, and pertinent laboratory and imaging (such as ischemic stroke) or significant athero-
need to be obtained to differentiate between sclerosis (Fig 1).
hypertensive urgency and emergency. Overzealous lowering of BP can lead to organ
Headache, confusion, seizures, or visual hypoperfusion.14,15 Therefore, cautious lowering
disturbances can indicate hypertensive encepha- of BP should be performed, and patients with
lopathy,9 whereas chest pain and shortness of hypertensive emergency are best managed in an
breath can point toward cardiac ischemia or intensive care setting.
aortic dissection. The issues that need to be addressed to guide
The initial evaluation needs to include at least optimal therapy are the BP goal, the timing of
a complete blood count (rule out hemolysis), attainment, mode of administration, and type of
chemistry basic panel (acute renal insufficiency), antihypertensive.
urine analysis, chest radiograph (congestive For hypertensive urgencies, the clinician
heart failure or aortic dissection), and ECG should aim for a progressive lowering of the BP
(cardiac ischemia). Appropriate ordering of CT over 1 to 2 days. In some cases, an even longer
scan of the head or chest can be considered as time period may be appropriate. In the absence
well as cardiac echocardiography, depending on of end-organ damage, a rapid decrease in BP
the circumstances.10 In pregnant patients, tests may cause more harm than good. Oral medica-
for values of a urine protein and creatinine and tions should be used, and the clinician should
blood uric acid need to be ordered. Furthermore, restart the patients regular medications. Addi-
we typically order a urinary drug screen on all tional oral medications can be used to lower as
patients. needed to treat spikes in BP (see section on oral
Plasma renin activity, aldosterone, and meta- medications).
nephrines can also be obtained if a secondary For hypertensive emergencies, the goal BP
cause is suspected. Of note, hypokalemia is not should be a reduction of the mean arterial
an infrequent finding and should not by itself pressure of 20% to 25% within 1 h.16 Afterward,

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Table 1Treatment of Hypertensive Emergencies

Clinical Setting Goal Blood Pressure Timing Preferred Agents Comment

Aortic dissection Systolic BP ,120 or ,20 min Esmolol followed by Adequate b-blockade
normalizing BP nicardipine or should precede initiation
nitroprusside or of vasodilators
labetalol
Acute ischemic Systolic BP ,220 Within 1 h Labetalol, nicardipine Goal systolic BP ,185 in
cerebrovascular patients eligible for
accident thrombolytic therapy
Acute hemorrhagic Systolic BP ,140 Within 1 h Labetalol, nicardipine Reduces hematoma
stroke growth
Hypertensive MAP lower by 20% Within 1 h Labetalol, nicardipine, or Avoid sodium
encephalopathy to 25% nitroprusside nitroprusside
Pregnancy Diastolic BP ,110 Within 1 h if IV hydralazine or Addition of magnesium
preeclampsia labetalol, nicardipine for preeclampsia
(ultimate treatment is
delivery)
Postoperative Systolic BP ,180 Within 1 h Nicardipine or labetalol Treat reversible factors
hypertension first

a more progressive and much slower lowering If a peripheral line is used, it should be rotated
can be done. Patient should be treated in a every 12 h. This medication is contraindicated in
controlled setting with IV antihypertensive with patients with advanced aortic stenosis.19
close monitoring of BP using an arterial line. Oral The initial infusion rate is 5 mg/h with an
medications should be started in conjunction onset of action less than 20 min. It can be titrated
with the parenteral infusion as soon as possible. by increments of 2.5 mg/h up to 30 mg/h.
Unfortunately, there is a paucity of head-to- One study20 of patients admitted through the
head trials and a strong lack of good-quality ED with hypertensive crisis (of which 64% had
studies about superiority of one agent over end-organ damage) randomized subjects to
another in regard to morbidity and mortality either IV nicardipine or IV labetalol. The authors
outcomes.17 When choosing an IV antihyperten- found that at 30 min, patients who received
sive, physicians should take into account the
nicardipine had a higher likelihood of achieving
clinical presentation, patients demographics,
their goal BP compared with those who received
side effects, and route of elimination of the
labetalol.
medication.
Clevidipine
IV Agents
Clevidipine is a third-generation calcium
Nicardipine
channel blocker that was recently approved for
IV nicardipine is a second-generation calcium use in the United States. It is metabolized by ester
channel blocker that acts primarily by arterial hydrolysis, thus is not affected by hepatic or
vasodilation and crosses the blood-brain barrier. renal dysfunction.21 Similar to nicardipine, it
Since it acts mainly on arterioles with small does not decrease cardiac index.
resistance, it does not increase intracranial Its main drawback is that it is prepared as a
pressure and maintains cerebral blood flow.18 It 20% phospholipid emulsion. Therefore, it should
increases cardiac index and coronary blood flow not be administered to patients with abnormal
and is unlikely to induce cardiac ischemia.19 lipid metabolism, and clinicians need to account
The parenteral form of nicardipine has an for the infused calories. Because of the risk for
acidic pH (between 3.7 and 4.7) thus should infection, the vial should be changed 4 h after
preferentially be administered via a central line. puncturing.

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The initial infusion rate is 1 to 2 mg/h with a chronotropic control. It has, however, substantial
very rapid onset of action (less than 5 min) and importance in the treatment of aortic dissection,
short half-life (1 min). It can be titrated by where decreased inotrophy and avoidance of
doubling the rate every 90 s, but caution is tachycardia are important features of treatment.
advised since there are limited data for high It is administered as an infusion with a loading
doses (.21 mg/h) or when used for a prolonged dose 1 mg/kg followed by a drip at 50 lg/kg/
period (72 h). min.
Aronson et al22 analyzed the results from
three prospective open-label parallel studies that Enalaprilat
included 1,512 patient after cardiac surgery. The
authors found a similar impact of clevidipine Enalaprilat is an IV ACE inhibitor that
compared with nicardipine on BP control but exhibits vasodilatory properties by reducing the
better than nitroglycerine or sodium nitroprus- production of angiotensin II. It is administered as
side. In addition, clevidipine had a mortality intermittent IV doses with similar effect at doses
benefit compared with sodium nitroprusside but of 0.625 mg or greater.30
not to the other drugs. It does not reliably reduce BP within 60 min
Clevidipine was also shown to be effective for and can have a peak effect up to 4 h after
treating patients who presented to the ED or the administration that may last up to 24 h. Thus,
ICU with hypertensive crises.23 compared with other medications, it constitutes a
Overall, clevidipine is an attractive but more less attractive option.
expensive option for rapid, tight, and short-term It is contraindicated in the third trimester of
BP control, especially in the postoperative setting. pregnancy. It may be particularly useful in severe
hypertension associated with scleroderma and
Labetalol high levels of circulating angiotensin II.

IV labetalol is a combined a- and b-blocker Sodium Nitroprusside


with a 1:7 ratio.24 Because of this dual property, it
reduces heart rate without decreasing cardiac Sodium nitroprusside (NTP) is a nitric oxide
output. It also does not decrease cerebral or renal donor that induces a potent arteriolar and venous
blood flow and does not increase intracranial vasodilation. Although it quickly lowers BP, some
pressure.25 of its systemic effects are potentially problematic.
It can be administered as intermittent IV Sodium nitroprusside has been reported to
doses starting at 20 mg followed by increments of induce coronary and cerebral steal syndromes as
20 to 80 mg every 10 min or by a constant well as increase intracranial pressure, although
infusion starting at 1 mg/minute to a total dose these are unlikely to be of clinical issue.3133 When
of 300 mg.2628 If the desired BP effect in not combining several studies comparing clevidipine
achieved with a total dose of 300 mg, then an (CLV) with nitroglycerin, sodium nitroprusside,
alternate medication should be initiated. The or nicardipine in patients after cardiac surgery.
anticipated duration of BP control after labetalol there was no difference in the incidence of
loading is 6 to 8 h. myocardial infarction, stroke, or renal dysfunction
It can be used in most hypertensive emer- for CLV-treated patients compared with the other
gency cases. treatment groups. There was also no difference in
mortality rates between the CLV and nitroglycer-
Esmolol ine or CLV and nicardipine. However, mortality
was slightly greater with NTP compared with
Esmolol is an IV b-blocker, being fairly CLV (P .04).22 Sodium nitroprusside also has the
selective with a short half-life (less than 10 min) potential to induce cyanide and thiocyanate
and quick onset of action (1 min).29 In our toxicity, although neither is likely to occur when
experience, it does not constitute a potent following US Food and Drug Administration-
antihypertensive agent and is more useful for recommended dosing. Despite these concerns,

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NTP has been used in thousands of patients with action of 15 min. It can induce a reliable drop in
clinical success, including a vast number of the BP that lasts for 4 to 6 h.36,37 The starting dose
patients with hypertensive encephalopathy with is 6.25 mg.
effective treatment of cerebral edema. In a
controlled study comparing NTP with fenodo- Clonidine
pam, a dopamine-1 antagonist with similar
vasodilator characteristics as NTP, NTP was Clonidine is a central-acting a2 agonist. It
shown to be equally effective and safe. induces a decrease in the sympathetic tone with a
The use of IV NTP requires hemodynamic significant reduction in BP.38,39 It can also cause
monitoring with an arterial line in place. Sodium sedation and is most useful in patients with drug
nitoprusside has the shortest half-life of all the or alcohol withdrawal. Doses start at 0.1 mg/h.39
effective arteriolar vasodilators used to treat A rebound effect has been reported on
hypertensive emergencies, offering a distinct discontinuation. This side effect is worsened
advantage in that regard. with concomitant b-blockade therapy.40

Hydralazine Labetalol
IV hydralazine is a peripheral vasodilator
with less predictable onset of action and magni- The oral form of labetalol has an a- to b-
tude of effect.34 It may induce reflex tachycardia, blocker ratio 1:4 and can be used at doses starting
which could be detrimental in the presence of at 100 to 200 mg/h with good results.41
myocardial ischemia or aortic dissection. It is
thought to be a very effective drug for the Nifedipine
treatment of preeclampsia and eclampsia. It also
has utility in the immediate postop period, as Nifepidine can result in significant hypoten-
patients bridge from nil per os to capability for sion shortly after administration with risk for
oral intake (as does IV bolus metoprolol in this major morbidity and mortality. Its use in a short-
circumstance). acting form for treatment of hypertensive urgen-
cy should be avoided in most circumstances.42 It
Other does have characteristics that may offer advan-
tages in severe preeclampsia associated hyper-
Diuretics and nitroglycerin can be considered tension.
for patients with acute pulmonary edema or
decompensated congestive heart failure with Specific Clinical Situations
very high filling pressures. Nitroglycerin is a
predominantly venous dilator that can decrease Hypertensive Encephalopathy
both preload and cardiac index.
Diuretic administration should be confined to A 52-year-old man had generalized seizures
these cases since most other patients with and a BP of 244/160 mm Hg. The patient
hypertensive crises are volume depleted. received lorazepam IV with the cessation of
Fenoldopam is a peripheral dopamine-1 ago- seizures. He was intubated and mechanically
nist with similar BP-lowering effects as nitroprus- ventilated. A fundus examination revealed pap-
side but without any concerns as to cyanide illedema, supporting the diagnosis of hyperten-
toxicity in the presence of renal insufficiency.35 sive encephalopathy. Clinical manifestations of a
Oral Medications hypertensive encephalopathy-induced increase
in intracranial pressure include headache, nau-
Captopril sea, vomiting, confusion, lethargy, generalized
seizures, and coma. A differential diagnosis of
Captopril is the fastest-acting angiotensin- hypertensive encephalopathy includes severe
converting enzyme inhibitor with an onset of hypertension in association with subarachnoid

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hemorrhage, intracerebral hematoma, or stroke. aimed at overcoming changes in vessel autoreg-
A CT scan may be required to ensure that these ulation.48,49 Precipitous changes in BP can aggra-
entities are absent. In hypertensive encephalop- vate or induce ischemic events.
athy, as well as in most hypertensive emergencies The impact of BP on outcomes in stroke has a
and urgencies, the initial BP therapeutic target is U-shaped curve effect with worse outcomes
to decrease the mean arterial pressure by 15% to present at both low and high pressures.50,51
25%. In an observational study of 304 patients,
Castillo et al52 found that the use of antihyper-
Acute Aortic Dissection tensive medications and a drop of greater
.20mm Hg of BP in the first 24 h were
Aortic dissection is caused by a tear in the significantly associated with adverse outcomes
intima of the aorta and is propagated by pulse (death, neurologic deterioration).
wave. It is diagnosed usually by CT scan imaging If a patient is not considered candidate for
of the aorta with IV contrast or by transesoph- thrombolytic therapy, recent guidelines recom-
ageal echocardiography. It is classified into types mend initiation of antihypertensive treatment
A or B, depending on whether it involves the only when the systolic BP is greater than 220 mm
ascending aorta (type A involves the ascending Hg or diastolic .120 mm Hg. A lower threshold
aorta). The mainstay of management of type A (systolic of 185 and diastolic of 110) is recom-
aortic dissection is surgery coupled with BP mended for patients eligible for reperfusion
control. For type B, however, aggressive BP therapy.53
control is considered equivalent to surgical Nicardipine and labetalol are considered
intervention if vital organ perfusion is not drugs of choice. Sodium nitroprusside is recom-
compromised by dissection-induced obstruction mended as a second-line treatment
of major vessels coming off the aorta.43
Since propagation of the arterial tear is depen- Intracerebral and Subarachnoid
dent mainly on the cardiac pulse wave, therapy is Hemorrhage
aimed at decreasing shear forces while avoiding
tachycardia (but also avoiding bradycardia). In the setting of an intracerebral hemorrhage,
Thus, a combined approach using effective b- marked elevation in BP is thought to put the
blockade followed by a vasodilator is considered patient at risk for hematoma expansion.54 This
the most effective treatment.44 The goal of occurs mainly in the first 24 h, may occur in the
treatment is to achieve a systolic BP of less than absence of significant BP elevation, and is
120 mm Hg using parenteral agents in less than 20 associated with increased mortality.55
min.45 A recent prospective controlled study ran-
Although it is only approved for use in the domized 404 patients into an aggressive BP
perioperative settings, esmolol is considered the treatment goal of 140 mm Hg within 1 h and
b-blocker agent of choice for treatment of aortic subsequently to maintain this target level for the
dissection.26,46 After adequate b-blockade, we next 7 days or a systolic BP of 180 mm Hg. This
usually add IV NTP or nicardipine. Alternatively, study showed that intensive BP control was
IV labetalol can also be used as a single drug.47 associated with less hematoma growth over the
72 h following admission.56,57
Acute Ischemic Stroke Thus, indirect evidence suggests that early
intensive BP control (systolic BP ,140 mm Hg
Soon after an acute ischemic cerebral-vascu- within 1 h) could improve outcomes in patient
lar event, blood vessels surrounding the affected with intracranial hemorrhage.
area lose their capacity to autoregulate and Hypertension is seen in about one-third of
maintain a constant blood flow. Perfusion of the patients with subarachnoid hemorrhage.58 There
affected and surrounding area will depend is a general agreement that BP should be lowered
mainly on pressure gradient. BP elevation should to normal prior to the coiling or clipping of the
therefore be viewed as a physiologic response aneurysm and that afterward a higher BP not

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only is more tolerated but also can potentially comorbid conditions) and types of procedure
have beneficial effects.59 (vascular or intracranial). In some situations,
maintaining adequate pressure can be crucial
Pregnancy for organ perfusion (such as in thoracic aneu-
rysm repair). In the specific setting of cardiotho-
Hypertension can precede, occur, or compli- racic surgery, treatment should be initiated when
cate pregnancy and is defined as an elevation of BP reaches 140/90 mm Hg or with a mean
BP .140/90 mm Hg.60 arterial pressure of 105.66
The treatment of hypertension in the preg- When facing significant elevations of BP in
nant patient needs to balance the potential the postoperative setting, we usually start by
adverse effects of BP in the mother with the identifying and correcting reversible factors and
decrease in placental perfusion. The threshold for then discuss goals and timing of BP control with
treatment is not clear, and tight BP control has the operating surgeon.
been shown to decrease only the need for Most postoperative blood hypertension lasts
emergent hospitalization, not the incidence of less than 6 h,68 and good pressure control can be
either preeclampsia or eclampsia.61 performed using nicardipine or labetalol, de-
There was no BP difference between nicardi- pending on the clinical setting.47
pine and labetalol and no hypotensive episodes
in a study that randomized 60 pregnant patients Hypertensive Crisis With High-
with hypertensive crises to one of the two Pressure Pulmonary Edema
treatments.62
Guidelines recommend treatment at a dia- Clinical features of a severe hypertension-
stolic .105 mm Hg or in the presence of end- induced rise in left ventricular (LV) end-diastolic
organ damage, and IV hydralazine is considered pressure with associated high pulmonary capil-
the drug of choice for hypertensive crisis.60 lary pressure and pulmonary edema include
Patients with preeclampsia also need to receive severe hypoxemia, CO2 retention, pink frothy
intravenous magnesium sulfate. sputum, and pulmonary edema seen on a chest
radiograph. The typical patient will have chronic
Catecholamine-Induced Hypertension LV hypertrophy with diastolic function and
normal or increased ejection fraction. Initial
Most of the time, this is seen in the setting of therapy targets any intervention that lowers the
cocaine abuse or clonidine withdrawal. In pa- LV end-diastolic pressure. This includes an
tients taking cocaine, b-blockers and even com- increase in venous capacitance, a decrease in
bined a- and b-blockers (labetalol) should likely arteriolar resistance, and increasing compliance
be avoided because of a concern of an unopposed (softening) of the LV. Diuresis is an effective
a effect on BP.63 Elevated BP should be managed therapy, although studies have demonstrated
with benzodiazepines along with nicardipine or that most patients with this diagnosis do not
verapamil.64,65 have increased intravascular blood volume;
therefore, vasodilatation is the most effective
Postoperative Hypertension therapy. The use of diuretics, although effective
in abating pulmonary edema, may leave the
The incidence of postoperative hypertension patients intravascular volume depleted with
is hard to quantify since there is a lack of a prerenal azotemia. Since diastolic function is
consensual definition.66 Abrupt elevation of sys- often present, therapy with b-blockers is also
temic pressure is not unusual after surgery and very effective. Labetalol may also be useful as a
can be due to pain, increased sympathetic tone,67 combination a-/b-blocker. Acute ischemia, asso-
or rapid fluid shifts and may be a short-lived ciated with hypertension, may occur during
event that will not lead to adverse consequences. weaning from mechanical ventilation and also
Treatment threshold should be individual- may produce an increase in BP, an associated rise
ized to patient characteristics (risk of bleeding, in LV end-diastolic pressure, and pulmonary

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edema as a cause of weaning failure. This 9. Hickler RB. Hypertensive emergency: a useful
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Dunbar L, Peacock, WF. Clevidipine, an intrave- 35. Reisin E, Huth MM, Nguyen BP, Weed SG,
nous dihydropyridine calcium channel blocker, is Gonzalez FM. Intravenous fenoldopam versus
safe and effective for the treatment of patients sodium nitroprusside in patients with severe
with acute severe hypertension. Ann Emerg Med. hypertension. Hypertension. 1990;15(2 suppl):
2009;53(3):329338. I59I62.
24. Lund-Johansen P. Pharmacology of combined 36. Angeli P, Chiesa M, Caregaro L, et al. Comparison
alpha-beta-blockade: II. Haemodynamic effects of sublingual captopril and nifedipine in imme-
of labetalol. Drugs. 1984;28(suppl 2):3550. diate treatment of hypertensive emergencies: a
randomized, single-blind clinical trial. Arch Intern
25. Olsen KS, Svendsen LB, Larsen FS, Paulson OB.
Med. 1991;151(4):678682.
Effect of labetalol on cerebral blood flow, oxygen
37. Barry DI. Cerebrovascular aspects of antihyper-
metabolism and autoregulation in healthy hu-
tensive treatment. Am J Cardiol. 1989;63(6):
mans. Br J Anaesth. 1995;75(1):5154.
14C18C.
26. Haas AR, Marik PE: Current diagnosis and
38. Jaker M, Atkin S, Soto M, Schmid G, Brosch F.
management of hypertensive emergency. Semin
Oral nifedipine vs oral clonidine in the treatment
Dial. 2006;19(6):502512.
of urgent hypertension. Arch Intern Med. 1989;
27. Huey J, Thomas JP, Hendricks DR, Wehmeyer AE,
149(2):260265.
Johns LJ, MacCosbe PE. Clinical evaluation of
39. Houston MC. Treatment of hypertensive emer-
intravenous labetalol for the treatment of hyper-
gencies and urgencies with oral clonidine loading
tensive urgency. Am J Hypertens. 1988;1(3 pt 3):
and titration. A review. Arch Intern Med. 1986;
284S289S.
146(3):586589.
28. Leslie JB, Kalayjian RW, Sirgo MA, Plachetka JR,
40. Lilja M, Jounela AJ, Juustila HJ, Paalzow L.
Watkins WD. Intravenous labetalol for treatment
Abrupt and gradual change from clonidine to
of postoperative hypertension. Anesthesiology.
beta blockers in hypertension. Acta Med Scand.
1987;67(3):413416. 1982;211(5):375380.
29. Gray RJ: Managing critically ill patients with 41. McDonald AJ, Yealy DM, Jacobson S. Oral
esmolol: an ultra short-acting beta-adrenergic labetalol versus oral nifedipine in hypertensive
blocker. Chest. 1988;93(2):398403. urgencies in the ED. Am J Emerg Med. 1993;11(5):
30. Hirschl MM, Binder M, Bur A, et al. Clinical 460463.
evaluation of different doses of intravenous 42. Grossman E, Messerli FH, Grodzicki T, Kowey P.
enalaprilat in patients with hypertensive crises. Should a moratorium be placed on sublingual
Arch Intern Med. 1995;155(20):22172223. nifedipine capsules given for hypertensive emer-
31. Immink RV, van den Born BJ, van Montfrans GA, gencies and pseudoemergencies? JAMA. 1996;
Kim YS, Hollmann MW, van Lieshout JJ. Cerebral 276(16):13281331.
hemodynamics during treatment with sodium 43. Estrera AL, Miller CC III, Safi HJ, et al Outcomes
nitroprusside versus labetalol in malignant hy- of medical management of acute type B aortic
pertension. Hypertension. 2008;52(2):236240. dissection. Circulation. 2006;114(1 suppl):I384
32. Cottrell JE, Patel K, Turndorf H, Ransohoff J. I389.
Intracranial pressure changes induced by sodium 44. Khan IA, Nair CK. Clinical, diagnostic, and
nitroprusside in patients with intracranial mass management perspectives of aortic dissection.
lesions. J Neurosurg. 1978;48(3):329331. Chest. 2002;122(1):311328.

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45. Elliott WJ. Clinical features and management of and poor outcome after intracerebral hemorrhage.
selected hypertensive emergencies. J Clin Hyper- Neurology. 2006;66(8):11751181.
tens (Greenwich). 2004;6(10):587592. 56. Anderson CS, Huang Y, Arima H, et al. Effects of
46. Hoshino T, Ohmae M, Sakai A. Spontaneous early intensive blood pressure-lowering treatment
resolution of a dissection of the descending aorta on the growth of hematoma and perihematomal
after medical treatment with a beta blocker and a edema in acute intracerebral hemorrhage: the
calcium antagonist. Br Heart J. 1987;58(1):8284. Intensive Blood Pressure Reduction in Acute
47. Marik PE, Varon J. Hypertensive crises: challenges Cerebral Haemorrhage Trial (INTERACT). Stroke.
and management. Chest. 2007;131(6):19491962. 2010;41(2):307312.
48. Dawson SL, Panerai RB, Potter JF. Serial changes 57. Kazui S, Naritomi H, Yamamoto H, Sawada T,
in static and dynamic cerebral autoregulation Yamaguchi T. Enlargement of spontaneous intra-
after acute ischaemic stroke. Cerebrovasc Dis. cerebral hemorrhage: incidence and time course.
2003;16(1):6975. Stroke. 1996;27(10):17831787.
49. Marshall RS: The functional relevance of cerebral 58. Wartenberg KE, Schmidt JM, Claassen J, et al.
hemodynamics: why blood flow matters to the Impact of medical complications on outcome after
injured and recovering brain. Curr Opin Neurol. subarachnoid hemorrhage. Crit Care Med. 2006;
2004;17(6):705709. 34(3):617623 [quiz 624].
50. Leonardi-Bee J, Bath PM, Phillips SJ, Sandercock 59. Dankbaar JW, Slooter AJ, Rinkel GJ, Schaaf IC.
PA. Blood pressure and clinical outcomes in the Effect of different components of triple-H therapy
International Stroke Trial. Stroke. 2002;33(5): on cerebral perfusion in patients with aneurysmal
13151320. subarachnoid haemorrhage: a systematic review.
51. Stead LG, Gilmore RM, Decker WW, Weaver AL, Crit Care. 2010;14(1):R23.
Brown RD Jr. Initial emergency department blood 60. Report of the National High Blood Pressure
pressure as predictor of survival after acute Education Program Working Group on high
ischemic stroke. Neurology. 2005;65(8):11791183. blood pressure in pregnancy. Am J Obstet Gynecol.
52. Castillo J, Leira R, Garcia MM, Serena J, Blanco M, 2000;183(1):S1S22.
Davalos A. Blood pressure decrease during the 61. von Dadelszen P, Magee LA. Fall in mean arterial
acute phase of ischemic stroke is associated with pressure and fetal growth restriction in pregnancy
brain injury and poor stroke outcome. Stroke. hypertension: an updated metaregression analy-
2004;35(2):520526. sis. J Obstet Gynaecol Can. 2002;24(12):941945.
53. Adams HP Jr., del Zoppo G, Alberts MJ, et al. 62. Elatrous S, Nouira S, Ouanes Besbes L, et al.
Guidelines for the early management of adults Short-term treatment of severe hypertension of
with ischemic stroke: a guideline from the pregnancy: prospective comparison of nicardipine
American Heart Association/American Stroke and labetalol. Intensive Care Med. 2002;28(9):
Association Stroke Council, Clinical Cardiology 12811286.
Council, Cardiovascular Radiology and Interven- 63. Boehrer JD, Moliterno DJ, Willard JE, Hillis LD,
tion Council, and the Atherosclerotic Peripheral Lange RA. Influence of labetalol on cocaine-in-
Vascular Disease and Quality of Care Outcomes in duced coronary vasoconstriction in humans. Am J
Research Interdisciplinary Working Groups: the Med. 1993;94(6):608610.
American Academy of Neurology affirms the 64. Moore NA, Rees G, Sanger G, Awere S. Effect of
value of this guideline as an educational tool for L-type calcium channel modulators on stimulant-
neurologists. Circulation. 2007;115(20):e478e534. induced hyperactivity. Neuropharmacology. 1993;
54. Ohwaki K, Yano E, Nagashima H, Hirata M, 32(7):719720.
Nakagomi T, Tamura A. Blood pressure manage- 65. Negus BH, Willard JE, Hillis LD, et al. Alleviation
ment in acute intracerebral hemorrhage: relationship of cocaine-induced coronary vasoconstriction
between elevated blood pressure and hematoma with intravenous verapamil. Am J Cardiol. 1994;
enlargement. Stroke. 2004;35(6):13641367. 73(7):510513.
55. Davis SM, Broderick J, Hennerici M, et al. 66. Haas CE, LeBlanc JM. Acute postoperative hy-
Hematoma growth is a determinant of mortality pertension: a review of therapeutic options. Am J

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Health Syst Pharm. 2004;61(16):16611673 [quiz surgery: a study of hemodynamic and humoral
16741665]. factors. Am J Cardiol. 1980;46(4):559565.
67. Wallach R, Karp RB, Reves JG, Oparil S, Smith LR, 68. Gal TJ, Cooperman LH. Hypertension in the
James TN. Pathogenesis of paroxysmal hyperten- immediate postoperative period. Br J Anaesth.
sion developing during and after coronary bypass 1975;47(1):7074.

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Chapter 5. Pregnancy and Critical Illness
Mary E. Strek, MD, FCCP

Objectives: will be reviewed with a focus on the diagnosis


 Review normal maternal physiologic adaptations to and treatment of hypoperfused states such as
pregnancy. cardiogenic, hemorrhagic and septic shock, and
 Understand oxygen delivery to and the effects of critical
preeclampsia. Common pulmonary disorders
illness on the fetus.
 Recognize and treat acute cardiovascular disorders and such as asthma and venous thromboembolism
shock in pregnancy. will be reviewed with an emphasis on guideline-
 Diagnose and manage acute pulmonary disease and based care. For all the disorders reviewed in this
causes of acute hypoxemic respiratory failure in preg-
nancy.
chapter, the emphasis is on the changes to
 Review pregnancy-specific disorders such as preeclamp- diagnosis and treatment necessitated by preg-
sia, amniotic fluid embolism and acute fatty liver. nancy.

Key words: critical illness; preeclampsia; pregnancy; shock; Epidemiology


venous thromboembolism

Synopsis: Causes of maternal mortality and admission


Critical illness in pregnancy can be a devastating occur-
to the ICU during pregnancy vary, depending on
rence. The physiologic changes of pregnancy may both the time period and location of data collection. A
mask and worsen the underlying critical illness, and all study using data from the Centers for Disease
interventions must take into account the well-being of the
Control and Prevention shows that in the United
fetus as well as the mother. While it is fortunate that critical
illness in pregnancy is infrequent, most intensivists will States from 1998 to 2005, medical and cardiovas-
have little experience to draw on when caring for these cular conditions accounted for a quarter of
patients. This chapter will review the physiologic changes of maternal deaths.1 Pregnancy-related complica-
pregnancy with an emphasis on those organ systems most
tions such as hemorrhage, hypertensive disor-
affected by critical illness. Cardiac disorders will be
reviewed with a focus on the diagnosis and treatment of ders, and venous thromboembolism were no
hypoperfused states such as cardiogenic, hemorrhagic, and longer the leading causes of maternal death.
septic shock. Preeclampsia, a disease characterized by Mortality was increased in older and African
widespread vascular endothelial dysfunction, has a variable
presentation, as it affects many organ systems. For optimal American patients. Perhaps the most important
maternal and fetal outcomes, early diagnosis and treatment finding was that pregnancy-related mortality is
of preeclampsia is essential. Pulmonary disorders such as higher now (14.5 pregnancy related deaths per
acute asthma exacerbations and venous thromboembolism
100,000 live births) than in the past 20 years. It is
are more common in pregnancy and have guidelines to
direct management. In some cases, critical illness results unclear whether this reflects changes in reporting
from a worsening of underlying disease or the onset of a and coding, an older and more obese maternal
pregnancy related illness. In all cases, understanding the population with chronic cardiopulmonary con-
physiologic changes of pregnancy, knowledge of the most
advanced approach to diagnosis and treatment, and
ditions, or a failure of medical care. In a small
inclusion of the obstetric team in care will result in the study from a university hospital in Argentina,2
optimal outcome for both mother and fetus. the majority of admissions to the ICU were of
obstetric cause (74%) from hypertensive disease
(40%), hemorrhage (16%), and infection (12%).
Critical illness in pregnancy is infrequent; there-
fore, most intensivists have little experience in Physiologic Adaptations and General
caring for these patients. This chapter will review Approach
the physiologic changes of pregnancy with an
emphasis on those organ systems most affected Throughout pregnancy, physiologic changes
by critical illness. Acute cardiovascular disorders occur in multiple organ systems to meet the

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Table 1Cardiopulmonary Adaptations in Normal Pregnancy

Parameter Change Time Course

Blood volume Increases 40% Peaks 34 weeks


Stroke volume Increases Throughout
Heart rate Increases 15 to 20 bpm Peaks 32 to 36 weeks
Cardiac output Increases 30% to 50% Peaks 25 to 32 weeks
Blood pressure Decreases 10% to 20% Nadir 28 weeks
Oxygen consumption Increases 20% to 35% Peaks term
Minute ventilation Increases 20% to 40% Peaks term
Tidal volume Increases 30% to 35% Peaks term
Respiratory rate No change

metabolic demands of the fetus, placenta, and occurs. Tidal volume increases, but respiratory
mother and to prepare the mother for delivery. rate remains unchanged. This hyperventilation
An understanding of these adaptations, especially is offset by renal compensation, which results in
in regard to the cardiac and pulmonary systems, is a mild respiratory alkalosis. The typical blood
essential when evaluating a critically ill gravid gas values of pregnancy are as follows: PO2, 105
patient in order to distinguish normal adaptation mm Hg in the first trimester and .95 mm Hg in
from signs of critical illness in pregnancy (Table 1). the third trimester; PCO2, 28 to 32 mm Hg;
bicarbonate, 18 to 21 mEq/L; and pH, 7.45.
Maternal and Fetal Adaptations Decreased chest wall compliance decreases
functional residual capacity by 20%. A compen-
Numerous cardiovascular changes occur that satory increase in the transverse and anterior-
may result from maternal blood flow through the posterior diameter of the chest increases the
low resistance uteroplacental unit and increased inspiratory capacity so that only a modest
production of hormones such as aldosterone and decrease in TLC occurs. No change is noted in
progesterone.3,4 This decreases systemic vascular FVC, FEV1, or measures of respiratory muscle
resistance and blood pressure. An increase in strength.
circulating blood volume results from both Renal adaptation is directed at both the
increased red blood cell production and plasma increased excretory load from the fetus and
volume. The greater increase in plasma volume increased maternal metabolism. The glomerular
causes a fall in colloid osmotic pressure and filtration rate and urinary volume increase,
hemoglobin. Heart rate, stroke volume, and resulting in a fall in levels of serum creatinine
cardiac output all increase early in pregnancy. (,0.09 mg/mL) and blood urea nitrogen (,15
These cardiac parameters are affected by the mg/dL). Displacement of Gl organs cephalad,
gravid uterus; a significant fall in cardiac output lateral, and posterior occurs. Progesterone relat-
occurs in the supine position in the third ed alteration in smooth muscle relaxation causes
trimester. This awareness allows the clinician to a decreased lower esophageal sphincter tone and
turn the hypotensive patient to the left side, hypomotility of the GI tract. Alkaline phospha-
which moves the gravid uterus off the inferior tase value increases and albumin level decreases
vena cava and aorta, thereby augmenting venous with no change in hepatic enzyme levels.
return and decreasing systemic vascular resis- In caring for the critically ill gravid patient, it
tance. Right ventricular, pulmonary artery, and is important to understand how oxygen is
pulmonary artery wedge pressures are generally delivered and then transferred to the fetus.6
unchanged from prepartum values. Oxygen delivery depends on uterine artery blood
Pulmonary adaptations result from in- flow and maternal oxygen content. Uterine artery
creased progesterone, which increases oxygen blood flow is maximally dilated at baseline and
consumption.5 Minute ventilation rises in excess unable to adapt to stress by local vascular
of the increased carbon dioxide production that adjustment. Conditions that decrease maternal

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against hypoxemia that would be catastrophic by
adult criteria. Fetal oxygenation is maintained
until fetal oxygen content is reduced by more
than 75%. Irreversible fetal brain damage begins
only after 10 min without oxygen.

General Approach to Evaluation and Treatment

As noted above, numerous physiologic ad-


aptations occur during pregnancy (Table 1).
These are important to remember in order to
distinguish normal adaptation from signs of
critical illness and suggest general principles of
ICU management. On examination during preg-
nancy, heart rate is increased, blood pressure
decreased, a third heart sound may be physio-
Figure 1. Maternal-fetal oxygen transfer. Numbers in circles logic, and pedal edema is common. Normal
are partial pressure of oxygen (mm Hg). Reproduced with laboratory values include a mild dilutional
permission from Lapinsky et al.6
anemia and decreased serum albumin value.
cardiac output or uterine artery blood flow will An enlarged cardiac silhouette is seen as preg-
nancy progresses. Assessing the adequacy of
adversely affect oxygen delivery to the fetus.
blood flow may be difficult on examination and
Uterine artery vasoconstriction with decreased
may require a bedside echocardiogram. The
flow results from maternal hypotension, exoge-
initial approach to the critically ill gravid patient
nous or endogenous catecholamines, and mater-
is directed at maximizing oxygen delivery by
nal alkalosis. Uterine contractions also decrease
placing the patient in the left lateral decubitus
uteroplacental perfusion. Once oxygenated blood
position and supplying supplemental oxygen.
is delivered by the uterine artery to the placenta,
Noninvasive positive pressure ventilation for
oxygen transfer occurs by an elegant concurrent
acute respiratory failure has not been studied in
exchange mechanism (Fig 1). The difference in
pregnancy. In the awake patient needing tempo-
oxygen tension between the maternal and fetal
rary assistance, noninvasive positive pressure
circuits results in transfer of oxygen from the ventilation is a reasonable first step, but the
maternal to the fetal circulation. Equilibration is patient must be monitored closely. Theoretical
incomplete with umbilical venous blood going to limitations include pregnancy-related upper air-
the fetus having a lower oxygen tension (PO2, 30 way edema and aspiration. Early intubation and
to 40 mm Hg) than in the uterine vein. After mechanical ventilation is appropriate to maintain
combining with deoxygenated blood in the fetal oxygen delivery to the fetus. The decrease in
inferior vena cava, fetal arterial PO2 is 20 to 25 functional residual capacity, combined with
mm Hg. increased oxygen consumption, makes the preg-
Despite the hypoxic fetal environment, com- nant woman and fetus more vulnerable to
pensatory mechanisms maintain a relatively high hypoxia. This is an important consideration
fetal oxygen content and oxygen delivery and during endotracheal intubation. Fetal well-being
protect the fetus against hypoxic insult. Fetal is best assessed by monitoring the fetal heart rate
hemoglobin concentration is high (15 g/dL) and in conjunction with obstetrics.
has increased affinity for oxygen. Fetal cardiac The placenta is not a barrier for most
output is increased with both ventricles pumping medications, and it must be assumed that drugs
blood to the systemic circulation. In times of given to the mother cross the placenta. The
stress, the fetal circulation preferentially directs exceptions are medications with high molecular
blood flow to fetal heart, brain, and adrenals. weight, such as insulin and heparin. Drug
There is evidence that these mechanisms protect absorption and metabolism are affected by

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Table 2US Food and Drug Administration Pregnancy Risk Classification

Category Definition Comments

A Well-controlled studies fail to demonstrate fetal risk in the Few medications in this category.
first trimester. No evidence of risk in later trimesters.
B Animal reproduction studies fail to demonstrate fetal risk.
No well-controlled studies in pregnant women.
C Animal reproduction studies show adverse fetal effect. No Most medications are in this category. Obtain
well-controlled studies in humans. Potential benefits may additional information from literature to
warrant use in pregnant women despite potential risks. decide on use.
D Evidence of human fetal risk from investigational data, Use only if no other option in life-threatening
marketing experience or studies in humans. Potential situations.
benefits may warrant use in pregnant women despite
potential risks.
X Studies in animals or humans have demonstrated fetal Never use these medications in pregnancy!
abnormalities and/or there is positive evidence of human
fetal risk. Risks in pregnant women clearly outweigh
potential benefits.

increased plasma volume and glomerular filtra- rhage, and sepsis may result in shock. Should a
tion rate and decreased albumin and gastric cardiopulmonary arrest occur, guidelines suggest
motility.7 These pharmacokinetic changes sug- alterations to the performance of cardiopulmo-
gest that medications with multiple daily doses nary resuscitation (Table 4). Preeclampsia is a
may be preferred over once-daily administration. common pregnancy related complication that
While it is imperative to know the US Food and results from endothelial dysfunction with end-
Drug Administration pregnancy risk classifica- organ hypoperfusion. It has a variable and
tion for medications used in the ICU, these sometimes subtle presentation given the many
guidelines do not supplant clinical judgment organs affected.
(Table 2). Most drugs are category C with varying
quality of data to support this classification. Cardiovascular Disease and Cardiogenic Shock
Large long-term prospective trials have not been
performed for most medications, thus; these A wider spectrum of cardiac disease now
guidelines are inadequate as the sole source of results in critical illness in pregnancy. Advanced
information. maternal age; an increasing number of gravidas
with risk factors for ischemic heart disease such
Cardiac Disorders and Hypoperfused as obesity, hypertension and diabetes mellitus;
States and women with congenital heart disease sur-
viving into adulthood likely explain this obser-
Cardiovascular disease is the leading cause of vation.8 Antecedent subclinical heart disease
maternal mortality in the United States.1 The may manifest for the first time as a result of the
physiologic changes of pregnancy, advanced increased cardiovascular demands of pregnancy.
maternal age, and obesity increase the risk of a Preexisting cardiovascular conditions with high
cardiovascular complication. The tremendous adverse event rates for both mother (mortality
increase in blood volume delivered to the uterus .10%) and child include severe pulmonary
and placenta increases the risk of hemorrhage, arterial hypertension (risk of maternal death
especially postpartum. The physiologic and im- 25% to 40%), Eisenmengers syndrome, severe
munologic changes of pregnancy may predispose aortic stenosis and other left-sided obstructive
to certain infections and alter their presentation lesions, severe, symptomatic mitral stenosis and
and severity. The focus below is on the diagnosis regurgitation, and pulmonic stenosis and dilated
and treatment of these hypoperfused states in cardiomyopathy or aortopathy.9 Fetal complica-
pregnancy (Table 3). Cardiac dysfunction, hemor- tions are also increased and include prematurity,

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Table 3Causes of Hypotension in Pregnancy

Clinical Syndrome Common Etiologies

Acute myocardial infarction Coronary artery disease


Coronary artery dissection, vasospasm or thrombosis
Aortic dissection Hormonal and hemodynamic changes of pregnancy
Cardiogenic shock Congenital heart disease
Valvular heart disease
Peripartum cardiomyopathy
Hemorrhagic shock Uterine atony
Retained placenta
Trauma
Right-heart dysfunction Pulmonary hypertension
Amniotic fluid embolism
Pulmonary embolism
Venous air embolism
Septic shock Abortion
Chorioamnionitis
Endometritis
Pyelonephritis
Pneumonia

intrauterine growth retardation, and fetal de- postpartum.11 Risk factors include African Amer-
mise. The incidence of acute myocardial infarc- ican race, advanced maternal age, twin gesta-
tion (AMI) increases three- to fourfold because of tions, anemia, preeclampsia, and gestational
the hyperdynamic and hypercoagulable state hypertension. The typical patient is over the age
noted in pregnancy. The diagnosis is often of 30 years old and peripartum. Patients report
missed. Coronary artery dissection, spasm, and dyspnea, orthopnea, and pedal edema that may
thrombosis are all causes of AMI in pregnancy.10 initially be attributed to the physiologic changes
AMI may occur in all stages of pregnancy and of pregnancy. Echocardiography demonstrates
has been noted in patients as young as 19 years systolic dysfunction. The majority of patients
old. Aortic dissection also occurs most commonly have a gradual recovery of ventricular function.
during the third trimester and should be in the The use of implantable defibrillators may have
differential diagnosis of chest or interscapular decreased mortality. Pulmonary embolism is
pain during pregnancy. noted with increased frequency in these patients.
Peripartum cardiomyopathy develops in the The diagnosis of cardiovascular disease is
last month of pregnancy up to 5 months most often made by a chest radiograph, electro-

Table 4Modifications to Advanced Cardiovascular Life Support in Pregnancy

ABCs Modifications

Airway Insert early to prevent aspiration


Use smaller tracheal tube
Preoxygenation essential
Rapid sequence intubation with cricoid pressure
Breathing Clinical assessment of tracheal tube placement
Less oxygen reserve
Circulation Manual leftward displacement uterus
Chest compressions higher on the sternum
Avoid femoral vein for venous access
Defibrillation Remove fetal or uterine monitors
Decisions Consider pregnancy related causes of arrest
Perform emergency cesarean section within 5 min of arrest if fetus viable

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cardiogram, and echocardiogram. Transesopha- bleeding does not rule out hemorrhage. Postpar-
geal echocardiography and magnetic resonance tum hemorrhage is most common and results
imaging are the most sensitive and specific tests primarily from uterine atony (60% to 70%)
for aortic dissection, although computed tomog- followed by retained placental products (20% to
raphy is more readily available. The diagnosis of 30%) and obstetric trauma (10%).12 Causes of
an AMI may be complicated by the fact that ST- antepartum hemorrhage include ectopic preg-
segment changes can be seen during cesarean nancy, abortion, placenta previa (placenta im-
section and an increase in creatinine kinase may planted below the fetus), or abruption
occur for 24 h after delivery. Troponin levels (separation of placenta before delivery) and
increase marginally and remain below normal trauma from motor vehicle accidents, falls, and
except in patients with preeclampsia therefore assaults. Rare causes of hemorrhage include
may be more reliable for diagnosis of AMI.10 uterine rupture or inversion and disseminated
Cardiac catheterization with percutaneous coro- intravascular coagulation (DIC) from sepsis,
nary intervention with bare metal stents is amniotic fluid embolism, preeclampsia, and fetal
preferred over thrombolytic therapy given the demise.13
increased incidence of coronary artery dissection. Suspected obstetrical hemorrhage requires a
Cardiac drugs best avoided in pregnancy coordinated and fast-acting multidisciplinary
include angiotensin converting enzyme inhibi- approach to care. Ultrasound and careful bedside
tors and receptor antagonists, amiodarone, war- obstetrical examination are helpful in diagnosis.
farin, and spironolactone. Dobutamine is the Resuscitation includes identification and control
preferred vasoactive medication for the treat- of the bleeding source and rapid administration
ment of cardiogenic shock. In severe pulmonary of blood products through large-bore IV access.
hypertension, intravenous prostacyclin has been This is one situation where unmatched type
given without fetal harm. Preliminary studies specific rather than fully cross-matched packed
suggest that prolactin inhibitors, such as bromo- red blood cells may need to be given. Fresh
criptine, may be of benefit in treating peripartum frozen plasma, cryoprecipitate, and platelets are
cardiomyopathy.12 Labor and delivery are high transfused as needed to prevent a dilutional
risk for women with cardiac disease. The optimal coagulopathy and thrombocytopenia. Laboratory
delivery method is assisted vaginal delivery with studies should be sent and reviewed to look for a
epidural anesthesia to control pain. Indications coagulation disorder (DIC). Once DIC is estab-
for cesarean section include obstetric complica- lished, factor replacement and fresh frozen
tions, fetal distress, or inability to tolerate labor plasma are given based on laboratory findings
and delivery. General anesthesia and surgical and bleeding. Obstetrics should be called imme-
delivery may be preferred for hypertrophic diately to evaluate for lacerations, ensure com-
cardiomyopathy, aortic stenosis, or pulmonary plete removal of the placenta, and assist with
hypertension, conditions that place the patient at compression and contraction of the uterus.
risk of decompensation during the increased Uterine atony is treated with bimanual uterine
cardiac demand and large fluid shifts of labor massage, bladder drainage, uterotonic medica-
and delivery. tion, and removal of retained placental prod-
ucts.14 IV oxytocin is given first followed by
Acute Hemorrhage and Hemorrhagic Shock methylergonovine (contraindicated in hyperten-
sive states) or prostaglandin therapy if bleeding
Hemorrhagic shock is a major cause of both persists.15 There may be a role for administration
maternal death and ICU admission (Table 3). of human recombinant activated factor VII; such
When it occurs, the bleeding can be both massive use is off label at present. Case reports attest to its
and swift with major blood loss having occurred effectiveness in controlling life-threatening ob-
before it is clinically apparent at the bedside. In a stetrical hemorrhage after other measures have
setting of increased risk, a mild increase in heart failed. Interventions that may be required to
rate or fall in blood pressure should prompt control bleeding include uterine balloon tampon-
consideration of hemorrhage. Lack of overt ade, arterial embolization of uterine vessels by

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interventional radiology, and surgical uterine indicator of circulating volume, which is gener-
compression sutures or ligation of pelvic arteries. ally unchanged in pregnancy. Bedside echocar-
Hysterectomy is performed if the above mea- diography may aid in assessment of volume
sures fail. status. Computed tomography scan or magnetic
resonance imaging of the pelvis may aid in the
Infection and Septic Shock diagnosis of septic pelvic thrombophlebitis.
Broad-spectrum antibiotics are given, directed
Infections account for 10% of maternal at likely polymicrobial infection. Aminoglyco-
mortality in the United States and up to 25% of sides are toxic to the fetus and should be avoided
ICU admissions in a small study from Argentina.1,2 antepartum. If chorioamnionitis is present, the
Decreased cell-mediated immunity predisposes to fetus must be delivered. Heparin, in addition to
disseminated infections with Listeria monocytogenes, antibiotics, is recommended to treat septic
herpes virus, and varicella. Many infections result thrombophlebitis. Source control is crucial to a
directly from the pregnant state. These include good outcome, with surgical drainage or hyster-
septic abortions, chorioamnionitis, endometritis, ectomy required in some cases.
septic pelvic thrombophlebitis, and incisional
infection (Table 3). The increased incidence of Cardiopulmonary Resuscitation
urinary tract infections and pyelonephritis may
result from ureteral stasis as pregnancy progresses. Pregnancy requires modifications to ad-
Pneumonia in pregnancy is reviewed below. vanced cardiovascular life support, as shown in
Infections are often polymicrobial, caused by Table 4.19,20 If magnesium overdose is possible,
gram-positive, gram-negative, and anaerobic or- calcium chloride should be given. A recent
ganisms that normally colonize the lower genital systematic review suggests that chest compres-
tract. Infection with toxin-producing strains of sions with a left lateral tilt are less forceful than in
Clostridium, Streptococcus, and Staphylococcus may the supine position.21 They recommend manual
be rapidly fatal. Toxic shock syndrome should be leftward displacement of the gravid uterus. An
considered when severe or quickly evolving sepsis emergency cesarean section should be consid-
follows a medical abortion (Clostridium sordellii) or ered if the resuscitation is unsuccessful since
is noted postpartum (Streptococcus).16 Cholecystitis maternal circulation may dramatically improve
and appendicitis are not more common, but their with uterine evacuation. This should occur
clinical presentations may be altered in pregnancy. within 5 min of initiating resuscitation.21,22
Sepsis may be complicated by ARDS, multiorgan Although fetal survival has been reported in
system failure, cardiac dysfunction, and DIC, as cases where it was performed later, 93% of
well as adverse fetal outcomes. surviving infants were delivered within 15 min
Diagnosis is complicated by the normal in one review of the literature.
physiologic changes of pregnancy, which include
a mildly decreased blood pressure and a mildly Preeclampsia
elevated heart rate and white blood cell count. A
thorough abdominal and pelvic examination and Preeclampsia is a unique disorder of preg-
ultrasound evaluation are essential to look for nancy with serious adverse consequences both
occult sites of infection. Blood, urine, and pelvic for the mother and the fetus. Abnormal placental
sites should be cultured. Chorioamnionitis is implantation may cause altered production of
suggested by fever, maternal or fetal tachycardia, angiogenic factors that disrupt the maternal
abdominal tenderness, and foul-smelling amni- vascular endothelium in multiple organ systems.
otic fluid; however, the presentation may be Although the classic triad of hypertension,
occult.17 As in the nonpregnant population, early generalized edema, and proteinuria after 20
goal-directed therapy is recommended to pre- weeks of gestation suggests the diagnosis, the
vent the development of severe sepsis and presentation is often subtle and may even occur
shock.18 This includes fluid resuscitation and postpartum, so a high index of suspicion is
measurement of central venous pressure as an necessary to recognize this life-threatening dis-

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Table 5Multisystem Organ Involvement in Preeclampsia

Organ Clinical Syndrome

Central nervous system Eclamptic seizure


Posterior reversible encephalopathy
Cerebral vascular accident
Cerebral hemorrhage or edema
Lungs ARDS
Cardiac Pulmonary edema
Renal Acute kidney injury
Liver Hepatocellular damage, hepatic infarction, subcapsular hemorrhage or rupture
Systemic vasculature Vasoconstriction
Coagulation HELLP syndrome, DIC, placental abruption

HELLP hemolysis, elevated liver enzymes, low platelets.

order. Management depends on severity, with tivity to endogenous and exogenous pressor
delivery of the placenta the only curative therapy. agents, and activation of the coagulation cascade.
Blood pressure control is essential to prevent The reduction in placental perfusion and
end-organ damage but does not affect progres- increased circulating concentrations of markers
sion of the underlying disease process. Numer- of endothelial activation and intravascular coag-
ous clinical trials have demonstrated the benefit ulation occurs before the onset of clinical disease
of magnesium sulfate in preventing and treating and may affect many organ systems (Table 5).
eclamptic seizures. Cerebral vasospasm, ischemia, or edema and
Pathophysiology: Preeclampsia occurs in 2% to hypertensive encephalopathy may contribute to
8% of pregnant women.23 Risk factors besides the eclamptic seizures. Glomeruloendotheliosis is the
primigravid state include chronic hypertension, characteristic finding in the kidney on histopath-
renal disease, diabetes mellitus, obesity, age 40 ologic study, but renal dysfunction may also
years, autoimmune disease, and the presence of result from renal ischemia and intravascular
antiphospholipid antibodies.24 Multiple gestation volume depletion. Pulmonary edema may result
and hydatidiform mole are also risk factors, as is from increased left ventricular afterload, myo-
preeclampsia in a prior pregnancy or a family cardial dysfunction, decreased colloid osmotic
history of preeclampsia. Preeclampsia may pro- pressure, vigorous fluid therapy, and increased
gress to a convulsive and potentially deadly capillary permeability. While it most commonly
phase, termed eclampsia, without warning or occurs after parturition, in a subgroup of obese
overt preeclampsia. Eclampsia may occur up to 1 and chronically hypertensive patients with left
month postpartum and greatly increases the risk ventricular hypertrophy and diastolic dysfunc-
of poor outcome for mother and fetus. An tion, antepartum pulmonary edema develops.
especially fulminant complication of preeclamp- The HELLP syndrome is characterized by more
sia is hemolysis, elevated liver enzymes, low extreme multiorgan dysfunction from secondary
platelets (HELLP) syndrome, which complicates fibrin deposition and organ hypoperfusion. A
10% to 20% of cases of severe preeclampsia.25 microangiopathic hemolytic anemia and con-
The exact etiology of preeclampsia is un- sumptive coagulopathy may lead to DIC. In
known, but a genetic predisposition and host HELLP, the liver involvement is characterized by
factors favor its development. Failed or abnormal periportal or focal parenchymal necrosis with
development of blood vessels supplying the elevated liver function test results.
placenta causes placental ischemia and oxidative Diagnosis: The diagnosis of preeclampsia may
stress followed by the altered production of be difficult since the hypertension may be subtle
angiogenic factors that enter the maternal circu- and proteinuria minimal or absent. The majority
lation and cause vascular endothelial dysfunc- of normal pregnancies are complicated by ede-
tion. This results in increased loss of fluids from ma, so this nonspecific finding is no longer
the intravascular compartment, increased sensi- necessary for diagnosis. Diagnostic criteria vary

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Table 6Management of Severe Preeclampsia

Intervention Comment

Delivery Immediately if .36 weeks gestation


Corticosteroids If between 24 and 34 weeks gestation
Magnesium sulfate Loading dose 4 g over 15 to 20 min
Continuous infusion 1 g/h
Hydralizine 5 mg IV, then 5 to 10 mg every 20 to 40 min (max 20 mg)
Labetalol 10 to 20 mg IV, then 20 to 80 mg at 20- to 30-min intervals until target blood pressure
(maximum 300 mg), or
Infusion starting at 1 to 2 mg/min and titrated up until the target blood pressure achieved
Surveillance Measure blood pressure at least every 2 h
Frequent measurement of values for serum creatinine, magnesium, hemoglobin, platelet
count, and transaminase

but include new onset hypertension with a mon and seen most often in patients with the
systolic blood pressure 140 mm Hg or diastolic HELLP syndrome, placental abruption, massive
blood pressure 90 mm Hg on two or more hemorrhage, or coagulopathy.
occasions and 300 mg protein in a 24-h urine Management: The principles of management
collection. There has been considerable interest in include early diagnosis, close medical observa-
the development of a reliable biomarker. Elevat- tion, and a well-timed delivery in order to
ed levels of antiangiogenic factors, such as fms- maximize both maternal and fetal well-being
like tyrosine kinase 1 and endoglin, and de- (Table 6). Preeclampsia may be mild or severe
creased levels of the proangiogenic protein with the aggressiveness of therapy based on
placental growth factor have been useful in disease severity and fetal maturity. Markers of
suggesting the diagnosis in research settings disease severity that should alert the physician to
but are not yet recommended for general use.24 an increased risk of complications include sys-
Since preeclampsia may involve the central tolic or diastolic blood pressures of 160 and
nervous system, lungs, liver, kidneys, systemic 110 mm Hg, respectively; proteinuria 2 g/24 h
vasculature, coagulation, and the heart, it may or 100 mg/dL in a random specimen; oliguria;
have a varied presentation (Table 5). Signs and pulmonary edema; and early onset disease (,34
symptoms of preeclampsia may be mild or 35 w). Elevation in systolic rather than diastolic
nonspecific with malaise, headache, visual blood pressure may correlate with risk of stroke.
changes, nausea, vomiting, and epigastric or Patients who are 36 weeks gestation should
right upper quadrant pain being reported. undergo delivery since removal of the placenta is
Hemolysis on a peripheral blood smear, in- the only curative therapy. Earlier in gestation,
creased serum bilirubin level, increased serum delivery is recommended for patients with severe
transaminase levels, and thrombocytopenia sug- preeclampsia, eclampsia, HELLP, multiorgan
gest the diagnosis of the HELLP syndrome. The involvement, or fetal distress, while conservative
differential includes acute fatty liver of pregnan- management with close monitoring to improve
cy and, when renal dysfunction is also present, neonatal survival and morbidity may be appro-
hemolytic uremic syndrome (HUS) or thrombotic priate in select cases at tertiary perinatal centers.
thrombocytopenic purpura (TTP). Blood pressure is controlled with either
Maternal complications of severe preeclamp- labetalol or hydralazine. The objective of antihy-
sia are shown in Table 5. Posterior reversible pertensive therapy is to prevent end-organ
encephalopathy syndrome, a recently described complications. While hydralazine has been the
acute cerebral condition characterized by tran- traditional treatment, in the ICU setting, IV
sient headache, altered mental status, seizures, labetalol is now the drug of choice.27 Diuretics
and loss of vision with findings of posterior should be used with caution, as they may
leukoencephalopathy on imaging studies, is seen aggravate the reduction in intravascular volume
in preeclampsia.26 Acute renal failure is uncom- that is often seen in preeclampsia.

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Table 7Causes of Hypoxmic Respiratory Failure in Pregnancy

Etiology Time of Presentation

Asthma Risk greatest second trimester


Unusual in labor and delivery
Aspiration Labor and delivery
Amniotic fluid embolism Up to 48 h after labor and delivery
First- and second-trimester abortion
Pulmonary embolism Any trimester
After cesarean section
Risk greatest peripartum
Venous air embolism Instrumentation
Labor and delivery
Preeclampsia After 20 weeks
Up to 2 weeks postpartum
Pneumonia Severity in certain infections increased third trimester
Tocolytic pulmonary edema Preterm labor

Magnesium sulfate has been shown in nu- mortality (Table 7). Asthma is the most common
merous well-conducted studies summarized in a disease to complicate pregnancy, affecting 4% to
Cochrane review to prevent eclamptic seizures 8% of all gravidas. Amniotic fluid or venous air
and is superior to phenytoin and nimodipine.28 embolism, tocolytic-associated pulmonary edema,
Magnesium halves eclampsia risk in patients pneumonia, and aspiration may result in acute lung
with preeclampsia and likely reduces the risk of injury or ARDS.29 The institution of mechanical
maternal death. The two trials comparing mag- ventilation in the pregnant patient requires careful
nesium with diazepam were too small for reliable attention to the special needs of both mother and
conclusions about their effects. Magnesium sul- fetus. Venous thromboembolic disease is a major
fate has been shown to be better than diazepam cause of maternal mortality in the United States.
and phenytoin in preventing recurrent seizures
in patients with eclampsia. Toxicity is decreased Asthma
if after the traditional loading dose of 4 g IV, an
infusion of 1 g/h is given. Monitoring serum Asthma remains a high-risk condition for
magnesium levels is not required at this dose. both mother and fetus.30 Active treatment to
Magnesium sulfate should be given to all women control asthma improves both maternal and fetal
with either preeclampsia or eclampsia for 24 h. outcomes. The course of asthma during preg-
Patients with persistent thrombocytopenia, nancy is variable. Patients with more severe
hemolysis, or organ dysfunction may actually asthma are more likely to experience worsening
have TTP or HUS and may benefit from asthma during pregnancy. Asthma is most severe
plasmapheresis with fresh frozen plasma. Man- during the second and third trimesters of
agement of intrahepatic hemorrhage with sub- pregnancy, with improvement the last month of
capsular hematoma includes administration of pregnancy. Adverse maternal outcomes in preg-
blood products, delivery, and control of liver nant woman with asthma include pregnancy-
hemorrhage. Embolization of the hepatic artery is related hypertension, preeclampsia, and cesarean
often successful, but evacuation of the hematoma delivery. Adverse fetal outcomes include preterm
and packing of the liver may be required. birth and infants small for gestational age.
The management of the pregnant patient
Respiratory Disorders and Acute with status asthmaticus is similar to that of the
Hypoxemic Respiratory Failure nonpregnant patient, with a few exceptions.31
Mild hypoxemia should be treated aggressively
Respiratory disorders are a less frequent because it may be detrimental to the fetus. An
cause of admission to the ICU and maternal arterial blood gas with a PaCO2 of .35 mm Hg

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may be a sign of impending ventilatory failure patients presented similarly to nonpregnant
given the baseline respiratory alkalosis in normal patients, but they experienced greater delay in
pregnancy. Most asthma medications are safe for receiving antiviral treatment. Rapid antigen tests
use during pregnancy. Inhaled albuterol may be for influenza are less sensitive than culture, so
mixed with ipratropium bromide. Guidelines pregnant patients should be treated empirically
recommend systemic corticosteroids, such as with antiviral medications as soon as infection is
methylprednisolone, 120 to 180 mg/d in three suspected even if the rapid influenza test is
or four divided doses for 48 h. An IV infusion of negative. Documented bacterial coinfection was
magnesium sulfate can be considered for its rare in H1N1-infected pregnant women.
potential bronchodilator effect in refractory cases. In the pregnant woman, HIV infection is
Heliox, a low-density mixture of helium and complicated by the risk of perinatal transmission
oxygen, may decrease the work of breathing and to the fetus, preterm delivery, and opportunistic
preclude intubation and mechanical ventilation. infection, especially pneumonia. Pneumocystis
Noninvasive positive pressure ventilation can be jiroveci pneumonia may complicate pregnancy
considered for the hemodynamically stable pa- and be especially virulent. It is the most common
tient without impending respiratory failure. Any cause of AIDS-related death in pregnant woman
pregnant patient with impending respiratory in the United States with respiratory failure
failure should be intubated for mechanical requiring mechanical ventilation common. Both
ventilation. Ventilation strategies are similar to maternal and fetal mortality are high. The clinical
the nonpregnant patient but include a lower presentation is not altered by pregnancy.
tolerance of permissive hypercapnia as maternal The choice of antibacterial agents must take
academia impairs fetal oxygen extraction. The into account potential fetal toxicity. Penicillins,
use of a lower tidal volume, a lower respiratory cephalosprins, and second-generation macro-
rate, and an increased inspiratory flow minimiz- lides are safe. Tetracycline and chloramphenicol
es intrinsic positive end-expiratory pressure are contraindicated; sulfa-containing regimens
(PEEP). should be avoided near term except for the
treatment of Pneumocystis. Oseltamavir is the
Respiratory Infections drug of choice to treat influenza during preg-
nancy and when given within the first 4 days of
The incidence of pneumonia during preg- symptom onset has been associated with de-
nancy may be increasing.32 It is the most creased rates of complications and death. Favor-
common cause of fatal nonobstetric infection in able results have been obtained using acyclovir
pregnancy. The decreased cell mediated immu- to treat pregnant women with varicella pneumo-
nity of pregnancy may increase the severity of nia, especially when used early. Amphotericin B
infection with varicella, coccidioidomycoses, and should be used to treat disseminated coccidioidal
influenza A (H1N1). Primary infection with infections in pregnancy. No adverse effects on the
varicella virus progresses to pneumonia more fetus have been reported with amphotericin.
often in adults than children. Coccidioidomyco- Fluconazole and other azole antifungals are
sis is the fungal infection associated with potentially teratogenic. Pneumocystis is treated
increased risk of dissemination during pregnancy, with trimethoprim-sulfamethoxazole, which re-
especially if it is contracted in the third trimester. sults in an improved outcome compared with
Obstetric complications of pneumonia include other therapies. Corticosteroids are added as for
preterm labor and delivery, respiratory failure, the nonpregnant patient.
and maternal and fetal mortality.
A number of studies during the influenza A Amniotic Fluid Embolism
(H1N1) epidemic demonstrated increased dis-
ease severity and mortality.33 Sixty percent of the Amniotic fluid embolism is uncommon but
deaths during the 2009 influenza season occurred likely underrecognized. Maternal mortality is
in the third trimester, when influenza morbidity much lower (13% to 30%) than previously
and mortality are known to be higher. Pregnant estimated (80% to 90%), but most survivors

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develop permanent neurologic deficits from tritis, septic abortion, and eclampsia, while
cerebral hypoxia. Risk factors include advanced ARDS may also result from aspiration, sepsis,
maternal age, cesarean or assisted vaginal deliv- transfusion, and trauma (Table 7). Acute lung
ery and eclampsia.34 Most cases occur during injury is more likely to result in pulmonary
labor and delivery, but it has been reported edema given the increased plasma volume and
during abortions and following trauma. decreased plasma oncotic pressure noted in
The classic presentation is characterized by pregnancy. Fetal distress and premature labor
the abrupt onset of severe dyspnea, tachypnea, are common. The management of ARDS is
and hypoxemia, followed by cardiovascular directed at treatment of the underlying cause,
collapse and altered mental status or seizures. supportive care, and close monitoring of the
Shock, cardiogenic pulmonary edema, ARDS, fetus. Intubation and mechanical ventilation are
and DIC are seen and may be the presenting usually necessary.
manifestation. There is great debate regarding
the mechanism by which these clinical findings Airway and Ventilator Management
occur. While amniotic fluid and particulate
matter may enter the maternal circulation, The indications for intubation and mechani-
pulmonary vascular obstruction is thought to be cal ventilation are not significantly changed by
a minor factor in the pathogenesis. An anaphy- pregnancy. Since securing an airway in an
lactoid reaction to circulating fetal material has obstetrical patient may be challenging, this
been suggested but remains unproven. Vasocon- should be achieved by a skilled individual (Table
strictor arachidonic acid metabolites present in 8). Mallempati scale score increases as pregnancy
the amniotic fluid may contribute to pulmonary progresses and predicts difficulty of obtaining an
hypertension and associated acute right-sided airway.35 Preintubation airway inspection and
heart failure. Pulmonary edema is also noted due proper positioning is key. Airway edema is
to both capillary leak and left-sided heart failure.
common, and the highly vascular upper airway
Bleeding secondary to DIC occurs in up to 50% of
may bleed from minor intubation-related trauma.
patients who survive the first 30 to 60 min.
Use of cricoid pressure to minimize the risk of
Cytologic examination of pulmonary artery
pulmonary aspiration is recommended.
catheter blood may show fetal cells but is not
Tidal volume should be determined using
sufficient to make the diagnosis because this has
nonpregnant predicted ideal body weight.36
been observed in patients without clinical evi-
There are no studies to guide whether the initial
dence of amniotic fluid embolism.
ventilator settings should maintain the mild
Treatment is supportive and aimed at ensuring
respiratory alkalosis of pregnancy (PCO2, 27 to
adequate oxygenation, stabilizing the circulation,
and controlling bleeding. Initial management 34 mm Hg). Marked respiratory alkalosis should
includes intubation and mechanical ventilation be avoided because animal models suggest that
with lung-protective ventilation. PEEP is titrated hyperventilation can decrease uteroplacental
to achieve a PaO2 of .90 mm Hg and a FIO2 ,0.6. blood flow. The patient with ARDS should be
An echocardiogram may help determine the ventilated with a small tidal volume (46 mL/kg)
degree of left-sided and right-sided heart failure. and high respiratory rate to avoid ventilator-
Case reports attest to successful use of inhaled induced lung injury, although the safety of
nitric oxide and extracorporeal membrane oxy- permissive hypercapnia in pregnancy has not
genation (ECMO) and antraaortic balloon bump been studied. In case reports of lung-protective
therapies for right-sided and left-sided heart ventilation in pregnancy, no adverse effects were
failure, respectively. noted when PCO2 was maintained at or below 60
mm Hg. Close monitoring of the fetal heart
ARDS should occur during ventilatory changes, avoid-
ing settings that are associated with fetal distress.
Pregnancy-specific causes of ARDS include During the third trimester of pregnancy, chest
placental abruption, chorioamnionitis, endome- wall stiffness from the gravid uterus may cause

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Table 8Risks of Intubation respiratory failure persists despite maximizing
ventilatory strategies, ECMO may be considered.
Risk Response
Data on the use of ECMO during pregnancy are
Low oxygen reserve Preoxygenate limited, but several case reports support its use as
Airway highly vascular Avoid nasotracheal a salvage intervention.
intubation
Airway edema Use smaller tracheal tube (6
Venous Thromboembolic Disease
to 7 mm)
Weight gain obscures Proper positioning
anatomy DVT and pulmonary embolism (PE) remain a
Aspiration risk Sodium citrate and citric acid significant cause of maternal mortality occurring
(Bicitra), rapid sequence
induction
in all three trimesters and postpartum.38 The risk
of VTE is increased fourfold during pregnancy
and is highest during the postpartum period.39
high airway pressures unrelated to lung stiffness Hypercoagulability, venous stasis, and endothe-
or overdistension. lial damage to pelvic vessels during delivery
When ARDS from a diffuse lung lesion is occur in normal pregnancies; thus, all pregnant
women are at increased risk of VTE. Additional
present requiring high levels of oxygen, sufficient
risk factors include age .35 years, cesarean
PEEP should be used to correct arterial hypoxemia
section, obesity, heart disease, diabetes, sickle
at a nontoxic FIO2 (,0.6). In the pregnant patient,
cell disease, African American race, smoking,
oxygen tension is monitored rather than saturation
and multiple pregnancy. Thrombophilia increases
because the difference in PaO2 between maternal
the risk even further and is noted in approximately
and fetal circulations drives oxygen transfer. The
50% of woman with VTE during pregnancy. More
aim is to keep the PaO2 .90 mm Hg, a value higher
DVTs in pregnancy are ileofemoral and more
than that used in the nonpregnant patient, to
likely to embolize than in the nonpregnant
prevent fetal distress.37 To minimize the decrease
individual. There is a 70% to 90% incidence of left
in venous return that occurs with positive pressure
leg DVT thought due to increased compression of
ventilation, it is important that the pregnant
the left iliac vein, where it is crossed by the right
patient be managed in a left lateral position when
iliac artery as the gravid uterus enlarges.
possible. Diagnosis and treatment of both DVT and PE
In patients with ARDS requiring high levels of are more complicated in pregnancy. The diagno-
PEEP or with hemodynamic instability, muscle sis of VTE requires a high index of suspicion
relaxation and sedation may decrease oxygen because dyspnea, tachycardia, and mild lower
consumption. Nondepolarizing neuromuscular extremity edema are often noted in normal
blocking agents, such as cisatracurium, pancuro- pregnancy. Pregnant women with pelvic vein
nium, vecuronium, and atracurium, produce no DVT occasionally present with lower abdominal
adverse fetal effects with short-term use. Cis- pain, fever, and an elevated white blood count
atracurium is preferred because it does not mimicking acute appendicitis. If clinical features
depend on renal or hepatic function for elimina- suggest DVT or PE, some authorities recommend
tion. Most patients require sedation during treatment with low-molecular-weight heparin
intubation and mechanical ventilation. If benzo- (LMWH) while diagnostic testing is pursued.38
diazepines are used early in pregnancy, the lowest Bilateral venous compression ultrasound is the
dose and shortest possible duration are recom- diagnostic test of choice for DVT, although it is
mended, as there is theoretical risk of cleft palate. less accurate for isolated calf and iliac vein
Propofol is a pregnancy category B hypnotic agent thrombosis. A positive study result is considered
and has been used safely in pregnancy. Morphine sufficient to justify continued treatment with
and fentanyl are generally safe during pregnancy. anticoagulation. A negative study result man-
These agents cross the placenta, and if given near dates further testing, which, depending on the
the time of delivery, immediate intubation of the clinical suspicion, might involve repeat compres-
neonate may be required. If life-threatening sion ultrasonography in 5 to 7 days or further

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imaging of proximal veins with magnetic reso- fetal hemorrhage and fetal loss. Recombinant
nance imaging or computed tomography. Since tissue plasminogen activator does not cross the
the D-dimer increases as pregnancy progresses, it placenta and is the preferred thrombolytic agent.
is not a useful diagnostic test.39,40
While some experts have recommended Other Disorders of Pregnancy
bilateral venous compression ultrasound as the
initial diagnostic test in the setting of suspected Acute Renal Failure
PE, a recent American Thoracic Society clinical
practice guideline recommends chest radiograph The incidence of acute kidney injury (AKI)
followed by lung scintigraphy (V/Q scan) if the leading to renal failure in pregnancy has fallen
chest radiograph is normal.40 If the V/Q scan is significantly.42 AKI may complicate preeclamp-
nondiagnostic, a CT pulmonary angiogram is sia, amniotic fluid embolism, and acute fatty liver
performed, which has the advantage of provid- of pregnancy. Idiopathic acute renal failure is an
ing additional imaging of the chest. Radiation unusual complication of pregnancy and may
exposure to the fetus from either test is low and occur days to weeks after a normal pregnancy
within the amount considered safe in pregnancy. and delivery. The disorder may be a variant of
Lung scintigraphy compared with CT, angiogra- HUS or TTP. Sepsis may cause AKI, especially in
phy has a lower risk of maternal breast and lung the setting of pyelonephritis. There are case
cancer. Echocardiography may be useful to reports of acute renal failure from genitourinary
document right-sided clot or right-heart strain. compression from the gravid uterus, which may
It is important to make a definitive diagnosis, be more likely to occur in the setting of increased
and the clinical presentation alone cannot be uterine distention from polyhydramnios, multi-
relied on to diagnose or exclude VTE. ple gestation, or uterine fibroids.
Adjusted-dose subcutaneous LMWH is rec- In general, the treatment of AKI in pregnancy
ommended for treatment of acute VTE in is similar to that in the nonpregnant patient, with
pregnancy.41 Heparin should be continued for supportive care and dialysis as necessary. Renal
at least 6 weeks postpartum for a minimum dysfunction associated with preeclampsia and the
duration of therapy of 3 months. Current HELLP syndrome should respond to delivery of
guidelines recommend LMWH because the risks the fetus, while TTP and HUS require plasma-
of bleeding, heparin-related thrombocytopenia, pheresis with fresh frozen plasma. An evaluation
and osteoporosis are all decreased with this for occult sepsis should be performed when the
agent. The half-life of LMWH is shorter in etiology of acute renal failure is unclear.
pregnancy as the volume of distribution changes
and glomerular filtration rate increases as preg- Acute Liver Failure
nancy progresses. Despite this, recent guidelines
suggest that once-daily dosing may be used. Acute liver failure is an uncommon compli-
Routine dose adjustment based on weight gain cation of pregnancy and rarely complicates
during pregnancy and periodic antifactor Xa preeclampsia and the HELLP syndrome.43 Acute
LMWH levels is not necessary for most patients. fatty liver of pregnancy may result in acute liver
For patients with heparin-induced thrombocyto- failure if not recognized and treated. Risk factors
penia, danaparoid (a LMWH) is recommended. include twin gestations and first pregnancy.
Warfarin crosses the placenta and is absolutely Evidence suggests it results from deficiencies of
contraindicated (category X) because of the high the enzymes of mitochondrial fatty acid b-
incidence of embryopathy in the first trimester, oxidation. When a woman heterozygous for
small incidence of fetal CNS abnormalities these enzyme defects is pregnant with a homo-
throughout pregnancy, and possible fetal hemor- zygous fetus, fetal fatty acids accumulate and are
rhage. Life-threatening VTE should prompt detected in maternal circulation. This accumula-
consideration of thrombolytic therapy. Throm- tion leads to hepatic fat deposition and impaired
bolysis can be performed safely in pregnancy, hepatic function. The mean onset is at 36 weeks
although there is the potential risk of maternal or of gestation, although the disorder can be seen as

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early as 26 weeks and postpartum. Patients 2. Vasquez DN, Estenssoro E, Canales HS, et al.
present with headache, nausea and vomiting, Clinical characteristics and outcomes of obstetric
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follow 1 to 2 weeks later. Cholestasis with mild Daniel DL. Obstretric complications in pulmonary
to moderate elevations in serum aminotransfer- and critical care medicine. Chest. 1996;110(3):791
ases is the rule. Abdominal CT scans may 809.
demonstrate decreased attenuation, although this 4. Naylor DF Jr, Olson MM. Critical care obstetrics
imaging exposes the fetus to significant radia- and gynecology. Crit Care Clin. 2003;19(1):127149.
tion. Acute fatty liver of pregnancy progresses to 5. Hegewald MJ, Crapo RO. Respiratory physiology
fulminant hepatic failure complicated by enceph- in pregnancy. Clin Chest Med. 2011;32(1):113.
alopathy, renal failure, pancreatitis, hemorrhage, 6. Lapinsky SE, Kruczynski K, Slutsky AS. Critical
care in the pregnant patient. Am J Respir Crit Care
DIC, seizures, coma, and death. Because deteri-
Med. 1995;152(2):427455.
oration may occur rapidly, expectant manage-
7. Mehta N, Larson L. Pharmacotherapy in preg-
ment is not advised. The treatment is delivery of
nancy and lactation. Clin Chest Med. 2011;32(1):43
the fetus. Jaundice, liver dysfunction, and DIC
52.
may worsen for a few days after delivery but
8. Simpson LL. Maternal cardiac disease: update for
then should improve. Maternal and fetal mortal-
the clinician. Obstet Gynecol. 2012;119(2):345359.
ity has improved with early delivery. Full
9. Bowater SE, Thorne SA. Management of pregnan-
maternal recovery is to be expected. Because
cy in women with acquired and congenital heart
long-chain 3-hydroxyacyl-coenzyme dehydroge-
disease. Postgrad Med J. 2010;86(1012):100105.
nase deficiency in the fetus is associated with
10. Roth A, Elkayam U. Acute myocardial infarction
acute fatty liver of pregnancy, infants may have
associated with pregnancy. J Am Coll Cardiol. 2008;
hypoglycemia, hypotonia, acute or chronic skel- 52(3):171180.
etal and cardiac muscle dysfunction, and sudden 11. Murali S, Baldisseri MR. Peripartum cardiomyop-
infant death syndrome. athy. Crit Care Med. 2005;33(10):S340S346.
12. Neligan PJ, Lafffey JG. Clinical review: special
Acknowledgments populationscritical illness and pregnancy. Crit-
ical Care. 2011;15(4):227236.
Many thanks to my colleagues Karen C. 13. Montagnana M, Franchi M, Danese E, Gotsch F,
Patterson, MD, and Michael OConnor, MD, for Guidi GC. Disseminated intravascular coagula-
their ongoing collaboration on this topic and to tion in obstretric and gynecologic disorders. Semin
Nancy Jackson for her assistance in the prepara- Thromb Hemost. 2010;36(4):404418.
tion of this manuscript. 14. Mercier FJ, Van de Velde M. Major obstetric
hemorrhage. Anesthesiol Clin. 2008;26(1):5366.
Nothing to Disclose 15. Oyelese Y, Ananth CV. Postpartum hemorrhage:
epidemiology, risk factors, and causes. Clin Obstet
The author has disclosed that no relation- Gynecol. 2010;53(1):147156.
ships exist with any companies/organizations 16. Fischer M, Bhatnagar J, Guarner J, et al. Fatal toxic
whose products or services may be discussed in shock syndrome associated with clostridium
this chapter. sordellii after medical abortion. N Engl J Med.
2005;353(22):23522360.
References 17. Tita ATN, Andrews WW. Diagnosis and manage-
ment of clinical chorioamnionitis. Clin Perinatol.
1. Berg CJ, Callaghan WM, Syverson C, Henderson 2010;37(2):339354.
Z. Pregnancy-related mortality in the United 18. Guinn DA, Abel DE, Tomlinson MW. Early goal
States, 1998 to 2005. Obstet Gynecol. 2010;116(6): directed therapy for sepsis during pregnancy.
13021309. Obstet Gynecol Clin N Am. 2007;34(3):459479.

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19. American Heart Association Guidelines for Car- during pregnancy: recommendations for pharmacologic
diopulmonary Resuscitation, Part 10.8: Cardiac treatment. Update 2004 (NIH publication 053279).
arrest associated with pregnancy. Circulation. 32. Brito V, Niederman MS. Pneumonia complicating
2005;112:150153. pregnancy. Clin Chest Med. 2011;32(1):121132.
20. Atta E, Gardner M. Cardiopulmonary resuscita- 33. Louie JK, Acosta M, Jamieson DJ, Honein MA, for
tion in pregnancy. Obstet Gynecol Clin N Am. 2007; the California Pandemic (H1N1) Working Group.
34(3):585597. Severe 2009 H1N1 influenza in pregnant and
21. Jeejeebhoy FM, Zelop CM, Windrim R, Carvalho postpartum women in California. N Engl J Med.
JCA, Dorian P, Morrison LJ. Management of 2010;362(1):2735.
cardiac arrest in pregnancy: a systematic review. 34. Conde-Agudelo A, Romero R. Amniotic fluid
Resuscitation. 2011;82(7):801809. embolism: an evidence-based review. Am J Obstet
22. Dijkman A, Huisman CMA, Smit M, et al. Cardiac Gynecol. 2009;201(5):445.e1e13.
arrest in pregnancy: increasing use of perimortem 35. Munnur U, de Boisblanc B, Suresh MS. Airway
caesarean section due to emergency skills train- problems in pregnancy. Crit Care Med. 2005;33(10):
ing? BJOG. 2010;117(7):282287. S259S268.
23. Steegers EA, von Dadelszen P, Duvekot JJ, 36. Honiden S, Abdel-Razeq SS, Siegel MD. The
Pijnenborg R. Pre-eclampsia. Lancet. 2010; management of the critically ill obstetric patient.
376(9741):631644. J Intensive Care Med. [published online ahead of
24. Young BC, Levine RJ, Karamanchi SA. Pathogen- print August 12, 2011] 0885066611411408.
esis of preeclampsia. Annu Rev Pathol Mech Dis. 37. Munner U, Bandi V, Guntupalli KK. Management
2010;5:173192. principles of the critically ill obstetric patient. Clin
25. Gilson G, Izquierdo L, Curet L. Pregnancy- Chest Med. 2011;32(1):5360.
associated hemolysis, elevated liver function, 38. Marik PE, Plante LA. Venous thromboembolic
low platelets (HELLP) syndrome: an obstetric disease and pregnancy. N Engl J Med. 2008;359(19):
disease in the intensive care unit. J Intensive Care 20252033.
Med. 1996;11:173192. 39. James A. Committee on Practice Bulletins
26. Staykov D, Schwab S. Posterior reversible ence- Obstetrics. Practice bulletin no. 123: thromboem-
phalophathy syndrome. J Intensive Care Med. 2012; bolism in pregnancy. Obstet Gynecol. 2011;118(3):
27(1):1124. 718729.
27. Podymow T, August P. Update on the use of 40. Leung AN, Bull TM, Jaeschke R, et al. An official
antihypertensive drugs in pregnancy. Hyperten- American Thoracic Society/Society of Thoracic
sion. 2008;51(4):960969. Radiology Clinical Practice Guideline: evaluation
28. Duley L, Gulmezoglu AM, Henderson-Smart DJ. of suspected pulmonary embolism in pregnancy.
Magnesium sulphate and other anticonvulsants Am J Respir Crit Care Med. 2011;184(2):12001208.
for women with pre-eclampsia. Cochrane Database 41. Bates SM, Greer IA, Middeldorp S. VTE, throm-
Syst Rev. 2010;(11):CD000025. bophilia, antithrombotic therapy and pregnancy.
29. Pereira A, Krieger BP. Pulmonary complications Chest. 2012;141(2)(suppl):e691S-e736S.
of pregnancy. Clin Chest Med. 2004;25(2):299310. 42. Gammill HS, Jeyabalan A. Acute renal failure in
30. Murphy VE, Gibson PG. Asthma in pregnancy. pregnancy. Crit Care Med. 2005;33(10)(suppl):S372-
Clin Chest Med. 2011;32(1):93110. S384.
31. National Asthma Education and Prevention Pro- 43. Pan C, Perumalswami PV. Pregnancy-related liver
gram. Working group report on managing asthma diseases. Clin Liver Dis. 2011;(15):199208.

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Chapter 6. Venous Thromboembolic Disease
R. Phillip Dellinger, MD, MSc, FCCP; and Wissam Abouzgheib, MD, FCCP

Objectives: the 19th century,1 and from this Virchows triad is


 Know the risk factors for pulmonary embolism. derived: vascular endothelial injury, hypercoagu-
 Understand the importance of pretest probability for the lability, and venous stasis. Those three states
diagnostic approach to pulmonary embolism.
 Be able to contrast sensitivity versus specificity of CT
represent the combination of host factors that
angiogram and leg ultrasound in the diagnostic ap- predispose to VTE. Embolization of blood clots
proach to pulmonary embolism. into the pulmonary arterial circulation often leads
 Know the indications and contraindications for throm- to significant cardiopulmonary dysfunction. Di-
botic therapy of pulmonary embolism.
agnosis, treatment, and prevention of PE are of
particular interest to critical care practitioners and
Key words: CT pulmonary angiogram; deep vein thrombo-
sis; massive pulmonary embolism; pulmonary embolism; will be the focus of this chapter.
thrombolytic therapy
Incidence
Synopsis:
Venous thromboembolic disease is a pathologic formation of VTE is a common disorder and associated
a thrombus within the venous system of the lower with significant mortality, morbidity, and signif-
extremities or the pulmonary arteries. Pulmonary embolism icant socioeconomic costs. VTE is the third most
(thromboembolism) is responsible for 200,000 to 300,000
hospital admissions per year. Risk factors include those that common cardiovascular disease after myocardial
are inherited or acquired and affect Virchows triad: infarction and stroke.2 The estimated incidence
vascular endothelial injury, hypercoagulable state, and ranges between 1 to 2 per 1,000 person-years. The
venous stasis. Clinical findings are nonspecific and include
signs and symptoms suggestive of either deep vein
incidence is expected to increase with the current
thrombosis or pulmonary embolism. A chest radiograph aging population.2,3 In the United States alone,
may be normal in up to 25% of patients. Arterial blood the incidence of new or recurrent cases of VTE
gasses may also be normal. A nonelevated D-dimer is a exceed 900,000 cases.4 PE, a substantial subset of
useful test to make pulmonary embolism unlikely. B-type
natriuretic peptide and troponin may be elevated. CT these cases, is responsible for 200,000 to 300,000
pulmonary angiography is the best diagnostic test as to hospital admissions per year.
sensitivity and specificity other than digital subtraction dye
angiogram that, although remaining the gold standard, is
much more invasive and less often used. Ventilation
Risk Factors
perfusion lung scan, venous compression ultrasonography,
and echocardiography may also be very useful adjuncts for VTE has genetic (inherited thrombophilia)
diagnosis or exclusion of pulmonary embolism. Anticoag- and acquired risk factors. Knowledge of the latter
ulation is initially with unfractionated or low-molecular-
is important for prevention measures (Table 1).
weight heparin. Thrombolytic therapy, if not contraindicat-
ed, is used in patients with pulmonary embolisminduced More than 50% of patients with VTE have
hemodynamic instability. Inferior vena cava filters are used combined risk factors, acquired and inherited. It
in patients with contraindication to anticoagulation or with is generally accepted that patients with provoked
hemodynamic instability and contraindication to thrombo-
lytic therapy. Surgical thrombectomy may be considered in
VTE do not require screening for inherited
situations of severe hemodynamic instability with contrain- thrombophilia.
dication to thrombolytic therapy and close proximity to the
operating room and cardiopulmonary bypass. Inherited Thrombophilia

Inherited thrombophilia occurs from in-


VTE is defined as pathologic formation of a creased levels or function of coagulation factors,
thrombus within the venous system; it includes defects of coagulation factor inhibitors, defects of
DVT and pulmonary embolism (PE). Rudolph fibrolysis, hyper homocysteinemia or altered
Virchow first described the term embolism in platelet function.

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Table 1Risk Factors for DVT/PE Venous stasis is also a major risk factor. Long-
distance air travel has been linked to PE. There is
Inherited Thrombophilia
Increased levels or function of coagulation factors
an estimated 40% risk of VTE and a 5% incidence
Activated protein C resistance of PE in patients with traumatic spinal cord injury
Factor V Leiden mutation and associated paralysis of lower extremities. The
Prothrombin gene mutation period of greatest risk is during the first 2 weeks
Elevated factor VII levels
Defects of coagulation factor inhibitors after the initial injury; death occurs rarely in this
Antithombin patient group after 3 months. Although precise
Protein C estimates of risk increase in malignancy are
Protein S
difficult to ascertain, advanced cancer is associat-
Defects in fibrolysis
Hyperhomocysteinemia ed with a high risk of VTE. With other factors
Altered platelet function considered equal, surgery for malignant disease
Acquired risk factors results in a twofold to threefold increase in
Advancing age
Prolonged bed rest
thromboembolism compared with surgery for
Postoperative period nonmalignant conditions. Patients with a history
Trauma of VTE who undergo major surgery, period of
Advanced malignancy
immobility, or who are hospitalized for serious
Previous DVT
Right-side heart failure medical illnesses must be aggressively targeted
Prolonged travel for prophylaxis therapy.6
Pregnancy
Birth control pills
Clinical Findings
Acquired Risk Factors The clinical presentations of pulmonary
embolism are diverse and often difficult to
Acquired risk factors are more prevalent than recognize. Many patients will experience only a
inherited thrombophilia and account for the subset of the characteristic symptoms, sometimes
majority of cases of VTE.4 Advancing age is the exhibit atypical symptoms, or may even be
most significant acquired risk factor followed by asymptomatic.
recent surgery, venous stasis, trauma, advanced
malignancy, pregnancy, postpartum state, birth Signs and Symptoms
control pills, and previous DVT.
The frequency of VTE increases exponentially The most common symptoms/signs of dysp-
between the ages of 20 and 80 years old.5 nea, tachypnea, and tachycardia are seen with
Although an age of .40 years has often been myriad other disorders and are often transient.
used as a break point for age-related increase in Clinical judgment, however, is a critical first step
VTE, increasing age increases risk beginning in the evaluation and suspicion of PE as
with adulthood and continues to increase after highlighted in the PIOPED study.7
the age of 40 years, nearly doubling with each Physical examination is not typically helpful,
decade. Stein et al. demonstrated a 0.23% with the exception of findings of increased right-
incidence of PE with linear relation to age in a sided pressure such as increased jugular venous
tertiary care general hospital. The incidence of distension, or widely split-second heart sound,
women was higher in individuals greater than 50 murmur of tricuspid regurgitation, or an accen-
years old but not in those less than 50 years old.5 tuated pulmonary closure sound. Examination of
Abdominal operation requiring general anes- the lower extremity is unreliable for predicting
thesia .30 min increases the risk for VTE. the presence or absence of DVT. Nevertheless,
Orthopedic surgery of the lower extremity has new findings supportive of acute deep-vein
been recognized as one of greatest risk factors. obstruction, particularly unilateral leg swelling
DVT occurs in .50% of patients who do not in the setting of pulmonary symptoms compat-
receive prophylactic therapy when undergoing ible with thromboembolism, should strengthen
elective total hip and knee replacement surgery.6 the possibility of PE. Fever (temperature of

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100.08 F) has been demonstrated in 14% of presence of very high right-heart pressures, this
angiographically documented PE with no other right-to-left shunt produces hypoxemia unrespon-
cause of fever.8 Only 2 of 228 had temperatures sive to oxygen therapy and also places patients at
103.08 F. risks for embolic cerebral vascular events.

ECG and Chest Radiography D-Dimer

ECG and chest radiographs are commonly Plasmin-derived degradation product is com-
used in the initial evaluation of patients with monly included in the initial evaluation of
chest pain or dyspnea. However, both lack patients with suspected PE. Although extremely
sensitivity and specificity in diagnosing or ex- sensitive, D-dimer lacks specificity for PE (30%-
cluding pulmonary embolism. It is nevertheless 75%).10 Many other conditions (surgery, trauma,
important to appreciate ECG findings suggestive inflammation, infection) may elevate plasma D-
of increased right-sided pressure such as new dimer levels. The strength of D-dimer is its high
right axis deviation, new right bundle branch sensitivity and ability, with a normal test able to
block, sinus tachycardia, and atrial fibrillation. rule out VTE in low-risk patients.
Chest radiograph is also insensitive but helpful in
excluding other causes of chest pain such as B-Type Natriuretic Peptide (BNP)
pneumonia or pneumothorax. Typically de-
scribed findings are as follows: ipsilateral eleva- BNP is released by ventricular myocardial
tion of the diaphragm on the affected side, cells in response to wall distension and overload.
wedge-shaped pleural based infiltrate (Hampton It is a prognostic and not diagnostic biomarker for
hump), focal oligemia (Westermark sign), or PE. When measured within 4 h of admission for
enlarged right descending pulmonary artery PE, elevated BNP levels (.90 pg/mL) have a
(Palla sign), atelectasis and cardiomegaly. Chest sensitivity of 85% and a specificity of 75% in
radiograph may be normal up to 25%. predicting PE-related worse clinical outcomes
such as need for emergent thrombolysis, mechan-
Arterial Blood Gases ical ventilation, need for vasopressor therapy,
emergent surgical embolectomy, cardiopulmo-
Respiratory alkalosis is a common finding in nary resuscitation, or death.11
the tachypneic patient with PE. With massive
pulmonary embolus, respiratory acidosis may be Troponin
present because of increased dead space. The
partial pressure of oxygen may be decreased, Similar to BNP, elevated troponin levels indi-
normal, or increased. Normal A-a gradient lacks cate high incidence of complications while normal
negative predictive value to exclude PE9 and is troponin levels have a 97% to 100% negative
more likely to occur in the presence of previous predictive value for in-hospital deaths.12,13
normal cardiopulmonary status. Nonmassive PE
produces hypoxemia by release of bronchocon- Growth Differentiation Factor 15 (GDF-15)
strictors, production of atelectasis, and reperfu-
sion injury to the endothelial-epithelial barrier. GDF-15 is a distant member of the transform-
Massive PE is almost always associated with ing growth factor b family of cytokines. It is
hypoxemia and frequently with CO2 retention. overproduced in cardiomyocytes in response to
Other potential causes of hypoxemia in massive stress such as pressure overload or ischemia. It
PE include low mixed venous oxygen caused by also may be elevated because of cancer, diabetes,
low cardiac output as well as the potential for congestive heart failure, or renal failure. GDF-15
opening of a probe-patent foramen ovale caused has been shown to be an independent predictor
by high right-sided pressures. A probe-patent of PE-related complications such as need for
foramen ovale is present in a small but significant vasopressors, mechanical ventilation, cardiopul-
percentage of the general population. In the monary resuscitation, or death.14

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Diagnosis Ventilation/Perfusion (V/Q) Lung Scan

The treatment of PE or DVT is essentially the Perfusion lung scanning (usually done in
same; therefore, either diagnosis is sufficient for combination with ventilation scanning) is typi-
decision making. cally classified into high probability, intermediate
probability, low probability, and normal. Proba-
CT Angiography (CTA) bility of PE increases with size of perfusion defect,
number of moderate to large size defects, and
CTA is of significant value in detecting perfusion defects that are significantly larger than
pulmonary emboli. Several practical advantages ventilation defects or present in the absence of
have made CTA the favored diagnostic study for ventilation defects. Although ventilation scan-
suspected PE, including availability, rapid inter- ning is usually performed in combination with
pretation, and evaluation of the chest for alter- perfusion scanning to quantify ventilation de-
native diagnoses. The PIOPED II trial was fects, chest radiographs can be used in place of
designed to study the ability of the CTA to ventilation scanning in patients without chronic
predict presence or absence of PE.15 All patients pulmonary disease or acute bronchospasm. The
who were evaluated for possible PE underwent a Pioped I study7 supported the following findings:
ventilation/perfusion scan and leg ultrasound. (1) normal lung scans make PE very unlikely; (2) a
CTA also was performed but was not used to high-probability scan can usually be used to
make or exclude the diagnosis of PE, and PE was confer the diagnosis of PE; (3) a minority of
considered present in the presence of a high- patients have high-probability perfusion scans;
probability ventilation/perfusion scan or a pos- (4) a clinical impression of low likelihood of PE
itive leg ultrasound. PE was considered absent in when combined with a low-probability scan
the presence of a normal perfusion scan. All increases the predictive value of the low-proba-
other subjects, for research question purpose, bility scan; (5) intermediate-probability scans
received digital subtraction angiography for cannot be used for definitive decision making;
definitive diagnosis of presence or absence of (6) the great majority of patients with suspected
PE. Sensitivity and specificity were ascertained. PE cannot have PE excluded with perfusion
Pretest probability of PE was ascertained for all scanning; and (7) it is best to call low-probability
subjects. It is apparent that, like perfusion and intermediate-probability scans nondiagnos-
scanning, CTA loses diagnostic yield in circum- tic, with the classification system then becoming
stances of extreme discordance (high clinical high-probability, nondiagnostic, and normal.
probability/negative CTA and low clinical prob- Nondiagnostic scans require additional testing
ability/positive CTA). because they do not allow a decision as the
Recently, multidetector scanners have signif- presence or absence of PE. In recent years, CT
icantly improved the sensitivity as well as the angiography has replaced the V/Q scan as the
positive and negative predictive value of CTA. favored diagnostic test. However, V/Q scan
Recent studies have found the sensitivity and remains an important alternative diagnostic
specificity of CTA to be greater than 95%, and a modality to CT scan in patients with pregnancy,
negative CTA carries a 3-month risk of VTE of 1% contrast allergy, or renal insufficiency or as
to 2%, similar to a negative pulmonary angio- additive testing when CT angiogram is negative
gram.1517 One sensitivity issue with the CTA and risk is high. V/Q may be the modality of
diagnosis of PE was the decreased ability to detect choice to evaluate patients for chronic thrombo-
vessels beyond the segmental arteries. Current embolic pulmonary hypertension.
multidetector scanners allow resolution and
evaluation of filling defects down to the sixth- Venous Compression Ultrasonography
order branches of the pulmonary arteries. Con-
sidering all advantages mentioned above, CTA is Compression ultrasound (CUS) combines
now the predominant imaging modality used in Doppler venous flow detection with venous
diagnostic algorithms for the evaluation of PE. imaging and has become the leg imaging

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procedure of choice in most medical centers in the therapy. It is nowadays rarely performed for
United States. The diagnostic utility of CUS is practical and medical reasons. It is more expen-
related to imaging of a venous filling defect sive than CTA and often unavailable in small
associated with noncompressible vein in that centers. In addition, studies have shown compa-
location. When initial diagnostic tests are incon- rable results between PA and CTA.19 The death
clusive, ultrasonography of the deep venous rate from PA in the PIOPED study7 was 0.5%
system is a useful adjunctive test in the diagnosis with a low incidence (0.8%) of major nonfatal
and treatment of PE. Practically, the approach to complications (respiratory failure, renal failure,
treatment of both DVT and submassive PE is the or hematoma necessitating transfusion). Major
same, and thus a positive ultrasonogram for DVT nonfatal complications were four times more
obviates the immediate need for further diagnos- likely to occur in ICU patients. Despite early
tic studied to demonstrate PE. A negative studies that suggested a higher incidence of
ultrasonogram is somewhat more challenging mortality caused by pulmonary angiography in
and requires consideration of several clinical patients with high pulmonary artery pressures,
factors. DVT is detectable by ultrasonography in this was not found to be true in the PIOPED I
only 50% of patients with an acute PE. Thus, a study.7 Pulmonary angiography done within 1
negative ultrasonogram does not rule out PE. week of acute symptoms should reliably detect
Conversely, absence of DVT by CUS, in combi- pulmonary emboli even in the presence of
nation with some combination of low-probability anticoagulation. In patients with angiographical-
perfusion scan or failure to detect PE on helical ly proven PE, perfusion defects persist for at least
CT scan and the absence of high clinical suspi- 7 days without resolution and in the majority for
cion, usually allow withholding treatment.18,19 14 days. This is an important consideration since
patients may be referred to a tertiary-care center
Echocardiography with uncertain diagnosis of PE, having received
therapy for a considerable period of time.
Transthoracic or transesophageal echocardi-
ography has limited diagnostic value for ruling Diagnosis of PE in Pregnancy
out PE in the absence of hemodynamic instabil-
ity. It is very useful for critically ill and unstable The diagnosis of PE in pregnant patients can
patients who are unable to be moved to have be challenging. Ventilation/perfusion scan car-
conclusive testing where it may diagnose alter- ries a low risk in this specific patient group. In
native etiologies of hypotension or support PE as pregnant patients with negative ultrasound
the cause of hypotension by demonstrating right findings, identifying the location of perfusion
ventricular hypokinesis, dysfunction, or dilata- defects on an indeterminate diagnosis perfusion
tion. Rarely, thrombus within the pulmonary scan and following with selective pulmonary
arteries or right ventricle can be visualized. angiography targeting those defects is likely the
However, it carries prognostic value when the best approach because it potentially minimizes
diagnosis of PE is known. Several studies have dye load if PE is present. Warfarin is an absolute
shown that RV dysfunction or dilatation is contraindication in the first trimester and a
associated with worse outcomes, including in- relative contraindication in the second and third
creased mortality.2022 trimesters. Long-term heparin administration in
the pregnant woman is a significant risk for
Pulmonary Angiography (PA) osteoporosis.

PA remains the gold standard for diagnosis Treatment


of PE; morbidity and mortality rates from PA are
low and usually acceptable. Angiography is Early recognition and diagnosis of VTE lead
considered positive when a persistent filling to early initiation of anticoagulation, which
defect or cut-off sign is noted. Risk is increased remains the cornerstone of VTE treatment. Early
if angiography is followed by thrombolytic anticoagulation is very effective and often life

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saving. Several pharmacological changes have require immediate discontinuation of heparin.
been recently added to the treatment of VTE Arterial thrombosis (white clot) and worsening
along with significant interventional procedures. venous thrombosis may be part of this more severe
A number of new anticoagulants have been syndrome. When the platelet count drops more
introduced, with some providing the ability of than 50% and HIT-2 is suspected, heparin therapy
outpatient treatment. should be stopped. The addition of a direct
thrombin inhibitor to prevent or treat heparin-
Anticoagulation induced thrombosis is indicated. There is also a
chance for cross-reactivity with low-molecular-
Anticoagulation is highly effective in patients weight heparin (LMWH), and that is not advisable
with VTE. It reduces the incidence of recurrent as a therapeutic option. With HIT-2, warfarin
disease from 25% to 3% during the first 6 to 12 should not be instituted for 2 days because of the
months of therapy.23 Blocking further clotting, possibility of increased clot formation.
stabilizing the clot, and allowing the endogenous
thrombolytic system to break down the clot are LMWH
the main pathophysiological benefits of antico-
agulation. LMWH was first studied and approved for
the prevention of DVT, then was subsequently
Unfractionated Heparin (UFH) demonstrated to have similar mortality and
morbidity outcomes to UFH in the treatment of
For many years, the initiation of UFH in a VTE.25 Several advantages make LMWH prefer-
hospital setting along with oral vitamin K antago- able over UFH, including more predictable and
nist has been the standard of care. UFH therapy is reliable anticoagulation, increased patient satis-
continued for 4 to 5 days. The activated partial faction, ability to self-administer, possibility of
thromboplastin time (aPTT) should be maintained home-based treatment, decreased administration
at 1.5 to 2.0 times control. Although subtherapeutic, costs, and no need for monitoring anticoagula-
aPTT is strongly correlated with thromboembolic tion. Thrombocytopenia is uncommon enough
recurrence, a supratherapeutic aPTT does not that no more than one platelet count is recom-
appear to correlate with important bleeding com- mended during a treatment period of 5 to 7 days.
plications.24 Based on this information, targeting a If therapy is prolonged more than 7 days,
PTT of 2.0 times normal rather than 1.5 times subsequent platelet count is recommended. A
normal may be ideal. In patients without contrain- disadvantage in the critically ill patient is the
dication for anticoagulation, UFH should be started longer half-life if bleeding occurs if urgent
as soon as VTE is considered. A loading dose of procedures are required. LMWH does not pro-
5,000 to 10,000 U of heparin is indicated for PE. It is long aPTT. Antifactor Xa levels reflect LMWH
important to remember that warfarin is contrain- activity but are not routinely necessary in most
dicated in pregnancy, and anticoagulation should treated patients. LMWH dose adjustment is
be maintained with heparin. In addition, heparin required in patients with renal insufficiency
dosage requirements are increased in pregnancy. (creatinine clearance of 30 mL/min) and in obese
Decreases in platelet count or heparin-induced (.150 kg) or thin (,50 kg) patients. Antifactor Xa
thrombocytopenia (HIT) may occur with heparin levels may be needed to optimize dosing if
therapy. A nonimmunologically mediated decrease LMWH is used in these groups. When bleeding
in heparin (HIT-1) may occur and is usually occurs after recent administration of LMWH,
without dramatic drops in platelet count. It occurs protamine is may be of utility for reversal, but the
early in treatment and does not usually require degree of effectiveness is difficult to judge.
discontinuation of heparin. A more dramatic and
clinically significant decrease in platelet count Factor Xa Inhibitors
(HIT-2) may rarely occur with heparin therapy
(days 3 to 4 or earlier with previous heparin Factor Xa is a common factor for both intrinsic
exposure), is immunologically mediated, and does and extrinsic coagulation pathways, making it an

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ideal target for anticoagulation. The first available cerebrovascular procedure (2 months). One re-
Factor Xa inhibitor was fondaparinux, adminis- port noted, however, the successful use of
tered subcutaneously and once daily with a long urokinase therapy of PE in nine neurosurgical
half-life of 17 h. It has been shown to be equally patients (mean, 19 days after surgery) with no
efficacious to UFH in the initial treatment of intracranial hemorrhage. Intracranial bleeding, a
pulmonary embolism.26 Idrabiotaparinux is an- primary concern, occurs in about 3% of patients
other agent that is currently under evaluation and with massive PE who are treated with thrombo-
has an even longer half-life of 80 h. If approved, it lytic therapy.28 Retroperitoneal hemorrhage can
will be administered subcutaneously once a week also be life threatening and most frequently
for the treatment of VTE. Recently, a new oral occurs as a sequela of previous femoral vein
factor Xa (rivaroxaban) has been introduced. access for pulmonary angiography or other
Dose-finding studies in patients undergoing associated femoral lines. Relative contraindica-
orthopedic procedures suggested that an oral tions include any history of cerebrovascular
dose of 10 mg/day was suitable for prevention of event; a ,10-day postpartum period; recent
VTE. Also, a recent study showed noninferior- organ biopsy or puncture of a noncompressible
ity in the treatment of VTE compared with vessel; recent serious internal trauma; surgery
LMWH.27 within the last 7 days; uncontrolled coagulation
defects; pregnancy; cardiopulmonary resuscita-
Direct Thrombin Inhibitors tion with rib fracture; thoracentesis; paracentesis;
lumbar puncture; and any other conditions that
Several direct thrombin inhibitors (DTIs) place the patient at risk for bleeding. In general,
have been approved and are available for the angiographic or CTA documentation of PE
treatment of VTE, including hirudin, bivalrudin, should be obtained before thrombolytic therapy
dabigatran, and argatroban. The main indications because of the potential serious complications.
for use of DTIs are contraindication to heparin or Occasionally, thrombolytic therapy may be con-
HIT2, mainly because their lack of interaction sidered in hemodynamically unstable patients at
with platelets and their inability to potentiate high risk for PE who cannot be moved to receive
heparin-induced thrombocytopenia. Their main additional testing. Bedside echocardiography, if
drawbacks are unpredictable anticoagulation, immediately available, offers support for diag-
need for frequent monitoring, potential drug nosis in this circumstance since right ventricular
interactions, and continuous infusion. dilation must be present if the shock is caused by
PE. When angiography, CTA, or perfusion
Thrombolytic Therapy scanning are possible, the patient is at risk for
death, and the clinical scenario is strongly
Several clinical trials using thrombolytic suggestive, echocardiography supporting PE
therapy have showed improved hemodynamic should be adequate for initiating therapy. Hep-
and radiologic findings with faster clot resolution arin should not be administered during throm-
but were unable to show improved mortality. bolysis, but heparin therapy should be resumed
Streptokinase, urokinase, and recombinant without a bolus when the aPTT is 1.5 to 2 times
plasminogen activator (rTPA) are all thrombolyt- control. No coagulation tests are necessary
ic agents studied in the treatment of PE. rTPA is during thrombolytic infusion. If bleeding occurs
almost exclusively use in the United States. FDA- during thrombolytic therapy, drug should be
approved dosing is 100 mg over 2 h; more rapid discontinued (short half-life). If bleeding should
administration may be appropriate in imminent persist, cryoprecipitate or fresh frozen plasma
death such as 40 mg over minutes followed by 60 infusion should be considered. The use of
mg over the remainder of the 2-h period. thrombolytic therapy has been advocated in the
Traditional absolute contraindications are presence of large clot burden or echocardio-
history of hemorrhagic stroke, active internal graphic evidence of right ventricular dysfunc-
bleeding, active intracranial neoplasm, recent tion. The use of thrombolytic therapy in free-
acute cerebrovascular event (2 months), or recent floating RV thrombi also remains controversial.

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The American College of Chest Physicians anticoagulation may prevent further clot forma-
consensus statement on thrombolytic agents tion and increase the patency rate of the filter
continues to recommend that decisions be highly overtime. In patients with a transient increased
individualized for that patient, and clinicians risk of VTE, retrievable filters are available. They
should have latitude in using or not using. They theoretically protect against PE in the short term
are, however, recommended in general for while avoiding the long-term complications of
hemodynamic instability and massive ileofemor- IVC filters. These retrievable filters are usually
al thrombosis.29 removed 2 to 6 weeks after deployment. Com-
plications of filter placement include vessel
Pulmonary Embolectomy injury during deployment, subsequent venous
thrombosis at the insertion site, filter migration
Embolectomy can be performed using cath- and embolization into the heart or the pulmonary
eters or surgically. It is usually indicated in arteries, filter erosion through the IVC, and IVC
patients with massive pulmonary embolism and obstruction. A decrease of recurrent PE has been
shock who have failed thrombolytic therapy or documented, but a decrease in mortality has not
have absolute contraindications. Pulmonary em- been conclusively demonstrated.31
bolectomy is usually performed in selected
centers depending on the operators expertise Hemodynamics of Massive PE
and availability. It carries a high reported
mortality (up to 30%) considering that eligible Hemodynamic instability and shock are the
patients usually have significant comorbidities most important factors contributing to PE-related
(recent surgery, bleeding diathesis, recent cere- death. The hemodynamic response to acute
brovascular events).30 occlusion of the pulmonary vessels depends on
several factors that increase pulmonary vascular
Inferior Vena Cava Filters (IVC Filters) resistance (PVR) and pressure overload, includ-
ing clot size and the degree to which the clot is
An IVC filter serves as a trap in the inferior centrally positioned. Hypoxemia further elevates
vena cava. While allowing the passage of flowing PVR, and pulmonary artery (PA) pressures as do
blood, it prevents large blood clots traveling from mediators that include serotonin, platelet-activat-
the pelvis or the lower extremities to embolize ing factor, thrombin, vasoactive peptides (C3,
into the pulmonary circulation. Traditional indi- C5a), and histamine. The increase in PVR
cations for IVC filter placement include contra- translates into an elevated PA pressure as long
indication to anticoagulation, onset of bleeding as cardiac output is sustained. As pressure
with anticoagulation, and failure of anticoagula- loading worsens, RV stroke volume may drop.
tion to prevent recurrent thromboembolic events. Initial compensation by catecholamine-mediated
Other indications for filter placement include tachycardia may delay the drop in cardiac
hemodynamic instability in patients with contra- output. Right ventricular dilation maintains
indications to thrombolytic therapy and patients cardiac output by preserving stroke volume,
with HIT as bridge to therapeutic warfarin even if the ejection fraction falls. However, in
therapy. The empiric use of IVC filter in patients the most severe cases, a combination of RV
with a large pulmonary clot burden or borderline pressure overload, dilation, and ischemia even-
cardiopulmonary reserve is more controversial. tually leads to a drop in stroke volume and
IVC filter placement may also be considered in cardiac output. Increased RV size increases wall
patients with high risk for DVT and contraindi- stress and tension. Wall stress reduces RV oxygen
cations for anticoagulation prophylaxis, such as uptake and, combined with increased oxygen
trauma patients with lower extremity or pelvic demand, sets the stage for ischemia. Perfusion of
fractures, or patients with severe neurologic the RV depends on the gradient between mean
deficits or severe brain trauma. The decision to arterial pressure and subendocardial pressure in
anticoagulate patients who have had an IVC filter the RV. Elevated RV end-diastolic pressures
placed remains controversial, but the use of impair subendocardial perfusion and oxygen

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supply. The loss of subendocardial perfusion, most forms of treatment to be effective.34 Without
increased RV wall tension, and increased oxygen prophylaxis, the frequency of fatal PE is approx-
demand result in RV ischemia and infarction. imately 7% for emergency hip surgery, 2% after
Studies of hemodynamic profiles in patients with elective hip surgery, and 1% after elective surgery.
acute PE have demonstrated mean pulmonary Autopsy findings suggest that PE causes 5% of
artery pressures .40 mm Hg only in patients deaths in patients receiving mechanical ventila-
with pre-existing cardiopulmonary disease, sug- tion.34 The great majority of patients in the ICU
gesting that the normal right ventricle is incapa- should receive heparin prophylaxis for thrombo-
ble of generating mean pulmonary artery embolic disease. The dose for general surgical
pressures .40 mm Hg in the setting of acute patients or in medical patients is typically 5,000 U
pulmonary vascular bed obstruction. Based on twice or three times daily of unfractionated
the above, volume therapy is typically ineffective heparin subcutaneously or LMWH daily. Low-
and may be deleterious, with resultant overdis- dose LMWH is the heparin of choice in knee
tension of the right ventricle. Therapy should be surgery patients, hip surgery patients, and CNS
targeted toward reducing RV afterload by reduc- trauma patients. It also offers the advantage of
ing pulmonary clot burden, avoiding volume- one injection vs three in all patients.
induced RV overdistension (right atrial pressure Hemorrhagic side effects of low-dose heparin
.20 mm Hg), and maintaining adequate aortic are rare (,2%) in patients without hemorrhagic
diastolic pressure (upstream filling pressure for diathesis. High-risk patients or those who have
the left and right ventricles) Vasopressors may be contraindications for heparin should receive
beneficial by increasing aortic diastolic pressure intermittent pneumatic venous compression
when it is critically low. Combination inotrope/ (IPVC) additively or as a replacement. IPVC is
vasoconstrictor therapy such as dopamine or contraindicated in the face of arterial compro-
norepinephrine plus dobutamine is recommend- mise of extremity. Clinically significant DVT
ed in the hypotensive patient. Vasoconstriction of develops in many trauma cases. Risk factors
systemic vascular bed with selective vasodilation include advanced age, prolonged immobiliza-
of pulmonary vascular be would be ideal. tion, severe head trauma, paralysis, pelvic and
Inhaled nitric oxide has anecdotally been dem- lower extremity fractures, direct venous trauma,
onstrated to improve thermodynamics in PE by shock, and multiple transfusions. Low-dose
this mechanism. Surgical thrombectomy may be heparin and/or IPVC may not be effective in
considered in situations of severe hemodynamic the highest risk patient. In trauma patients at
instability with a contraindication to thrombolyt- high risk for bleeding and those at high risk for
ic therapy and close proximity to the operating pulmonary emboli, some investigators have
room. Bypass capability is necessary and the recommended prophylactic IVC filter placement,
clinical scenario should indicate a certain or especially if leg injury prevents application of
almost certain clinical diagnosis of massive PE. pneumatic compression devices. Similar ratio-
Interventional radiology use of mechanical frag- nale has been offered when PE is diagnosed in
mentation may be an alternative to surgery in advanced malignancy. Neither of these uses has
patients with severe hemodynamic instability been validated. Despite the availability of nu-
and contraindication to thrombolytic therapy. merous prophylactic agents and numerous
guidelines for the prevention of VTE, there is
Prevention of PE strong evidence that appropriate prophylaxis is
not offered to a large number of patients,
Despite significant advances in the preven- particularly those hospitalized with medical
tion and treatment of VTE, pulmonary embolism conditions.35
remains the most common preventable cause of
hospital death.32 It is in fact responsible for Summary
150,000 to 200,000 deaths per year in the United
States.33 When death occurs, usually it is within VTE is common and often associated with
30 min of the event, which is not long enough for significant morbidity and mortality. Factors that

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promote the development of DVT also increase (PIOPED). The PIOPED Investigators. JAMA. 1990;
the risk of PE. Clinical presentation is often 263(20):27532759.
nonspecific, hindering fast and accurate diagno- 8. Stein PD, Afzal A, Henry JW, Villareal CG. Fever
sis. PE is associated with high mortality rate in acute pulmonary embolism. Chest. 2000;117(1):
without treatment; however, rapid recognition 3942.
and effective treatment significantly reduce mor- 9. Stein PD, Goldhaber SZ, Henry JW, Miller AC.
bidity and mortality. CT angiography has become Arterial blood gas analysis in the assessment of
the primary diagnostic test. Predictive capability suspected acute pulmonary embolism. Chest.
of negative CT findings in high-risk patients is 1996;109(1):7881.
enhanced by additional studies (normal D-dimer 10. Righini M, Perrier A, De Moerloose P, Bouna-
level, negative leg ultrasound, and low-probabil- meaux H. D-Dimer for venous thromboembolism
ity perfusion scan). Thromboembolic therapy is diagnosis: 20 years later. J Thromb Haemost. 2008;
primarily recommended in patients with hemo- 6(7):10591071.
dynamic instability and no contraindications. 11. Kucher N, Printzen G, Goldhaber SZ. Prognostic
role of brain natriuretic peptide in acute pulmo-
Nothing to Disclose nary embolism. Circulation. 2003;107(20):
25452547.
The author has disclosed that no relation- 12. Becattini C, Vedovati MC, Agnelli G. Prognostic
ships exist with any companies/organizations value of troponins in acute pulmonary embolism:
whose products or services may be discussed in a meta-analysis. Circulation. 2007;116(4):427433.
this chapter. 13. La Vecchia L, Ottani F, Favero L, et al. Increased
cardiac troponin I on admission predicts in-hos-
References pital mortality in acute pulmonary embolism.
Heart. 2004;90(6):633637.
1. Cervantes J, Rojas G. Virchows legacy. Deep vein 14. Lankeit M, Kempf T, Dellas C, et al. Growth
thrombosis and pulmonary embolism. World J differentiation factor-15 for prognostic assessment
Surg. 2005;29(suppl 1):S30S34. of patients with acute pulmonary embolism. Am J
2. Naess IA, Christiansen SC, Romundstad P, Can- Respir Crit Care Med. 2008;177(9):10181025.
negieter SC, Rosendaal FR, Hammerstrom J. 15. Stein PD, Fowler SE, Goodman LR, et al. Multi-
Incidence and mortality of venous thrombosis: a detector computed tomography for acute pulmo-
population-based study. J Thromb Haemost. 2007; nary embolism. N Engl J Med. 2006;354(22):
5(4):692699. 23172327.
3. Van Es J, Eerenberg ES, Kamphuisen PW, Buller 16. Blachere H, Latrabe V, Montaudon M, et al.
HR. How to prevent, treat, and overcome current Pulmonary embolism revealed on helical CT
clinical challenges of VTE. J Thromb Haemost. 2011; angiography: comparison with ventilation-perfu-
9 (suppl 1):265274. sion radionuclide lung scanning. AJR Am J Roent-
4. Hunt JM, Bull TM. Clinical review of pulmonary genol. 2000;174(4):10411047.
embolism: diagnosis, prognosis, and treatment. 17. Perrier A, Roy PM, Sanchez O, et al. Multi-
Med Clin North Am. 2011;95(6):12031222. detector-row computed tomography in suspected
5. Stein PD, Huang H, Afzal A, Noor HA. Incidence pulmonary embolism. N Engl J Med. 2005;352(17):
of acute pulmonary embolism in a general 17601768.
hospital: relation to age, sex, and race. Chest. 18. Turkstra F, Kuijer PM, van Beek EJ, Brandjes DP,
1999;116(4):909913. ten Cate JW, Buller HR. Diagnostic utility of
6. Arcelus JI, Monreal M, Caprini JA, et al. Clinical ultrasonography of leg veins in patients suspected
presentation and time-course of postoperative of having pulmonary embolism. Ann Intern Med.
venous thromboembolism: results from the RIETE 1997;126(10):775781.
Registry. Thromb Haemost. 2008;99(3):546551. 19. Musset D, Parent F, Meyer G, et al. Diagnostic
7. Value of the ventilation/perfusion scan in acute strategy for patients with suspected pulmonary
pulmonary embolism. Results of the prospective embolism: a prospective multicentre outcome
investigation of pulmonary embolism diagnosis study. Lancet. 2002;360(9349):19141920.

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20. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. nary embolism. Frequency of intracranial hemor-
Prognostic role of echocardiography among pa- rhage and associated risk factors. Chest. 1997;
tients with acute pulmonary embolism and a 111(5):12411245.
systolic arterial pressure of 90 mm Hg or higher. 29. Opinions regarding the diagnosis and manage-
Arch Intern Med. 2005;165(15):17771781. ment of venous thromboembolic disease. ACCP
21. Kasper W, Konstantinides S, Geibel A, Tiede N, Consensus Committee on Pulmonary Embolism.
Krause T, Just H. Prognostic significance of right American College of Chest Physicians. Chest.
ventricular afterload stress detected by echocar- 1998;113(2):499504.
diography in patients with clinically suspected 30. Dauphine C, Omari B. Pulmonary embolectomy
pulmonary embolism. Heart. 1997;77(4):346349. for acute massive pulmonary embolism. Ann
22. Kreit JW. The impact of right ventricular dysfunc- Thorac Surg. 2005;79(4):12401244.
tion on the prognosis and therapy of normoten- 31. Decousus H, Leizorovicz A, Parent F, et al. A
sive patients with pulmonary embolism. Chest. clinical trial of vena caval filters in the prevention
2004;125(4):15391545. of pulmonary embolism in patients with proximal
23. Barritt DW, Jordan SC. Anticoagulant drugs in the deep-vein thrombosis. Prevention du Risque
treatment of pulmonary embolism. A controlled dEmbolie Pulmonaire par Interruption Cave
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24. Segal JB, Streiff MB, Hofmann LV, Thornton K, 32. Stein PD, Henry JW. Prevalence of acute pulmo-
Bass EB. Management of venous thromboembo- nary embolism among patients in a general
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25. Nurmohamed MT, Rosendaal FR, Buller HR, et al. 33. Horlander KT, Mannino DM, Leeper KV. Pulmo-
Low-molecular-weight heparin versus standard nary embolism mortality in the United States,
heparin in general and orthopaedic surgery: a 19791998: an analysis using multiple-cause mor-
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26. Buller HR, Davidson BL, Decousus H, et al. 17111717.
Subcutaneous fondaparinux versus intravenous 34. Wood KE. Major pulmonary embolism: review of
unfractionated heparin in the initial treatment of a pathophysiologic approach to the golden hour
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16951702. bolism. Chest. 2002;121(3):877905.
27. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral 35. Cohen AT, Tapson VF, Bergmann JF, et al. Venous
rivaroxaban for symptomatic venous thromboem- thromboembolism risk and prophylaxis in the
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28. Kanter DS, Mikkola KM, Patel SR, Parker JA, multinational cross-sectional study. Lancet. 2008;
Goldhaber SZ. Thrombolytic therapy for pulmo- 371(9610):387394.

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Notes

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Chapter 7. Acute Coronary Syndromes
Phillip A. Horwitz, MD; and Hjalti Gudmundsson, MD

Objectives: STEMI syndromes are characterized by myocar-


 Understand the common pathophysiology in acute dial cell death and cardiac biomarker release.
coronary syndrome subtypes. Approximately 1.4 million Americans are
 Understand the role of early risk stratification and choice
hospitalized for ACS yearly; 800,000 of those
of management strategy in non-ST-elevation acute
coronary syndromes. patients will have an acute myocardial infarction
 Understand the indications and options for emergent (MI), and the remainder will have a troponin-
reperfusion in ST-elevation myocardial infarction. negative syndrome. Costs associated with ACS
 Review the mechanical complications of myocardial
hospitalization in the United States have been
infarction.
 Review the pharmacologic and lifestyle modifications to estimated at 150 billion dollars annually.1
improve the long-term prognosis in acute coronary
syndrome patients. Pathophysiology of ACS
Key words: acute coronary syndrome; anticoagulation; Coronary risk factors such as smoking,
cardiogenic shock; coronary artery disease; coronary
hypertension, dyslipidemia, and diabetes influ-
intervention; fibrinolysis; myocardial infarction; unstable
angina ence the risk of atherosclerotic plaque formation.
These risk factors result in endothelial damage.
Synopsis: Circulating inflammatory cells bind to areas of
Acute coronary syndrome (ACS) represents a spectrum of damaged endothelium and, along with low
acute cardiac ischemic syndromes that include unstable density lipoprotein particles, migrate into the
angina (UA), non-ST-elevation myocardial infarction vascular intima. Macrophages take up oxidized
(NSTEMI), and ST-elevation myocardial infarction
low density lipoprotein, initiate an inflammatory
(STEMI). They share the common pathophysiology of
vulnerable atherosclerotic plaque rupture and subse- response, and become foam cells that make up an
quent thrombus formation. The management of STEMI initial vascular fatty streak. These macrophag-
centers on emergent coronary artery reperfusion with es, in combination with activated smooth muscle
either fibrinolytic therapy or primary percutaneous coro-
nary intervention. Anticoagulation strategies and risk
cells and other inflammatory cells, lead to
stratification followed by appropriate use of coronary development of the fibrous cap that characterizes
revascularization are the focus of management in UA and the mature atherosclerotic plaque.
NSTEMI. All ACS patients need to have preventative The stability of atherosclerotic plaques is
treatments and lifestyle modifications instituted to prevent
future adverse events.
variable. The risk of developing ACS appears
more related to composition of individual plaques
than to the degree of coronary artery stenosis.
Acute coronary syndrome (ACS) represents a ACS is caused by thrombus formation at the site
spectrum of acute myocardial ischemic syn- of a ruptured culprit atherosclerotic plaque.
dromes that include unstable angina (UA), non- Characteristics of these so-called vulnerable
ST-elevation myocardial infarction (NSTEMI), plaques consist of a large lipid core (occupying
and ST-elevation myocardial infarction (STEMI). .50% of plaque volume), inflammatory infiltrate
All of these clinical syndromes share a common with increased density of macrophages and T
pathophysiology related to the rupture of unsta- lymphocytes, low density of smooth muscle cells
ble coronary atherosclerotic plaques. UA and (thin fibrous cap), increased content of tissue
NSTEMI are differentiated primarily by their factor, and a cap with a disorganized collagen
severity; in NSTEMI, thrombus formation and structure.2 Elevated levels of C-reactive protein
ischemia is severe and prolonged enough to have been associated with the presence of plaques
cause myocardial cell necrosis. Essentially all at increased risk of rupture.3

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Table 1Signs and Symptoms Suggesting the Diagnosis of Acute Coronary Syndrome

High Likelihood of ACS Intermediate Likelihood of ACS Low Likelihood of ACS

History Syndrome similar to previously Chest pain/arm pain Atypical symptoms


documented angina Age 70 Cocaine use
Known history of CAD Diabetes
Male
Physical exam CHF Peripheral vascular disease Pain reproducible
Diaphoresis by palpation
Hypotension
Transient MR murmur
ECG New ST-segment deviation (1 mm) Q waves Normal
T-wave inversion in multiple ST depression 0.5-1.0 mm
precordial leads T-wave inversion .1 mm
Cardiac biomarkers Elevated Normal Normal

ACS acute coronary syndrome; CAD coronary artery disease; CHF congestive heart failure; MR mitral regurgitation.
Adapted with permission from Braunwald et al.4

Thrombin and platelet activation/aggrega- atypical symptoms in the absence of a chest


tion play a central role in the pathogenesis of pain syndrome. These findings are similar to
ACS. Rupture of a plaque exposes thrombogenic those of chronic angina, but they can occur either
contents, such as tissue factor, which activate the at rest or with minimal activity or can increase in
extrinsic clotting cascade. This leads to thrombin frequency or severity (crescendo angina). A
generation and fibrin deposition. Collagen and significant proportion of ACS patients will have
von Willebrand factor lead to platelet activation, no symptoms. Up to one-third of patients with
aggregation, and crosslinking. Ultimately, coro- MI will be asymptomatic; so-called silent MIs
nary artery thrombus is formed. This can are more likely to occur in the elderly, women,
progress to occlusion and transmural infarction and in patients with diabetes.
or can limit flow and embolize, causing ischemic Patients with ACS can present with signs and
symptoms and more limited cell necrosis. symptoms of left ventricular failure due to
ischemia, hypotension, a new murmur of mitral
Clinical Findings in ACS regurgitation, pulmonary edema, or an S3 gallop.
The presence of these signs may be markers for
History, physical exam, assessment of cardiac
higher-risk patient subsets.
biomarkers, and examination of the ECG are
used to establish the diagnosis, severity, and
Cardiac Markers
prognosis of patients presenting with ACS. Table
1 summarizes clinical signs, symptoms, and
Markers of myocardial cell necrosis, such as
initial testing used to determine the likelihood
myoglobin, CK, CK-MB, and troponin I and T,
that an ACS is the cause of a patients acute
are used to identify acute MI. Most institutions
syndrome.4
rely on the measurement of cardiac-specific
Signs and Symptoms troponins (I or T), given their high sensitivity
and specificity for myocardial cell necrosis.
Patients with ACS will have signs or symp- Because troponin levels usually do not rise until
toms of myocardial ischemia either at rest or with 6 h after symptom onset, these biomarkers might
minimal activity. Symptoms can include subster- be normal early in the course of both ST-elevation
nal chest pain or pressure that radiates to the arm and non-ST-elevation syndromes. The long half-
or jaw. Chest pain syndromes are frequently life of troponins limits their utility in diagnosing
accompanied by shortness of breath, diaphoresis, reinfarction, as they remain elevated in the
or nausea. Some patients may only present with circulation for 6 to 14 days postinfarct.

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ECG anti-ischemic therapies. Early risk stratification is
critical for patients presenting with UA or
Patients presenting with a suspect ACS NSTEMI and helps guide the choice of anticoag-
should have an ECG performed within 10 min ulant therapies as well as treatment pathways.
of arrival. Diagnostic ST-segment elevation on Patients can be stratified into high-risk and
ECG has a high specificity for STEMI and is used low-risk subsets by their clinical characteris-
to guide decisions about emergent reperfusion tics, cardiac enzyme profiles, and ECG. Patients
therapies. The presence of ST-segment depres- with an increased risk of adverse outcomes
sion or diffuse T-wave inversion can identify include those with older age, decompensated
higher-risk subsets of patients presenting with congestive heart failure (CHF), diabetes, malig-
UA/NSTEMI. Dynamic ST-segment changes are nant arrhythmias, and peripheral vascular dis-
utilized in risk algorithms to guide initial ease. ECG is a strong predictor of risk with
therapies, as discussed below. NSTE-ACS. The presence of dynamic ECG
changes, most specifically ST-segment changes,
Early Hospital Care and Treatment is a strong predictor of adverse outcomes.
Pathways Transient ST-segment elevation, or, more com-
monly, ST-segment depression on ECG, portends
All patients with a suspected ACS should be a worse prognosis. T-wave changes tend to have
admitted to an acute care hospital. Patients less specificity for recurrent events. Cardiac
should be kept on bed rest and have continuous troponin elevation is highly predictive of prog-
telemetry monitoring. Pulse oximetry should be nosis for patients presenting with ACS. Troponin
utilized to ensure adequate arterial oxygen elevations identify patient subsets that may
saturations, and supplemental oxygen should benefit from more aggressive/invasive treatment
be used to correct any hypoxemia. strategies and more aggressive antithrombotic
History, exam, and ECG findings are used to therapies such as glycoprotein IIb/IIIa receptor
triage patients presenting with possible ACS antagonists.
syndromes to potential diagnostic categories: A number of scoring systems have been
developed from large trials with the purpose of
1. Noncardiac/nonischemic syndromes;
risk stratifying patients presenting with ACS.
2. Stable coronary ischemic syndromes;
The Thrombolysis In Myocardial Infarction (TI-
3. UA/NSTEMI; and
MI) risk score is one such algorithm that was
4. STEMI.
developed and validated to guide prognostica-
Patients without coronary ischemia should be tion and treatment strategy in patients with
managed according to their suspected diagnosis. NSTE-ACS (Table 2). The TIMI risk score uses
Stable angina patients can often be managed on clinical variables to determine a 0 to 7 point score
an outpatient basis with optimization of anti- that is predictive of a 14-day combination
ischemic regimens and noninvasive evaluations. endpoint of death, recurrent MI, and urgent
True ACS patients (UA/NSTEMI or STEMI)
are managed according to their specific diagnos- Table 2TIMI Risk Score for NSTE-ACS
tic and treatment guidelines, as discussed in the
Patient Characteristic
following sections.
Age .65 y
UA and NSTEMI 3 CAD risk factorsa
Previous coronary stenosis 50%
ST-segment deviation
Risk Stratification in UA/NSTEMI Severe symptoms (eg, 2 anginal episodes in the past 24 h)
Aspirin use within 1 wk
Treatment goals for non-ST-elevation ACS Elevated cardiac biomarkers
(NSTE-ACS) include rapid relief of ischemic
NSTE-ACS non-ST-elevation acute coronary syndrome.
symptoms and prevention of recurrent coronary a
Includes family history, dyslipidemia, diabetes, active
events. Symptom relief includes treatment with smoking.

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Table 3TIMI Risk Score for Unstable Angina/Non-ST after presentation) or a conservative manage-
Elevation MI: All-Cause Mortality, MI, and Severe Ische-
ment strategy. The rate of the composite endpoint
mia at 14 Days
of death, MI, and rehospitalization for ACS was
Rate Composite reduced in the early invasive arm (15.9% vs
TIMI Score Endpoint, % 19.4%; P .025) at 6 months.6 In a meta-analysis
of seven trials of management strategy in UA/
0/1 4.7
2 8.3
NSTEMI, an early invasive strategy was shown
3 13.2 to have a 25% reduction in mortality compared
4 19.9 with conservative treatment in high-risk ACS
5 26.2
patients.7 Data from other trials of early vs
6/7 40.9
delayed intervention appear to favor performing
coronary intervention in the first 12 to 24 h after
presentation with high-risk UA/NSTEMI, par-
revascularization (Table 3).5 Stratifying UA/
ticularly in those who have positive cardiac
NSTEMI patients into high-risk and low-risk
biomarkers.8 All studies showing a benefit of an
subsets with this algorithm aids in directing
early invasive strategy do so in the setting of
subsequent inpatient management.
intensive antithrombotic therapy.
These findings guide the American Heart
Early Invasive vs Conservative Management
Association/American College of Cardiology
Strategy
(AHA/ACC) guidelines in choosing manage-
ment strategy in these patients. Table 4 summa-
For patients presenting with UA/NSTEMI,
rizes recommendations for treatment strategy
an initial treatment strategy needs to be deter-
decisions in UA/NSTEMI.9
mined. Two major treatment options are em-
ployed in the management of these patients: Early Hospital Care in UA/NSTEMI
An early invasive strategy includes coronary
angiography within the first 4 to 48 h after Initial management of patients presenting
presentation with a UA/NSTEMI. Angiography with suspected NSTE-ACS includes observation
is performed with the intent to revascularize a in a facility with cardiac monitoring (eg, chest
culprit coronary stenosis with either percutaneous pain unit, telemetry unit) where serial cardiac
coronary intervention (PCI) or coronary artery biomarkers and 12-lead ECGs can be performed.
bypass surgery dependent on coronary artery
anatomy and individual patient characteristics.
Table 4Selection of Initial Treatment Strategy in UA/
A conservative management strategy em-
NSTEMI
ploys an initial period of medical stabilization
with anticoagulation and anti-ischemic therapies. Conservative
This is typically followed by risk stratification Invasive Strategy Strategy
with noninvasive cardiac stress testing. Invasive
Recurrent or refractory Low TIMI risk score (3)
coronary angiography is deferred unless the ischemia Patient preference
patient has recurrent ischemic symptoms or they Positive cardiac markers Physician preference
have high-risk findings on noninvasive testing. New ST-segment deviation Poor revascularization
Hemodynamic instability candidate
Multiple randomized trials have been per- Acute CHF Patients with extensive
formed to determine the optimal treatment Ischemic mitral comorbidities
strategy for patients with UA/NSTEMI. The regurgitation
Recent PCI (within 6 mo)
Treat Angina with Aggrastat and determine Cost
Prior CABG
of Therapy with an Invasive or Conservative Reduced left ventricular
Strategy (TACTICS) TIMI-18 trial randomized function (,40%)
2,220 high-risk UA/NSTEMI subjects treated Elevated TIMI risk score (4)
with aspirin, heparin, and a glycoprotein IIb/ CHF congestive heart failure; CABG coronary artery
IIIa inhibitor to either an early invasive (,48 h bypass graft.

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Anti-ischemic and analgesic therapies are institut- Angiotensin-Converting Enzyme (ACE) Inhibi-
ed. Antithrombotic treatment should be initiated tors: Treatment guidelines recommend treatment
and include aspirin and antithrombin therapy. with an oral ACE inhibitor (or an angiotensin II
Early risk stratification then guides the initial receptor blocker in the ACE inhibitor intolerant)
management strategy and additional antithrom- for those patients with signs of CHF or depressed
botic treatment. ejection fraction (40%). Therapy should be
instituted in first 24 h in patients without
Anti-ischemic/Analgesic Treatment contraindications such as relative hypotension.
IV ACE inhibitors should not be used early in
Nitroglycerin: Nitrates are first-line therapies ACS patients due to an increased risk of
for patients presenting with symptomatic ACS precipitating hypotension.9
and reduce ischemia by decreasing ventricular
preload through venodilation. Sublingual nitro- Antithrombotic Therapy in UA/NSTEMI
glycerin (0.4 mg) is recommended for patients
with ongoing chest pain in the absence of The pathophysiology of ACS centers on
contraindications. IV nitroglycerin can be con- culprit plaque rupture and subsequent coronary
sidered for patients with ongoing or recurrent thrombus formation. Antithrombotic therapy is
symptoms after multiple doses of sublingual the mainstay of treatment in patients who
nitrates. Initial dose is 10 mcg/min and can be present with UA/NSTEMI. Antithrombotic treat-
uptitrated to a maximum of 200 mcg/min. ment has two components: (1) anticoagulant
Therapeutic goals include resolution of chest therapy directed against components of the
pain or a decrease in arterial pressure. coagulation cascade, and (2) antiplatelet therapy
b-Blockers: AHA/ACC guidelines recom- designed to limit platelet activation and aggre-
mend that oral b-blocker therapy be instituted gation. AHA/ACC guidelines for use of anti-
in the first 24 h for patients who do not have thrombotic therapy are summarized in Figure 1.9
contraindications for use.9 These agents reduce
myocardial oxygen demands by direct effects on Anticoagulant Therapy
heart rate and BP. Oral medication is adequate in
most patients, but IV dosing such as IV meto- Guidelines recommend institution of antico-
prolol in 5-mg doses can achieve more rapid agulant therapy in all patients presenting with
effects. b-Blockade should be avoided or used ACS. IV heparin, both the unfractionated and
cautiously in UA/NSTEMI patients with signs of low-molecular-weight formulation, is the most
heart failure, low cardiac output, bradycardia, widely used agent. Two other agents are ap-
and active asthma. b-Blockers may also be proved for use in ACS, the direct thrombin
contraindicated in patients at increased risk of inhibitor bivalirudin and the factor X inhibitor
cardiogenic shock. Oral b-blocker can be upti- fondaparinux.
trated as heart rate and BP permit. Heparin: Heparins, in conjunction with anti-
Calcium Channel Blockers: These agents are not thrombin III, bind and inactivate thrombin,
clearly beneficial in the treatment of ACS. Their leading to its anticoagulant effects. Trials of
use should be reserved for patients who cannot unfractionated heparin have demonstrated re-
be safely treated with nitrates or b-blockade. duced rates of death and MI in ACS patients.
Calcium blockers such as verapamil and diltia- Limitations of unfractionated heparin include
zem have more anti-ischemic effects than the unpredictable dosing patterns, need for frequent
dihydropyridine agents. monitoring, and the risk of developing heparin-
Morphine: Morphine acts as an analgesic and induced thrombocytopenia.
anxiolytic as well as having ventricular preload Low-molecular-weight heparins (LMWH) in-
reducing actions. Morphine sulphate (2 to 4 mg hibit both factor Xa and thrombin. They have
IV) can be administered to ACS patients who more predictable anticoagulant effects and do not
have continued ischemic symptoms despite require anticoagulant monitoring. The risk of
treatment with nitrates. developing heparin-induced thrombocytopenia

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Figure 1. Summary of AHA/ACC guidelines for the treatment of UA/NSTEMI emphasizing antithrombotic strategies
(recommendation class, level of evidence).
*Tirofiban or eptifibatide

Prasugrel not recommended in patients 60 kg, history of TIA or stroke, .75 years of age, propensity to bleed.

is reduced but not eliminated with the use of have the advantage of being able to inhibit clot
LMWH. Clinical trials of LMWH compared with bound thrombin. They do not cause heparin-
unfractionated heparin have shown mixed re- induced thrombocytopenia and can be used in
sults. In the Superior Yield of the New Strategy of heparin-allergic patients. The Acute Catheteriza-
Enoxaparin, Revascularization and Glycoprotein tion and Urgent Intervention Triage Strategy
IIb/IIIa Inhibitors (SYNERGY) trial, enoxaparin (ACUITY) trial tested the direct thrombin inhib-
was not superior to unfractionated heparin in itor bivalirudin against the combination of
preventing ischemic events in high-risk ACS heparin plus a glycoprotein (GP) IIb/IIIa inhib-
patients.10 Some studies have suggested the itor for moderate- to high-risk ACS patients
superiority of LMWH in patients managed being managed with an early invasive strategy.
conservatively. AHA/ACC guidelines state that Bivalirudin alone was shown to have a non-
enoxaparin is preferable to unfractionated hepa- inferior effect on ischemic endpoints and had
rin for UA/NSTEMI being managed with a reduced rates of major bleeding (3.0% vs 5.7%, P
conservative strategy unless coronary artery , .001) compared with the combination of
bypass graft surgery within 24 h is planned. heparin and GP IIb/IIa inhibitor.11
Direct Thrombin Inhibitors: Direct thrombin Guidelines have given bivalirudin a class I
inhibitors bind directly to thrombin in the recommendation for use in UA/NSTEMI pa-
absence of a cofactor (like antithrombin III) and tients being managed with an early invasive

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strategy.9 A second direct thrombin inhibitor, trials and analyses have demonstrated a 30% to
argatroban, is approved for management of ACS 40% decrease in major adverse cardiovascular
patients with a history of heparin-induced events in patients pretreated with clopidogrel
thrombocytopenia. prior to PCI.14,15
Factor X Inhibitors: Fondaparinux is a synthetic Clopidogrel has a prolonged half-life after
pentasaccharide that binds to antithrombin and discontinuation. In patients undergoing major
inhibits factor Xa. It has predictable bioavailability surgery (including coronary artery bypass graft),
and anticoagulant effects that obviate the need for clopidogrel and other ADP receptor antagonists
anticoagulant monitoring. In the Organization to should be stopped for 5 to 7 days prior to the
Assess Strategies for Ischemic Syndromes (OASIS- procedure if possible. Based on the CURE trial
5) trial of fondaparinux vs enoxaparin in ACS results, CABG patients should have their clopi-
patients, fondaparinux was shown to have similar dogrel restarted postoperatively and continued
ischemic endpoint outcomes with a reduction in for 30 days to 1 year.
major bleeding events.12 However, an unexpected Other ADP Receptor Antagonists: Prasugrel is a
complication of increased catheter clot formation potent thienopyridine ADP receptor antagonist
during PCI was noted, which has led to limited with more rapid and higher levels of platelet
use of this agent. Despite this issue, the guidelines inhibition than clopidogrel. The TRial to assess
have incorporated fondaparinux as an option for Improvement in Therapeutic Outcomes by opti-
anticoagulant treatment of ACS patients managed mizing platelet inhibitioN with prasugrel
with both conservative and invasive strategies. (TRITON) TIMI-38 studied 13,600 moderate- to
high-risk UA/NSTEMI patients scheduled for
Antiplatelet Therapy PCI. Patients were randomized to prasugrel (60-
mg load, 10 mg daily) or clopidogrel. A 2.2%
Acetylsalicylic Acid (Aspirin): Aspirin is an absolute risk reduction in the primary endpoint
irreversible cyclooxygenase inhibitor leading to a of cardiovascular death, nonfatal MI, or stroke
decreased production of thromboxane. Aspirin was seen in the prasugrel group (P , .001). There
treatment reduces thromboxane mediated plate- was an increase in life-threatening bleeding (1.4%
let activation and aggregation. Aspirin should be vs 0.9%) seen with prasugrel.16 AHA/ACC
administered to all patients with ACS as soon as guidelines have included prasugrel as an alter-
possible after hospital presentation. At least 162 native to clopidogrel in this patient population.8
mg is required in the aspirin-nave patient to Prasugrel is contraindicated in patients with an
achieve rapid and maximal antiplatelet effects. increased risk of bleeding including: age 75
Typical initial dosing would be 325 mg of aspirin years, body weight 60 kg, and history of stroke
followed by a daily 81-mg maintenance dose or transient ischemic attacks. In addition, prasu-
continued indefinitely. Treatment with clopidog- grel is a reasonable choice for patients that have
rel is indicated in the aspirin-allergic patient. developed thrombotic complications such as
Clopidogrel: The thienopyridine agent, clopi- stent thrombosis despite clopidogrel therapy.
dogrel, is an irreversible inhibitor of the platelet Ticagrelor is an oral, reversible, nonthieno-
P2Y12 adenosine diphosphate (ADP) receptor. pyridine antagonist of the P2Y12 receptor and
This receptor is central to mechanisms of platelet provides more rapid and predictable levels of
activation and aggregation. antiplatelet activity than clopidogrel. In a large
The CURE (Clopidogrel in Unstable Angina randomized trial of ACS patients, subjects on
to Prevent Recurrent Events) trial randomized ticagrelor had a 16% reduction in vascular death,
12,500 aspirin-treated UA/NSTEMI patients to MI, and stroke (P , .001) at 1 year and a 1.1%
either clopidogrel (300-mg load/75-mg daily absolute reduction in cardiovascular death (P.01)
dose) or placebo. CURE demonstrated a 20% compared with those treated with clopidogrel.
reduction in the primary endpoint of cardiovas- There were no significant increases in major
cular death, nonfatal MI, or stroke. This benefit bleeding.17 Ticagrelor has recently been approved
was seen in patients treated medically, with by the US Food and Drug Administration for the
coronary intervention and with CABG.13 Other treatment of patients with ACS. Loading dose is 180

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mg followed by 90-mg dose bid. Like clopidogrel, or demonstrable ischemia on noninvasive
this drug should be stopped 5 days prior to major testing.
surgery. Due to a potential interaction with higher 4. Patients in whom PCI is not optimal or
doses, patients receiving ticagrelor should take possible.
100 mg of daily aspirin.
PCI, if technically feasible, can be appropriate
Glycoprotein IIb/IIIa Inhibitors: The platelet
for UA/NSTEMI patients with one- to two-vessel
glycoprotein (GP) IIb/IIIa receptor regulates the
coronary artery disease, in nondiabetics with
final common pathway for platelet aggregation
multivessel disease and intact left ventricular
in response to various stimuli. Platelet aggrega-
function, and in patients at high risk for CABG
tion is mediated by binding to fibrinogen and the
surgery.
von Willebrand factor leading to platelet cross-
linking. GP IIb/IIIa antagonists have been shown
Management of STEMI
to reduce ischemic cardiac complications after
extensive evaluation in a large series of random-
STEMI is a medical emergency most often
ized clinical trials. Clinical efficacy with these
caused by a rupture of a plaque in a coronary
agents has been demonstrated during PCI in
artery resulting in a complete occlusion of the
patients with stable and unstable coronary
vessel. Patients with STEMI present with similar
syndromes, as adjunctive therapy for the medical
symptoms as patients with other ACS, such as
management of ACS, and in combination thera-
UA and NSTEMI, although the symptoms are
py for patients with acute ST-elevation infarc-
often greater in intensity and duration. Typical
tions.1822
symptoms are severe, with crushing substernal
Three IV agents are currently available in the
chest pain described as pressure or squeezing
United States. The two small molecule GP IIb/IIa
sensation. The chest pain often radiates to the
inhibitors, tirofiban and eptifibatide, are ap-
jaw, neck, epigastrium, left shoulder, and down
proved for the upfront management of patients
the left arm. This is often associated with
presenting with ACS. The monoclonal antibody,
dyspnea, diaphoresis, nausea, lightheadedness,
abciximab, should not be administered to ACS
and palpitations. Evidence of compromised left
patients unless PCI is already planned.
ventricular function and low cardiac output may
be prominent with altered mental status, vaso-
Revascularization in UA/NSTEMI
constriction, bibasilar crackles, and third and
fourth heart sounds.
Coronary revascularization options in pa-
The presenting ECG is central to making the
tients with UA/NSTEMI include PCI or coronary
early diagnosis of STEMI and initiating decisions
bypass surgery. Deciding between these two
regarding emergent reperfusion. Candidates for
options requires accounting for individual pa-
emergent reperfusion therapies have all of the
tients clinical characteristics (age, presence of
following:
diabetes, left ventricular dysfunction, etc.), their
comorbidities, technical features of their specific 1. A clinical syndrome consistent with acute
coronary anatomy, and patient preference. In myocardial ischemia/injury.
general, AHA/ACC guidelines9 recommend 2. ST-segment elevation 1 mm in two or more
CABG surgery in ACS patients with: contiguous leads or new left bundle branch
block.
1. Presence of significant left main coronary
3. Symptom onset of 12 h.
disease.
2. Patients with three-vessel coronary disease, Early reperfusion of an infarct-related artery
especially if left ventricular dysfunction is limits infarct size, preserves left ventricular
present. function, and improves patient survival. The
3. Patients with two-vessel disease including term time is muscle is often used as there is
significant proximal left anterior coronary overwhelming evidence that time to treatment is
artery disease with left ventricular dysfunction directly related to mortality reduction and

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Table 5Common Fibrinolytic Regimens and Adjunctive Anticoagulation

Drug Dose Adjunctive Therapy

Alteplase (tPA) Front-loaded dosing: 15 mg bolus, ASA 325 mg


then 0.75 mg/kg over 30 min, then Heparin 60 U/kg bolus (max 4,000 U) then 12 U/kg/h
0.50 mg/kg over 60 min (total, 100 mg) (max 1,000 U/h)
Clopidogrel 300-mg load
Tenecteplase (TNK) 3050-mg single bolus based on weight ASA 325 mg
Enoxaparin 30 mg IV, then 1 mg/kg bid
Clopidogrel 300-mg load
Reteplase (rPA) 10 U and repeat 10 U in 30 min ASA 325 mg
Heparin 60 U/kg bolus (max 4,000 U) then 12 U/kg/h
(max 1,000 U/h)
Clopidogrel 300-mg load

ASA aspirin.

myocardial salvage. All patients who present even greater reduction (25%) in patients that
within 12 h of symptom onset should be presented with a new left bundle branch block.
considered for immediate reperfusion therapy. Overall there was a 1% risk of stroke and 0.7%
Symptoms after 12 h may be an indication of a risk of major, noncerebral bleeding.23 In contrast
stuttering course of occlusion and spontaneous to the treatment of STEMI, fibrinolytic agents
reperfusion and reocclusion, and the patient may have shown no benefit when used for the
benefit from aggressive early therapy (mainly treatment of UA/NSTEMI.24
primary PCI). Streptokinase, a first-generation lytic agent
Treatment advances over the last few decades that is not fibrin specific, is still widely used
have dramatically lowered the mortality and around the world. The more potent, third-
morbidity from STEMI. Reperfusion of the generation, fibrin-specific agents are the agents
infarct-related coronary artery in STEMI is of choice in the United States. Several newer
central to optimal STEMI treatment, reducing fibrinolytic agents are available with similar
infarct size, minimizing myocardial damage, efficacy and risk profiles but with slightly
preserving left ventricular function, and decreas- different administration protocols and adjunctive
ing morbidity and mortality such as heart failure antithrombotic regimens (Table 5). There is no
and electrical instability. Two strategies exist for significant difference among different fibrinolytic
restoring culprit coronary flow in STEMI pa- agents or plasminogen activators in reduction in
tients: (1) pharmacological reperfusion with mortality or the incidence of stroke.25 The benefit
fibrinolytic agents and (2) mechanical, catheter- of the newer agents is easier dosing, which
based, reperfusion (primary PCI). minimizes errors. Clinical trials of fibrinolytic
agents have shown 90-min open artery and flow
Reperfusion Strategies (normal perfusion) rates of about 60%.
Once a fibrinolytic agent has been adminis-
Fibrinolytic Therapy: Fibrinolytic therapy is tered as a treatment for STEMI, the patient is
one of the best and most rigorously studied assessed for evidence of clinical reperfusion. This
treatments in cardiovascular medicine. Tens of has been defined as resolution of chest pain,
thousands of STEMI patients have been random- resolution of ST-segment elevation of more than
ized to fibrinolytics in a series of large clinical 50%, and reperfusion arrhythmias. This is im-
trials. The Fibrinolytic Therapy Trialists Collab- portant in light of availability of rescue PCI
orative Group combined analysis of nine large discussed below.
trials including over 58,000 patients randomized Bleeding is the major risk of fibrinolytic
to thrombolytic therapy vs medical management. agents. Table 6 summarizes the major absolute
This study showed an overall 18% reduction in and relative contraindications for receiving these
mortality with the use of fibrinolytic therapy and agents.26 Hemorrhagic stroke is rare but may

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result in catastrophic disability and mortality. Table 6Contraindications for Thrombolytic Use
Fibrinolytic therapy for STEMI is a proven and
Absolute Contraindications
effective treatment in eligible patients. However,
many eligible patients do not receive fibrinolytics Prior intracranial hemorrhage
due to a fear of treatment-related complications. Known structural cerebral vascular lesion
Large registries of STEMI patients have reported Known intracranial neoplasm
Recent ischemic stroke (3 mo)
that 25% to 50% of eligible patients presenting to Suspected aortic dissection
US hospitals do not receive fibrinolytics, largely Active bleeding or bleeding dyscrasia
due to fear of bleeding.27 Significant recent head trauma (3 mo)
Primary PCI: Primary PCI has now become
Relative Contraindications
the preferred strategy for prompt early reperfu-
sion if appropriate resources are available. History of chronic, severe, poorly controlled hypertension
Primary PCI offers several important potential Severe hypertension on presentation (SBP .180 mm Hg
or DBP .110 mm Hg)
advantages over fibrinolytic therapy, including: Traumatic CPR (.10 min)
higher patent artery rates, less recurrent ische- Recent major surgery (3 wk)
mia, less intracranial hemorrhage, and the ability Recent internal bleeding or active peptic ulcer disease
Pregnancy
to treat fibrinolytic-ineligible patients. The bene-
Current use of anticoagulant
fits from primary PCI are attributed to improved
myocardial salvage resulting from achieving SBP systolic BP; DBP diastolic BP.
higher rates of normal coronary flow (90-min
coronary patency in up to 90% of patients) and a acceptable transfer times.31 This even further
lower risk of reocclusion and reinfarction. PCI emphasizes the importance of time to treatment
minimizes the risk of intracranial hemorrhage in STEMI.
and is preferable to alternative treatments in Rescue PCI: A subset of STEMI patients
high-risk patients, such as those with cardiogenic treated with fibrinolytic drugs fails to reperfuse
shock, severe CHF, or hemodynamic or electrical as evidenced by persistent symptoms and ST-
instability.28 A meta-analysis of clinical trials com- segment elevation. So called rescue PCI has
paring primary PCI to fibrinolytic agents dem- been performed in such patients. Fibrinolytic
onstrated a 22% relative reduction in mortality, failure patients are at higher risk for subsequent
50% reduction in stroke, and a 57% reduction in morbidity and mortality with their infarctions.
recurrent MI in favor of primary PCI.29 They are also at higher risk of complications
The primary disadvantage of primary PCI is during rescue PCI, particularly with bleeding
the potential for significant treatment delays. The complications and stroke. Fibrinolytics have been
majority of US STEMI patients present to shown to activate platelets, and concerns about
hospitals that are not primary PCI capable. One bleeding have limited the use of combinations of
potential management strategy for these patients full-dose thrombolytics and potent antiplatelet
is rapid transfer to a primary PCI hospital. This agents such as GP IIb/IIIa inhibitors. A meta-
strategy was examined in the Danish DANAMI-2 analysis of trials of rescue PCI revealed no
trial, in which such patients were randomized improvements in mortality but significant reduc-
between fibrinolytic therapy and immediate tions in heart failure and reinfarction compared
transfer to a primary PCI center. This study with conservative treatment.32 Rescue PCI was
demonstrated a 5.7% absolute reduction in death, also associated with increased risk of stroke and
reinfarction, and disabling stroke in the primary minor bleeding. Repeat fibrinolytic administra-
PCI arm.30 However, the vast majority of these tion had no effect on mortality or reinfarction but
patients were transferred rapidly (time from led to increased bleeding. Guidelines recommend
initial presentation to catheter reperfusion a strategy of rescue PCI for patients in whom
[door-to-balloon time] of less than 2 h). Registries fibrinolytic therapy has failed (ST-segment ele-
of US STEMI patients have shown both large vation ,50% resolved 90 min following fibrino-
increases in mortality if door-to-balloon times are lytic) and a moderate or large area of myocardi-
delayed and poor performance in achieving um is at risk (anterior infarcts and inferior

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infarcts with right ventricle or posterior involve- other groups appear to benefit. Oral agents
ment).28 should be given to all STEMI patients who
AHA/ACC guidelines emphasize treatment tolerate them and should be continued long
times in recommending choice of reperfusion term. IV ACE inhibitors are contraindicated due
therapy for STEMI.28 to a high risk of hypotension.36 Angiotensin
receptor blockers should be used in the ACE
 Patients presenting to a hospital with PCI
inhibitor-intolerant patient.
capability should be treated with primary PCI
Aldosterone Antagonists: The Eplerenone Post-
(goal: 90 min door-to-balloon time).
acute Myocardial Infarction Heart Failure Efficacy
 Patients presenting to a hospital without PCI
and Survival Study (EPHESUS) trial demonstrated
capability and who cannot be transferred to a
a 17% reduction in cardiovascular death in post-
PCI center and undergo primary PCI within 90
STEMI patients with left ventricular dysfunction
min of first medical contact should be treated
and heart failure treated with the oral aldosterone
with fibrinolytic therapy (goal: 30 min to
antagonist eplerenone.37 Guidelines recommend
time of fibrinolytic administration).
use of aldosterone blockade in postinfarction
patients with depressed ejection fraction and
Adjunctive Treatments in STEMI clinical heart failure who are already on therapeutic
doses of b-blockers and ACE inhibitors.28 Care
Thienopyridine: Clopidogrel reduces vessel must be taken to avoid the development of
thrombosis in patients treated with coronary hyperkalemia with these agents.
stents during primary PCI. Clopidogrel has also
been shown to increase culprit vessel patency Complications of MI
and reduce rates of major adverse cardiac events
when utilized in conjunction with fibrinolytic Cardiogenic Shock: Acute MI is the most com-
therapy for STEMI.33 Guidelines recommend mon cause of cardiogenic shock. Shock compli-
clopidogrel loading (300 mg) and maintenance cates approximately 6% to 8% of infarcts.38 Shock
therapy in patients under the age of 75 who patients typically manifest hypotension (systolic
receive fibrinolytic therapy. Early treatment with pressure ,80 to 90 mm Hg), elevated pulmonary
clopidogrel or prasugrel therapy is also reason- artery wedge pressures, and depressed cardiac
able in patients referred for primary PCI.16,28 index (,1.8 to 2.0 L/min/m2). The most common
b-Blockers: The use of early b-blocker therapy cause of cardiogenic shock is pump failure
in STEMI reduces the risks of reinfarction and (.40% of myocardium involved) following in-
ventricular fibrillation but increases the risk of farction, typically STEMI. Other causes of shock
cardiogenic shock.34 Oral b-blocker therapy include acute mitral regurgitation, acute ventric-
should be instituted in the first 24 h after STEMI ular septal defect, and right ventricular infarction
in patients who do not have signs of heart failure, (discussed below). When shock due to pump
evidence of low cardiac output, or other contra- failure complicates infarction, the mortality is as
indications to treatment. IV b-blockers can be high as 60% to 80%.
administered at the time of presentation in The majority of patients in large registries do
hypertensive STEMI patients without an in- not undergo revascularization. The SHould we
creased risk of cardiogenic shock or other emergently revascularize Occluded Coronaries
contraindications. for cardiogenic shocK (SHOCK) trial examined
ACE Inhibitors: ACE inhibitors have been the role of early revascularization by randomiz-
shown to reduce mortality and the development ing cardiogenic shock patients to early revascu-
of clinical heart failure in patients following MI.35 larization vs a strategy of aggressive initial
ACE inhibitors should be started in all patients medical stabilization. Six-month survival was
without a contraindication who have a depressed improved in the patients who had coronary
ejection fraction (,40%) after STEMI. The bene- revascularization as compared to conservative
fits are greatest in those who have a history of management (56.0% vs 46.7%), although overall
previous infarction or clinical heart failure, but mortality was still very high.39

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Initial management of cardiogenic shock Acute Mitral Regurgitation (MR): There are
complicating acute infarction includes, in addi- several mechanisms for the development of MR
tion to emergent revascularization, correction of in the setting of an acute infarction, including:
hypovolemia, avoidance of negative inotropes left ventricular dilatation leading to enlargement
(eg, b-blockers), and vasopressor support. Echo- of the mitral annulus, papillary muscle dysfunc-
cardiography can identify mechanical complica- tion from ongoing ischemia, and papillary
tions of infarction that may precipitate shock. muscle rupture. The Global Utilization of Strep-
Patients may require ventilatory support and tokinase and Tissue Plasminogen Activator to
invasive hemodynamic monitoring. Finally, Treat Occluded Arteries (GUSTO-1) trial demon-
many patients may benefit from mechanical strated that new MR is a predictor of poor
support devices such as the intraaortic balloon prognosis.42 While mild MR is more common,
pump. While there is no definitive randomized severe MR occurs in only 2% to 4% of patients
data showing reduced mortality, intraaortic postinfarct and is associated with a mortality of
balloon pump support remains standard care 25%. MR typically occurs 7 to 10 days after an
for patients with shock that is refractory to acute infarction, though this onset may vary
medical therapy.40 Newer mechanical support according to the mechanism. Papillary muscle
devices have recently become available that rupture with resultant severe MR is a life-
provide even greater hemodynamic support than threatening condition and typically occurs within
the intraaortic balloon pump and may prove 2 to 7 days postinfarct. This diagnosis should be
considered in a patient with a new pansystolic
efficacious in treating cardiogenic shock patients.
murmur and sudden pulmonary edema. Rupture
Ventricular Septal Rupture: The incidence of
is more common after inferior or posterior
interventricular septal rupture has dramatically
infarction because the vascular supply to the
fallen with reperfusion therapy and was reported
posteromedial papillary muscle is less robust
to be around 0.2% in early thrombolytic trials.41
than supply to the anterolateral papillary. Trans-
Ventricular septal rupture may occur within the
thoracic echocardiography with color flow map-
first 24 h after infarction but more commonly is
ping is the diagnostic tool of choice, although the
seen between days 3 and 7. There appears to be
transesophageal approach often is helpful to
an increased risk of rupture in patients with
further quantify the severity of the MR and to
single-vessel disease, particularly of large left
plan surgical repair. Initial treatment is afterload
anterior descending arteries, and there is a higher reduction with drugs such as nitroprusside and
prevalence of this complication during first MIs. intra-aortic balloon pump support, but the
This diagnosis should be suspected in a patient definitive therapy is surgical.
with a recent infarction that appears stable, who Cardiac Free-Wall Rupture: Free-wall rupture is
suddenly deteriorates with hypotension, shock, a recognized cause of mortality in patients with
and pulmonary edema. Rupture is often accom- acute MI and was reported to be the cause of
panied by heart block, signs of biventricular cardiogenic shock in 3% of patients presenting
failure, and a new, harsh holosystolic murmur. with shock after an acute MI. This is a devastating
This condition is best diagnosed with echocardi- complication of STEMI or NSTEMI and in most
ography with color flow imaging. Diagnosis can cases leads to tamponade and death. However, a
also be made by documentation of a large left-to- subacute course has also been described in
right shunt at the time of right heart catheteriza- patients with a contained rupture or pseudoan-
tion. The treatment of choice is surgical closure, eurysm that have a more benign course. Survival
although, more recently, techniques and devices is poor even with surgical intervention.
have been developed allowing percutaneous Right Ventricular Infarction: Of patients with
closure. Survival is grim in both treatment inferior or inferoposterior infarct, 10% to 20%
strategies, with overall survival of ,30% in some develop hemodynamically significant right ven-
series. Ventricular septal rupture patients who tricular dysfunction. Right ventricular infarction
can be initially stabilized allowing delayed repair can also complicate some anterior infarctions.
have improved survival. The treatment for right ventricular infarct is

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86From: http://books.publications.chestnet.org/ on 07/19/2012 Chapter 7. Acute Coronary Syndromes (Horwitz and Gudmundsson)
different compared to other complications of Table 7Post-ACS Preventive Medications and Lifestyle
myocardial infarcts, and, therefore, timely diag- Modification

nosis is important. The clinical manifestation of Aspirin 75 to 160 mg daily, indefinitely


right ventricular dysfunction is the triad of Clopidogrela 75 mg daily for 30 d to 1 y
hypotension, elevated jugular venous pressure Indicated for at least 1 y after
with clear lung auscultation, and the absence of drug-eluting stent PCI
b-blockade Indicated for all post-MI patients
dyspnea. Frequently these patients have a posi- ACE inhibitor Indicated for all post-MI patients,
tive Kussmauls sign with the failure of the especially if EF ,40%
jugular venous pressure to drop with inspiration. Statin therapy Target LDL-C ,100 mg/dL;
consider ,70 mg/dL
The ECG typically shows an inferior infarct with
Smoking cessation Counseling, referral to cessation
1-mm ST elevations in right-sided leads (V4R), program
and the chest radiograph is usually without Physical activity 30 min daily physical activity,
pulmonary vascular congestion. An echocardio- 5 d/wk
Cardiac rehabilitation Risk factor assessment and
gram shows right ventricular dysfunction and is modification, education,
a critical test to differentiate this condition from prescribed exercise
cardiac tamponade. Pulmonary wedge pressure Weight loss In overweight patients
is normal, but right atrial pressure is elevated.
EF ejection fraction; LDL-C low-density lipoprotein
Left ventricular filling is decreased with resulting cholesterol.
a
low cardiac output, and fluid loading is therefore Treatment with prasugrel or ticagrelor an option.
important in the initial management of right
ventricular infarctions. Fluid resuscitation with
revascularization, have revolutionized the treat-
isotonic saline and avoidance of drugs that
ment of ST-elevation infarction. After a thorough
reduce preload is first-line therapy. However,
patient history, exam, and appropriate use of
temporary inotropic therapy may be required if a
ECG and cardiac biomarkers, ACS patients can
fluid challenge fails to improve the cardiac
be efficiently risk stratified and directed into
output. Long-term survival is most related to
management pathways that have been shown to
the extent of left ventricular infarction as the
improve outcomes. Medical, mechanical, and
right ventricle typically recovers most of its
behavioral therapies implemented can effectively
function.38
enhance both short-term and long-term survival,
Post-ACS Treatment reduce symptoms, and improve quality of life.
Recommendations
Relationships Disclosed
Post-ACS preventive medications and lifestyle
The author has disclosed the following
modifications are critical in prevention of recur-
rent events as ACS patients transition from the relationships: Grant monies (from industry relat-
acute illness to chronic coronary artery disease. ed sources): Industry supported grants for
Table 7 summarizes the guideline-recommended clinical trials in Acute Coronary Syndrome
therapies after a hospitalization for ACS. subjects: AstraZeneca, GlaxoSmithKline, Scher-
ing Plough, Roche. The ACCP Education Com-
Conclusion mittee has reviewed these relationships and has
resolved any potential conflict of interest.
Major advances in the treatment of ACS
patients have been made in the last 2 decades. References
The central role of the activated platelet in the
pathogenesis of ACS has been recognized. The 1. Thom T, Haase N, Rosamond W, et al. Heart
development of novel anticoagulants that target disease and stroke statistics2006 update: a
this abnormal physiology in ACS has been an report from the American Heart Association
important breakthrough. Improvements in reper- Statistics Committee and Stroke Statistics Sub-
fusion therapies, specifically in catheter-based committee. Circulation. 2006;113(6):e85151.

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Care Medicine Board Review:on21st
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Edition 87
2. Davies MJ. The pathophysiology of acute coro- acute coronary syndromes without st-segment
nary syndromes. Heart. 2000;83(3):361366. elevation. N Engl J Med. 2001;345(7):494502.
3. Corrado E, Rizzo M, Coppola G, et al. An update 14. Mehta S, Yusuf S, Peters R, et al. Effects of
on the role of markers of inflammation in pretreatment with clopidogrel and aspirin fol-
atherosclerosis. J Atheroscler Thromb. 2010;17(1): lowed by long-term therapy in patients undergo-
111. ing percutaneous coronary intervention: the PCI-
4. Braunwald E, Jones RH, Mark DB, et al. Diagnos- CURE study. Lancet. 2001;358(9281):527533.
ing and managing unstable angina. Agency for 15. Steinhubl SR, Berger PB, Mann JT, et al. Early and
Health Care Policy and Research. Circulation. sustained dual oral antiplatelet therapy following
1994;90(1):613622. percutaneous coronary intervention. JAMA. 2002;
5. Antman EM, Cohen M, Bernink PJLM, et al. The 288(19):24112420.
TIMI risk score for unstable angina/nonST 16. Wiviott SD, Braunwald E, McCabe CH, et al.
elevation MI. JAMA. 2000;284(7):835842. Prasugrel versus clopidogrel in patients with
6. Cannon CP, Weintraub WS, Demopoulos LA, et al. acute coronary syndromes. N Engl J Med. 2007;
Comparison of early invasive and conservative 357(20):20012015.
strategies in patients with unstable coronary 17. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor
syndromes treated with the glycoprotein IIb/IIIa versus clopidogrel in patients with acute coronary
inhibitor tirofiban. N Engl J Med. 2001;344(25):
syndromes. N Engl J Med. 2009;361(11):10451057.
18791887.
18. The EPIC Investigators. Use of a monoclonal
7. Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL,
antibody directed against the platelet glycopro-
Askari AT. Benefit of early invasive therapy in
tein IIb/IIIa receptor in high-risk coronary angio-
acute coronary syndromes: a meta-analysis of
plasty. N Engl J Med. 1994;330(14):956961.
contemporary randomized clinical trials. J Am Coll
19. The IMPACT-II Investigators. Randomised place-
Cardiol. 2006;48(7):13191325.
bo-controlled trial of effect of eptifibatide on
8. Anderson JL, Adams CD, Antman EM, et al. 2011
complications of percutaneous coronary interven-
ACCF/AHA focused update incorporated into
tion: IMPACT-II. Lancet. 1997;349(9063):14221428.
the ACC/AHA 2007 guidelines for the manage-
20. Inhibition of platelet glycoprotein IIb/IIIa with
ment of patients with unstable angina/nonST-
eptifibatide in patients with acute coronary
elevation myocardial infarction. Circulation. 2011;
syndromes. N Engl J Med. 1998;339(7):436443.
123(18):e426e579.
21. Inhibition of the platelet glycoprotein IIb/IIIa
9. Anderson JL, Adams CD, Antman EM, et al.
receptor with tirofiban in unstable angina and
ACC/AHA 2007 guidelines for the management
of patients with unstable angina/nonST-eleva- nonq-wave myocardial infarction. N Engl J Med.
tion myocardial infarctionexecutive summary. J 1998;338(21):14881497.
Am Coll Cardiol. 2007;50(7):652726. 22. A comparison of aspirin plus tirofiban with
10. SYNERGY Trial Investigators. Enoxaparin vs aspirin plus heparin for unstable angina. N Engl
unfractionated heparin in high-risk patients with J Med. 1998;338(21):14981505.
nonst-segment elevation acute coronary syn- 23. Fibrinolytic Therapy Trialists Collaborative
dromes managed with an intended early invasive Group. Indications for fibrinolytic therapy in
strategy. JAMA. 2004;292(1):4554. suspected acute myocardial infarction: collabora-
11. Stone GW, McLaurin BT, Cox DA, et al. Bivalir- tive overview of early mortality and major
udin for patients with acute coronary syndromes. morbidity results from all randomised trials of
N Engl J Med. 2006;355(21):22032216. more than 1000 patients. Lancet. 1994;343(8893):
12. Fifth Organization to Assess Strategies in Acute 311322.
Ischemic Syndromes Investigators, Yusuf S, Mehta 24. Effects of tissue plasminogen activator and a
SR, Chrolavicius S, et al. Comparison of fonda- comparison of early invasive and conservative
parinux and enoxaparin in acute coronary syn- strategies in unstable angina and non-Q-wave
dromes. N Engl J Med. 2006;354(14):14641476. myocardial infarction. Results of the TIMI IIIB
13. Yusuf S, Zhao F, Mehta SR, et al. Effects of Trial. Thrombolysis in Myocardial Ischemia. Cir-
clopidogrel in addition to aspirin in patients with culation. 1994;89(4):15451556.

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25. The Global Use of Strategies to Open Occluded myocardial infarction: a meta-analysis of random-
Coronary Arteries (GUSTO III) Investigators. A ized trials. J Am Coll Cardiol. 2007;49(4):422430.
comparison of reteplase with alteplase for acute 33. Sabatine MS, Cannon CP, Gibson CM, et al.
myocardial infarction. N Engl J Med. 1997;337(16): Addition of clopidogrel to aspirin and fibrinolytic
11181123. therapy for myocardial infarction with st-segment
26. 2005 American Heart Association guidelines for elevation. N Engl J Med. 2005;352(12):11791189.
cardiopulmonary resuscitation and emergency 34. Early intravenous then oral metoprolol in 45 852
cardiovascular care. Part 8: Stabilization of the patients with acute myocardial infarction: rando-
patient with acute coronary syndromes. Circula- mised placebo-controlled trial. Lancet. 2005;
tion. 2005;112(24 suppl):IV89IV-110. 366(9497):16221632.
27. Eagle KA, Goodman SG, Avezum A, Budaj A, 35. Flather MD, Yusuf S, Kber L, et al. Long-term
Sullivan CM, Lopez-Sendon J. Practice variation ACE-inhibitor therapy in patients with heart
and missed opportunities for reperfusion in ST- failure or left-ventricular dysfunction: a system-
segment-elevation myocardial infarction: findings atic overview of data from individual patients.
from the Global Registry of Acute Coronary Lancet. 2000;355(9215):15751581.
Events (GRACE). Lancet. 2002;359(9304):373377. 36. Antman EM, Anbe DT, Armstrong PW, et al.
28. Kushner FG, Hand M, Smith SC Jr., et al. 2009 ACC/AHA guidelines for the management of
Focused updates: ACC/AHA guidelines for the patients with ST-elevation myocardial infarc-
management of patients with ST-elevation myo- tionexecutive summary. Circulation. 2004;
cardial infarction (updating the 2004 guideline 110(5):588636.
and 2007 focused update) and ACC/AHA/SCAI 37. Pitt B, Remme W, Zannad F, et al. Eplerenone, a
guidelines on percutaneous coronary intervention selective aldosterone blocker, in patients with left
(updating the 2005 guideline and 2007 focused ventricular dysfunction after myocardial infarc-
update): a report of the American College of tion. N Engl J Med. 2003;348(14):13091321.
Cardiology Foundation/American Heart Associ- 38. Menon V, Hochman JS. Management of cardio-
ation Task Force on Practice Guidelines. J Am Coll genic shock complicating acute myocardial in-
Cardiol. 2009;54(23):22052241. farction. Heart. 2002;88(5):531537.
29. Keeley EC, Boura JA, Grines CL. Primary angio- 39. Hochman JS, Sleeper LA, Webb JG, et al. Early
plasty versus intravenous thrombolytic therapy revascularization in acute myocardial infarction
for acute myocardial infarction: a quantitative complicated by cardiogenic shock. N Engl J Med.
review of 23 randomised trials. Lancet. 2003; 1999;341(9):625634.
361(9351):1320. 40. Sjauw KD, Engstrom AE, Vis MM, et al. A
30. Andersen HR, Nielsen TT, Rasmussen K, et al. A systematic review and meta-analysis of intra-
comparison of coronary angioplasty with fibrino- aortic balloon pump therapy in ST-elevation
lytic therapy in acute myocardial infarction. N myocardial infarction: should we change the
Engl J Med. 2003;349(8):733742. guidelines? Eur Heart J. 2009;30(4):459468.
31. Nallamothu BK, Bates ER, Herrin J, et al. Times to 41. Crenshaw BS, Granger CB, Birnbaum Y, et al. Risk
treatment in transfer patients undergoing primary factors, angiographic patterns, and outcomes in
percutaneous coronary intervention in the United patients with ventricular septal defect complicat-
States. Circulation. 2005;111(6):761767. ing acute myocardial infarction. Circulation. 2000;
32. Wijeysundera HC, Vijayaraghavan R, Nallamothu 101(1):2732.
BK, et al. Rescue angioplasty or repeat fibrinolysis 42. GUSTO trial results. American Federation of
after failed fibrinolytic therapy for st-segment Clinical Research. Clin Res. 1993;41:207208.

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Notes

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90From: http://books.publications.chestnet.org/ on 07/19/2012 Chapter 7. Acute Coronary Syndromes (Horwitz and Gudmundsson)
Chapter 8. Heart Failure and Cardiac Pulmonary Edema
Steven M. Hollenberg, MD, FCCP

Objectives: The causes of heart failure are protean and


 Review the definition, demographics, and etiology of are listed in Table 1. The predominant causes,
congestive heart failure diagnosis. however, are ischemia, hypertension, alcoholic
 Understand the pathophysiology of the heart failure
cardiomyopathy, myocarditis, and idiopathic
syndrome.
 Review general treatment goals and medical therapy for cardiomyopathy. Coronary artery disease is also
heart failure, with an emphasis on acute heart failure in increasing, both as a primary cause and as a
the ICU. complicating factor of CHF.
Heart failure can be broken down into several
Key words: aldosterone antagonism; angiotensin-convert- different classifications, as follows: acute versus
ing enzyme inhibition; angiotensin receptor blockers;
cardiogenic shock; congestive heart failure; remodeling;
chronic; left-sided versus right-sided; and systolic
vasodilators versus diastolic dysfunction. It is important for the
clinician to distinguish between systolic and
Synopsis: diastolic dysfunction, as both the diagnostic
Congestive heart failure (CHF) can be defined as the workup and therapeutic sequence differ. Although
inability of the heart to provide an adequate cardiac output CHF results most commonly from decreased
without invoking maladaptive compensatory mechanisms.
systolic performance, diastolic dysfunction, which
This chapter will review the definition, demographics, and
etiology of CHF diagnosis and will present the general is defined clinically as cardiogenic pulmonary
treatment goals and medical therapy. Additionally, the congestion in the presence of normal systolic
pathophysiology of the heart failure syndrome will be performance, is becoming more common as a
explored.
cause of CHF, particularly in the elderly. The
estimated prevalence of diastolic heart failure is
30% to 35% overall, and .50% in patients .70
Definition and Epidemiology years old.2,3
The severity of chronic heart failure is most
Congestive heart failure (CHF) can be defined as commonly delineated using the classification
the inability of the heart to provide an adequate developed by the New York Heart Association
cardiac output without invoking maladaptive (NYHA). This classification divides patients into
compensatory mechanisms. CHF affects .5 functional classes depending on the degree of
million patients in the United States, which is effort needed to elicit symptoms (Table 2). More
an estimated 2.5% of the adult population.1 Heart recently, stages in the evolution of heart failure
failure develops in 550,000 patients for the first have been proposed by an American College of
time every year, and CHF results in .280,000 Cardiology/American Heart Association task
cardiovascular deaths and about 1.1 million force to emphasize its progressive nature and to
hospital admissions per year in the United States. focus on preventive measures and early inter-
CHF is now the most common reason for vention (Table 3). These stages have been linked
hospitalization in the elderly, and annual costs to therapeutic approaches.
are estimated at more than $33 billion.1 The
incidence of heart failure has been increasing, not Pathophysiology
only because of the aging of the population but
also because improved treatment of hypertension Heart failure is a syndrome caused not only
and coronary disease is allowing patients to by the low cardiac output resulting from com-
avoid early mortality only to have heart failure promised systolic performance but also by the
develop later. effects of compensatory mechanisms. Myocardial

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Table 1Etiologies of CHF Table 2NYHA Functional Classification of Heart Failure

Ischemic Class Description


Hypertensive
Idiopathic I Symptoms of heart failure only at levels that
Valvular would limit healthy people
Peripartum II Symptoms of heart failure with ordinary exertion
Familial III Symptoms of heart failure on less than ordinary
Toxic exertion
Alcoholic IV Symptoms of heart failure at rest
Radiation
Drug-related (anthracyclines)
Heavy metals (cobalt, lead, or arsenic)
Metabolic/nutritional maladaptive.4 Early local remodeling after MI
Systemic diseases may expand the infarct zone, but late remodeling,
Hypothyroidism which likely involves neurohormonal mecha-
Connective tissue disease
Diabetes
nisms initiated by hemodynamic stress, involves
Sarcoidosis the left ventricle (LV) globally and is associated
Infiltrative with dilation that increases over time, distortion of
Amyloidosis
ventricular shape, and hypertrophy of the walls.
Hemochromatosis
Tachycardia induced The failure to normalize increased wall stresses
Autoimmune results in progressive dilatation and deterioration
in contractile function. Similar processes are
operative in other sorts of cardiomyopathy as
damage from any cause can produce myocardial well. Ventricular remodeling can be considered a
failure. To compensate for the reduced cardiac primary target for treatment and a reliable
output of a failing heart, ventricular filling surrogate for long-term outcomes.3
pressure rises in an attempt to maintain output
via the Frank-Starling law. These elevated dia- Diagnosis
stolic filling pressures can compromise subendo-
cardial blood flow and cause or worsen ischemia. The symptoms and signs of CHF relate to low
With continued low cardiac output, additional cardiac output and elevated ventricular filling
compensatory mechanisms come into play, in- pressures. Low output produces the symptoms of
cluding sympathetic nervous system stimulation, weakness and fatigue and an ashen appearance,
activation of the renin-angiotensin system, and sometimes with mottling. Increased left-sided
vasopressin secretion. All of these mechanisms filling pressures result in symptoms of pulmonary
lead to sodium and water retention and veno- congestion, such as dyspnea, cough, orthopnea,
constriction, increasing both preload and after- and paroxysmal nocturnal dyspnea as well as
load. These increases in preload and afterload, signs that may include tachycardia; pulmonary
rales; a diffuse, enlarged, and laterally displaced
although initially compensatory, can exacerbate
point of maximal impulse; an S3 and S4 gallop;
the heart failure because elevated preload in-
and a murmur of mitral regurgitation. Elevated
creases pulmonary congestion, and elevated
afterload impedes cardiac output.
Table 3Stages of Heart Failure
Recent attention has focused on cardiac
remodeling, the process by which ventricular size, Stage Description
shape, and function are regulated by mechanical,
neurohormonal, and genetic factors, as a patho- A High risk for heart failure; no structural disease or
symptoms
physiologic mechanism in heart failure. Remod- B Heart disease with asymptomatic left ventricle
eling may be physiologic and adaptive during dysfunction
normal growth, but excessive remodeling after C Prior or current symptoms of heart failure
D Advanced heart disease and severely symptomatic
myocardial infarction (MI), cardiomyopathy, hy- or refractory heart failure
pertension, or valvular heart disease can be

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92From: http://books.publications.chestnet.org/ on 07/19/2012 Chapter 8. Heart Failure and Cardiac Pulmonary Edema (Hollenberg)
right-sided preload can lead to such symptoms as measurement of BNP has been used to distin-
anorexia, nausea, and abdominal pain, along with guish between heart failure and pulmonary
signs of systemic congestion, such as jugular causes of dyspnea. In the Breathing Not Properly
venous distention, right-sided S3 gallop, murmur study of 1,586 patients presenting to the emer-
of tricuspid regurgitation, hepatomegaly, ascites, gency department with a chief complaint of
and peripheral edema. dyspnea, a plasma BNP level .400 pg/mL
The presentation of acute heart failure and accurately predicted CHF, whereas levels ,100
pulmonary edema can be dramaticthe sudden pg/mL indicated noncardiac dyspnea; values
onset of shortness of breath and tachypnea with between 100 and 400 pg/mL were less useful.6
use of accessory muscles. Crackles and, often, Such intermediate values may be caused by CHF
wheezing can be heard throughout the lung but may also represent preexisting LV dysfunc-
fields, at times obscuring some of the cardiac tion or right-sided heart failure. The addition of
auscultatory findings. Hypotension and evidence echocardiography in the acute setting may be
of peripheral vasoconstriction and hypoperfu- especially valuable in patients with intermediate
sion may be present if cardiac output is de- BNP levels.7
creased. The differential diagnosis of cardiac Echocardiography can provide important in-
pulmonary edema includes other causes of acute formation about cardiac size and function, and it
dyspnea, such as pulmonary embolism, pneu- should be performed in all patients with new-onset
mothorax, and bronchial asthma as well as heart failure. Echocardiography is simple and safe,
causes of noncardiac pulmonary edema, such as and it permits the systemic interrogation of cardiac
aspiration, infection, toxins, or trauma. chamber size, LV and right ventricle function,
The initial evaluation of a patient with valvular structure and motion, atrial size, and
pulmonary edema should include an ECG and pericardial anatomy. Regional wall motion abnor-
chest radiograph. The ECG may show evidence malities are compatible with coronary heart disease
of myocardial ischemia and can also detect but are not specific for ischemia as they are also seen
arrhythmias; conduction abnormalities, such as in 50% to 60% of patients with idiopathic dilated
AV block and bundle branch block, may be cardiomyopathy. Fibrotic and thinned akinetic
diagnosed. In addition, Q waves indicative of areas, however, indicate previous infarction. Dopp-
previous infarction or criteria diagnostic of ler echocardiography can be used to evaluate the
ventricular hypertrophy may provide clues about severity of mitral and tricuspid regurgitation, and
the substrate for heart failure; atrial enlargement tricuspid regurgitation velocity can be used to
speaks to the chronicity of elevated filling estimate pulmonary artery pressure. In addition,
pressures. The chest radiograph can demonstrate Doppler echocardiography is increasingly used in
pulmonary vascular redistribution, with or with- the diagnosis of diastolic dysfunction.8
out bilateral hazy pulmonary infiltrates, classi-
cally perihilar, as well as cardiomegaly. Pleural Therapy
effusions may be identified but are neither
sensitive nor specific. Treatment Goals
Laboratory evaluation should include base-
line measurement of serum electrolytes, creati- The goals of CHF therapy are to control
nine, and blood glucose; liver function tests; and symptoms, improve exercise tolerance, prolong
a CBC count. Measurement of plasma B-type life, and, where possible, correct the underlying
natriuretic peptide (BNP) has also been intro- cause. Different therapies can have disparate
duced5 into the diagnostic algorithm for CHF. effects on these goals.
BNP is produced by ventricular myocytes in Therapeutic agents can be viewed in the light
response to increased wall stress (ie, increased of the pathophysiologic mechanisms of CHF
filling pressures and stretch).5 Plasma BNP levels development. Traditionally, these have been
are increased in patients with heart failure, and considered in hemodynamic terms. Fluid restric-
the plasma concentration of BNP has been shown tion and diuretic and venodilator agents decrease
to correlate with NYHA functional class. The cardiac preload. Angiotensin-converting enzyme

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Table 4Remodeling and Survival by Drug Class Table 5Precipitating Causes of CHF

Established Remodeling Survival Myocardial ischemia or infarction


Therapy Effects Effects Excess salt or fluid intake
Noncompliance or inadequate drug regimen
ACE-I Benefit Benefit Renal failure
ARB Benefit Benefit Arrhythmias
(ACE better) (ACE better) Anemia
Aldosterone Benefit Benefit Infection
antagonists Fever
b-blocker Benefit Benefit Thyrotoxicosis
Diuretic No benefit No benefit Pregnancy
Digoxin No benefit No benefit Pulmonary embolism
Other therapies
Endothelin No benefit No benefit
antagonists
TNF-a No benefit No benefit the notion that in the presence of significant
Inotropes Adverse Adverse amounts of ischemic yet viable myocardium,
TNF tumor necrosis factor. revascularization confers a survival benefit.9 For
patients with arrhythmias, either cardioversion
or rate control can produce marked improve-
(ACE) inhibitors, angiotensin receptor blockers ment.
(ARBs), and aldosterone antagonists counteract Patients with acute heart failure should be
the activation of the renin-angiotensin-aldoste- put on bed rest (which by itself can produce
rone system and reduce afterload. Arterial diuresis), with sodium restriction to ,2 g/d and
dilators can also reduce afterload. Inotropic fluid restriction in severe cases. Attention should
agents can improve cardiac pump function and be paid to prophylaxis for deep venous throm-
increase output. More recently, attention has been bosis.
given to the way therapy affects counterproduc-
tive neurohormonal activation. b-Blockers can Pharmacologic Therapy
counteract sympathetic activation and are being
used more commonly in heart failure manage- Diuretics
ment. The most current approaches, however,
take into account the effects of different therapies Diuretics cause renal sodium and water loss,
on ventricular remodeling. Agents used for decreasing preload, and thus pulmonary and
therapy that have been shown to have a systemic congestion. For inpatient treatment of
beneficial effect on remodeling, such as ACE decompensated heart failure, loop diuretics such
inhibitors, ARBs, aldosterone antagonists, and b- as furosemide are usually chosen initially be-
blockers, reduce mortality and are effective cause of their rapid onset and are administered
across the whole spectrum of heart failure in IV bolus doses. When used for patients who
severity (Table 4). Mechanical approaches to present with pulmonary edema, most of the
remodeling, most notably cardiac resynchroniza- rapid effect of furosemide is attributable to
tion therapy (CRT), also appear to be effective. venodilation.
If there is no response to a bolus dose of a
General Measures loop diuretic, the dose is titrated to achieve the
desired effect, usually by doubling the dose.
The first order of business in the therapy for Loop diuretics enter the glomerulus primarily by
patients with new or decompensated CHF is to tubular secretion into the proximal tubule and so
address the precipitating causes, the most prom- exhibit a threshold effect. Once the effective dose
inent of which are listed in Table 5. Bypass has been determined, the degree of diuresis is
surgery or percutaneous intervention for cardiac usually adjusted by changing the frequency of
ischemia can improve symptoms and ventricular diuretic administration. If intermittent bolus
performance. Registry data consistently support doses of loop diuretics are ineffective or are

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94From: http://books.publications.chestnet.org/ on 07/19/2012 Chapter 8. Heart Failure and Cardiac Pulmonary Edema (Hollenberg)
poorly tolerated because of large fluid shifts and hypertrophy and remodeling, and their inhibi-
consequent hypotension, continuous infusion tion by ACE inhibitors may explain part of their
may be preferable.10 Alternatively, another di- beneficial effects.13 ACE inhibitors also modulate
uretic with a different mechanism of action, such sympathetic nervous system activity, and in-
as metolazone or chlorothiazide, may be added. creased nitric oxide production may exert direct
The use of diuretics can lead to significant beneficial effects on cardiac myocytes.
hypokalemia or hypomagnesemia, which can ACE inhibitors improve hemodynamics,
predispose the patient to arrhythmias. Careful functional capacity, and survival in patients
addition of a potassium-sparing diuretic can be across the spectrum of severity of chronic CHF
considered in some settings. and after MI. The CONSENSUS group14 com-
pared therapy with enalapril to placebo in 253
Nitrates patients with advanced heart failure (NYHA
class III or IV) and showed a 40% reduction in
Nitrates are still the first-line agents for the 6-month mortality; this benefit was sustained,
symptomatic relief of angina pectoris and in and the risk reduction averaged over the 10-year
cases when MI is complicated by CHF. Given the duration of the trial was 30%. The SOLVD
high incidence of coronary artery disease in treatment trial15 compared therapy with enala-
patients with CHF, the use of nitrates to reduce pril to placebo in 2,569 patients with symptom-
preload is often desirable. In patients with atic heart failure (NYHA class II to III) and
severely decompensated CHF, therapy with IV showed a 16% mortality reduction. Moreover,
nitroglycerin is preferred because of the ques- therapy with ACE inhibitors also prevented the
tionable absorption of oral and transdermal development of CHF in patients with asymp-
preparations and for the ease of titration; IV tomatic LV dysfunction in the SOLVD prevention
nitroglycerin should be started at 5 lg/min and trial.16
increased in increments of 5 lg/min every 3 to 5 ACE inhibitors also improve the outcome in
min as needed for symptomatic relief. The major patients with asymptomatic LV dysfunction or
adverse effects of nitrates are hypotension and overt heart failure after an acute MI. In the
headache. Survival and Ventricular Enlargement Trial (or
Long-term therapy with oral nitrates alone SAVE trial),17 2,231 asymptomatic patients with
does not affect ventricular remodeling and, thus, an ejection fraction (EF) ,40% were randomly
in the absence of ongoing ischemia, is not usually assigned to receive either captopril or placebo.
a first-line choice. When combined with hydral- Captopril therapy decreased mortality by 19% at
azine, however, salutary effects on outcome have 42 months; it also decreased hospitalization for
been demonstrated, first in the V-Heft,11 and heart failure and, interestingly, recurrent MI.17
more recently in the A-HeFT trial.12 These trials The latter effect may have been due to an
are described in the Hydralazine section. improvement in endothelial function. The Acute
Infarction Ramipril Efficacy (or AIRE) trial18
ACE Inhibitors compared therapy with ramipril to placebo in
2,006 patients with clinical heart failure and
ACE inhibitors inhibit the conversion of showed a 27% reduction in mortality at 15
angiotensin I to angiotensin II and the break- months. The survival benefit was maintained
down of bradykinin. Both of these actions over the long term in both trials.
produce vasodilation, the latter through brady- Patients should be started on therapy with low
kinin-induced nitric oxide production; however, doses and titrated upward to the range demon-
the increased inhibition of ventricular remodel- strated to be beneficial in clinical trials (ie, captopril,
ing seen with ACE inhibitors, compared to that 50 mg three times daily; enalapril, 20 mg twice
seen with other vasodilators, speaks to the daily; or lisinopril, 40 mg once daily). Side effects of
potential for involvement of other mechanisms. ACE inhibitors include cough, renal failure (usual-
Local renin-angiotensin systems, both intracardi- ly occurring in the setting of renal artery stenosis),
ac and intravascular, contribute to myocardial hyperkalemia, and angioedema.

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ARBs Aldosterone Antagonists

An alternative approach to inhibiting the Although aldosterone is predominantly


effects of angiotensin II is the use of agents that known for its role in the regulation of renal
block the angiotensin II receptor (ie, ARBs). sodium and potassium excretion, its neurohu-
Because these agents do not increase bradykinin moral effects are gaining increased recognition.
levels, the incidence of some side effects, such as Aldosterone inhibition also affects ventricular
cough and angioedema, is greatly reduced. In a remodeling. The RALES trial23 randomized 1,653
number of trials, the hemodynamic effects of patients with NYHA class III and IV heart failure
ARBs have been shown to be similar to those of to receive spironolactone or placebo, and found a
ACE inhibitors. Trials comparing ACE inhibitors reduction in the 24-month mortality rate from 46
to ARBs in patients with heart failure have to 35% (relative risk, 30%; P , .001). Hyperkale-
suggested similar mortality reductions.19 None- mia was uncommon, and the main side effect
theless, the number of patients with heart failure was gynecomastia. The recently reported
treated with ARBs and followed up for mortality EPHESUS trial24 randomized 6,632 patients with
is still relatively small compared with those LV dysfunction after MI to receive eplerenone or
treated with ACE inhibitors, and so therapy with placebo and found a 15% reduction in mortality
ARBs is usually reserved for patients who cannot (relative risk, 0.85; 95% confidence interval, 0.75
tolerate ACE inhibitors; however, ARBs are a to 0.96; P , .01). In this trial, hyperkalemia was
good alternative. noted in 5.5% of the eplerenone group compared
to 3.9% of the placebo group (P , .01), but,
The recognition that angiotensin II is pro-
interestingly, the incidence of hypokalemia was
duced by pathways other than ACEs has
reduced from 13.1% to 8.4%.
provided a rationale for using ACE inhibitors
It should be noted that the doses of aldoste-
and ARBs in combination therapy. This approach
rone antagonists used in these heart failure trials
was tested in the 2001 V-Heft,20 in which
were well below those used for diuresis. None-
valsartan or placebo was added to usual therapy
theless, careful attention to serum potassium
in patients with heart failure. Although mortality
levels is warranted when using these agents for
was unchanged, a combined end point of
any indication.
mortality and hospital admission for CHF was
reduced with valsartan therapy. A subset analy- b-Blockers
sis of this trial yielded the provocative finding
that although valsartan therapy improved mor- Symptomatic heart failure results in the
tality in patients who were receiving ACE activation of neurohumoral mechanisms, includ-
inhibitors but not b-blockers, and in those ing the sympathetic nervous system, which
receiving b-blockers but not ACE inhibitors, initially support the performance of the failing
when valsartan was added as triple therapy on heart. Long-term activation of the sympathetic
top of ACE inhibitors and b-blockers, mortality nervous system, however, exerts deleterious
was increased.20 Other trials, however, have not effects. Circulating catecholamine levels correlate
shown adverse effects of triple combination with survival in these patients.25 Sympathetic
therapy. In the VALIANT trial,21 which com- activation can increase ventricular volumes and
pared therapy with valsartan, captopril, and the pressure by causing peripheral vasoconstriction
combination of the two agents in patients with and impairing sodium excretion by the kidneys;
acute MI and CHF, an adverse effect of the it can also provoke arrhythmias. The long-term
combination of ARBs, ACE inhibitors, and b- stimulation of b-receptors reduces the respon-
blockers was not seen. Increased mortality was siveness to b-adrenergic agonists because of the
also not observed when the ARB candesartan downregulation and desensitization of the b-
was added to therapy with ACE inhibitors and b- receptor and its coupled signaling pathways; b-
blockers in patients with heart failure in the blockade can upregulate adrenergic receptor
CHARM-Added trial.22 density, restoring inotropic and chronotropic

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96From: http://books.publications.chestnet.org/ on 07/19/2012 Chapter 8. Heart Failure and Cardiac Pulmonary Edema (Hollenberg)
responsiveness.26 Catecholamines induce oxida- of b-blockers will need to begin anew after the
tive stress in cardiac myocytes, potentially resolution of acute CHF. It is usually best to
leading to programmed cell death, which is a attempt to resolve acute episodes of heart failure
process counteracted by b-blockers.27 b-Blockers by diuresis and the adjustment of other medica-
also reduce the circulating level of vasoconstric- tions while holding b-blocker doses constant, and
tors and mitigate their effects, decreasing after- to halve the dose if heart failure persists.
load. Perhaps most importantly, catecholamines
promote deleterious ventricular remodeling, and Hydralazine
b-blockers can decrease LV end-systolic and end-
diastolic volume.26 Thus, although it is perhaps Hydralazine reduces afterload by directly
counterintuitive on hemodynamic grounds, there relaxing smooth muscle. Its effects are almost
is now compelling evidence that b-blockers are exclusively confined to the arterial bed. In
beneficial not only for patients with acute MI healthy subjects, the hypotensive actions of
complicated by heart failure but also with hydralazine provoke a marked reflex tachycar-
chronic heart failure from all causes.26 dia, but this response is often blunted in patients
b-Blockers have now been evaluated in with heart failure.
.10,000 patients with heart failure and systolic Hydralazine therapy is effective in increasing
dysfunction. This collective experience indicates cardiac output in patients with heart failure.
that long-term treatment with b-blockers can Therapy with hydralazine in combination with
relieve symptoms, improve ventricular perfor- oral nitrates was the first therapy shown to
mance, and reduce mortality and the need for
improve mortality in CHF patients, reducing
hospitalization. The following three agents have
mortality in patients with NYHA class III and IV
been shown to decrease mortality in patients with
heart failure in the V-Heft trial.11 Enalapril was
NYHA class II and III heart failure: metoprolol
shown to be superior to this combination.32 In
XL28, bisoprolol29, and carvedilol.30 Studies31 with
addition, oral hydralazine must be administered
carvedilol have suggested that the benefits extend
four times a day, and prolonged administration is
to patients with NYHA class IV heart failure.
attended by the development of a lupus-like
These benefits of b-blockers are seen in patients
syndrome in up to 20% of patients; thus,
with or without coronary artery disease, patients
hydralazine has usually been reserved for ACE-
with or without diabetes, and patients who are
already receiving ACE inhibitors. intolerant patients.
Initiation of therapy with b-blockers, however, In 2004, a fixed dose of both isosorbide
can be problematic during the acute phase of heart dinitrate and hydralazine administered twice
failure, as they can depress contractility. When daily was tested in black patients with NYHA
administered for the treatment of heart failure class III and IV heart failure, a subgroup that was
indications per se, b-blockers should be introduced previously noted to have a favorable response to
when the patient is in a well-compensated and this therapy and that may not respond as well to
euvolemic state, typically in the ambulatory ACE inhibition.12 Therapy with hydralazine and
setting and at low doses. Patients who experience nitrates improved mortality, hospitalization for
an exacerbation of heart failure while receiving heart failure, and quality of life.12
maintenance b-blocker therapy, particularly at a
higher dose, present a previously rare dilemma Nesiritide
that is becoming more common. No controlled
observations are available to guide therapy, so Nesiritide is a recombinant form of human
current practice remains largely at the discretion of BNP. Assays of circulating BNP levels have been
individual clinicians. Discontinuing therapy with used in the diagnosis of heart failure and have
b-blockers, or decreasing their dose, may expose some prognostic value, but the therapeutic use of
myocardial b-receptors to endogenous catechol- BNP differs. When infused intravenously, nesiri-
amines and may result in a brief increase in tide is a balanced arterial and venous vasodilator
contractility. On the other hand, the slow titration that may also have a modest natriuretic effect.

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In patients with heart failure, IV nesiritide Digoxin
has been shown to increase stroke volume and
cardiac output and to decrease right atrial and Digitalis, which has been used to treat heart
pulmonary capillary wedge pressure.33 Its ef- failure for .200 years, works by inhibiting Na-K-
fects, compared with those of IV nitroglycerin, in dependent adenosine triphosphatase activity,
patients with acute heart failure were tested in causing intracellular sodium accumulation and
the randomized VMAC trial.34 In this trial, 489 increasing intracellular calcium via the sodium
patients, including 246 who underwent pulmo- calcium exchange system. Digoxin improves
nary artery catheterization, were randomly as- myocardial contractility and increases cardiac
signed to receive nesiritide, IV nitroglycerin, or output, but its inotropic effects are mild com-
placebo for 3 h. After this initial placebo- pared with those of catecholamines. The effect of
controlled period, the placebo-treated patients digoxin on patient survival was definitively
were randomly reassigned to receive either addressed in the Digoxin Investigators Group
nesiritide or IV nitroglycerin, and all patients (or DIG) trial,38 a study of 6,800 patients with
were observed for 24 h (ie, the active-treatment symptomatic CHF and systolic dysfunction.
phase).34 Therapy with nesiritide decreased the There was no difference in survival between the
mean pulmonary capillary wedge pressure sig- digoxin and placebo groups, but survival did
nificantly more than therapy with either IV significantly decrease during hospitalization for
nitroglycerin or placebo at 3 h (5.8 vs 3.8 and patients with heart failure.38 Thus, apart from its
2.0 mm Hg, respectively) and significantly more use as an antiarrhythmic agent, digoxin is
than therapy with nitroglycerin at 24 h (8.2 vs 6.3 recommended for therapy in patients with
mm Hg, respectively). Symptoms of dyspnea systolic dysfunction and symptomatic heart
were decreased and global clinical status was failure despite therapy with diuretics, ACE
improved with nesiritide therapy compared with inhibitors, and b-blockers.
placebo, but there was no significant difference in
these parameters compared to therapy with IV Inotropic Agents
nitroglycerin. There was no significant difference
in the 30-day rehospitalization rate or the 6- In severe decompensated heart failure, ino-
month mortality rate.34 tropic support may be initiated. Dobutamine is a
Nesiritide is given as an initial IV bolus of 2 selective b1-adrenergic receptor agonist that can
lg/kg followed by a continuous infusion of 0.01 improve myocardial contractility and increase
lg/kg/min; the dose can be increased every 3 h cardiac output. Dobutamine is the initial inotro-
by 0.005 lg/kg/min up to a maximum of 0.03 pic agent of choice in patients with decompen-
lg/kg/min. Hypotension is the most common sated acute heart failure and adequate systolic
side effect. BP. Dobutamine has a rapid onset of action and a
Although nesiritide has natriuretic proper- plasma half-life of 2 to 3 min; infusion is usually
ties, it has not been shown to improve the initiated at 5 lg/kg/min and then titrated.
glomerular filtration rate or renal plasma flow.35 Tolerance of the effects of dobutamine may
In addition, meta-analyses of data from the develop after 48 to 72 h, possibly because of the
VMAC trial33 and other trials have suggested downregulation of adrenergic receptors. Dobu-
that nesiritide may worsen renal function36 and tamine has the potential to exacerbate hypoten-
decrease survival at 30 days compared with sion in some patients and can precipitate
conventional therapies.37 The degree to which tachyarrhythmias.
these issues are applicable for use in patients Milrinone is a phosphodiesterase inhibitor
with acute heart failure and hemodynamic with positive inotropic and vasodilatory actions.
decompensation is controversial, but the poten- Because milrinone does not stimulate adrenergic
tial adverse effect on long-term outcome is a receptors directly, it may be effective when
significant concern, the resolution of which added to therapy with catecholamines or when
awaits the completion of appropriately powered b-adrenergic receptors have been downregulat-
prospective clinical trials. ed. Compared to catecholamines, phosphodies-

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98From: http://books.publications.chestnet.org/ on 07/19/2012 Chapter 8. Heart Failure and Cardiac Pulmonary Edema (Hollenberg)
terase inhibitors have fewer chronotropic and Arrhythmias
arrhythmogenic effects.
Although they are clearly useful in improv- Arrhythmias are common in patients with
ing hemodynamics in the acute setting, contro- heart failure. Nonsustained ventricular tachycar-
versy has arisen regarding the use of inotropic dia may occur in as many as 50% of patients, and
agents (other than digoxin) as outpatient main- complex ventricular depolarizations in as many as
tenance therapy for chronic heart failure. Con- 80%. Forty to 50% of these deaths are sudden, and
cerns have included exacerbation of arrhythmic many are attributable to arrhythmias.
complications by induction of myocardial ische- The mortality benefits of some of the stan-
mia or by independent pathways and the dard therapies for heart failure, particularly b-
perpetuation of neurohumoral activation that blockers, may be attributable in part to antiar-
might accelerate the progression of myocardial rhythmic properties. Specific antiarrhythmic
damage. Milrinone has been examined in a agents, however, have not proven to be very
prospective manner in the OPTIME-CHF trial39 effective for preventing sudden death in patients
in order to determine whether its use could with heart failure,40 and so attention has focused
reduce hospitalization time after an exacerbation on identifying patients who would benefit from
of acute heart failure. Although these observa- the placement of an implantable cardiac defibril-
tions did not demonstrate any advantage for lator (ICD).
patients who were treated with milrinone, The insertion of an ICD as secondary pre-
patients whom the investigators thought need- vention in survivors of sudden cardiac death or
ed acute inotropic support were not included in patients with hemodynamically significant sus-
the trial, thereby biasing the enrollment toward a tained ventricular tachycardias has been well
less severely afflicted cohort.39 Therefore, the demonstrated to improve survival in clinical
utilization of such agents today remains at the trials.40 Virtually all of the patients enrolled in
discretion of the clinician. The proof that these the study had LV dysfunction, and about half
agents have beneficial effects on hard clinical end had clinical heart failure.
points remains elusive, but their hemodynamic ICDs are also effective as primary prevention
effects are attractive for treating patients with in selected patients with heart failure. The
decompensation. MADIT I trial41 and MUSST42 showed a mortal-
Inotropic infusions need to be titrated care- ity benefit with ICD therapy in patients with LV
fully in patients with ischemic heart disease to dysfunction (EF, ,35% to 40%) and nonsustained
maximize coronary perfusion pressure with the ventricular tachycardia in whom sustained ven-
least possible increase in myocardial oxygen tricular tachycardia was inducible in an electro-
demand. Invasive hemodynamic monitoring physiologic study.41,42 The MADIT II trial43
can be extremely useful for the optimization of showed a mortality benefit with ICD therapy in
therapy in these unstable patients, because a trial in which the entry criterion was simply an
clinical estimates of filling pressure can be EF ,30%. Most of the patients in these trials had
unreliable, and because changes in myocardial ischemic cardiomyopathy. More recently, the
performance and compliance and therapeutic SCD-HeFT44 compared ICD implantation to
interventions can change cardiac output and amiodarone therapy in patients with heart failure
filling pressures precipitously. The optimization due either to ischemic or nonischemic cardiomy-
of filling pressures and serial measurements of opathy (EF, ,35%) and found a mortality benefit
cardiac output (and other parameters, such as with ICD in both groups.
mixed venous oxygen saturation) allow for the
titration of inotropes and vasopressors to the Cardiac Resynchronization
minimum dosage required to achieve the chosen
therapeutic goals, thus minimizing the increases Left bundle-branch block or other conduction
in myocardial oxygen demand and arrhythmo- system abnormalities can cause dyssynchronous
genic potential. ventricular contraction. Such dyssynchrony

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Care Medicine Board Review:on21st
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Edition 99
causes abnormal septal motion, decreasing con- Acknowledgment
tractile performance and myocardial efficiency. It
also reduces diastolic filling times and can This chapter is reprinted with permission
increase the duration and degree of mitral from the ACCP Critical Care Medicine Board
regurgitation. The goal of CRT is to pace the LV Review. 20th ed. Northbrook, IL: American
and right ventricle to restore physiologic atrio- College of Chest Physicians; 2009.
ventricular timing and contraction synchrony.
This is accomplished by placing the standard Relationship Disclosed
leads in the right atrium and right ventricle and
by placing a special lead through the coronary The author has disclosed the following
sinus to enable pacing of the lateral aspect of the relationships: Speakers bureau: Novartis-makers
LV. of Valsartan. The ACCP Education Committee
CRT, by optimizing the coordination of has reviewed these relationships and resolved
contraction, improves LV contractile function, any potential conflict of interest.
stroke volume, and cardiac output, with de-
creased pulmonary capillary wedge pressures. References
This improved performance is associated with a
decrease or no increase in myocardial oxygen 1. Rosamond W, Flegal K, Friday G, et al. Heart
consumption, thus increasing myocardial effi- disease and stroke statistics: 2007 update; a report
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associated with reverse ventricular remodeling. Committee and Stroke Statistics Subcommittee.
In the MIRACLE trial,45 biventricular pacing Circulation. 2007;115(5):e69e171.
produced significant decreases in LV end-systolic 2. Zile MR, Brutsaert DL. New concepts in diastolic
and end-diastolic dimensions, a significant re- dysfunction and diastolic heart failure: part I.
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reduction in LV mass, all of which are signs of stolic function. Circulation. 2002;105(11, 12):
reverse remodeling. Cardiac resynchronization 13871393, 15031508.
also improved exercise capacity, functional class, 3. Zile MR, Brutsaert DL. New concepts in diastolic
and quality of life in patients in this trial.45 dysfunction and diastolic heart failure: part II.
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to emerge.45 The COMPANION trial46 compared 2002;105(12):15031508.
optimal medical therapy with CRT with and 4. Sutton MG, Sharpe N. Left ventricular remodeling
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class III to IV heart failure and an LV EF ,35%. therapy. Circulation. 2000;101(25):29812988.
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ization compared with medical therapy. failure can be diagnosed by comprehensive

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33. Colucci WS, Elkayam U, Horton DP, et al. tients with coronary disease at high risk for
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2000;343(4):246253. ized study of the prevention of sudden death in
34. VMAC Investigators. Intravenous nesiritide vs patients with coronary artery disease: Multicenter
nitroglycerin for treatment of decompensated Unsustained Tachycardia Trial Investigators. N
congestive heart failure: a randomized controlled Engl J Med. 1999;341(25):18821890.
trial. JAMA. 2002;287(12):15311540. 43. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic
35. Wang DJ, Dowling TC, Meadows D, et al. implantation of a defibrillator in patients with
Nesiritide does not improve renal function in myocardial infarction and reduced ejection frac-
patients with chronic heart failure and worsening tion. N Engl J Med. 2002;346(12):877883.
serum creatinine. Circulation. 2004;110(12): 44. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or
16201625. an implantable cardioverter-defibrillator for con-
36. Sackner-Bernstein JD, Skopicki HA, Aaronson gestive heart failure. N Engl J Med. 2005;352(3):
KD. Risk of worsening renal function with 225237.
nesiritide in patients with acutely decompensated 45. Abraham WT, Fisher WG, Smith AL, et al. Cardiac
heart failure. Circulation. 2005;111(12):14871491. resynchronization in chronic heart failure. N Engl
37. Sackner-Bernstein JD, Kowalski M, Fox M, et al. J Med. 2002;346(24):18451853.
Short-term risk of death after treatment with 46. Bristow MR, Saxon LA, Boehmer J, et al. Cardia-
nesiritide for decompensated heart failure: a c-resynchronization therapy with or without an
pooled analysis of randomized controlled trials. implantable defibrillator in advanced chronic
JAMA. 2005;293(15):19001905. heart failure. N Engl J Med. 2004;350(21):
38. Digitalis Investigation Group. The effect of digox- 21402150.
in on mortality and morbidity in patients with 47. Cleland JG, Daubert JC, Erdmann E, et al. The
heart failure. N Engl J Med. 1997;336(8):525533. effect of cardiac resynchronization on morbidity
39. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-- and mortality in heart failure. N Engl J Med. 2005;
term intravenous milrinone for acute exacerbation 352(15):15391549.

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102 Chapter 8. Heart Failure and Cardiac Pulmonary Edema (Hollenberg)
Chapter 9. Acute and Chronic Liver Failure in the ICU
Jesse B. Hall, MD, FCCP

Objectives: injury are viruses, alcohol, or medications. When


 Review the causes of acute liver failure and the the injury is sufficiently severe as to produce
management of patients with acute liver failure who jaundice, coagulopathy, and encephalopathy, the
may require liver transplantation.

patient is deemed to have acute liver failure
Explain the pathophysiology of CNS dysfunction in both
acute and chronic liver failure and the justification for (ALF). If the time from jaundice to the onset of
invasive intracranial pressure monitoring. encephalopathy is less than a week the ALF is
 Describe complications seen in the early postoperative termed hyperacute; longer than 728 days, acute;
period after liver transplantation.
 Describe the causes of acute deterioration in patients
and longer than 526 weeks, subacute.
with cirrhosis and how stabilization can be achieved
early in the ICU course. Etiology

Key words: acetaminophen overdose; cirrhosis; hepatorenal In almost all registries of patients with ALF,
syndrome; liver failure; liver transplantation; portosystemic which are dominated by patients referred to liver
encephalopathy; spontaneous bacterial peritonitis; variceal
transplant centers, more than half of the cases are
hemorrhage
related to drug exposure and the great majority of
Synopsis: these are exposure to acetaminophen. Accordingly,
a thorough drug history is essential in evaluating
Patients with acute liver failure (ALF) or chronic liver failure
(CLF) may require care in the ICU. Patients with ALF often these patients, and because of their frequent
require ICU care because of associated encephalopathy and encephalopathy, this history may need to be
cerebral edema, and they may require invasive monitoring obtained through collateral sources, including
of intracranial pressure to guide therapies to reverse
elevated intracranial pressure and determine prognosis. In
pharmacy records. Another notable cause is acute
addition to supportive treatment and guided therapy to viral infection, although the incidence of acute
reverse causes of liver injury, the most severely ill patients viral hepatitis may be decreasing related to
with ALF often require simultaneous evaluation for liver immunization.
transplantation. Accordingly, the critical care physician
must be familiar with pretransplantation evaluation and
transplant complications that may be encountered in the Antidote Therapy for Acetaminophen
ICU. Patients with CLF, which is invariably related to Intoxication
underlying cirrhosis, often require ICU care for acute
deteriorations related most often to infection, portosystemic
encephalopathy (PSE), or GI hemorrhage. These patients Because intentional or accidental acetamino-
may also be under consideration for liver transplantation phen overdose is the most common cause of ALF
but most frequently the goals of ICU care are to reverse their and because an antidoteN-acetylcysteine
acute condition so they may be optimized for transplanta-
(NAC)is available, it is essential to consider
tion at some point in the future, if appropriate. For a patient
with ALF or CLF, the critical care physician functions within this possible drug toxicity early in the course of
the nexus of colleagues from hepatology, GI endoscopy, patient evaluation and to treat appropriate
transplant medicine, surgery, and interventional radiology patients. Acetaminophen metabolism is complex.
and will often need to coordinate these subspecialists to
This drug may be converted to a sulfated or
optimize care of the patient.
glucuronidated form, and these metabolites and
the parent compound are excreted in the urine.
As urinary clearance becomes maximal, increas-
Acute Liver Failure ing amounts of drug are conjugated in the liver
via a glutathione-dependent pathway, and these
Acute hepatitis is defined as acute damage to the metabolites are also renally excreted. When
liver parenchyma related to exposure to hepato- glutathione stores are exhausted and all of these
toxins or infectious agents; common agents of pathways are saturated, metabolism proceeds via

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Table 1Grades of Encephalopathy

Grade Description

Grade 0 No alteration of mental status


Grade 1 Awake and responsive with mild confusion and disorientation
Grade 2 Awake but agitated; increasingly confused and disoriented; may exhibit hallucinations
Grade 3 Increasing suppression of mental status
Grade 4 Stuperous but arousable to vocal or tactile stimulation; essentially comatose but with intact
pupillary responses

cytochrome P450 pathways with the production Patients in the ICU with ALF should have
of hepatotoxic metabolites. NAC, as a glutathi- frequent neurologic exams, and their level of
one donor, enhances metabolism of nontoxic encephalopathy should be formally assessed and
metabolites. recorded. A grading system is given in Table 1.
If the exact time of a single large ingestion is When patients progress to grade 3 encepha-
known, a serum level can be applied to an lopathy, they usually require intubation to
established nomogramthe Rumack-Matthew protect the airway and prevent aspiration. At
nomogramto predict the risk of toxicity. How- this juncture consideration should be given to
ever, the timing of ingestion is often not known, placement of a monitoring device to track
or the patient may have more chronic exposure to intracranial pressure. This can be challenging in
drug or may have used a time-release prepara- this group of patients, who invariably exhibit
tion. These confounding conditions, coupled degrees of coagulopathy reflected by their re-
with the facts that NAC may confer benefits duced platelet counts and elevated international
even in patients without detectable acetamino- normalized ratio (INR), but with transient cor-
phen levels and is a fairly safe drug, should rection this procedure can be performed with
guide the clinician to a very low threshold for acceptable risk and complications. Once moni-
initiating NAC therapy. toring is initiated, treatments, as suggested in
NAC may be given enterally or intravenous- Figure 1, can be instituted to avoid injury related
ly, and the drug appears to be equally efficacious to intracranial hypertension. Failure to control
when administered by either route. Because there intracranial hypertension associated with an
is a significant incidence of anaphylactoid reac- unacceptably low cerebral perfusion pressure
tions with IV therapy, the enteral route is should prompt assessment for irreversible brain
preferred unless GI dysfunction precludes it. injury, which would preclude the patient being
considered for liver transplantation.
Monitoring Intracranial Pressure and Treating
Intracranial Hypertension Acute Alcoholic Hepatitis

As noted earlier, encephalopathy is a hall- Given the widespread consumption of alco-


mark and defining characteristic of ALF. Al- hol in excessive quantities and hepatic toxicity of
though the early phases of encephalopathy in ethanol, alcoholic hepatitis (AH) is a common
ALF relate to metabolic failure of the liver with cause of patients presenting with acute liver
accumulation of metabolites that depress CNS injury, but many will not exhibit all of the
function, patients with ALF are also at risk for manifestations of ALF. AH usually presents after
rapid evolution of cerebral edema, creating many years of alcohol use, although it is not
elevated intracranial pressure and risk of ische- unusual for a patient to have ceased alcohol
mic injury of the brain. Accordingly, one of the consumption in the days to weeks before
goals of ICU care for ALF is careful and frequent presentation. AH is characterized by a rapid
neurologic assessment to determine when this onset of jaundice, often with fever, ascites, and
evolution may be occurring. proximal muscle loss. The liver is typically

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104 Chapter 9. Acute and Chronic Liver Failure in the ICU (Hall)
enlarged and tender on examination. In more
severe cases encephalopathy may develop, and
hence, the patient may be determined to have
ALF and require ICU admission. Laboratory
testing often reveals elevation of serum aspartate
aminotransferase levels more than twice the
normal range but rarely above 300 IU/mL, while
alanine aminotransferase levels are less elevated,
and the ratio of aspartate aminotransferase to
alanine aminotransferase is usually .2. Elevation
of creatinine at the time of presentation often
signals the development of hepatorenal syn-
drome (HRS) and is a laboratory marker for
poor prognosis.
A number of scoring systems have been
developed to prognosticate mortality in patients
with AH, including the Maddrey discriminant
function, Model for End-Stage Liver Disease
(MELD) score, Glasgow score, and Lille score.
These scores variably use age and a number of
laboratory valuesbilirubin, prothrombin time
or INR, creatinine, WBC count, urea nitrogen,
albumin, and bilirubin change over timeto
predict outcome. The other major use of these
scores is to identify the highest-risk patients in
whom therapies beyond supportive treatment
in particular, corticosteroids and NACmay be
used to promote hepatic recovery, although the Figure 1. Algorithm for treating intracranial hypertension.
results of prospective trials evaluating these CPP indicates cerebral perfusion pressure; ICP, intracranial
agents are mixed. pressure.
In the past, recent alcohol use has been
considered an absolute contraindication to liver
transplantation, and most transplant programs justified. This judgment is best made by careful
require patients to demonstrate abstinence from consideration by the transplant and critical care
alcohol for 6 months before they would be teams and occurs in the context of the knowledge
considered for transplantation. This notion has that an estimated 17,000 patients are awaiting
been challenged, however, and one recent study liver transplantation in the United States at any
reported results of patients with AH and a high given time though only 5,000 transplants are
risk of death during the acute phase of their liver performed per year.
disease who underwent transplantation and had A number of different scoring systems have
a relatively low rate of documented posttrans- been used to achieve the best allocation of organs
plant alcohol use. to patients. In the United States, perhaps the
most widely used is the MELD score, given as
Selecting Patients for Transplantation
MELD score 100:957 * Creatinine
A major challenge in the management of 1:12 * total bilirubin 1:12
patients with ALF is to determine those who will
* INR 0:643:
recover with medical treatment, those for whom
surgery is futile, and those in whom the risks of The MELD score has the benefit of using
surgery and lifelong immunosuppression are simple laboratory tests that are readily available

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Edition 105
for all patients, and it has been shown to achieve invasive IV catheters. Accordingly, when mani-
a more efficient distribution of available organs festations of sepsis emerge, empiric antibiotic
when implemented as a severity score that coverage should be appropriate to hospital-
prioritizes patients for transplantation. acquired pathogens then narrowed by culture
results. With longer exposure to immunosup-
Complications of Transplantation pression, a wider range of potential infectious
agents must be considered.
Complications of transplantation in the peri-
operative period are closely related to premorbid Chronic Liver Failure (CLF):
disease and condition, the particular transplant Management of Patients With
procedure undertaken, rejection of the graft or Cirrhosis in the ICU
host, and consequences of immunosuppression.
These complications may be divided into nonin- Patients with CLF who are typically admit-
fectious and infectious processes. ted to the ICU include those with previously
Early noninfectious complications that may stable liver disease and a new problem, such as
be seen when patients return to the ICU after variceal hemorrhage, encephalopathy, or spon-
liver transplantation include hemorrhage, pri- taneous bacterial peritonitis or other cause of
mary graft failure, hepatic artery thrombosis, sepsis, or patients listed for liver transplantation
bile leaks, and acute rejection. Primary graft who are suffering a similar acute insult. In the
failure is estimated to occur in 1% to 5% of latter case a crucial decision needs to be made
transplants and is of course catastrophic, requir- regarding the patients stabilization for eventual
ing retransplantation on an emergent basis. It transplantation. For all of these patients, the
may be suggested by the appearance of the critical care team will be working within the
transplanted liver at the end of the surgical nexus of liver transplant, hepatology, interven-
procedure and clinically continues as massive tional radiology, and endoscopy to diagnose and
hepatic necrosis until retransplantation is ac- manage problems in the context of advanced
complished. Hepatic artery thrombosis can also liver disease.
manifest as massive liver necrosis in the imme-
diate postoperative period or may be more Pathophysiology of Portal Hypertension
subacute in presentation with accompanying
bile leak or the development of hepatic abscess- In health, approximately two-thirds of he-
es. An extremely low threshold should be patic blood flow is portal. This circulation
applied to interrogation of the circulation to the exhibits an extremely low resistance, with a
transplanted organ by ultrasound, which has a pressure gradient of about 2 to 3 mm Hg. With
high sensitivity and specificity for this compli- injury to the liver producing fibrosis and
cation and should guide early interventions to bridginghallmark histologic signs of cirrho-
establish a patent arterial supply to the trans- sisthis gradient rises, and eventually, portal
planted organ. Acute rejection tends to occur 4 to flow is reduced as collateral channels develop.
14 days after transplant and is signaled by fever These channels may be visible on the abdominal
and modest elevation of serum transaminases. wall or may be the source of bleeding, such as
Excluding other processes should permit diag- esophageal varices. With portal hypertension,
nosis of rejection, along with biopsy if necessary, there is typically splenomegaly with a tendency
and the immunosuppressive regimen can be for sequestration of blood components in the
increased when infection is excluded. spleen. Ascites develops and, at this juncture, the
Infections in the immediate posttransplant combination of diverted flow and diminished
period tend to result from bacterial agents hepatic function results in the systemic circula-
typically infecting a critically ill patient in the tion exhibiting a diminished resistance as well
ICU. The distribution of sites of infection are a hyperdynamic state mimicking in cardiovas-
similar to those in most postoperative patients, cular terms the high output hypotension of early
including the lung, urinary tract, wound, and phases of sepsis.

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106 Chapter 9. Acute and Chronic Liver Failure in the ICU (Hall)
Infection in Patients With Cirrhosis Table 2Causes of PSE

Drugs
Patients with CLF should be considered to be GI hemorrhage
immunocompromised, apart from treatments they Infection
may be receiving. Fungal disease, including inva- Dehydration
Electrolyte disturbances
sive aspergillosis, has been described in greater Hepatic decompensation
frequency in patients with cirrhosis who have no Increased protein intake
other risk factors. In addition, patients with Uremia
Acidosis
cirrhosis often have extensive contact with the
Portosystemic shunts
health-care system and may become infected with
nosocomial organisms exhibiting significant anti-
biotic resistance. The adjusted risk ratio for
hospitalization secondary to sepsis related to PSE
cirrhosis has been estimated to be 2.6, and the risk
ratio for death at 2. The most common site for Although deterioration of brain function in
infection in patients with cirrhosis is the urine, ALF may result from cerebral edema and
followed by ascites, blood, and the respiratory tract. elevation of intracranial pressure, this phenom-
enon is not very common in patients with
Spontaneous bacterial peritonitis (SBP)
cirrhosis, who more typically develop PSE
should be considered in any patient with cirrhosis
related to accumulation of nitrogenous toxins
who has ascites and abdominal pain, systemic
that are normally cleared by the liver but have a
signs of sepsis, or deterioration of mental status
variety of CNS effects. The plasma ammonia
consistent with PSE. The clinician should have an
level is a rough guide to the accumulation of such
extremely low threshold for ultrasound-guided
toxins, and it is used to diagnose PSE and to
paracentesis for diagnosis. An ascetic fluid
gauge treatment. Causes of PSE or its worsening
polymorphonuclear (PMN) WBC count .250
are given in Table 2.
PMN/lL, visible organisms, or a positive culture
Treatment of PSE entails careful serial neuro-
are confirmatory. Extremely high PMN counts,
logic examination of the patient to follow the
particularly in association with multiple organ-
course of the process and to determine the need
isms on culture, protein levels .1 g/dL, high
for airway protection. Underlying causes, as
lactate dehydrogenase, and low glucose should
given in Table 2, should be sought and corrected.
prompt consideration of secondary peritonitis, Because cerebral edema is not typical of PSE,
implying a ruptured viscous, a catastrophic intracranial pressure monitoring is not usually
occurrence in patients with cirrhosis given their needed. Treatment to reduce nitrogen load
high risk for surgical intervention. should be undertaken in most patients, and these
Most SBP infections are caused by gut flora, treatments are usually directed to reduce the gut
raising the possibility of gut translocation, but burden of nitrogenous material by promoting
Streptococcus and Staphylococcus species may be evacuation or reducing bacterial load. Lactulose
seen. Cefotaxime is a reasonable empiric antibiotic can be given to promote diarrhea and as a
choice, but if the patient has been received nonspecific binder, and the antibiotics neomycin
fluoroquinolone prophylaxis against SBP as an or rifaximin are often beneficial.
outpatientan effective strategy in this settinga
wider-spectrum antibiotic may be needed. Because HRS
renal failure is a common complication in the setting
of SBP with sepsis, many authors recommend Renal failure is common in the critically ill
colloid volume expansion at the time diagnosis is patients with cirrhosis, and in addition to the
made. In one study, the incidence of acute renal usual causes, one must consider HRS, a form of
failure and death was reduced by treatment with renal dysfunction particular to advanced liver
albumin (1.5 g/kg) at the time of diagnosis followed disease. Many of the characteristics of HRS are
by 1 g/kg given on day three after diagnosis. similar to those of severe prerenal azotemia

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increasing creatinine levels, oliguria, low urine also important to avoid cooling during the resus-
sodium concentration, and a bland microscopic citation because of the consequent adverse effects
urinalysisbut they occur in the face of adequate on coagulation. Given that massive volume loss is
circulation and absent hypovolemia. It is thought often coupled with worsening of encephalopathy
that dysregulation of intrarenal distribution of in these patients, early attention to securing the
blood flow may contribute. Diagnosis is based on airway is also warranted.
a serum creatinine concentration .1.5 mg/dL, If early bleeding continues such that endos-
which is not reduced with volume loading and copy is not feasible, consideration should be
assurance of resolution of hypovolemia, in the given to placing a balloon tamponade system in
absence of treatment with nephrotoxic agents the stomach and esophagus. This is very much a
and absent evidence of renal parenchymal injury temporizing measure but can stanch hemorrhage
(eg, proteinuria, cellular casts). sufficiently to gain control of the situation in the
HRS occurs in more than a third of patients early hours. Patients invariably require place-
with cirrhosis followed for more than 5 years and ment of an airway and immobilization with
is a marker for poor outcome. Two types of HRS sedatives, if not paralytics, during placement of
have been described. Type 1 is defined as rapid the balloons. A specialized large-bore catheter is
progression of renal failure over 2 weeks or less placed through the mouth and into the stomach
with a twofold increase in creatinine levels or a and position is confirmed. The gastric balloon
50% reduction in creatinine clearance. Type 2 portion of the tube is then inflated, and the tube
develops steadily over months, with creatinine is pulled back until the balloon stops at the
clearance becoming ,40 mL/min. Without trans- gastroesophageal sphincter, tamponading varices
plantation, median survival is less than 2 weeks here. Irrigation is conducted through channels in
for type 1 and less than 6 months for type 2. the tube terminating above and below the gastric
Interestingly, if liver transplantation is performed balloon. At this juncture the distal port should be
before the patient progresses to a need for clear of blood, which would indicate bleeding
protracted dialytic therapy, renal function can above the level of the gastric balloon. If bleeding
often recover. continues as monitored from the distal port, a
In the acute setting, HRS is best treated by source of bleeding in the stomach must be
therapies directed at the underlying liver failure sought. If bleeding continues above the gastric
or causes of acute deterioration. A variety of balloon, a separate esophageal balloon is inflated
vasodilator therapies have been used, but the to tamponade esophageal varices. This should
data supporting their benefit are not compelling. resolve or greatly diminish hemorrhage, and
There may be a role for large-volume paracente- continuous suction should be applied to a
sis coupled with intravascular volume loading. channel terminating above the esophageal bal-
This strategy assumes a beneficial effect derived loon to avoid aspiration. At this point the next
from lowering intra-abdominal pressure coupled strategy is determined because this tube can
with maximizing renal perfusion. produce necrosis if left in place for hours to days.
Many recommend intermittent balloon deflation
Massive Variceal Hemorrhage to minimize the risk of necrosis.
As early as feasible, endoscopy should be
Massive hemorrhage from esophageal varices conducted to confirm the source of bleeding. If
is a life-threatening complication for patients with the bleeding is variceal, bands should be placed
cirrhosis, and a highly orchestrated approach to to establish hemostasis. Once variceal hemor-
their management is mandatory in the ICU. Early rhage is confirmed, octreotide is begun as a
management requires large-bore catheter place- continuous infusion to reduce portal blood flow.
ment coupled with blood product replacement that The additional salvage therapy that may be
includes red cells, clotting factors, and platelets. used if these measures are unsuccessful is
Because these patients often have baseline throm- placement of a transjugular intrahepatic porto-
bocytopenia and factor deficits, very aggressive systemic shunt (TIPS). These devices very effec-
correction of coagulation status is necessary. It is tively reduce portal pressure and achieve

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108 Chapter 9. Acute and Chronic Liver Failure in the ICU (Hall)
Table 3Complications of TIPS Bibliography
Misplacement
Portosystemic encephalopathy Bass NM, Mulln KD, Sanyal A, et al. Rifaximin
Hemolytic anemia treatment in hepatic encephalopathy. N Engl J Med.
Device stenosis
2010;362(12):10711081.
Vegetative infections (rare)
Cerebral edema (very rare) Bernal W, Auzinger G, Dhauran A, Wendon J. Acute
liver failure. Lancet. 2010;376(9736):190201.
hemostasis in more than 90% of patients. Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J
Although in the past use of a TIPS was reserved Med. 2009;361(13):12791290.
for patients in whom bleeding could not be
Lucey MR, Morgan TR. Alcoholic hepatitis. N Engl J
controlled with endoscopic interventions, a re-
Med. 2009;360(26):27582769.
cent trial demonstrated benefit when used early
in the course of management of all patients with Mathurin P, Moreno C, Samuel D, et al. Early liver
advanced cirrhosis (Child class B with continued transplantation for severe alcoholic hepatitis. N Engl J
bleeding or Child class C). Complications of the Med. 2011;365(19):17901800.
TIPS are shown in Table 3. Nguyen-Khac E, Thevenot T, Piquet MA, et al.
Glucocorticoids plus N-Acetylcysteine in severe alco-
Nothing to Disclose
holic hepatitis. N Engl J Med. 2011;365(19):17811789.

The author has disclosed that no relation- Prodanovic H, Ciacco C, Meissard J, et al. Invasive
ships exist with any companies/organizations pulmonary aspergillosis in patients with decompen-
whose products or services may be discussed in sated cirrhosiscase series. BMC Gastroenterology.
this chapter. 2007;7:27.

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Notes

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110 Chapter 9. Acute and Chronic Liver Failure in the ICU (Hall)
Chapter 10. Hemodynamic Monitoring
John P. Kress, MD, FCCP

Objectives: interrogating a patients hemodynamic status.


 Describe tools to assess adequacy of tissue perfusion. This chapter will present the various tools
 Describe etiologies of hypoperfusion. available to assess the hemodynamic status of
 Describe ways to assess the response of the cardiopul-
critically ill patients.
monary system to interventions for managing a hypo-
perfused state.
Urinary Studies
Key words: Echocardiogram; hemodynamic; perfusion;
shock A urinary output of .0.5 mL/kg/h suggests
that renal perfusion is adequate. This goal is
Synopsis: frequently sought in the early stages of resusci-
Hemodynamic monitoring may be defined as the collection tation of patients with hypovolemic and/or
and interpretation of various parameters that determine: (1) septic shock.2 Another measure of renal perfu-
the adequacy of tissue perfusion; (2) the etiology of a
sion that is frequently measured is the fractional
hypoperfused state; and (3) the response of the cardiopul-
monary system to interventions such as fluid therapy, excretion of sodium (FeNa) in the urine. The
vasoactive drugs, or adjustments in positive pressure formula for this endpoint is the product of
ventilation. For many patients, adequate monitoring is urinary sodium times serum creatinine divided
achieved by routine vital signs along with collection of data
such as history and physical examination, laboratory data
by the product of serum sodium times urinary
(eg, BUN/creatinine, HCO 3 , lactate, ScvO2, SvO2), input/
creatinine ([UNa 3 SCr]/[SNa 3 UCr] 3 100). The
output, and urine electrolytes. In other patients, invasive cutoff of 1% is typically used to distinguish a
measurements are made, including use of arterial catheters,
prerenal condition from a state of acute tubular
central venous catheters, and right heart catheters. These
catheters provide for continuous transduction of pressure in necrosis. Since loop diuretic therapy falsely raises
either the arterial or venous circuit and sampling of blood the FeNa, one may use the fractional excretion of
for determination of oxygen saturation. Simultaneous urea ([UUrea 3 SCr]/[SUrea 3 UCr] 3 100) to
determination of arterial and mixed venous blood gases
also permits determination of oxygen content, oxygen
assess renal perfusion in oliguric patients who
delivery, oxygen consumption, arteriovenous oxygen con- have received loop diuretics. The FeNa may be
tent difference, and calculation of cardiac output by Fick falsely lowered in patients who have received IV
determination. contrast agents, cyclosporine, and tacrolimus.

Chest Imaging (Vascular Pedicle


The use of invasive methods for assessing Width)
hemodynamicsarterial and right heart cathe-
tersgrew during the evolution of critical care The intrathoracic veins become engorged
medicine despite a lack of prospective trials when their volume and/or pressure is increased.
demonstrating efficacy and improved patient The vascular pedicle widthdefined by the
outcome. Indeed, one retrospective study sug- horizontal distance between the lateral border of
gested that use of the right heart catheter is the superior vena cava and the left subclavian
associated with an independent negative effect artery originhas been shown to correlate with
on survival.1 More recently, ultrasonographic cardiac filling pressures, even in portable chest
assessment of hemodynamics has begun to move radiographs. Thomason and colleagues3 reported
into the mainstream of monitoring in the ICU. that a vascular pedicle width greater than 63 mm
Clearly no single test is perfectall have on a portable chest radiographs was a reliable
limitations. Accordingly, it is important for the predictor of elevated cardiac filling pressures. The
clinician to integrate multiple data points when portable chest radiographs showing distension of

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the azygous vein and widening of the vascular into an increase in blood flow to tissues is not
pedicle suggests that the great veins have clear (see above). Details on interpretation of
increased volume and/or pressure. atrial pressure waveforms are discussed later in
this chapter.
Central Venous Catheterization
Valvular Disease
Static central venous pressures (CVPs) have
been used traditionally as indicators of intravas- The impact of valvular disease on hemody-
cular volume status; however, the use of atrial namics can be substantial. In aortic stenosis, most
pressures as surrogate measures of intravascular patients suffer from a hypertrophied left ventricle.
volume is fraught with imprecision.4 Atrial pres- Accordingly, tachycardia is detrimental to hemo-
sure is affected by many variables, which include dynamic stability since there is less time for
intravascular volume, cardiac chamber compli- diastolewhen perfusion of the subendocardium
ance, and external (eg, pleural) pressures. Accord- occurs. Therefore, it is optimal to have a reduced
ingly, increased CVPs and pulmonary capillary heart rate. The hypertrophied left ventricle with its
wedge pressures (PCWPs) can occur in many accompanying reduced compliance is also more
circumstances. As such, static CVPs and PCWPs dependent on atrial contraction for filling than is
are not reliable indicators of intravascular volume. the normal ventricle. Accordingly, a sinus rhythm
For example, Osman and colleagues5 reported on with a slow heart rate is optimal. Atrial fibrillation
static measures of CVP and PCWP as predictors of with a rapid ventricular response is often very
responsiveness to a fluid challenge. The investiga- poorly tolerated. The management of shock in this
tors found that neither CVP nor PCWP at any level circumstance may include IV fluid administration,
reliably predicted whether or not a patient would phenylephrine (no chronotropic effects), and ur-
respond to an IV fluid challenge. gent cardioversion. In aortic insufficiency, optimal
The landmark paper on early goal-directed hemodynamic management includes the use of
therapy by Rivers and colleagues2 deserves chronotropic agents (eg, dobutamine, milrinone)
comment in the context of the above statements. to decrease regurgitant filling time and afterload-
Some may suggest that the CVP is a useful reducing agents (eg, nitroprusside, nicardipine,
endpoint to guide resuscitation in patients with fenoldopam, angiotensin-converting-enzyme in-
septic shock since a target CVP of 8 to 12 mm Hg hibitors) to facilitate forward flow. Mitral stenosis
was used in this trial. However, there are a is managed optimally by negative chronotropic
couple of important points to clarify about this agents (eg, b-blockers), which seek to maximize
study in the context of the topic of hemodynamic diastolic filling time across the stenotic valve. The
monitoring. First, all patients in the trial had a loss of atrial contraction is detrimental to left
CVP target of 8 to 12 mm Hg; this was not a ventricular filling, though typically less so than in
component of the intervention for the study aortic stenosis, since the left ventricle is not usually
group only. Accordingly, one cannot conclude hypertrophied. As left atrial size increases in the
from this trial that targeting a CVP of 8 to 12 mm patient with mitral stenosis, the likelihood of
Hg in the resuscitation of patients with septic maintaining a sinus rhythm is decreased. Accord-
shock is evidence based. Rather, one can ingly, control of ventricular response rate is
conclude that targeting a central venous oxygen extremely important in these patients. Mitral
saturation .70% using a multimodal approach to regurgitation may occur acutely (eg, ischemic
resuscitation (ie, IV fluids, vasoactive drug injury to papillary muscles) or present as a chronic
support, mechanical ventilation, packed RBC condition in an ICU patient. Optimization of
transfusion) leads to improved outcomes. In- hemodynamic status occurs via attempts to
deed, one could wonder if the CVP target was establish and maintain sinus rhythm, as well as
different (eg, 1015 mm Hg or 610 mm Hg) afterload reduction (eg nitroprusside, nicardipine,
whether the study outcomes would have dif- fenoldopam, angiotensin-converting-enzyme in-
fered. Administration of IV fluids typically hibitors) to decrease the percentage of regurgitant
increases the CVP, but whether this translates blood flow.

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112 Chapter 10. Hemodynamic Monitoring (Kress)
Pericardial Disease
The hemodynamic management of patients
with pericardial tamponade is centered on defin-
itive drainage of the pericardial space. IV fluid
administration to increase venous return can be
used as a temporizing measure while definitive
treatment is being arranged. The classic physical
findings of acute cardiac tamponade are a falling
arterial pressure, a rising venous pressure, and
distant muffled heart sounds (a small quiet
heart).6 Kussmauls sign (rising jugular venous
pressure with inspiration) and pulsus paradoxus
are other findings on physical examination.
Echocardiographic features include abnormal
inspiratory increase of right ventricular dimen-
sions and abnormal inspiratory decrease of left
ventricular dimensions, right atrial compression,
right ventricular diastolic collapse, abnormal
inspiratory increase of blood flow velocity
through the tricuspid valve and abnormal inspi-
ratory decrease of mitral valve flow velocity,
dilated inferior cava with lack of inspiratory
collapse, and a swinging heart.7 Right ventric-
ular filling is impaired throughout diastole;
accordingly, the y-descent (ie, the right atrial
pressure fall immediately after tricuspid opening Figure 1. Atrial waveforms-normal, cardiac tamponade,
as blood rushes into the right ventricle) on the constrictive pericarditis.
right atrial pressure tracing is blunted. A rapid y-
descent essentially rules out cardiac tamponade. volume overloaded are being replaced with the
The right atrial pressure tracing in pericardial more relevant question of whether or not a patient
constriction is different. In constrictive pericardi- is volume responsive (ie, will the cardiac output
tis, the earliest phase of diastolic right ventricular increase if a discreet fluid challenge is admin-
filling is not impaired; therefore, the y-descent is istered?). Dynamic assessments of a patients
not blunted. Rather, the y-descent may be hemodynamic status challenge the circulation
accentuated (rapid y-descent) because the with a fluid bolus (IV fluid challenge or passive
pressure is descending from higher right atrial raising of the legs). The impact of such a fluid
pressure. Figure 1 illustrates the characteristic challenge on the cardiac output allows one to
right atrial pressure findings in pericardial determine the patients position on the Frank-
tamponade and constrictive pericarditis. Starling curve. One can also take advantage of the
fact that the pleural pressure swings associated
Dynamic Waveform Analysis in with breathing perturb the circulation by virtue of
Hemodynamic Monitoring altering venous return. This relationship has been
most extensively validated during positive pres-
The approach to hemodynamic monitoring in sure ventilation, which induces cyclic changes in
critical illness has undergone some relatively the loading conditions of both ventricles. During
recent changes. As noted above, static measures a positive pressure breath, there is a decrease in
of preload (eg, CVP, PCWP) are not helpful in right ventricular preload as well as an increase in
predicting fluid responsiveness.8 Terms such as right ventricular afterload, both of which lead to a
hypovolemic, dehydrated, hypervolemic, decrease in right ventricular stroke volume. After

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a delay of two or three (depending on the heart The benefits of ultrasound include its noninva-
rate) heart beats, a decrease in left ventricular sive nature, which lends itself to real-time
filling and stroke volume ensues (this is due to assessment of pump function, ventricular cavity
transit time of blood through the lungs and is size, wall thickness, and regional wall motion
typically seen during exhalation). These cyclic abnormalities. In addition, one can perform real-
changes in right and left ventricular stroke time assessment of valve function and interrogate
volume are more notable on the steep portion of for the presence of pericardial disease. Echocar-
the Frank-Starling curve. diography can also be used to measure cardiac
Since the pulse pressure (PP) (systolic blood output. Studies have demonstrated that fluid
pressure minus diastolic blood pressure) corre- responsiveness can be established in hypotensive
lates well with the stroke volume, one can patients subjected to a passive leg raise whose
measure the variation in PP with positive pressure cardiac output change was measured by echocar-
breathing. The PP variation can be measured diography using aortic blood flow measure-
easily with an indwelling arterial catheter. The ments.16,17 Furthermore, the stroke area (SA) can
formula is: DPP(%) 100 3 (PPmax PPmin)/ be measured using transesophageal echocardiog-
[(PPmax PPmin)/2], where DPP(%) indicates raphy. SA can be defined as the difference
PP variation, PPmax indicates the maximal PP between the end-diastolic area and the end-
during the respiratory cycle and PPmin indicates systolic area using a transgastric, cross-sectional
the minimal PP during the respiratory cycle. A view of the left ventricle at the midpapillary
DPP(%) threshold of 12.5% (range ~10%15%) has
muscle level. Using a calculation similar to that
been shown to predict fluid responsiveness across
used for PP variation, respiratory variations in SA
a broad domain of patients.9 However, the use of
can be assessed. The DSA can be calculated as:
PP variation as a measure of fluid responsiveness
{[SAmax SAmin]/[(SAmax SAmin)/2]} 3
has limitations. The patient must have a regular
100%, where DSA is the SA variation as a function
cardiac rhythm (ie, stable R-R interval), and the
of breathing, SAmax is the maximal SA and
tidal volume during positive pressure ventilation
SAmin is the minimal SA. Cannesson and
must be relatively large (eg, 810 mL/kg) in order
colleagues18 reported that a DSA cutoff value of
to perturb the venous return enough to result in a
16% allowed fluid responsiveness prediction with
detectable variation in stroke volume.4,10
a sensitivity of 92% and a specificity of 83%.
Another endpoint worth mentioning is the
Obviously, the skills necessary to use echocardi-
change in CVP as a function of breathing. There
is less certainty as to the value of this endpoint, ography in the ICU require training and practice.
since some studies have shown that a fall in CVP Another useful endpoint is the measurement
greater than 1 mm Hg predicts fluid responsive- of inferior vena cava (IVC) diameter. An absolute
ness in spontaneously breathing patients,11,12 IVC diameter less than 1 cm in hypotensive
while others have not.13 From a practical per- patients generally predicts fluid responsive-
spective, a change in CVP of only 1 mm Hg ness.19,20 Variation in IVC diameter as a function
magnitude can be difficult to detect; accordingly, of respiration is also a useful endpoint to predict
caution should be used when targeting this fluid responsiveness. One study of mechanically
endpoint to assess volume responsiveness.14 ventilated patients with septic shock noted that a
Indeed, assessing fluid responsiveness in the change in IVC diameter greater than 18% was a
spontaneously breathing patient is difficult,15 reliable predictor of fluid responsiveness.21 Like-
since most studies have evaluated patients wise, variation in superior vena cava diameter as
undergoing positive pressure ventilation. a function of respiration can be used to predict
fluid responsiveness, with one study reporting a
Ultrasound/Echocardiography threshold of 36% diameter change with during
positive pressure ventilation.22 However, the
The use of bedside ultrasound in critical care superior vena cava can only be visualized with
has increased substantially in recent years. transesophageal echocardiography, limiting its
Portable devices are now available in most ICUs. widespread applicability.

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114 Chapter 10. Hemodynamic Monitoring (Kress)
Other Noninvasive Measures of to the oxygen content in arterial blood. Normally,
Cardiac Output the content of oxygen in mixed venous blood
(CvO2) is 15.95 mL O2 per dL blood, since the
The PiCCOe system (Pulsion Medical Sys- mixed venous blood saturation is 75%. Accord-
tems) uses transpulmonary thermodilution to ingly, the normal tissue extraction ratio for oxygen
calibrate stroke volume. This is done with an is CaO2 CvO2/CaO2 (21.16 15.95/21.16) or ap-
internal jugular vein catheter and a thermistor- proximately 25%. Central venous oxygen satura-
tipped femoral arterial catheter, which measures tion is not identical to mixed venous oxygen
cardiac index through transpulmonary thermodi- saturation; however, these two values are relative-
lution and pulse contour analysis. The device is ly close and tend to track in a similar direction.
able to report continuous cardiac output values.23 The differential diagnosis for a low venous oxygen
Pulse-contour analysis (eg, FloTrac-Vigileo [Ed- saturation includes a reduced cardiac output (the
ward Lifesciences] device) provides continuous most common reason), a reduced hemoglobin
stroke volume measurements from the arterial level with an inability to generate a compensatory
pressure wave. It analyzes the pressure waveform increase in cardiac output, a reduced arterial
100 times per second over 20 s. The resulting oxygen saturation, and an increased tissue oxygen
2,000 data points are analyzed to calculate stroke consumption rate.
volume using a complex formula.24 Discussion of
this formula is beyond the scope of this chapter. Pulmonary Artery (PA)
Lastly, bioreactance is a tool that analyzes relative Catheterization
phase shifts of an oscillating current that occur
when this current traverses the thoracic cavity. The use of PA catheterization in critical care
Commercially available devices placed on the has fallen out of favor in routine practice. This
chest can be used to generate such currents across has occurred because numerous clinical investi-
the thorax in order to measure cardiac output. gations across a wide range of patient popula-
Discussion of the details of this technology is tions have failed to demonstrate a benefit with
beyond the capacity of this chapter; however, the the use of this device.2631 Nonetheless, the
device has been validated as a noninvasive tool device provides important information about
for measuring cardiac output.25 cardiopulmonary physiology and is still used in
many ICUs. Accordingly, it is important for the
Blood Transport of Oxygen critical care physician to have an understanding
of this device.
Oxygen delivery (QO2) is the product of The PA catheter is capable of acquiring many
cardiac output (Qt) and the content of oxygen in data points. These are listed below with normal
the arterial blood (CaO2) (QO2 Qt 3 CaO2). The values in parentheses.
CaO2 is determined by the hemoglobin concentra-  Cardiac chamber pressures and waveforms
tion, the arterial hemoglobin saturation and
dissolved oxygen not bound to hemoglobin. The  Right atrium (28 mm Hg), right ventricle
formula for CaO2 is 1.39 (constant) 3 hemoglobin (1624/04 mm Hg), PA (1624/512 mm
(g/dL) 3 arterial oxygen saturation (SaO2) Hg), PCWP (512 mm Hg)
0.0031 3 PaO2. In normal adults, the QO2 is  Cardiac output
approximately 50 dL/min (Qt) 3 [1.39 3 15 g/
dL (hemoglobin concentration) 3 1.0 (hemoglobin  Thermodilution (may be inaccurate with
percent saturation) 0.0031 3 100 (PaO2)], or 50 tricuspid regurgitation)
dL/min (Qt) 3 21.16 mL oxygen/dL blood (CaO2).  Fick equation [VO2 Qt 3 (CaO2 CvO2)]
This formula calculates to 1,058 mL O2 per minute.  SvO2
It is clear from this formula that most oxygen  Systemic vascular resistance 80 3 (mean
delivered to tissues is bound to hemoglobin. arterial pressure right atrial pressure/Qt)
Dissolved oxygen (PaO2) contributes minimally (dynes 3 s/cm5)

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Table 1Complications Related to Insertion and Use of the wedged position are readily identified as char-
Pulmonary Artery (PA) Catheter
acteristic of each segment of the circulation as it
A. Complications related to central vein cannulation is traversed, as demonstrated in Figure 2. While
B. Tachyarrhythmias waveform recognition is extremely helpful in
C. Right bundle branch block positioning the catheter, and often makes the use
D. Complete heart block (preexisting left bundle
branch block)
of fluoroscopic techniques unnecessary, it is
E. Cardiac perforation essential for the measurement and interpretation
F. Thrombosis and embolism of waveforms displayed during PA catheteriza-
G. Pulmonary infarction due to persistent wedging
tion to be correlated to the ECG tracing so that
H. Catheter-related sepsis
I. Pulmonary artery rupture specific components of the waveform can be
J. Knotting of the catheter identified and various pitfalls in measurement of
K. Endocarditis, bland and infective intravascular pressure can be avoided.
L. Pulmonic valve insufficiency
M. Balloon fragmentation and embolization
The Normal Atrial Pressure Waveform
Reprinted with permission from ACCP Critical Care Medicine
Board Review. 20th ed. Northbrook, IL: American College of
Chest Physicians; 2009. In sinus rhythm, the atrial pressure wave-
form is characterized by two major positive
 Pulmonary vascular resistance 80 3 (mean deflections (A and V waves) and two negative
PA pressure PCWP/Qt) (dynes 3 s/cm5) deflections (x- and y-descents) (Fig 3). A third
positive wave, the C wave, is sometimes seen.
Complications of PA catheterization are listed The A wave results from atrial systolic contrac-
in Table 1. tion and is followed by the x-descent as the atria
relax following contraction. The C wave results
Interpretation of Pressure Waveforms from closure of the atrioventricular valves and
interrupts the x-descent. After the x-descent, the
Under most conditions, the waveforms ob- V (ventricular) wave is generated by passive
tained as the PA catheter is advanced through the filling of the atria during ventricular systole.
right atrium, right ventricle, and into the PA to a Lastly, the y-descent reflects the reduction in

Figure 2. Normal waveform tracings during pulmonary artery catheter insertion.

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116 Chapter 10. Hemodynamic Monitoring (Kress)
wave normally occurs simultaneously with the T
wave of the ECG, provided that the Q-T interval
is normal.
The PA waveform has a systolic pressure
wave and a diastolic trough. A dicrotic notch due
to closure of the pulmonic valve may be seen on
the terminal portion of the systolic pressure
wave. Like the right atrial V wave, the PA
systolic wave typically coincides with the elec-
trical T wave. The PA diastolic pressure (Ppad) is
recorded as the pressure just before the begin-
ning of the systolic pressure wave. The PCWP
tracing contains the same sequence of waves and
descents as the right atrial tracing. However,
when the atrial waveform is referenced to the
ECG, the mechanical events arising in the left
atrium (PCWP) will be seen later than those of
the right atrium, because the left atrial pressure
waves must travel back through the pulmonary
vasculature and a longer length of catheter.
Figure 3. Atrial waveform.
Therefore, in the PCWP tracing the A wave
usually appears after the QRS complex and the V
atrial pressure as the atrioventricular valves wave is seen after the T wave. As such, the
open. In correlating these waveforms to the systolic pressure wave in the PA tracing precedes
ECG, the first positive pressure wave to follow the V wave of the PCWP tracing. An appreciation
the P wave is the A wave. The right atrial A wave of the latter relationship is critical when tracings
is usually seen at the beginning of the QRS are being analyzed to ensure that balloon
complex, provided that atrioventricular conduc- inflation has resulted in a transition from an
tion is normal. The peak of the right atrial V arterial (PA) to atrial (PCWP) waveform, and to

Figure 4. Transition from pulmonary artery tracing (right side of figure) to wedged position with mitral regurgitation and
giant V wave (arrow).

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Edition 117
Figure 5. Rapid flush test: A, appropriately damped system;
B, over damped system. Reprinted with permission from
ACCP Critical Care Medicine Board Review. 20th ed. North-
brook, IL: American College of Chest Physicians; 2009.

detect the presence of a giant V wave in the


PCWP tracing (Fig 4, see arrow).
Common Problems Producing Erroneous Pressure
Waveforms: Of the many problems causing artifact
or erroneous tracings, the most commonly en-
countered are overdamping, catheter whip, over-
wedging, incomplete wedging, and Zone I
catheter conditions.
Overdamping results from air bubbles within
the catheter system or kinking, clotting, and Figure 7. Incomplete wedge pressure (PCWP). Top: With
balloon inflation, there is a decrease in pressure to a value
fibrin deposition along the catheter course; many that approximates pulmonary artery diastolic pressure
times these problems can be resolved by catheter (Ppad). The clinical setting (ARDS) is usually associated
flushing. with a large Ppad-PCWP gradient. Review of the tracings
indicates that there is a single positive wave coinciding with
The main effect of overdamping on the the electrocardiographic T wave after balloon inflation, a
pressure waveform is to artifactually lower the pattern inconsistent with a left atrial waveform. Bottom:
systolic pressure and raise the diastolic pressure Waveforms after the catheter had been retracted, the balloon
inflated, and the catheter floated to a full wedge position.
with consequent effects on interpretation (Fig 5). Now, there is a large Ppad-PCWP gradient and the tracing
Catheter whip arises from cardiac contrac- after balloon inflation is consistent with a left atrial
tions causing shock transients transmitted to the waveform. The incomplete wedge tracing yielded an
incorrect measurement of the wedge pressure as 28 mm
catheter. The results on the right ventricular or Hg, substantially higher (in a very clinically relevant sense)
pulmonary arterial waveforms are an exaggerat- than the true wedge pressure of approximately 12 mm Hg.
ed diastolic pressure in some cycles, highlighting Reprinted with permission from ACCP Critical Care Medicine
Board Review. 20th ed. Northbrook, IL: American College of
the need to avoid readings obtained by electronic
Chest Physicians; 2009.
systems.
Overwedging (Fig 6) is signaled by a rise in ingress elevating the measured pressure. Over-
recorded pressure with balloon inflation as the wedging requires repositioning of the catheter.
balloon herniates over the catheter tip or the tip is Incomplete wedging (Fig 7) and Zone I
pushed into the vessel wall with continued fluid positioning of the catheter can be subtle but are
important to identify since erroneous and often
overestimation of PCWP occur.
Zone I conditions of the lung refer to those
segments of the lung in which alveolar pressure
exceeds pulmonary vascular pressure and hence
there is no flow (Fig 8). This phenomenon is
uncommon when the catheter is floated into
Figure 6. Overwedged catheter (see text). Reprinted with
position since this typically results in Zone II or
permission from ACCP Critical Care Medicine Board Review.
20th ed. Northbrook, IL: American College of Chest III positioning. It would be more likely to result
Physicians; 2009. from forceful positioning of the catheter, hypo-

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118 Chapter 10. Hemodynamic Monitoring (Kress)
Figure 10. Respiratory effects on PCWP tracing. PCWP
tracing is seen on the upper tracing, pleural pressure is seen
on the lower tracing. Reprinted with permission from ACCP
Critical Care Medicine Board Review. 20th ed. Northbrook, IL:
American College of Chest Physicians; 2009.

The Correlation of Pressure to Ventricular Preload


Figure 8. Lung zones. Reprinted with permission from and Volume: The use of PCWP as a measure of left
ACCP Critical Care Medicine Board Review. 20th ed. North- ventricular end-diastolic pressure and hence
brook, IL: American College of Chest Physicians; 2009. preload depends on the PCWP closely reflecting
pulmonary venous, left atrial, and left ventricular
volemia emerging after placement, or with large pressures, that is, with minimal pressure gradient
increases in positive end-expiratory pressure across the system. One potential confounder to
(PEEP). This condition should be considered interpretation of intravascular pressures is the
when changes in PCWP track PEEP changes fluctuation in intrathoracic pressure related to the
exactly or when the respiratory excursion in PA respiratory cycle. The effect of varying intratho-
systolic pressures exceeds the PCWP significant- racic pressure on the wedge (PCWP) pressure is
ly (Fig 9). seen in Figure 10. The top line is a PCWP tracing
and the bottom is the intrapleural (Ppl) pressure.
In this example the patient is receiving assisted
ventilation. Arrows indicate end-expiratory pres-
sures. Negative deflections in Ppl and PCWP
pressures result from inspiratory muscle activity,
and subsequent positive deflections represent
lung inflation by the ventilator. At end expiration,
the respiratory system has returned to its relaxed
state and Ppl is back to baseline (2 cm H2O).
Transmural wedge pressure remains approxi-
mately constant throughout the ventilating cycle.
Since Ppl is not usually measured clinically, it is
necessary that PCWP be recorded at a point where
Ppl can be reliably estimated (ie, end-exhalation,
assuming no expiratory muscle activity).
The correlation of pressure to volume is
further complicated by a variety of conditions
that cause the ventricle to be effectively stiff
Figure 9. Pressure tracings recorded in the same patient at (diastolic dysfunction or pericardial disease) or
different levels of end-expiratory pressure zero on the top conditions that cause juxtacardiac pressure to
panel, 15 cm H2O in the center panel, and 20 cm H2O in the rise related to positive pressure ventilation
bottom panel. Reprinted with permission from ACCP Critical
Care Medicine Board Review. 20th ed. Northbrook, IL: (PEEP, intrinsic PEEP [PEEPi], active expiratory
American College of Chest Physicians; 2009. effort) (Fig 11).

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Figure 11. Elevated PCWP pressure (20 mm Hg) caused by
three different physiological circumstances: high ventricular
end diastolic pressure (LVEDP) in dilated cardiomyopathy
with overfilled LV (upper figure on the right); high LVEDP Figure 13. Giant V wave in right atrial waveform indicates
tricuspid regurgitation. Reprinted with permission from
in hypertrophied LV that is not overfilled (middle figure on
ACCP Critical Care Medicine Board Review. 20th ed. North-
the right); high LVEDP with a normal heart and increased
brook, IL: American College of Chest Physicians; 2009.
pleural pressure due to intrinsic PEEP (lower figure on the
right). Reprinted with permission from ACCP Critical Care
Medicine Board Review. 20th ed. Northbrook, IL: American
active expiratory muscle effort, cardiovascular
College of Chest Physicians; 2009. effects may be large. This effect is shown in
Figure 12, where the increase in blood pressure
The effects of PEEP in conditions such as and cardiac output despite a fall in wedge
ARDS are often blunted, since the stiff lungs of pressure and esophageal pressure is shown
these patients do not distend greatly with high during a brief interruption in positive pressure
ventilator pressures, and hence minimal increases ventilation in a patient with COPD.
This constellation of problems is best avoided
in juxtacardiac pressure are encountered. How-
by:
ever, in cases in which PEEPi exists in COPD/
asthma patients undergoing mechanical ventila-  Awareness of their existence
tion, or in agitated/obstructed patients with very  Reading pressure tracings at end expiration
 Considering measures (sedation, ventilator
adjustment, paralysis) that diminish or elimi-
nate PEEPi
 Considering a ventilator disconnect in patients
with severe airflow obstruction and PEEPi to
demonstrate limitation to venous return
 Using a fluid challenge when effective dia-
stolic dysfunction may be present, to deter-
mine preload reserve
In determining the response to a fluid
challenge, it is necessary to note that a minimum
of 500 mL of crystalloid is required, and even
then small effects on cardiac output and arterial
blood pressure are typically seen.
Specific Disorders: Tricuspid regurgitation is
Figure 12. Effects of intrinsic PEEP on cardiac output (upper encountered in conditions with direct valvular
figure), blood pressure (middle figure), and PCWP/esoph- injury (eg, endocarditis) and generally in right
ageal pressure (lower figure). See text. Reprinted with
heart failure. It is characterized by a prominent
permission from ACCP Critical Care Medicine Board Review.
20th ed. Northbrook, IL: American College of Chest and broad V wave and a steep y-descent; the
Physicians; 2009. latter is often most useful for making this

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120 Chapter 10. Hemodynamic Monitoring (Kress)
secondary to increases in pulmonary vascular
resistance (eg, pulmonary embolus), but in these
latter conditions there will be a large Ppad-
PCWP gradient reflecting the increase in pulmo-
nary vascular resistance.

Relationships Disclosed

The author has disclosed the following


relationships: Grant monies (from industry relat-
ed sources): Unrestricted research grant from
Hospira. Consultant fee, speaker bureau, adviso-
ry committee, etc.: Hospira speaker bureau. The
ACCP Education Committee has reviewed these
relationships and resolved any potential conflict
of interest.

References

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ly ventilated patients: a systematic review of the 21. Barbier C, Loubieres Y, Schmit C, et al. Respira-
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