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NICU

Primer for Pharmacists

Amy P. Holmes, PharmD


Neonatal Clinical Pharmacy Specialist
Novant Health Forsyth Medical Center
Winston Salem, North Carolina
and
Adjunct Assistant Professor
Wingate School of Pharmacy
Wingate, North Carolina
Any correspondence regarding this publication should be sent to the publisher, American Society of Health-
System Pharmacists, 7272 Wisconsin Avenue, Bethesda, MD 20814, attention: Special Publishing.
The information presented herein reflects the opinions of the contributors and advisors. It should not be
interpreted as an official policy of ASHP or as an endorsement of any product.
Because of ongoing research and improvements in technology, the information and its applications contained
in this text are constantly evolving and are subject to the professional judgment and interpretation of the
practitioner due to the uniqueness of a clinical situation. The editors and ASHP have made reasonable efforts
to ensure the accuracy and appropriateness of the information presented in this document. However, any user
of this information is advised that the editors and ASHP are not responsible for the continued currency of the
information, for any errors or omissions, and/or for any consequences arising from the use of the information
in the document in any and all practice settings. Any reader of this document is cautioned that ASHP makes
no representation, guarantee, or warranty, express or implied, as to the accuracy and appropriateness of the
information contained in this document and specifically disclaims any liability to any party for the accuracy
and/or completeness of the material or for any damages arising out of the use or non-use of any of the
information contained in this document.
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Cover Design: David Wade
Page Design: Carol Barrer

Library of Congress Cataloging-in-Publication Data


NICU primer for pharmacists / [edited by] Amy P. Holmes.
p. ; cm.
Neonatal intensive care unit primer for pharmacists
Includes bibliographical references and index.
ISBN 978-1-58528-475-7
I. Holmes, Amy P., editor. II. American Society of Health-System Pharmacists, publisher. III. Title:
Neonatal intensive care unit primer for pharmacists.
[DNLM: 1. Infant, Premature, Diseases--drug therapy. 2. Pharmaceutical Preparations--administration
& dosage. 3. Intensive Care Units, Neonatal. WS 410]
RJ251
618.92’0028--dc23
2015024504

© 2016, American Society of Health-System Pharmacists, Inc. All rights reserved.


No part of this publication may be reproduced or transmitted in any form or by any means, electronic
or mechanical, including photocopying, microfilming, and recording, or by any information storage and
retrieval system, without written permission from the American Society of Health-System Pharmacists.
ASHP is a service mark of the American Society of Health-System Pharmacists, Inc.; registered in the U.S.
Patent and Trademark Office.
ISBN: 978-1-58528-475-7
10 9 8 7 6 5 4 3 2 1
Dedication

In memory of my dad who taught me the value of hard work.

To my mom and my sister Debbie who are always there for me; to my sweet
daughter Abby for being the best cheerleader a girl could have and for all
the time you’ve sacrificed with mom so I could work on “the book”; to all
the students and residents who have challenged me to broaden my under-
standing; and to all the babies who have inspired and amazed me with their
resilience.

Special thanks to Brock Harris and the other authors who were willing to
come along on this journey with me.

iii
iv NICU Primer for Pharmacists

Table of Contents

Foreword .................................................................................................................. vi

Preface ..................................................................................................................ix

Contributors ..................................................................................................................xi

Reviewer ................................................................................................................ xiii

Common Abbreviations in Neonatal Medicine....................................................... xv

Chapter 1. General NICU Considerations..................................................................1


Megan Lunberry, PharmD, and Miyuki Nakayama Shouse, RPh, MS

Chapter 2. Developmental Pharmacology, Pharmacokinetics, and


 Pharmacodynamics..............................................................................17
John Brock Harris, PharmD, BCPS

Chapter 3. Parenteral Nutrition................................................................................27


Ying-Tang Ng, PharmD

Chapter 4. Drugs in Lactation....................................................................................43


Amy P. Holmes, PharmD

Chapter 5. Neonatal Abstinence Syndrome..............................................................55


Amy P. Holmes, PharmD

Chapter 6. Apnea of Prematurity..............................................................................65


John Brock Harris, PharmD, BCPS

Chapter 7. Respiratory Distress Syndrome and Bronchopulmonary Dysplasia.........77


Julia Lau, PharmD, BCPS

Chapter 8. Patent Ductus Arteriosus........................................................................93


Betsy Walters Burkey, PharmD, BCPS

Chapter 9. Pain and Sedation...................................................................................111


Ashley McCallister, PharmD, and Amy P. Holmes, PharmD

Chapter 10. Neonatal Bacterial Sepsis and Meningitis...............................................131


John Brock Harris, PharmD, BCPS
Table of Contents v

Chapter 11. TORCH Infections.................................................................................141


Amy P. Holmes, PharmD

Chapter 12. Respiratory Syncytial Virus....................................................................155


Betsy Walters Burkey, PharmD, BCPS, and Michelle F. F. Poole, PharmD

Chapter 13. Necrotizing Enterocolitis.......................................................................167


John Brock Harris, PharmD, BCPS

Chapter 14. Gastrointestinal Disorders.....................................................................179


John Brock Harris, PharmD, BCPS

Chapter 15. Vaccine Use in Infants............................................................................187


Amy P. Holmes, PharmD

Chapter 16. Persistent Pulmonary Hypertension of the Newborn...........................197


Julia Lau, PharmD, BCPS

Chapter 17. Neonatal Seizures..................................................................................209


John Brock Harris, PharmD, BCPS

Chapter 18. Extracorporeal Membrane Oxygenation...............................................215


Wyn Wheeler, PharmD, FCCM

Index ...............................................................................................................229
Foreword

A s pharmacists take on increasing responsibility for care of critically


ill patients, providing pharmaceutical care for critically ill newborns
in neonatal ICU can be particularly challenging. What other practice
includes patients with weights that may vary 10-fold (i.e., 500 grams to
5,000 grams at birth) or can be expected to more than quadruple their weight
while concurrently going through organ maturation and periods of organ
damage during their hospital stay? Add to this the challenge of multiple concur-
rent diseases, changing therapeutic strategies based on conflicting scientific
data, and NICU-specific pharmaceutical products or compounded preparation
requirements using drugs with concentrations designed for administration
to older patients. Consequently, it is readily apparent why a book such as the
NICU Primer for Pharmacists can be a useful, rapid resource for practicing
hospital pharmacists who serve a NICU in addition to all the other patient
populations within the hospital.
When I started NICU practice in 1977, there was virtually nothing
to guide clinicians regarding best doses or practices for treating neonatal
diseases; later evidence demonstrated that much of what we did was actually
harmful to the newborn. Most NICUs had little to offer newborns below
28 weeks gestation, before surfactant became available, and mortality rates
were extremely high. The increasing survival rates for preterm infants as
young as 24 weeks gestation means that clinicians are confronted with a
whole new set of challenges to maximize the likelihood of not only survival,
but survival without serious long-term damage and neurodevelopmental
delays. As methods to optimize outcomes evolve, timely interventions are

vi
Foreword vii

likely required to interrupt the cascade of physiologic and biochemical events


that produce damage. In many cases, this will mean optimal drug selection
at the correct dose delivered to the patient within hours of recognizing the
problem. For the pharmacist, it will require an excellent knowledge of drugs
and diseases, or at least a reference that provides concise and pragmatic
information, such as provided in this book. No doubt the information will
come as a welcome resource when the pharmacist tries to deal with an array
of rapid and complicated decisions.
In much of my career, lack of products specifically manufactured for
neonatal care and the ever-present danger of dosing errors, often reflecting
decimal place errors, made the possibility for drug-related complications
unacceptably high and required constant vigilance by the healthcare team.
Today’s pharmacists are confronted with additional, unique challenges to
optimal care. This includes the dilemma of drug shortages and consequent
use restrictions, which require pharmacists to have creative approaches to
deliver the desired products to the most vulnerable patients. It also involves
managing inventory and availability of very expensive new products needed
to treat uniquely neonatal diseases. Other important functions include
overseeing dosing adjustments as patients mature, increase or lose body
weight, or suffer organ damage that alters drug elimination or results in
changes in drug distribution. When situations arise where rapid adminis-
tration of drugs to the patient is required to reduce mortality or long-term
damage, drug distribution systems will need to adapt and procedures to
be in place to ensure such orders are processed and delivered in a timely
manner to the bedside. Pharmacists must be facile in detecting and correct-
ing product dilutions to verify the correct dose because drugs often come
in different strengths and different dilutions may need to be made. Many
considerations must go through pharmacists’ minds as they collaborate with
the healthcare team to promote safe and effective drug therapy.
The NICU Primer for Pharmacists provides a valuable overview of several
common diseases, drug therapy, and critical preparation or administration
considerations. The disclaimer in the front of the text wisely cautions the reader
to consider whether the information remains current in this rapidly changing
field. Nevertheless, even if the facts change, there is a logical organization and
thought process reflected throughout this book that will provide pharmacists
with a strategy for dealing with NICU patients and therapeutic approaches
needed to care for them. This makes the book a useful resource for pharmacists,
viii NICU Primer for Pharmacists

especially those who do not specialize in NICU, and students and residents
who may do clinical clerkships in NICU.

Peter Gal, PharmD, BCPS, FCCP, FASHP, FPPAG


Professor and Associate Dean for Academic Affairs
High Point University School of Pharmacy
High Point, North Carolina
Preface

M
any pharmacists working in hospital pharmacies today have
little or no formal training in neonatology, yet they are faced
with dispensing medications to this fragile NICU population.
Some units have neonatal specialists who oversee medication-use practices;
however, many units are too small to justify having the full time support
of a specialist. Even in units where there is a specialist, they are not avail-
able 24/7 to verify orders, mix IVs, and dispense medications. This book
is meant as an introduction to the world of the NICU for those front-line
pharmacists who serve neonatal patients. Beyond checking for accuracy of
weight-based dosing, this book strives to provide an overall understanding
of the most common disease states in the neonatal population as well as the
role of the most commonly used pharmaceutical agents in the NICU.
In addition, this book serves as an introduction to NICU for pharmacy
learners. For years I have struggled with finding the right reading assign-
ments for students and residents taking my NICU rotation. Many of the
textbook chapters and journal articles that I have used assume some baseline
knowledge of neonatal medicine. Even the learner who has opted to take an
elective course in pediatrics has had little or no exposure to neonatology. This
book serves as baseline information to familiarize those learners with this
unique population and prepare them to delve into the primary literature.
Each chapter gives basic information on disease states specific to the
neonatal population or describes scenarios that make common disease states
different in neonates. At the end of every chapter, except the first one, you

ix
x NICU Primer for Pharmacists

will find a Suggested Reading list to dig further into a particular topic.
(The Suggested Readings for Chapter 1 is the rest of the book!) Chapter 1
does include a list of recommended neonatal references. These are “go to”
resources that may be helpful in researching neonatal topics not found in
this book.
In reading and using the NICU Primer for Pharmacists, you will see that
neonates are not just small adults. They are a very unique and specialized
patient population warranting extra attention and care.

Amy P. Holmes
Contributors

Betsy Walters Burkey, PharmD, Megan Lunberry, PharmD


BCPS Novant Health Forsyth Medical Center
Women & Children’s Pharmacy Winston Salem, North Carolina
Specialist
Fairview Hospital/Cleveland Clinic Ashley McCallister, PharmD
Children’s Hospital Candidate
Strongsville, Ohio Advance, North Carolina

John Brock Harris, PharmD, BCPS Ying-Tang Ng, PharmD


Pharmacy Assistant Professor— Assistant Professor
Pediatrics Husson University School of Pharmacy
Pediatric Clinical Pharmacy Specialist Bangor, Maine
Presbyterian Medical Center
Hemby Children’s Hospital Michelle F. F. Poole, PharmD
Matthews, North Carolina PGY1 Clinical Pharmacy Resident
Fairview Hospital
Amy P. Holmes, PharmD Cleveland, Ohio
Neonatal Clinical Pharmacy Specialist
Novant Health Forsyth Medical Center Miyuki Nakayama Shouse, RPh, MS
Winston Salem, North Carolina Clinical Staff Pharmacist
and Winston Salem, North Carolina
Adjunct Assistant Professor
Wingate School of Pharmacy Wyn Wheeler, PharmD, FCCM
Wingate, North Carolina Clinical Pharmacy Specialist, Neonatal
and Pediatric Critical Care
Julia Lau, PharmD, BCPS Levine Children’s Hospital at Carolinas
Novant Health Presbyterian Medical Medical Center
Center Charlotte, North Carolina
Charlotte, North Carolina

xi
Reviewer

M. Petrea Cober, PharmD, BCNSP


Clinical Pharmacy Coordinator—
Neonatal Intensive Care Unit
PGY1 Pharmacy Practice Residency
Director
Akron Children’s Hospital
Akron, Ohio
and
Associate Professor of Pharmacy
Practice
Northeast Ohio Medical University
College of Pharmacy
Rootstown, Ohio

xiii
Common Abbreviations in
Neonatal Medicine

AA: Amino acid A.S.P.E.N.: American Society for


AAP: American Academy of Pediatrics Parenteral and Enteral Nutrition
ABG: Arterial blood gas BBT: Baby’s blood type
ACEI: Angiotensin-converting enzyme BIO: Binocular indirect ophthalmoscope
inhibitor
BPD: Bronchopulmonary dysplasia
ACOG: American College of
BSA: Body surface area
Obstetricians and Gynecologists
BUN: Blood urea nitrogen
AED: Antiepileptic drugs
AEDF: Absent end diastolic flow cAMP: Cyclic adenosine monophosphate
AGA: Appropriate for gestational age CBC: Complete blood count
AMPA: α-amino-3-hydroxyl-5-methyl-4- CDC: Centers for Disease Control and
isoxazolepropionic acid Prevention
ANC: Absolute neutrophil count CDH: Congenital diaphragmatic hernia
AOP: Apnea of prematurity CGA: Corrected gestational age
APAP: Acetaminophen cGMP: Cyclic guanosine monophosphate
APGAR: Appearance, Pulse, Grimace, CI: Confidence interval
Activity, and Respiration CLABSI: Central line-associated blood
ART: Antiretroviral treatment stream infection
ASHP: American Society of Health- CLD: Chronic lung disease
System Pharmacists
xv
xvi NICU Primer for Pharmacists

CMV: Cytomegalovirus g: gram


CMV HIG: Cytomegalovirus GA: Gestational age
hyperimmune globulin GABA: Gamma-aminobutyric acid
CNS: Central nervous system GBS: Group B Streptococcus
CoNS: Coagulase-negative staphylococci GC: Gonorrhea/chlamydia
CPAP: Continuous positive airway GER: Gastroesophageal reflux
pressure
GERD: Gastroesophageal reflux disease
CPS: Canadian Paediatric Society
GFR: Glomerular filtration rate
CRIES: Crying, Requires O2 for SaO2
GI: Gastrointestinal
<95%, Increased vital signs (blood
pressure and heart rate), Expression, GIR: Glucose infusion rates
Sleeplessness GPA: gravida/para/abortus (obstetric
CRP: C-reactive protein history)
CS: Caesarean section H2RA: H2-receptor antagonist
CSF: Cerebrospinal fluid HBIG: Hepatitis B immune globulin
CVS: Congenital varicella syndrome HEP: Hepatitis
CYP: Cytochrome P450 HepB: Hepatitis B
DA: Ductus arteriosus Hib: Haemophilus influenza
DART: Dexamethasone: A Randomized HIV: Human immunodeficiency virus
Trial HMF: Human milk fortifier
DC: Direct Coombs HSV: Herpes simplex virus
DIC: Disseminated intravascular
IAP: Intrapartum antibiotic prophylaxis
coagulation
IDM: Infant of diabetic mother
DTaP: Diphtheria, tetanus, and pertussis
IFALD: Intestinal failure-associated liver
ECMO: Extracorporeal membrane disease
oxygenation IgG: Immunoglobulin G
EEG: Electroencephalogram IgM: Immunoglobulin M
ELBW: Extremely low birth weight IM: Intramuscular
EMLA: Eutectic mixture of local iNO: Inhaled nitric oxide
anesthetics
INR: International normalized ratio
EOS: Early-onset sepsis
IPV: Inactivated polio virus
EPT: Extremely preterm
IUGR: Intrauterine growth restriction
ET: Endotracheal or endothelial
IV: Intravenous
FDA: Food and Drug Administration IVFE: Intravenous fat emulsion
FiO2: Fraction inspired oxygen IVH: Intraventricular hemorrhage
concentration
FTA-ABS: Fluorescent treponemal kg: kilogram
antibody-absorption KMC: Kangaroo mother care
Common Abbreviations in Neonatal Medicine xvii

LBW: Low birth weight PCT: Procalcitonin


LGA: Large for gestational age PDA: Patent ductus arteriosus
LOS: Late-onset sepsis PDE: Phosphodiesterase
LPT: Late preterm PDE3: Phosphodiesterase type 3
PDE5: Phosphodiesterase type 5
M3G: Morphine-3-glucuronide
PEEP: Positive end-expiratory pressure
M6G: Morphine-6-glucuronide PGE2: Prostaglandin E2
MAP: Mean airway pressure PGI2: Prostacyclin I2
MAS: Meconium aspiration syndrome PICC: Peripherally inserted central
MBT: Maternal blood type catheter
MCT: Medium chain triglyceride PIPP: Premature Infant Pain Profile
MDI: Metered dose inhaler PIV: Peripheral IV
mm: Millimeter PMA: Post-menstrual age
mL: Milliliter PN: Parenteral nutrition
PNA: Postnatal age
NAS: Neonatal abstinence syndrome PNALD: Parenteral nutrition-associated
NEC: Necrotizing enterocolitis liver disease
NICU: Neonatal intensive care unit PNC: Prenatal care
NIH: National Institutes of Health PO: By mouth or oral
NIPS: Neonatal Infant Pain Scale PPHN: Persistent pulmonary
hypertension of the newborn
NMBA: Neuromuscular blocking agents
PPI: Proton-pump inhibitor
NMDA: N-methyl-D-aspartate
PPROM: Prolonged premature rupture of
NO: Nitric oxide membranes
N-PASS: Neonatal Pain, Agitation, and PPV: Positive pressure ventilation
Sedation Scale PRBC: Packed red blood cell
NPO: Nothing by mouth PVL: Periventricular leukomalacia
NRFHT: Non-reassuring fetal heart trace PVR: Pulmonary vascular resistance
NSAIDs: Nonsteroidal anti-inflammatory
RDS: Respiratory distress syndrome
drugs
ROM: Rupture of membranes
OI: Oxygenation index
ROP: Retinopathy of prematurity
OR: Odds ratio
ROS: Rule out sepsis
PAH: Pulmonary arterial hypertension RPR: Rapid plasma reagin or reagent
PAMF-TSL: Palo Alto Medical (screening test for syphilis)
Foundation−Toxoplasma Serology RR: Relative risk
Laboratory
RSV: Respiratory syncytial virus
PaO2: Partial pressure of oxygen
RUB: Rubella
PCR: Polymerase chain reaction
xviii NICU Primer for Pharmacists

SaO2: Arterial oxygen saturation VariZIG: Varicella zoster immune


SEM: Skin, eyes, and mouth globulin
SGA: Small for gestational age Vd: Volume of distribution
SIDS: Sudden infant death syndrome VD: Vaginal delivery
SP-B: Surfactant protein B VEGF: Vascular endothelial growth factor
SP-C: Surfactant protein C VKDB: Vitamin K deficiency bleeding
SQ: subcutaneous VLBW: Very low birth weight
SSRI: Serotonin discontinuation VPT: Very preterm
syndrome
WAT-1: Withdrawal Assessment Tool-1
SVR: Systemic vascular resistance
WBC: White blood cell
TD: Tardive dyskinesia
TIPP: Trial of Indomethacin Prophylaxis
in Preterm
TOF: Train-of-four
TORCH: Toxoplasmosis, Rubella,
Cytomegalovirus, and Herpes
Simplex
TP-EIA: Treponema pallidum enzyme
immunoassay
TPN: Total parenteral nutrition
TP-PA: Treponema pallidum particle
agglutination
TTN: Transient tachypnea of the neonate

UAC: Umbilical artery catheter


UVC: Umbilical venous catheter
1
General NICU
Considerations

Megan Lunberry, PharmD,


and Miyuki Nakayama Shouse, RPh, MS

Introduction

A
nnually, an estimated 15 million
babies worldwide are born
before 37 weeks of gestation,
and approximately 1 million children
die each year due to complications
of preterm birth.1 Many babies who
survive preterm birth face a lifetime of
disabilities. Moreover, preterm births
are increasing in almost all countries.
Prematurity is the leading cause of death
in newborns during the first 4 weeks of
life, and it is the second leading cause of
death after pneumonia in children under
the age of 5.1
2 NICU Primer for Pharmacists

Premature babies are at high risk for hypothermia, hypoglycemia,


electrolyte imbalance, hyperbilirubinemia, respiratory distress syndrome
(RDS), patent ductus arteriosus, infections, necrotizing enterocolitis, and
intraventricular hemorrhage (IVH). In the long term, they are at risk for
chronic lung disease, cognitive delays, cerebral palsy, and visual and hearing
loss. Late-preterm and moderate-preterm babies are at risk for complications
such as learning disabilities.2
Being part of the healthcare team caring for infants in the neonatal
intensive care unit (NICU) is exciting as well as challenging. As pharma-
cists, we play a vital role in the pharmacological care of NICU patients
just as with any other patient population. We ensure that medications are
appropriate for each indication, dosed, filled, and monitored correctly. This
is especially vital for NICU patients where the margin for error is much
smaller than in adult and pediatric populations.
The drug formulary used in the NICU is rather limited compared
with that used in other patient populations. The majority of medications
for NICU babies are dosed by weight—sometimes to the tenth and even
hundredth of a milligram. Such precise attention to detail cannot be taken
lightly and requires a vigilant pharmacist’s careful scrutiny. Timing is crucial.
Because of their tiny body mass, infants’ health status can change rapidly.
Antibiotics and intravenous (IV) dextrose are just two examples of treat-
ments that need to be implemented quickly to ensure timely treatment in
such a delicate patient population.
Many pharmacists shy away from working with NICU patients due
to the high risks in this specialized clinical environment. Although it is
always good to have a healthy fear regarding the responsibility of caring for
any patient population, pharmacists should not be intimidated by the care
required in the NICU. This book will equip you with the necessary tools to
provide such care. The purpose of this first chapter is to provide an introduc-
tion to neonatal care that will aid in effective patient care in a NICU setting.

Definitions
❖❖ Neonates—babies from birth to the age of 30 days of postnatal life,
including both preterm and post-term babies.
❖❖ Gestational age (GA)—the age from the time of conception to birth.
❖❖ Postnatal age (PNA)—the age in days of life after birth.
General NICU Considerations 3

❖❖ Post-menstrual age (PMA)—also known as corrected gestational age


(CGA) the sum of these two ages: PMA = GA + PNA
❖❖ Appropriate for gestational age (AGA)—babies born at the appropriate
weight for their gestational age (10th–90th percentile).
❖❖ Large for gestational age (LGA)—babies who weigh more than expected
for their gestational age. This condition is commonly caused by maternal
diabetes (>90th percentile).
❖❖ Small for gestational age (SGA)—babies who weigh less than expected for
their gestational age (<10th percentile).
❖❖ Intrauterine growth restriction (IUGR)—condition that is often a result
of maternal uteroplacental vascular insufficiency, which in turn is caused
by preeclampsia, hypertension, or tobacco use and the inherent genetic
growth potential of the fetus. SGA is the neonatal manifestation of IUGR,
and SGA infants are at increased risk for fetal distress and neonatal
hypoglycemia, neonatal complications, and perinatal death.3

Preterm Classifications
❖❖ Preterm—babies born alive before 37 weeks of pregnancy are completed.
There are subcategories of preterm birth based on gestational age.
❖❖ Moderate-to-late preterm (LPT)—babies who are 32 weeks to less than
37 weeks of gestational age.
❖❖ Very preterm (VPT)—babies who are 28 weeks to less than 32 weeks of
gestational age.
❖❖ Extremely preterm (EPT)—babies who are less than 28 weeks of gestational
age.

Classifications by Birth Weight


❖❖ Low birth weight (LBW)—less than 2,500 g.
❖❖ Very low birth weight (VLBW)—less than 1,500 g.
❖❖ Extremely low birth weight (ELBW)—less than 1,000 g.

Obstetric History Classifications


Obstetric history is expressed in gravida/para/abortus (GPA):
❖❖ Gravida—the total number of times a woman has been pregnant regard-
less of whether those pregnancies were carried to term.
❖❖ Para—the number of viable births.
4 NICU Primer for Pharmacists

❖❖ Abortus—the number of pregnancies that were lost for any reason,


including miscarriages.
When a woman has not had any pregnancy loss, history may be expressed
simply as gravida/para (GP). For example, a woman who was pregnant three
times, who gave birth to two infants and suffered one miscarriage, would
be expressed G3-P2-A1. A woman who had four pregnancies and four live
births and no abortions or miscarriages would be expressed G4-P4.

Causes of Premature Birth


Delivery of babies prematurely occurs for various reasons. However, a
common reason for preterm delivery is the result of early induction of
labor or cesarean section birth due to medical reasons. Such reasons include
pre-eclampsia, placental abruption, uterine rupture, cholestasis, fetal
distress, and fetal growth restriction with abnormal tests.4 Spontaneous
preterm labor is another reason. Identified causes of spontaneous preterm
labor include multiple pregnancies, infections (e.g., urinary tract infections,
bacterial vaginitis, human immunodeficiency virus, syphilis, and infection
of the amniotic membrane), chronic maternal health conditions (e.g., diabe-
tes, high blood pressure), being African American, maternal age younger
than 16 or older than 35 years, poor nutrition before and during pregnancy,
obesity, lack of prenatal care, tobacco or/and alcohol use, and low socioeco-
nomic status.

Prevention of Preterm Labor


To prevent preterm birth for all pregnant women, it is important to identify
women at high risk. All pregnant women are screened for signs and
symptoms of any infection, including sexually transmitted diseases and
nutrition conditions, and educated about identification of early labor.5
Pregnant women who have hypertensive disorder, diabetes, multiple gesta-
tions, bleeding, and/or are younger than 16 or older than 35 years are
considered to be at higher risk for preterm birth. For mothers at GA of 32
weeks or less, use of corticosteroids (betamethasone 12 mg every 24 hours
times two doses or dexamethasone 6 mg every 12 hours times four doses)
ensures babies have a lower risk of developing RDS. Some studies suggest
that for every 100 women treated with corticosteroids, four cases of neona-
tal deaths, nine cases of RDS, four cases of IVH, and 12 cases of surfactant
General NICU Considerations 5

use would be avoided.3 If a mother has a history of spontaneous preterm


birth less than 37 weeks’ gestation, 17-alpha-hydroxyprogesteron caproate
intramuscularly (IM) 250 mcg weekly can be given to maintain pregnancy
until 36 weeks’ GA.6

Management of Preterm Labor


The treatment goal of preterm labor is to prolong pregnancy to term
because a longer GA reduces complications of premature birth, or even to
halt labor long enough to get antenatal steroids administered. Tocolytics are
used to inhibit muscle contractions and include magnesium sulfate, terbu-
taline, nifedipine, nicardipine, and indomethacin.

Assessment of the Infant


One tool used to assess an infant’s condition right after birth is the APGAR
scoring system. It is named for Dr. Virginia Apgar who invented this
assessment tool in the early 1950s.7 APGAR (Appearance, Pulse, Grimace,
Activity, and Respiration) scoring for each category is numerical from 0 to
2, with 0 as the least responsive and 2 as the healthiest response. Appearance
includes observations such as color of the extremities and the rest of the
body. Grimace refers to response to stimulation, and activity refers to muscle
tone. This evaluation is performed on the infant at 1, 5, and 10 minutes of
life. A total score ranging from 7 to 10 indicates that the baby’s condition is
normal. Scores of 0 to 3 are low and indicate that immediate medical inter-
vention is required.
The Ballard scoring system, developed by Dr. Jeanne Ballard,8 is also
widely used to assess a newborn infant’s neuromuscular and physical matu-
rity. This assessment is done at 24 hours of life. Arm recoil; posture; and
appearance of skin, eyes, and genitals are examples of criteria measured
using the Ballard scoring charts. The scores range from −1 to 5, and the sum
of scores helps to determine the gestational maturity of the baby in weeks.
A maturity rating chart is part of the Ballard score assessment and helps to
determine the infant’s GA.9 For example, a Ballard score of 35 correlates
to the maturity rating that indicates the GA of a 38-week infant. This is
particularly helpful if the infant’s GA is unknown or if the infant is unusu-
ally large or small for the determined age. Determining GA is crucial for
accurately dosing medications.
6 NICU Primer for Pharmacists

Management of Newborns
Newborn and most late-preterm babies need simple essential care for
warmth, breastfeeding, and a clean environment. For younger GA babies,
NICUs can provide infection control measures, temperature control, feeding
support, safe oxygen use, and respiratory care in addition to medical care by
a multidisciplinary team including neonatologists, nurses, respiratory thera-
pists, and pharmacists.
Early initiation of breastfeeding within 1 hour after birth has been
shown to reduce neonatal mortality. Kangaroo mother care (KMC), direct
skin-to-skin contact with mother, has a proven effect in decreasing mortality
for babies less than 2,000 g.10 KMC provides stable warmth; reduces neona-
tal mortality, infections, and hypothermia; and encourages frequent and
exclusive breastfeeding, resulting in weight gain and mother−baby bonding.
At the birth of a baby, a series of preventive medication is given such as
the following:
❖❖ Erythromycin ophthalmic ointment is applied to the baby’s eyes to
prevent ophthalmia neonatorum that may lead to blindness for infants
who do not receive prophylaxis.
❖❖ Vitamin K intramuscular injection is given for prevention of vitamin K
deficiency bleeding (VKDB).
❖❖ The first dose of hepatitis B vaccine is given to babies who weigh more
than 2,000 g or to any baby whose mother is hepatitis B surface antigen
positive.
❖❖ Caffeine may be initiated in the first days of life of premature infants
to treat apnea of prematurity or as a preventive measure against chronic
lung disease.
❖❖ Indomethacin IV may be given for prevention of IVH in premature
infants.
❖❖ Antibiotics such as gentamicin and ampicillin IV may be given for the
first 48 hours while ruling out sepsis for babies who meet the criteria,
such as history of maternal infection or preterm labor.
Each of these medications is discussed in more detail later in this book.

Vascular Access
NICU infants may need several lines for vascular access at one time. A
common point of vascular access is via the umbilical cord. Due to its tempo-
General NICU Considerations 7

rary presence in any newborn, this is only feasible during the first week or
so of life. An umbilical venous catheter is placed into the vein of the cut
umbilical cord and is mostly limited to 1 week of use due to risk of infec-
tion. The line runs through the vein to the inferior vena cava, which enables
medications and parenteral nutrition (PN) fluids to be distributed quickly
throughout the body. Because veins of a premature infant are quite fragile,
this also enables the delivery of more hypertonic solutions.11 An umbilical
artery catheter (UAC) is placed in one of the arteries of the cut umbilical
cord and threaded to the descending aorta.11 This allows for the continuous
monitoring of blood pressure as well as frequent and convenient laboratory
draws, such as arterial blood gases, without using needle sticks. Heparinized
fluids are usually infused continuously through the UAC to prevent it from
clotting off.
A peripherally inserted central catheter is placed in the arm, leg, or scalp
of the infant and fed through to the vena cava. The tip is centrally placed
in the superior vena cava if placed in the arm and in the inferior vena cava
if placed in the leg. This type of IV line can be used for several weeks and is
useful for long-term IV therapy. Peripheral IV lines are placed in the hands,
feet, or scalp and can be used for a few days to deliver medication, fluids, or
nutrition. Because most NICU patients need IV treatment for an extended
period of time, most will have central lines.
Premature infants have an estimated blood volume of 80 mL/kg.12
Because of the premature infants’ tiny blood volumes, it is important to be
conservative and to minimize ordering blood draws for laboratory work.
Occasionally, the administration of an IV medication may result in extrava-
sation or the drug leaking from the vein into the surrounding extravascular
space. In any case, the IV push or infusion should be stopped immediately.
If pharmacologic management of extravasation is indicated for a neonate,
hyaluronidase can safely be injected subcutaneously (SQ) in tiny aliquots
around the affected area.13 This breaks down hyaluronic acid, making tissues
more permeable and aids in fluid reabsorption. Blanched skin resulting from
extravasation usually returns to normal color within minutes of application.
Dopamine extravasation should be treated using phentolamine 0.5 mg to
1 mg SQ injection around the site of extravasation if available or topical
nitroglycerin paste 4 mm/kg.13
8 NICU Primer for Pharmacists

Medication Safety
NICU patients are at a higher risk for medication errors compared with
other patient populations because the majority of dosing depends on
weight-based calculations. A ten-fold or more dosing error due to incorrect
decimal placement can be easily overlooked if one is not careful. Pharma-
cists play a vital role in checking—and rechecking—during the ordering,
dispensing, and delivery of NICU medications. All general medication
safety guidelines should be followed as well as those specific to neonatal
medication. When checking a provider’s order, it is important to check
the indication for an ordered medication to make sure it matches what is
intended to be treated. Many drugs such as dexamethasone have different
dosing regimens depending on the indication. Make sure to use a reputable
neonatal drug reference as not all drug references focus specifically on the
most current drug therapy for neonates (e.g., Neofax, Pediatric & Neona-
tal Dosage Handbook, Pediatric Injectable Drugs: The Teddy Bear Book). All
calculations should be double-checked for accuracy.
Correct scheduling of antibiotic administration is essential and must be
closely monitored. This is also the case with medications dosed and sched-
uled based on around-the-clock feedings. Many oral electrolyte replacement
supplement doses are divided and given with feeds. An observed example of
this potential error is a medication order entered as mg/kg/dose instead of
mg/kg/day. This would result in an eight-fold increase of the intended dose
if, for example, the dose was administered every 3 hours.
Medication standardization is critical for any facility caring for NICU
patients. A collaborative practice team should decide on limiting concen-
trations of certain formulary options (e.g., what the facility will allow for
percentages of IV dextrose). Titratable IV admixtures, including dopamine
and midazolam concentrations, should also be standardized. Heparin
concentrations for IV admixtures as well as line flushes must be consistent
with preferably no deviations, especially because this drug has been notori-
ous for major medication errors in neonates.14
Limiting options of drug concentrations decreases chance of errors.
Also, having predetermined and calculated instructions for IV admixtures
on hand in the pharmacy is essential. Establishing a separate area in the
pharmacy to store NICU medications away from the rest of the inventory
further ensures medication safety. A spot should even be designated for
NICU medications in the refrigerated section. Designated areas decrease
General NICU Considerations 9

the chances of using the wrong medication or concentration when filling a


NICU medication order.
Because the amount of injectable medication is small and often mixed in
minimal fluid, it is vital to dispense injectable products in a way that clearly
distinguishes them from oral medications. Often the syringe size is very
similar for both medication routes. Not using Luer lock oral syringes ensures
that the medication will not be administered IV. Other effective ways to
distinguish between oral and injectable medication syringes are clearly
labeling medications and using visibly different syringe caps. Needles should
not be greater than 1 inch in length when administering IM medications to
infants. Using a needle longer than 1 inch increases the risk of neurovascu-
lar injuries because the neonate has decreased muscle mass. Also, the total
volume per IM injection should be limited to 0.5 mL for premature infants
and should not exceed 1 mL for newborns up to 1 year in age. Using larger
volumes for IM administration can cause sterile abscess formation, muscle
contractures, and vascular compression injuries.15
Expiration dates and times are important to consider in dispensing
medications for a NICU patient. Many medications prepared for NICU use
will be short-dated in an effort to be extremely vigilant in preventing micro-
bial growth from being transferred during administration. Moreover, all
dispensed medications should have clearly printed date/time of expiration
on the label. It is important to keep medication rooms free from expired
drugs by checking storage areas routinely. Medication safety for the NICU is
an actively evolving practice and should be a high priority among all staff at
any facility.

Medications to Avoid in Neonates


Caution is recommended with some medications for pediatric patients, and
some medications are contraindicated in newborns less than 6 to 8 weeks
old. Most pharmacists are aware of the warnings with tetracyclines and
fluoroquinolones in pediatric patients. Tetracycline may cause permanently
discolored teeth in neonates and children less than 8 years of age. Due to
reports of injury in weight-bearing joints in juvenile animals, quinolones
should be used with caution in pediatric patients. Contraindications more
specific to neonates include nitrofurantoin, sulfonamides, and ceftriaxone.
Nitrofurantoin is contraindicated in the early weeks of life due to the risk
of hemolytic anemia. Sulfonamides and ceftriaxone are contraindicated
10 NICU Primer for Pharmacists

in patients younger than 6 to 8 weeks of age due to their displacement of


bilirubin from protein-binding sites and potential for kernicterus. Kernicter-
us is caused by an excess amount of bilirubin, which binds to brain cells, and
may cause permanent brain damage, hearing loss, and possible death.
When the benefits of ceftriaxone therapy outweigh some inherent risks,
ceftriaxone may be used for neonates. The Food and Drug Administration
(FDA) has issued a warning based on reports of fatal cases in neonates where
ceftriaxone was used in conjunction with calcium-containing IV fluids. The
FDA recommends avoiding concomitant administration of ceftriaxone and
any IV calcium-containing products such as Lactated Ringer’s solution or
PN containing calcium. This combination is contraindicated in neonates
less than 28 days old.16

Complications with Premature Babies


Vitamin K and VKDB17
IM vitamin K (phytonadione) is essential to newborns to prevent VKDB
(formerly called hemorrhagic disease). VKDB can be subclassified to early,
classic, and late VKDB (see Table 1-1). The American Academy of Pediat-
rics recommends giving IM vitamin K within 6 hours of birth. The dose of

Table 1-1. Classifications for VKDB17


Prevention by
Subtypes Common Vitamin K IM
of VKDB Onset Timing Bleeding Sites Injection
Early VKDB First 24 hours Cephalohematomas Newborns whose
of life and intracranial mothers are taking
hemorrhages anticonvulsants or
anticoagulant
medications
Classic VKDB First week of Cutaneous, nasal, Newborns who did
life circumcision, and not receive vitamin K
GI bleeding prophylaxis at birth
Late VKDB 2 weeks to 3 Intracranial, Exclusively breastfed
months of life cutaneous, newborns who did
GI bleeding not receive vitamin K
prophylaxis at birth
GI: gastrointestinal; VKDB: vitamin K deficiency bleeding
General NICU Considerations 11

vitamin K is 0.5 mg IM for newborns who weigh less than 1,500 g and 1
mg IM for newborns who weigh equal to or more than 1,500 g.
Vitamin K has three different forms:
1. Vitamin K1 is consumed from foods such as green leafy vegetables (kale,
spinach). Adults and children can obtain vitamin K1 from their diet.
2. Vitamin K2 forms are synthesized by gastrointestinal (GI) bacterial flora
in adults and children.
3. Vitamin K3 is a synthetic water-soluble form, which is used as medicine
in oral, IM, and IV form.17
VKDB can occur because newborns have almost undetectable vitamin
K in their bodies when they are born. Vitamin K does not cross the placenta
and babies do not have bacterial flora in their GI tract, so they cannot yet
synthesize their own vitamin K. Although a mother’s milk has some vitamin
K for babies to absorb, the level increases very gradually.17

Retinopathy of Prematurity
Premature infants are at risk for a condition known as retinopathy of prema-
turity (ROP). The development of blood vessels around the retina can be
delayed due to preterm birth. This is especially true for SGA infants as they
have low serum growth factor IGF-1, which is necessary for vascular devel-
opment.18 This abnormal growth of vasculature around the retina can lead
to damage that can result in retinal detachment and blindness.
Fortunately, blindness caused by ROP is largely preventable. It is
common practice to perform eye exams on premature infants at risk for
ROP to determine if further intervention is required. Exams utilize the
binocular indirect ophthalmoscope to view the retina, allowing the ophthal-
mologist to stage the progression of vasculature growth.18 Cyclopentolate,
an anticholinergic agent with paralytic properties, dilates the pupil allowing
for enhanced visualization of the retina. Local anesthetic eye drops, such as
proparacaine, are used in preparation for this exam. Both cyclopentolate and
proparacaine are eye drops that may be used in neonates prior to eye exams.
Treatment of advanced ROP is often eye laser surgery. Another treat-
ment option is intravitreal bevacizumab, a vascular endothelial growth
factor inhibitor,19 which is effective only in certain regions of the eye. It
allows vessels to grow again around the retina unlike the laser procedure that
destroys them permanently and results in some loss of peripheral vision. Not
12 NICU Primer for Pharmacists

all neonates will respond to ROP treatment and may require eye surgery to
fix a detached retina.

Indomethacin for Prevention of IVH


Intraventricular hemorrhage or IVH can be a serious complication of prema-
ture birth. This has been observed particularly in infants born at less than
32 weeks gestation.20 IVH commonly occurs within 72 hours after birth and
in infants weighing less than 1 kg.20 Classification of IVH is done by grades
I through IV, with IV being the most severe. Various risk factors can lead to
this complication such as maternal chorioamnionitis/infection/inflammation,
maternal fertility treatment, early sepsis, hypotension, RDS, seizures, and
several others.20
Prophylactic treatment of IVH with indomethacin has been a contro-
versial topic. Indomethacin can inhibit the alteration of the blood−brain
barrier permeability caused by ischemia and aid in maturation of vessels.
It inhibits cyclooxygenase, COX 1 and COX 2, which synthesize prosta-
glandins. Despite protective outcomes of indomethacin treatment, the
blockage of COX activity may also prevent the synthesis of prostaglandins
that have neuroprotective roles.20 Indomethacin continues to be a good
option to prevent the detrimental outcomes of IVH in high-risk infants,
regardless of this risk and others such as GI bleeding, hypoglycemia, and
thrombocytopenia.21
Pharmacists taking care of infants should be aware of the drug interaction
between indomethacin and glucocorticoids. Concomitant use of these medica-
tions has been associated with an increased incidence of spontaneous intesti-
nal perforations and should be avoided if possible. Unfortunately, this drug
interaction is not included in most drug references and often does not fire a
warning in order entry/verification software. There is no one simple recom-
mendation regarding the best way to avoid the interaction because so much
depends on whether one drug is used for prevention rather than treatment.
Discussion with the medical team about management of the baby can help to
avoid concomitant administration of indomethacin and glucocorticoids.

Conclusion
Practicing pharmacy in a NICU setting provides challenges and opportuni-
ties to learn clinical facets exclusive to this special patient population. The
General NICU Considerations 13

remainder of this book continues exploring vital clinical topics necessary to


provide excellent pharmaceutical care for the neonate.

References
1. Howson CP, Kimmey MV, McDougall L, et al. Born too soon: preterm birth matters.
Reprod Health. 2013;10(Suppl 1):S1.
2. Siva Subramanian, Barton AM, Montazami S, et al. Extremely low birth weight infant.
New York, NY: Medscape; 2014. http://emedicine.medscape.com/article/979717-over-
viewKN
3. Martin RJ, Faranoff MB. Fanaroff & Martin’s Neonatal-Perinatal Medicine: Diseases of
the Fetus and Infant. 9th ed. St. Louis, MO: Mosby; 2011:245-75.
4. Blencowe H, Cousens S, Chou D, et al. Born too soon: the global epidemiology of 15
million preterm births. Reprod Health. 2013;10(Suppl 1):S2.
5. Requejo J, Merialdi M, Althabe F, et al. Born too soon: care during pregnancy and
childbirth to reduce preterm deliveries and improve health outcomes of the preterm
baby. Reprod Health. 2013;10(Suppl 1):S4.
6. Bombrys AE, Lewis DF. Preterm labor and delivery. In: Briggs GC, Nageotte MP, eds.
Diseases, Complications, and Drug Therapy in Obstetrics: A Guide for Clinicians.
Bethesda, MD: American Society of Health-System Pharmacists; 2009:123-37.
7. Finster M, Wood M. The Apgar score has survived the test of time [abstract]. Anesthe-
siology. 2005; Apr 102(4):855-7. http://www.ncbi.nlm.nih.gov/pubmed/15791116.
Accessed November 10, 2014.
8. The New Ballard Score. http://www.ballardscore.com. Accessed November 10, 2014.
9. Cloherty JP, Eichenwald EC, Hansen AR, et al. Manual of Neonatal Care. 7th ed. Phil-
adelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2012:77.
10. Lawn JE, Davidge R, Paul VK, et al. Born too soon: care for the preterm baby. Reprod
Health. 2013;10(Suppl 1):S5.
11. Neonatal lines, tubes and catheters. http://www.wikiradiography.net/page/Neona-
tal+Lines,+Tubes+and+Catheters?t=anon. Accessed November 10, 2014.
12. Aladangady N, Leung T, Costeloe K, et al. Measuring circulating blood volume in
newborn infants using pulse dye densitometry and indocyanine green. Paediatr An-
aesth. 2008;18(9):865-71.
13. Ramasethu J. Pharmacology review: prevention and management of extravasation
injuries in neonates. Neoreviews. 2004;5:e491-7.
14. Suresh G, Levine S, Mandrack M. Prevention of medication errors in neonates. Neo-
natology Today. 2007;2:2. http://www.neonatologytoday.net/newsletters/nt-feb07.pdf.
Accessed November 10, 2014.
14 NICU Primer for Pharmacists

15. Losek JD, Gyuro J. Pediatric intramuscular injections: do you know the procedure and
complications? Pediatr Emerg Care. 1992;8(2):79-81.
16. FDA Drug Safety Newsletter. Intravenous Ceftriaxone (Marketed as Rocephin and
Generics) and Calcium Drug-Drug Interaction: Potential Risk for Cardiovascular
Adverse Events in Neonates. http://www.fda.gov/drugs/drugsafety/drugsafetynewsletter/
ucm189806.htm
17. Woods CW, Woods AG, Cederholm CK. Vitamin K deficiency bleeding: a case study.
Adv Neonatal Care. 2013;13(6):402-7.
18. Fleck BW, McIntosh N. Retinopathy of prematurity: recent developments. Neoreviews.
2009;10:e20-30.
19. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for
stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603-15.
20. McCrea HJ, Ment LR. The diagnosis, management, and postnatal prevention of in-
traventricular hemorrhage in the preterm neonate. Clin Perinatol. 2008;35(4):777-vii.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901530/
21. Neofax. Indomethacin drug monograph. http://neofax.micromedexsolutions.com/neo-
fax/neofax.php?sa=&area=1&subarea=0&drugName=Indomethacin&mode=NEO&-
Category=0&keyword=indome&Drug=neo%2F150#8. Accessed November 11, 2014.

Recommended Neonatal References


Drug Dosing
Neofax. http://neofax.micromedexsolutions.com/neofax/neofax.php?strTitle=NeoFax-
&area=1&subarea=0
Phelps SJ, Hagemann TM, Lee KR, et al. Pediatric Injectable Drugs: The Teddy Bear Book.
10th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013.
Taktomo CK. Pediatric & Neonatal Dosage Handbook. 21st ed. Hudson, OH: LexiComp;
2014.

Drugs in Lactation
Briggs GG, Freeman RK. Drugs in Pregnancy and Lactation. 10th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2015.
Hale TW, Rowe HE. Medications & Mothers’ Milk. 16th ed. Plano, TX: Hale Publishing;
2014.
LactMed. http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm
General NICU Considerations 15

Handbook
Cloherty JP, Eichenwald EC, Hansen A, et al., eds. Manual of Neonatal Care. 7th ed. Phila-
delphia, PA: Lippincott Williams & Wilkins; 2012.

Infectious Disease
Kimberlin DW, Brady MT, eds. RedBook: 2015 Report of the Committee on Infectious Diseases.
30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.
Remington JS, Klein JO, Wilson CB, et al., eds. Infectious Diseases of the Fetus and Newborn
Infant. 7th ed. Philadelphia, PA: Elsevier; 2011.

Text Books
MacDonald MG, Seshia MMK, eds. Avery’s Neonatology: Pathophysiology and Management
of the Newborn. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015.
Martin RJ, Fanaroff AA, Walsh MC, eds. Farnaoff & Martin’s Neonatal-Perinatal Medicine:
Diseases of the Fetus and Infant. 9th ed. St. Louis, MO: Elsevier Mosby; 2011.

Websites
Extremely Preterm Birth Outcome Data. http://www.nichd.nih.gov/about/org/der/branches/
ppb/programs/epbo/pages/epbo_case.aspx
NICHD Cochrane Systematic Neonatal Reviews. http://www.nichd.nih.gov/cochrane/
Pages/cochrane.aspx
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Trans-
mission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected
Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission
in the United States. https://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf
2
Developmental
Pharmacology,
Pharmacokinetics, and
Pharmacodynamics
John Brock Harris, PharmD, BCPS

Introduction

M
edication pharmacodynamic
and pharmacokinetic charac-
teristics vary based on age-
related effects, especially in neonatal and
pediatric populations. (Age-related differ-
ences in neonatal versus adult populations
are discussed later.) Four main principles
are involved in medication dosing strate-
gies, effectiveness, and adverse event risk:
1. Absorption—how the medication gets
into the body and blood stream.
2. Distribution—where the medication
goes after it is in the body and blood
stream.
18 NICU Primer for Pharmacists

3. Metabolism—what happens to medication inside the body.


4. Elimination—how the parent medication and metabolites leave the
body.

Absorption
To reach systemic circulation, medications administered extravascularly
undergo absorption. All patient populations, neonatal and adult, have barriers
limiting absorption including medication-related properties and physiologic-
related patient characteristics. The differences between patient populations are
the extent of medication absorption and the rate of absorption. Extravascular
absorption is required for medications administered enterally, intramuscularly
(IM), percutaneously, and rectally.

Gastrointestinal Absorption
Gastric pH decreases to a pH of 1 to 3 from a neutral pH at birth during
the first 48 hours of life. Over the first week of life, gastric pH again neutral-
izes. Gastric pH gradually decreases over the first 2 years of life to adult
pH.1-3 More neutral gastric pH may contribute to increased bioavailability
of acid-labile medications, such as penicillin,4 and decreased bioavailability
of weak bases, such as phenytoin,5 in preterm and term neonates. Prolonged
gastric emptying and decreased intestinal motility reduce the rate of both
active and passive medication absorption in neonates. A nonlinear relation-
ship independent of small bowel pH and brush border metabolism exists
between age and rate of medication absorption where absorption rate
increases with patient age.6 Other factors that may contribute to absorp-
tion variances in neonates are variable brush border enzymatic function,
decreased intestinal surface area, varying pancreatic enzyme activity and
biliary function, and shorter gut transit time.1

IM Absorption
Decreased skeletal muscle blood flow in neonates may reduce absorption
of IM administered medications. Less muscle contraction may also reduce
absorption. However, neonates typically have capillary dense muscle, which
may increase absorption.7,8 IM administered medication absorption is
considered unpredictable and not routinely recommended.1
Developmental Pharmacology, Pharmacokinetics, and Pharmacodynamics 19

Percutaneous Absorption
Due to skin structure development, medication absorption through the
skin may be increased in neonates. Three contributing factors include a
larger body surface area to mass ratio, greater hydration of epidermis, and
better perfusion of the cutaneous layer in neonates. Preterm neonates also
have thinner stratum corneum.1,7,8 Caution is recommended when applying
localized, topical medication to neonates due to increased risk of systemic
exposure.

Rectal Absorption
Medications administered rectally should have increased bioavailability
in neonates. The anticipated increase in bioavailability may be attributed
to limited first-pass metabolism or decreased hepatic enzyme metabolism
in neonates.7 However, rectal contractions in neonates pulsate resulting in
frequent medication evacuation that may limit absorption.7,9,10

Distribution
After a medication enters the body of a patient, the medication is then
distributed throughout the body. One main medication parameter, volume
of distribution (Vd), encapsulates medication characteristics related to
distribution throughout the body. Volume of distribution is a ratio of total
body medication amount to plasma medication concentration. Small Vds
indicate a relatively higher plasma medication concentration compared to
the amount of medication in the body. The inverse is true for large Vds.
Factors influencing medication Vd include medication properties related to
lipophilicity and hydrophilicity, patient body composition, and protein and
tissue binding.1
As a patient ages, body composition as a percentage of total body weight
changes. Total body water and total body fat approximate 85% and 1 to 2%
in preterm neonates, respectively. Term neonate total body water and total
body fat composition approximate 75% and 10 to 15%, respectively.1,7 Due
to the large percentage of total body water in neonates, both preterm and
term, hydrophilic medications have larger Vds and require larger weight-
based dosing strategies. Vds are larger for aminoglycosides in younger
patients requiring larger weight-based dosing approaches. Gentamicin doses
may be 4.5 to 5 mg/kg/dose for preterm neonates compared to 4 mg/kg/dose
20 NICU Primer for Pharmacists

for term neonates.11 Conversely, lipophilic medications have smaller Vds in


neonates compared to adults.1,7
Protein and tissue binding also affect medication distribution. Plasma
protein concentrations and protein-binding affinities for medications are
often reduced in neonates.1 Protein-bound medications, such as phenytoin
and benzodiazepines, may have increased Vds in neonates compared to
adults due to the decreased number of plasma-binding proteins and the
decreased binding affinity of medications compared to bilirubin and free
fatty acids.12 Circulating competitive protein-bound compounds are increased
in neonates limiting medication binding to serum albumin, especially
fetal albumin.1,7 More unbound medication increases effect, toxicity risk,
and clearance. Medication examples that compete with bilirubin for
albumin-binding sites, increasing the risk of kernicterus, are ceftriaxone
and sulfonamides.13-15 These medications are not recommended for use in
neonates.

Metabolism
There are two phases of medication metabolism or biotransformation: phase
I and phase II. Phase I metabolism increases hydrophilicity of medications by
adding or removing functional groups, increasing renal elimination of the
medication or metabolite. Phase II metabolism adds a large hydrophilic
substrate to either the parent medication or metabolite via conjugation.1
Metabolic enzyme processes mature and change developmentally with patient
age. The developmental changes impact medication dosing approaches due to
half-life differences in patient populations. Metabolism via cytochrome P450
(CYP) isoenzymes typically reaches adult levels at 1 year of age.
Cytochrome 3A subfamily is the largest subfamily of isoenzymes with
nearly 50% of all medications metabolized via this group. The subfamily
consists of isoenzymes 3A4, 3A7, and others. Cytochrome 3A7 is signifi-
cantly expressed through 6 months of age, whereas CYP3A4 concentrations
increase with postnatal age surpassing CYP3A7 expression around
6 months of age.16 Preterm neonates have decreased clearance of midazolam,
a CYP3A4 substrate, and formation of 1-OH midazolam, the metabolite
formed via CYP3A4, compared to term neonates. The decrease in metab-
olite formation correlates with decreased concentrations of CYP3A4 in
neonatal populations and the increase of enzyme activity and concentration
with age.17,18
Developmental Pharmacology, Pharmacokinetics, and Pharmacodynamics 21

Methylxanthine metabolism is primarily through CYP1A2. Activity


is low during the neonatal period with function increasing throughout
the first year of life as evident in caffeine and theophylline metabolite
concentrations.19-21 Due to decreased enzymatic activity, the half-lives of
methylxanthines are increased in neonatal populations compared to adults.
Cytochrome 2D6 function is limited during the first year of life. However,
O-methylation genotype enzyme activity is measureable at approximately
2 weeks of age as demonstrated using dextromethorphan, tramadol, and
their metabolites.22,23 Beta antagonists such as propranolol are metabolized
via CYP2D6 and may require monitoring to reduce adverse event potential.
Cytochrome 2C subfamily metabolizes approximately 20% of medica-
tions in adults. The two main subfamily cytochromes are CYP2C9 and
CYP2C19. Neonates born in the third trimester have 30% of mature activity
of CYP2C9, and activity increases during the first 5 months of age to adult
levels. Cytochrome CYP2C19 activity at birth is 15% of adult levels and
increases linearly to adult capacity at approximately 10 years of age.24
Phenytoin metabolism via CYP2C9 varies based on patient age and requires
different initial dosing regimens, careful monitoring, and dosing regimen
adjustment as patients age due to the pharmacokinetic differences.25-27 Benzo-
diazepines and proton pump inhibitors undergo metabolism via CYP2C19.
Increased adverse events may be experienced in younger neonates compared
to older pediatric patients with diazepam due to prolonged exposure.28
Low activity levels of CYP2C19 may increase exposure to proton pump
inhibitors, resulting in increased acid suppression in neonates.29
Phase II metabolism (i.e., glucoronidation) also varies based on age.
Uridine 5'-phosphoglucuronic acid glucuronyl transferases (UGTs) account
for approximately 15% of medication metabolism. Glucuronidation of
acetaminophen via UGT1A6 and UGT1A9 is decreased in neonates
compared to older patients. However, acetaminophen metabolism through
sulfation pathways are increased in neonates compared to older patients.30,31
Chloramphenicol and morphine are metabolized via UGT2B7. In neonates,
chloramphenicol concentrations build resulting in gray-baby syndrome due
to decreased glucuronidation activity.1,32 Morphine metabolism is decreased
in neonates compared to older pediatric populations.33,34 Term neonates
have increased metabolism of morphine compared to preterm neonates.35
Metabolism in neonates compared to older populations varies. The
variation in enzymatic activity accounts for differences in medication
22 NICU Primer for Pharmacists

pharmacokinetics and should be taken into account when using medications


in neonatal patients.

Elimination
Three processes account for elimination of renally cleared medications:
glomerular filtration, tubular excretion, and tubular reabsorption. Glomer-
ular filtration involves free medication filtration across the glomerular
membrane. Tubular excretion allows additional passage of medication into
the renal tubule. Tubular reabsorption is diffusion of lipophilic medications
back into the blood stream from the tubules. The components of renal elimi-
nation mature at different rates.1,36 Complete renal function approximates
adult function around 1 year of age.1,7 In the first weeks of life, glomerular
filtration rate may increase little until 34 weeks post-menstrual age when it
increases drastically due to increased cardiac output and decreased vascular
resistance in the kidneys and approximates adult levels at 6 months of age.
Renal tubular function improves steadily over the first year of life. Small
tubular size, reduced blood flow, urine pH variances, and limited concentra-
tion abilities contribute to the reduced tubular excretion and reabsorption.
As a neonate ages, the limitations improve to reach adult renal function.37
Decreased renal function accounts for initial dosing regimen differences in
neonatal populations compared to pediatric and adult patients.

Conclusion
Pharmacologic, pharmacokinetic, and pharmacodynamic differences in
neonates compared to adults require special attention when utilizing medica-
tions in this population. An understanding of the developmental changes and
medication properties is essential in deciding appropriate medication usage.
As more details are discovered about developmental processes in neonates,
the neonatal pharmacist’s role can improve patient outcomes and minimize
adverse events.

References
1. Lu H, Rosebaum S. Developmental pharmacokinetics in pediatric populations. J Pedi-
atr Pharmacol Ther. 2014;19(4):262-76.
2. Hyman PE, Clarke DD, Everett SL, et al. Gastric acid secretory function in preterm
infants. J Pediatr. 1985;106(3):467-71.
Developmental Pharmacology, Pharmacokinetics, and Pharmacodynamics 23

3. Agunod M, Yamaguchi N, Lopez R, et al. Correlative study of hydrochloric acid,


pepsin, and intrinsic factor secretion in newborns and infants. Am J Dig Dis.
1969;14(6):400-14.
4. Huang NN, High RH. Comparison of serum levels following the administration of
oral and parenteral preparations of penicillin to infants and children of various age
groups. J Pediatr. 1953;42(6):657-68.
5. Albani M, Wernicke I. Oral phenytoin in infancy: dose requirement, absorption, and
elimination. Pediatr Pharmacol. 1983;3:229-36.
6. Heimann G. Enteral absorption and bioavailability in children in relation to age. Eur J
Clin Pharmacol. 1980;18(1):43-50.
7. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology—
drug disposition, action, and therapy in infants and children. N Engl J Med.
2003;349(12):1157-67.
8. Tetelbaum M, Finkelstein Y, Nava-Ocamo AA, et al. Back to basics: understanding
drugs in children: pharmacokinetic maturation. Pediatr Rev. 2005;26(9):321-8.
9. van Lingen RA, Deinum JT, Quak JM, et al. Pharmacokinetics and metabolism of
rectally administered paracetamol in preterm neonates. Arch Dis Child Fetal Neonatal
Ed. 1999;80:F59-63.
10. Coulthard KP, Nielson HW, Schroder M, et al. Relative bioavailability and plasma
paracetamol profiles of Panadol suppositories in children. J Paediatr Child Health.
1998;34(5):425-31.
11. Truven Health Analytics. Pediatrics and Neofax. http://neofax.micromedexsolutions.
com/neofax/neofax.php?strTitle=NeoFax&sa=&area=1&mode= . Accessed March 20,
2015.
12. McNamara PJ, Alcorn J. Protein binding predictions in infants. AAPS PharmSci.
2002;4(1):E4.
13. Martin E, Fanconi S, Kalin P, et al. Ceftriaxone-bilirubin-albumin interactions in the
neonate: an in vivo study. Eur J Pediatr. 1993;152(6):530-4.
14. Gulian JM, Gonard V, Dalmasso C, et al. Bilirubin displacement by ceftriaxone in
neonates: evaluation by determination of ‘free’ bilirubin and erythrocyte-bound
bilirubin. J Antimicrob Chemother. 1987;19(6):823-9.
15. Ahlfors CE. Unbound bilirubin associated with kernicterus: a historical approach.
J Pediatr. 2000;137(4):540-4.
16. Stevens JC, Hines RN, Gu C, et al. Developmental expression of the major human
hepatic CYP3A enzymes. J Pharmacol Exp Ther. 2003;307(2):573-82.
17. de Wildt SN, Kearns GL, Hop WC, et al. Pharmacokinetics and metabolism of intra-
venous midazolam in preterm infants. Clin Pharmacol Ther. 2001;70(6):525-31.
18. de Wildt SN, Kearns GL, Hop WC, et al. Pharmacokinetics and metabolism of oral
midazolam in preterm infants. Br J Clin Pharmacol. 2002;53(4):390-4.
24 NICU Primer for Pharmacists

19. Tateishi T, Asoh M, Yamaguchi A, et al. Developmental changes in urinary elimination


of theophylline and its metabolites in pediatric patients. Pediatr Res. 1999;45:66-70.
20. Carrier O, Pons G, Rey E, et al. Maturation of caffeine metabolic pathways in infancy.
Clin Pharmacol Ther. 1988;44:145-51.
21. Kraus DM, Fischer JH, Reitz, SJ, et al. Alterations in theophylline metabolism during
the first year of life. Clin Pharmacol Ther. 1993;54:351-9.
22. Blake MJ, Gaedigk A, Pearce RE, et al. Ontogeny of dextromethorphan O- and
N-demethylation in the first year of life. Clin Pharmacol Ther. 2007;81(4):510-6.
23. Allegaert K, Verbesselt R, Rayyan M, et al. Urinary metabolites to assess in vivo ontog-
eny of hepatic drug metabolism in early neonatal life. Methods Find Exp Clin Pharma-
col. 2007;29(4):251-6.
24. Koukouritaki SB, Manro JR, Marsh SA, et al. Developmental expression of human
hepatic CYP2C9 and CYP2C19. J Pharmacol Exp Ther. 2004;308(3):965-74.
25. Bourgeois BF, Dodson WE. Phenytoin elimination in newborns. Neurology. 1983;
33(2):173-8.
26. Suzuki Y, Mimaki T, Cox S, et al. Phenytoin age-dose-concentration relationship in
children. Ther Drug Monit. 1994;16(2):145-50.
27. Loughnan PM, Greenwald A, Purton WW, et al. Pharmacokinetic observations of
phenytoin disposition in the newborn and young infant. Arch Dis Child.
1977;52(4):302-9.
28. Treluyer JM, Gueret G, Cheron G, et al. Developmental expression of CYP2C and
CYP2C-dependent activities in the human liver: in-vivo/in-vitro correlation and
inducibility. Pharmacogenetics. 1997;7(6):441-52.
29. Kearns GL, Winter HS. Proton pump inhibitors in pediatrics: relevant pharmaco-
kinetics and pharmacodynamics. J Pediatr Gastroenterol Nutr. 2003;37(Suppl 1):S52-9.
30. Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates,
children, and adults. Clin Pharmacol Ther. 1976;19(3):284-94.
31. van der Marel CD, Anderson BJ, van Lingen RA, et al. Paracetamol and metabolite
pharmacokinetics in infants. Eur J Clin Pharmacol. 2003;59(3):243-51.
32. Chen M, LeDuc B, Kerr S, et al. Identification of human UGT2B7 as the major
isoform involved in the O-glucoronidation of chloramphenicol. Drug Metab Dispos.
2010;38(3):368-75.
33. Choonara IA, McKay P, Hain R, et al. Morphine metabolism in children. Br J Clin
Pharmacol. 1989;28(5):599-604.
34. Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse
events. Pharmacol Ther. 2008;118:250-67.
35. Scott CS, Riggs KW, Ling EW, et al. Morphine pharmacokinetics and pain assessments
in premature newborns. J Pediatr. 1999;135:423-9.
Developmental Pharmacology, Pharmacokinetics, and Pharmacodynamics 25

36. Rubin MI, Bruck E, Rapoport M, et al. Maturation of renal function in childhood:
clearance studies. J Clin Invest. 1949;28(5):1144-62.
37. Alcorn J, McNamara PJ. Pharmacokinetics in the newborn. Adv Drug Deliv Rev.
2003;55(5):667-86.

Suggested Readings
Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse events.
Pharmacol Ther. 2008;118:250-67.
Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology—
drug disposition, action, and therapy in infants and children. N Engl J Med.
2003;349(12):1157-67.
Lu H, Rosebaum S. Developmental pharmacokinetics in pediatric populations. J Pediatr
Pharmacol Ther. 2014;19(4):262-76.
3
Parenteral Nutrition

Ying-Tang Ng, PharmD

Introduction

N
utrition, an important element
in a neonate’s care, promotes
growth and development.
When infants are unable to take enteral
nutrition or enteral nutrition is contra-
indicated, parenteral nutrition (PN) is
provided. Most times PN is started as
soon as intravenous (IV) access is estab-
lished in the neonate. Early nutrition
improves weight gain and decreases
growth failure.1,2 PN for neonates is
not only used with gastrointestinal (GI)
disorders (e.g., gastroschisis, omphalo-
celes) but also provides nutrition because
28 NICU Primer for Pharmacists

enteral nutrition is advanced. Many components make up a PN comprised


of different macronutrients and micronutrients.

Fluids and Nutrition


Fluid and nutrition management typically go hand in hand. These two
components are vital in the day-to-day care of a neonate. As pharmacists
we can help track daily fluid input, output, and caloric intake to optimize
nutrition support toward ensuring proper weight gain. Pharmacists can be a
great resource in fluid and nutrition management of a neonate.

IV Fluid Management
Fluid management in neonates is a major part of nutrition support. It can
often be challenging to manage due to different disease states and comorbid-
ities. Neonates are comprised mainly of water and have decreased body fat
when compared to children and adolescents.3 On average, neonates lose about
10% of their weight in the first 24 to 48 hours of life due to shifts in fluids
and natural diuresis. Term neonates should be back to their birth weight by
1 week of life, although preterm neonates may take 2 or more weeks.
At birth, a neonate requires about 60 to 70 mL/kg/day and increases by
10 to 20 mL/kg/day to goal. An average fluid goal for neonates ranges from
120 to 150 mL/kg/day.4-6 Extremely low birth weight infants may require
up to 170 to 180 mL/kg/day due to immaturity of skin and increased fluid
losses. When thinking about fluid requirements, pharmacists should take
into account sensible and insensible water losses. Insensible water losses
include conditions such as prematurity, phototherapy, and tachypnea. Fluids
should not be advanced too vigorously in patients with respiratory distress,
bronchopulmonary dysplasia (BPD), congenital heart defects, and heart
failure as it can worsen their condition.

Nutrition Management
Calorie requirements are higher for preterm neonates than for term
neonates. Preterm neonates require about 90 to 120 kcal/kg/day compared
to term neonates who require 80 to 100 kcal/kg/day.6 Weights should be
monitored daily to ensure proper nutrition and growth. Term neonates on
average should gain 15 to 30 g/day. Preterm infant weight gain is measured
in terms of g/kg/day. They should regain their birth weight by day of life
Parenteral Nutrition 29

14; then, the goal average weight gain per week is 15 to 18 g/kg/day until
they reach 2 kg. After preterm infants reach 2 kg, their average weight gain
per week is 25 to 35 g/day. Growth in neonates may fluctuate depending on
severity of current illnesses and nutrition status. The World Health Organi-
zation and the Fenton growth charts are used to assess growth in preterm
and term infants.

Macronutrients
Carbohydrates
Dextrose is a major component in a neonate PN. It should provide 40 to
50% of total calories from the PN. Dextrose concentration typically ranges
from 10 to 15%. Specific patient populations such as infants of diabetic
mothers may require higher dextrose concentration and glucose infusion
rates (GIR), which are important in starting and advancing PN. Normal
starting GIR is 3 to 5 mg/kg/hr and is advanced by 2 to 3 mg/kg/hr to a
maximum of 10 to 12 mg/kg/hr. When advancing dextrose and IV fluid
rates, pharmacists should remember that both affect GIR. In some instances
if both dextrose and IV fluid goals are increased at the same time, this may
increase GIR by more than 2 to 3 mg/kg/hr. Every 1 gram of dextrose
provides 3.4 kcal. Blood glucose is monitored for hypo- and hyperglycemia.
Excessive increase in glucose load can cause hyperglycemia, excessive
carbon dioxide, and potential liver damage. Blood glucose levels of greater
than 150 mg/mL are associated with adverse outcomes in neonates. Hyper-
glycemia increases the risk of intraventricular hemorrhage (IVH), necrotiz-
ing enterocolitis, and infections and is associated with prolonged hospital
stays. To manage hyperglycemia, either the dextrose concentration or the
IV fluid rate should be adjusted, resulting in a change in GIR to prevent
further complications. Although it may not be feasible or cost effective to
change dextrose concentrations of a PN right away, IV fluids with a lower
dextrose concentration may be administered via Y-site with the PN. For
example, a neonate has a PN containing dextrose 10% currently infusing at
a rate of 8 mL/hr and the neonate becomes hyperglycemic after running the
D10% PN for 4 hours. To provide a lower dextrose concentration, an IV
fluid containing dextrose 5% may be co-administered 1:1 with the D10%
PN in the same IV line. This results in the D10% PN running at 4 mL/hr
and the D5% IV fluid at 4 mL/hr. This decreases the dextrose concentration
to 7.5%, which in turn decreases the GIR.
30 NICU Primer for Pharmacists

While decreasing dextrose concentrations, it is also important to make


sure GIR does not drop significantly in order to prevent hypoglycemia.
Insulin therapy may be warranted for consistent hyperglycemia despite
other efforts. Insulin therapy may be used to treat infants with hyperglyce-
mia; however, the American Society for Parenteral and Enteral Nutrition
(A.S.P.E.N.) guidelines do not recommend using insulin to prevent hyper-
glycemia.8 Other factors can increase blood glucose in neonates that should
be considered when initiating or changing dextrose content. Often times,
stress from procedures or surgery and medications (e.g., steroids) can cause
an increase in blood glucose. These should be taken into consideration when
advancing dextrose and fluid goals.
On the flip side, it is also crucial that neonates do not get hypoglycemic
(<45 mg/mL). Premature infants and infants of diabetic mothers are at high
risk of hypoglycemia. Patients exhibiting signs of hypoglycemia should be
treated with increased GIR regardless of blood sugar levels.8

GIR (mg/kg/min) = dextrose (%) × rate (mL/hr)


wt (kg) × 6

Protein
Initiation of parenteral protein, provided as amino acids (AAs), is crucial
to the growth and development of neonates. AAs are initiated at a goal of
3 to 4 g/kg/day depending on the age of the neonate. Protein requirements
are highest for the premature neonates, and requirements decrease with
increasing age. Early administration with high doses of AAs up to 4 g/kg/
day has been shown to improve growth.9-11 Specific types of AA products
(e.g., TrophAmine, Premasol, Aminosyn) are made for neonates and provide
additional AAs that other formulations do not contain. These products
provide arginine, tyrosine, and taurine, which are conditionally essential
in neonates. Some AAs such as TrophAmine have a lower pH, which helps
with calcium and phosphorus solubility.12 Every 1 gram of AAs provides
4 kcal; however, there is controversy on whether calories from AAs should
be counted in the total calorie count.13 Opinions leading toward not includ-
ing them in the calorie count argue that dextrose and fats are for energy and
that AAs are for protein synthesis.14 Blood urea nitrogen and renal function
are monitored.
Parenteral Nutrition 31

Fat Emulsions
Intravenous fat emulsions (IVFEs) provide a major concentrated source of
calories. The majority of fat emulsions provided to neonates are soy-based,
which consist mainly of omega-6 fatty acids. Linoleic and α-linolenic acid
are the essential fatty acids that make up fat emulsions. Fats provide 9 kcal
for every 1 gram received; however, the emulsifying agents and glycerol
in IVFEs increase the calories. IVFEs are available at concentrations of
10%, 20%, and 30%. The 20% concentration is preferred over 10%
because of the decreased phospholipids. The 30% concentration is rarely
used in neonates because it has to be used only in 3-in-1 PNs.15 IVFE at
20% concentration provides 2 kcal per milliliter. Fat emulsions not only
provide calories but also prevent and treat fatty acid deficiency syndrome.
Fat emulsions should be initiated at low doses (0.5 to 1 g/kg/day) and titrated
up to maximum doses (3 g/kg/day) to prevent hypertriglyceridemia and
other complications. Triglycerides should be monitored with any increase in
doses and at least once weekly when goal dose is achieved.
Dissimilar to soybean oil, a product called Omegaven consists of omega-3
fatty acids, specifically eicosapentaenoic acid and docosahexaenoic acid.
Omegaven has been shown to have benefits when used in patients with PN-
associated liver disease (PNALD) also known as intestinal failure-associated
liver disease (IFALD). Omegaven is not currently approved in the United
States but may be administered for compassionate use. An investigational
new drug application is required prior to administering and obtaining
Omegaven from the manufacturer, Fresenius Kabi, in Germany. Omegaven
works to improve bile flow and interferes with the metabolism of omega-6
fatty acids, which can cause inflammation. Omegaven has been shown
to decrease bilirubin levels, slow the rate of liver disease progression, and
reverse cholestasis. It is associated with restoration of liver function in
patients with short bowel syndrome and advanced liver disease.16-18

Micronutrients
Electrolytes
Electrolytes added to PN include sodium, potassium, calcium, phosphorus,
and magnesium. Electrolyte requirements differ between preterm neonates
and term neonates as shown in Table 3-1. When assessing the need for
electrolytes, pharmacists should consider a patient’s laboratory test results as
32 NICU Primer for Pharmacists

Table 3-1. Micronutrient Daily Requirements for Neonates and Infants


Preterm Neonates Term Neonates
Calcium 2–4 mEq/kg 0.5–4 mEq/kg
Chromium 0.05–0.2 mcg/kg 0.2 mcg/kg
Copper 20 mcg/kg 20 mcg/kg
Magnesium 0.3–0.5 mEq/kg 0.3–0.5 mEq/kg
Manganese 1 mcg/kg 1 mcg/kg
Phosphorus 1–2 mmol/kg 0.5–2 mmol/kg
Potassium 2–4 mEq/kg 2–4 mEq/kg
Selenium 1.5–2 mcg/kg 2 mcg/kg
Sodium 2–5 mEq/kg 2–4 mEq/kg
Zinc 400 mcg/kg 40–250 mcg/kg
Source: Adapted with permission from Mirtallo J, Canada T, Johnson D, et. al. Safe Practices for
Parenteral Nutrition. JPEN. 2004;28(6):S39-70.

well as any underlying disease states. For example, patients with renal insuf-
ficiency or failure may require less potassium and phosphorus compared
to someone with normal renal function. Neonates require a tremendous
amount of calcium and phosphorus for bone growth and heart function.
The majority of bone mineralization in utero occurs in the third trimester,
so this may not happen if the neonate is born prematurely.19 Neonates on
short-term PN should receive 76 mg/kg of elemental calcium per day with
a calcium-to-phosphorus ratio of 1.7:1 (mg:mg).20 Calcium is available
as calcium gluconate or calcium chloride. Calcium gluconate is preferred
because it provides less dissociated calcium ions and, therefore, decreases
the possibility to precipitate with phosphate ions. Calcium is a vesicant and
can cause serious damage if extravasation occurs. Calcium gluconate is less
irritating to blood vessels when compared to calcium chloride. In the occur-
rence of extravasation, hyaluronidase may be used as an antidote around the
extravasated area. Acetate and chloride are added in forms of sodium and/or
potassium acetate or chloride to PN for acid−base balance.

Role of Trace Elements


Trace elements play an important role in enzyme activity. Trace elements
included in neonatal PN are selenium, zinc, copper, chromium, manganese,
and molybdenum. Selenium is recommended for use in all patients and is
Parenteral Nutrition 33

more critical for patients on long-term PN therapy. Selenium deficiency can


lead to cardiomyopathy and thyroid dysfunction.21 Zinc is used for growth
and promotes wound healing and immune system function. Zinc deficiency
can lead to growth restriction, alopecia, and skin rash.22 Due to recent drug
shortages, neonates are at a high risk of becoming zinc deficient and present
with skin breakdown and rash. Chromium is used as an insulin regulator;
thus, if a patient becomes chromium deficient it can lead to glucose intoler-
ance. Because zinc, selenium, and chromium are excreted renally, doses may
need to be decreased or may need to be completely removed in the presence
of renal dysfunction.
Copper is found in the liver, bones, and muscles. Copper toxicity can
lead to renal dysfunction and anemia. Copper can be deficient in prema-
ture neonates and in those with excessive diarrhea. Copper deficiency can
lead to central nervous system and hematologic disorders.23 Manganese is
used for bone growth and glucose regulation. Manganese deficiency can
lead to glucose intolerance and bone abnormalities. Manganese toxicity can
also lead to neurological dysfunctions. Because copper and manganese are
excreted via the liver, liver dysfunction can lead to accumulation. In these
patients, copper and manganese may need to be removed from the PN or be
given at a lower dose.22 If available, copper and manganese levels may help
to guide therapy in patients with liver dysfunction.
Molybdenum is a trace element needed for enzymes involved in deoxy-
ribonucleic acid metabolism. Molybdenum toxicity impedes copper
metabolism. It is recommended at doses of 1 mcg/kg for low-birth-weight
neonates on PN longer than 1 month.7
Many different formulations of trace elements are available as combina-
tion products (i.e., Neotrace, Peditrace) or as individual products. Providing
trace elements individually is an alternative to using combination products,
and it provides more flexibility with dosing. Different products contain
different amounts of each trace element. When using combination products,
it is important to know the recommended doses of each individual trace
element and compare it with the product to determine if it provides the
necessary amount of trace elements. This is even more crucial in times of
drug shortages where certain combination and/or individual products are not
available and alternative products are used. If trace elements are not provid-
ed due to limited availability, they should be reserved for the most critical
patients. It is important to monitor for trace element deficiency and know
both the signs of toxicity and deficiency.
34 NICU Primer for Pharmacists

Importance of Cysteine
Cysteine, available as L-cysteine hydrochloride, is a conditionally essential
AA for preterm and term neonates. Cysteine is a precursor of glutathione
and taurine. Glutathione has antioxidant properties while taurine provides
benefits for the eyes, brain, liver, and intestine.24 Cysteine is dosed at 40 mg
per gram of AAs in PN.6 Cysteine also decreases the pH in PN and, there-
fore, can improve the solubility of calcium and phosphorus.6 The addition
of cysteine will shift calcium and phosphorus solubility curves toward a
higher calcium and phosphorus ratio. When looking at the many different
solubility curves, pharmacists should determine if the PN contains cysteine.
In times of cysteine shortage, cysteine may be restricted to certain neonatal
PNs. If there is a cysteine shortage, the American Society of Health-System
Pharmacists (ASHP) website (www.ashp.org) or A.S.P.E.N.’s website (www.
nutritioncare.org) provides guidance in these circumstances.

AAs in Neonatal PN
Many other additives can be added to PN for additional nutrition or as a
medication. Carnitine is important in fatty acid metabolism at doses of
20 mg/kg/day.25 Carnitine deficiency can present with hypertriglyceridemia,
hypotonia, muscle weakness, and cardiac abnormalities.26 Multivitamins
added to PN include a wide range of vitamins, including lipid soluble
vitamins, and should be supplemented daily in neonates receiving PN.
Neonates <1 kg, 1 to 3 kg, and >3 kg should be supplemented with 1.5 mL,
3.25 mL, and 5 mL of multivitamins daily, respectively.6 H2-receptor antag-
onists (H2RAs) are occasionally used in neonates for GI bleeds and post
GI surgery. These medications increase the risk of necrotizing enterocolitis
in preterm neonates; therefore, they should be used cautiously.27,28 H2RAs,
including ranitidine and famotidine, are compatible with PN and may be
added for ease and cost savings. Heparin is often times added to IV fluids
for catheter patency of central lines to keep them from clotting. However,
A.S.P.E.N. guidelines do not recommend the regular use of heparin in PN.20
Neonates should be monitored with daily weights and regular labora-
tory tests, especially in those initiating and advancing PN. In patients on
PN with stable electrolytes and laboratory results, weekly to twice weekly
laboratory tests may be sufficient during hospitalization. It is important
to balance the need for labs with the limited blood volume of preterm
neonates/micropreemies.
Parenteral Nutrition 35

PN Complications
PNALD (IFALD)
Neonates may depend on long-term PN due to various factors, including
extreme prematurity and short bowel syndrome or intestinal failure.
Long-term PN use can lead to complications of the liver and bone. PNALD
occurs in 40 to 60% of neonates on long-term PN.29 Patients at high risk
for PNALD are typically why they need long-term PN (e.g., prematurity,
intestinal failure, sepsis). Patients who develop PNALD will present with
direct hyperbilirubinemia (direct bilirubin >2 mg/dL) and elevated liver
enzymes.30 Long-term infusion of dextrose and/or fat emulsions is thought
to be a cause of cholestasis. The best way to prevent PNALD is to start
enteral nutrition even at minimal feeds. Trophic feeds can stimulate bowel
function and improve bile flow. Where feeds are contraindicated, lipid
restriction from the beginning may prevent PNALD in patients determined
to be on long-term PN.31
Evidence varies on the benefits of using ursodiol for cholestasis.32-34
Studies that support the use of ursodiol showed improvement in cholestasis
and decreased bilirubin levels when used at the initial signs of liver dysfunc-
tion.33 Ursodiol use is limited because it is available only via oral route,
and the majority of patients who develop PNALD are not able to tolerate
enteral feedings. Phenobarbital may be used for hyperbilirubinemia. There
is minimal evidence of its efficacy for PNALD. One benefit phenobarbital
has over ursodiol is that it is available orally and IV. Caution should be used
with phenobarbital due to potential negative effects on neurological devel-
opment. In patients who develop PNALD, decreasing the dose and frequency
of fat emulsions to 1 g/kg/day administered 2 to 7 times per week may be
beneficial.31,34,35 Essentially, lipids may be reduced to the minimum amount
to prevent essential fatty acid deficiency syndrome. Cycling PN may also be
effective for lowering direct bilirubin levels in cholestasis. Another benefit
of cycling PN is it provides the liver with a break from continuous infusion
of dextrose and fat emulsions.29 The use of Omegaven, which was discussed
previously, is one major treatment for PNALD.

Infection Risk with PN


Central line-associated blood stream infections (CLABSIs) are a major
complication of receiving long-term PN due to the indwelling catheter.
CLABSIs can lead to hospitalizations and increased morbidity and mortality.
36 NICU Primer for Pharmacists

Most common organisms associated with CLABSIs are coagulase-


negative staphylococci, Staphylococcus aureus, enterococci, and Candida
spp.36 Resistant organisms are a concern in the NICU and in those with
recurrent infections. Depending on the causative organism and patient’s
status, the Infectious Diseases Society of America recommends removing
the central lines to effectively treat CLABSIs.36 In patients with recurrent
infections, ethanol locks may be useful in infection prevention. Studies in
pediatric patients show that ethanol locks decrease the number of catheter
removal- and catheter-related infections.37,38 Ethanol locks have not been
greatly studied in the NICU population and may not be an option in
premature neonates. However, some studies included patients as young as
3 months of age; thus, ethanol locks may be an option in older neonates.38

Calcium and Phosphorus Solubility


Calcium and phosphorus are often limited due to solubility issues, which
result in decreased amounts of calcium and phosphorus, and can lead to
metabolic bone disease and osteopenia. Metabolic bone disease is increasing.
It affects 55% of infants <1,000 g and 23% of infants <1,500 g at birth.19
To prevent metabolic bone disease, calcium and phosphorus should be
optimized as much as possible in PN. Vitamin D is recommended to help
with calcium absorption in neonates able to take oral medications.19

Aluminum Toxicity
Another risk factor for metabolic bone disease in PN is aluminum. Alumi-
num is a common contaminant in the different elements used to create PNs.
The contamination occurs at the manufacturing level. Renal impairment
can increase the risk of aluminum toxicity and can lead to renal impairment,
metabolic bone disease, and central nervous system problems. According to
the Food and Drug Administration, aluminum exposure to pediatric and
neonatal patients should be limited to 5 mcg/kg/day.6 Beyond this limit,
patients are at increased risk for toxicity. Pharmacists can implement several
strategies to reduce aluminum exposure. One way is to purchase products
containing lower amounts of aluminum. Purchasing products in plastic
containers versus glass containers can decrease aluminum contamination
because aluminum can leach from glass containers. Alternating stock bottles
of electrolytes and IV bags can minimize the amount of aluminum leached
from glass containers. When possible, pharmacists should select products
Parenteral Nutrition 37

that contain less aluminum such as those with sodium phosphate over
potassium phosphate or calcium chloride over calcium gluconate. Although
less aluminum contamination exists with calcium chloride, calcium gluco-
nate is generally preferred as stated previously in this chapter. When using
calcium chloride in PN, be aware of limited data on solubility curves and
the amount of chloride that is provided. If possible, a useful way to limit
aluminum exposure is to calculate cumulative aluminum content in PN
from each product.39

PN Preparations
Vanilla PNs
Vanilla PNs (also referred to as starter PNs) are used in neonates as nutrition
until a custom PN can be prepared. Vanilla PNs are typically comprised of
dextrose, amino acids, and calcium. This provides crucial nutrients right
after birth that standard IV fluids cannot provide. Studies have shown AA
administration in the first 24 hours of life can improve weight gain and
growth as well as neurodevelopmental outcomes.1,2 Vanilla PNs are typically
created for premature neonates <1,500 g in the first 24 to 48 hours of life.

3-in-1 versus 2-in-1 PN


The majority of adult PNs are 3-in-1 PNs. These PNs contain dextrose,
amino acids, and fat emulsions in one bag for infusion. A 2-in-1 PN contains
dextrose and amino acids in one bag, and the fat emulsions are in a separate
bag/syringe. Precipitation is high with neonatal PNs due to high calcium and
phosphorus components. To help with calcium and phosphorus solubility,
use more acidic products, such has TrophAmine, to lower pH. Fat emulsions
increase the pH, making the solution less acidic when added to a PN, which
would create a more conducive environment for calcium and phosphorus
to precipitate. Not only do fat emulsions increase pH, but they also prevent
pharmacists and nurses from seeing any visible precipitation that may occur
in a PN. Therefore, 2-in-1 PNs are preferred for neonates.40

PN Administration
Central Line versus Peripheral Line Access
Line access can often be an issue with neonates, especially in the micro-
premies. When ordering or dispensing a PN, it is important to determine
38 NICU Primer for Pharmacists

the neonate’s type of line access. Does this patient have a central line or
peripheral line? The answer to this question often determines the dextrose
concentration and how much of other contents can be put into the PN.
Some experts recommend maximum PN osmolarity of 900 mOsmol/L and
maximum dextrose concentration of 12.5% for a patient who has a periph-
eral line.20 Potassium concentration is also limited by line assess. Potassium
concentrations greater than 40 mEq/mL should be infused in a central line.

PN Compatibility with Medications


Neonates require not only PN but also may require multiple drips and
medications. This can cause compatibility issues with administration of
medication and PN, especially if line access is an issue. NICU nurses will
have questions regarding the medication’s compatibility with PN. Various
tertiary resources can provide guidance in these situations (e.g., Handbook
on Injectable Drugs, King Guide to Parenteral Admixtures). Robinson et
al. provides a compilation of medication compatibility with PN and fat
emulsions.41

PN Light Exposure Issues


Oxidation can occur to multiple components (e.g., multivitamins, fat
emulsions) of a PN and fat emulsions when exposed to light.39,41 The
peroxides and oxidative products produced from oxidation are difficult for
neonates to eliminate.42,43 Increased oxidative stress can lead to hypergly-
cemia and hypertriglyceridemia.40,42 There are theories hypothesizing an
association between light-exposed PN and increased risk of BPD.44,45 The
risk of oxidation would be greater in infants undergoing phototherapy due
to increased and closer light source to the PN. The oxidation and forma-
tion peroxides can be prevented when the PN bag/syringe and tubing are
protected from light.43 Based on limited studies, there may be benefits in
protecting PN from light especially in neonates receiving phototherapy.

Conclusion
PN plays a major part in the care of neonates where pharmacists can play a
significant role. It is important that neonates obtain proper nutrition and
calories for growing and developing. Pharmacists should understand the
major and minor nutritional components that compose neonatal PN to
effectively monitor neonatal patients. Although monitoring nutrition status
Parenteral Nutrition 39

in neonates is key, pharmacists’ knowledge on safety and preparation is vital


especially in times of medication shortages. Pharmacists can work with the
neonatology team during shortages to help utilize resources and prevent
complications that may result in nutrition deficiencies.
Safety is the key for preparing and administering PN to the neonatal
population. Many components go into a PN bag, and pharmacists have
numerous opportunities for intervention to optimize nutritional care in
neonatal patients.

References
1. Valentine CJ, Fernandez S, Rogers LK, et al. Early amino-acid administration improves
preterm infant weight. J Perinatol. 2009;29:428-32.
2. Radmacher PG, Lewis SL, Adamkin DH. Early amino acids and the metabolic
response of ELBW infants (≤1000 g) in three time periods. J Perinatol. 2009;29:433-7.
3. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology–
drug disposition, action, and therapy in infants and children. N Engl J Med.
2003;349:1157-67.
4. Oh W. Fluid and electrolyte management of very low birth weight infants. Pediatr
Neonatol. 2012;53(6):329-33.
5. Bhatia J. Fluid and electrolyte management in the very low birth weight neonate.
J Perinatol. 2006;26:S19-21.
6. Mirtallo J, Canada T, Johnson D, et al. Safe practices for parenteral nutrition. JPEN.
2004;28(6):S39-70.
7. El Hassan NO, Kaiser JR. Parenteral nutrition in the neonatal intensive care unit.
NeoReviews. 2011;12:e130-40.
8. Arsenault D, Brenn M, Kim S, et al. A.S.P.E.N. clinical guidelines: hyperglycemia and
hypoglycemia in the neonate receiving parenteral nutrition. JPEN. 2012;36:81-95.
9. Scattolin S, Gaio P, Betto M, et al. Parenteral amino acid intakes: possible influences of
higher intakes on growth and bone status in preterm infants. J Perinatol. 2013;33:33-9.
10. Stephens BE, Walden RV, Gargus RA, et al. First-week protein and energy intakes
are associated with 18-month developmental outcomes in extremely low birth weight
infants. Pediatrics. 2009;123(5):1337-43.
11. Poindexter BB, Langer JC, Dusick AM, et al. Early provision of parenteral amino acids
in extremely low birth weight infants: relation to growth and neurodevelopmental
outcome. J Pediatr. 2006;148:300-5.
12. Shulman RJ, Phillips S. Parenteral nutrition in infants and children. J Pediatr Gastroen-
terol Nutr. 2003;36:587-607.
40 NICU Primer for Pharmacists

13. Trophamine [package insert]. Bethlehem, PA: BBraun; June 2014. http://www.bbraun-
usa.com/products.html?prid=S9361-SS. Accessed January 7, 2015.
14. Van Way CW. Total calories vs nonprotein calories [editorial]. Nutr Clin Prac.
2001;16:271-2.
15. Liposyn III 30 [package insert]. Lake Forest, IL: Hospira; August 2005. http://www.
hospira.com/Images/EN-1012_81-5469_1.pdf. Accessed October 14, 2014.
16. Gura KM, Lee S, Valim C, et al. Safety and efficacy of fish-oil based fate emul-
sions in the treatment of parenteral nutrition associated liver disease. Pediatrics.
2008;121:e678-86.
17. Diamond IR, Sterscu A, Pencharz PB, et al. Changing the paradigm: Omegaven for
the treatment of liver failure in pediatric short bowel syndrome. J Pediatr Gastroenterol
Nutr. 2009;48:209-15.
18. Puder M, Valim C, Meisel JA, et al. Parenteral fish oil improves outcomes in patients
with parenteral nutrition-associated liver injury. Ann Surg. 2009;250:395-402.
19. Nehra D, Carlson SJ, Fallon EM, et al. A.S.P.E.N. clinical guidelines: nutrition
support of neonatal patients at risk for metabolic bone disease. JPEN. 2013;
37(5):570-98.
20. Boullata JI, Gilbert K, Sacks G, et al. A.S.P.E.N. clinical guidelines: parenteral nu-
trition ordering, order review, compounding, labeling and dispensing. JPEN. 2014;
38(3):334-77.
21. Shenkin A. Selenium in intravenous nutrition. Gastroenterology. 2009;137:S61-9.
22. Greene HL, Hambidge KM, Schanler R, et al. Guidelines for the use of vitamins,
trace elements, calcium, magnesium, and phosphorus in infants and children receiving
total parenteral nutrition: report of the Subcommittee on Pediatric Parenteral Nutrient
Requirements from the Committee on Clinical Practice Issues of the American Society
for Clinical Nutrition. Am J Clin Nutr. 1988;48:1324-42.
23. Shike M. Copper in parenteral nutrition. Gastroenterology. 2009;137:S13-7.
24. Verner A, Craig S, McGuire W. Effect of taurine supplementation on growth and
development in preterm or low birth weight infants. Cochrane Database Syst Rev.
2007;Oct 17(4):CD006072.
25. Bonner CM, DeBrie KL, Hug G, et al. Effects of parenteral L-carnitine supplementation
on fat metabolism and nutrition in premature neonates. J Pediatr. 1995;126:287-92.
26. Crill C, Helms RA. The use of carnitine in pediatric nutrition. Nutr Clin Pract.
2007;22:204-13.
27. Terrin G, Passariello A, DeCurtis M, et al. Ranitidine is associated with infections,
necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics. 2012;129(1):e40-5.
28. More K, Athalye-Jape G, Rao S, et al. Association of inhibitors of gastric acid secretion
and higher incidence of necrotizing enterocolitis in preterm very low-birth-weight
infants. Am J Perinatol. 2013;30(10):849-56.
Parenteral Nutrition 41

29. Kelly DA. Preventing parenteral nutrition liver disease. Early Hum Dev. 2010;86:683-7.
30. Calkins KL, Venick RS, Devaskar SU. Complications associated with parenteral nutri-
tion in neonates. Clin Perinatol. 2014;41(2):331-45.
31. Sanchez SE, Braun LP, Mercer LD, et al. The effect of lipid restriction on the preven-
tion of parenteral nutrition-associated cholestasis in surgical infants. J Pediatr Surg.
2003;48(3):573-8.
32. Arslanoglu S, Moro G, Tauschel H, et al. Ursodeoxycholic acid treatment in preterm
infants: a pilot study for the prevention of cholestasis associated with total parenteral
nutrition. J Pediatr Gastroenterol Nutr. 2008;46:228-31.
33. Chen CY, Tsao PN, Chen HL, et al. Ursodeoxycholic acid (UDCA) therapy in very-
low-birth-weight infants with parenteral nutrition-associated cholestasis. J Pediatr.
2004;145:317-21.
34. Wales PW, Allen N, Worthington P, et al. A.S.P.E.N. clinical guidelines: support of
pediatric patients with intestinal failure at risk of parenteral nutrition-associated liver
disease. JPEN. 2014; 38(5):538-57.
35. Levit OL, Calkins KL, Gibson LC, et al. Low-dose intravenous soybean oil emulsion
for prevention of cholestasis in preterm neonates. JPEN. 2014; June 24 [epub ahead of
print].
36. Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and
management of intravascular catheter-related infection: 2009 update by the Infectious
Diseases Society of America. Clin Infect Dis. 2009;49:1-45.
37. Pieroni KP, Nespor C, Ng M, et al. Evaluation of ethanol lock therapy in pediatric
patients on long-term parenteral nutrition. Nutr Clin Pract. 2013;28:226-31.
38. Mouw E, Chessman K, Lesher A, et al. Use of ethanol lock to prevent catheter-related
infections in children with short bowel syndrome. J Pediatr Surg. 2008;43:1025-9.
39. Wier HA, Kuhn RJ. Aluminum toxicity in neonatal parenteral nutrition: what can we
do? Ann Pharmacother. 2012;46:137-40.
40. Kerner JA, Poole RL. The use of IV fat in neonates. Nutr Clin Pract. 2006; 21:374-380.
41. Robinson CA, Sawyer JE. Y-site compatibility of medications with parenteral nutrition.
J Pediatr Pharmcol Ther. 2009;14:48-56.
42. Khashu M, Harrison A, Lalari V, et al. Impact of shielding parenteral nutrition from
light on routine monitoring of blood and triglyceride levels in preterm neonates. Arch
Dish Child Fetal Neonatal Ed. 2009;94:F111-5.
43. Sherlock R, Chessex P. Shielding parenteral nutrition from light: does the available
evidence support a randomized, controlled trial? Pediatrics. 2009;123:1529-33.
44. Bassiouny MR, Almarsafaway J, Abdel-Hady H, et al. A randomized controlled trial
on parenteral nutrition, oxidative stress, and chronic lung diseases in preterm infants.
J Pediatr Gasteroenterol Nutr. 2009;48:363-9.
45. Chessex P, Harrison A, Khashu M, et al. In preterm neonates, is the risk of developing
42 NICU Primer for Pharmacists

bronchopulmonary dysplasia influenced by the failure to protect total parenteral nutri-


tion from exposure to ambient light? J Pediatr. 2007;151:213-4.

Suggested Readings
American Society of Health-System Pharmacists. Handbook on Injectable Drugs. 18th ed.
Bethesda, MD: American Society of Health-System Pharmacists; 2015.
Boullata JI, Gilbert K, Sacks G, et al. A.S.P.E.N. clinical guidelines: parenteral nutrition
ordering, order review, compounding, labeling and dispensing. JPEN. 2014;
38(3):334-77.
El Hassan NO, Kaiser JR. Parenteral nutrition in the neonatal intensive care unit.
NeoReviews. 2011;12:e130-40.
Gargasz A. Neonatal and pediatric parenteral nutrition. AACN. 2012;23(4):451-64.
King JC. King Guide to Parenteral Admixtures. Napa, CA: King Guide Publications; 2015.
Migaki, EA, Melhart BJ, Dewar CJ, et al. Calcium and sodium phosphate in neonatal
parenteral nutrition containing Trophamine: precipitation studies and aluminum
content. JPEN. 2012;36:470-5.
Omegaven information. http://www.fda.gov/Drugs/Development ApprovalProcess/
HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNew
DrugINDApplication/ucm368740.htm
Tucker A, Ybarra J, Bingham A, et al. American Society for Parenteral and Enteral Nutri-
tion (A.S.P.E.N.) standards of practice for nutrition support pharmacists. Nutr Clin
Pract. 2015; 30(1)139-46.
Wier HA, Kuhn RJ. Aluminum toxicity in neonatal parenteral nutrition: what can we do?
Ann Pharmacother. 2012;46:137-40.
4
Drugs in Lactation

Amy P. Holmes, PharmD

Introduction

A
catchy phrase that expectant and
newly delivered moms will typically
hear is “breast is best.” Although
breast milk is best for newborn babies, this
is especially true for premature babies in the
neonatal intensive care unit (NICU). It is
important for pharmacists to be aware of
the advantages of mother’s milk for these
vulnerable babies so that they can adequate-
ly assess the risk−benefit scenario when
faced with whether or not it is safe to use a
mother’s milk. There are very few contra-
indications to breastfeeding, but there are
definite risks in not providing mother’s milk.
44 NICU Primer for Pharmacists

Mother’s Milk
Composition
Mother’s milk is produced based on the law of supply and demand. The
hormones oxytocin and prolactin work in a positive feedback loop to estab-
lish the breastfeeding cycle.1 A suckling baby or a breast pump empties the
breasts, stimulating the creation of more milk. This is not always as simple
as it sounds. In the early days following delivery, some women fight to
produce drops of milk. This milk should not be taken for granted!
Colostrum, the first milk a new mother produces, is usually somewhat
thick and yellow in color and lasts for 1 to 3 days. Drugs pass more readily
into colostrum; however, due to the nature of the very small volume
produced, exposure to any substance is minimal and clinically neglible.2

Benefits
Mother’s milk has been associated with reduced incidence of necrotizing
enterocolitis (NEC), a potentially fatal disease in premature babies (see
Chapter 13).3 In addition to fat, protein, carbohydrates, and vitamins,
mother’s milk provides immune globulins and probiotics to colonize the
newborn intestine. These properties protect babies from other infections
besides NEC, such as otitis media and respiratory tract infections. Breastfed
babies also have a lower risk for sudden infant death syndrome as well as a
decreased risk of some childhood cancers (e.g., leukemia, lymphoma). The
effects reach into adolescence and adulthood with formerly breastfed babies
having lower incidence of diabetes and asthma.
Another advantage of mother’s milk is that the protein in human milk is
better tolerated than the cow protein in infant formulas because it is easier
for babies to digest.3

Length of Breastfeeding
Experts recommend exclusive breastfeeding for the first 6 months of life.3
Even as solid foods begin to be added to the diet, breastfeeding is recom-
mended during the first year of life. The Healthy People 2020 Goals include
a goal to increase the number of mothers who are breastfeeding at hospital
discharge to 80% and for at least 60% to breastfeed through the first 6
months of the child’s life.4
Drugs in Lactation 45

Contraindications
Maternal contraindications to breastfeeding include human immunodefi-
ciency virus, herpes simplex virus lesion on the breast, exposure to radioac-
tive materials, antimetabolites or other chemotherapy, active tuberculosis,
and human T-cell lymphocyctic virus infection.3 Additionally, infants who
have galactosemia should not receive maternal milk. There are very few
medications that are absolute contraindications to breastfeeding. Women
frequently stop breastfeeding secondary to medication use, although that
may not be the optimal decision.2 Pharmacists can play a role in meeting the
Healthy People 2020 goal by providing accurate, reliable information that
may allow the mother to continue to provide milk safely to her infant.

Donor Milk
Prior to the invention of artificial feedings, women who could not provide
milk for their babies relied on wet nurses. Since the early twentieth century,
this practice has fallen out of favor due to understanding about the passage
of communicable diseases. Interestingly, we have come full circle with several
milk banks across the United States that provide pasteurized donor breast
milk to NICUs. Donors are screened and are preferred not to be taking any
medications regularly; however, specific medications (e.g., prenatal vitamins,
human insulin, asthma inhalers) are allowed due to their proven safety.5

Additives to Mother’s Milk


Premature babies miss much of the nutrient accretion that occurs normally
during the third trimester. To help them catch up, a supplement known as
human milk fortifier is added in the NICU to maternal milk. This product
adds protein and minerals such as phosphorus and calcium to the milk.
Mother’s milk has low concentrations of iron, which has poor bioavailability.
For this reason, premature babies receiving the majority of their calories from
breast milk also require iron supplementation with at least 2 mg/kg/day. The
American Academy of Pediatrics (AAP) recommends that all babies receive
400 units of vitamin D daily regardless of diet.6 For additional calories in
babies who are not gaining adequate amounts of weight, medium chain
triglycerides oil or a protein supplement (e.g., Beneprotein) may be added to
increase caloric density. Oat cereal may be added to thicken feeds in babies
who are experiencing symptomatic reflux. Rice cereal has fallen out of favor
due to concerns over potential arsenic contamination.
46 NICU Primer for Pharmacists

Drug Transfer into Milk


Many properties affect the transfer of medications into human milk.
Primarily, drugs pass into breast milk by passive diffusion from the mother’s
blood stream.2 If the drug is not present in the systemic circulation, then
it cannot pass into milk. A few drugs have active transport mechanisms
into breast milk. The most commonly used drugs that can pass via active
transport include acyclovir, cimetidine, and iodine. Of these, iodine poses
the greatest concern because large quantities of iodine can affect thyroid
function. Normal dietary intake of iodine is not problematic, but supple-
ments rich in iodine should be avoided during lactation. Even with active
transport, the amount of acyclovir and cimetidine passed into milk is not
clinically significant.
Understanding the pharmacokinetic and pharmacodynamic properties
that affect drug transfer and sequestration into milk can assist and reassure
pharmacists as they assess medication safety in lactation and make recom-
mendations related to medication use in lactation.

Molecular Weight
The smaller the molecular weight, the more easily the drug will pass into
milk.2 For example, medications that are less than 200 daltons are most
likely to pass into milk. Proteins such as insulin are very large molecules and
would, therefore, not be expected to pass into milk at all.

Bioavailability
Bioavailability is an important factor to consider in assessing a medication’s
safety in milk.2 First, consider if the medication is absorbed by the mother.
For example, if gastrointestinal (GI) contrast is administered during radio-
logic imaging of the GI tract, it is not absorbed. Because the contrast is not
absorbed by the mother, it cannot pass into her milk. Second, consider if
the medication has oral bioavailability. Enoxaparin is a large molecule that
would not be expected to pass into milk. Even if it were passed into milk,
the baby would not absorb it orally from the milk.

Volume of Distribution
Volume of distribution is important to consider because, as previously
stated, substances that are not in the blood stream cannot pass into
Drugs in Lactation 47

milk.2 An example is the bisphosphonate zoledronic acid (Zometa) that is


sometimes used to treat hyperparathyroidism. This medication distributes
immediately to bone and does not remain in the serum, so it cannot be
expected to pass into breast milk.

Peak Serum Concentration


Medications can sometimes be administered to avoid feeding or pumping
milk during the time that a medication is at its peak serum concentration.2
Just as medications diffuse into milk, they can also diffuse back into serum
as the concentration decreases. This strategy can reduce the exposure that an
infant has to a medication via lactation.

Acid Ionization Constant


Another factor that affects concentration of medications in breast milk is the
acid ionization constant also known as the pKa. Although most pharmacists
have not thought about pKa since pharmacy school, it is helpful to have
an appreciation for the effect known as ion trapping. As a reminder, pKa
is the pH at which half the drug is ionized and half is unionized. Medica-
tions with a pKa greater than 7.2 are at higher risk to become sequestered
in milk.2 Lactation references will note if ion trapping has been observed,
although most pharmacy references do not list the pKa.

Milk-to-Plasma Ratio
Milk-to-plasma ratio is the ratio of the drug’s concentration in the mother’s
milk divided by the amount in the mother’s plasma.2 Low milk-to-plas-
ma ratio (<1) indicates that minimal levels of the drug are transferred into
milk, while a high milk-to-plasma ratio (>1 to 5) indicates that medication
may be sequestered in milk. This information is sometimes found in the
monographs of medications listed in medication and lactation references.

Relative Infant Dose


Relative infant dose is a weight-based method to determine the amount that
the baby receives relative to the mother’s dose.2 It can be found by divid-
ing the theoretic infant dose (in mg/kg/day) by the maternal dose (in mg/
kg/day). This seems to be growing in popularity as a way to describe drug
passage into milk. This, too, is a value usually found specifically in lactation
references.
48 NICU Primer for Pharmacists

Nicotine
It is always in patients’ best interest to quit smoking, and pharmacists
should advise them accordingly. Mothers who continue to smoke and wish
to breastfeed can do so. Some nicotine does pass into breast milk; however,
the overall benefit of the breast milk outweighs the risk from exposure to
components of cigarette use that pass into the milk.7
Nicotine replacements are generally considered safe in breastfeeding.2
The inhaler provides the lowest serum level of nicotine so it may have an
advantage over other forms. The patch provides a consistent level as opposed
to the gum, which may have large spikes in concentration. For lactating
mothers attempting to quit smoking, these factors may be helpful in deter-
mining the agent that is preferred.

Alcohol
The AAP recommends that breastfeeding women avoid alcohol but considers
small amounts of alcohol compatible with breastfeeding.3 Women who have
an occasional social drink should avoid breastfeeding for 2 hours following
the alcohol consumption. Alcohol may adversely affect milk production.8
The old wives’ tale about beer enhancing milk production is false. Advise
mothers not to drink beer for the purpose of augmenting milk production.

Breastfeeding and Substances of Abuse


Breastfeeding is contraindicated in mothers who are actively using illicit
substances. Cocaine ingestion by lactating women is specifically very
dangerous to their breastfeeding infants.2 In addition to the dangers associ-
ated with drug passage into breast milk, neonates may be exposed to infec-
tious disease associated with intravenous (IV) drug use.
Mothers with a history of addiction who are maintained on methadone
or buprenorphine are not only candidates for breastfeeding but should be
encouraged to breastfeed.9 For more information, see Chapter 5.

Galactogogues
Place in Therapy
When mothers fail to produce an adequate supply of milk on their own,
they often look for substances that can help them in producing milk.
Drugs in Lactation 49

Galactogogues are substances that stimulate the production of breast milk.


Currently the Academy of Breastfeeding Medicine does not endorse the use
of a particular galactogogue as many of them have been found not to work
or are associated with significant adverse effects.10 Before initiating a galac-
tagogue, women should attempt nonpharmacologic methods of increasing
milk production such as ensuring adequate hydration; skin-to-skin holding
with baby (also known as kangaroo care); self-breast massage; relaxation
techniques; and unrestricted frequency and duration of breastfeeding. Lacta-
tion consultants are also helpful in recommending techniques to overcome
barriers in breastfeeding.
A multitude of herbal and alternative medicines have been touted to
increase maternal milk production, but no scientific evidence supports their
use. The most commonly recommended agents for increasing mother’s milk
supply are described below.

Metoclopramide
Metoclopramide is the only prescription drug routinely used for the purpose
of stimulating or enhancing lactation. Its mechanism of action is via the
increase of prolactin levels; therefore, it would not be expected to work in
women with elevated prolactin levels.10 Although most providers do not
routinely measure prolactin levels, understanding this mechanism of action
helps to understand why some women do not respond to metoclopramide.
The usual dose is 10 mg orally three times daily for 7 to 14 days.10 To
prevent decline in milk production, consider weaning the dose rather than
stopping abruptly. Metoclopramide use has been dampened somewhat by
the addition of the black box warning regarding tardive dyskinesia (TD).
Although TD has long been a well-known complication of metoclopramide
use, the addition of the black box warning brought attention to the poten-
tial for irreversible TD. Metoclopramide is considered to have minimal risk
to the breastfeeding infant.2

Fenugreek
Fenugreek is an ancient herb that has been used for various things through-
out history, including Egyptian embalming and cattle fodder. In modern
times, it is an herbal supplement that has long been used for the purpose of
increasing milk production. It is classified as “Generally Regarded as Safe”
under the Code of Federal Regulations.11 Fenugreek is theorized to work by
50 NICU Primer for Pharmacists

increasing sweat production because mammary glands are modified sweat


glands.12 Fenugreek has a reputation in the lay community for assistance
with lactation, and mothers continue to recommend it to their breastfeeding
friends. Clinical trials have failed to demonstrate efficacy of fenugreek in
increasing milk production.10
Fenugreek products vary in potency and, therefore, in dosing. The most
common dose is two to three capsules three times daily. Passage of fenugreek
into milk is unknown, but reports of adverse effects in infants are rare.
Adverse effects in mothers include a maple syrup scent to urine and sweat,
diarrhea, hypoglycemia, dyspnea (exaggeration of asthma symptoms), and
allergic reactions. Of note, fenugreek can affect the international normalized
ratio (INR). Women who are taking warfarin may be wise to avoid use of
fenugreek. If they do use the herb, they should consult the practitioner who
manages their warfarin dosing.

Domperidone
Although domperidone is not available in the United States, patients still
manage to obtain it either from other countries such as Canada or from
compounding pharmacies within the United States. Pharmacists should have
an understanding of its use. Domperidone, like metoclopramide, increases
milk production by increasing prolactin levels.13 Unlike metoclopramide,
domperidone does not cross the blood−brain barrier or cause TD. Domper-
idone was removed from the market following reports of life-threatening
arrhythmias associated with IV dosing for chemotherapy-induced nausea and
vomiting.
Very little domperidone is passed into breast milk, and no adverse effects
have been reported in infants despite its widespread use in Canada and
other countries. The usual dose is 10 mg orally three times daily for 7 days.
As mentioned with metoclopramide, gradual weaning may be advantageous
over abrupt discontinuation if successful lactation is established.

Reliable References
Many references contain information on the safety of medications and lacta-
tion but few have accurate, reliable information. Historically, package inserts
have not been a reliable source of information for the safety of medication
use during lactation. In December 2014, the Food and Drug Administra-
Drugs in Lactation 51

tion (FDA) announced a new labeling rule, which requires that data on
medication passage into milk be included in the product insert.14 This new
labeling requirement includes a subsection on lactation with information
on the concentration of medication expected in mother’s milk, as well as
potential side effects of infants receiving milk with the given medication.
Furthermore, manufacturers are required to include a risk−benefit statement
along with recommendations for minimizing exposure to the drug via breast
milk and suggest interventions to monitor and/or prevent adverse reactions
to the medication. This new rule became effective June 30, 2015, and drug
manufacturers have from 3 to 5 years to submit data for their new labels to
the FDA depending on when their initial drug application was effective.
During this transition, careful attention must be paid to which type of
insert is available when using it as a reference for information on the safety
of breastfeeding.
Other traditional pharmacy references may include information on
breastfeeding but tend to be conservative in nature. Three medication
references stand out as preferred when assessing the safety of medications
in lactation. The first is Thomas Hale’s Medications & Mothers’ Milk. This
reference is published biannually and includes a scoring system that makes
it easy to assess a medication at first glance (Table 4-1). Monographs also
include text describing available data, pediatric concerns, and alternative
medications. The second resource is LactMed, a web-based tool supported
by the National Institutes of Health. This website is free of charge and
contains in-depth information on studies related to a specific medication
and its passage into breast milk. LactMed also has a free app that can be
downloaded on any smartphone. Finally, Briggs’ Drugs in Pregnancy and
Lactation is a well-known reference for assessing a medication’s compatibility
with breastfeeding.
A study conducted by pharmacists compared the safety in lactation
information provided by 10 different references for 14 commonly used
medications.15 They found a great deal of variation between resources even
for medications well established as safe in breastfeeding. When advising
physicians, patients, or lactation consultants about the safety of medication
use in breastfeeding, please use a reliable and up-to-date resource. It is also
beneficial to check with more than one reference to verify that the informa-
tion is consistent.
52 NICU Primer for Pharmacists

Table 4-1. Dr. Hale’s Lactation Risk Category


Category Definition
L1—Compatible Drug that has been taken by a large number of
breastfeeding mothers without any observed in-
crease in adverse effects in the infant. Controlled
studies in breastfeeding women fail to demonstrate
a risk to the infant and the possibility of harm to the
breastfeeding infant is remote; or the product is not
orally bioavailable in an infant.
L2—Probably Drug that has been studied in a limited number of
Compatible breastfeeding women without an increase in adverse
effects in the infant and/or the evidence of a demon-
strated risk, which is likely to follow use of this medi-
cation, in a breastfeeding woman is remote.
L3—Probably There are no controlled studies in breastfeeding
Compatible women; however, the risk of untoward effects to
a breastfed infant is possible, or controlled studies
show only minimal nonthreatening adverse effects.
Drugs should be given only if the potential benefit
justifies the potential risk to the infant. (New med-
ications that have absolutely no published data are
automatically placed in this category, regardless of
how safe they may be.)
L4—Possibly There is positive evidence of risk to a breastfed
Hazardous infant or to breast milk production, but the benefits
from use in breastfeeding mothers may be accept-
able despite the risk to the infant (e.g., if the drug is
needed in a life-threatening situation or for a serious
disease for which safer drugs cannot be used or are
ineffective).
L5—Hazardous Studies in breastfeeding mothers have demonstrated
that there is significant and documented risk to the
infant based on human experience, or it is a medica-
tion that has a high risk of causing significant damage
to an infant. The risk of using the drug in breastfeed-
ing women clearly outweighs any possible benefit
from breastfeeding. The drug is contraindicated in
women who are breastfeeding an infant.
Source: Used with permission from Hale TW, Rowe HE. Medications & Mothers’ Milk.
16th ed. Plano, TX: Hale Publishing; 2014.
Drugs in Lactation 53

Other Considerations
As with any medication, the first question should be, “Is this medication
necessary?” Also important to consider is whether or not there is an alterna-
tive drug in the same class that is preferred in breastfeeding. Consider who
is getting the milk—a premature baby will be more vulnerable to medica-
tion risks than a term infant or older child who is no longer receiving an
exclusively milk diet.9 Finally, the medication that the baby may be exposed
to through breast milk should be assessed for drug interactions, which may
occur with any medications being administered directly to the baby.
Keep in mind that some women may opt to not take a medication that
they really need rather than to stop breastfeeding. This reinforces the need
to get the most accurate and objective information as well as provide effec-
tive communication when discussing these issues with mothers and/or their
healthcare providers.

Conclusion
Most medications are not contraindicated in breastfeeding. In fact, the
benefit of the milk usually outweighs the risk of substance exposure for
most medications. Use reliable, up-to-date resources to provide information
to mothers or healthcare providers regarding the safety of medication use
during lactation.

References
1. Lawrence RA, Lawrence RM. Physiology of lactation. In: Lawrence RA, Lawrence
RM, eds. Breastfeeding. 7th ed. Maryland Heights, MO: Mosby; 2011:62-97.
2. Hale TW, Rowe HE. Medication & Mothers’ Milk. 16th ed. Plano, TX: Hale Publish-
ing; 2014.
3. Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics.
2012;129(3):e827-41.
4. Maternal, Infant, and Child Health. http://www.healthypeople.gov/node/3492/objec-
tives#4825. Accessed December 31, 2014.
5. Human Milk Banking Association of North America. Donate milk. https://www.
hmbana.org/donate-milk. Accessed March 17, 2015.
6. Wagner CL, Greer FR, and the Section on Breastfeeding and Committee on Nutrition.
Prevention of rickets and vitamin D deficiency in infants, children, and adolescents.
Pediatrics. 2008;122(5):1142-52.
54 NICU Primer for Pharmacists

7. Woodward A, Douglas RM, Graham NM, et al. Acute respiratory illness in Adelaide
children: breastfeeding modifies the effect of passive smoking. J Epidemiol Community
Health. 1990;44(3):224-30.
8. Mennella JA, Pepino MY. Breastfeeding and prolactin levels in lactating women with a
history of alcoholism. Pediatrics. 2010;125(5):e1162-70.
9. Sachs HC and Committee on Drugs. The transfer of drugs and therapeutics into
human breast milk: an update on selected topics. Pediatrics. 2013;132:e796-809.
10. The Academy of Breastfeeding Medicine Protocol Committee ABM. Clinical Protocol
#9: Use of galactogogues in initiating or augmenting the rate of maternal milk
secretion (first revision January 2011). Breastfeed Med. 2011;6:1.
11. Code of Federal Regulations General Provisions: Substances Generally Recognized as
Safe. 21 CFR 182.10. 2012.
12. Wambach K, Riordan J. Breastfeeding and Human Lactation. 5th ed. Burlington, MA:
Jones and Bartlett Publishers; 2014:586.
13. Zuppa AA, Sindico P, Orchi C, et al. Safety and efficacy of galactogogues: substances
that induce, maintain and increase breast milk production. J Pharm Pharm Sci.
2010;13(2):162-74.
14. Federal Register. Content and format of labeling for human prescription drug and
biological products; requirements for pregnancy and lactation labeling. https://www.
federalregister.gov/articles/2014/12/04/2014-28241/content-and-format-of-labeling-
for-human-prescription-drug-and-biological-products-requirements-for#h-54. Accessed
February 13, 2015.
15. Akus M, Bartick M. Lactation safety recommendations and reliability compared in
medication resources. Ann Pharmacother. 2007;41(9):1352-60.

Suggested Readings
Rowe H, Baker T, Hale TW. Maternal medication, drug use, and breastfeeding. Pediatr
Clin N Am. 2013;60:275-94.
Sachs HC and Committee on Drugs. The transfer of drugs and therapeutics into human
breast milk: an update on selected topics. Pediatrics. 2013;132:e796-809.
The Academy of Breastfeeding Medicine Protocol Committee. ABM Clinical Protocol #9:
Use of galactogogues in initiating or augmenting the rate of maternal milk secretion
(first revision January 2011). Breastfeed Med. 2011;6:1.
5
Neonatal Abstinence
Syndrome

Amy P. Holmes, PharmD

Introduction

N
eonatal abstinence syndrome
(NAS) is recognized as the
effect of intrauterine exposure
to substances that can cause physi-
cal dependence.1 In other words, it
is withdrawal of the neonate from
substances that the mother ingested
during pregnancy. Addiction is a behav-
ior-related problem, which is different
from physical dependence. It is import-
ant to distinguish between addiction
and physical dependence. Babies are
born physically dependent on substances
(particularly opiates) and can become
56 NICU Primer for Pharmacists

seriously ill due to abrupt discontinuation of them. However, babies are


NOT born addicted to drugs. Opiate withdrawal is the most common and
most studied withdrawal syndrome. For purposes of this chapter, NAS will
refer to opiate withdrawal.
The incidence of NAS following in utero exposure is reported between
55 and 94%.2 From 2000 to 2009, a three-fold increase in the incidence
was reported.3 This correlates to the reported five-fold increase in opiate use
during pregnancy over the last 10 years.4 One study found that although
infants born to substance-abusing mothers accounted for 2.9% of hospi-
tal births, they accounted for 18.2% of neonatal intensive care bed days
demonstrating the economic burden this problem can create.5 Furthermore,
long hospital stays can disrupt family life and affect an infant’s attachment
to his or her parents.6
NAS is associated with chronic use at or near the time of delivery. If
more than 2 weeks have passed since the last exposure, then withdrawal in
the newborn is unlikely. Onset of withdrawal can range from 3 to 14 days
and varies depending on several factors, including half-life of the substance
and time of last exposure. The American Academy of Pediatrics (AAP)
Policy Statement on NAS recommends that infants exposed to short-acting
opiates (e.g., hydrocodone, oxycodone) be monitored for 3 to 5 days for
signs and symptoms of NAS and those exposed to longer acting opiates
(e.g., methadone) be monitored for 7 days prior to discharge from the
hospital.7 If a baby requires treatment, lengths of stay vary greatly. Most
infants are treated in an inpatient setting until pharmacologic treatment is
complete, but some are discharged to home to complete their treatment.

Substances of Abuse
There are multiple substances of abuse, and many users will abuse more
than one substance leading to multiple exposures in the infant. Marijuana
may be one of the most frequently abused substances, but its use is not
associated with withdrawal in infants. Because cocaine causes a psycholog-
ical addiction but does not result in a physical dependence, it is not associ-
ated with withdrawal in infants. When cocaine is used in conjunction with
opiates, symptoms associated with the opiate withdrawal may be worsened.
Maternal opiate and benzodiazepine use are both associated with withdrawal
in the neonate.
Neonatal Abstinence Syndrome 57

Serotonin reuptake inhibitors (SSRIs) are not associated with NAS.


The irritability that results from maternal SSRI use is referred to by some
as serotonin discontinuation syndrome.7 This self-limiting condition occurs
early after birth with symptoms mimicking NAS and usually resolves in 48
to 72 hours of life. Rather than withdrawal, this syndrome is thought to be
associated with the drug’s direct effect and symptom resolution correlates
with drug excretion.
It is important to note that not all NAS is a result of illicit or recreational
drug use. As women delay having children to a later stage of life, more
women are getting pregnant while dealing with chronic medical conditions.
Infants born to women who are taking prescribed opiates for chronic pain
conditions may develop NAS and, therefore, need to be observed.
Opiate maintenance therapy (particularly methadone) is associated
with more frequent and more severe withdrawal in the neonate than active
drug abuse or illicit drug use.8 Maintenance therapy is preferred in pregnant
women because it stabilizes the mother’s lifestyle, reduces risk-taking
behavior, and decreases the incidence of preterm birth and intrauterine
growth restriction. Buprenorphine use for opiate addiction management in
pregnancy has been associated with less severe NAS and decreased overall
treatment dose in the infant than methadone but may not be an acceptable
alternative for all substance abusers.8-11 Women in opiate maintenance therapy
should not attempt to wean from their medication during pregnancy.12
Contrarily, they often require dose increases as their pregnancy progresses.

Screening and Scoring


Different tools can be used for screening for maternal substance abuse.
Testing of the newborn’s urine is of use only when collected in the early
post-delivery hours. Meconium, the first stool passed by a newborn, is a
good source for screening and gives a broader picture of exposure through-
out the later stages of pregnancy. Hair and umbilical cord can also be used
for screening. One should pay close attention to what is screened for at
the institution as these tests have different panels associated with them. Be
aware that opiate screens look only for natural opiates such as morphine,
codeine, and heroin. Exposure to methadone, a synthetic opiate, can lead
to a negative opiate screen. Methadone and other synthetic opiates (e.g.,
oxycodone) must be tested for specifically in order to capture them.
58 NICU Primer for Pharmacists

Symptoms of NAS can be categorized as respiratory, gastrointestinal


(GI), or central nervous system (CNS) symptoms.4,6,7 Respiratory symptoms
include tachypnea, sneezing, nasal flaring, and nasal stuffiness. GI symptoms
include excessive sucking, poor feeding, regurgitation, and watery diarrhea.
CNS symptoms include excessive high-pitched cry, sleep disturbance,
tremors, increased tone, and convulsions. Following treatment and/or hospi-
tal discharge, subclinical symptoms may persist for weeks or months.
Several tools are available for scoring NAS symptoms.7 The modified
Finnegan tool is the most commonly used scoring system (Figure 5-1).
Other commonly used tools include the Lipsitz and Neonatal Withdrawal
Inventory. These tools assign a symptom-based score that is used to deter-
mine treatment initiation, titration, and weaning.
Each tool has its own trigger point for treatment. With the modified
Finnegan tool, scores of eight are considered an indication for treatment.
Institutions take different approaches to interpreting this number. Some
institutions use the average of three scores, some look for two of three scores
to be greater than eight, and others need two consecutive scores greater than
or equal to eight to initiate pharmacologic treatment. Dose is titrated and
weaned based on these scores.

Treatment
All babies at risk for NAS should be treated with nonpharmacologic
measures, including swaddling them in a light blanket; dimming lights;
stimulating them minimally; holding them skin-to-skin with parents (also
known as kangaroo care); covering their hands to protect skin; changing
their diapers frequently; offering them a pacifier; and breastfeeding (if
mother is a candidate).4,7

Opiate Therapy
Opiate therapy is recommended for NAS treatment.4,7 Either morphine
or methadone may be used. Doses of various ranges have been used and
include both weight-based as well as symptom-based dosing approaches.
To date no head-to-head studies comparing the two treatment approaches
have been published; however, this is currently an area of focus in neona-
tal medicine. Although AAP does not recommend a specific agent for the
management of NAS, it recommends that each hospital develop a protocol
to standardize the treatment approach.7
Neonatal Abstinence Syndrome 59

Neonatal Abstinence Scoring System


System Signs and Symptoms Score AM PM Comments
Excessive high-pitched (or other) cry 2   Daily Weight:
Continuous high-pitched (or other) cry 3
Central Nervous System Disturbances

Sleeps < 1 hour after feeding 3


Sleeps < 2 hours after feeding 2
Sleeps < 3 hours after feeding 1

Hyperactive Moro reflex 2


Markedly hyperactive Moro reflex 3
Mild tremors disturbed 1
 
Moderate-severe tremors disturbed 2
Mild tremors undisturbed 3
Moderate-severe tremors undisturbed 4
Increased muscle tone 2
Excoriation (specific area) 1      
Myoclonic jerks 3      
Generalized convulsions 5      
Sweating 1
Fever <101 (99–100.8 F, 37.2–38.2 C) 1
Respiratory Disturbances

Fever > 101(38.4 C and higher) 2


Metabolic/ Vasomotor/

Frequent yawning (> 3–4 times/interval) 1      


Mottling 1      
Nasal stuffiness 1      
Sneezing (> 3–4 times/interval) 1      
Nasal flaring 2
Respiratory rate > 60/min 1
Respiratory rate > 60/min with retractions 2
Excessive sucking 1      
Gastrointestinal
Disturbances

Poor feeding 2      
Regurgitation 2
Projectile vomiting 3
Loose stools 2
Watery stools 3
Total Score
Initials of Scorer

Figure 5-1. Modified Finnegan Scoring Tool


Source: Used with permission from Finnegan LP. Neonatal abstinence syndrome: assessment
and pharmacotherapy. In: Nelson N, ed. Current Therapy in Neonatal-Perinatal Medicine.
2nd ed. Ontario, Canada: BC Decker; 1990:317. Copyright© Elsevier.
60 NICU Primer for Pharmacists

Phenobarbital
Phenobarbital is no longer recommended for first-line treatment, but it
may have a place as an adjunct in some babies.4,7,13 Adjunctive therapy may
be warranted when initial treatment has escalated to inducing side effects
without managing the NAS symptoms. Any adjunctive treatment that is
added also needs to be weaned and, therefore, should be used judiciously.

Clonidine
Clonidine has demonstrated efficacy in treating NAS and may also reduce
the duration of pharmacologic treatment.14,15 Clonidine affects the part
of the brain that responds to the excessive norepinephrine released during
withdrawal.16 Based on its mechanism of action, it would be expected to
treat the CNS effects of NAS but not the GI effects. It has the potential
advantage of being safer than opiate replacement from a neurodevelopmen-
tal standpoint. The average dose used for NAS is 1 mcg/kg/dose every 4
hours.14 Monitoring blood pressure and heart rate during treatment should
be considered.

Buprenorphine
Buprenorphine is under investigation as an alternative treatment for NAS.
Interestingly, the pilot study that was conducted to assess its use in NAS was
also the first study in neonates to use the sublingual route of administra-
tion.17

Possible Adverse Effects


Adverse effects of opiates in neonates who have been exposed in utero are
uncommon. Due to their tolerance, they do not often experience respira-
tory depression unless large doses are given. Occasionally, urinary retention
becomes the dose-limiting effect.
Treatment should be assessed daily and weaned as often as every 48
hours if scores are stable and less than eight. Neonatal abstinence scores
consistently in the zero to one range and/or a baby who will not wake up
to eat are indications that he or she is overmedicated and the dose should
be decreased, regardless of the wean schedule. Babies who have completed
treatment with replacement opiate are generally observed for 48 hours prior
to discharge to ensure that no rebound withdrawal requiring treatment is
going to occur.
Neonatal Abstinence Syndrome 61

Breastfeeding
Mothers who are compliant with their sobriety program should be encour-
aged to breastfeed their infant.7 Aside from the multitude of benefits that
breastfeeding offers the mother/infant dyad, there are specific advantages
for babies suffering from NAS. Babies with NAS who have received their
mother’s breast milk have a decreased need for pharmacological treatment
and a shorter treatment duration.18,19 Breastfeeding is soothing and comfort-
ing to infants and probably accounts for a part of this benefit, but some
babies included in these studies also received expressed breast milk from
a bottle. The amount of methadone in breast milk is less than 3% of the
maternal dose.20 Even though it is a very small amount, this milk may help
to ameliorate symptoms of NAS. Breast milk has the added advantage of
being more easily digested and likely helps with the feeding intolerance that
NAS babies experience. Mothers should be counseled that abrupt discontin-
uation of breastfeeding can lead to withdrawal, possibly requiring hospital
admission and pharmacologic treatment.21 The Academy of Breastfeeding
Medicine has published guidelines advising which mothers are candidates to
breastfeed their babies.22

Family Considerations
The social aspect of NAS can be complex. It is important for everyone
working with these families to understand that addiction is a disease process
and not a moral failure.23 The American College of Obstetricians and
Gynecologists states that “Addiction is a chronic, relapsing biological and
behavioral disorder with genetic components. The disease of substance addic-
tion is subject to medical and behavioral management in the same fashion as
hypertension and diabetes.”24 Taking this statement into consideration while
assisting in NAS management will create a better environment for the baby
as well as the parents.

Conclusion
NAS management is an area where pharmacists can play an important role.
Pharmacists should look for opportunities to get involved in the develop-
ment of protocols and to advocate for breastfeeding in appropriate candi-
dates within their institutions.
62 NICU Primer for Pharmacists

References
1. O’Grady MJ, Hopewell J, White MJ. Management of neonatal syndrome: a national
survey and review of practice. Arch Dis Child Fetal Neonatal Ed. 2009;94:F249-52.
2. Burgos AE, Burke BL. Neonatal abstinence syndrome. NeoReviews. 2009;10:e222-9.
3. Patrick SW, Schumacher RE, Benneyworth BD, et al. Neonatal abstinence syn-
drome and associated health care expenditures (United States, 2000–2009). JAMA.
2012;307(18):1934-40.
4. Wiles JR, Isemann B, Ward LP, et al. Current management of neonatal abstinence
syndrome secondary to intrauterine opioid exposure. J Pediatr. 2014;165(3):440-6.
5. Dryden C, Young D, Hepburn M, et al. Maternal methadone use in pregnancy: factors
associated with the development of neonatal abstinence syndrome and implications for
healthcare resources. BJOG. 2009;116:665-71.
6. Pritham UA, Paul JA, Hayes MJ. Opioid dependency in pregnancy and length of stay
for neonatal abstinence syndrome. JOGNN. 2012;41:180-90.
7. Hudak ML, Tan RC. Neonatal drug withdrawal. Pediatrics. 2012;129(2):e540-60.
8. Brogly SB, Saia KA, Walley AY, et al. Prenatal buprenorphine versus methadone
exposure and neonatal outcomes: systematic review and meta-analysis. Am J Epidemiol.
2014;180(7):673-86.
9. Jones HE, Harrow C, O’Grady KE, et al. Neonatal abstinence syndrome after metha-
done or buprenorphine exposure. N Engl J Med. 2010;363(24):2320-31.
10. Gaalema DE, Scott TL, Heil SH, et al. Differences in the profile of neonatal absti-
nence syndrome signs in methadone-versus buprenorphine-exposed neonates. Addic-
tion. 2012;107(Suppl 1):53-62.
11. Shainker SA, Saia K, Lee-Parritz A. Opioid addiction in pregnancy. Obstet Gynecol
Surv. 2012;67(12):817-25.
12. Committee Opinion: ACOG and ASAM. Opioid abuse, dependence, and addiction in
pregnancy. Committee Opinion Number 524. American College of Obstetricians and
Gynecologists. Obstet Gynecol. 2012;119:1070-6.
13. Osborn DA, Jeffery HE, Cole MJ. Opiate treatment for opiate withdrawal in newborn
infants. Cochrane Database Sys Rev. 2010;Oct 6(10):CD002059.
14. Agthe AG, Kim GR, Mathias KB, et al. Clonidine as an adjunct therapy to opi-
oids for neonatal abstinence syndrome: a randomized controlled trial. Pediatrics.
2009;123(5):e849-56.
15. Leikin JB, Mackendrick WP, Maloney GE, et al. Use of clonidine in the prevention
and management of neonatal abstinence syndrome. Clin Toxicol. 2009;47:551-5.
16. Broome L, Tsz-Yin S. Neonatal abstinence syndrome: the use of clonidine as a treat-
ment option. NeoReviews. 2011;12:e575-84.
Neonatal Abstinence Syndrome 63

17. Kraft WK, Gibson E, Dysart K, et al. Sublingual buprenorphine for treatment of neo-
natal abstinence syndrome: a randomized controlled trial. Pediatrics. 2008;122:e601-7.
18. Abdel-Latif ME, Pinner J, Clews S, et al. Effects of breast milk on the severity and
outcome of neonatal abstinence syndrome among infants of drug-dependent mothers.
Pediatrics. 2006;117(6):e1163-9.
19. Jansson LM, Choo R, Velez ML, et al. Methadone maintenance and breastfeeding in
the neonatal period. Pediatrics. 2008;121(1):106-14.
20. Hale TW. Medications and Mothers’ Milk. 15th ed. Amarillo, TX: Hale Publishing;
2012.
21. Malpas TJ, Darlow BA. Neonatal abstinence syndrome following abrupt cessation
of breastfeeding. NZ Med J. 1999;112:12-3.
22. The Academy of Breastfeeding Medicine Protocol Committee. ABM Clinical Protocol
#21: Guidelines for breastfeeding and substance use or substance use disorder, revised
2015. Breastfeed Med. 2015;10(3):135-41.
23. Maguire D. Drug addiction in pregnancy: disease not moral failure. Neonatal Netw.
2014;33(1):11-8.
24. American College of Obstetricians and Gynecologists. Substance abuse reporting and
pregnancy: the role of the obstetrician-gynecologist. Committee Opinion No. 473.
Obstet Gynecol. 2011;117:200-1.

Suggested Readings
Hudak ML, Tan RC; Committee on Drugs, Committee on Fetus and Newborn; American
Academy of Pediatrics. Neonatal drug withdrawal. AAP Policy Statement on NAS.
Pediatrics. 2012;129(2):e540-60.
Shainker SA, Saia K, Lee-Parritz A. Opioid addiction in pregnancy. Obstet Gynecol Surv.
2012;67(12):817-25.
The Academy of Breastfeeding Medicine Protocol Committee. ABM Clinical Protocol #21:
Guidelines for breastfeeding and substance use or substance use disorder, revised 2015.
Breastfeed Med. 2015;10(3):135-41.
6
Apnea of Prematurity

John Brock Harris, PharmD, BCPS

Introduction

A
pnea is defined as pauses in breathing
for 5 to 10 seconds and is often
pathologic after pauses of
20 seconds or greater.1 The American Acade-
my of Pediatrics defines apnea of prematurity
(AOP) as a “cessation of breathing for at least
20 seconds or as a briefer episode of apnea
associated with bradycardia, cyanosis, or
pallor.”2 AOP treatment is required to prevent
short- and long-term adverse outcomes.

Epidemiology
Young gestational age and extremely low
birth weight neonates have increased
66 NICU Primer for Pharmacists

incidences of AOP. Seven percent of neonates born at 34 weeks gestation


or older and 80% of neonates with a birth weight under 1 kilogram (kg)
experience apnea.3,4 Apnea may be classified as obstructive, central, or mixed.
Mixed apnea represents greater than 50% of episodes followed by central
and obstructive apneas.5

Pathophysiology
Obstructive apnea is related to decreased airflow with functioning breathing
mechanics (chest wall motion). Central apnea is related to decreased stimula-
tion from the central nervous system (CNS) to the respiratory musculature.
Both airflow and breathing mechanics are deficient in central apnea. Mixed
apnea has components of both obstructive and central apneas. Obstructive
apnea typically results from pharyngeal collapse caused by either upper
airway muscle inability to maintain patency of airway or negative pressures
produced during inhalation.6 The obstruction location may also be in the
larynx or a combination of the pharynx and larynx. Central apnea is directly
correlated with brainstem maturity; specifically, it is related to functional
maturity based on delayed neuronal conduction and not anatomic maturity.7
The more immature a neonate’s brainstem, the more likely the patient will
experience central apnea. The brainstem respiratory center in early gesta-
tional age neonates also has a decreased response to carbon dioxide, leading
to apnea instead of hyperventilation as in older patients.6
AOP consists of pauses in respiratory airflow for 5 to more than 20
seconds. After 20 seconds of apnea, neonates become hypoxemic. This leads
to the patient becoming cyanotic and bradycardic. Airflow pauses greater
than 30 seconds lead to hypotonia and pallor. AOP usually resolves by 36
weeks’ postconception.6

Presentation
Experts recommend that neonates younger than 35 weeks’ gestation should
be monitored during the first 7 days of life for AOP.8 Within the first 48
hours of life, premature neonates with no mechanical respiratory support
commonly present with apneic episodes. Neonates who require mechanical
support may not experience apneic episodes until after support has been
weaned or discontinued.9 Patients requiring no mechanical support who
have delayed episodes of apnea after the first 7 days of life or experience
Apnea of Prematurity 67

new-onset apnea episodes 7 days after a previous episode require evalua-


tion for other causes of apnea including anemia, infection, and electrolyte
disturbances.10

Diagnosis
AOP is a diagnosis of exclusion. All causes of apnea in a neonate should be
evaluated prior to initiating treatment therapies. Potential causes of apnea
are provided in Table 6-1. Physical assessment, laboratory monitoring, and
patient history should be evaluated to rule out secondary causes of apnea.
❖❖ Physical assessment includes
●● temperature
●● respiratory evaluation
❖❖ Laboratory monitoring includes
●● complete blood cell count (white blood cells with differential, red
blood cells, and platelets) assessing for potential infectious or anemic
causes
●● metabolic panels (electrolytes and glucose) evaluating potential meta-
bolic disorders and arterial blood gases evaluating oxygenation
status11-13
❖❖ Patient and maternal histories provide information on possible medica-
tion exposures and infection risks.

Table 6-1. Causes of Apnea in Neonates


Anemia AOP
Gastroesophageal reflux Hypoxemia
Infection (meningitis, sepsis) Intracranial hemorrhage
Maternal medications (magnesium Metabolic disorders (electrolytes,
sulfate, opioids) hypoglycemia)
Neonatal medications (anesthesia, Perinatal asphyxia
opioids)
Seizures Temperature instability
AOP: Apnea of prematurity
See references 11–13 for more information.
68 NICU Primer for Pharmacists

Goals of Therapy
Limiting or eliminating apnea episodes lasting over 20 seconds or episodes
resulting in bradycardia or cyanosis is the principal goal of therapy when
treating AOP. Treatment, either nonpharmacologic or pharmacologic, is
required with increased frequency and prolonged apnea episodes or episodes
that result in bradycardia or hypoxemia.14 Typically, both treatment modali-
ties are used in combination to achieve therapeutic goals.

Treatment Therapies
Nonpharmacologic Treatments
Nonpharmacologic treatments are often initiated prior to starting or in
combination with pharmacologic options. Nonpharmacologic treatment
options include manual stimulation, airway patency maintenance, red blood
cell transfusions, supplemental oxygen therapy, and respiratory support.
Manual stimulation is a first step used by a member of the healthcare
team when a neonate is experiencing an acute apneic event. The neonate is
stimulated by the healthcare team member rubbing on the neonate’s chest,
back, or extremities prompting spontaneous breathing.
Airway patency can be compromised by neonatal patient positioning
and instrumentation. Neck positioning may lead to obstruction of the
airway. Limiting extension and flexion of the neck decreases risk of apnea
due to obstruction.8 Instrumentation may also obstruct the airway, leading
to apneic episodes. Nasogastric tubes may hinder airflow.
Hypoxemia is a cause of apnea. Decreasing hypoxemia decreases risk of
apnea. Two options to reduce hypoxemia are transfusing red blood cells to
increase the neonate’s ability to deliver oxygen to the body and providing
supplemental oxygen to increase the oxygen saturation. Both nonpharma-
cologic options preventing hypoxemia have potential risks resulting in other
neonatal conditions, such as retinopathy of prematurity and necrotizing
enterocolitis. (See Chapters 1 and 13 for discussions.) Blood transfusions in
moderately anemic neonates did not decrease duration, severity, or frequency
of apnea episodes.15 Oxygen saturation goals for neonates at risk for retinop-
athy of prematurity, including neonates with AOP, remain unclear. Supple-
mental oxygen may not exacerbate threshold retinopathy of prematurity.16
Respiratory ventilation support such as continuous positive airway
pressure (CPAP) helps with obstructive components of apnea by splinting
Apnea of Prematurity 69

the upper airway open to maintain patency.17 CPAP also increases function-
al residual capacity, prolonging time from apnea to desaturations, and
ultimately time to bradycardia.7 When neonates continue to experience
apneic episodes after CPAP and pharmacologic therapy maximization,
endotracheal intubation may be required to limit episodes.8

Pharmacologic Treatments
For over 25 years the pharmacologic treatment class of choice is methyl-
xanthines—aminophylline, caffeine, and theophylline. Efficacy is similar
between the three agents.18,19 Caffeine is the medication of choice in practice
due to a favorable adverse event profile, wide therapeutic index, and admin-
istration advantages.20,21

Mechanism of Action
The complete mechanism of action of methylxanthines in AOP is unclear.
Methylxanthines inhibit phosphodiesterase (PDE) and adenosine. Although
nonselective, weak inhibition of PDE, cyclic adenosine monophosphate,
and cyclic guanosine monophosphate cellular concentrations increase which
result in pulmonary smooth muscle relaxation. Adenosine depresses respi-
ratory drive. Antagonism of adenosine receptors in the respiratory center
within the brainstem increases respiratory drive.22
Methylxanthines stimulate the CNS, specifically the respiratory center,
improve diaphragmatic contraction force, and increase carbon dioxide
sensitivity.5 Other effects include decreasing peripheral vascular resistance,
increasing cardiac output, and increasing heart rate.23

Dosing Strategies
Theophylline
Theophylline is available as an 80 mg per 15 mL (5.3 mg/mL) immediate
release enteral (PO) solution and 0.8 mg/mL and 1.6 mg/mL concentration
intravenous (IV) premixed solutions.24 Loading dosing for the immediate
release oral solution is 5 to 6 mg/kg once followed by maintenance dosing of
2 to 6 mg/kg/day divided 2 to 3 times per day.21,24,25
Interpatient variability impacts theophylline dosing. Metabolism and
renal function vary as neonates age. Cytochrome P450 isoenzyme matura-
tion (specifically 1A2) increases metabolism of theophylline and improve-
70 NICU Primer for Pharmacists

ments in renal function clear theophylline quicker. As neonates age, devel-


opmental changes contribute to the variability in dosing and the extensive
monitoring required when using theophylline for AOP. Patient age—gesta-
tional, post-natal, or postconceptual—may impact theophylline dosing
independently or in combination. Equations have been derived attempting
to account for the age dependency of theophylline dosing, targeting plasma
concentrations between 5 to 12 mg/liter (L).26,27
Theophylline has known drug interactions. One drug interaction
in neonates treated with theophylline for AOP and phenobarbital for a
seizure disorder is documented due to cytochrome P450 isoenzyme induc-
tion. Theophylline dosing may require an increase due to induction of
cytochrome P450 isoenzyme 1A2 to maintain therapeutic plasma concen-
trations.28

Caffeine
Caffeine is the preferred agent for pharmacologic AOP treatment due to
once daily dosing, a wide therapeutic index, and a favorable adverse event
profile.21 Caffeine is available as a manufactured citrate salt product in both
IV and PO formulations. IV and PO caffeine citrate products are available
as branded or generic 60-mg (20 mg/mL) vials. Caffeine may be dosed
as the salt or as the caffeine base. The caffeine base is 50% of salt dosing.
Recommended dosing for caffeine administration, IV or PO, is 20 to
40 mg/kg caffeine citrate (10 to 20 mg/kg caffeine base) once as a loading
dose followed by maintenance dosing of 5 to 10 mg/kg caffeine citrate
(2.5 to 5 mg/kg caffeine base) daily.24,29-33 Both higher (5 mg/kg caffeine
base) and lower maintenance doses (2.5 mg/kg caffeine base) decreased
apneic episodes. However, neonates in the lower maintenance dosing group
experienced fewer gastrointestinal issues and less tachycardia.33 Resolu-
tion of apneic episodes was experienced with higher maintenance doses of
caffeine.31

Monitoring
Plasma concentration monitoring provides information on effectiveness of
pharmacologic treatment with methylxanthines.21 The therapeutic plasma
concentrations of theophylline and caffeine are 6 to 12 mg/L and 8 to
20 mg/L, respectively. Theophylline has a narrow therapeutic window with
a threshold of toxicity above 15 mg/L. Due the narrow therapeutic window,
Apnea of Prematurity 71

plasma concentrations of theophylline are required after initiation, dose


modifications, addition of cytochrome P450 inhibitors or inducers, and
periodically during maintenance dosing to ensure therapeutic concentra-
tions and limit risk of medication-related adverse events. In contrast to
theophylline, caffeine’s therapeutic window is wide with toxicities at plasma
concentrations greater than 50 mg/L. Due to this wide window, therapeutic
drug monitoring is not necessary for all neonates.34 If a neonate continues to
experience apneic episodes or suspected toxicity, obtaining a caffeine plasma
concentration may be warranted.
Cardiorespiratory monitoring including heart rate, cardiac rhythm,
respiratory rate, and oxygen saturation is imperative when assessing AOP
especially with methylxanthine administration. Continuous monitoring is
often performed. Sustained tachycardia may require methylxanthine dose
adjustment or omission.

Duration of Treatment
AOP resolution normally occurs between 36 to 40 weeks’ postconceptual
age. Some neonates, especially younger gestational age patients, may require
longer courses of treatment.7 Resolution may exceed term postconceptual
age in neonates born between 24 and 28 weeks’ gestation.35 In anticipation
of discharge, treatment may be discontinued at earlier gestational ages. To
ensure resolution of AOP, neonates may be observed 5 to 7 days off treat-
ment due to medication prolonged half-lives in preterm neonates.

Adverse Drug Events


Methylxanthine toxicity may include irritability, feeding intolerance,
cardiac arrhythmias, tachycardia, gastroesophageal reflux, tachypnea, and
seizures.7,36-40 Methylxanthines may also increase energy consumption by
increasing metabolic rates.5,7,41 Neonates may experience a mild diuresis
while on methylxanthine therapy.5,7
When treating AOP, theophylline has illustrated short-term positive
outcomes.42-44 Theophylline may lead to long-term adverse events. Neonates
with a birth weight of 1.5 kg or less have increased incidence of cerebral
palsy compared to patients not treated with methylxanthines.45 Caffeine,
however, has proven both short- and long-term positive outcomes when
used to treat AOP. Neonates with birth weights between 0.5 and 1.25 kg
72 NICU Primer for Pharmacists

were randomized to caffeine of placebo until no longer required for AOP.


Bronchopulmonary dysplasia, a short-term outcome, was decreased in
the treatment group at discharge.46 At 18 to 21 months of age, the same
patient population was assessed for long-term outcomes. Neonates in the
treatment group had increased survival without neurodevelopmental delays
or disabilities.47

Conclusion
Multiple factors contribute to apnea experienced by preterm neonates. AOP
may be treated with both nonpharmacologic and pharmacologic modal-
ities, often in combination. The pharmacologic medication of choice is
caffeine citrate with its proven benefits in administration and dosing strat-
egies, adverse event profile, and short- and long-term outcomes. In AOP,
the pharmacist’s role is to optimize treatment regimens by monitoring for
efficacy, interactions, and adverse events as well as recommending regimen
adjustments when warranted.

References
1. Perlstein PH, Edwards NK, Sutherland JM. Apnea in premature infants and
incubator-air-temperature changes. N Engl J Med. 1970;282(9):461-6.
2. American Academy of Pediatrics Task Force on Prolonged Infantile Apnea. Prolonged
infantile apnea: 1985. Pediatrics. 1985;76(1):129-31.
3. Henderson-Smart DJ. The effect of gestational age on the incidence and duration of
recurrent apnoea in newborn babies. Aust Paediatr J. 1981;17(4):273-6.
4. Alden ER, Mandelkorn T, Woodrum DE, et al. Morbidity and mortality of infants
weighing less than 1,000 grams in an intensive care nursery. Pediatrics. 1972;50(1):40-
9.
5. Gauda EB, Martin RJ. Control of breathing. In: Gleason CA, Devaskar SU, eds. 
Avery’s Diseases of the Newborn. 9th ed. Philadelphia, PA: Elsevier; 2012:594-7.
6. Carlo WP. Apnea. In: Kliegman RM, Stanton BF, St. Geme JW III, et al., eds. Nelson
Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier; 2011:580-1.
7. Abu-Shaweesh JM. Respiratory disorders in preterm and term infants. In: Martin RJ,
Fanaroff AA, Walsh MC, eds. Fanaroff and Martin’s Neonatal–Perinatal Medicine;
Diseases of the Fetus and Infant. 9th ed. St. Louis, MO: Elsevier; 2011:1144-50.
8. Stark AR. Apnea. In: Cloherty JP, Eichenwald EC, Hansen AR, et al., eds. Manual of
Neonatal Care. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012:369-
73.
Apnea of Prematurity 73

9. Carlo WA, Martin RJ, Versteegh FG, et al. The effect of respiratory distress syndrome
on chest wall movements and respiratory pauses in preterm infants. Am Rev Respir Dis.
1982;126(1):103-7.
10. Hofstetter AO, Legnevall L, Herlenius E, et al. Cardiorespiratory development in
extremely preterm infants: vulnerability to infection and persistence of events beyond
term-equivalent. Acta Paediatr. 2008;97(3):285-92.
11. Rosenberg AA, Grover T. The newborn infant. In: Hay WW Jr, Levin MJ, Deterding
RR, et al., eds. CURRENT Diagnosis & Treatment: Pediatrics. 22nd ed. New
York, NY: McGraw-Hill; 2013. http://accessmedicine.mhmedical.com/content.
aspx?bookid=1016&Sectionid=61592149. Accessed January 2, 2015.
12. Martin RJ, Miller MJ, Carlo WA. Pathogenesis of apnea of preterm infants. J Pediatr.
1986;109(5):733-41.
13. Green M. Pediatric Diagnosis. 5th ed. Philadelphia, PA: WB Saunders; 1992:356-7.
14. Lawson EE. Nonpharmacologic management of idiopathic apnea of the premature
infant. In: Matthew OP, ed. Respiratory Control and Disorders in the Newborn.
New York, NY: Marcel Dekker; 2003:335-54.
15. Poets CF, Pauls U, Bohnhorst B. Effect of blood transfusions on apnoea, bradycardia,
and hypoxaemia in preterm infants. Eur J Pediatr. 1997;156(4):311-6.
16. The STOP-ROP Multicenter Study Group. Supplemental therapeutic oxygen of pre-
threshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I:
primary outcomes. Pediatrics. 2000;105(2):295-310.
17. Miller MJ, Carlo WA, Martin RJ. Continuous positive airway pressure selectively
reduces obstructive apnea in preterm infants. J Pediatr. 1985;106(1):91-4.
18. Bairam A, Boutroy MJ, Badonnel Y, et al. Theophylline versus caffeine: com-
parative effects in treatment of idiopathic apnea in the preterm infant. J Pediatr.
1987;110(4):636-9.
19. Brouard C, Moriette G, Murat I, et al. Comparative efficacy of theophylline and
caffeine in the treatment of idiopathic apnea in premature infants. Am J Dis Child.
1985;139(7):698-700.
20. Henderson-Smart DJ, De Paoli AG. Methylxanthine treatment for apnoea in preterm
infants. Cochrane Database Syst Rev. 2010;12:CD000140.
21. Bhatt-Mehta V, Schumacher RE. Treatment of apnea of prematurity. Paediatr Drugs.
2003;5(3):195-210.
22. Barnes PJ.  Pulmonary pharmacology. In: Brunton LL, Chabner BA, Knollmann
BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New
York, NY: McGraw-Hill; 2011. http://accesspharmacy.mhmedical.com/content.aspx?-
bookid=374&Sectionid=41266244. Accessed January 2, 2015.
23. Natarajan G, Lulic-Botica M, Aranda JV. Pharmacology review: Clinical pharmaco-
logic of caffeine in the newborn. NeoReviews. 2007;8(5):e214-21.
74 NICU Primer for Pharmacists

24. Taketomo CK, Hodding JH, Kraus DM. Pediatric & Neonatal Dosage Handbook. 21st
ed. Hudson, OH: Lexicomp; 2014.
25. Skouroliakou M, Bacopoulou F, Markantonis SL. Caffeine versus theophylline for
apnea of prematurity: a randomized controlled trial. J Paediatr Child Health.
2009;45(10):587-92.
26. Bhatt-Mehta V, Donn SM, Schork MA, et al. Prospective evaluation of two dosing
equations for theophylline in premature infants. Pharmacotherapy. 1996;16(5):769-76.
27. Hogue SL, Phelps SJ. Evaluation of three theophylline dosing equations for use in
infants up to one year of age. J Pediatr. 1993;123(4):651-6.
28. Yazdani M, Kissling GE, Tran TH, et al. Phenobarbital increases the theophyl-
line requirement of remature infants being treated for apnea. Am J Dis Child.
1987;141(1):97-9.
29. Erenberg A, Leff RD, Haack DG, et al. Caffeine citrate for the treatment of apnea of
prematurity: a double-blinded, placebo-controlled study. Pharmacotherapy.
2000;20(6):644-52.
30. Aranda JV, Gorman W, Bergsteinsson H, et al. Efficacy of caffeine in treatment of
apnea in the low-birth-weight infant. J Pediatr. 1977;90(3):467-72.
31. Anwar M, Mondestin H, Mojica N, et al. Effect of caffeine on pneumogram and
apnoea of infancy. Arch Dis Child. 1986;61(9):891-5.
32. Murat I, Moriette G, Blin MC, et al. The efficacy of caffeine in the treatment of recur-
rent idiopathic apnea in premature infants. J Pediatr. 1981;99(6):984-9.
33. Romagnoli C, De Carolis MP, Muzii U, et al. Effectiveness and side effects of two
different doses of caffeine in preventing apnea in premature infants. Ther Drug Monit.
1992;14(1):14-9.
34. Natarajan G, Botica ML, Thomas R, et al. Therapeutic drug monitoring for caffeine in
preterm neonates: an unnecessary exercise? Pediatrics. 2007;119(5):936-40.
35. Eichenwald EC, Aina A, Stark AR. Apnea frequently persists beyond term gestation in
infants delivers at 24 to 28 weeks. Pediatrics. 1997;100(3 pt 1):354-9.
36. Kulkarni PB, Dorand RD. Caffeine toxicity in a neonate. Pediatrics. 1979;64(2):254-5.
37. van den Anker JN, Jongejan HT, Sauer PJ. Severe caffeine intoxication in a preterm
neonate. Eur J Pediatrics. 1992;151(6):466-7.
38. American Academy of Pediatrics Committee on Drugs. Precautions concerning the use
of theophylline. Pediatrics. 1992;89(4 Pt 2):781-3.
39. Vandenplas Y, De Wolf D, Sacre L. Influence of xanthines on gastroesophageal reflux
in infants at risk for sudden infant death syndrome. Pediatrics. 1986;77(6):807-10.
40. Banner W Jr, Czajka PA. Acute caffeine overdose in the neonate. Am J Dis Child.
1980;134(5):495-8.
41. Carnielli VP, Verlato G, Benini F, et al. Metabolic and respiratory effects of theophyl-
line in the preterm infant. Arch Dis Child Fetal Neonatal Ed. 2000;83(1):f39-43.
Apnea of Prematurity 75

42. Shannon DC, Gotay F, Stein IM, et al. Prevention of apnea and bradycardia in
low-birthweight infants. Pediatrics. 1975;55(5):589-94.
43. Uauy R, Shapiro DL, Smith B, et al. Treatment of severe apnea in prematures with
orally administered theophylline. Pediatrics. 1975;55(5):595-8.
44. Sims ME, Yau G, Rambhatla S, et al. Limitations of theophylline in the treatment of
apnea of prematurity. Am J Dis Child. 1985;139(6):567-70.
45. Davis PG, Doyle LW, Rickards AL, et al. Methylxanthines and sensorineural outcome
at 14 years in children <1501 g birthweight. J Paediatr Child Health. 2000;36(1):47-50.
46. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N
Engl J Med. 2006;354(20):2112-21.
47. Schmidt B, Roberts RS, Davis P, et al. Long-term effects of caffeine therapy for apnea
of prematurity. N Engl J Med. 2007;357(19):1893-902.

Suggested Readings
Bhatt-Mehta V, Schumacher RE. Treatment of apnea of prematurity. Paediatr Drugs.
2003;5(3):195-210.
Dinh KL. Apnea of prematurity. In: Benavides S, Nahata MC, eds. Pediatric Pharmacother-
apy. Lenexa, KS: American College of Clinical Pharmacy; 2013:190-7.
Erenberg A, Leff RD, Haack DG, et al. Caffeine citrate for the treatment of apnea
of prematurity: a double-blinded, placebo-controlled study. Pharmacotherapy.
2000;20(6):644-52.
Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J
Med. 2006;354(20):2112-21.
Schmidt B, Roberts RS, Davis P, et al. Long-term effects of caffeine therapy for apnea of
prematurity. N Engl J Med. 2007;357(19):1893-902.
7
Respiratory Distress
Syndrome and
Bronchopulmonary
Dysplasia
Julia Lau, PharmD, BCPS

Respiratory Distress Syndrome


Introduction

H
ave you ever blown up a
balloon? The first couple of
breaths are especially challeng-
ing because the insides of new balloons
are often sticky. In newborn lungs, the
alveoli are similar to new balloons. In
term, healthy infants, the alveoli are
coated by pulmonary surfactant that
reduces surface tension and allows the
alveoli to expand as air flows into the
lungs. The primary cause of respiratory
distress syndrome (RDS) is inadequate
pulmonary surfactant that leads to
78 NICU Primer for Pharmacists

diffuse alveolar atelectasis, edema, and cell injury. The production of pulmo-
nary surfactant begins at 22 weeks’ gestation, and the fetal lungs mature
at 35 weeks. Prematurity is the most common cause of RDS. Despite the
improvement in perinatal and neonatal care, RDS remains a significant
cause of morbidity and mortality in premature infants and especially the
extremely premature group.1,2

Epidemiology and Risk Factors of RDS


Approximately 10% of premature infants in the United States develop RDS
every year.3 The highest incidence occurs in the most premature infants. In
infants born before 29 weeks’ gestation, the chance of developing RDS is
60%.4 Maternal risk factors include poor prenatal care, being uninsured,
poverty, being a member of a minority group, history of a preterm birth, low
maternal body mass, and periodontal disease. Maternal diabetes affects lung
development and increases the risk of RDS.5 Some thoracic malformations,
such as congenital diaphragmatic hernia, cause lung hypoplasia and can
increase the risk of RDS.
Prematurity is the most significant risk factor for RDS. Perinatal
asphyxia may acutely impair surfactant production, increasing the risk of
RDS. During the labor process, adrenergic and steroid hormone release
promotes surfactant release. Cesarean section without labor, therefore, can
increase the risk of RDS in term and late preterm infants. Among preterm
infants, the RDS risk also increases with male gender and Caucasian race.
Very rarely, genetic disorders of surfactant production and metabolism
cause RDS-like symptoms in term infants. Examples of these disorders
include surfactant protein B and surfactant protein C mutations as well as
mutations of the ABCA3 gene, which affects alveolar cells. These disorders
are usually fatal without lung transplantation.6

Pathophysiology of RDS
Surfactant Deficiency
The primary cause of RDS is pulmonary surfactant deficiency. Surfactant is
essential for alveoli to overcome surface tension and stay open, allowing gas
exchange to occur. Lacking surfactant and being structurally immature,
the premature neonatal lung has decreased compliance and a higher risk of
atelectasis.6
Respiratory Distress Syndrome and Bronchopulmonary Dysplasia 79

Hypoxemia, Hypercarbia, and Lactic Acidosis


The ventilation/perfusion (V/Q) mismatch seen with atelectasis is a result of
well perfused but poorly ventilated areas of the lung. V/Q mismatch causes
hypoxemia and hypercarbia. Severe hypoxemia and systemic hypoperfusion
lead to decreased oxygen delivery, anaerobic metabolism, and subsequent
respiratory and metabolic lactic acidosis.

Pulmonary Vasoconstriction
Hypoxemia and lactic acidosis may cause pulmonary vasoconstriction and
right-to-left shunting through the foramen ovale and ductus arteriosus,
further impairing oxygenation.

Oxygen Damage, Barotrauma, and Volutrauma


With atelectasis, pressure exerted trying to open the alveoli can rupture
the alveoli causing further damage to the lung tissue. A high fraction of
inspired oxygen may also injure the lung tissue because oxygen is a free
radical. These damages may initiate release of inflammatory cytokines and
chemokines, worsening the endothelial and epithelial cell injury. The injury
reduces surfactant synthesis and increases endothelial permeability, resulting
in pulmonary edema. The increased endothelial permeability also allows
leakage of protein into the alveolar space, inactivating surfactant and further
exacerbating surfactant deficiency.

Clinical Presentation of RDS


A premature infant with RDS shows clinical signs soon after birth. The
classic signs include tachypnea, intracostal and subcostal retractions, nasal
flaring, grunting, and cyanosis in room air.7

Management of RDS
The goals of RDS management are
❖❖ avoiding hypoxemia and acidosis
❖❖ minimizing lung injury from volutrauma and oxygen toxicity
❖❖ optimizing fluid management—to prevent hypovolemia and hypoten-
sion without overloading with fluid
❖❖ reducing metabolic demands and maximizing nutrition
80 NICU Primer for Pharmacists

Some important advances in preventing and treating RDS are antenatal


corticosteroids, surfactant replacement therapy, continuous positive airway
pressure, and positive end-expiratory pressure. This chapter will focus on the
pharmacologic interventions.

Antenatal Corticosteroids
Antenatal corticosteroids accelerate maturation of the fetal lung and other
fetal tissues, reducing the risk of RDS, intraventricular hemorrhage, and
necrotizing enterocolitis. Corticosteroids also induce surfactant production.
Antenatal corticosteroids should be given to pregnant women at 24 to 36
weeks’ gestation who are at risk for preterm delivery within 7 days. Antena-
tal corticosteroids can be given to pregnant women with intact or ruptured
membranes as long as they do not have chorioamnionitis, which is a contra-
indication to antenatal corticosteroids. A full course of antenatal cortico-
steroids consists of betamethasone 12 mg via intramuscular (IM) injection
every 24 hours for two doses or dexamethasone 6 mg IM every 12 hours for
four doses.7 Women in preterm labor may not always be able to complete
the full treatment course, but an incomplete course may still be beneficial.7
The efficacy of antenatal corticosteroids at gestational age under 24 weeks
is unknown, but antenatal corticosteroids in this population may still be
justified if the therapy benefits are believed to outweigh risks.

Surfactant Replacement Therapy


Surfactant replacement therapy was a significant advancement in the care of
infants with RDS. Since the introduction of surfactant replacement therapy,
the mortality rate from RDS has significantly declined from about 25,000
deaths each year in the 1960s to 860 deaths in 2005.8 Surfactant replace-
ment therapy is one of the most well-studied drug therapies in neonates
and has consistently been shown to benefit infants with RDS. Studies
with surfactant replacement therapy generally show improved oxygenation
and decreased ventilation support. Many studies also showed decreased
incidence of air leak syndrome and death.
Surfactant can be given to infants with high risk for RDS soon after
birth prophylactically before lung injury occurs. Compared to “rescue”
surfactant, prophylactic surfactant improves air distribution and reduces
lung injury. An “early rescue” treatment given within 2 hours of birth is also
proven to be beneficial over delayed treatment. The optimal administration
Respiratory Distress Syndrome and Bronchopulmonary Dysplasia 81

time for the first dose of replacement surfactant, whether it is at birth or


within 2 hours after birth, remains to be determined.
Infants with established RDS have been shown to benefit from a
repeated dose of surfactant. These benefits include improvement in
oxygenation and ventilation, decreased risk for pneumothorax, and
increased survival compared to infants who only received one dose of
surfactant. No additional benefit, however, has been observed beyond
three doses of poractant alfa, four doses of calfactant, or four doses of
beractant. Criteria for retreatment vary among neonatologists because
there is no established guideline on when and to whom retreatment should
be given. Very often, the decision to repeat surfactant therapy is made
based on facility-specific criteria or the patient’s clinical status.
Surfactant is administered via an endotracheal tube. Administration
of surfactant via nebulization has not been successful but continues to
be evaluated by ongoing trials. Currently, four products under the brand
names of Survanta, Infasurf, Curosurf, and Surfaxin are available in the U.S.
market. (Refer to Table 7-1 for further dosing information.) During the
administration of surfactant, ventilation needs to be briefly disconnected.
The most common adverse effects are apnea, bradycardia, and desaturation.
Pulmonary hemorrhage, which happens more frequently in extremely low
birth weight infants, is a rare but serious adverse effect of surfactants. Other
risk factors for developing pulmonary hemorrhage with surfactant therapy
include male gender and patent ductus arteriosus.

Long-Term Complications of RDS


Long-term complications of RDS include bronchopulmonary dysplasia
(BPD), neurodevelopmental impairment, retinopathy of prematurity, and
other complications of prematurity. The risk of developing these complica-
tions is inversely proportional to the infant’s gestational age.

Conclusion of RDS
To summarize, RDS is a significant cause of morbidity and mortality in
premature infants. It is primarily caused by surfactant deficiency. Prematu-
rity is the most significant risk factor for RDS. To reduce the risk of RDS,
antenatal corticosteroids should be initiated in women at risk for preterm
labor because they can accelerate lung maturation. The goals of RDS
management are avoiding hypoxemia, minimizing lung injury, and optimiz-
82 NICU Primer for Pharmacists

Table 7-1. Surfactants Available in the United States


Brand Name Survanta9 Infasurf10 Curosurf11 Surfaxin12
Generic Name Beractant Calfactant Poractant alfa Lucinactant
Source Bovine lung Calf lung Porcine lung Synthetic
extract lavage fluid extract
Dosing 4 mL/kg 3 mL/kg 2.5 mL/kg 5.8 mL/kg
through ET through ET through ET through ET
tube tube for tube tube
prophylaxis
Prophylaxis: and rescue Subsequent Subsequent
give within therapy doses doses: up to
15 minutes 1.25 mL/kg up four doses
of birth Up to three to two doses; can be given
doses at give at least in the first
Rescue therapy: least 12 hours apart 48 hours of
give when 12 hours life; doses
diagnosis of apart should be
surfactant given at
deficiency is least 6 hours
made apart

Up to four
doses at least
6 hours apart
Phospholipid 25 mg/mL 35 mg/mL 76 mg/mL 30 mg/mL
concentration
Protein <1 mg/mL 0.7 mg/mL 1 mg/mL SP-B —
concentration SP-B and SP-C SP-B and and SP-C
SP-C
Refrigeration Yes Yes Yes No
Reconstitution No No No No
ET: endotracheal; SP-B: surfactant protein B; SP-C: surfactant protein C
Respiratory Distress Syndrome and Bronchopulmonary Dysplasia 83

ing fluid management and nutritional support. Surfactant replacement


therapy has well documented benefits in neonates with RDS and should be
given soon after birth in neonates with high risk for RDS. The numerous
long-term complications of RDS include BPD.

Bronchopulmonary Dysplasia
Introduction
BPD, also known as chronic lung disease of prematurity, is a long-term
complication of RDS and the most common chronic lung disease of child-
hood. BPD is a result of the oxygen and mechanical ventilation required in
managing severe RDS in premature infants.13 It is an important cause of respi-
ratory illness in preterm infants and has a high morbidity and mortality rate.

Definition of BPD
The presence and severity of BPD is defined by a set of criteria released
by the National Institute of Child Health and Human Development
(NICHHD).14,15 According to the NICHHD, an infant has BPD if he

Table 7-2. Diagnosis of BPD14


Gestational Age Gestational Age
<32 weeks ≥32 weeks
Time of assessment 36 weeks PMA or on dis- >28 days but <56 days
charge, whichever comes PNA or on discharge,
first whichever comes first
Infant has BPD if Oxygen treatment >21% for at least 28 days
Mild BPD Room air at 36 weeks PMA Room air by 56 days PNA
or on discharge, whichever or on discharge, which-
comes first ever comes first
Moderate BPD <30% oxygen at 36 weeks <30% oxygen at 56 days
PMA or on discharge, PNA or on discharge,
whichever comes first whichever comes first
Severe BPD ≥30% oxygen and/or pos- ≥30% oxygen and/or
itive pressure at 36 weeks positive pressure at 56
PMA or on discharge, days PNA or on dis-
whichever comes first charge, whichever comes
first
BPD: bronchopulmonary dysplasia; PMA: post-menstrual age; PNA: postnatal age
84 NICU Primer for Pharmacists

or she has received treatment with oxygen >21% for at least 28 days. The
NICHHD further stratifies infants with BPD into different risk categories
based on their birth gestational age and oxygen requirement at the time of
assessment (see Table 7-2). These diagnosing criteria help predict the likeli-
hood of BPD survivors requiring pulmonary medication and rehospitaliza-
tion for pulmonary disease. Furthermore, per the NICHHD criteria, infants
with severe BPD also have a higher risk for neurodevelopmental impairment.

Epidemiology and Risk Factors of BPD


In the United States, approximately 15,000 infants develop BPD each year.
Infants with a birth weight of less than 1,250 g are at the highest risk of
developing BPD, accounting for 97% of the cases (see Table 7-3). Increased
severity of BPD was associated with the male gender, race (relatively higher
incidence for Caucasian infants and lower incidence for African American
infants), and decreasing gestational age.

Pathophysiology of BPD
Acute Lung Injury Phase
Injury from mechanical ventilation. The combination of oxygen toxic-
ity, barotrauma, and volutrauma from mechanical ventilation causes acute
lung injury. Interstitial and cellular injuries trigger the release of proinflam-
matory cytokines that recruit inflammatory cells into interstitial and alveolar
spaces and change alveolar permeability.17-19
Inflammation. Proteases, oxidants, additional chemokines, and chemo-
attractants further injure the lung causing an influx of inflammatory cells and
leakage of water and protein. Inflammation may alter pulmonary vascular tone
and interrupt alveolar development, leading to emphysematous changes.17-19

Table 7-3. Incidence of BPD by Birth Weight16


Birth Weight Incidence of BPD
501−750 g 46%
751−1,000 g 33%
1,001−1,250 g 14%
1,251−1,500 g 6%
BPD: bronchopulmonary dysplasia
Respiratory Distress Syndrome and Bronchopulmonary Dysplasia 85

Peripheral airway obstruction. Sloughed cells and excessive secretions


from inflammatory process cannot be cleared adequately by the compro-
mised mucociliary transport system, causing inhomogeneous peripheral
airway obstruction. Inhomogeneous peripheral airway obstruction then
leads to alternating areas of collapse and hyperinflation and proximal airway
dilation.17-19

Chronic Lung Injury Phase


Excessive release of growth factors and cytokines result in fibrosis and
cellular hyperplasia. Interstitial fluid clearance is impaired, resulting in
pulmonary fluid retention. Increased muscularization and hyperreactivity
are observed in the airway. The results of these changes are increased airway
resistance, decreased lung compliance, impaired gas exchange with ventila-
tion/perfusion mismatch, and air trapping.

Clinical Presentation of BPD


Infants with BPD typically present with tachypnea, retractions, and rales.
Hypoxemia and hypercarbia are often seen in arterial blood gas analysis,
accompanied by respiratory acidosis and eventually metabolic compen-
sation. Pulmonary structural changes in BPD can also be seen in chest
radiographs.17-19

Management of BPD
The goals of BPD management in the NICU are
❖❖ minimizing O2 consumption
❖❖ minimizing further lung injury from oxygen toxicity, barotrauma, and
volutrauma
❖❖ maximizing nutrition
These goals are achieved through mechanical ventilation, supplemental
oxygen, and pharmacologic treatments.

Pharmacologic Management of BPD


Diuretics
Diuretic therapy reduces interstitial and peribronchial fluid, leading to less
pulmonary resistance and better lung compliance. Although diuretic therapy
improves short-term pulmonary mechanics, evidence is scant on its benefit
86 NICU Primer for Pharmacists

for the long-term outcome of infants with BPD.20 Thiazide diuretics and
loop diuretics are the two classes of diuretics currently used in managing
BPD. Electrolytes of infants receiving diuretics should be monitored because
replacements may be necessary.
Loop diuretics. Furosemide is the loop diuretic most commonly used
and best studied in infants with BPD. If furosemide is initiated intravenously
(IV), it is usually given at a dose of 0.5 to 1 mg/kg IV (or 1 to 2 mg/kg
orally; due to poor bioavailability, the oral dose is usually twice the IV
dose) once or twice daily.20-22 A dose of furosemide may also be given after
blood transfusions to prevent a fluid overload state if the infant requires a
transfusion. The half-life of furosemide is prolonged in premature infants;
therefore, they are at a higher risk for toxicity, especially with higher doses
and increased frequency. Side effects of furosemide include ototoxicity,
hypercalciuria, nephrocalcinosis, nephrolithiasis, and electrolyte imbalance.
Furosemide causes major urinary losses of sodium, potassium, and chloride
so the electrolyte levels should be monitored. Infants who are receiving
other ototoxic or renal toxic medications, such as aminoglycoside, should be
closely monitored for signs and symptoms of toxicity.
Thiazide diuretics. Chlorothiazide is another option in managing BPD.
Because it has a milder adverse effect profile, it is sometimes used in place of
furosemide. A typical dose of chlorothiazide in infants with BPD is 20 to
40 mg/kg/day orally divided twice daily.20-22 The IV route is not recom-
mended due to a lack of data. Similar to furosemide, chlorothiazide causes
electrolyte abnormalities. Electrolytes, particularly calcium and phosphorus,
should be monitored in infants receiving chlorothiazide. Compared to
furosemide, chlorothiazide causes less calcium excretion and, therefore,
reduces the risk for diuretic-induced metabolic bone disease in infants.

Bronchodilators
Acute pulmonary obstructive episodes or chronically increased pulmo-
nary resistance may be a result of bronchospasm or increased airway tone
and may respond to bronchodilator therapy. In particular, older infants
with severe BPD who remain ventilated may experience acute episodes of
bronchoconstriction. Inhaled bronchodilators have been shown to acutely
decrease airway resistance and increase compliance.23,24 There were no signif-
icant benefits, however, in the long-term outcome of BPD.
Respiratory Distress Syndrome and Bronchopulmonary Dysplasia 87

Beta-agonists. Albuterol is usually initiated at a dose of metered dose


inhaler (MDI) one puff every 4 to 6 hours or 0.02 to 0.04 mL/kg (up to
0.1 mL total in 2 mL normal saline solution) of the 0.5% solution
nebulized every 4 to 6 hours.23 In ventilated patients, the MDI is the
preferred dosage form because it can be connected directly to the ventilator.
Tachycardia is the major dose-limiting side effect of albuterol.
Muscarinic agents. Ipratropium MDI one puff or nebulized at
25 mg/kg/dose has been shown to decrease pulmonary resistance but has
not been studied in preterm infants.24 The use of ipratropium is not routinely
recommended for BPD.

Inhaled Corticosteroids
The benefit of inhaled corticosteroid in managing BPD is uncertain.
Inhaled corticosteroid can be considered in selected infants with severe BPD
who are mechanically ventilated and require a high concentration of oxygen.

Outpatient Medications
Diuretics. Patients who are discharged on diuretics should have electro-
lyte monitoring. After the patient is stable, diuretics can be weaned by
letting him or her outgrow the dose. Diuretics can be discontinued when
the dose has been outgrown by approximately 50%.
Bronchodilators. Bronchodilators can be tapered off after respiratory
status is stable in room air.

Prevention Strategies of BPD


Caffeine
Caffeine was shown to reduce the incidence of BPD at doses used to treat
apnea of prematurity. A multicenter trial of 2,006 premature infants were
randomly assigned to receive caffeine or placebo.25 Infants in the caffeine
group all received one loading dose of 20 mg/kg caffeine citrate. A mainte-
nance dose of 5 mg/kg caffeine citrate once daily was then initiated. Clini-
cians could adjust the maintenance dose up to 10 mg/kg caffeine citrate
once daily. Of the infants who received caffeine, 36.3%, compared to 46.9%
of the infants who received placebo (p <0.001), developed BPD (defined as
supplemental oxygen at 36 weeks’ postmenstrual age). The trial’s authors
attributed the difference in incidence to a shorter period of positive pressure
88 NICU Primer for Pharmacists

support observed in the caffeine group. A post-hoc subgroup analysis also


found that the reduction of duration of respiratory support was greater in
infants started on caffeine on or before 3 days of age, compared to 4 and
10 days of age.26 In addition to preventing BPD, caffeine also improved
long-term survival in this trial to a corrected age of 18 to 21 months
without neurodevelopmental disability. The additional benefit makes
caffeine the drug of choice in preventing BPD.

Systemic Corticosteroids
Systemic corticosteroids improve lung mechanics and reduce the need for
ventilation in infants with BPD. However, corticosteroids do not appear to
have any benefits over long-term outcomes of BPD such as length of stay,
duration of oxygen supplementation, and mortality. The short-term side
effects of systemic corticosteroids include hyperglycemia, hypertension,
and spontaneous gastrointestinal (GI) perforation. Long-term studies of
infants who received systemic corticosteroids raised concerns for neuro-
logical sequelae such as cerebral palsy. For these reasons, the American
Academy of Pediatrics and Canadian Paediatric Society both recommend
restricted use of systemic corticosteroids in preterm infants. Systemic corti-
costeroids should be reserved for infants with progressive respiratory failure
that is refractory to all other therapies.27
A short course and low dose of systemic corticosteroid can be used to
potentially reduce ventilator settings and facilitate extubation in infants
at a higher risk of developing BPD. Dexamethasone is the most studied
systemic corticosteroid in BPD prevention. The dosing protocol from
DART (Dexamethasone: A Randomized Trial) is widely utilized in NICUs
across the United States.28 Dexamethasone is administered IV slow push or
orally as follows: 0.075 mg/kg/dose every 12 hours for 3 days;
0.05 mg/kg/dose every 12 hours for 3 days; 0.025 mg/kg/dose every
12 hours for 2 days; and 0.01 mg/kg/dose every 12 hours for 2 days.
The use of low-dose dexamethasone should be restricted to patients with
the highest risk for developing BPD. Because early treatment was associ-
ated with cerebral palsy and neurodevelopmental impairment, treatment
should be started after 7 days of life. Due to the increased risk for GI perfo-
ration, dexamethasone should not be used concurrently with indomethacin.
Blood glucose and blood pressure should be monitored in patients receiving
dexamethasone. If treatment lasts longer than 7 days, an echocardiogram is
Respiratory Distress Syndrome and Bronchopulmonary Dysplasia 89

recommended as cardiac changes have been reported with prolonged use of


dexamethasone. The use of dexamethasone is contraindicated in patients with
systemic infection.27-29

Vitamin A
Vitamin A is essential in growth promotion and regulation of many cells,
including lung cells. Preterm infants have low vitamin A levels at birth. It
has been proposed that vitamin A deficiency may promote the develop-
ment of BPD. A meta-analysis that included nine trials showed vitamin A
supplementation was beneficial in reducing the incidence of BPD (defined
as oxygen requirement at 36 weeks’ postmenstrual age) and death.30 In
the largest of these trials, 807 infants with birth weight less than 1,000 g
were randomized to receive vitamin A 5,000 units IM three times per week
for 4 weeks or a placebo. Compared to the placebo group, the vitamin A
group had a lower incidence of BPD or death (55% versus 62%; p = 0.03).
Vitamin A was well tolerated in this trial. A follow-up study, however, did
not find significant difference between the two groups after discharge in
pulmonary problems, hospitalization rate, mortality, or developmental
impairments. Overall, vitamin A appears to be a safe and effective preventa-
tive strategy for BPD.

Outcomes of BPD
The mortality rate of BPD is estimated to be 10 to 20% in the first year of
life. The most common cause of death is infection, and the risk of death is
increased with duration of both oxygen support and mechanical ventila-
tion. Patients with BPD continue to have signs of compromised pulmonary
function such as tachypnea, cough, wheezing, and retraction months to
years after they leave the NICU. Some of the underlying changes in pulmo-
nary function may persist beyond adolescence. BPD patients are at a higher
risk for reactive airway disease, pneumonia, and bronchiolitis. Within the
first 2 years of life, their rehospitalization rate for respiratory illness is also
twice as high as infants without BPD.

Conclusion of BPD
BPD is an important cause of respiratory illness in preterm infants and has
a high morbidity and mortality. The mainstays of BPD management are
mechanical ventilation, supplemental oxygen, and pharmacologic treat-
90 NICU Primer for Pharmacists

ments. Pharmacologic treatments for BPD have been studied only in small
trials and case reports thus far. Due to the lack of large-scale, randomized,
controlled trials, optimal pharmacologic treatment for BPD remains to be
determined. Because long-term safety data are scarce, patients receiving
these treatments should be monitored closely.

References
1. Hamvas A. Pathophysiology and management of respiratory distress syndrome. In:
Martin RJ, Fanaroff AA, Walsh MC, eds. Farnaoff and Martin’s Neonatal–Perinatal
Medicine: Diseases of the Fetus and Infant. 9th ed. St. Louis, MO: Elsevier Mosby;
2011:1106-16.
2. Goldenberg RL, Culhane JF, Iams JD, et al. Epidemiology and causes of preterm birth.
Lancet. 2008;371:1:75-84.
3. What Is Respiratory Distress Syndrome? Available at: http://www.nhlbi.nih.gov/
health/health-topics/topics/rds. Accessed December 1, 2014.
4. Robertson PA, Sniderman SH, Laros RK Jr, et al. Neonatal morbidity according to
gestational age and birth weight from five tertiary care centers in the United States,
1983 through 1986. Am J Obstet Gynecol. 1992;166:1629-41.
5. Angus DC, Linde-Zwirble WT, Clermont G, et al. Epidemiology of neonatal respi-
ratory failure in the United States: projections from California and New York. Am J
Respir Crit Care Med. 2001;164:1154-60.
6. Nkadi PO, Merritt TA, Pillers DA. An overview of pulmonary surfactant in the neo-
nate: genetics, metabolism, and the role of surfactant in health and disease. Mol Genet
Metab. 2009;97:95-101.
7. Bhakta K. Respiratory distress syndrome. In: Cloherty JP, Eichenwald EC, Hansen AR,
et al., eds. Manual of Neonatal Care. 7th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2011:406-28.
8. Raj JU, Wright JR. Respiratory distress syndrome of the newborn. In: Schraufnagel
DE, ed. Breathing in America: Diseases, Progress, and Hope. New York, NY: The Ameri-
can Thoracic Society; 2010.
9. Survanta [package insert]. AbbVie Inc. North Chicago, IL: December 2012. http://
www.rxabbvie.com/pdf/survanta_pi.pdf. Accessed December 1, 2014.
10. Infasurf [package insert]. Ony Inc. Amherst, NY: June 2011. http://www.onyinc.com/
pdf/infasurfPackageInsert.pdf. Accessed December 1, 2014.
11. Curosurf [package insert]. Chiesi Farmaceutici, S.p.A. Parma, Italy: October 2014.
http://curosurf.com/UI/pdfs/Curosurf_PI.pdf. Accessed December 1, 2014.
12. Surfaxin [package insert]. Discovery Laboratories, Inc. Warrington, PA: October 2012.
http://surfaxin.com/downloads/prescribinginfo.pdf. Accessed December 1, 2014.
Respiratory Distress Syndrome and Bronchopulmonary Dysplasia 91

13. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respiratory
therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med.
1967;276:357.
14. Ehrenkranz RA, Walsh MC, Vohr BR, et al. Validation of the National Insti-
tutes of Health Consensus definition of bronchopulmonary dysplasia. J Perinatol.
2005;116:1353.
15. Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants
from NICHD Neonatal Research Network. Pediatrics. 2010;126:443.
16. Fanaroff AA, Stoll BJ, Wright LL, et al. Trends in neonatal morbidity and mortality for
very low birthweight infants. Am J Obstet Gynecol. 2007;196(147):E1.
17. Baraldi E, Fillippone M. Chronic lung disease after premature birth. N Engl J Med.
2007;357:1946.
18. Bose C, Van Marter LJ, Laughon M, et al. Fetal growth restriction and chronic
lung disease among infants born before the 28th week of gestation. Pediatrics.
2009;124:e450.
19. Keller RL, Ballard RA. Bronchopulmonary dysplasia. In: Gleason CA, Devaskar S, Juul
SE, eds. Avery’s Diseases of the Newborn. 9th ed. Philadelphia, PA: Elsevier; 2012:658.
20. Stewart A, Brion LP. Routine use of diuretics in very-low birth-weight infants in the
absence of supporting evidence. J Perinatol. 2011;31:633.
21. Stewart A, Brion LP, Ambrosio-Perez I. Diuretics acting on the distal renal tubule for
preterm infants with (or developing) chronic lung disease. Cochrane Database Syst Rev.
2011;9:CD001453.
22. Stewart A, Brion LP. Intravenous or enteral loop diuretics for preterm infants
with (or developing) chronic lung disease. Cochrane Database Syst Rev. 2011;
Sep7(9):CD001453.
23. Wilkie RA, Bryan MH. Effect of bronchodilators on airway resistance in ventilator-
dependent neonates with chronic lung disease. J Pediatr. 1987;11:278.
24. Sosulski R, Abbasi S, Bhutani VK, et al. Physiologic effects of terbutaline on pul-
monary function of infants with bronchopulmonary dysplasia. Pediatr Pulmonol.
1986;2:269.
25. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity.
N Engl J Med. 2006;54:2112.
26. Davis PG, Schmidt B, Roberts RS, et al. Caffeine for apnea of prematurity trial:
benefits may vary in subgroups. J Pediatr. 2010;156:382.
27. Committee on Fetus and Newborn. Postnatal corticosteroid to treat or prevent chronic
lung disease in preterm infants. Pediatrics. 2002;109:330.
28. Doyle LW, Davis PG, Morley CJ, et al. Low-dose dexamethasone facilitates extubation
among chronically ventilator-dependent infants: a multicenter, international, random-
ized, controlled trial. Pediatrics. 2006;117(1):75-83.
92 NICU Primer for Pharmacists

29. Schmidt B, Roberts R, Millar D, et al. Evidence-based neonatal drug therapy for pre-
vention of bronchopulmonary dysplasia in very-low-birth-weight-infants. Neonatology.
2008;93:284-7.
30. Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and short-
and long-term morbidity in very low birthweight infants. Cochrane Database Syst Rev.
2011;Oct 5(10):CD000501.

Suggested Readings
Bhakta K. Respiratory distress syndrome. In: Cloherty JP, Eichenwald EC, Hansen AR, et
al., eds. Manual of Neonatal Care. 7th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2011:406-28.
Davis JM, Abman SH. Bronchoplumonary dysplasia. In: Spitzer AR, ed. Intensive Care of
the Fetus and the Neonate. 2nd ed. Philadelphia, PA: Elsevier; 2005:567.
Keller RL, Ballard RA. Bronchopulmonary dysplasia. In: Gleason CA, Devaskar S, Juul SE,
eds. Avery’s Diseases of the Newborn. 9th ed. Philadelphia, PA: Elsevier; 2012:658.
Solarin KO, Zubrow A, Delivoria-Papadopoulos M. Differential diagnosis of newborn
respiratory disorders. In: Spitzer AR, ed. Intensive Care of the Fetus and the Neonate.
2nd ed. Philadelphia, PA: Elsevier; 2005:567.
8
Patent Ductus Arteriosus

Betsy Walters Burkey, PharmD, BCPS

Introduction

T
he management of patent ductus
arteriosus (PDA) in the prema-
ture neonate is an area of care
that is not straightforward. Despite the
general paucity of literature available
for short- and long-term outcomes in
premature infants, there is a respectable
amount of evidence when using medica-
tions with PDA. However, data are not
always clear in terms of what to use,
when to treat, or for how long. Although
significant morbidities are associated with
PDA, they are not proven as cause and
effect per se. The physiologic role of the
94 NICU Primer for Pharmacists

ductus arteriosus (DA) during gestation and the normal transition from
intrauterine to extrauterine life in the preterm neonate is reviewed. Under-
standing how blood flows provides the basis for understanding why a PDA
post-delivery could have harmful consequences. Ductal-dependent lesions
associated with other congenital heart malformations are not addressed in
this chapter.
The DA is a large vessel that connects the pulmonary artery to the
descending aorta.1 During pregnancy, it shunts the highly oxygenated
blood from the placenta past the pulmonary vasculature; this blood can
bypass pulmonary circulation because oxygenation occurs in the placenta.
Fetal systemic vascular resistance is very low and pulmonary vascular resis-
tance is very high prior to birth, resulting in a left to right flow of blood
through the heart. The high pulmonary and very low placental and systemic
pressures are one mechanism to keep the antenatal shunt open. After birth,
the pulmonary pressures dramatically fall and systemic resistance increases
with removal of the placenta, allowing blood to flow through the pulmo-
nary artery to the lungs and then back via the pulmonary vein establishing
normal post-natal circulation.
The transition from intrauterine to extrauterine life is quite complex,
involving essentially every organ system. Two major areas are the cardiovas-
cular and respiratory systems with support from the endocrine system. A
review of all the changes that occur during and following birth is beyond
this chapter’s scope, but it is important to realize that most of the informa-
tion originates from animal research, primarily in sheep or baboons. For an
infant to survive post-delivery, lung fluid must be resorbed, surfactant must
be made, oxygenation must occur via the alveoli, and the in-utero shunts
that facilitate fetal circulation must close.2 Figure 8-1 illustrates blood flow
with and without a PDA.

Incidence
The DA’s failure to close increases with decreasing gestational age (GA). It is
estimated that approximately 54% of infants born between 22 and 26 weeks
will have a PDA, with a 47% incidence in all infants below 28 weeks gesta-
tion.3,4 The presence of respiratory distress syndrome also increases the risk
of a ductus remaining patent. In term infants, functional closure of the DA
occurs within 24 hours and within 1 to 5 days in the majority of preterm
infants.
Patent Ductus Arteriosus 95

Figure 8-1. Blood Flow with and without the PDA


Source: National Heart, Lung, and Blood Institute; National Institutes of Health. U.S.
Department of Health and Human Services.

Pathophysiology
Many factors contribute to the DA remaining open after birth. Lower GA
is the largest risk factor. Other factors that increase the risk or are associated
with PDA include excessive fluid administration, birth asphyxia, congenital
syndromes (including congenital rubella syndrome, Trisomy 13, and
Trisomy 18), congenital heart disease, and respiratory distress syndrome
(RDS). PDA is found in 60 to 70% of infants with certain congenital
syndromes.1 Data in both preterm animals and humans, which add yet
another layer of complexity, demonstrate that PDA is linked not only to
RDS but also to surfactant administration. The development of a signifi-
cantly hemodynamic PDA has been described by multiple authors and
is likely related to the mechanism of the surfactant. When administered,
surfactant causes lung compliance to increase resulting in a drop of pulmo-
nary vascular resistance, allowing blood to shunt back across the DA.5-8
The histology of the DA is quite different from the two vascular struc-
tures it connects. The DA’s medial layer is composed of longitudinal and
96 NICU Primer for Pharmacists

spiral layers of smooth muscle fibers within concentric layers of elastic tissue,
whereas the medial layers of the aorta and pulmonary artery are primarily
concentric elastic tissue.9 When a term infant is born, the sharp increase
in the partial pressure of oxygen (PaO2) and reduction in prostaglandin E2
(PGE2) and prostacyclin I2 (PGI2) begin the process of ductal constriction.10
This extreme ductal constriction results in tissue ischemia and cell death,
followed by recruitment of inflammatory cells and growth factors that cause
anatomical changes to form the ligamentum arteriosum as a permanent
closure where the DA was located. A newer mechanism also describes the
importance of platelet activation in the mouse model, theorizing that plate-
let coagulation also impacts successful and permanent closure of the DA.11
It is theorized that the tissues in the preterm DA are not as sensitive
to the change in PaO2 after birth and that circulating levels of PGE2 and
PGI2 do not drop off as quickly. Further, low platelets have been identified
as an independent risk factor for failure of a PDA to close or respond to
pharmacologic treatment.12 Even though the placenta is removed (the major
source of prostaglandin and prostacyclin production) and oxygenation rises
post-birth, the ductus is less likely to close and/or stay closed over the course
of the first or second week of postnatal adaptation.
It has also been found that late-onset (after 2 weeks) sepsis can “reopen”
the DA. This is due to the fact that anatomic closure of the PDA has not yet
occurred in the preterm infant. The sepsis syndrome increases the circulat-
ing levels of tumor necrosis factor alpha and prostaglandins, which allow
blood to flow again in a left to right direction.4

Importance of PDA in Neonates


In the preterm infant, a persistently open DA has been associated with
significant morbidity and disease states that can have high mortality.
Although not clearly linked as cause and effect, observational trials have
reported that babies with PDA have a higher incidence of bronchopulmo-
nary dysplasia (BPD), necrotizing enterocolitis (NEC), and intraventricular
hemorrhage (IVH).13 If left to right shunting continues, blood can back up
into the pulmonary vasculature and cause pulmonary edema. At the same
time, systemic blood flow is compromised and ischemic damage may occur.
Therefore, it would seem logical that if PDA is successfully treated, then
these adverse outcomes should be reduced. However, the available outcomes
data are quite heterogeneous, and only prophylactic use of indomethacin
Patent Ductus Arteriosus 97

has been shown to reduce the rate of morbidity (i.e., IVH). Furthermore, no
improvement of neurodevelopmental outcomes has been proven in studies,
even with the reduction in severe IVH (defined as grade III or IV) with
prophylactic indomethacin. Rates of BPD—another major focus of NICU
outcomes in preterm neonates—have not been reduced with any PDA treat-
ment strategy.

Non-Steroidal Anti-Inflammatory Drug Therapy


Two nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin and
ibuprofen lysine, have been studied for closing or preventing PDA. The
primary mechanism of action is an inhibition of circulating prostaglandins
via inhibition of the cyclooxygenase pathways. In 1985, indomethacin was
approved for use and is indicated to “close a hemodynamically significant
PDA in premature infants weighing between 500 and 1,750 g when 48
hours of usual medical management (e.g., fluid restriction, diuretics, respira-
tory support) is ineffective.”15 Ibuprofen lysine labeling is indicated to “close
a clinically significant PDA in premature infants weighing between 500 to
1,500 g who are no more than 32 weeks’ GA when usual medical manage-
ment with diuretics, fluid restriction, and respiratory support is ineffective.”16
Many trials compare oral or intravenous (IV) ibuprofen to placebo;
however, some studies directly compare ibuprofen to indomethacin. The
largest meta-analysis available concludes that there is no difference in
successful closure of a PDA between the two medications, but ibuprofen
may have fewer adverse effects on renal and cerebral blood flow and possibly
fewer gastrointestinal (GI) side effects.17 Although fewer negative effects are
cited with ibuprofen, Abdel-Hady et al. also note that long-term conse-
quences as a result of these differences have not been seen. In cases where
neonates have moderately impaired renal function defined as urine output
greater than 0.6 to 1 mL/kg/hour, ibuprofen is preferred in some units
based on the above data, even though long-term data have yet to substanti-
ate whether these acute side effects result in long-term harm. In vitro studies
have demonstrated that ibuprofen displaces bilirubin from albumin and
increases the plasma levels of unbound bilirubin. However, in vivo studies
did not show similar effects in preterm infants treated with the current
recommended doses of 10-5-5 mg/kg/day particularly if total bilirubin levels
were below 10 mg/dL before treatment.18
98 NICU Primer for Pharmacists

Finally, both medications have also been evaluated (but only in


subgroup analyses) for prevention of pulmonary hemorrhage, and only
indomethacin was beneficial.
Ultimately, either agent has been found to close a PDA up to 75% of
the time in clinical trials. In day-to-day practice, successful closure rates
are lower. It is important for the pharmacist to be cognizant that success-
ful closure becomes less likely as time progresses, in part because levels of
circulating prostaglandin (the target of NSAID therapy) are reduced with
postnatal adaptation. It is suggested that PDA closure with NSAIDs is not
a reasonable option beyond 3 to 4 weeks of age, as success is very unlikely;
some centers consider surgical closure beyond 1 month of age.1

Dosing
Dosing of indomethacin for PDA closure consistently has an initial dose of
0.2 mg/kg and is followed by 0.1 mg/kg, 0.2 mg/kg, or 0.25 mg/kg for
post-natal age less than 48 hours, 2 to 7 days, or greater than 7 days,
respectively. The dosing intervals vary between 12 to 24 hours depend-
ing on the clinical situation. The success of ductal closure is reduced as
the infant approaches 2 weeks of age, so higher doses and more frequent
administration may be considered. Conversely, if there are baseline renal
function concerns because of reduced urine output (less than 1 to 2 mL/kg/
hour), less frequent dosing may be used and repeat laboratory tests may be
performed to assess tolerability with each daily dose.15 Finally, some NICUs
evaluate for ductal closure after each indomethacin dose and, if successful,
do not administer additional doses.
Ibuprofen has been studied in a limited number of infants at higher
doses; however, unlike indomethacin, the frequency is always every 24
hours. Standard dosing is 10 mg/kg followed by 5 mg/kg at 24 and 48 hours
after the first dose. A handful of trials have evaluated higher dosing with
20 mg/kg followed by 10 mg/kg at 24 and 48 hours.20,21 These trials reported
a higher success rate of DA closure with no increase in adverse effects. The
former was a pre-symptomatic design and the latter a retrospective prophy-
lactic design; however, the total number of neonates remains small.
Repeating or extending the course of either medication is an option and
fairly common. Outcomes data are heterogeneous in terms of additional
benefit and adverse effects. Clinicians may express some concern, as one
meta-analysis of five randomized trials found no increased success of PDA
Patent Ductus Arteriosus 99

closure rate with an extended duration of indomethacin treatment but an


increase in NEC.22 Another trial found that 44% of infants who did not
respond to the first course will close their DA with a second course without
additional negative sequelae.23 At this time, research is limited on evaluating
a treatment course beyond three doses of ibuprofen because most authors
have investigated higher doses on a mg/kg/day basis as noted above.24,25
The percentage of DA that will close with a repeated or extended course is
consistently smaller than the closure in the initial treatment course, but
surgical ligation (discussed below) is generally avoided in most NICUs
until after the DA fails to close with two treatment courses of medica-
tion. In many units, surgical ligation requires an infant to be transferred
to another facility altogether; thus, two or sometimes three courses of
medication may be administered.
Although uncommon, two small studies evaluated extending the
duration of indomethacin administration (continuous infusion versus tradi-
tional 30-minute bolus infusion). This approach, based on the theory that
an extended infusion time might reduce the vasoconstrictive and ischemic
effects of bolus administration, found no significant differences in terms of
PDA, NEC, IVH, or mortality; however, the restriction of blood flow was
less in the cerebral, renal, and mesenteric arteries with the extended infusion
time.26 A similar trial with ibuprofen compared a continuous infusion (over
24 hours) with bolus dose of labeling dosing (10-5-5 mg/kg/day). This
prospective, double-dummy trial of more than 100 randomized infants
found higher PDA closure rates, fewer NEC symptoms, and fewer surgical
ligations in the continuous infusion arm.27

Side Effects, Contraindications, and Drug Interactions


The serious side effects of NSAIDs relate to their mechanism of action.
Reduced cerebral, GI, and renal blood flow can result in multiple morbid-
ities. IVH or periventricular leukomalacia, NEC, and transient decreases
in urinary output and increases in blood urea nitrogen and creatinine can
result. Although reported less frequently with ibuprofen than indometh-
acin, labeling for both agents include these adverse events. Platelet
dysfunction is also a known side effect of all NSAIDs; thus, other bleeding
complications or even disseminated intravascular coagulation has been
reported. If urine output drops below 0.6 mL/kg/hour, subsequent doses
of either agent should be held.15,16
100 NICU Primer for Pharmacists

Contraindications for NSAID use are also a class effect. Neither


ibuprofen nor indomethacin should be used in a neonate with any of the
following: proven or suspected infection that is untreated, bleeding (includ-
ing active intracranial hemorrhage or GI bleeding), thrombocytopenia or
coagulation defects, suspicion or actual diagnosis of NEC, severe renal
impairment (urine output below 0.6 to 1 mL/kg/day), and congenital
heart disease where DA patency is necessary for satisfactory pulmonary
or systemic blood flow (e.g., pulmonary atresia, severe tetralogy of Fallot,
severe coarctation of the aorta).15,16
As mentioned in Chapter 1, pharmacists need to remember the drug
interaction between NSAIDs and glucocorticoids, which results in an
increased risk of spontaneous intestinal perforations (indomethacin data).
This combination of drug therapy is often not included in references nor
does an alert fire in all order entry/verification systems. It should be possible
to avoid concomitant use in most clinical situations; however, discussion
with the medical team is of the utmost importance.

Oral Options
Administration of NSAIDs via the oral route to close a PDA has been
investigated and proven to be successful. In some cases, the oral closure rate
is actually superior to that of the IV drug. However, oral administration of
medications with known adverse GI effects (e.g., NSAIDs in preterm infants
receiving little to no enteral feedings) limit their utility. Consideration of
enteral administration may be most useful in resource-poor areas.13,18

When to Treat
Determining the optimal timing to treat a PDA is the most difficult
question to answer. Management strategies are studied and evaluated based
largely on when treatment begins. Although the pharmacist is not directly
involved in diagnosing PDA or the adverse effects that may result from it,
recommending appropriate pharmacologic treatment is built on an accurate
clinical picture. The answer to which PDAs are pathologic and the optimal
time to close it remains a subject of much debate. Many clinicians use a
“watch and wait” approach based on the premise that the duct only becomes
a problem as time goes by and the volume of flow becomes larger, backing
up into the pulmonary vasculature. Some clinicians will treat when a large
duct is seen, even if the patient is not showing signs of volume overload.
Patent Ductus Arteriosus 101

Recently, researchers questioned the effects of the flow through DA during


the first 3 to 6 hours of life and the role that it may play in outcomes such
as BPD and even NEC.13

How to Treat
Treatment of PDA with medication can be approached three different ways:
❖❖ symptomatic or “rescue”
❖❖ pre-symptomatic
❖❖ prophylactic
The symptomatic approach waits until an infant appears to have clinical signs
of distress related to a medium-to-large open duct, and then medication
(or surgery at some institutions) will be employed. Pre-symptomatic treat-
ment involves screening preterm infants for an open duct and then treating
it before any ill effects are seen. Finally, the prophylactic approach treats all
infants shortly after birth who meet the criteria set out in a clinical trial or
in a specific NICU.

Symptomatic Management
The practice of waiting until an infant is symptomatic may be the most
common approach when medications are used to close the DA. A symptom-
atic DA in a neonate may be recognized under the following circumstances:
rising oxygen requirements and/or the inability to wean ventilator settings,
bounding pulses, or an active precordium in the face of a medium-to-
large open duct with left to right blood flow. One strong rationale for this
approach is that it avoids exposing an infant to an unneeded medication
that is not devoid of side effects, especially because one cannot predict
which two of every three preterm infants will close their ducts without
outside intervention. However, it is compelling to realize that this practice
has the least amount of data to support it. The largest trial, published in the
1990s, had a very high rate of “rescue” treatment versus the original placebo
group, was open label, and found little to no differences in outcomes.28 Two
other smaller trials were conducted in the 1970s and1980s;13 however, most
clinicians would agree that neonatal practice has changed greatly since that
time (routine use of antenatal corticosteroids, surfactant use, and differing
ventilation strategies) making the results difficult to interpret even if they
had proven solid positive conclusions.
102 NICU Primer for Pharmacists

Pre-symptomatic Management
Pre-symptomatic treatment generally uses cardiac ultrasound to identify
a PDA and then treat only those patients who meet a certain criteria. The
inclusion criteria of these types of trials have not been uniform, and daily
practice may differ from NICU to NICU. These patients are treated earlier
in the course of the NICU, usually between days 3 to 5. This exposes a
larger number of preterm infants to medication therapy but still fewer
than prophylactic therapy. The studies available include a Cochrane review,
which combines three studies with a total of 97 infants. All studies were
completed before 1990 and thus only evaluated indomethacin, again leaving
clinicians with little ability to draw conclusions based on current respiratory
management strategies in preterm infants.13,29 An indomethacin early-versus-
late (day 3 versus day 7) trial (published in 2001) enrolled over 125 babies
but was excluded from the Cochrane review because of its inclusion criteria.
Although the early treatment group had earlier PDA closure, ultimately there
were more serious side effects and no proven respiratory benefit. In line with
many other trials, 40% of the control arm had medical treatment.30 The
same authors also conducted a trial in 136 preterm infants between 500 to
1,000 g to evaluate a pre-symptomatic strategy with ibuprofen versus placebo
within 72 hours of life based on echocardiographic criteria. This trial also
found no difference in clinical outcomes; however, 49% of the placebo arm
received medical or surgical intervention to close their duct.31 Ultimately,
the intention to try to select out those infants at highest risk for developing
a hemodynamically significant PDA for treatment is a logical, but unsup-
ported treatment approach.

Prophylactic Management
Prophylactic treatment by definition exposes every infant to medication
therapy to prevent the DA’s failure to close. This is an area with the largest
number of infants studied and the most robust outcomes data. Medication
is generally started within 24 hours of birth based on GA or birth weight.
Indomethacin has the largest amount of data, not surprisingly because it is
the oldest drug used for PDA treatment. Almost 20 trials exist evaluating
prophylactic indomethacin, with almost 3,000 infants studied.13 Although
meta-analysis has been done, it is important to realize that the majority of the
infants studied came from one trial—the Trial of Indomethacin Prophylaxis
in Preterm infants (TIPP) trial.32 The meta-analysis determined that prophy-
Patent Ductus Arteriosus 103

lactic treatment reduces the need to treat or ligate PDA and also reduces the
incidence of major (defined as grade III or IV) IVH.33 These appear to be
very important outcomes data, especially in comparison to the other treat-
ment strategies that have a lack of proven positive effect for major outcomes
of concern. However, no significant differences were reported in neuro-
developmental outcomes between the two groups at 18 months, leading
many clinicians to avoid use of indomethacin prophylaxis in their NICUs. 32
Ibuprofen has also been studied for prophylaxis in over 900 neonates.
This meta-analysis included both IV and oral ibuprofen, had a closure rate
of 58% in the placebo groups, and found no benefit in the treatment arm.
The review concludes that ibuprofen should not be studied further, and
therefore not used, for prophylaxis until long-term outcomes are available
from the trials already conducted.34 This conclusion was not only because of
a lack of positive effect, but also because of the renal and GI adverse effects
observed with ibuprofen.

Changes and Constants


It is important to revisit some facts about all the trials that have been done
to treat PDA in preterm infants. The number of infants who cross over from
the placebo arm to the treatment arm is incredibly high in all treatment
strategies; thus, data largely illustrate the effect that delaying therapy has on
PDA and outcomes. Stating that there is actual placebo-controlled data is
largely untrue because the majority of infants cross over from the placebo
group to medical therapy or surgical management in all trials. Finally, none
of these medications, no matter the treatment strategy, has been successful
in reducing serious morbidity or mortality in long-term outcomes. This
doesn’t necessarily prove beyond a doubt that these medical therapies are not
helping some infants survive and have better outcomes (such as the lack of
proven neurodevelopmental benefit seen at 18 months when prophylactic
indomethacin reduces serious IVH).32 However, it does discourage univer-
sal prophylaxis of all infants even though some NICUs still choose to use
indomethacin for prophylaxis of PDA and pulmonary hemorrhage.

Acetaminophen: A New Option


The use of acetaminophen (APAP) for closure of PDA has recently become
a new area of interest. The exact mechanism is not fully understood but
104 NICU Primer for Pharmacists

APAP was found to close a DA in an infant who was receiving the medica-
tion for pain relief.35 APAP (known as paracetamol outside of the United
States) is reported to inhibit prostaglandin synthesis like NSAIDs, but via
interaction at the peroxidase site of prostaglandin H2 synthetase.36
NSAIDs inhibit the cyclooxygenase site one step earlier in arachidonic
acid metabolism thus leading to more vasoconstriction, which can result in
GI damage and renal and platelet dysfunction. Based on its labeled indica-
tion for analgesia, adverse effects of APAP range from less serious, including
rash and fever, to more serious such as hepatoxicity, leukopenia, and neutro-
penia.37 Two potential advantages to APAP over NSAIDs are the ability to
get multiple doses out of a 1,000-mg vial and the per-vial cost.
Only two randomized, controlled trials have been conducted world-
wide with APAP; both authors report similar efficacy in ductal closure with
minimal adverse effects (elevation of liver enzymes being the most signif-
icant). These randomized trials, however, compare oral formulations of
ibuprofen to oral paracetamol.38 The only data reported in the United States
are some case reports or case series, which had varied success rates in closing
PDA, but each report’s definition of successful closure varies significantly.
Many reports used APAP when traditional medications were contraindicated,
whereas the one randomized trial evaluated non-inferiority. Ultimately, APAP
shows promise and could be an option when NSAIDS are contraindicated;
however, IV data are sparse and no long-term outcomes data are available.
The most common dose studied was 15 mg/kg/dose every 6 hours orally or
IV, which exceeds the usual frequency when used as an analgesic in preterm
infants, raising additional concern about liver and other potential toxicities.39

Pharmacologic Medical Management


Based on data that PDA is possibly more of an innocent bystander and not
necessarily a pathologic condition, some centers have chosen to manage
symptomatic PDAs without trying to close them. In these situations,
diuretics, including loop diuretics (most commonly furosemide) or thiazide
diuretics with or without spironolactone, can be used to attempt reducing
afterload and fluid in the pulmonary vasculature. Loop diuretics, however,
increase renal production of prostaglandin E2 and their use has been
associated with an increased risk of PDA.40 Other investigators found that
furosemide in preterm neonates with PDA did not increase urine output but
resulted in hyponatremia and increased serum creatinine.41
Patent Ductus Arteriosus 105

Some centers have used angiotensin-converting enzyme inhibitors


(ACEI) such as lisinopril or enalapril to reduce after-load and help infants
manage a symptomatic duct.42 However, these medications have no
long-term outcomes data with this indication, and case reports of serious
renal failure have been reported. Concurrent use of diuretics with ACEI in
preterm or low birth weight infants appear to increase the risk of serious
adverse effects.43-45 Use of ACEI should be reserved for post cardiac surgery
patients and monitored very closely.

Nonpharmacologic Management
If pharmacologic treatment is avoided in general, what other options exist?
In the past, restriction of total daily fluid intake as low as 80 to 100 mL/kg/
day was employed to encourage a PDA to close, reduce pulmonary edema,
and reduce mechanical ventilator dependence. This has significant implica-
tions for neonatal nutrition because a limit of fluids beyond that which is
generally acceptable (150 mL/kg/day as a target) will restrict the ability to give
optimal amounts of protein, glucose, calcium, and phosphorus. In extremely
sick preterm infants, pressor agents such as dopamine or epinephrine, other
cardiac support drips, or even multiple antibiotic doses can take more of the
daily fluid allowance. Ultimately, it was found that strict fluid restriction
during the first week of life did not appear to offer any advantages, and
many institutions now limit total daily fluid to a more moderate 130 to
140 mL/kg/day.46,47
Some providers will also attempt to manage PDA with different venti-
lator strategies. The basis for this strategy is to attempt reduction of the
workload on the right side of the heart and increase the cardiac output,
thereby reducing fluid backup into the lungs. One prospective, single-
center, non-randomized trial included 30 neonates who were conservatively
managed via adjustment of ventilation. They reduced inspiratory time
and gave more positive end expiratory pressure, in combination with fluid
restriction not exceeding 130 mL/kg a day beyond day 3 with an overall
ductal closure rate of 100%.48

Surgical Ligation
Finally, surgical ligation of the PDA is an option. Although data are, again,
not clear-cut, this management strategy has become less common due to
trials showing significant concerns in developmental outcomes and mortality
106 NICU Primer for Pharmacists

in those infants with surgically ligated PDAs, whether ligation occurs shortly
after birth or after failed course(s) of NSAIDs.13,49,50

Enteral Feedings and NSAID Therapy


Consistent with the theme of mixed practice and heterogeneous data, much
debate exists about enteral feeds during the course of NSAID treatment
for PDA closure. The majority of clinicians report that all enteral feeds and
medications should be stopped (NPO [nothing by mouth] status) during
any NSAID treatment. Some clinicians allow trophic feeds or continue the
current feeding volume but do not advance the feeding regimen during
treatment. The argument can be made that perhaps it is safer to continue
enteral feeds with ibuprofen because data overall show fewer adverse GI
effects versus indomethacin. However, the current sparse data on the subject
is almost exclusively with indomethacin.51,52

Conclusion
Treatment of PDA in the preterm neonate has many facets. When to
treat patients or if to treat them can affect what medication to use. The
medication choice, at what dose, for how long, comprises yet another set
of questions. Practice can vary from NICU to NICU, but every pharmacist
must understand the rationale and basis for each treatment approach to
guide providers in choosing the best medication while taking into account
formulary, availability and cost issues, and comparison of the adverse effect
profile and specific clinical situation.

References
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11. Echtler K, Stark K, Lorenz M, et al. Platelets contribute to postnatal occlusion of the
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15. Indocin [package insert]. http://www.accessdata.fda.gov/drugsatfda_docs/la-
bel/2010/018878s027lbl.pdf
16. Neoprofen [package insert]. http://www.onyinc.com/pdf/NeoProfen%20final%20
21903s008%20PI%20(clean)%20(4)%20(web%20site)%202014_01-09.pdf
17. Abdel-Hady H, Nasef N, Shabaan A, et al. Patent ductus arteriosus in preterm infants:
do we have the right answers? Biomed Res Int. 2013;2013:676192.
18. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus
in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. 2015 Feb
18;2:CD003481.
19. Gersony WM, Peckham GJ, Ellison RC, et al. Effects of indomethacin in premature
infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr.
1983;102:895.
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20. Dani C, Vangi V, Bertini G, et al. High-dose ibuprofen for patent ductus arteriosus
in extremely preterm infants: a randomized controlled study. Clin Pharmacol Ther.
2012;91(4):590-6.
21. Meibner U, Chakrabarty R, Topf HG, et al. Improved closure of patent ductus arterio-
sus with high doses of ibuprofen. Pediatr Cardiol. 2012;33:586-90.
22. Herrera C, Holberton J, Davis P. Prolonged versus short course of indomethacin for
the treatment of patent ductus arteriosus in preterm infants. Cochrane Database Syst
Rev. 2007 Apr 18;(2):CD003480.
23. Keller RL, Clyman RI. Persistent doppler flow predicts lack of response to multiple
courses of indomethacin in premature infants with recurrent patent ductus arteriosus.
Pediatrics. 2003;112(3):583-7.
24. Adrouche-Amrani L, Green RS, Gluck KM, et al. Failure of a repeat course of cycloox-
ygenase inhibitor to close a PDA is a risk factor for developing chronic lung disease in
ELBW infants. BMC Pediatr. 2012;12:10.
25. Richards J, Johnson A, Fox G, et al. A second course of ibuprofen is effective in the clo-
sure of a clinically significant PDA in ELBW infants. Pediatrics. 2009;124(2):e287-93.
26. Görk AS, Ehrenkranz RA, Bracken MB. Continuous infusion versus intermittent
bolus doses of indomethacin for patent ductus arteriosus closure in symptomatic
preterm infants. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006071.
27. Lago P, Salvadori S, Opocher F, et al. Continuous infusion of ibuprofen for treat-
ment of patent ductus arteriosus in very low birth weight infants. Neonatology
2014;105(1):46-54.
28. Gersony WM, Peckham GJ, Ellison RC, et al. Effects of indomethacin in premature
infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr.
1983 Jun;102(6):895-906.
29. Cooke, L Steer P, Woodgate P. Indomethacin for asymptomatic patent ductus arterio-
sus in preterm infants. Cochrane Database Syst Rev. 2003;(2):CD003745.
30. Van Overmeire B, Van de Broek H, Van Laer P, et al. Early versus late indomethacin
treatment of patent ductus arteriosus in premature infants with respiratory distress
syndrome. J Pediatr. 2001;138:205-11.
31. Aranda JV, Clyman R, Cox B, et al. A randomized, double-blind, placebo-controlled
trial on intravenous ibuprofen l-lysine for the early closure of nonsymptomatic patent
ductus arteriosus within 72 hours of birth in extremely low-birth-weight infants Am J
Perinatol. 2009;26:235-45.
32. Schmidt B, Davis P, Moddemann D, et al. Trial of indomethacin prophylaxis in
preterms (TIPP) investigators. Long-term effects of indomethacin prophylaxis in
extremely-low-birth-weight infants. N Engl J Med. 2001;344:1966-72.
33. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for pre-
venting mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2010
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34. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in
preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2011 Jul
6;(7):CD004213.
35. Hammerman C, Bin-Nun A, Markovitch E, et al. Ductal closure with paracetamol:
a surprising new approach to patent ductus arteriosus treatment. Pediatrics.
2011;128:e1618-21.
36. Anderson BJ. Paracetamol (acetaminophen): mechanisms of action. Paediatr Anaesth.
2008;18:915-21.
37. Acetaminophen monograph. Pediatric & Neonatal Lexi-Drugs. Hudson, OH: Lexi-
Comp, Inc.; 2015. Accessed May 21, 2015.
38. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus
in preterm or low-birth-weight infants. Cochrane Database Syst Rev. 2015 Mar 11;
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39. Le, J, Gales MA, Gales BJ. Acetaminophen for patent ductus arteriosus. Ann Pharma-
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40. Green TP, Thompson TR, Johnson DE, et al. Furosemide promotes patent ductus
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1983;308:743.
41. Andriessen P, Struis NC, Niemarkt H, et al. Furosemide in preterm infants treated
with indomethacin for patent ductus arteriosus. Acta Paediatr. 2009;98:797.
42. Shaw NJ, Wilson N, Dickinson DF. Captopril in heart failure secondary to a left to
right shunt. Arch Dis Child. 1988;63(4):360-3.
43. Dutta S, Narang A. Enalapril-induced acute renal failure in a newborn infant. Pediatr
Nephrol. 2003;18(6):570-2.
44. Russo A, Mirani A, Perlman J, et al. Enalapril-induced acute kidney injury in neonates.
J Neonatal Perinatal Med. 2013;6(2):179-81.
45. Lindle KA, Dinh K, Moffett BS, et al. Angiotensin-converting enzyme inhibitor neph-
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46. De Buyst, Rakza T, Pennaforte T, et al. Hemodynamic effects of fluid restriction in
preterm infants with significant patent ductus arteriosus. J Pediatr. 2012;161(3):404-8.
47. Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing mor-
bidity and mortality in preterm infants Cochrane Database Syst Rev. 2008;Jan
23(1):CD000503.
48. Vanhaesebrouk S, Zonnenberg I, Vandervoort P, et al. Conservative treatment for
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92(4):F244-7.
49. Jhaveri N, Moon-Grady A, Clyman RI. Early surgical ligation versus a conservative
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110 NICU Primer for Pharmacists

50. Kabra NS, Schmidt B, Roberts RS, et al; Trial of Indomethacin Prophylaxis in
Preterms Investigators. Neurosensory impairment after surgical closure of patent duc-
tus arteriosus in extremely low birth weight infants: results from the Trial of Indometh-
acin Prophylaxis in Preterms. J Pediatr. 2007;150:229-34.
51. Clyman R, Wickremasinghe A, Jhaveri N, et al. Enteral feeding during indomethacin
and ibuprofen treatment of a patent ductus arteriosus. J Pediatr. 2013;163(2):406-11.
52. Yanowitz TD, Reese J, Gillam-Krakauer M, et al. Superior mesenteric artery blood
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Suggested Readings
Hamrick SEG, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics.
2010;125(5):1020-30.
Van Overmeire B. Common clinical and practical questions on the use of intravenous ibu-
profen lysine for the treatment of patent ductus arteriosus. J Pediatr Pharmacol Ther.
2007;12(3):194-206.
9
Pain and Sedation

Ashley McCallister, PharmD, and Amy P. Holmes, PharmD

Introduction

P
ain and sedation are controversial
topics in the world of neonatology.
Despite significant clinical trial
data, there is still no definitive evidence
regarding the best method for assessment
or management of pain and sedation
needs in critically ill infants.

Principles of Sedation
Neonates lack the ability to communi-
cate pain and discomfort; therefore, the
healthcare team is responsible for identi-
fying the need for adequate sedation and
providing it. Previous research examining
112 NICU Primer for Pharmacists

preterm births have determined that, at the time of birth, neonates are
undergoing critical nervous system development. Disruption or prolonged
exposure to noxious stimuli may lead to neurologic remodeling.1 The
American Academy of Pediatrics (AAP) strongly recommends the use of
protocols for the management of sedation in the neonatal population;
however, the AAP acknowledges the need for further studies before it can
establish treatment guidelines.2-4

Assessment
Sedation of neonates can be a deleterious task. It is imperative to find a
balance by ensuring the infant is appropriately sedated while monitoring
for over-sedation. The N-PASS—Neonatal Pain, Agitation, and Sedation
Scale—may be utilized for this purpose. N-PASS is a reliable tool for
assessing neonatal pain and sedation. Patients are assessed based on crying
irritability, behavior state, facial expression, extremities tone, and vital signs;
they are scored on a scale of −2, meaning well-sedated to +2, in which the
neonate is experiencing pain and agitation. This scale may be utilized in
neonates receiving all types of sedatives.5
In neonates receiving neuromuscular blocking agents (NMBA), health-
care professionals may utilize train-of-four (TOF) in monitoring effective-
ness. TOF monitoring consists of peripheral nerve stimulation that produces
four stimuli over 2 seconds. Patients display zero to four twitches. Paralysis
is indicated by a decrease in the number of twitches. Although this tool is
highly utilized in the adult and some pediatric populations, it is generally
not used in neonatal patients. Due to the size of the electrodes and fragil-
ity of the neonates, it is possible to stimulate the muscle itself, leading to
movement, regardless of whether the neuromuscular junction is blocked.
Thus, clinical monitoring—observation of visual and tactile stimulation on
muscle movement and breathing patterns—is often utilized.6

Nonpharmacologic Modalities
Although there is not much research available on nonpharmacologic sedation
methods, limiting environmental light and noise may aid in decreasing agita-
tion. Neonates may potentially have a reduced need for sedative medications
by limiting their exposure to interruptions and stimuli.7
Pain and Sedation 113

Pharmacologic Agents for Sedation


GABA Modulators
Barbiturates
Phenobarbital—a depressant used for seizure control in neonates (see
Chapter 17). Phenobarbital may also be used in combination with opioids
for sedation; however, there is a lack of evidence proving its effectiveness.8

Benzodiazepines
Midazolam—a short-acting benzodiazepine that acts on gamma-
aminobutyric acid (GABA) receptors, which are present in the fetus around
week 7 of gestation. Midazolam, which is highly water-soluble and rapidly
cleared, is the preferred benzodiazepine for sedation. Although midazolam
is short acting, reduced hepatic function in neonates results in a longer
duration of action.9
Midazolam may be administered orally, intranasally, or parenterally.
Because the bioavailability of oral midazolam is half of intravenous (IV)
midazolam, the dose of oral (PO) midazolam should be double the IV
dose.8 Due to its rapid onset of action, intranasal midazolam is often used
in neonates requiring surfactant in the delivery room.10 Studies in ventilated
patients have demonstrated that better sedation is achieved when midazolam
is coadministered with morphine.
Lorazepam—a benzodiazepine with a long duration of action used
in neonates unresponsive to phenobarbital for both sedation and seizure
prevention (see Chapters 17 and 18).8

Propofol
Propofol is a short-acting lipophilic anesthetic that rapidly penetrates the
blood−brain barrier.3 Although propofol is commonly used in the adult and
pediatric populations, research in neonates is lacking. When compared to
morphine, atropine, and succinylcholine for intubation, propofol reduced
intubation times, increased oxygen saturations, and incurred less trauma
compared to the combination regimen in neonates.11
All neonates receiving propofol should be closely monitored throughout
therapy. Propofol should be used with caution in neonates because
❖❖ clearance is inversely related to neonatal and postmenstrual age.
114 NICU Primer for Pharmacists

❖❖ intermittent bolus or continuous administration can lead to accumula-


tion in neonates, causing toxicity.8
❖❖ postnatal age, concurrent medications, and the presence of cardio-
myopathy may also affect clearance.3

Neuromuscular Blocking Agents


Vecuronium—an intermediate-acting NMBA and a structural derivative
of pancuronium (no longer on the market). Compared to pancuronium,
vecuronium is shorter acting and 1.2 to 1.5 times more potent. Vecuronium
is cleared primarily through hepatic elimination, yet its metabolite,
3-descacetylvecuronium, is renally eliminated.12,13 Studies demonstrated that
on discontinuation of vecuronium, time to recovery ranged from 27 to
80 minutes. Evidence correlating with infusion and recovery times is conflict-
ing. However, studies showed that vecuronium does not significantly change
respiratory mechanics but does decrease hypoxemic episodes in neonates.13
Rocuronium—an intermediate-acting analog of vecuronium. Compared
to vecuronium, it is approximately one-sixth as potent, and its onset of action
is 2.5 times faster. Rocuronium is hepatically metabolized and renally elimi-
nated. It has mild vagolytic activity, which increases the risk of tachycardia.
Patients have developed tolerance to this agent, and a significant dose increase
was noted after 5 days of therapy. On discontinuation of therapy, spontaneous
recovery of neuromuscular function was observed within 24 to 44 minutes.12
Rocuronium has been associated with an increase in pulmonary vascular resis-
tance (PVR). This agent should be used cautiously due to the increased risk of
bronchopulmonary dysplasia and lung injury in this population.
Atracurium—an intermediate-acting NMBA metabolized via Hoffman
elimination. Hoffman elimination is dependent on pH and temperature;
therefore, when those variables are altered, such as in hypothermia or acido-
sis, elimination may be reduced.12
Adverse effects related to histamine release on bolus injection include
❖❖ hypotension
❖❖ tachycardia, bronchospasm
❖❖ erythema
❖❖ rash
There is a potential seizure risk secondary to the formation of
laudanosine, which is a long-acting metabolite produced by Hoffman
Pain and Sedation 115

elimination that is both hepatically and renally eliminated. In neonates


with reduced hepatic and renal function, laudanosine has the ability to
accumulate.12
Cisatracurium—an intermediate-acting NMBA and a derivative of
atracurium. Cisatracurium is 4 times as potent as atracurium, has minimum
histamine release, and has a higher neuromuscular blockade. It undergoes
Hoffman degradation, resulting in a 5- to 10-time decrease in concentration
of laudanosine as opposed to atracurium. In one prospective study, all patients
required a statistically significant dose increase after 3 days of therapy, likely
due to the development of tolerance.12
In comparison to vecuronium, the recovery time after discontinuing
infusion was significantly greater for vecuronium-treated patients than for
cisatracurium-treated patients. It has been suggested that the prolonged
recovery time with vecuronium may be due to reduced clearance and
accumulation of its active metabolite.12

Alpha Agonists
Dexmedetomidine
Dexmedetomidine is a new alternative agent used to prolong sedation in
mechanically ventilated neonates. Dexmedetomidine, classified as an alpha-2
agonist, leads to sedation and anxiolysis.5,14 A case control study showed that
neonates who received dexmedetomidine required less adjunctive sedation
and a shorter duration of mechanical ventilation as well as experienced
fewer occurrences of culture-positive sepsis.5,14 Unlike opioids, dexmedeto-
midine does not affect respiratory drive or gastrointestinal (GI) motility. A
prospective study showed that patients had a significantly shorter duration
of mechanical ventilation than patients who received fentanyl because they
could be removed from mechanical ventilation prior to dexmedetomidine
discontinuation. Patients also had a reduced time to first stool.14
Because dexmedetomidine is hepatically metabolized, neonates require
lower doses compared to pediatric patients. Dexmedetomidine is also highly
protein bound. Neonates typically present with lower albumin and a large
volume of distribution (Vd). With the addition of an immature blood−brain
barrier, dexmedetomidine’s sedative properties may be potentiated, leading
to increased sedative and analgesic effects.5
Adverse effects are generally dose dependent and include hypotension
and bradycardia. No respiratory side effects have been documented in
116 NICU Primer for Pharmacists

Phase III trials; however, no long-term developmental studies have been


performed.5,15

NMDA Antagonists
Ketamine
Ketamine is a potent NMDA (N-methyl-D-aspartate) receptor antagonist
that acts as both a sedative and analgesic agent.15 Unlike other sedatives,
ketamine does not affect cerebral blood flow. It has the potential to cause
bronchodilation and slight increases in blood pressure and heart rate, so it
could be used for hypotensive neonates undergoing airway procedures such
as mechanical ventilation.8 Although rare, research has found that use in
neonates may lead to apnea, hypoxemia, and laryngospasm (phenomenon
was likely procedure related rather than to ketamine use). However, some
healthcare facilities prohibit the use of ketamine in infants less than
3 months of age.16 Additional studies are needed to determine its safety and
efficacy as an anesthetic in neonates.8

Opioids
Research has demonstrated the therapeutic need for both morphine and
fentanyl. For more information, see the following section.

Principles of Analgesia
Pain in the neonate was not accepted and acknowledged until the late
1980s.17 Even though neonates in the NICU are exposed to numerous
painful procedures during their hospitalization, their pain is frequently
under recognized and undertreated. Adverse long-term outcomes such as
poorer cognitive and motor scores, growth impairment, and hyperalgesia
(an exaggerated response to pain) associated with untreated pain must be
weighed against the adverse outcomes associated with the medications used
to treat pain.18,19
Research has shown that peripheral nerve receptors develop very early in
fetal life and are plentiful by 22 weeks’ gestation.19 Infants are consciously
aware of pain as early as 29 weeks’ gestation.19 Although experts agree that
opioids should be used to manage postoperative pain, controversy exists
over use of analgesia for ventilated infants because there appears to be an
imbalance between the risks of agents used to treat pain and the adverse
effects of pain itself.20
Pain and Sedation 117

Multiple procedures, both major and minor, are performed on infants in


the NICU. Experts agree that pre-procedural analgesia should be utilized.20
NICU procedures that are considered to be painful include lumbar puncture,
mechanical intubation, peripherally inserted central catheter (PICC) line
insertion, and endotracheal suctioning. An obvious way to reduce the
pain associated with a NICU stay is to decrease the number of procedures
whenever possible.20

Assessment
Pain is generally subjective. Infants cannot tell you or show you where it
hurts, so pain is difficult to assess. To quantify pain in an infant and deter-
mine when treatment is needed, proper assessment is necessary.17 Premature
neonates may not exhibit physiologic or behavioral signs of pain due to
their immaturity. With long-term pain, the sympathetic nervous system can
become fatigued and conceal any indication that the infant is in pain.
Several tools are available to assess pain in neonates, but none has been
determined to be superior to others. When selecting a scale, consider whether
it is valid for the intended gestational age group as well as feasible to institute
in the intended setting. Furthermore, preference is given to scales that assess
both behavioral and physiologic indicators.20 Examples of neonatal pain
scoring tools include
❖❖ PIPP (Premature Infant Pain Profile)
❖❖ NIPS (Neonatal Infant Pain Scale)
❖❖ CRIES (Crying, Requires O2 for SaO2 < 95%, Increased vital signs
[blood pressure and heart rate], Expression, Sleeplessness)
Tools use differing assessment items such as facial expressions, limb
movement, and vital signs to assign a pain score. NICUs should select a
tool and ensure interdisciplinary understanding and competence in use on a
regular basis.20

Nonpharmacologic Interventions
A variety of nonpharmacologic interventions have been studied for the use
of pain and/or sedation in neonates. They may be used alone or in combi-
nation with pharmacologic agents.21 Non-nutritive sucking (i.e., pacifiers)
and infant swaddling, staples of daily infant care, serve to soothe and assist
in infant self-comforting. Cluster care is a term used to describe a combina-
118 NICU Primer for Pharmacists

tion of multiple activities into one “touch time.” For example, cluster care is
used when coordinating the provider who completes the physical exam and
the respiratory therapist who collects a blood gas at the same time that the
nurse is doing routine care, such as a diaper change, rather than having each
person perform these functions independently at random times. Clustering
care is important when possible to decrease the times that the baby’s sleep
is disturbed and to make more efficient use of nonpharmacologic inter-
ventions.22 Cluster care provides the infant with longer periods of rest and
recovery from procedures.
Parental interaction and involvement in pain management should be
solicited/endorsed when appropriate.17 Breastfeeding can reduce pain and
stress response in infants and should be used when feasible.21 Along with
breastfeeding, kangaroo care (skin-to-skin holding) is also associated with
reduced pain response. Specifically, kangaroo care has been demonstrated to
reduce pain scores following intramuscular (IM) injection of phytonadione.
Infant massage, maternal rocking, and music therapy are other nonpharma-
cologic interventions that may provide pain relief.

Pharmacologic Agents for Analgesia


Nonopioids
Sucrose
Sucrose or a sweet-tasting solution has been widely studied for treatment of
pain related to minor neonatal procedures. Although the exact mechanism
of action is unknown, sucrose is thought to work at least partly by release of
natural endorphins that act on opiate receptors.22 Sucrose is effective only
when it comes in contact with the sweet-tasting taste buds so it must be
administered orally.22 Therefore, it is ineffective to administer sucrose via an
enteral feeding tube. Sucrose is most effective when administered 2 minutes
prior to a procedure, and the dose may be repeated once during the proce-
dure. Procedures for which sucrose (24% solution) should be administered
include, but are not limited to, heel lancing, venipuncture, arterial puncture,
PICC insertion, lumbar puncture, and retinopathy of prematurity screening.23
The optimal dose for sucrose has not been determined. Doses that have
been studied range from 0.05 to 0.5 mL in preterm neonates to 1 to 2 mL
in term neonates.17 Although sucrose in the short term is well tolerated, the
effects of long-term exposure to repeat doses on neurodevelopment have not
Pain and Sedation 119

been studied.24 Experts recommend limiting sucrose to no more than 8 to


10 doses per day.17

Acetaminophen
Acetaminophen should not be used alone for severe pain but is useful as an
adjunct for pain management in neonates. It is available as an enteral, rectal,
and IV form. Enteral is the preferred route if feasible. Acetaminophen can
be used for treatment of post circumcision pain as well as pain associated
with minor procedures.20 Acetaminophen is sometimes used for pain associ-
ated with birth-related injuries such as cephalohematoma or broken bones.

Local Anesthetics
Local anesthetics such as lidocaine or lidocaine–prilocaine are useful in
treating procedure-related pain.20 Specifically, infiltrated lidocaine or topical
anesthetic can be used prior to venipuncture, lumbar puncture, or IM injec-
tion (see Chapter 15).
Local anesthetics are not effective in preventing pain from heel lancing or
PICC insertion in neonates. Lidocaine can be painful on administration, but
buffering it with sodium bicarbonate can decrease the burning sensation.

Opioids
Morphine
Morphine, a potent mu-opioid receptor agonist, is perhaps the best studied
agent for pain in the NICU; however, it remains unclear whether it actually
is effective in treating pain in neonates. In the NEOPAIN study, Anand et
al. compared the effects of morphine versus placebo on the frequency of
early neurological injury in ventilated preterm infants.25 The authors’ theory
was that by treating acute pain, they could prevent these adverse outcomes
thought to be a result of untreated pain. The investigators found that
morphine reduced clinical signs of pain; however, morphine use was associ-
ated with marginally higher rates of death, periventricular leukomalacia, or
severe intraventricular hemorrhage.
Another disadvantage to morphine use in neonates is the increased
production of the metabolite morphine-3-glucuronide (M3G) compared
to morphine-6-glucuronide (M6G). M3G is actually an opioid antagonist.
The shift in ratio of M3G compared to M6G in premature neonates may
account for the reduced analgesia provided by morphine.26
120 NICU Primer for Pharmacists

Fentanyl
Fentanyl is a synthetic mu-opioid receptor agonist frequently used in
the management of pain in neonates. Potential advantages to the use of
fentanyl include a quicker onset of action and less associated histamine
release than morphine. Less histamine release equates to less effect on the
cardiovascular system, making fentanyl more suitable for infants with
hypovolemia, hemodynamic instability, or congenital heart disease.17,21
Additionally, fentanyl can decrease PVR making it an attractive option for
babies with persistent pulmonary hypertension or those recovering from
cardiac surgery.21 Fentanyl also has demonstrated less effect on GI motility
compared to morphine, which may affect the time it takes for an infant to
reach full enteral feeds.27 Conversely, infants receiving fentanyl may require
higher ventilator rates and peak inspiratory pressures at 24 hours and may
experience rapid development of tachyphylaxis requiring significant increases
in dose to achieve the desired effect.28
Fentanyl can be administered as a bolus or by continuous infusion.
Bolus doses of fentanyl should be infused slowly (over 5 to 10 minutes) to
prevent chest wall rigidity.
A retrospective cohort study evaluated the long-term neurodevelopmen-
tal effects of fentanyl. In a multivariable, linear regression model, they found
no association between cumulative fentanyl dose and age-standardized
composite scores for language, cognition, and motor skills.29

Methadone
Methadone is a synthetic opioid. In addition to acting as a mu receptor
agonist, methadone also has effects on delta opioid and NMDA receptors.17,30
Methadone has a very long half-life in neonates with the respiratory depres-
sant effect outlasting the analgesic effect.21
Appendix 9A summarizes dosing information for the medications
discussed throughout this chapter.

Iatrogenic Opioid Dependence


Infants exposed to continuous infusion opioids for more than 5 days are
at risk for withdrawal. Opiate infusions should be weaned slowly prior
to discontinuation. If IV access is lost or no longer needed, necessitating
a change from IV to PO opioid to finish the wean, then standard opiate
conversion charts should not be used to calculate the new dose because this
Pain and Sedation 121

often greatly overestimates the oral dose. It is advisable to select a dose of an


appropriate oral replacement medication that corresponds to the appropriate
point in the dosing spectrum. Tools typically used to evaluate and score iatro-
genic withdrawal were actually developed to evaluate symptoms of neonatal
abstinence syndrome associated with in utero exposure to opiates. (Refer to
Chapter 5.) The Withdrawal Assessment Tool-1 (WAT-1) was developed as a
scoring tool specifically to assess iatrogenic withdrawal in pediatric intensive
care unit patients and may also be useful in assessing NICU patients.31

Reversal of Sedatives and Analgesics


Naloxone
Naloxone is an opiate antagonist used to reverse overdose or adverse effects
of opioids. Specifically in neonates, naloxone is sometimes used to reverse
chest wall rigidity that can result from too rapid administration of fentanyl.
It should not routinely be used in the immediate postpartum period to
reverse the effect of maternal opioid use because this may lead to acute onset
of withdrawal precipitating seizures. The dose for naloxone is 0.1 mg/kg IV
push, although doses as low as 0.01 mg/kg may be effective for reversing
opiate-induced depression.32 The IM route is not preferred but may be used
if IV access is unavailable and perfusion appears adequate.

Flumazenil
Flumazenil is a GABA/benzodiazepine receptor antagonist that is used to
reverse the effects of benzodiazepines (e.g., midazolam). Multiple routes of
administration have been studied for flumazenil including IV, intranasal,
and rectal. Doses vary based on route of administration, and all routes utilize
the commercially available parenteral product (Table 9-1). Re-sedation may
occur approximately 20 to 50 minutes following the flumazenil dose.32

Pharmacokinetic Changes in the Critically Ill Neonate


Neonates undergo dramatic pharmacokinetic changes within the first year of
life. Premature neonates often suffer from health conditions that place them
in a critical state. As a result, additional pharmacokinetic changes may occur
that require further consideration in drug dosing and administration. These
conditions include utilization of ECMO and induction of hypothermia.
(Refer to Chapter 18.)
122 NICU Primer for Pharmacists

Table 9-1. Flumazenil Dosing


Route Dose Repeat
IV 5–10 mcg/kg over 15 seconds May repeat every 45 seconds
until patient is awake.
Maximum cumulative dose =
50 mcg/kg
Intranasal 40 mcg/kg/dose divided equally
between both nostrils; use
TB syringe for accurate, equal
dosing
Rectal 15–30 mcg/kg/dose; administer May repeat if sedation is not
undiluted through an air- reversed in 15–20 minutes.
washed cannula
IV: intravenous; TB: tuberculin
For more information, see reference 32.

Hypothermia reduces cardiac output and shunts blood flow away from
the extremities, kidneys, and liver and increases blood flow to the brain and
heart. In turn, it leads to reduced metabolism and elimination of drugs—
primarily renally and hepatically cleared—as renal clearance is reduced and
cytochrome P450 (CYP) enzymes are downregulated.33,34 The shunting
reduces the Vd and leads to elevated serum concentrations. Due to increased
drug concentrations, hypothermic patients are at a heightened risk for
adverse events including changes in pH leading to altered drug ionization.34
It is imperative that clinicians account for temperature when determining
pH values. If not corrected, weak bases will exhibit an increased Vd whereas
weak acids will demonstrate a decreased Vd. Temperature also influences
lipid solubility. As temperatures decline, lipid solubility is lowered.33
It is important to consider pharmacokinetics on rewarming from a
hypothermic state. Drugs previously sequestered in peripheral tissues prior
to the start of hypothermia may recirculate on rewarming, resulting in the
patient’s exposure to potentially high drug concentrations producing toxic-
ity. However, there is also a risk that agents with a previously prolonged
half-life will undergo rapid elimination, leading to subtherapeutic drug
concentrations and resulting in treatment failure.34
Preterm neonates may experience other critical conditions, including
infections that will alter how the liver metabolizes drugs. CYP enzymes are
Pain and Sedation 123

downregulated during inflammation. As a result, hepatic clearance of drugs


is reduced.

Conclusion
Although there are a plethora of published studies examining pain manage-
ment and sedation in infants, no official guidelines are available for determi-
nation of therapy. Practitioners and pharmacists must use existing research
and knowledge as well as their best judgment when initiating neonates
on analgesics and sedatives. Ethically, practitioners should not universally
administer analgesia or sedation routinely to ventilated babies until more
information is available regarding the immediate and long-term risks and
benefits.27

References
1. McPherson C. Sedation and analgesia in mechanically ventilated preterm neonates:
continue standard of care or experiment? J Pediatr Pharmacol Ther. 2012;17(4):351-64.
2. Deindl P, Unterasinger L, Kappler G, et al. Successful implementation of a neonatal
pain and sedation protocol at 2 NICUs. Pediatrics. 2013;132(1):e211-8.
3. Shah PS, Shah VS. Propofol for procedural sedation/anaesthesia in neonates. Cochrane
Database Syst Rev. 2011;3:CD007248.
4. Feltman DM, Weiss MG, Nicoski P, et al. Rocuronium for nonemergent intubation of
term and preterm infants. J Perinatol. 2011;31(1):38-43.
5. Chrysostomou C, Schulman SR, Herrera Castellanos M, et al. A phase II/III, multi-
center, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and
term neonates. J Pediatr. 2014;164(2):276-82.
6. Honsel M, Giugni C, Brierley J. Limited professional guidance and literature are
available to guide the safe use of neuromuscular block in infants. Acta Paediatr.
2014;103(9):e370-3.
7. Eichenwald EC. Mechanical ventilation. In: Cloherty JP, Eichenwald EC, Stark A,
et al eds. Manual of Neonatal Care. 5th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2008:341-3.
8. Hall RW, Shbarou RM. Drugs of choice for sedation and analgesia in the neonatal
ICU. Clin Perinatol. 2009;36(2):215-26.
9. Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of infants in
the neonatal intensive care unit. Cochrane Database Syst Rev. 2012;6:CD002052.
10. Baleine J, Milési C, Mesnage R, et al. Intubation in the delivery room: experience with
nasal midazolam. Early Hum Dev. 2014;90(1):39-43.
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11. de Kort EH, Reiss IK, Simons SH. Sedation of newborn infants for the INSURE pro-
cedure, are we sure? Biomed Res Int. 2013;2013:892974. doi: 10.1155/2013/892974.
12. Johnson PN, Miller J, Gormley AK. Continuous-infusion neuromuscular blocking
agents in critically ill neonates and children. Pharmacotherapy. 2011;31(6):609-20.
13. McEvoy C, Sardesai S, Schilling D, et al. Acute effects of vecuronium on pulmonary
function and hypoxemic episodes in preterm infants. Pediatr Int. 2007;49(5):631-6.
14. O’Mara K, Gal P, Wimmer J, et al. Dexmedetomidine versus standard therapy with
fentanyl for sedation in mechanically ventilated premature neonates. J Pediatr Pharma-
col Ther. 2012;17(3):252-62.
15. McPherson C, Grunau RE. Neonatal pain control and neurologic effects of anesthetics
and sedatives in preterm infants. Clin Perinatol. 2014;41(1):209-27.
16. Berkenbosch JW, Graff GR, Stark JM. Safety and efficacy of ketamine sedation for
infant flexible fiberoptic bronchoscopy. Chest. 2004;125(3):1132-7.
17. Walter-Nicolet E, Annequin D, Biran V, et al. Pain management in newborns: from
prevention to treatment. Pediatr Drugs. 2010;12(6):353-65.
18. Walker SM. Neonatal pain. Pediatric Anesthesia. 2014;24:39-48.
19. Turnage CS, LaBrecque MA. Preventing and treating pain and stress among infants in
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Manual of Neonatal Care. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2012:870-85.
20. American Academy of Pediatrics Committee on Fetus and Newborn, American Acad-
emy of Pediatrics Section on Surgery, Canadian Paediatric Society Fetus and Newborn
Committee. Prevention and management of pain in the neonate: an update. Pediatrics.
2006;118(5):2231-41.
21. Maycock DE, Gleason CA. Pain and sedation in the NICU. NeoReviews. 2013;14(1):
e22-30.
22. Hardy W. Facilitating pain management. Adv Neo Care. 2011;11(4):279-81.
23. Lago P, Garetti E, Merazzi D, et al. Guidelines for procedural pain in newborns. Acta
Pediatr. 2009;98:932-9.
24. Holsti L, Grunau RE. Considerations for using sucrose to reduce procedural pain in
preterm infants. Pediatrics. 2010;125:1042-7.
25. Anand KJS, Hall RW, Desai N, et al. Effects of morphine analgesia in ventilated
preterm neonates: primary outcomes from the NEOPAIN randomized trial. Lancet.
2004;363:1673-82.
26. Kaneyasu M. Pain management, morphine administration, and outcomes in preterm
infants: a review of the literature. Neonatal Netw. 2012;31(1):21-30.
27. Menon G, McIntosh N. How should we manage pain in ventilated neonates? Neona-
tology. 2008;93:316-23.
Pain and Sedation 125

28. Hall RW. Anesthesia and analgesia in the NICU. Clin Perinatol. 2012;39(1):239-54.
29. Lammers EM, Johnson PN, Ernst KD. Association of fentanyl with neurodevelopmen-
tal outcomes in very-low-birth-weight infants. Ann Pharmacother. 2014;48(3):335-42.
30. Anand KJS, Hall RW. Pharmacological therapy for analgesia and sedation in the new-
born. Arch Dis Child Fetal Neonatal Ed. 2006;91:F448-53.
31. Franck LS, Harris SK, Soentenga DJ, et al. The withdrawal assessment tool-1 (WAT-1):
an assessment instrument for monitoring opioid and benzodiazepine withdrawal
symptoms in pediatric patients. Pediatr Crit Care Med. 2008;9(6):573-80.
32. Neofax. http://neofax.micromedexsolutions.com/neofax/neofax.php?strTitle=NeoFax-
&area=1&subarea=0. Accessed May 27, 2015.
33. Wildschut ED, van Saet A, Pokorna P, et al. The impact of extracorporeal life support
and hypothermia on drug disposition in critically ill infants and children. Pediatr Clin
North Am. 2012;59(5):1183-204.
34. Zanelli S, Buck M, Fairchild K. Physiologic and pharmacologic considerations for
hypothermia therapy in neonates. J Perinatol. 2011;31(6):377-86.

Suggested Readings
American Academy of Pediatrics, Committee on Fetus and Newborn and Section on Sur-
gery, Section on Anesthesiology and Pain Medicine, Canadian Paediatric Society, Fetus
and Newborn Committee. Prevention and management of pain in the neonate: an
update. Pediatrics. 2006;118(5):2231-41.
Johnson PN, Miller J, Gormley AK. Continuous-infusion neuromuscular blocking agents
in critically ill neonates and children. Pharmacotherapy. 2011;31(6):609-20.
McPherson C, Grunau RE. Neonatal pain control and neurologic effects of anesthetics and
sedatives in preterm infants. Clin Perinatol. 2014;41(1):209-27.
McPherson C. Sedation and analgesia in mechanically ventilated preterm neonates:
continue standard of care or experiment? J Pediatr Pharmacol Ther. 2012;17(4):351-64.
Walter-Nicolet E, Annequin D, Biran V, et al. Pain management in newborns: from pre-
vention to treatment. Pediatr Drugs. 2010;12(6):353-65.
126 NICU Primer for Pharmacists

Appendix 9A
Commonly Used Agents for Sedation and Analgesia
Name Indication Route Dose Notes
Phenobarbital Sedation IV LD: 20 mg/kg Dose is
Seizure IV over 20–30 indicated for
minutes seizures, but
some sedation
MD: 3 to 5 activity will be
mg/kg/day provided at
this dose.
Midazolam Sedation IV 0.05– Repeat dose
0.15 mg/kg every 2 to 4
hours
Continuous 0.01– Increase dose
IV 0.06 mg/kg/hr after several
days
Intranasal 0.2–
0.3 mg/kg
Lorazepam Sedation IV 0.05–
0.1 mg/kg
Propofol Sedation IV 125– Not FDA
300 mcg/kg/ approved
minute in infants
less than
2 months old
Vecuronium Sedation IV 0.1 mg/kg IV
push every
1–2 hours
Rocuronium Sedation IV 0.3– Increased risk
0.6 mg/kg of PVR
IV push
Atracurium Sedation IV 0.3– Not FDA
0.4 mg/kg approved in
IV initially infants less
followed by than 1 month
0.08–
0.1 mg/kg
IV 20–45
minutes later
Pain and Sedation 127

Commonly Used Agents for Sedation and Analgesia (continued)


Name Indication Route Dose Notes
Cisatracurium Sedation IV 3 mcg/kg/ Not FDA
min initially approved in
followed by infants less
1–3 mcg/kg/ than 1 month
min continu-
ous IV
Dexmedetomidine Sedation
14
IV LD: Not FDA
0.5 mcg/kg approved for
pediatric use;
MD: caution with
0.3– bradycardia
0.7 mcg/kg/hr or hypoten-
sion with LD
Ketamine Sedation IV 0.5–2 mg/kg/
dose
Sucrose Analgesia PO Pre-term:
0.05–0.5 mL

Term:
1–2 mL
Acetaminophen Analgesia PO ≤32 weeks:
20–25 mg/kg,
then 12–
15 mg/kg
q12h

≥32 weeks
to 36 weeks:
20–25 mg/kg,
then 12–
15 mg/kg q8h

Term infants:
20–25 mg/kg,
then 12–
15 mg/kg q6h
128 NICU Primer for Pharmacists

Commonly Used Agents for Sedation and Analgesia (continued)


Name Indication Route Dose Notes
Acetaminophen Analgesia Rectal ≤32 weeks:
(continued) 30 mg/kg,
then 12–
18 mg/kg
q12h

≥32 weeks to
36 weeks:
30 mg/kg,
then 12–
18 mg/kg q8h

Term infants:
30 mg/kg,
then 12–
18 mg/kg q6h
IV Preterm
infants
32 weeks
and older:
10 mg/kg q6h
(may consider
20 mg/kg
loading dose)

Term infants:
7.5 mg/kg q6h
Morphine Analgesia IV 0.05 to Can also be
0.2 mg/kg given IM or
SQ
Continuous LD: 100–
IV 150 mcg/kg
over 1 hour

MD: 10–
20 mcg/kg/hr
Pain and Sedation 129

Commonly Used Agents for Sedation and Analgesia (continued)


Name Indication Route Dose Notes
Fentanyl Analgesia IV 0.5–4 mcg/kg Infuse slowly
Sedation to prevent
Repeat every chest wall
2–4 hr rigidity
Continuous 1–2 mcg/kg/hr Preferred
IV less due to
increased
risk for
development
of tolerance
Methadone Analgesia IV/PO More
research is
needed to
recommend a
dose
IV: intravenous; IM: intramuscular; LD: loading dose; MD: maintenance dose; PO:
oral; PVR: pulmonary vascular resistance; SQ: subcutaneous
For more information, see references 14 and 32.
10
Neonatal Bacterial Sepsis
and Meningitis

John Brock Harris, PharmD, BCPS

Introduction

S
epsis is defined as symptoms and
signs of systemic infection caused
by a pathogen in the blood. Menin-
gitis is defined as inflamed meninges
typically caused by a pathogen in the
central nervous system. Because neonates
have an immature immune system,
they are at increased risk for sepsis and
meningitis caused by bacterial pathogens.
Complement, granulocyte, humoral,
macrophage, and T cell functions are
decreased in neonates (compared to older
pediatric and adult populations), limiting
response to pathogens. Skin, a protective
132 NICU Primer for Pharmacists

barrier to pathogen exposure, is often immature and compromised when


obtaining laboratory tests and performing procedures.1 Neonatal infections
are classified by time as either early onset or late onset. Early-onset infections
or early-onset sepsis (EOS) occur during the first 72 hours of life, and late-
onset infections or late-onset sepsis (LOS) occur after 72 hours of life.

Early-Onset Infections
Presentation and Laboratory Evaluation
Signs and symptoms of early-onset infections often mirror signs and
symptoms of other neonatal conditions such as respiratory distress or apnea
of prematurity. Neonatal birth history and maternal obstetric history may
increase risk of early-onset infections. Key histories and neonatal signs and
symptoms for suspected early-onset infections are provided in Table 10-1. If
indicated, cultures should be obtained from blood and cerebral spinal fluid
(CSF). Urine cultures have minimal diagnostic value in early-onset infections.
Complete blood cell counts with differential may be used to aid diagno-
sis of early-onset infections in neonates. Sensitivities to rule out EOS in
neonates are low when using complete blood cell count indices. However,
patients with a low white blood cell (WBC) count, low absolute neutrophil
count (ANC), or high immature to total neutrophil percentage (i:T ratio)
have an increased probability of being infected.5 Escobar and colleagues also
noted increased odds of sepsis in neonates weighing ≥2 kg at birth with a
low ANC.6 Abnormal WBC counts, bands, segmented neutrophils, and
platelets used jointly assist in identifying infected neonates.7
Elevated C-reactive protein (CRP) may also indicate presence of infec-
tion.8 CRP increases within 8 hours of infection and peaks around 24 hours.
Values obtained within the first few hours after birth should not be used in
assessment. Two normal CRP values obtained within the first 48 hours of life
approximately 12 to 24 hours apart is a negative predictor of infection.9,10
Elevated procalcitonin (PCT) concentrations may also be used to identify
infection in neonates. PCT increases within 2 to 4 hours after infection and
peaks around 6 to 12 hours, potentially allowing for earlier identification of
infection. However, neonates have a physiologic increase in PCT during the
first day of life. Using PCT alone is not recommended at this time.9,11
A group of abnormal biomarkers is more indicative of infection in
neonates than a single abnormal biomarker.7,8 Other biomarkers studied or
Neonatal Bacterial Sepsis and Meningitis 133

Table 10-1. Important Histories and Signs and Symptoms in Neonatal


Infections
Neonatal Neonatal
Birth History Maternal History Presentation
❖❖ 5 minute APGAR ❖❖ Fetal distress ❖❖ Abnormal laboratory
score <6 studies
❖❖ GBS colonization
❖❖ Low birth weight ❖❖ CRP (>1 mg/dL)
❖❖ Infections
❖❖ Prematurity ❖❖ Immature to total
❖❖ Chorioamnionitis
neutrophil ratio
❖❖ Traumatic delivery ❖❖ Urinary tract
(>0.2)
❖❖ Immature immunity infection
❖❖ Platelets
❖❖ Meconium-stained (<100,000/mm3)
amniotic fluid
❖❖ Apnea
❖❖ Prolonged rupture
❖❖ Bradycardia
of membranes
❖❖ Cyanosis
❖❖ Emesis
❖❖ Feeding intolerance
❖❖ Hyperthermia
❖❖ Hypertonia
❖❖ Hypotension
❖❖ Hypothermia
❖❖ Oxygen requirement
❖❖ Seizures
APGAR: Appearance, Pulse, Grimace, Activity, and Respiration scoring;
CRP: C-reactive protein; GBS: Group B Streptococcus
For more information, see references 2−4.

currently being studied include interleukins 1β, 6, and 8 as well as tumor


necrosis factor α and neutrophil cluster of differentiation 11β and 64.8,10,11

Common Pathogens
In neonatal populations, the two most common pathogens in early-onset
infections are Streptococcus agalactiae (group B Streptococcus [GBS]) and
134 NICU Primer for Pharmacists

Escherichia coli (E. coli) in the era of maternal intrapartum antibiotic prophy-
laxis (IAP) for GBS.2,12,13 The most common pathogen in term neonates is
GBS compared to E. coli in preterm neonates.2 The incidence of early-onset
GBS infections decreased from 3.5 cases per 1,000 NICU admissions 5 years
prior to introduction of universal IAP to 2.6 cases per 1,000 NICU admis-
sions the following 9 years. Early-onset E. coli infections remain consistent at
1.4 cases per 1,000 NICU admissions during the 14-year analysis.14

Pharmacologic Treatment
To limit neonatal morbidity and mortality, empiric antibiotic treatment
should be initiated when early-onset risk factors are present or infection is
suspected.1,15 The selected regimen should be efficacious against common
pathogens. Neonates are often started on ampicillin and gentamicin for
early-onset infections.2,9,12 Third-generation cephalosporins such as cefotax-
ime may be initiated instead of an aminoglycoside in combination with
ampicillin. However, bacterial resistance to cefotaxime may develop quicker
compared to aminoglycosides.16
There may also be an increased risk of invasive fungal infections when
third-generation cephalosporins are used to treat early-onset infections.17,18
Cefotaxime should be reserved for patients with meningitis.9 Empiric antibi-
otic dosing regimens of ampicillin and aminoglycosides vary based on age
(postconceptual, postnatal, and/or gestational age) and/or weight, depend-
ing on institution-preferred neonatal and pediatric dosing reference.19,20
When using aminoglycosides, therapeutic drug monitoring should be
performed by obtaining serum peak and trough concentrations or obtaining
serum concentrations for patient-specific pharmacokinetic determinations.
Neonates <37 weeks gestation who have one of the following mater-
nal risk factors should receive empiric antibiotics for potential early-onset
infection: chorioamnionitis; inadequate IAP, when indicated; or prolonged
premature rupture of membranes (PPROM). Prior to initiating empiric
therapy, a blood culture should be obtained. A WBC count with differential
should be obtained between 6 to 12 hours of age. A CRP may also be drawn
with the WBC count. If the blood culture does not contain a pathogen after
48 hours and the laboratory diagnostics are within normal limits for gesta-
tional age, empiric antibiotics may be discontinued. However, if the blood
culture is positive, empiric therapy should be continued and CSF should be
assessed via lumbar puncture. Also, empiric therapy should be continued if
Neonatal Bacterial Sepsis and Meningitis 135

the neonate doesn’t appear well, the laboratory values are abnormal, and the
blood culture is negative for a pathogen in the setting of maternal adminis-
tration of antibiotics during labor.9
Neonates ≥37 weeks gestation born to mothers diagnosed with chorio-
amnionitis should be started on empiric antibiotics after obtaining a blood
culture. Treatment follows the above algorithm for neonates born <37 weeks
gestation. Neonates born ≥37 weeks gestation with either inadequate mater-
nal IAP when indicated or maternal PPROM should have WBC count with
differential alone, or in combination with CRP, obtained between 6 to
12 hours of age without initiating empiric antibiotics. If laboratory assess-
ment is abnormal, a blood culture should be obtained. If the blood culture
contains a pathogen, antibiotics should be initiated. A neonate who appears
well and has a pathogen negative blood culture and normal laboratory assess-
ment should be discharged.9
After a specific pathogen has been identified and sensitivities have been
assessed, antibiotic therapy should be de-escalated. The duration of thera-
py varies based on pathogen identification. Clinical sepsis is defined as a
neonate who is ill-appearing with or without abnormal laboratory studies
and a pathogen negative blood culture. Empiric therapy is continued for a
7- to 10-day course. If the patient improves readily after empiric antibiotic
therapy, a 7-day course may be considered. However, a 10-day course is
recommended.9 Table 10-2 contains specific durations of antibiotics based
on pathogen and infection type.

Table 10-2. Duration of Antibiotic Therapy for Specific Pathogens


Pathogen Sepsis Duration (days) Meningitis Duration (days)
Empiric 7–10 —
GBS 10 14
E. coli 10–14 21*
L. monocytogenes 14 21
CoNS 5–14 14
S. aureus 10–14 14
CoNS: coagulase-negative staphylococci; E. coli: Escherichia coli; GBS: group B strep-
tococcus; L. monocytogenes: Listeria monocytogenes; S. aureus: Staphylococcus aureus
*Or 14 days after proven CSF sterility, whichever is longer.
For more information, see references 9 and 21–24.
136 NICU Primer for Pharmacists

Late-Onset and Nosocomial Infections


Presentation and Laboratory Evaluation
Late-onset and nosocomial infection presentation is similar to early-onset
infection presentation. Neonatal presentation characteristics are provided
in Table 10-1. Blood cultures should be obtained. Neonates may have
central line access due to prolonged parenteral nutrition or another indica-
tion. If central access is present, a blood culture should be obtained from
both a peripheral site and the central line if feasible. CSF cultures should
be obtained if indicated. Meningitis is more common as a late-onset
infection compared to early-onset infections.25 Urine cultures should also
be obtained in neonates presenting after 72 hours of age. Furthermore,
complete blood cell counts with differential should be obtained with
biomarkers used at the institution and assessed similarly to early-onset
infections. CSF should be evaluated, too. CSF suggestive of bacterial
meningitis is provided in Table 10-3.

Common Pathogens
Causative pathogens in late-onset infections are the same as early-onset
infections with the addition of coagulase-negative staphylococci (CoNS)
and Enterobacteriaceae. Candida may also be seen in late-onset infections if
prevalent within the institution.1

Pharmacologic Treatment
Empiric antibiotic therapy should be initiated when infection is suspected.
The empiric regimen should target pathogens common to the unit. Typical
empiric antibiotics are vancomycin in combination with an aminoglycoside.

Table 10-3. CSF Study Values in Bacterial Meningitis


Study Normal Bacterial
WBC (cells/mm )3
0−25 1,000−5,000
Differential >90% monocytes 80–95% neutrophils
Glucose to serum ratio 75–80% ≤60%
Protein (mg/dL) <170 100−500
CSF: cerebrospinal fluid; WBC: white blood cell
For more information, see reference 26.
Neonatal Bacterial Sepsis and Meningitis 137

An antifungal agent such as amphotericin B may be initiated if fungal infec-


tions are common in the unit. As in early-onset infections, de-escalation of
therapy is warranted after a pathogen is identified and susceptibilities are
known. Table 10-2 contains specific durations of antibiotics based on patho-
gen and infection type. Therapeutic drug concentrations and renal function
should be monitored when using vancomycin and aminoglycosides.

Conclusion
Both early- and late-onset infections increase mortality and morbidity in
neonates. Immediate initiation of empiric antibiotics is essential to decrease
the risk of adverse patient outcomes. For practitioners within the NICU,
awareness of common pathogens based on type of infection and local
pathogen patterns is important. De-escalating therapy after a pathogen and
susceptibilities have been identified decreases exposure to broad-spectrum
antibiotics. Decreasing antibiotic exposure reduces risk of future severe
infections. The importance of appropriate antibiotic management is empha-
sized for pharmacists as advancements continue in assessment techniques
related to biomarkers and microbiology efficiency.

References
1. Sauberan JB. Neonatal sepsis. In: Benavides S, Nahata MC, eds. Pediatric Pharmaco-
therapy. Lenexa, KS: American College of Clinical Pharmacy; 2013:493-510.
2. Stoll BJ, Hansen NI, Sanchez PJ, et al. Early onset neonatal sepsis: the burden of
group B Streptococcal and E. coli disease continues. Pediatrics. 2011;127(5):817-26.
3. Shane AL, Stoll BJ. Recent developments and current issues in the epidemiology,
diagnosis, and management of bacterial and fungal neonatal sepsis. Am J Perinatol.
2013;30:131-42.
4. Wynn JL, Levy O. Role of innate host defenses in susceptibilities to early-onset neona-
tal sepsis. Clin Perinatol. 2010;37:307-37.
5. Hornik CP, Benjamin DK, Becker KC, et al. Use of the complete blood cell count in
early-onset neonatal sepsis. Pediatr Infect Dis J. 2012;31(8):799-802.
6. Escobar GJ, Li D, Armstrong MA, et al. Neonatal sepsis workups in infants ≥2000
grams at birth: a population-based study. Pediatrics. 2000;106(2):256-63.
7. Wang K, Bhandari V, Chepustanova S, et al. Which biomarkers reveal neonatal sepsis?
PloS ONE. 2013;8(12):1-8.
8. Kingsmore SF, Kennedy N, Halliday HL, et al. Identification of diagnostic biomarkers
for infection in premature neonate. Mol Cell Biol. 2008;7:1863-75.
138 NICU Primer for Pharmacists

9. Polin RA. Management of neonates with suspected or proven early-onset bacterial


sepsis. Pediatrics. 2012;129(5):1006-15.
10. Gerdes JS. Diagnosis and management of bacterial infections in the neonate. Pediatr
Clin N Am. 2004;51:939-59.
11. Shah BA, Padbury JF. Neonatal sepsis: an old problem with new insights. Virulence.
2014;5(1):170-8.
12. Santos RP, Tristram D. A practical guide to the diagnosis, treatment, and prevention of
neonatal infections. Pediatr Clin N Am. 2015;62:491-508.
13. Bizzaro MJ, Raskind C, Baltimore RS, et al. Seventy-five years of neonatal sepsis at
Yale: 1928−2003. Pediatrics. 2005;116(3):595-602.
14. Bauserman MS, Laughon MM, Hornik CP, et al. Group B Streptococcus and Esche-
richia coli infections in the intensive care nursery in the era of intrapartum antibiotic
prophylaxis. Pediatr Infect Dis J. 2013;32(3):208-12.
15. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopment and growth
impairment among extremely low-birth-weight infants with neonatal infection. JAMA.
2004;292(19):2357-65.
16. Bryan CS, John Jr JF, Pai MS, et al. Gentamicin vs cefotaxime for therapy of neonatal
sepsis. Relationship to drug resistance. Am J Dis Child. 1985;139(11):1086-9.
17. Manzoni P, Farina D, Leonessa ML, et al. Risk factors for progression to inva-
sive fungal infection in preterm neonates with fungal colonization. Pediatrics.
2006;118(6):2359-64.
18. Cotton CM, McDonald S, Stoll B, et al. The association of third-generation cephalo-
sporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics.
2006;118(2):717-22.
19. Taketomo CK, Hodding JH, Kraus DM. Pediatric & Neonatal Dosage Handbook. 21st
ed. Hudson, OH: Lexicomp; 2014.
20. Micromedex Healthcare Series Website. http://neofax.micromedexsolutions.com/neo-
fax/neofax.php?strTitle=NeoFax&sa=&area=1&mode= . Accessed May 21, 2015.
21. American Academy of Pediatrics. Group B Streptococcal Infections. In: Kimberlin
DW, Brady MT, Jackson MA, et al., eds. Red Book: 2015 Report of the Committee on
Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2015:746-7.
22. American Academy of Pediatrics. Escherichia coli and other gram negative bacilli.
In: Kimberlin DW, Brady MT, Jackson MA, et al., eds. Red Book: 2015 Report of the
Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediat-
rics; 2015:341-2.
23. American Academy of Pediatrics. Listeria monocytogenes infections. In: Kimberlin DW,
Brady MT, Jackson MA, et al., eds. Red Book: 2015 Report of the Committee on
Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2015:514-5.
Neonatal Bacterial Sepsis and Meningitis 139

24. American Academy of Pediatrics. Staphylococcal infections. In: Kimberlin DW, Brady
MT, Jackson MA, et al., eds. Red Book: 2015 Report of the Committee on Infectious
Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2015:727.
25. Stoll BJ, Hansen N, Fanaroff AA, et al. To tap or not to tap: high likelihood of menin-
gitis without sepsis among very low birth weight infants. Pediatrics. 2004;113(5):1181-6.
26. McDade EJ. Meningitis in infants and children. In: Benavides S, Nahata MC, eds.
Pediatric Pharmacotherapy. Lenexa, KS: American College of Clinical Pharmacy;
2013:511-27.

Suggested Readings
McDade EJ. Meningitis in infants and children. In: Benavides S, Nahata MC, eds. Pediatric
Pharmacotherapy. Lenexa, KS: American College of Clinical Pharmacy; 2013:511-27.
Polin RA. Management of neonates with suspected or proven early-onset bacterial sepsis.
Pediatrics. 2012;129(5):1006-15.
Sauberan JB. Neonatal sepsis. In: Benavides S, Nahata MC, eds. Pediatric Pharmacotherapy.
Lenexa, KS: American College of Clinical Pharmacy; 2013:493-510.
11
TORCH Infections

Amy P. Holmes, PharmD

Introduction

T
ORCH is an acronym for a
group of congenital infections
(Toxoplasmosis, Rubella,
Cytomegalovirus, and Herpes Simplex).
Several other congenital infections
are now considered part of TORCH,
although they do not fit the acronym.
The initial presentation of TORCH
infections may be nonspecific, such as
being small for gestational age, or may
present as thrombocytopenia in a baby
with no other clinical reason for these
findings. TORCH infections are differ-
ent from cases of maternally acquired
142 NICU Primer for Pharmacists

neonatal sepsis because they are often accompanied by long-term sequelae


long after the initial infection has resolved.

Toxoplasmosis
Toxoplasmosis gondii is a parasite that usually causes infection only in
immunocompromised patients. The immunosuppression inherent in
pregnancy increases a woman’s susceptibility to this organism. The risk of
transmission and severity of disease varies depending on the trimester during
which exposure occurs. Exposure of the fetus during the first 10 weeks of
pregnancy equates to infrequent transmission.1 Weeks 26 to 40 of gestation
have the highest rate of associated transmission but equate to overall milder
disease in the infant. Toxoplasmosis infection in weeks 10 to 24 is associated
with the highest risk for transmission and severity of subsequent disease.
Clinical signs, although often not present at birth, can include maculo-
papular rash, lymphadenopathy, splenomegaly, hepatomegaly, jaundice, and
thrombocytopenia.2 Chorioretinitis is the most common finding in these
infants.3 Long-term sequelae of untreated disease may include visual impair-
ment, deafness, learning disabilities, or death.
Diagnosis may be made by assessing serum antibodies and/or by obtain-
ing polymerase chain reaction (PCR) of the amniotic fluid or cerebrospinal
fluid (CSF). Specifically, toxoplasma-specific immunoglobulin G (IgG) and
immunoglobulin M (IgM) are elevated in acute infection.4 IgM antibod-
ies may persist for up to 1 year following infection; however, an infection
acquired in the distant past often results in elevated IgG but a negative IgM
antibody test.5 PCR is useful in amniotic fluid only if obtained after 18
weeks’ gestation. Reference laboratories such as Palo Alto Medical Founda-
tion Toxoplasma Serology Laboratory (PAMF-TSL) can offer more special-
ized testing options and assist in guiding treatment of pregnant women.5

Prevention
Potential sources of infection include cats, undercooked meat, and
unwashed vegetables. Pregnant women should always wear gloves when
cleaning cat litter, cook meat to the appropriate temperature, and thorough-
ly wash all vegetables.
Spiramycin and/or a combination of pyrimethamine, sulfadiazine,
and folinic acid may be used in infected pregnant women in an attempt
TORCH Infections 143

to prevent transmission to the fetus. For cases of toxoplasmosis diagnosed


during pregnancy, consultation with a physician expert in toxoplasmosis
is recommended. Spiramycin is not commercially available in the United
States, but it can be obtained after consultation with PAMF-TSL by calling
the U.S. Food and Drug Administration at (301) 796-1400.

Treatment
Both symptomatic and asymptomatic newborns with congenital toxoplasmosis
should be treated.6 Recommended initial therapy includes a combination of
pyrimethamine and sulfadiazine (supplemented with folinic acid) for up to 1
year of treatment. Due to lack of an established optimal dosage and duration,
the 2015 RedBook advises that infectious diseases specialists should be involved
in developing regimens for individual patients. For infants with mild disease,
some experts recommend alternating pyrimethamine/sulfadiazine/folinic acid
with spiramycin during the second half of the treatment year. Infants with
moderate-to-severe disease should receive pyrimethamine/sulfadiazine/folinic
acid for the full year. Corticosteroids may be recommended in cases involving
ocular complications or central nervous system (CNS) disease.2

Rubella
Due to the advent of the rubella vaccine in 1969, cases of congenital rubella
infections have become extremely rare in the United States. From 2004 to
2012, six congenital rubella syndrome cases were reported in the United
States, which were all considered to be imported cases or from an unknown
source.6 Management of rubella is supportive; therefore, the most import-
ant thing for pharmacists to know about rubella is prevention strategies.
Rubella screening is required during pregnancy. It is estimated that 20% of
reproductive-age women in the United States are not immune to rubella.3
Because the rubella vaccine is a live virus vaccine, it is not recommended
during pregnancy. Women who are nonimmune should be vaccinated after
delivery of their baby prior to discharge from the hospital.

Varicella
Varicella (chickenpox) is often considered a benign childhood disease. To
an unborn fetus or to a newborn baby, it can be very dangerous. Congenital
varicella syndrome (CVS) occurs when a fetus is exposed to varicella prior
144 NICU Primer for Pharmacists

to 20 weeks’ gestation.7 CVS is associated with devastating consequences


such as limb deformities and eye abnormalities. Perinatally acquired varicella
is considered an infection that develops from 5 days before delivery up to
2 days following delivery. This infection can be fatal to the infant due to
the lack of maternal antibody passage. The severity of varicella infections
that occur after 28 weeks’ gestation and more than 5 days before delivery
is modified by maternal antibodies. Perinatal maternal herpes zoster, also
known as shingles, is generally not considered a risk to the fetus due to the
protection of established maternal antibodies.

Prevention
Varicella zoster immune globulin (VariZIG) became available in December
2012 and is indicated as described below. Dosing of VariZIG is 125 inter-
national units for each 10 kilogram (kg) of body weight administered
intramuscularly (IM) to a maximum dose of 625 units.8 The fixed dose for
infants less than 2 kg is 62.5 units. Patients weighing 2.1 to 10 kg should
receive 125 units. The dose should be administered as soon after virus
exposure as possible for up to 10 days following the exposure.
Patient groups recommended by Centers for Disease Control and
Prevention (CDC) to receive VariZIG include the following:
❖❖ Immunocompromised patients without evidence of immunity.
❖❖ Newborn infants whose mothers have signs and symptoms of varicella
around the time of delivery (i.e., 5 days before to 2 days after).
❖❖ Hospitalized premature infants born at ≥28 weeks of gestation whose
mothers do not have evidence of immunity to varicella.
❖❖ Hospitalized premature infants born at <28 weeks of gestation or
who weigh ≤1,000 g at birth, regardless of their mothers’ evidence of
immunity to varicella.
❖❖ Pregnant women without evidence of immunity.9
Prevention of varicella infection includes immunizing nonimmune mothers
following delivery as well as airborne and contact precautions/isolation of
those infected.

Cytomegalovirus
Cytomegalovirus (CMV) is the most commonly acquired congenital infec-
tion, although only 10% of affected infants exhibit signs or symptoms at
TORCH Infections 145

birth.6 Common signs of CMV infection at birth include small for gesta-
tional age, microcephaly, and thrombocytopenia with petechiae/purpura
known as “blueberry muffin” spots. CMV is the most common cause of
nonhereditary sensorineural hearing loss in children.2 Half of those affected
continue to have progression of their hearing loss. More than half of infants
who develop hearing loss will have no hearing loss detectable in the first
month of life. Potential long-term sequelae of congenital CMV infection
(other than hearing loss) include chorioretinitis, blindness, and moder-
ate-to-severe mental retardation. Among viral causes, CMV is the most
frequently identified culprit in cases of mental retardation.10
Diagnosis can be made by testing urine and/or saliva for CMV via
PCR or culture, ideally in the first 2 to 3 weeks of life. Passage to the infant
is most common in primary infection and occurs more often in younger
women and those who work with young children (e.g., daycare workers).

Prevention
Hand washing after contact with any secretions from a child is the primary
method of prevention. Small children tend to put everything in their
mouths; therefore, hand washing is essential after contact with saliva from
toys or other objects that have been placed in the mouth. Hand washing is
also essential following diaper changes or wiping the nose. The American
Congress of Obstetricians and Gynecologists recommends counseling all
pregnant women regarding hand washing and proper handling of infected
items (e.g., diapers) when interacting with children or immunocompro-
mised individuals.10 In addition, the CDC recommends that pregnant
women avoid sharing utensils or kissing young children on the lips or cheek.
Preliminary studies suggest that cytomegalovirus hyperimmune globulin
(CMV HIG/Cytogam) may reduce the damage done by CMV to the fetus
of an infected mother.10 Various CMV HIG administration techniques have
been attempted, including administering it to the mother and other more
direct routes to the fetus; however, the optimum dose and route of admin-
istration have not been determined. Due to lack of consistent and rigor-
ous data, this strategy is not currently recommended. A large prospective
randomized trial is currently underway to determine the role of CMV HIG
in the management of pregnant women with primary CMV infection.6
Finding a vaccine to prevent transmission of CMV has been identified
as a top priority for public health by the Institute of Medicine.11,12 Multiple
strategies for vaccine development and clinical trials are ongoing.
146 NICU Primer for Pharmacists

Treatment
Until recently, treatment of CMV was reserved for life-threatening or
sense-threatening disease because of the severe side effects of ganciclovir.
Previously, it was considered the medication of choice. Accepted treatment
of symptomatic disease involving the CNS now includes either intravenous
(IV) ganciclovir or oral valganciclovir, a prodrug of ganciclovir, for a total
of 6 weeks. Recent evidence demonstrates improved hearing or maintained
hearing at 12 months when valganciclovir (16 mg/kg given orally twice
daily) is continued for 6 months of treatment in symptomatic CMV-positive
infants.13 For purposes of the aforementioned study, “Symptomatic disease
was defined as one or more of the following: thrombocytopenia, petechiae,
hepatomegaly, splenomegaly, intrauterine growth restriction, hepatitis, or
CNS involvement such as microcephaly, intracranial calcifications, abnor-
mal cerebrospinal fluid indexes, chorioretinitis, sensorineural hearing loss, or
the detection of CMV DNA in cerebrospinal fluid.”13 Neutropenia seemed
to be of primary concern during the initial 6 weeks of treatment and was
reduced when the entire 6-month course was exclusively valganciclovir.
In addition to concern about neutropenia, ganciclovir has been associated
with effects on the gonads as well as carcinogenic effects in animal models.
Parents should be informed when this treatment is being considered.
Infants receiving ganciclovir/valganciclovir should be monitored weekly
for the first 6 weeks of treatment for neutropenia. For patients receiving the
longer course of treatment, an absolute neutrophil count (ANC) should also
be assessed at week 8 and then monthly through the end of treatment.6

Herpes Simplex
Congenital herpes infection may be caused by either herpes simplex virus
(HSV) 1 or 2. It manifests in three different manners in the neonate: skin,
eyes, and mouth (SEM), which is associated with lesions in any of those
areas; disseminated disease, which can affect multiple organ systems; and
CNS infection, which may accompany disseminated disease or present
independently. Mortality is highest in those infants with disseminated
disease, with as many as 20% perishing despite antiviral treatment. Approxi-
mately half of the infants who survive congenital HSV infection continue to
have cutaneous outbreaks.6
Clinical manifestations of congenital HSV may present at any time from
birth up to 6 weeks of age.6 Initial signs may include vesicular eruptions.
TORCH Infections 147

Without the telltale skin lesions, diagnosis can be difficult. HSV should be
considered in infants with sepsis-like symptoms in the setting of negative
bacterial blood cultures, severe liver dysfunction, or consumptive coagulop-
athy. Likewise, infants who present with seizures, fever, or abnormal CSF
findings should be evaluated for HSV.
Congenital HSV infection can occur in infants whose mothers have no
prior history of herpes infection. Transmission of the infection is highest
during the initial infection. Mothers may pass herpes on to their babies
before they have had their first outbreak. For this reason, empiric initiation
of acyclovir should not be delayed or withheld in symptomatic infants based
on the absence of maternal HSV history.
Testing for a baby includes HSV cultures of the skin, eyes, rectum, and
mouth along with serum PCR and CSF PCR when indicated.

Treatment
Parenteral acyclovir is the gold standard treatment. Infants should receive
20 mg/kg IV q8h (Neofax recommends adjusting to q12h if gestational age
<30 weeks) while PCR results are pending.14 New evidence suggests that
infants 36 to 41 weeks may benefit from receiving acyclovir 20 mg/kg IV
q6h, although not all references have adopted this in their dosing recom-
mendations. Treatment of SEM disease is 14 days.6 Disseminated and CNS
disease should be treated for a minimum of 21 days. The American Academy
of Pediatrics (AAP) has made alternate recommendations during times of
parenteral acyclovir shortage, which include IV ganciclovir as first line and
IV foscarnet as second line.15
Asymptomatic infants may be a candidate for a 10-day treatment course
of acyclovir if born to mothers with active lesions during delivery.16 Babies
born to mothers experiencing a primary infection during pregnancy are
candidates for acyclovir despite negative testing for HSV. Furthermore,
infants born to mothers with a history of HSV who have positive surface
cultures should receive 10 days of acyclovir even if they remain asymptomatic.
Suppressive therapy should be initiated for infants who have been
treated for congenital HSV. Acyclovir 300 mg/m2 given orally three times
daily for 6 months has been shown to decrease adverse neurodevelopmental
outcomes in babies who have recovered from CNS infection.17 Suppressive
therapy can also reduce the frequency of skin eruptions.
148 NICU Primer for Pharmacists

Acyclovir is generally considered to be a well-tolerated medication.


However, pharmacists can assist in monitoring and/or preventing a few
adverse effects. Acyclovir can cause neutropenia; therefore, complete blood
counts should be monitored during treatment. Specifically during suppres-
sive therapy, ANC should be assessed biweekly for the first 4 weeks and
monthly thereafter.6 Another common adverse effect of acyclovir is crystal-
luria, which can be prevented by slowing infusion rates and ensuring that
the patient is adequately hydrated.14 Finally, acyclovir can be very irritating
and lead to phlebitis; it can be very damaging to tissue if extravasation
occurs. Pharmacists can help prevent phlebitis by adequately diluting
acyclovir for administration. Furthermore, they can prevent adverse effects
by following PCR results and getting acyclovir discontinued promptly in
infants who no longer warrant treatment.

Syphilis
Treponema pallidum is a spirochete responsible for the sexually transmitted
disease known as syphilis. Rapid plasminogen reagent (RPR) screening
is performed on all women at least once during pregnancy in an effort
to identify, prevent, and/or treat congenital syphilis. No baby should be
discharged from the hospital without having a record of a maternal RPR
during the current pregnancy! Positive RPR requires follow up. RPR may
remain positive following treatment and may also be a false positive. Confir-
mation of syphilis must be made with a treponemal antibody test (e.g.,
Treponema pallidum particle agglutination [TP-PA], Treponema pallidum
enzyme immunoassay [TP-EIA], fluorescent treponemal antibody-absorp-
tion [FTA-ABS]).
The majority of infants born to mothers with untreated (or inadequately
treated) disease will not have clinical signs and symptoms of disease at birth.1
The most common clinical findings in early congenital syphilis include
snuffles (i.e., syphilitic rhinitis), rash, hepatomegaly, generalized lymphade-
nopathy, anemia, and thrombocytopenia. Severe manifestations of the disease
may not appear for weeks, months, or years following birth. Examples of
long-term sequelae include bone and joint problems, eighth nerve deafness,
cranial nerve palsies, mental retardation, dental deformities, and multiple
ophthalmic manifestations.
TORCH Infections 149

Prevention
If a mother is adequately treated during pregnancy with penicillin dosed
appropriately for her stage of disease, she can prevent transmission to her
fetus.6 Pregnant women who are allergic to penicillin should be desensitized
so that they can receive penicillin treatment. The usual alternative treat-
ments for penicillin-allergic patients (e.g., tetracyclines, macrolides) are not
acceptable for treatment in pregnancy. Due to concerns over the effect on
the infant’s teeth and bones, tetracyclines are not used in pregnancy. Macro-
lides do not cross the placenta, but the Treponema pallidum organism can
cross it so treatment with a macrolide may potentially leave a repository of
untreated disease.

Treatment
Penicillin is the treatment of choice for syphilis. Infants with congenital
syphilis should be treated with penicillin based on the algorithm from the
AAP (Figure 11-1). Treatment options include one dose of IM benzathine
penicillin 50,000 units per kg or 10 days of either aqueous IV penicillin G
(50,000 units per kg q12h for first 7 days of life then q8h) or IM procaine
penicillin (50,000 units/kg daily) depending on the circumstances. If
dispensing either benzathine or procaine penicillin, be sure that it is properly
labeled for IM use only. Medication errors involving inadvertent IV admin-
istration of benzathine penicillin have led to cardiorespiratory arrest and
death.18

Human Immunodeficiency Virus


Although human immunodeficiency virus (HIV) has not traditionally been
considered a TORCH infection, this is a logical place to discuss prevention
of perinatal transmission of this virus. Women are screened for HIV during
pregnancy. The established history of HIV infection or recent diagnosis
affects the treatment of both the mother and baby. An early study demon-
strated that zidovudine administered ante- and intra-partum to HIV-positive
mothers in conjunction with zidovudine administration to their infants
can decrease transmission of HIV by approximately two-thirds.19 Although
research in this area continues, the recommendation still stands that all
infants born to mothers who are HIV positive should receive zidovudine
150 NICU Primer for Pharmacists

Reactive maternal RPR/VDRL•

Nonreactive maternal treponemal test* Reactive maternal treponemal test*, ∆

False-positive reaction;
no further evaluation Maternal treatment: Maternal penicillin Adequate maternal
• None, OR treatment during treatment before
• Undocumented, OR pregnancy and more pregnancy with
• 4 weeks or less than 4 weeks before stable low titer
before delivery, OR delivery, and no (serofast),§ AND
• Nonpenicillin drug, evidence of maternal infant examination
OR reinfection or relapse normal; if infant
• Maternal evidence examination is
of reinfection/relapse abnormal, proceed
(fourfold or greater with evaluation¥
increase in maternal
titers)◊
No evaluation
No treatment‡

Evaluate¥ Infant RPR/VDRL Infant RPR/VDRL


fourfold or greater same or less than
than maternal fourfold the maternal
RPR/VDRL titer◊ RPR/VDRL titer◊
Infant physical Infant physical
examination examination
normal; abnormal; OR
evaluation evaluation Infant physical Infant physical
normal; infant abnormal or examination examination
RPR/VDRL incomplete; OR abnormal normal
same or less RPR/VDRL at
than fourfold least fourfold
the maternal greater than
RPR/VDRL titer◊ maternal
RPR/VDRL titer◊

Treatment† Treatment Evaluation¥ and No evaluation;


(Option 1) Treatment Treatment
(Option 1) (Option 2)

TREATMENT OPTIONS;
1. Aqueous penicillin G, 50,000 U/kg, intravenously, every 12 hours (1 week of age or younger)
or every 8 hours (older than 1 week); or procaine penicillin G, 50,000 U/kg, intramuscularly,
as a single daily dose for 10 days. If 24 or more hours of therapy is missed, the entire course
must be restarted.
2. Benzathine penicillin G, 50,000 U/kg, intramuscularly, single dose.

Figure 11-1. Algorithm for Evaluation and Treatment of Infants Born to Mothers with
Reactive Serologic Tests for Syphilis
Source: From AAP Committee on Infectious Disease. In: Kimberlin D, Brady MT, eds.
RedBook. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015:755-68.
Copyright © 2015 American Academy of Pediatrics. Reproduced with permission.
TORCH Infections 151

RPR: rapid plasma reagin; VDRL: Venereal Disease Research Laboratory; TP-PA: Treponema pallidum
particle agglutination; FTA-ABS: fluorescent treponemal antibody absorption; TP-EIA: T. pallidum
enzyme immunoassay; MHA-TP: microhemagglutination test for antibodies to T. pallidum.
• This algorithm does not apply if maternal samples are screened in reverse order (i.e., treponemal
test is performed before the RPR/VDRL). For a discussion of interpretation of reverse sequence
testing, please refer to UpToDate topic on diagnosis of syphilis.
* TP-PA, FTA-ABS, TP-EIA, or MHA-TP.
∆ Test for human immunodeficiency virus (HIV) antibody. Infants of HIV-infected mothers do not
require different evaluation or treatment.

A fourfold change in titer is the same as a change of 2 dilutions. For example, a titer of 1:64 is
fourfold greaterthan a titer of 1:16, and a titer of 1:4 is fourfold lower than a titer of 1:16.
§ Women who maintain a VDRL titer 1:2 or less or an RPR 1:4 or less beyond 1 year after successful
treatment are considered serofast.
¥ Complete blood cell (CBC) and platelet count; cerebrospinal fluid (CSF) examination for cell count,
protein, and quantitative VDRL; other tests as clinically indicated (e.g., chest radiographs, long-bone
radiographs, eye examination, liver function tests, neuroimaging, and auditory brainstem response).
‡ Some experts would consider a single intramuscular injection of benzathine penicillin (Treatment
Option 2), particularly if follow-up is not certain.
† Treatment (Option 1 or Option 2, above) with many experts recommending Treatment Option 1. If
a single dose of benzathine penicillin G is used, then the infant must be fully evaluated, full
evaluation must be normal, and follow-up must be certain. If any part of the infant's evaluation is
abnormal or not performed, or if the CSF analysis is rendered uninterpretable, then a 10-day course
of penicillin is required.

Figure 11-1 (continued). Algorithm for Evaluation and Treatment of Infants Born to
Mothers with Reactive Serologic Tests for Syphilis
152 NICU Primer for Pharmacists

Table 11-1. Neonatal Antiretroviral Dosing


All HIV-Exposed Infants (initiated as soon after delivery as possible)
Zidovudine
(ZDV) Dosing Duration
≥35 weeks’ gestation at birth: 4 mg/kg/dose PO Birth
twice daily, started as soon after birth as possi- through
ble and preferably within 6–12 hours of delivery 4−6 weeksa
(or, if unable to tolerate oral agents, 3 mg/kg/
dose IV, beginning within 6–12 hours of delivery,
then every 12 hours)
≥30 to <35 weeks’ gestation at birth: 2 mg/kg/ Birth
dose PO (or 1.5 mg/kg/dose IV), started as soon through
after birth as possible, preferably within 6–12 6 weeks
hours of delivery, then every 12 hours, advanced
to 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV)
every 12 hours at age 15 days
<30 weeks’ gestation at birth: 2 mg/kg body Birth
weight/dose PO (or 1.5 mg/kg/dose IV) started through
as soon after birth as possible, preferably within 6 weeks
6–12 hours of delivery, then every 12 hours,
advanced to 3 mg/kg/dose PO (or 2.3 mg/kg/dose
IV) every 12 hours after age 4 weeks
Additional Antiretroviral Prophylaxis Agents for HIV-Exposed Infants
of Women Who Received No Antepartum Antiretroviral Prophylaxis
(initiated as soon after delivery as possible)
In addition to Birth weight 1.5–2 kg: Three doses in the first week of
ZDV as shown 8 mg/dose PO life
above, administer Birth weight >2 kg:
First dose within 48 hours of
NVP 12 mg/dose PO
birth (birth–48 hours)
Second dose 48 hours after first
Third dose 96 hours after
second
IV: intravenous; NVP: nevirapine; PO: oral
a
A 6-week course of neonatal zidovudine is generally recommended. A 4-week
neonatal zidovudine chemoprophylaxis regimen may be considered when the mother
has received standard antiretroviral therapy during pregnancy with consistent viral
suppression and there are no concerns related to maternal adherence.
For additional information, see http://aidsinfo.nih.gov/contentfiles/lvguidelines/
perinatalgl.pdf
TORCH Infections 153

beginning within 6 to 12 hours of birth.20 Zidovudine is continued for 6


weeks. Infants whose mothers have not received treatment during pregnancy
should also receive three doses of nevirapine. Table 11-1 is based on the
national guidelines for perinatal management of HIV and outlines dosing
of these medications. Infectious disease specialists may recommend the
addition of a third agent for infants whose mothers have a high viral load
despite treatment, a history of resistance, or are recently diagnosed.

Conclusion
TORCH infections originate from a variety of organisms, including viruses
and bacteria. They are commonly seen in many NICUs. Pharmacists can
play a role in assessing proper treatment selection, dosing, and length of
therapy as well as ensuring appropriate monitoring of medication therapy.

References
1. Remington JS, Klein JO, Wilson CB, et al., eds. Infectious Diseases of the Fetus and
Newborn Infant. 6th ed. Philadelphia, PA: Elsevier; 2006.
2. Tian C, Ali SA, Weitkamp JH. Congenital infections, part 1: cytomegalovirus, toxo-
plasma, rubella, and herpes simplex. NeoReviews. 2010;11:e436-46.
3. Anderson B, Gonik B. Perinatal infections. In: Fanaroff AA, Martin RJ, eds. Neonatal–
Perinatal Medicine: Diseases of the Fetus and Infant. 9th ed. Vol. 1. Philadelphia, PA:
CV Mosby; 2010:399-422.
4. CDC website. Parasites—toxoplasmosis (Toxoplasma infection): Resources for Health
Professionals. http://www.cdc.gov/parasites/toxoplasmosis/health_professionals/ April
14, 2014. Accessed April 8, 2015.
5. Montoya JG, Remington JS. Management of Toxoplasmosis gondii infection during
pregnancy. CID. 2008;47:554-66.
6. Kimberlin DW, Brady MT, eds. RedBook: 2015 Report of the Committee on Infectious
Diseases, 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.
7. Satti KF, Ali SA, Weitkamp JH. Congenital infections, part 2: parvovirus, listeria,
tuberculosis, syphilis, and varicella. NeoReviews. 2010;11:e681-95.
8. VariZIG [package insert]. Winnipeg, Canada: Cangene Corporation; 2012.
9. Marin M, Bialek S, Seward JF. Updated recommendations for VariZIG—United States
2013. MMWR. 2013;62(28):574-6.
10. Carlson A, Norwitz ER, Stiller RJ. Cytomegalovirus infection in pregnancy: should all
women be screened? Obstet Gynecol. 2010;3(4):172-9.
154 NICU Primer for Pharmacists

11. Sung H, Schleiss MR. Update on current status of cytomegalovirus vaccines. Expert
Rev Vaccines. 2010;9(11):1303-14.
12. Rieder F, Steininger C. Cytomegalovirus vaccine: phase II clinical trial results. Clin
Microbiol Infect. 2014;20(supp 5):95-102.
13. Kimberlin DW, Jester PM, Sanchez PJ, et al. Valganciclovir for symptomatic congeni-
tal cytomegalovirus disease. N Engl J Med. 2015;372:933-43.
14. Neofax. http://neofax.micromedexsolutions.com/neofax/neofax.php?strTitle=NeoFax-
&area=1&subarea=0. Accessed May 16, 2015.
15. Intravenous Acyclovir Shortage Recommendations for Pediatrics. http://redbook.
solutions.aap.org/selfserve/ssPage.aspx?SelfServeContentId=acyclovir-shortage. Novem-
ber 2012. Accessed May 4, 2015.
16. Kimberlin DW, Bailey J. Guidance on management of asymptomatic neonates born to
women with active genital herpes lesions. Pediatrics. 2013;131(2):e635-46.
17. Kimberlin DW, Whitley RJ, Wan W, et al. Oral acyclovir suppression and neurodevel-
opment after neonatal herpes. N Engl J Med. 2011;365:1284-92.
18. Smetzer JL, Cohen MR. Lesson from Denver medication error/criminal negligence
case: look beyond blaming individuals. Hosp Pharm. 1998;33:640-56.
19. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission
of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med.
1994;331(18):1173-80.
20. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal
Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-
1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV
Transmission in the United States. Available at: http://aidsinfo.nih.gov/contentfiles/
lvguidelines/perinatalgl.pdf. March 24, 2014. Accessed May 4, 2015.

Suggested Readings
Kimberlin DW, Brady MT, eds. RedBook: 2015 Report of the Committee on Infectious Diseases.
30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015. See sections on
CMV, HSV, syphilis, and toxoplasmosis.
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Trans-
mission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected
Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission
in the United States. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/
perinatalgl.pdf. March 24, 2014.
12
Respiratory Syncytial Virus

Betsy Walters Burkey, PharmD, BCPS,


and Michelle F. F. Poole, PharmD

Introduction

R
espiratory syncytial virus (RSV)
is a common cause of lower
respiratory infection and is
highly contagious. By 2 years of age, it
is estimated that all children will have
been infected with this virus.1 Signs and
symptoms vary; the majority of children
present with an upper respiratory infec-
tion with rhinitis and cough. One-third
of children also develop acute otitis
media, and some may present with a
low-grade fever. In the most severe cases,
lower respiratory infection can cause
bronchiolitis and/or pneumonia.1
156 NICU Primer for Pharmacists

Epidemiology
Annually in the United States, RSV accounts for approximately 58,000
hospitalizations and 2.1 million outpatient visits in young children less than
5 years of age.2 Infants less than 1 month old are at greatest risk for RSV
hospitalizations.3 From 1976 to 1980, data from the Institute of Medicine
estimated RSV deaths in children less than 5 years of age to be approximately
4,500 per year. However, current rates for children less than 2 years of age
with a primary diagnosis of RSV are low—three to four deaths per 10,000
hospitalizations. Furthermore, almost all patients who died during a hospi-
talization associated with RSV infection had complex, chronic, underlying
medical conditions.4
In the United States, RSV typically circulates during the fall, winter,
and spring. Highest infection rates occur between December and March,
but regional variations exist (Figure 12-1).5 Florida has an earlier seasonal
onset of RSV with a longer duration.5,6 Urban areas also typically experience
longer durations of the RSV season, which may be attributed to the increased
spread of disease due to population size.7 To monitor onset, offset, peak, and
duration of RSV, the Centers for Disease Control and Prevention monitors
data voluntarily reported to the National Respiratory and Enteric Virus
Surveillance System.8 Data are updated weekly, are publicly available, and can
be used to determine the appropriate timing for RSV immunoprophylaxis.

Etiology and Pathogenesis


RSV is a single-stranded RNA-enveloped virus from the Paramyxovirus
family and Pneumovirus genus. The viral genome encodes 10 viral proteins,
including two glycoproteins that play a role in the pathogenesis of the virus.
The F (fusion) and G (glyco) proteins are involved in the viral attachment
of RSV to the host cells.9
The virus is spread through respiratory secretions with an incubation
period of approximately 5 days.10,11 During early infection, viral replica-
tion occurs in the nasopharynx and then directly spreads to the respiratory
epithelium.12,13 Bronchiolitis and/or pneumonia can occur as the virus
spreads from the upper to the lower respiratory tract. During severe RSV
infection, the necrosis of ciliated epithelial cells, infiltration of peribron-
chiolar mononuclear cells, and submucosal edema can lead to bronchiolar
obstruction with patchy atelectasis.14-16 Infants with lower respiratory tract
Respiratory Syncytial Viruss 157

Figure 12-1. Regional Variations and Duration of RSV Season. Centers for Disease
Control and Prevention. Respiratory syncytial virus (RSV) infection trends and surveil-
lance. CDC website: http://www.cdc.gov/rsv/research/us-surveillance.html. Accessed
March 14, 2015.
158 NICU Primer for Pharmacists

infections may present with wheezing, rales, and/or tachypnea 1 to 3 days


after the onset of rhinorrhea.11,16 Bronchiolitis can lead to acute respiratory
failure with hypoxia, hypercarbia, and severe bronchospasm. The most
severe presentations typically occur in infants less than 2 months of age and
in those born prematurely.1

RSV in Neonates
In the NICU, RSV can cause significant morbidity and mortality especial-
ly in premature neonates or infants with lung disease or congenital heart
disease.17 Neonates with a low gestational age may be at higher risk for RSV
infection because protection against the virus correlates with higher levels of
maternal antibodies against RSV. With premature birth, transplacental trans-
fer of protective maternal antibodies is interrupted, leaving neonates with an
increased risk of acquiring infections.18,19
Because RSV transmission is usually seen with direct contact, health-
care workers or caregivers can bring the virus into neonatal units when it is
typically circulating throughout the general population. Current recommen-
dations emphasize hand hygiene; wearing of gowns, masks, and gloves; and
isolation of any infected neonate. During an RSV outbreak in the NICU,
some institutions have studied immunoprophylaxis with palivizumab, but
due to the lack of data this practice is not supported by the 2014 American
Academy of Pediatrics (AAP) guidelines.20-25

Prevention of RSV and Palivizumab


Palivizumab (Synagis®) was approved in 1998 for the prevention of serious
lower respiratory tract disease caused by RSV in children at high risk.26 In
the IMpact-RSV study, the clinical trial that led to palivizumab’s approval, the
study showed a reduction in the incidence of RSV hospitalization from 10.6
to 4.8% (P <0.001) in those who received palivizumab. Children included
in this study were less than or equal to 24 months of age with chronic lung
disease and those less than or equal to 6 months of age and born preterm (at
or before 35 weeks’ gestational age).27 In another trial conducted in children
with hemodynamically significant congenital heart disease aged less than or
equal to 24 months, palivizumab reduced the rate of RSV hospitalization
from 9.7 to 5.3% (P = 0.003).28 To date, these two trials are the only random-
ized, placebo-controlled, double-blind studies that have been conducted to
Respiratory Syncytial Viruss 159

assess the safety and efficacy of palivizumab. Neither trial, nor any other trials
that followed, has shown a statistically significant reduction in mortality from
RSV with palivizumab.
Palivizumab provides passive immunity against RSV. It is a recombinant
humanized monoclonal antibody that binds to the RSV F protein located
on the envelope of the virus. The binding of the antibody to the F protein
blocks viral fusion to host cells and blocks cell-to-cell fusion of RSV-infected
cells.26 Although palivizumab may block cell-to-cell transmission of RSV, it
is not indicated for the treatment of RSV and has not been shown to reduce
the severity of the infection in children who have had breakthrough infec-
tion while receiving palivizumab prophylaxis.26
Palivizumab is a monthly 15 mg/kg intramuscular injection, typically
administered in the thigh. It does not interfere with other live or inactivated
vaccines, which allows childhood vaccines to be administered as scheduled.
The first dose is administered prior to the start of the RSV season and
monthly thereafter for a total maximum of five monthly doses per RSV
season.21,26 In neonates born during the RSV season, palivizumab should be
given only during the defined season and will require fewer than five doses.21
Palivizumab provides protection against the RSV virus for approximately 1
month; common side effects include fever and rash. After initial exposure or
re-exposure, some children have experienced severe allergic reaction.26

Palivizumab Guidelines for Use


The AAP receives input from within and outside organizations such as the
American College of Chest Physicians, American College of Emergency
Physicians, American Thoracic Society, Emergency Nurses Association,
National Association of Neonatal Nurses, National Association of Neonatal
Nurse Practitioners, and Society of Hospital Medicine.21 Since palivizumab’s
approval in 1998, the AAP has updated its guidelines four times—most
recently in 2014. The current guidelines (after unanimous consensus from
21 committees, councils, sections, and advisory groups) define children as
having the greatest risk of serious RSV disease.
Infants in the neonatal unit who qualify for prophylaxis are recommended
to receive the first dose of palivizumab 48 to 72 hours before discharge
home or soon after discharge. Those in the NICU who qualify for prophy-
laxis include infants born before 29 weeks’ gestation or those with chronic
lung disease or congenital heart disease.21
160 NICU Primer for Pharmacists

Previous guidelines recommended that prophylaxis be administered


during the first year of life in infants born before 32 weeks’ gestation or
those less than 35 weeks’ gestation if the infant would attend childcare or
had siblings younger than 5 years old in the same household.29 More recent
studies show that, in the absence of chronic lung disease, those born before
29 weeks’ gestation have a hospitalization rate two to four times higher than
other preterm neonates.3,30 The results of these studies support immuno-
prophylaxis with palivizumab only in those born before 29 weeks of age in
otherwise healthy infants.
The 2014 guidelines also support the use of palivizumab in the first year
of life in preterm infants with chronic lung disease of prematurity, which is
defined as those born less than 32 weeks’ gestational age with the require-
ment for greater than 21% oxygen for at least 28 days after birth. These
guidelines are similar to previous recommendations but have added the
definition of chronic lung disease.29,31
Children with hemodynamically significant congenital heart disease are
supposed to receive palivizumab prophylaxis in the first year of life. Previ-
ous guidelines recommended prophylaxis also in the second year of life, but
retrospective analysis found that the incidence of RSV hospitalization of
infants with congenital heart disease in the second year of life was significantly
less than low-risk infants for whom prophylaxis was never recommended.
The recommendation for prophylaxis during the second year of life was
removed.17,31
Other recommendations for palivizumab prophylaxis include
❖❖ continuing prophylaxis during the second year of life in children with
chronic lung disease who require medical intervention such as supple-
mental oxygen, chronic corticosteroids, or diuretics
❖❖ considering the use of palivizumab in the first year of life in children
with pulmonary abnormalities or neuromuscular disease that impair the
ability to clear secretions from upper airways
❖❖ children younger than 24 months who are immunocompromised21
❖❖ broader use in Alaska Native and some American Indian populations
because of difficulties transporting patients from remote locations and
the higher incidences of hospitalizations32-37
❖❖ discontinuing monthly prophylaxis in any child experiencing break-
through RSV hospitalization
Respiratory Syncytial Viruss 161

❖❖ ceasing palivizumab for prevention of healthcare-associated RSV


disease21

Bronchiolitis Management
Treatment for viral bronchiolitis is primarily symptomatic. Most children
can be managed at home, but patients need to be admitted in moderate or
severe cases where hypoxia is present. The 2014 AAP bronchiolitis guide-
lines emphasize hydration and supplemental oxygen as the mainstays of
therapy.38,39
Various pharmacological treatments have been studied for the treatment
of bronchiolitis, but available evidence does not support their use. The
antiviral ribavirin has not been proven to reduce RSV mortality or hospital-
izations, and nebulized epinephrine has not been shown to have a clinically
significant benefit in the inpatient setting.40,41 Systemic corticosteroids also
are not recommended for the treatment of bronchiolitis, and systematic
reviews show that this treatment does not significantly reduce outpatient
admissions or length of stay of inpatients.42 Moreover, the use of antibiotics
is not recommended unless there is a concurrent bacterial infection or
strong suspicion of one.39
Current AAP guidelines no longer support a trial of albuterol or salbu-
tamol in infants and children with bronchiolitis. Systematic reviews have
shown that bronchodilators may improve clinical symptom scores, but this
is an invalidated measure of the efficacy of bronchodilators and scores may
vary by observer.39 In systematic reviews, the use of bronchodilators did not
improve disease resolution, need for hospitalization, or length of stay.43,44
Therapy using nebulized hypertonic saline has shown benefit in treating
bronchiolitis and is included in the AAP guidelines. Hypertonic saline may
play a role in increasing mucociliary clearance and/or rehydrating the airway
surface liquid.45,46 Results in a Cochrane Review demonstrated that nebulized
saline (most utilized 3% saline) may reduce length of stay by 1 day in
patients with longer lengths of stay of 5 to 6 days.47 The 2014 guidelines
recommend that nebulized hypertonic saline may be considered in children
who are hospitalized with bronchiolitis. However, this recommendation is
considered weak because it was based on randomized, controlled trials with
inconsistent findings in patients with mild or moderate disease and did not
include hypertonic saline use in intensive care settings.39
162 NICU Primer for Pharmacists

Conclusion
RSV infections continue to cause significant morbidity in select high-risk
groups. Although the recent analyses provide substantial reassurance, poten-
tial for mortality remains. Currently, no antiviral treatments provide good
efficacy for RSV treatment so prevention is the mainstay of therapy. It is
important that healthcare personnel in contact with RSV patients disinfect
their hands before and after care with alcohol-based rubs or soap and water
to prevent the spread of this virus. Because no vaccine is available for RSV,
palivizumab is the only recommended immunoprophylaxis that can be
administered. Strict adherence to guidelines ensures the most at-risk popula-
tions receive the benefit of this costly drug, in light of its lack of proven
mortality benefit.

References
1. Simoes EA. Respiratory syncytial virus infection. Lancet. 1999;354:847-52.
2. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus
infection in young children. N Engl J Med. 2009;360:588-98.
3. Hall CB, Weinberg GA, Blumkin AK, et al. Respiratory syncytial virus-associated
hospitalizations among children less than 24 months of age. Pediatrics. 2013
Aug;132(2):e341-8.
4. Byington CL, Wilkes J, Korgenski K, et al. Respiratory syncytial virus—asso-
ciated mortality in hospitalized infants and young children. Pediatrics. 2015
Jan;135(1):e24-31.
5. Mullins JA, Lamonte AC, Bresee JS, et al. Substantial variability in community respira-
tory syncytial virus season timing. Pediatr Infect Dis J. 2003;22:857-62.
6. Panozzo CA, Fowlkes AL, Anderson LJ. Variation in timing of respiratory syncytial
virus outbreaks: lessons from national surveillance. Ped Infect Dis J. 2007;26
(11 Suppl):S41-5.
7. Zachariah P, Shah S, Gao D, et al. Predictors of the duration of the respiratory syncy-
tial virus season. Ped Infect Dis J. 2009 Sep;28(9):772-6.
8. Centers for Disease Control and Prevention. Respiratory syncytial virus circulation in
the United States, July 2012–June 2014. MMWR. 2014;62:141-4.
9. Domachowske JB, Rosenberg HF. Respiratory syncytial virus infection: immune
response, immunopathogenesis, and treatment. Clin Microbiol Rev. 1999
Apr;12(2):298-309.
10. Kapikian AZ, Bell JA, Mastrota FM, et al. An outbreak of febrile illness and pneumo-
nia associated with respiratory syncytial virus infection. Am J Hyg. 1961;74:234-48.
Respiratory Syncytial Viruss 163

11. Sterner G, Wolontis S, Bloth B, et al. Respiratory syncytial virus: an outbreak of acute
respiratory illnesses in a home for infants. Acta Paedriatr Scand. 1966;55:273-9.
12. Hall CB, Douglas RG, Geiman JM. Quantitative shedding patterns of respiratory
syncytial virus in infants. J Infect Dis. 1975;132(2):151-6.
13. Hall CB, Douglas RG, Geiman JM. Respiratory syncytial virus infection in infants:
quantitation and duration of shedding. J Pediatr. 1976;89(1):11-5.
14. Aherne W, Bird T, Court SDM, et al. Pathologic changes in virus infections of the
lower respiratory tract in children. J Clin Pathol. 1970;23:7-18.
15. Gardner PS. How etiologic, pathologic, and clinical diagnoses can be made in a cor-
related fashion. Pediatr Res. 1977;11:254-61.
16. Gardner PS, McQuillin J, Court SDM. Speculation on pathogenesis in death from
respiratory syncytial virus infection. Br Med J. 1970;1:327-30.
17. Boyce TG, Mellen BG, Mitchel EF Jr, et al. Rates of hospitalization for respiratory syn-
cytial virus infection among children in Medicaid. J Pediatr. 2000 Dec;137(6):865-70.
18. de Dierra TM, Kumar ML, Wasser TE, et al. Respiratory syncytial virus-specific
immunoglobulins in preterm infants. J Pediatr. 1993 May;122(5 Pt 1):787-91.
19. Ogilvie MM, Vathenen AS, Radford M, et al. Maternal antibody and respiratory syn-
cytial virus infection in infancy. J Med Virol. 1981;7:263-71.
20. Abadesso C, Almeida HI, Virella D, et al. Use of palivizumab to control an outbreak of
syncytial respiratory virus in a neonatal intensive care unit. J Hosp Infect. 2004;58:38-
41.
21. American Academy of Pediatrics Committee on Infectious Diseases, American Acad-
emy of Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivi-
zumab prophylaxis among infants and young children at increased risk of hospitaliza-
tion for respiratory syncytial virus infection. Pediatrics. 2014 Aug;134(2):415-20.
22. Dizdar EA, Aydemir C, Erdeve O, et al. Respiratory syncytial virus outbreak defined
by rapid screening in a neonatal intensive care unit. J Hosp Infect. 2010;75:292-4.
23. Kilani RA. Respiratory syncytial virus (RSV) outbreak in the NICU: description of
eight cases. J Trop Pediatr. 2002 Apr;48(2):118-22.
24. Kurz H, Herbich K, Janata O, et al. Experience with the use of palivizumab together
with infection control measures to prevent respiratory syncytial virus outbreaks in
neonatal intensive care units. J Hosp Infect. 2008;70:246-52.
25. Silva C, Dias L, Baltieri SR, et al. Respiratory syncytial virus outbreak in neonatal
intensive care unit: Impact of infection control measures plus palivizumab use. Antimi-
crob Resist Infect Control. 2012 May 2;1(1):16.
26. Synagis [package insert]. Gaithersburg, MD: MedImmune, LLC; 2014.
27. IMpact-RSV study group. Palivizumab, a humanized respiratory syncytial virus mono-
clonal antibody, reduces hospitalization from respiratory syncytial virus infection in
high-risk infants. Pediatrics. 1998;102(3):531-7.
164 NICU Primer for Pharmacists

28. Feltes TF, Cabalka AK, Meissner HC, et al. Palivizumab prophylaxis reduces hospi-
talization due to respiratory syncytial virus in young children with hemodynamically
significant congenital heart disease. J Pediatr. 2003 Oct;143(4):532-40.
29. Committee on Infectious Diseases. From the American Academy of Pediatrics: Policy
statements—Modified recommendations for use of palivizumab for prevention of
respiratory syncytial virus infections. Pediatrics. 2009 Dec;124(6):1694-701.
30. Stevens TP, Sinkin RA, Hall CB, et al. Respiratory syncytial virus and premature
infants born at 32 weeks’ gestation or earlier: hospitalization and economic
implications of prophylaxis. Arch Pediatr Adolesc Med. 2000;154(1):55-61.
31. American Academy of Pediatrics Committee on Infectious Diseases, American Acad-
emy of Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivi-
zumab prophylaxis among infants and young children at increased risk of hospitaliza-
tion for respiratory syncytial virus infection. Pediatrics. 2014 Aug;134(2):e620-38.
32. Banerji A, Bell A, Mills EL, et al. Lower respiratory tract infections in Inuit infants on
Baffin Island. CMAJ. 2001;164(13):1847-50.
33. Bockova J, O’Brien KL, Oski J, et al. Respiratory syncytial virus infection in Navajo
and White Mountain Apache children. Pediatrics. 2002;110(2 pt 1):e20.
34. Lowther SA, Shay DK, Holman RC, et al. Bronchiolitis associated hospitalizations
among American Indian and Alaska Native children. Pediatr Infect Dis J.
2000;19(1):11-7.
35. Singleton RJ, Bulkow LR, Miernyk K, et al. Viral respiratory infections in hospitalized
and community control children in Alaska. J Med Virol. 2010;82(7):1282-90.
36. Tam DY, Banerji A, Paes BA, et al. The cost effectiveness of palivizumab in term Inuit
infants in the Eastern Canadian Arctic. J Med Econ. 2009;12(4):361-70.
37. Young M, Kandola K, Mitchell R, et al. Hospital admission rates for lower respiratory
tract infections in infants in the Northwest Territories and the Kitikmeot region of
Nunavut between 2000 and 2004. Paediatr Child Health. 2007;12(7):563-6.
38. Fitzgerald DA, Kilham HA. Bronchiolitis: assessment and evidence-based management.
Med J Aust. 2004;180:399-404.
39. Ralston SL, Lieberthal AS, Meissner HC, et al. Clinical practice guideline:
the diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014
Nov;134(5):e1474-502.
40. Ventre K, Randolph AG. Ribavirin for respiratory syncytial virus infection of the
lower respiratory tract in infants and young children. Cochrane Database Syst Rev.
2007;(1):CD000181.
41. Wainwright C, Altamirano L, Cheney M, et al. A multicentre, randomized, double-
blind controlled trial of nebulized epinephrine in infants with acute bronchiolitis. N
Engl J Med. 2003;349:27-35.
Respiratory Syncytial Viruss 165

42. Fernandes RM, Bialy LM, Vandermeer B, et al. Glucocorticoids for acute viral
bronchiolitis in infants and young children. Cochrane Database Syst Rev.
2013;(6):CD004878.
43. Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database
Syst Rev. 2014;(6):CD001266.
44. King VJ, Viswanathan M, Bordley WC, et al. Pharmacologic treatment of bron-
chiolitis in infants and children: a systematic review. Arch Pediatr Adolesc Med.
2004;158:127-37.
45. Daviskas E, Anderson SD, Gonda I, et al. Inhalation of hypertonic saline aerosol
enhances mucociliary clearance in asthmatic and healthy subjects. Eur Respir J.
1996;9(4):725-32.
46. Mandelberg A, Amirav I. Hypertonic saline or high volume normal saline for viral
bronchiolitis: mechanisms and rationale. Pediatr Pulmonol. 2010;45(1):36-40.
47. Zhang L, Mendoza-Sassi RA, Wainwright C, et al. Nebulised hypertonic
saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev.
2013;(7):CD006458.

Suggested Readings
American Academy of Pediatrics Committee on Infectious Diseases, American Academy of
Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivizumab
prophylaxis among infants and young children at increased risk of hospitalization for
respiratory syncytial virus infection. Pediatrics. 2014;134(2):e620-38.
Andabaka T, Nickerson JW, Rojas-Reyes MX, et al. Monoclonal antibody for reducing the
risk of respiratory syncytial virus infection in children. Cochrane Database Syst Rev.
2013 Apr 30;(4):CD006602.
13
Necrotizing Enterocolitis

John Brock Harris, PharmD, BCPS

Introduction

N
ecrotizing enterocolitis (NEC) is
a gastrointestinal (GI) infectious
disease most often experienced by
preterm neonates. NEC is characterized by
ischemia within any part of the intestine
usually involving the terminal ileum.
Although the exact mechanisms leading to
NEC are unknown, the disease state is related
to the interplay of intestinal flora, intestinal
perfusion, enteral nutrition, and stress.1

Epidemiology
With neonatal care advances and
increased survival in preterm neonates,
168 NICU Primer for Pharmacists

the incidence of NEC has increased. The median onset is 10 days after
birth. Fifty percent of NEC occurrences are in neonates with birth weights
less than 1.5 kg. Eighty percent of cases occur in neonates weighing less
than 2.5 kg at birth.2 Neonates weighing less than 1.5 kg at birth have an
incidence of 6 to 12%,3,4 and one-third of them with a diagnosis of NEC
will die.4 Overall mortality rates range from 10 to 50%.5

Pathophysiology
The pathophysiology of NEC is multifactorial and not fully understood.
The underlying hypothesis for NEC is unregulated inflammatory responses
to colonization of bacteria within the intestine.4 NEC may be a response by
an immature GI tract to an injury.6 Feeding strategy and genetic predisposi-
tion may also contribute (Figure 13-1).7

Prematurity

Immaturity of Intestine

Barrier Function Circulatory Regulation Immune Defense Motility and Digestion

Necrotizing Enterocolitis

Genetic Predisposition Abnormal Bacterial Colonization Feeding

Figure 13-1. NEC Pathophysiology


Source: Adapted from Semin Perinatol. 2008 Apr;32(2):70-82. Lin PW, Nasr TR, Stroll BJ.
Necrotizing enterocolitis: recent scientific advances in pathophysiology and prevention.
©2008 with permission from Elsevier.
Necrotizing Enterocolitis 169

Presentation
NEC has a spectrum of presentation. One of the first staging criteria was devel-
oped by Bell et al.8 Staging gives a starting point for treatment approaches.
❖❖ Bell Stage I—Suspected NEC
Characteristics include history of stress; GI signs such as abdominal
distention (mild), bloody stools, emesis (bilious or bloody), increasing
pre-feeding residuals, and poor toleration of feedings; and systemic
indicators such as apnea, bradycardia, lethargy, and temperature instabil-
ity. Abdominal radiography illustrates abdominal distention with mild
ileus.
❖❖ Bell Stage II—Definite NEC
Characteristics include Stage I features with the following differences:
gross or persistent GI bleeding and significant abdominal distention.
Abdominal radiography shows significant abdominal distention with
ileus, small bowel edema, pneumatosis intestinalis (intestinal intralumi-
nal gas), portal venous gas, or unchanging rigid or fixed loops of bowel.
❖❖ Bell Stage III—Advanced NEC
Characteristics include features of Stage I and Stage II with the follow-
ing differences: worsening of vital signs, septic shock, and GI bleeding.
Abdominal radiography illustrates pneumoperitoneum in addition to
Stage II findings.8
A modified Bell staging approach was described by Kliegman and Walsh,
incorporating subcategories and therapeutic options for each subcategory
(Table 13-1).9
The most common parts of the GI system affected—in order of decreas-
ing frequency—are the terminal ileum, right colon, colon (transverse and
descending), appendix, jejunum, stomach, duodenum, and esophagus.2
Peritonitis may also be present. Abdominal signs of peritonitis include
discoloration, edema, induration, and resistance to palpation.10 Neonates
may also experience leukopenia, leukocytosis, bandemia, thrombocytopenia,
metabolic acidosis, or hyperglycemia.2,3

Diagnosis
Diagnostic characteristics are abdominal distention or tenderness, bloody
stools, evidence of intolerance to feedings by emesis or pre-feeding residuals,
170 NICU Primer for Pharmacists

Table 13-1. Modified Bell’s Staging Criteria and Treatment


Approaches for NEC
Intestinal Systemic Radiographic Treatment
Stage Signs Signs Signs Approach
Suspected Emesis, guaiac Apnea, Normal or NPO;
NEC– positive stools, bradycardia, intestinal antibiotics
Stage IA increased lethargy, dilation, mild for 72 hours
pre-feeding temperature ileus pending
residuals, mild instability microbiology
abdominal results
distention
Suspected Bright, red Stage IA signs Stage IA signs Stage IA
NEC– blood from approaches
Stage IB rectum
Definite Stage IA and Stage IA signs Ileus, intestinal NPO;
NEC– IB signs PLUS dilation, antibiotics for
Stage IIA absent or pneumatosis 7−10 days
(mildly ill) diminished intestinalis with normal
bowel examination
sounds with at 1−2 days
or without
abdominal
tenderness
Definite Stage IIA signs Stage IA signs Stage IIA NPO;
NEC– PLUS absent PLUS mild signs with antibiotics
Stage IIB bowel sounds, metabolic or without for 14 days,
(moderately abdominal acidosis and ascites, with or sodium
ill) tenderness, mild thrombo- without portal bicarbonate
with or without cytopenia venous gas for acidosis
abdominal correction
cellulitis, with
or without
right lower
quadrant mass
Necrotizing Enterocolitis 171

Table 13-1 (continued). Modified Bell’s Staging Criteria and


Treatment Approaches for NEC
Intestinal Systemic Radiographic Treatment
Stage Signs Signs Signs Approach
Advanced Stage IIB Stage IIB signs Stage IIB signs Stage IIB
NEC– signs PLUS PLUS anuria, with ascites approaches
Stage IIIA abdominal disseminated PLUS
(intact distention, intravascular increased
bowel, abdominal coagulation, fluids and
severely ill) wall erythema, hypotension, blood
peritonitis, respiratory products,
marked and metabolic inotropic
abdominal acidosis, medications,
tenderness neutropenia, intubation,
and severe paracentesis,
apnea mechanical
ventilation,
and possibly
surgical
approaches
without
improvement
at 1−2 days
Advanced Stage IIIA signs Stage IIIA Stage IIB signs Stage IIIA
NEC– signs with pneumo- PLUS
Stage IIIB peritoneum surgical
(perforated intervention
bowel,
severely ill)
NEC: necrotizing enterocolitis; NPO: nothing by mouth
Sources: Adapted with permission from Bell MJ, Ternberg JL, Feigin RD, et al. Neona-
tal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Annals
of Surgery. 1978;187(1):1-7.
Adapted from Curr Probl Pediatr. 1987 Apr;17(4):213-88. Kliegman RM, Walsh MC.
Neonatal necrotizing enterocolitis: pathogenesis, classification, and spectrum of dis-
ease. ©1987 with permission from Elsevier.
172 NICU Primer for Pharmacists

and abdominal radiographic findings (e.g., pneumatosis intestinalis).3 Other


characteristics are components of the Bell staging criteria and physical
examination. Presence of pneumatosis intestinalis confirms diagnosis of NEC.

Medical Treatment
The first step in medical management is to stop enteral intake, while
initiating bowel rest and GI decompression, and start empiric parenteral
antibiotics preventing bacterial invasion and translocation. Parenteral
nutrition (PN) support may also be initiated. An infectious workup should
be performed including microbiologic evaluation of blood, cerebral spinal
fluid, and urine.11 Specific approaches for PN support are not discussed.
(For information on PN, see Chapter 3.)

Empiric Antibiotics
Parenteral empiric antibiotics should be initiated when NEC is suspected
and then continued with diagnosis. The antibiotic regimen should cover
gram-negative, gram-positive, and possibly anaerobic bacteria. Empiric
regimens may include an aminoglycoside or third-generation cephalosporin
for gram-negative bacteria coverage, ampicillin or vancomycin for gram-
positive coverage, and possibly clindamycin or metronidazole for anaerobic
coverage.11 Empiric antibiotic regimens should be de-escalated after a
pathogen is identified and susceptibilities are available. Serum concentration
monitoring is recommended for aminoglycoside- and vancomycin-containing
regimens if continued beyond 48 to 72 hours. Renal function monitoring,
which includes laboratory assessment and urine output assessment, is also
recommended.

Anaerobic Antibiotic Treatment


Anaerobic antibiotic use is defined as administration of an antimicrobial
medication with anaerobic spectrum coverage in vitro against intestinal
anaerobic bacilli on day 1 of NEC treatment. Medications with anaerobic
coverage include amoxicillin−sulbactam, ampicillin−sulbactam, cefoxitin,
clindamycin, metronidazole, moxifloxacin, piperacillin−tazobactam, or
any carbapenem. Very low birth weight (VLBW) (≤1.5 kg) neonates were
assessed for a composite end point of death during hospital admission and
intestinal strictures as well as the end points individually by comparing
to matched neonates who did not receive anaerobic coverage for NEC
Necrotizing Enterocolitis 173

treatment. Patients were stratified to either medical or surgical treatments.


Neonates receiving anaerobic treatment as part of the antibiotic regimen did
not differ from comparators for the overall end point. However, the anaer-
obic treatment group did have more intestinal strictures (odds ratio [OR]
1.73; 95% confidence interval [CI] 1.11−2.72). Mortality was decreased in
surgically treated neonates who received anaerobic coverage as part of the
regimen (OR 0.71; 95% CI 0.52−0.95). Anaerobic coverage as part of the
antimicrobial treatment regimen for medically treated NEC may not add
benefit.12 In the presence of pneumoperitoneum, anaerobic coverage should
be considered.13

Duration of Antibiotic Therapy


Neonates with suspected NEC may receive antibiotics for 72 hours. After
48 to 72 hours, few patients progress to higher stages. Definitive NEC may
be treated with antibiotics for 7 to 14 days. Severe NEC requiring surgical
management may receive antibiotics up to 21 days after surgery.9

Surgical Treatment
Surgical treatment is used in conjunction with medical treatment approaches.
Published surgical NEC treatment rates are 20 to 60% of NEC occur-
rences.11,13 Surgical treatment may be warranted if a pneumoperitoneum is
present; radiographic, clinical, or laboratory signs worsen; or medically treat-
ed neonates do not improve.11
The two main surgical approaches are laparotomy or peritoneal drainage.
An overview is provided. Data have shown no difference between the two
methods in extremely low birth weight (ELBW) and unstable neonates.11,14
Portions of necrotic intestine are resected during a laparotomy followed by
either a primary reanastomosis or ostomy. If an ostomy is utilized, reanas-
tomosis is performed after neonatal recovery. Drainage removes inflamma-
tory and infected fluid from the peritoneum. If patients do not improve, a
laparotomy may be warranted.11

Risks
Antibiotic Administration
Greater than or equal to 5 days’ duration of empiric antibiotics initiated
during the first 72 hours of life for ELBW (0.4–1 kg) neonates with sterile
174 NICU Primer for Pharmacists

cultures increases risk of NEC.15 However, a direct association between


prolonged empiric antibiotic administration within the first week of life and
NEC cannot be confirmed. In neonates ≤32 weeks’ gestation and ≤1.5 kg at
birth, prolonged empiric antibiotic administration did not result in increased
risk of NEC.16

Red Blood Cell Transfusions


VLBW neonates may have increased risk of developing Bell Stage II or Stage
III NEC within 48 hours after a packed red blood cell (PRBC) transfusion.
NEC presented after 1.4% of PRBC transfusions in the patient population
(OR 2.3; 95% CI 1.2–4.2).17 A case-control study conducted in a similar
neonatal population also has increased risk of NEC development within
48 hours’ post PRBC transfusion (OR 2.97; 95% CI 1.46–6.05). Neonates
receiving enteral feeds 48 hours prior to a transfusion drastically increased
the risk of developing NEC (OR 8.68; 95% CI 2.45–30.8).18 A smaller
study contradicted the increased risk of Bell Stage II or Stage III NEC after
PRBC transfusions showed a decreased risk in the same population.19

Congenital Heart Disease


Ductal-dependent congenital heart lesions may have an increased risk for
developing NEC. When corrected for gestational age, neonates receiving
prostaglandin infusions for single-ventricle cardiac defects have an increased
risk of developing NEC compared to patients who do not receive prosta-
glandins (OR 2.82; 95% CI 1.23–6.49). Specifically, neonates with hypo-
plastic left heart syndrome have more risk for NEC development (OR 3.12;
95% CI 1.16–8.43).20 Neonates with single-ventricle cardiac physiology,
especially left ventricular outflow defects, have variation in blood circula-
tion. Along with physiologic circulatory variation, cardiac surgery stress,
increased serum pro-inflammatory cytokine and endotoxin concentrations,
and ischemia caused by cardiopulmonary bypass play an integral part in
NEC pathogenesis.21

Medications
A retrospective review concluded antenatal indomethacin use as a tocolytic
medication in preterm labor increases risk of NEC in neonates (relative
risk [RR] 1.36; 95% CI 1.08–1.71).22 A retrospective review of neonates
receiving caffeine for apnea of prematurity prophylaxis within 48 hours
Necrotizing Enterocolitis 175

of birth determined no increased risk of NEC in neonates (adjusted OR


0.88; 95% CI 0.65–1.2).23

Prevention
Human Milk
Human milk may decrease the risk of NEC in ELBW neonates. A larger
percentage of human milk during the first 14 days of life compared to total
enteral intake (human milk plus formula) reduces NEC risk proportionally
to percentage of human milk.24

Trophic Feeding
Initiation of trophic or non-nutritive feedings in preterm neonates decreases
NEC risk. Trophic feeding is defined as 20 mL/kg/day of human milk or
preterm formula. Trophic feedings induce GI enzyme activity and stimulate
peristalsis. Neonates who receive trophic feedings for up to 10 days have
decreased risk of NEC compared to neonates who advance feedings quicker.11

Probiotics
A systematic review concluded probiotics may be beneficial in preventing
severe NEC defined as Bell Stage II and Stage III (RR 0.43; 95% CI 0.33–0.56)
and decreasing mortality (RR 0.65; 95% CI 0.52–0.81) in preterm neonates.
However, neonatal population characteristics, probiotic choice, and dosing
varied between included studies. Lactobacillus species in combination or
alone were effective. 25

Antenatal Corticosteroids
Antenatal corticosteroids administered to mothers prior to preterm delivery
not only promote fetal lung maturation but decrease risk of NEC due to GI
tract maturation. Maternal administration of antenatal corticosteroids is the
mainstay of therapy for potential preterm deliveries (see Chapter 1).11

Conclusion
NEC is a disease caused by the interplay of multiple components. Treat-
ment consists of antibiotic therapy and possibly surgery. Minimizing known
risks and utilizing risk reduction strategies lessen the impact of the disease
on preterm neonates. Biomarkers are currently being investigated to screen
neonates for earlier detection in hopes of improving outcomes.26
176 NICU Primer for Pharmacists

References
1. Bhatt-Mehta V. Introduction to neonatology. In: Benavides S, Nahata MC, eds. Pediat-
ric Pharmacotherapy. Lenexa, KS: American College of Clinical Pharmacy; 2013:42-3.
2. Albanese CT, Sylvester KG.  Pediatric surgery. In: Doherty GM, ed. CURRENT
Diagnosis & Treatment: Surgery. 13th ed. New York, NY: McGraw-Hill; 2010.
http://accessmedicine.mhmedical.com/content. aspx?bookid=343&Sectionid=
39702831. Accessed January 7, 2015.
3. Rosenberg AA, Grover T. The newborn infant. In: Hay WW Jr, Levin MJ, Deterding
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4. Grave GD, Nelson SA, Walker WA, et al. New therapies and preventive approaches for
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5. Hackam DJ, Grikscheit TC, Wang KS, et al.  Pediatric surgery. In: Brunicardi F,
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6. Kliegman RM, Fanaroff AA. Necrotizing enterocolitis. N Engl J Med. 1984;310(17):
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7. Lin PW, Nasr TR, Stroll BJ. Necrotizing enterocolitis: recent scientific advances in
pathophysiology and prevention. Semin Perinatol. 2008;32:70-82.
8. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis: therapeutic
decisions based upon clinical staging. Ann Surg. 1978;187(1):1-7.
9. Kliegman RM, Walsh MC. Neonatal necrotizing enterocolitis: pathogenesis, classifica-
tion, and spectrum of disease. Curr Prob Pediatr. 1987;17(4):219-88.
10. Green M. Pediatric Diagnosis. 5th ed. Philadelphia, PA: WB Saunders Company;
1992:213.
11. Thompson AM, Bizzarro MJ. Necrotizing enterocolitis in newborns; pathogenesis,
prevention and management. Drugs. 2008;68(9):1227-38.
12. Autmizguine J, Hornik CP, Benjamin DK Jr, et al. Anaerobic antimicrobial therapy
after necrotizing enterocolitis in VLBW infants. Pediatrics. 2015;135(1):e117-25.
13. Lin PW, Stoll BJ. Necrotising enterocolitis. Lancet. 2006;368:1271-83.
14. Roa SC, Basani L, Simmer K, et al. Peritoneal drainage versus laparotomy as initial
surgical treatment for perforated necrotizing enterocolitis or spontaneous intestinal
perforation in preterm low birth weight infants (review). Cochrane Database Syst Rev.
2011;6:CD006182.
Necrotizing Enterocolitis 177

15. Cotton CM, Taylor S, Stroll B, et al. Prolonged duration of initial empirical antibiotic
treatment is associated with increased rates of necrotizing enterocolitis and death for
extremely low birth weight infants. Pediatrics. 2009;123(1):58-66.
16. Kuppala VS, Meinzen-Derr J, Morrow AL, et al. Prolonged initial empiric antibi-
otic treatment is associated with adverse outcomes in premature infants. J Pediatr.
2011;159(5):720-5.
17. Paul DA, Mackley A, Novitsky A, et al. Increased odds of necrotizing enterocolitis after
transfusion of red blood cells in premature infants. Pediatrics. 2011;127:635-41.
18. Wan-Huen P, Bateman D, Shapiro DM, et al. Packed red blood cell transfusions is an
independent risk factor for necrotizing enterocolitis in premature infants. J Perinatol.
2013;33(10):786-90.
19. Alfaleh K, Al-Jebreen A, Baqays A, et al. Association of packed red blood cell transfu-
sion and necrotizing enterocolitis in very low birth weight infants. J Neonatal Perinatal
Med. 2014;7(3):193-8.
20. Becker KC, Hornik CP, Cotton CM, et al. Necrotizing enterocolitis in infants with
ductal-dependent congenital heart disease Am J Perinatol. 2014. [Published ahead of
print December 8, 2014]. Accessed January 12, 2015.
21. Giannone PJ, Luce WA, Nankervis CA, et al. Necrotizing enterocolitis in neonates
with congenital heart disease. Life Sciences. 2008;82:341-7.
22. Hammers AL, Sanchez-Ramos L, Kaunitz AM. Antenatal exposure to indomethacin
increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and
periventricular leukomalacia: a systematic review with metaanalysis. Am J Obstet Gyne-
col. 2015;212:e1-3.
23. Lodha A, Seshla M, McMillian DD, et al. Association of early caffeine administration
and neonatal outcomes in very premature neonates. JAMA Pediatr. 2015;169(1):33-8.
24. Meinzen-Derr J, Poindexter B, Wrage L, et al. Role of human milk in extremely
low birth weight infants’ risk of necrotizing enterocolitis or death. J Perinatol.
2009;29(1):57-62.
25. Alfaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm
infants (review). Evid-Based Child Health. 2014;9(3):584-671.
26. Sim K, Shaw AG, Randell P, et al. Dysbiosis anticipating necrotizing enterocolitis in
very premature infants. Clin Infect Dis. 2015;60(3):389-97.

Suggested Readings
Alfaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm
infants (review). Evid-Based Child Health. 2014;9(3):584-671.
Henry MC, Moss RL. Neonatal necrotizing enterocolitis. Semin Pediatr Surg. 2008;17:98-
109.
178 NICU Primer for Pharmacists

Lin PW, Nasr TR, Stroll BJ. Necrotizing enterocolitis: recent scientific advances in
pathophysiology and prevention. Semin Perinatol. 2008;32:70-82.
Lin PW, Stoll BJ. Necrotising enterocolitis. Lancet. 2006;368:1271-83.
Thompson AM, Bizzarro MJ. Necrotizing enterocolitis in newborns; pathogenesis, preven-
tion and management. Drugs. 2008;68(9):1227-38.
Young CM, Kingma SD, Neu J. Ischemia-reperfusion and neonatal intestinal injury.
J Pediatr. 2011;158:e25-8.
14
Gastrointestinal Disorders

John Brock Harris, PharmD, BCPS

Introduction

G
astroesophageal reflux (GER)
and constipation are gastroin-
testinal (GI) disorders that may
affect patients while in the NICU. The
impact that GER and constipation have
on patient outcomes during admission
vary based on other patient conditions.
However, both disorders may adversely
affect a neonate’s enteral feeding toler-
ability. Properly addressing GER and
constipation through nonpharmaco-
logic or pharmacologic interventions is
paramount for adequate enteral feeding
in neonatal populations.
180 NICU Primer for Pharmacists

Gastroesophageal Reflux
Epidemiology
Regurgitation or GER is a normal process in neonates. Neonates have
anatomical and physiological characteristics leading to GER such as
decreased lower esophageal sphincter pressures, immature peristalsis, shorter
esophageal length, and delayed gastric emptying to a lesser extent.1,2 In the
first months of life, reflux is present with a peak incidence at approximately 4
months of age.3 GER typically resolves by 1 year of age.3-5 Gastroesophageal
reflux disease (GERD), pathologic GER, is rare in neonatal populations.

Presentation
Neonates presenting with anemia, blood in stool, failure to thrive, food
refusal, hematemesis, and swallowing difficulties should be evaluated for
GER and GERD. Risk factors for GERD are prematurity and congenital
abnormalities of the central nervous system, chest, GI tract, heart, lungs,
or oropharynx.6 Acute signs and symptoms of GERD in neonates are back
arching during or after feedings, crying and irritability, food refusal, and
regurgitation or vomiting. Long-term signs and symptoms include poor
weight gain and failure to thrive.7

Treatment
Nonpharmacologic
The goal of treatment is to relieve symptoms while preventing complica-
tions. In 2004, a survey was conducted of GERD treatment approaches in
77 NICUs. Body positioning (98%), feed thickening (98%), and placing
the neonate on a slope (96%) were used most often as nonpharmacologic
approaches.8 Body positioning improves GER symptoms. Approaches related
to body positioning include head of bed elevation, left lateral position, prone
position, and upright posture in seats.9,10 Prone and left lateral positioning
increase the risk of sudden infant death syndrome,7 although left lateral
position decreases GER compared to head of bed elevation.9 Thickening
feeds have proven to reduce nonacid GER frequency and height in infants.
However, no differences in acid GER were experienced. Thickening feeds
may be an option to reduce symptomatic nonacid GER.11 Both intermittent
and continuous enteral feeding strategies have been studied to determine the
best approach to reduce GER symptoms. Because data are inconclusive, no
Gastrointestinal Disorders 181

specific feeding method is recommended at this time.12 Insufficient evidence


suggests non-nutritive sucking as a treatment approach.13

Pharmacologic
In a survey of 77 NICUs conducted prior to the 2009 guideline publica-
tion,7 the pharmacologic treatment approaches consisted of H2-receptor
antagonists (H2RAs) (100%), antacids (96%), and proton-pump inhibitors
(PPIs) (65%).8 The two classes of medications most often used in practice
for recurrent symptoms are acid-suppressant agents: PPIs and H2RAs. PPIs
are superior to H2RAs in healing erosive esophagitis. Occasional symptoms
may be treated with alginate, buffering agents such as calcium carbonate, or
sucralfate. However, these agents are not recommended for long-term use.7
Most studies comparing lansoprazole, omeprazole isomers, or pantopra-
zole to placebo in neonates and infants have conflicting efficacy evidence
but demonstrate select benefit.14-19 A meta-analysis and reviews concluded
that even though PPIs are well tolerated in short-term use, they are not
effective in reducing GERD symptoms in infants.20-23 A prospective study
using both nonpharmacologic and pharmacologic approaches determined
a PPI in combination with left lateral positioning was most effective in
esophageal acid exposure and GER episode reductions.9 In infants, H2RAs
were more effective than placebo in controlling GER symptoms. PPIs and
H2RAs did not differ significantly in GER-related outcomes.24 H2RAs are
recommended for acute symptom treatment. When used in very low birth
weight infants, H2RAs have shown an increased risk of necrotizing entero-
colitis (NEC) requiring astute evaluation of risk versus benefit of acute GER
symptoms.25,26 Prokinetic agents such as bethanechol, erythromycin, and
metoclopramide are not recommended for GERD treatment.7

Constipation
Epidemiology
Constipation in the first year of life is close to 2.9% overall. Approximate
prevalence during the first 6 months of life for 0 to 2 months of age, 2 to
4 months of age, and 4 to 6 months of age are 1%, 6%, and 7%, respec-
tively.27 Infrequent bowel movements do not solely represent or diagnose
constipation in neonates. Constipation is often described by stool frequency
and consistency as well as the ease of bowel movements.28 Stooling frequency
182 NICU Primer for Pharmacists

varies based on neonatal diet. Human milk-fed patients stool several times
per day compared to formula-fed patients. Patients of the same age also have
varying bowel movements per day.29,30
A diagnosis of neonatal constipation is complicated by delayed meconium
passing. Approximately 10% of term neonates do not pass meconium
within the first day of life. Twenty percent of very low birth weight neonates
do not pass meconium during the first day of life.29 Compared to term
neonates, premature neonates often have delayed meconium passing.
Neonates with neurodevelopmental impairments or with a birth weight
<0.75 kg have higher incidences of constipation.6 Constipation in neonates
usually has an organic cause.30

Presentation
Constipation is often a sign or symptom of an underlying issue in neonates.
When meconium is not passed within the first 36 to 48 hours of life, intes-
tinal obstruction should be considered. Meconium ileus or plug, intesti-
nal strictures or atresia, and Hirschsprung’s disease may delay meconium
passing. Delayed or infrequent defecation in older neonates may also repre-
sent hypothyroidism, congenital megacolon, or post-operative strictures
of the intestinal tract.29,31 A physical exam should be performed in combi-
nation with a detailed history. A full abdomen with possible distention
or palpable stool in the pelvic area may indicate constipation in neonates.
Other physical anomalies may represent an underlying neurologic disorder
such as spina bifida, or anal and rectal fissures may be present. A detailed
history will identify potential causes of the constipation such as exposures to
medications (e.g., opioids, iron and calcium supplementation, clonidine),
dietary changes, and previous GI or abdominal surgical procedures. Changes
in diet may decrease stool frequency and consistency. Breastfed neonates
are rarely constipated. When the majority of enteral nutrition is breast milk
and a neonate is constipated, a neurologic condition should be investigated.
However, if breast milk is limited and formula is initiated or is the primary
enteral nutrition, a neonate may decrease bowel movement frequency from
4 to 6 stools per day to 1 to 2 stools per day.29-31

Treatment
Constipation treatment should begin with nonpharmacologic options after
other causes have been investigated, ruled out, or addressed. Rectal stimula-
Gastrointestinal Disorders 183

tion may be used to facilitate stooling. Re-initiation of breast milk may also
return stool frequency and consistency to baseline after increased formula
administration. Limiting exposure to constipating medications is recom-
mended. After nonpharmacologic approaches have been tried, pharmacists
may consider pharmacologic treatment. Alternative medication selection
for treatment of other disease states may be needed. If neonatal medication
exposure is the cause of constipation, removing or limiting the exposure is
recommended. Replacing opioid pain management strategies with non-
opioid approaches may reduce constipation postoperatively.
To evaluate other causes of constipation, barium enemas may be used to
help diagnose strictures or atresia or other GI abnormalities or disorders.30
Barium enemas also may be therapeutic, especially in the setting of meconium
plugs. The rectal stimulation in combination with the osmotic effects of the
barium may promote stooling.
When pharmacologic treatment is necessary, pharmacists often use
another osmotic approach in neonates—glycerin. Glycerin works by
increasing osmotic pressure in the colon drawing in fluids, which stimu-
lates stooling. Both rectal enemas and suppositories are available.32 Glycerin
treatment is often considered safe and effective. However, glycerin treatment
may not be benign. A meta-analysis of rectal glycerin administration to
premature neonates under 32 weeks’ gestation to facilitate meconium passing
did decrease time to first stool by 2 days and trended toward earlier transition
to enteral intake. But another trend is increased risk of NEC. Based on the
underpowered trials used in the meta-analysis, pharmacists should assess the
benefits and risks prior to administering glycerin to premature neonates.33
Underlying causes of constipation should be addressed in conjunction with
treatment, if needed.

Conclusion
GER is a normal physiologic process in neonates. Symptom management
with nonpharmacologic approaches should be the first-line approach. If
warranted, pharmacists should carefully consider the risks and benefits of
pharmacologic management of neonatal GERD. Constipation in neonates
is often a sign and symptom of other disease states. Treatment of the under-
lying cause should be the mainstay of therapy, limiting pharmacologic
approaches for management. A pharmacist’s role in selecting appropriate
184 NICU Primer for Pharmacists

medications and identifying medication-related causes of GI disorders is


vital to neonatal patients and the healthcare team.

References
1. Ewer AK, Durbin GM, Morgan MEI, et al. Gastric emptying and gastro-esophageal
reflux in preterm infants. Arch Dis Child. 1996;75:F117-21.
2. Singendonk MMJ, Rommel N, Omari TI, et al. Upper gastrointestinal motility:
prenatal development and problems in infancy. Nat Rev Gastroenterol Hepatol.
2014;11:545-55.
3. Khan S, Orenstein SR. Gastroesophageal reflux disease. In: Kliegman RM, Stanton BF,
St. Geme JW III, et al., eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA:
Elsevier; 2011:1266-70.
4. Nelson SP, Chen EH, Syniar GM, et al. Prevalence of symptoms of gastroesophageal
reflux during infancy. A pediatric practice-based survey. Pediatric Practice Research
Group. Arch Pediatr Adolesc Med. 1997;151:569-72.
5. Campanozzi A, Boccia G, Pensabene L, et al. Prevalence and natural history of gastro-
esophageal reflux: pediatric prospective study. Pediatrics. 2009;123:779-83.
6. Hyman PE, Milla PJ, Benninga MA, et al. Childhood functional gastrointestinal
disorders: neonate/toddler. Gastroenterology. 2006;130:1519-26.
7. Vandenplas Y, Randolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux
clinical practice guidelines: joint recommendations of the North American Society of
Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the Euro-
pean Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J
Pediatr Gastroenterol Nutr. 2009;49:498-547.
8. Dhillon AS, Ewer AK. Diagnosis and management of gastro-oesophageal reflux in
preterm infants in neonatal intensive care units. Acta Paediatr. 2004;93:88-93.
9. Loots C, Kritas S, van Wijk M, et al. Body positioning and medical therapy for infan-
tile gastroesophageal reflux symptoms. J Pediatr Gastroenterol Nutr. 2014;59(2):237-43.
10. Ewer AK, James ME, Tobin JM. Prone and left lateral positioning reduce gastro-
oesophageal reflux in preterm infants. Arch Dis Child Fetal Neonatal Ed.
1999;81:F201-5.
11. Wenzel TG, Schneider S, Scheele F, et al. Effects of thickening feeding on gastro
esophageal reflux in infants: a placebo-controlled crossover study using intraluminal
impedance. Pediatrics. 2003;111:e355-9.
12. Richards R, Foster JP, Psaila K. Continuous versus bolus intermittent tube feeding for
preterm and low birth weight infants with gastro-oesophageal reflux disease (review).
Cochrane Database Syst Rev. 2014;7:CD009719.
Gastrointestinal Disorders 185

13. Psaila K, Foster JP, Richards R, et al. Non-nutritive sucking for gastro-oesophageal
reflux disease in preterm and low birth weight infants (review). Cochrane Database Syst
Rev. 2014;10:CD009817.
14. Orenstein SR, Hassall E, Furmaga-Jablonska W, et al. Multicenter, double-blind,
randomized, placebo-controlled trial assessing the efficacy and safety of proton pump
inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J.
Pediatr. 2009;154:514-20.
15. Khoshoo V, Dhume P. Clinical response to 2 dosing regimens of lansoprazole in
infants with gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2008;46:352-4.
16. Winter H, Gunekaran T, Tolia V, et al. Esomeprazole for the treatment of GERD in
infants ages 1–11 months. J Pediatr Gastroenterol Nutr. 2012;55:14-20.
17. Omari TI, Haslam RR, Lundberg P, et al. Effect of omeprazole on acid gastroesopha-
geal reflux and gastric acidity in preterm infants with pathological acid reflux. J Pediatr
Gastroenterol Nutr. 2007;44:41-4.
18. Moore DJ, Tao BS, Lines DR, et al. Double-blind placebo-controlled trial of omepra-
zole in irritable infants with gastroesophageal reflux. J Pediatr. 2003;143:219-23.
19. Winter H, Kum-Nji P, Mahomedy SH, et al. Efficacy and safety of pantoprazole
delayed-release granules for oral suspension in a placebo-controlled treatment-
withdrawal study in infants 1–11 months old with symptomatic GERD. J Pediatr
Gastroenterol Nutr. 2010;50:609-18.
20. van der Pol RJ, Smits MJ, van Wijk MP, et al. Efficacy of proton-pump inhibitors in
children with gastroesophageal reflux disease: a systematic review. Pediatrics. 2011;
127(5):925-35.
21. Tjon JA, Pe M, Soscia J, et al. Efficacy and safety of proton pump inhibitors in the
management of pediatric gastroesophageal reflux disease. Pharmacotherapy. 2013;
33(9):956-71.
22. Kierkus J, Oracz G, Korczowski B, et al. Comparative safety and efficacy of proton
pump inhibitors in paediatric gastroesophageal reflux disease. Drug Saf. 2014;
37:309-16.
23. Higginbotham TW. Effectiveness and safety of proton pump inhibitors in infantile
gastroesophageal reflux disease. Ann Pharmacol. 2010;44:572-6.
24. van der Pol R, Langendam M, Benninga M, et al. Efficacy and safety of histamine-2
receptor antagonists. JAMA Pediatr. 2014;168(10):947-54.
25. More K, Athalye-Jape G, Rao S, et al. Association of inhibitors of gastric acid secretion
and higher incidence of necrotizing enterocolitis in preterm low-birth-weight infants.
Am J Perinatal. 2013;30(10):849-56.
26. Guillet R, Stroll BJ, Cotton CM, et al. Association of H2-blocker therapy and higher
incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics.
2006;117(2):e137-e142.
186 NICU Primer for Pharmacists

27. Loeing-Baucke V. Prevalence, symptoms and outcomes of constipation in infants and


toddlers. J Pediatr. 2005;146:359-63.
28. Tobias N, Mason D, Lutkenhoff, et al. Management principles of organic causes of
childhood constipation. J Pediatr Health Care. 2008;22:12-23.
29. Maheshwari A, Carlo WA. Digestive system disorders. In: Kliegman RM, Stanton BF,
St. Geme JW III, et al., eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA:
Elsevier; 2011:600.
30. Piro CC. Diarrhea and constipation. In: Benavides S, Nahata MC. eds. Pediatric
Pharmacotherapy. Lenexa, KS: American College of Clinical Pharmacy; 2013:260-78.
31. Montgomery DF, Navarro F. Management of constipation and encopresis in children.
J Pediatr Health Care. 2008;22:199-204.
32. Taketomo CK, Hodding JH, Kraus DM. Pediatric & Neonatal Dosage Handbook. 21st
ed. Hudson, OH: Lexicomp; 2014.
33. Livingston MH, Shawyer AC, Rosenbaum PL. Glycerin enemas and suppositories in
premature infants: a meta-analysis. Pediatrics. 2015;135(6):1093-1106.

Suggested Readings
Manasco K. Gastroesophageal reflux disease. In: Benavides S, Nahata MC, eds. Pediatric
Pharmacotherapy. Lenexa, KS: American College of Clinical Pharmacy; 2013:245-59.
Piro CC. Diarrhea and constipation. In: Benavides S, Nahata MC, eds. Pediatric Pharmaco-
therapy. Lenexa, KS: American College of Clinical Pharmacy; 2013:260-78.
Vandenplas Y, Randolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical
practice guidelines: joint recommendations of the North American Society of Pediatric
Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Soci-
ety of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr
Gastroenterol Nutr. 2009;49:498-547.
15
Vaccine Use in Infants

Amy P. Holmes, PharmD

Introduction

I
nfants born prematurely who spend
the first months of their lives in the
NICU will reach the age of vacci-
nation during their hospitalization. The
Centers for Disease Control and Preven-
tion (CDC) and the American Academy
of Pediatrics recommend that medically
stable infants begin receiving routine
immunizations at the same chronological
age, regardless of prematurity, with few
exceptions.1,2 Vaccine response rate is relat-
ed to postnatal age more so than gestation-
al age.3 Because most maternal antibodies
are passed to the fetus after 32 weeks’
188 NICU Primer for Pharmacists

gestation, they are missed by infants born prior to 32 weeks. This popula-
tion may be at increased risk for vaccine-preventable diseases for many
reasons including comorbid medical conditions; administration of medica-
tions, such as corticosteroids, that may alter their already immature
immune function; and disruption of protective barriers, such as skin, due
to central lines and other hardware.

Hepatitis B Vaccine
The hepatitis B virus has been targeted for worldwide eradication because
of its role in causing liver cancer.1 A staple in that plan is administration
of hepatitis B vaccine at birth for all babies. Part of prenatal testing in
the United States includes obtaining hepatitis B surface antigen in the
mother. For mothers who are positive, a dose of hepatitis B vaccine should
be administered to the baby as soon after birth as possible regardless of
weight.1,2,4 A dose of hepatitis B immune globulin 0.5 mL intramuscularly
(IM) should also be administered at the same time but in the opposite leg.
Infants less than 2 kilograms (kg) should receive three additional doses of
the vaccine beginning no earlier than 1 month of age. In essence, this initial
dose does not count in the three-shot series for these babies. By adminis-
tering both hepatitis B vaccine and the immune globulin to these infants
within 24 hours of birth, the effectiveness in preventing hepatitis B trans-
mission is 85 to 95%.5
Infants of mothers who are hepatitis B surface antigen negative should
also receive their first hepatitis B vaccine at birth with parental consent if
they are greater than 2 kg.2 Infants who are less than 2 kg at birth should
receive the hepatitis B vaccine at 30 days of age if medically stable or prior
to discharge, whichever comes first. Approximately 90% of newborns
who contract hepatitis B are at risk for developing chronic infection.5 By
immunizing infants early, pharmacists can ensure that they are protected
during this time when they are most vulnerable.
If maternal hepatitis B surface antigen is unknown initially, then
hepatitis B vaccine should be administered within 12 hours of birth regard-
less of weight.2
Despite recommendations for universal screening and immunization,
up to 90 cases of perinatally acquired hepatitis B infection are reported to
the CDC each year.5 Pharmacists can play a role in initiating protocols that
ensure (1) all mothers are tested and (2) all babies born to mothers who
Vaccine Use in Infants 189

are hepatitis B surface antigen positive receive appropriate post-exposure


prophylaxis.

Two-, Four-, and Six-Month Vaccines


All infant immunization schedules begin at 6 weeks of age6; however, depend-
ing on the time of administration of the first hepatitis B vaccine, NICU
babies may not receive immunizations until 2 months of age. A minimum of
28 days must separate the first and second doses of hepatitis B vaccine.4 At 2,
4, and 6 months of age, the following vaccines are currently recommended:
❖❖ Inactivated polio virus (IPV)
❖❖ Diphtheria, tetanus, and pertussis (DTaP)
❖❖ Hepatitis B (HepB)
❖❖ Haemophilus influenza (Hib)
❖❖ Pneumococcal conjugate (Prevnar-13)
See Table 15-1.6
Combination vaccines such as Pediarix (IPV/DTaP/HepB) and Pentacel
(IPV/DTaP/Hib) may be used to reduce the number of injections required
to administer these vaccines.
It is important to use the vaccine developed and approved for infants.
The pneumococcal vaccine developed for children is a conjugated vaccine as
opposed to the pneumococcal vaccine available for adults, which is a poly-
saccharide vaccine. Children less than 2 years of age cannot mount an
immune response to a polysaccharide vaccine, thus rendering it ineffective.1
Conjugate vaccines attach or conjugate a vaccine antigen to a protein that
is more immunogenic (e.g., tetanus toxoid, diphtheria). This stimulates a
more robust immune response to the vaccine antigen in infants.
For complete, up-to-date immunization recommendations, visit the
CDC website.6 This site also includes several catch-up and alternate dosing
schedules.

Rotavirus Vaccine
Rotavirus is a gastrointestinal virus, causing vomiting and watery diarrhea,
that lasts up to a week and can lead to dehydration.2 It is self-limiting in
immunocompetent hosts but can lead to hospitalization in children. Low
birth weight infants are at particularly high risk of hospitalization from
rotavirus infection.7 An earlier version of rotavirus vaccine was removed
190 NICU Primer for Pharmacists

Table 15-1. Vaccinations during the First Year of Life


Vaccine Disease Prevented Impact
Diphtheria Diphtheria Breathing problems,
paralysis, heart failure,
and death
Haemophilus influenza H. flu infections such as Prevention of disease in
meningitis, pneumonia, childhood
and epiglottitis
Hepatitis B Hepatitis B and Lifelong protection
virus subsequent liver cancer from debilitating
disease
Inactivated polio virus Polio Lifelong protection
from debilitating
disease
Pertussis Whooping cough Prevention of acute,
potentially deadly
infection
Pneumococcal Streptococcus pneumoniae Prevention of disease in
conjugate infections such as childhood
pneumonia
Tetanus Tetanus (lock-jaw) 1 in 10 cases leads to
death
See references 4 and 6 for more information.

from the market secondary to cases of intussusception. Newer forms of the


vaccines have proven to be safer with demonstrated intussusception rates
equivalent to expected backgrounds rates in the studied populations.
The rotavirus vaccine (RotaTeq, Rotarix) is the only live vaccine recom-
mended during the first year of life (see Table 15-2). Because it is a live virus
vaccine, most NICUs do not administer this vaccine during a hospital stay.
This vaccine is recommended at a minimum age of 6 weeks with the first
dose to be given no later than the maximum age of 14 weeks and 6 days.2
Due to the age recommendation, some neonatologists insist that the first
dose be given at discharge for older babies. That way, this important vaccine
is not being inadvertently missed.
Rotavirus vaccine is administered orally. The RotaTeq vaccine is 2 mL
in volume, and Rotarix is 1 mL. In theory, there is some advantage to
Vaccine Use in Infants 191

Table 15-2. Rotavirus Vaccines4,8,9


Vaccine Volume of Dose Number of Doses Serotypes Covered
RotaTeq 2 mL 3 doses at least G1, G2, G3, and G4
4 weeks apart
Rotarix 1 mL 2 doses at least G1 and non-G1 types
4 weeks apart (G3, G4, and G9)
See references 4, 8, and 9 for more information.

administering the smaller volume to NICU graduates, especially those who


are on thickened feeds for reflux. Despite product labeling that the vaccine
should not be mixed with a feeding,8,9 this may be necessary in some infants
to prevent aspiration of the vaccine. The Rotarix product requires mixing
and use of a specific diluent.9 Pharmacists should become familiar with
the specific product used in their institutions to anticipate and prevent any
potential medication errors related to its use.
If a baby receives the rotavirus vaccine during hospitalization or is
readmitted from the community where he or she has received the vaccine,
pharmacists should recall that the virus can be shed in the stool for up
to 14 days following vaccination.4 The issue sometimes arises when an
immunized twin is returning to the unit with parents and visiting the twin
who is still hospitalized. A reasonable solution is to ensure that the twin
who received the rotavirus vaccine does not have his or her diaper changed
in the unit. Also, this situation reinforces good hand hygiene expected of
healthcare personnel as well as visitors at all times in the NICU.

Vaccine Administration
With the exception of the rotavirus vaccine, immunizations should be
administered as IM or subcutaneous (SQ) injections according to manufac-
turer recommendations based on clinical trials. Route of administration is
not interchangeable. Whether IM or SQ, the preferred needle length for
administration is 5/8 inches.2 The preferred site of injection for immuniza-
tion of infants is the anterolateral thigh.3

Acetaminophen Use and Vaccination Response


Acetaminophen and ibuprofen have long been used to provide relief from
fever and discomfort associated with immunization. In 2009, Prymula et
192 NICU Primer for Pharmacists

al. demonstrated that the use of acetaminophen prior to immunization had


a negative effect on the immune response to vaccines.10 Although there has
been no clinical correlation to these infants’ lower titer response, acetamin-
ophen is no longer recommended to be given prior to immunizations.2
Rescue doses of acetaminophen for signs and symptoms of pain and fever
following vaccination were not linked with lower vaccine response rate and
are considered acceptable for use in infants. Acetaminophen 10–15 mg/kg
orally every 6–8 hours (based on post-menstrual age) as needed for fever or
sign of pain is a reasonable choice for treatment.4

Techniques for Minimizing Pain from Vaccinations


Sucrose with or without non-nutritive sucking and skin-to-skin holding
have been used to minimize pain from minor procedures performed in the
NICU.11,12 When possible, these techniques may be used to help reduce the
pain associated with immunizations. For maximum benefit of pain relief,
sucrose should be administered 2 minutes prior to the procedure.4
Studies have demonstrated that the eutectic mixture of lidocaine and
prilocaine (EMLA) is effective in reducing vaccination pain in infants13;
however, caution is advised when using it in infants less than 3 months of
age secondary to reports of methemiglobinemia.14 Lidocaine 4% cream may
be a safe substitute for EMLA. If used, either medication should be applied
to the site of injection 1 hour prior to vaccination.

Post-Immunization Apnea
Apnea is common in premature infants (see Chapter 6). By the time a NICU
infant has reached the age of immunization, he or she will most likely have
outgrown apnea. Evidence suggests that a history of pre-immunization apnea
is a risk factor for developing apnea secondary to vaccinations.15,16 Other risk
factors for post-immunization apnea include gestational age, postnatal age
less than 70 days and weight at immunization, history of mechanical venti-
lation, and chronic lung disease. This apnea can occur up to 48 hours after
receipt of the vaccines. Apnea can be confused as an early sign of sepsis, and
these babies may receive a sepsis evaluation. Awareness of this adverse effect
of vaccination may influence whether antibiotics are prescribed in these
infants. Of note, the C-reactive protein may be elevated for up to 48 hours
following vaccination leading to further suspicion for infection.
Vaccine Use in Infants 193

For infants at risk of post-immunization apnea, it is important to plan


vaccination in relation to discharge so significant adverse outcomes are
prevented. Infants identified as being at risk for post-immunization apnea
should be monitored in the hospital setting for at least 48 hours after
vaccination.3 Infants who will be discharged prior to the time that their
vaccinations are due, but considered at risk for apnea, should have vaccines
deferred until they are at least 70 days old. Again, refer to the CDC website
for recommended catch-up schedules.6

Other Adverse Outcomes


Immunizations in general may be associated with local reactions at the site
of injection. Fever may occur and is more common with Pediarix combi-
nation vaccine than with administration of individual vaccines.4 Irritability,
decreased appetite, and increased or decreased amount of sleep may also
occur. As with any IM injection, nerve damage and/or development of an
abscess may occur.2

Cocooning
Cocooning is the practice of immunizing immediate family and caregivers
of infants too young to be immunized against specific diseases.3 Because
pertussis is most deadly when spread to infants younger than 3 months of
age, it has been targeted for cocooning. Mothers and other close contacts
(including healthcare workers in the NICU) should be immunized against
pertussis to prevent spread to infants. Tdap booster is currently recommended
to be administered during each pregnancy between 27 and 36 weeks’
gestation for this reason.17 Mothers who do not receive the vaccine during
pregnancy should be offered the vaccine after delivery prior to discharge
from the hospital.
Because no influenza vaccine is presently endorsed for children less than
6 months of age, influenza vaccination is recommended for those who come
in contact with infants.3

Conclusion
Timely vaccination is important to protecting premature infants from
vaccine-preventable diseases. Infants should be immunized according to
the standard immunization recommendations based on postnatal age but
194 NICU Primer for Pharmacists

regardless of gestational age. Pharmacists can play a role in recommending


vaccinations and educating family members about vaccination. Pharmacists
can also facilitate cocooning by educating families and suggesting vaccines
that they can get to protect their babies.

References
1. Centers for Disease Control and Prevention. In: Atkinson W, Wolfe S, Hamborsky
J, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 12th ed., second
printing. Washington DC: Public Health Foundation; 2012.
2. Kimberlin DW, Brady MT, Jackson MA, et al., eds. Red Book: 2015 Report of the Commit-
tee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics;
2015.
3. Healy CM. Immunization strategies to protect preterm infants. NeoReviews. 2010;
11:e409-18.
4. Neofax. http://neofax.micromedexsolutions.com/neofax/neofax.php?strTitle=NeoFax&
area=1&subarea=0. Accessed February 1, 2015.
5. Willis BC, Wortley P, Wang SA, et al. Gaps in hospital policies and practices to prevent
perinatal transmission of hepatitis B virus. Pediatrics. 2010;125:704-11.
6. Recommended immunization schedule for persons aged 0 to 6 years—United States
2014. www.cdc.gov/vaccines. Accessed February 1, 2015.
7. Cortese MM, Parashar UD. Prevention of rotavirus gastroenteritis among infants and
children: recommendations of the Advisory Committee on Immunization Practices
(ACIP). MMWR. 2009;58(RR-2):1-24.
8. RotaTeq [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2014.
9. Rotarix [package insert]. Rixensart, Belgium: GlaxoSmithKline Biologicals; 2014.
10. Prymula R, Siegrist CA, Chlibek R, et al. Effect of prophylactic paracetamol adminis-
tration at time of vaccination on febrile reactions and antibody responses in children:
Two open-label, randomised controlled trials. Lancet. 2009;374:1339-50.
11. Ikuta L. The combined use of sucrose and nonnutritive sucking for procedural pain in
both term and preterm neonates: an integrative review of the literature. Adv Neonatal
Care. 2013;13(1):9-19.
12. Taddio A, Ilersich AL, Ipp M, et al. Physical interventions and injection techniques for
reducing injection pain during routine childhood immunizations: systematic review of
randomized controlled trials. Clin Ther. 2009;31(Supp B):S48-75.
13. Taddio A, Nulman I, Goldbach M, et al. Use of lidocaine-prilocaine cream for
vaccination pain in infants. J Pediatr. 1994;124:643-8.
14. EMLA [package insert]. Mississauga, Ontario: AstraZeneca; 2010.
Vaccine Use in Infants 195

15. Klein NP, Massolo ML, Greene J, et al. Risk factors for developing apnea after immu-
nization in the neonatal intensive care unit. Pediatrics. 2008;121(3):463-9.
16. Sen S, Cloete Y, Hassan K, et al. Adverse events following vaccination in premature
infant. Acta Paediatr. 2001;90:916-20.
17. Update on immunization and pregnancy, diphtheria, and pertussis vaccination.
Committee Opinion No. 566. American College of Obstetricians and Gynecologists.
Obstet Gynecol. 2013;121:1411-4.

Suggested Readings
See http://www.cdc.gov/vaccines/ for review of individual vaccines.
Healy CM. Immunization strategies to protect preterm infants. NeoReviews. 2010;11:e409-18.
Kimberlin DW, Long SS, eds. Active and passive immunization. RedBook: 2015 Report of
the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy
of Pediatrics; 2015.
16
Persistent Pulmonary
Hypertension of the
Newborn

Julia Lau, PharmD, BCPS

Introduction

C
ompared to a neonate, the pulmo-
nary vascular resistance (PVR) in a
fetus is almost twice as high. This
is the result of intrauterine relative hypox-
emia along with several other factors. After
birth, the neonatal PVR gradually reduces
and usually reaches adult level by 2 weeks
of age. When PVR fails to lower, it causes a
condition called persistent pulmonary hyper-
tension of the newborn (PPHN), which
affects 1.5 to 2 out of 1,000 newborns. If
left undiagnosed and untreated, PPHN is
associated with mortality and morbidity
rates as high as 10 to 20%.1,2
198 NICU Primer for Pharmacists

Transition from Intrauterine to Extrauterine Circulation


To understand PPHN, clinicians must first understand the differences between
fetal and postnatal (adult) circulation. Fetal circulation operates in parallel as
opposed to single direction adult circulation. The fetal organ of respiration
is the placenta. Oxygenated blood from the placenta is delivered to the right
side of the heart via the inferior vena cava. Because the fetal lung does not
participate in gas exchange, two channels in the fetal circulation allow blood to
bypass the lungs: the foramen ovale, which connects the right and the left atria,
and the ductus arteriole, which connects the aorta and the pulmonary trunk.
The right ventricle is dominant, and blood shunts from right to left.1
Postnatal circulation, in contrast, operates in series. All venous return
enters the right side of the heart and into the lungs. Gas exchange takes
place in the lungs, and then oxygenated blood returns to the left side of the
heart. The left ventricle pumps oxygenated blood into systemic circulation.
The left ventricle is dominant, and there is no mixing of blood between the
left and the right side of the heart.1
As a newborn takes the first breath, the removal of the placenta, the
catecholamine surge associated with birth, and the relatively cold extrauter-
ine environment all contribute to a steady rise in systemic vascular resistance
(SVR). Meanwhile, expansion of the lungs, establishment of adequate alveo-
lar ventilation and oxygenation, and successful clearance of fetal lung fluid
all lead to a fall in PVR. Conditions that interfere with this postnatal decline
of PVR/SVR ratio cause the persistence of a transitional circulation, resulting
in PPHN.1

Pathogenesis and Causes


The abnormalities that are causes of PPHN can be divided into three main
categories:
❖❖ underdevelopment
❖❖ maldevelopment
❖❖ maladaptation

Underdevelopment
In underdevelopment abnormalities, the cross-section of vasculature is
reduced, which results in increased elevation of PVR. Some conditions
in this category are congenital diaphragmatic hernia (CDH), pulmonary
Persistent Pulmonary Hypertension of the Newborn 199

hypoplasia, and intrauterine growth restriction. In patients with underdevel-


opment abnormalities, postnatal adaptation mechanism is limited. There-
fore, patients in this category have the highest mortality rate.1

Maldevelopment
In the maldevelopment category, the lungs are normally developed but
affected by an abnormally thick muscular layer of pulmonary arterioles.
This muscular layer also extends into small vessels that normally have no
muscle cells. Maldevelopment is associated with various conditions such as
post-term delivery, meconium staining, and meconium aspiration syndrome
(MAS) as well as premature closure of the foramen ovale or ductus arterio-
sus. Patients with idiopathic PPHN also fall under this category. Postnatal
remodeling of the vascular bed usually occurs 7 to 14 days after birth, which
leads to a gradual fall in PVR.1

Maladaptation
Even when lungs and pulmonary vasculatures are normally developed, the
natural postnatal fall in PVR can still be disrupted. Maladaptation causes of
PPHN are conditions that cause active vasoconstriction and, therefore, keep
PVR elevated. These conditions include perinatal depression, pulmonary
parenchymal disease, and bacterial infections. Group B Streptococcus (GBS)
infection in particular has a potent effect on PVR. The bacterial phospholipid
in GBS can activate vasoactive mediators and induce vasoconstriction.1
MAS is the most common cause of PPHN. Pulmonary hypertension in
MAS is a result of airway obstruction, inactivation of surfactant, and chemi-
cal pneumonitis. Other PPHN risk factors in MAS are asphyxia, pneumo-
thorax, and change of fetal heart beat pattern.

Risk Factors
The prevalence of PPHN is higher in male infants, infants born by cesarean
section, infants who are late preterm, and infants who are large for gestational
age. GBS infection is also a risk factor for PPHN.
Maternal risk factors include preconception body mass index >27,
diabetes mellitus, and asthma. Histological chorioamnionitis and funisi-
tis are also maternal risk factors. During pregnancy, maternal use of some
medications such as non-steroidal anti-inflammatory drugs has also been
linked to PPHN.1
200 NICU Primer for Pharmacists

Clinical Features and Diagnosis


Clinical Manifestations
Within 24 hours after birth, most infants with PPHN will develop signs of
respiratory distress such as tachypnea, retractions, grunting, and cyanosis.
Low APGAR (Appearance, Pulse, Grimace, Activity, Respiration) score and
early delivery room interventions (e.g., intubation, bag and mask ventila-
tion, oxygen) are also commonly observed. Meconium staining of skin and
nails—indicative of intrauterine stress—may also occur.
Infants with PPHN often present with other respiratory complications.
The Neonatal Research Network at the National Institute of Child Health
and Human Development conducted a multicenter cohort study that
included 385 infants. This study reported the relative frequencies of differ-
ent respiratory complications: MAS, 41%; respiratory distress syndrome
(RDS), 13%; pneumonia and/or RDS, 14%; CDH, 10%; and pulmonary
hypoplasia, 4%. Among the 385 infants, 17% had no other complications
and were diagnosed with idiopathic PPHN.1

Diagnosing PPHN
The following tests are helpful in differentiating the primary cause of hypox-
emia in a term infant and diagnosing PPHN:
❖❖ Hyperoxia Test—PPHN is characterized by hypoxemia that is non-
responsive to supplemental oxygen. The hyperoxia test is a simple test,
which can be performed at bedside. Place the infant in 100% oxygen. If
PPHN is present, the partial pressure of oxygen (PaO2) in the blood of
the infant usually does not increase.1
❖❖ Simultaneous Pre- and Postductal Arterial Blood Gases—This test helps
detect the right-to-left shunting across the patent ductus arteriosus
(PDA). An arterial blood gas is obtained from the right radial artery
(preductal) and umbilical artery catheter or posterior tibial artery (post
ductal) simultaneously. A higher PaO2 in the right radial sample by
~ 20 mmHg difference indicates right-to-left shunting.1
❖❖ Chest Radiography—Although no specific chest radiography can confirm
PPHN, the test is useful in suggesting or ruling out other diagnoses.1
❖❖ Echocardiogram—The echocardiogram plays a key role in diagnosing
PPHN and is an important tool in managing it. The initial echocar-
Persistent Pulmonary Hypertension of the Newborn 201

diogram rules out structural heart disease, determines the predomi-


nant direction of shunting at the patent foramen ovale and PDA, and
assesses ventricular function. The PPHN diagnosis is not certain until
predominantly bidirectional or right-to-left shunting is confirmed by
echocardiogram.1

Determining the Severity of PPHN


The oxygenation index (OI), used to assess the severity of hypoxemia in
PPHN, is a valuable tool in managing PPHN because it helps guide the
timing of interventions.
OI = [mean airway pressure × FiO2 ÷ PaO2] × 100
OI is calculated based on the infant’s mean airway pressure (MAP), oxygen
concentration of supplemental oxygen (FiO2), and PaO2. Most of the time
when the OI is used, the infant is receiving ventilation with a FiO2 of 1
(100% oxygen). The OI can be calculated simply from the MAP displayed
on the ventilator and the PaO2.
❖❖ An OI <25 indicates mild to moderate disease. General supportive care
is often adequate in this population.
❖❖ An OI ≥25 indicates severe hypoxemic respiratory failure. Further inter-
vention beyond general supportive care and more invasive intervention
are usually required.1

Management
The goal of PPHN management is to restore normal cardiopulmonary
adaptation while limiting cardiopulmonary injury. PPHN management
consists of the following:
❖❖ treatment of underlying etiology
❖❖ maintenance of a normal systemic blood pressure
❖❖ maintenance of adequate tissue oxygenation
General supportive cardiopulmonary care is indicated for all patients
with PPHN. In severe PPHN cases, further interventions beyond general
supportive cardiopulmonary care should be considered. This chapter will
focus on pharmacologic therapy of PPHN.
202 NICU Primer for Pharmacists

Extracorporeal Membrane Oxygenation


Extracorporeal membrane oxygenation (ECMO) is the ultimate rescue
therapy in PPHN management. When an infant with PPHN persistently
has an OI >40 despite treatment with inhaled nitric oxide (iNO) and
optimized mechanical ventilation, ECMO should be considered. The goal
of ECMO is to maintain adequate tissue perfusion and avoid further lung
injury from mechanical ventilation while PVR decreases and pulmonary
hypertension resolves.
To be candidates for ECMO, infants should weigh more than 2 kg,
have no contraindication to heparinization (such as intraventricular hemor-
rhage), and have no nonsurvivable congenital anomalies. The survival rate of
infants with PPHN after ECMO is about 80%. Most patients with PPHN
are weaned from ECMO within 7 days. Cardiovascular complication is the
most common complication associated with ECMO.1 To learn more about
ECMO, see Chapter 18.

Nitric Oxide
Nitric oxide (NO) is an endogenous molecule that regulates vascular tone by
relaxing vascular smooth muscle. When inhaled, NO is a selective pulmonary
vasodilator that decreases the pulmonary artery pressure and pulmonary-to-
systemic arterial pressure ratio. The iNO improves oxygenation because it
causes vasodilation in less ventilated parts of the lung that leads to blood
redistribution and reduced intrapulmonary shunting. Hemoglobin in the
circulation rapidly binds NO and converts to methemoglobin and nitrate,
eliminating iNO’s effect on systemic blood pressure and SVR. Methemoglo-
binemia is a potential toxicity of iNO, although iNO appears to be very safe
when used at 20 parts per million (ppm) or less. Conditions that increase
the risk for methemoglobinemia include excessive iNO concentration and
impaired metabolism.1
In term or late preterm infants with PPHN, iNO can be started when
the OI is >25 or when the partial pressure of oxygen (PaO2) is <100 mmHg
while the patient is receiving 1 FiO2 (100% oxygen). The most common
initiating dose of iNO is 20 ppm. An approximately 20% improvement in
PaO2 or arterial oxygen saturation (SaO2) is typically seen 15 to 20 minutes
after therapy initiation.3 As oxygenation improves, FiO2 can be slowly
weaned while maintaining adequate SaO2. After the patient is stabilized on a
lower FiO2, NO weaning can begin.3
Persistent Pulmonary Hypertension of the Newborn 203

A small percentage of patients who did not respond to the standard


dose of 20 ppm responded to 80 ppm in an early randomized, controlled
study. An iNO dose of 80 ppm is associated with a significantly higher risk
for methemoglobinemia. In patients who do not respond to 20 ppm of
iNO, a brief dose increase to 40 to 80 ppm can be attempted. In patients
receiving higher doses of iNO, methemoglobin level should be monitored
very closely.3
In term and late preterm infants with severe PPHN (OI >25), iNO has
been shown to reduce the need for ECMO by 40%. However, iNO may
not be effective in PPHN patients who do not belong to this subgroup. In
a randomized, multicenter trial that included 299 infants, earlier initiation
of iNO in patients with mild-to-moderate respiratory failure (OI > or = 15
and <25) compared to routine initiation (OI >25) improved oxygenation
but did not reduce the need for ECMO or mortality. The iNO also did not
appear to benefit infants with PPHN secondary to CDH.5,6 In a trial that
included 53 infants with severe PPHN (OI >25) and CDH, there was no
difference in mortality or need for ECMO between patients treated with
iNO and patients treated with 100% oxygen. The study did, however, find
transient improvement in some patients who received iNO, suggesting
iNO may have a role in stabilizing patients for transport and initiation of
ECMO.7

PDE5 Inhibitors
Sildenafil inhibits cGMP-specific phosphodiesterase type 5 (PDE5) and
increases the availability of cGMP, resulting in smooth muscle relaxation
and vasodilation. Sildenafil selectively reduces PVR and has been shown to
be effective in treating infants with PPHN.
Oral sildenafil at a dose of 0.5 to 2 mg/kg/dose every 6 to 12 hours
has been used in infants with PPHN. A higher dose of 3 mg/kg/dose every
6 hours has also been used in term and post-term neonates. In a recent
meta-analysis that included three small trials with 77 infants, the group that
received enteral sildenafil had a significant reduction in mortality compared
to the control group (relative risk 0.2, 95% confidence interval 0.07–0.57).8
Of note, all three studies were performed in settings where iNO and high
frequency ventilation were not available.
In 2009, Steinhorn et al. conducted an open-label, dose-escalation trial
of continuous intravenous (IV) sildenafil on 36 neonates with PPHN who
204 NICU Primer for Pharmacists

were already receiving iNO.9 A loading dose of 0.008 to 0.4 mg/kg over 3
hours was given to the neonates, followed by a continuous infusion of 0.08 to
1.6 mg/kg/day. A significant improvement in OI within 4 hours of silde-
nafil infusion was noted in patients who received a loading dose of 0.06 to
0.4 mg/kg but not in patients who received a lower loading dose. After the
addition of continuous, IV sildenafil, acute and sustained improvement in
oxygenation was noted.
The Food and Drug Administration (FDA) revised the sildenafil drug
label in August 2012 by adding the warning “use of Revatio (sildenafil),
particularly chronic use, is not recommended in children.”10 This warning
was based on a long-term study of children aged 1 to 17 years who received
sildenafil for pulmonary arterial hypertension. The study found that higher
sildenafil dose was associated with increased mortality without additional
benefit. Some healthcare professionals interpreted this warning as an absolute
contraindication. For this reason, the FDA issued a follow-up communica-
tion in 2014, stating that the use of sildenafil in children is acceptable when
benefits outweigh risks (e.g., limited treatment options).11
Sildenafil has been shown to decrease mortality only where NO was
not available. There have not been any large scale, randomized, controlled
trials demonstrating safety and efficacy in patients receiving NO, which is
the standard of care for PPHN in the United States. However, roughly 40%
of infants do not respond to NO. Sildenafil is an option when NO is not
available or when an adequate dose of NO failed to improve oxygenation in
infants with PPHN. Given the increased mortality observed in the long-term
use of high-dose sildenafil, clinicians should closely monitor patients receiv-
ing sildenafil for adverse effects and utilize the lowest effective dose.

PDE3 Inhibitors
Milrinone is a phosphodiesterase type 3 (PDE3) inhibitor that increases the
availability of cyclic adenosine monophosphate. Milrinone exerts its positive
inotropic effect by causing left ventricular afterload reduction and periph-
eral vasodilation. Milrinone also reduces PVR. The safety and efficacy of
milrinone have been reported in two case series and one open-label study.
In the first case series, four patients with a mean OI of 40 were loaded with
50 mcg/kg of milrinone followed by a continuous infusion of 0.33 mcg/kg/
min. The OI of all four patients improved (mean OI of 28), and all patients
were extubated and survived. One of the four patients, however, developed
Persistent Pulmonary Hypertension of the Newborn 205

serious IVH, and another patient developed a small IVH. Systemic


hypotension was not observed following milrinone.12,13 McNamara et al.
retrospectively reviewed data of nine patients treated with milrinone.14 All
patients were term infants with PPHN with a mean OI of 28. Milrinone
was started at 0.33 mcg/kg/min and titrated up to 0.99 mcg/kg/min, and
no loading dose was given. OI improved significantly in these patients, and
the mean OI 24 hours into treatment was 8. Eight of nine infants survived.
The cause of the ninth infant’s death was withdrawal of care. None of the
infants developed hypotension or IVH.12
After publishing the case series in 2006, McNamara et al. conducted an
open-label study on milrinone in neonates with PPHN.15 Eleven neonates
with PPHN were given a loading dose of milrinone 50 mcg/kg over
60 minutes. A continuous infusion of 0.33 mcg/kg/min was then started. If
the increase in PaO2 was <20 mmHg, milrinone was titrated up in incre-
ments of 0.33 mcg/kg/min every 2 hours to a maximum of 0.99 mcg/kg/
hr. In patients with an OI >25, iNO was coadministered according to a
standardized clinical practice guideline. Milrinone administration resulted
in improvement in oxygenation efficacy with a sustained reduction in FiO2,
MAP, OI, and iNO dose and an increase in PaO2. No case of IVH, electro-
lyte disturbance, abnormal liver function test or coagulation profile, throm-
bocytopenia, or need for ECMO were reported after milrinone therapy.
The administration of milrinone as an adjunct to iNO was shown to
improve oxygenation in neonates with PPHN. Milrinone, however, did not
reduce mortality and neurodevelopmental impairment in affected neonates.
Randomized, controlled trials are needed before milrinone can be routinely
recommended as a standard of care.

Surfactants
Surfactant therapy in infants with PPHN has had variable results. In a
multicenter, randomized, controlled trial comparing surfactant to placebo,
surfactant decreased the need for ECMO. Another study on surfactant
lung lavage showed a transient improvement in oxygenation and a decrease
in mean airway pressure and A-a gradient. This study, however, failed to
show long-term impact on duration of mechanical ventilation, the use of
iNO, or length of stay. Surfactant may benefit selective groups of infants
with PPHN. In infants with MAS and pneumonia, surfactant was shown to
improve the severity of pulmonary morbidity, air leaks, and length of stay.
206 NICU Primer for Pharmacists

Overall, the benefit of surfactant in the treatment of PPHN is uncertain, but it


may be beneficial in selected patients as an adjunct to standard therapy. More
robust data need to be presented before surfactant can be routinely recom-
mended as standard of care in PPHN.1

Prostaglandin Analogs
IV prostaglandins cause systemic and pulmonary vasodilation. Their efficacy
in pulmonary hypertension has been shown in adults and animal models.
Data on neonates, however, are limited to only case reports, which show that
inhaled prostacyclin I2 and its analog iloprost can be beneficial in infants with
PPHN. More studies are needed before prostaglandins can be routinely recom-
mended for treating PPHN.1

Endothelin Receptor Antagonists


Bosentan is an oral nonselective endothelin-1 (ET) receptor antagonist. Due to
its availability, it is an attractive option for the treatment of PPHN in settings
where iNO and ECMO are unavailable. The safety and efficacy of bosentan
in PPHN treatment has been reported in a case report and a small trial that
included 47 infants.16,17 In the trial, a dose of 1 mg/kg given orally twice a day
was more effective in improving OI and oxygen saturation as well as decreas-
ing the time of mechanical ventilation compared to placebo. Short-term use
also appeared to be safe. Larger studies are warranted before bosentan can be
routinely recommended for PPHN treatment. In settings with limited resources,
however, bosentan may be a useful option.
It is worth noting that bosentan should not be crushed but can be
dissolved in 5–25 mL of water in order to prepare a product that can be
administered to neonates.

Outcomes
iNO has been evaluated in multiple follow-up studies and does not appear to
cause long-term adverse effects. Long-term safety data on other PPHN treat-
ment options are limited.
Survivors of severe PPHN and/or ECMO treatment are at an increased
risk for developmental delay, feeding problems, short-term respiratory morbid-
ities, motor disability, and hearing deficit. These infants should have neuro-
developmental follow-ups after discharge and hearing tests performed before
and after discharge.
Persistent Pulmonary Hypertension of the Newborn 207

Conclusion
PPHN is a neonatal emergency that requires early intervention to prevent
severe hypoxemia and various morbidities. The management of PPHN consists
of general supportive cardiorespiratory care and treatment of underlying
pulmonary conditions. In patients with severe PPHN, some promising treat-
ment modalities have emerged including iNO, PDE inhibitors, prostaglandin
analogs, ET receptor antagonists, and ECMO. Most of these pharmacologic
treatments, however, are supported only by small studies and case reports. Due
to the lack of high-level, randomized, controlled studies, the optimal approach
to managing PPHN is yet to be determined. Patients who are receiving
pharmacologic treatment for PPHN should be carefully monitored for efficacy
and adverse effects. Long-term follow-up is warranted for PPHN patients after
discharge from the neonatal intensive care unit.

References
1. Puthiyachirakkal M, Mhanna MJ. Pathophysiology, management, and outcome of
persistent pulmonary hypertension of the newborn: a clinical review. Front Pediatr.
2013;1:23.
2. Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of
the newborn in the era before nitric oxide: practice variation and outcomes. Pediatr.
2000;105:14.
3. Davidson D, Barefield ES, Katwinkel J, et al. Inhaled nitric oxide for the early treatment
of persistent pulmonary hypertension of the term newborn: a randomized, double-
masked, placebo-controlled, dose-response, multicenter study. The I-NO/PPHN Study
Group. Pediatrics. 1998;101(3 Pt 1):325-34.
4. Soll RF. Inhaled nitric oxide in the neonate. J Perinatol. 2009;29(suppl 2):S63-7. Doi:
10.1038/jp.2009.40
5. Konduri GG, Solimano A, Sokol GM, et al. A randomized trial of early versus standard
inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respira-
tory failure. Pediatr. 2004;113:559.
6. Konduri GG, Vohr, Robertson C, et al. Early inhaled nitric oxide therapy for term
and near-term newborn infants with hypoxic respiratory failure: neurodevelopmental
follow-up. J Pediatr. 2007;150:235.
7. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and
hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics.
1997;99:838.
8. Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Data-
base Syst Rev 2011:CD005494.
208 NICU Primer for Pharmacists

9. Steinhorn RH, Kinsella HP, Pierce C, et al. Intravenous sildenafil in the treatment of
neonates with persistent pulmonary hypertension. J Pediatr. 2009;155:841.
10. FDA Drug Safety Communication. FDA recommends against use of Revatio in
children with pulmonary hypertension. http://www.fda.gov/Drugs/DrugSafety/
ucm317123.htm. Accessed on November 20, 2014.
11. FDA Drug Safety Communication: FDA clarifies warning about pediatric use of
Revatio (sildenafil) for pulmonary arterial hypertension. http://www.fda.gov/Drugs/
DrugSafety/ucm390876.htm. Accessed on November 20, 2014.
12. Bassler D, Choog K, McNamara P, et al. Milrinone for persistent pulmonary hyperten-
sion of the newborn. Cochrane Database Syst Rev. 2010;CD007802.
13. Bassler D, Choog K, McNamara P, et al. Neonatal persistent pulmonary hypertension
treated with milrinone: four case reports: Biol Neonate. 2006;89:1.
14. McNamara PJ, Laique F, Muag-In S, et al. Milrinone improves oxygenation in
neonates with severe persistent pulmonary hypertension of the newborn. J Crit Care.
2006;21:217.
15. McNamara PJ, Shivannanda SP, Sahni M, et al. Pharmacology of milrinone in neo-
nates with persistent pulmonary hypertension of the newborn and suboptimal response
to inhaled nitric oxide. Pediatr Crit Care Med. 2013;14(1):74-84.
16. Nakwan N, Choksuchat D, Saksawad R, et al. Successful treatment of persistent
pulmonary hypertension of the newborn with bosentan. Acta Paediatr. 2009;
98(10):1683-5.
17. Mohamed WA, Ismail M. A randomized, double-blind, placebo-controlled, prospective
study of bosentan for the treatment of persistent pulmonary hypertension of the new-
born. J Perinatol. 2012;32(8):608-13.

Suggested Readings
Puthiyachirakkal M, Mhanna MJ. Pathophysiology, management, and outcome of
persistent pulmonary hypertension of the newborn: a clinical review. Front Pediatr.
2013;1:23.
Steinhorn RH, Abmen SH. Persistent pulmonary hypertension. In: Gleason CA, Devaskar
SU, eds. Avery’s Diseases of the Newborn. 9th ed. Philadelphia, PA: Elsevier; 2012:732.
17
Neonatal Seizures

John Brock Harris, PharmD, BCPS

Introduction

A
seizure is a result of sudden
variations in neuronal electrical
discharges in the central nervous
system (CNS) that causes a behavioral or
functional change in a neonate. A neonate
has a decreased seizure threshold compared
to other pediatric patients due to hyper-
excitability of an immature brain.1-3 In
fact, neonatal seizures occur in 1.8 to
3.5 patients per 1,000 neonates. In very
low birth weight neonates, the incidence
increases drastically to 19 to 57.7 patients
per 1,000 neonates.4-6
210 NICU Primer for Pharmacists

Pathophysiology
There is a balance between excitatory and inhibitory neurotransmitters and
electrolyte-based pathways in mature brains. The immature brain pathways
are imbalanced, promoting brain development and increasing risk of
seizures.2 The intrinsic factors related to excitatory pathways are increased
N-methyl-D aspartate glutamate receptors, α-amino-3-hydroxyl-5-methyl-4-
isoxazolepropionic acid glutamate receptors, metabotropic glutamate recep-
tors, gamma-aminobutyric acid (GABA) transporters, and corticotropin-
releasing factors. The inhibitory pathway intrinsic factors are decreased
glutamate transporters, neuropeptide Y, and adenosine. There are also
variable GABAB receptors; the GABAA receptors are depolarizing, which
decreases the inhibitory pathway function.2,3 Head traumas during delivery,
neonatal CNS infections, metabolic abnormalities, intracranial hemorrhages,
hypoxic-ischemic brain injuries, and toxin exposures or withdrawals are
extrinsic factors that may lead to neonatal seizures.1,3 (CNS infection treat-
ments are discussed in Chapter 10 for group B Streptococcus and Escherichia
coli and in Chapter 11 for toxoplasmosis, cytomegalovirus, and herpes
simplex virus infections.) Metabolic abnormalities that increase the risk of
neonatal seizures include hypocalcemia, hypoglycemia, hypomagnesemia,
inborn errors of metabolism, and pyridoxine deficiency. Hypoxic-ischemic
brain injuries and intracranial hemorrhages account for 50 to 65% and 15%
of neonatal seizures, respectively.1

Presentation
Distinguishing between seizures or jitteriness in neonates is often difficult. A
simple approach to differentiating between the two is to suppress the move-
ment. If the movement ceases, the neonate is not having a seizure. Jitteriness
is also initiated by an acute stimulation event.7 Neonatal seizures are divided
into five main categories or types:
1. clonic
2. myoclonic
3. spasms
4. subtle
5. tonic
Neonatal Seizures 211

Generalized clonic seizures are uncommon in neonates due to partial


myelination in immature brains. Most clonic seizures in neonates are either
focal or multifocal, resulting in jerking of limbs.
Myoclonic seizures are generalized, focal, or multifocal in nature. The
rapidness and nonrhythmic jerkiness distinguishes myoclonic from clonic
neonatal seizures. Generalized myoclonic seizures consist of bilateral jerking
of mainly upper limbs. Focal myoclonic seizures typically affect upper
extremities. Multi-focal myoclonic seizures involve multiple asynchronous
movements. Generalized and focal myoclonic seizures often have an associa-
tion with electroencephalogram (EEG) changes.
Spasms are short, generalized jerks associated with a single neuronal
firing.
Subtle neonatal seizures involve abnormal movements of extremities,
eyes, or mouth in a rhythmic pattern. Other characteristics of subtle seizures
are brief periods of hypertension, apnea, and heart rate variation.
Generalized tonic neonatal seizures are more common than focal tonic
seizures. Generalized tonic seizures include flexion or extension of both
upper and lower limbs. Focal tonic seizures involve posturing of the neck,
trunk, or extremity with eye deviation.7,8

Evaluation and Diagnosis


If a seizure is presumed, clinicians should conduct a physical examina-
tion. The evaluation also may include a continuously monitored EEG and
magnetic resonance imaging of the CNS. Basic metabolic panels should be
obtained, which include magnesium and calcium; complete blood counts
with differential; cultures from blood, cerebral spinal fluid, and urine; and
toxicology screens. If a metabolic disorder other than electrolyte abnormal-
ity is suspected, clinicians should obtain inborn errors of metabolism panel
(to assess for disorders relating to metabolic process of amino acids, carbo-
hydrates, organic acids, and mitochondria).1,7

Treatment
The first step in treating neonatal seizures is to address the underlying
cause: correcting electrolyte abnormality or hypoglycemia, managing toxin
exposure or withdrawal, and treating infections. Antiepileptic drugs (AEDs)
may be initiated if seizures (1) are not controlled after addressing the under-
212 NICU Primer for Pharmacists

lying cause or (2) are not due to one of the above etiologies. The goal of
therapy is to end or reduce the patient’s number of seizures, thereby increas-
ing the quality of life.

Phenobarbital
The first-line therapy used most often for neonatal seizures is phenobarbital,
a barbiturate.7,9 A loading dose (20 mg/kg) is given intravenously (IV) to stop
active seizures. If seizures continue, repeated IV doses of 10 mg/kg every 20
minutes to a maximum total loading dose of 40 mg/kg may be administered.
Maintenance doses may be initiated 24 hours after loading dose administra-
tion.10 Pharmacokinetic parameters such as renal function, liver function,
and protein binding are variable in neonates. Therapeutic drug monitoring
should be performed for neonates receiving phenobarbital. Because pheno-
barbital depresses the respiratory system, mechanical ventilation support
may be required. Phenobarbital stops acute seizure activity in 29 to 50% of
neonates.11-13 A second therapy may need to be initiated to end seizure activity.

Phenytoin or Fosphenytoin
Phenytoin or fosphenytoin, often used as second-line therapies, may be used
to stop seizure activity in neonates. A loading dose of 20 mg/kg is admin-
istered IV, which may be repeated if needed. Maintenance doses may also
be used. Phenytoin has administration recommendations to limit adverse
infusion and cardiac events, but fosphenytoin administration recommen-
dations are less stringent. Moreover, fosphenytoin may be administered
with dextrose-containing fluids, easing use in neonatal populations requir-
ing dextrose in maintenance fluids or to maintain euglycemia. Phenytoin
controls seizures in 45% of neonates when used as first-line therapy and 59%
of neonates when used in combination with phenobarbital.12 Like phenobar-
bital, phenytoin and fosphenytoin should be therapeutically monitored.7,10

Benzodiazepines
Benzodiazepines (diazepam, lorazepam, midazolam) have also been used to
control seizures in neonates. Diazepam crosses the blood−brain barrier more
readily than lorazepam, which increases adverse cardiorespiratory medication
event risk. Diazepam is not recommended as first-line therapy.7 Diazepam
and lorazepam should not be administered as a continuous infusion. Loraz-
epam may be preferred over diazepam if an intermittent benzodiazepine
Neonatal Seizures 213

is utilized. Midazolam, which also controls seizures in neonates, may be


used as a continuous infusion. Benzodiazepines are not used often and have
variable efficacy ranging from 0 to 100%.13-17

Emerging Therapies
Levetiracetam is emerging as a new AED option for neonatal seizure
control. The medication also has a mechanism of action that addresses
many seizure disorders and may have a role as monotherapy in neonates
like adults. Compared to other treatment options, the medication has fewer
respiratory and cardiac adverse effects.18 The pharmacokinetic profile is
favorable in neonatal populations with predictable changes during the first
week of life.19,20 Additional therapies that have been utilized and studied
include bumetanide, carbamazepine, lamotrigine, lidocaine, topiramate,
valproate, vigabatrin, and zonisamide.

Conclusion
Although neonates have an increased risk of seizures due to an imbalance
of excitatory and inhibitory neuronal pathways and extrinsic factors, most
seizures do not require treatment with AEDs. However, when AEDs are
initiated, the pharmacist plays an important role in dosing strategies, chang-
ing pharmacokinetics associated with development and growth, therapeutic
drug monitoring, and adverse medication event monitoring and treatment.

References
1. Blumstein MD, Friedman MJ. Childhood seizures. Emerg Med Clin North Am.
2007;25:1061-86.
2. Wong M. Advances in the pathophysiology of development epilepsies. Semin Pediatr
Neurol. 2005;12:72-87.
3. Wirrell EC. Neonatal seizures: to treat or not to treat. Semin Pediatr Neurol. 2005;
12:97-105.
4. Saliba RM, Annergers JF, Waller DK, et al. Incidence of neonatal seizures in Harris
County, Texas. Am J Epidemiol. 1999;150:763-9.
5. Ronen GM, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in
Newfoundland: a population-based study. J Pediatr. 1999;134:71-5.
6. Lanska MJ, Lanska DJ, Baumann RJ, et al. A population-based study of neonatal
seizures in Fayette County, Kentucky. Neurology. 1995;45:724-32.
214 NICU Primer for Pharmacists

7. Mikati MA. Neonatal seizures. In: Kliegman RM, Stanton BF, St. Geme JW III, et


al., eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier; 2011:2033-7.
8. Volpe JJ. Neonatal seizures: current concepts and revised classification. Pediatrics.
1989;84(3):422-8.
9. van Rooij LG, Hellstrom-Westas L, de Vries LS. Treatment of neonatal seizures. Semin
Fetal Neonatal Med. 2013;18:209-15.
10. Taketomo CK, Hodding JH, Kraus DM. Pediatric & Neonatal Dosage Handbook. 21st
ed. Hudson, OH: Lexicomp; 2014.
11. Boylan GB, Rennie JM, Pressler RM, et al. Phenobarbitone, neonatal seizures, and
video-EEG. Arch Dis Child Fetal Neonatal Ed. 2002;86:f165-70.
12. Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for
the treatment of neonatal seizures. N Engl J Med. 1999;341:485-9.
13. Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant treatment of neo-
natal seizures: a video-EEG. Neurology. 2004;62(3):486-8.
14. Castro Conde JR, Hernandez Borges AA, Domenech Martinez E, et al. Midazolam in
neonatal seizures with no response to phenobarbital. Neurology. 2005;64:876-9.
15. Yamamoto H, Aihara M, Niijima S, et al. Treatments with midazolam and lidocaine
for status epilepticus in neonates. Brain Dev. 2007;29:559-64.
16. Sirsi D, Nangia S, LaMothe J, et al. Successful management of refractory neonatal
seizures with midazolam. J Child Neurol. 2008;23:706-9.
17. Shany E, Benzaqen O, Watemberg N. Comparison of continuous drip of midaz-
olam or lidocaine in the treatment of intractable neonatal seizures. J Child Neurol.
2007;22:255-9.
18. Pressler RM, Mangum B. Newly emerging therapies for neonatal seizures. Semin Fetal
Neonatal Med. 2013;18:216-23.
19. Sharpe CM, Capparelli EV, Mower A, et al. A seven-day study of the pharmacokinetics
of intravenous levetiracetam in neonates: marked changes in pharmacokinetics in the
first week of life. Pediatr Res. 2012;72:43-9.
20. Merher SL, Schibler KR, Sherwin CM, et al. Pharmacokinetics of levetiracetam in
neonates with seizures. J Pediatr. 2011;159(1):152-4.

Suggested Readings
Mikati MA. Neonatal seizures. In: Kliegman RM, Stanton BF, St. Geme JW III, et
al., eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier; 2011:2033-7.
Pressler RM, Mangum B. Newly emerging therapies for neonatal seizures. Semin Fetal
Neonatal Med. 2013;18:216-23.
van Rooij LG, Hellstrom-Westas L, de Vries LS. Treatment of neonatal seizures. Semin Fetal
Neonatal Med. 2013;18:209-15.
18
Extracorporeal Membrane
Oxygenation

Wyn Wheeler, PharmD, FCCM

Introduction

I
n 1976, Dr. Robert Bartlett and his
colleagues first reported successful
results from the use of extracorpo-
real membrane oxygenation (ECMO) in
neonates.1 As methodology improved to
form the backbone of ECMO practices
today, many more studies and publi-
cations were written. Advancements in
pump technology from roller to centrifu-
gal mechanisms as well as development of
hollow-fiber oxygenators have propelled
ECMO science forward. Improvements
continue moving toward a more awake
patient who is easier to assess. Numerous
216 NICU Primer for Pharmacists

extrapolations of these advancements have been adopted in the pediatric and


adult populations, and their use in neonatal circles has become a treatment
mainstay of many diseases of the newborn.
The Extracorporeal Life Support Organization, an international group
of subject matter experts in ECMO, estimates that 1 out of every 1,309 live
U.S. births could benefit from ECMO annually.2 Neonates tend to develop
respiratory failure as a result of immaturity, airway anomalies, or abnor-
malities of pulmonary circulation. Coupled with the limitations of conven-
tional ventilator practices, this created the need for a different approach to
treat diseases (e.g., congenital diaphragmatic hernia, meconium aspiration,
respiratory distress syndrome).3 Additionally, congenital cardiac defects
often require support for a neonatal cardiopulmonary system as a bridge
to surgical repair, a recovery mechanism postoperatively if weaning from
cardiopulmonary bypass fails or as a stopgap measure while awaiting cardiac
transplantation. The latter is perhaps a population waning in size because
data are emerging that indicate bridging with a ventricular assist device may
result in improved outcomes post-transplant.4,5

Veno-venous ECMO
ECMO utilizes an external pump, oxygenator, and heat exchanger to provide
a modified form of heart−lung bypass, and the method of ECMO selected
for a patient depends on the support required for the diagnosis. For patients
requiring pulmonary support, veno-venous (VV) ECMO is initiated where
blood is removed from a large vein, circulated external to the patient (to
provide oxygenation and removal of carbon dioxide), warmed, and returned
via a vein. Oxygen is delivered via a blender, and sweep gas flow allows
removal of carbon dioxide via rapid diffusion according to Fick’s law.6
Cannulation, performed by a surgeon, commonly involves the right internal
jugular vein and spares the arteries. Venous drainage often limits flow in VV
ECMO, and two-site venous drainage can be used to decrease recirculation.
Cannulae can be placed percutaneously or by venous cutdown.

Veno-arterial ECMO
Conversely, in patients with impaired cardiac physiology requiring full
cardiopulmonary support, veno-arterial (VA) ECMO is the selected method-
ology where blood return is conducted via an artery. The flow provided via
the ECMO pump supports cardiac output, bypassing the entire cardiovas-
Extracorporeal Membrane Oxygenation 217

cular system and decreasing cardiac work and oxygen demand. Cannulae for
VA ECMO are typically placed in the right internal jugular vein (providing
access to the right atrium) and right common carotid artery (providing access
to the aortic arch), often resulting in sacrifice of the aforementioned artery.
The side-graft technique can be employed for arterial return in cases when
artery ligation presents complications; some institutions have reported
success in reconstruction of the artery post-decannulation. Complication
rates in VA ECMO exceed those in VV ECMO and are most frequently
associated with systemic emboli.7 However, approximating normal left heart
filling pressures assists in the correction of pulmonary edema.

Inclusion Criteria and Indications


Inclusion criteria for neonatal ECMO vary by center but largely include
❖❖ gestational age > 34 weeks
❖❖ weight approaching 2 kg
❖❖ presence of a reversible process
❖❖ absence of lethal anomaly, uncorrectable defect, uncorrectable coagulo-
pathy, or major intracranial hemorrhage
Gestational age limits are often based on the required systemic hepariniza-
tion required during ECMO and the reported rates of intracerebral hemor-
rhage and mortality related to premature infants.8 However, a retrospective
review of these early ECMO patients concluded that with further improve-
ments in technique, lowering the gestational age requirement may be possi-
ble.9 The weight requirement of 2 kg is determined by two factors: the lack
of availability of ECMO cannulae smaller than 8 French and the resultant
flow limitations of such a small catheter. In 2012, Lazar and colleagues
published a report of successful use of a 13 French dual-lumen bicaval
catheter in nine neonates, weight range of 2.2 to 5.5 kg, and a survival rate
of 56%.10 However, some centers have reported delayed atrial perforation
with this particular catheter, which may limit its use in younger patients.11
Hermon and colleagues compared two-site cannulation with double lumen
ECMO and found similar outcomes in the two groups.12 Further work is
needed to investigate optimal cannulation techniques to maximize ECMO
flow while minimizing complications in premature neonates.
A common criterion to ECMO progression is referred to as the failure
of optimal medical management, although the definition of “optimal” varies
218 NICU Primer for Pharmacists

by center and often by provider. Most agree that modalities including


maximal pharmacologic support, high frequency oscillatory ventilation,
and use of nitric oxide should be trialed, where appropriate, prior to the
decision to cannulate. Wung et al. reported successful medical management
of persistent pulmonary hypertension in 15 patients who met institutional
criteria for ECMO.13 Additionally, Hintz and colleagues demonstrated a
decrease in ECMO utilization as newer treatment modalities were invoked
for hypoxemic respiratory failure.14 As more data are published, the inclu-
sion criteria for ECMO may be modified to maximize less invasive, more
targeted therapies. Data are emerging that document the use of ECMO in
many disease states with positive mortality results. For example, a German
center’s 20-year experience with neonatal ECMO showed increasing
numbers of patients, a preponderance of patients with congenital diaphrag-
matic hernia, and a survival-to-discharge rate of 67% (with the best rates
seen in meconium aspiration syndrome).15

Changes on ECMO
Organ System Changes
Most organ systems are affected by the initiation of ECMO, and changes
should be anticipated and managed proactively to maximize positive
outcomes. Although the cardiovascular system is supported on ECMO,
it must still be attended to during therapy. Ideally, intravascular volume
should be maintained to facilitate flow through the circuit. Native cardiac
output can also be supplemented by the use of pharmacologic inotropes,
with milrinone being the most commonly used in this population.

Pulmonary System
This system is supported relative to the modality of ECMO utilized. In
VA ECMO, minimal flow enters the pulmonary circuit and, therefore, rest
settings sufficient to maintain expansion and functional residual capacity
are optimal through appropriate levels of positive end-expiratory pressure
(PEEP). Conversely, VV ECMO ventilator settings may require adjustment
throughout the course of treatment because gas exchange from the native
pulmonary system contributes to a greater degree than on VA ECMO.16
Extracorporeal Membrane Oxygenation 219

Central Nervous System


This system is at significant risk in the neonate, so frequent assessment is
helpful in early identification of changes in mental status or seizures. Most
centers are moving away from chemical paralysis to facilitate frequent evalu-
ation of neurologic status. Serial cranial ultrasounds can offer assistance too.
Neurologic complications result in increased mortality, with risks correlat-
ing to patient factors, pre-ECMO illness severity, and use of VA ECMO.17
Neonates have the highest rate of adverse long-term neurological sequelae
from ECMO, including intraventricular hemorrhage and neurologic infarc-
tion.18,19

Hematologic System
This system is affected by the presence of a large, nonbiological circuit that
triggers an inflammatory reaction; acute changes in the complete blood
count and other hematologic markers must be recognized quickly. Mitigat-
ing reductions in hemoglobin levels and platelet counts with frequent trans-
fusions are critical to maintenance of oxygen-carrying capacity and hemosta-
sis, respectively. Thrombosis is prevented through the use of a continuous
infusion of unfractionated heparin titrated to an activated clotting time
congruent with the institution’s ECMO protocol. This is typically 180 to
200 seconds with some centers allowing patients to trend upward toward
240 seconds. Antithrombin III levels often drop during ECMO and require
supplementation, either with infusion of fresh frozen plasma or recombinant
antithrombin III alone.

Renal System
This system is also altered by the inflammatory cascade, and oliguric acute
tubular necrosis can occur. Frequently, support is provided in the form of
exogenous diuretic therapy, hemofiltration, or dialysis. Concurrent manage-
ment of fluid and electrolyte status is also imperative to a successful ECMO
treatment course. Electrolyte management itself can be problematic after
introduction of an extracorporeal circuit and requires close monitoring to
effectively predict derangements and manage them proactively. Total body
sodium levels tend to remain high because considerable volume expan-
sion with isotonic crystalloid saline, along with blood products, is often
220 NICU Primer for Pharmacists

necessary to maintain intravascular volume. Hemolysis within the circuit


can also increase extracellular potassium. Conversely, calcium levels can be
challenging to maintain in the setting of citrate binding from banked blood
products. Optimal calcium levels are critical to maintenance of myocardial
contractility because children tend toward more calcium dependence than
adults.

Gastrointestinal, Fluid, Electrolytes, and Nutrition Support Systems


Early ECMO patients often require total parenteral nutrition, increasing
the risk of complications (e.g., increased bilirubin levels, calculi, fungal
infections). However, when diagnosis allows, more centers are moving to
enteral feeding earlier in the ECMO course to minimize these complications
while supporting maintenance of the mucosal lining of the gastrointesti-
nal system.20 When parenteral nutrition is employed, macronutrient ratios
must be adjusted to minimize infusion of the intravenous fat emulsion
(IVFE) component that avoids emulsion disruption by the ECMO circuit.
Additionally, IVFE has been associated with procoagulant activity in the
presence of an exogenous circuit.21 The administration of IVFE to a separate
IV site, rather than to the circuit’s ports, is preferred to minimize the afore-
mentioned complications. Doses are often limited to 0.5 to 1.5 g/kg/day
depending on the center.

Immune System
Alterations in the system, coupled with invasive cannulae and a reduc-
tion in standard monitoring markers for infection, lead many providers to
conduct routine surveillance monitoring for infection. Febrile response is an
unreliable monitoring parameter due to the presence of a heater within the
ECMO system that maintains normothermia, while large volumes of blood
are circulated through the exogenous circuit. Leukocytosis also has poor
specificity for the identification of infection during the period of ECMO
support where demargination is common in response to a foreign circuit
being introduced. One retrospective review of neonates on ECMO showed
no predictive value in determining bacterial infection based on common
markers including total white blood cell counts, absolute neutrophil counts,
or the immature-to-total neutrophil ratio.22 Expert panels of ECMO special-
ists have recommended liberal use of diagnostic tests (e.g., bronchoscopy,
computerized tomography) while minimizing the collection of routine
Extracorporeal Membrane Oxygenation 221

surveillance cultures because their utility probably does not outweigh their
cost until later in therapy.23

Pharmacokinetic Changes
Absorption is perhaps the area of pharmacokinetics least affected by
ECMO due to the IV administration of the majority of medications.
Enteral feedings, ranging from trophic to full rates, are administered in
certain patient cases to preserve gastrointestinal fluid status, circulation, and
function; however, reliable oral absorption of medications is nearly impossi-
ble to predict so this route is avoided.
The distribution of medications is the phase of pharmacokinetics most
affected by ECMO because two major distributive factors are significantly
altered by the presence of an ECMO circuit: volume of distribution (Vd)
and binding. Shekar and colleagues published a concise review of the
overarching pharmacokinetic changes present during ECMO, specifically
citing lipophilic binding to circuit surfaces and hydrophilic increased Vd
resulting from hemodilution as complicating factors.24 Vd is increased most
in neonates due to the patient’s relative size in proportion to the volume
of the circuit. Additionally, circulating protein concentrations decrease
as an ECMO course progresses, potentially increasing the free fraction of
highly protein-bound medications. Hepatic metabolism has been shown to
be reduced in critical illness, and organ hypoperfusion adds to significant
decreases in metabolic capability. Excretion via the kidney can be impaired
as a result of stimulation of factors by the oxygenator, notably arachidonic
acid and renin. Subsequent decreases in renal blood flow result in an overall
reduction in the kidneys’ excretory capacity. Introduction of dialysis modali-
ties often occurs, and medication dosing must accommodate alterations that
result from ECMO as well as increased clearance via dialysis.

Pharmacologic Challenges on ECMO


For the critical care pharmacist, ECMO patients present a unique challenge.
In addition to physiologic changes and the resultant effect on organ systems,
the alteration of drug disposition in the ECMO patient is significant. These
changes—coupled with relatively scarce literature guiding medication dosing
during ECMO—require thoughtful consideration of the medications’
chemical properties and application of complex pharmacokinetic principles
to result in appropriate serum levels and evoke the desired outcome.
222 NICU Primer for Pharmacists

Medication-Specific Changes
Care must be taken when interpreting the literature regarding specific drug
dosing in ECMO. Many earlier studies were conducted using equipment
that varies significantly from what many centers currently use. The physical
composition of the circuit and oxygenator, pump mechanism, and age of the
circuit all play important roles in how medications are affected by a course
of ECMO. In the absence of literature, the medication’s physical properties
are the most reliable data to use in making decisions about a preferred agent
or an optimal dose and interval. Data in varying types of circuits show that
the higher the lipophilicity of a medication, the higher likelihood it will
adhere to ECMO circuitry and make less drug available to the patient.25,26

Anti-Infectives
Gentamicin. This drug is perhaps the most researched antibiotic in neo-
natal ECMO. Most studies agree that an increased Vd coupled with
decreased renal clearance result in a need to monitor peak and trough levels
diligently. Given that gentamicin is a concentration-dependent antibiotic,
verifying that peaks are sufficient for bacterial kill is imperative to successful
treatment of gram-negative pathogens. Adsorption should be negligible due
to the relative hydrophilicity of the compound and diluent.
Vancomycin. This drug is similar with regard to alterations in Vd and
clearance27 but is a time-dependent antibiotic and, therefore, monitoring of
troughs alone is sufficient.
Cefotaxime. In contrast, Ahsman and colleagues demonstrated only
distended Vd for cefotaxime without a concurrent decrease in clearance,
and infants in the study had sufficient time above the minimum inhibitory
concentration using standard dosing regimens.28
Fluconazole. A neonatal cohort of ECMO patients on fluconazole
demonstrated an increased Vd without major changes in clearance.
Additionally fluconazole lacks a lipophilic profile, in contrast to echinocan-
dins, making it a reasonable option for antifungal therapy during ECMO.29
Meropenem. Its use during ECMO is complex in that it seems challeng-
ing to maintain an appropriate serum level of the antibiotic. Theories about
circuit sequestration and increased clearance have been published, but
most notably meropenem is unstable in warmer temperatures. Moreover,
the heater contained within the ECMO circuit may play a role in reducing
the amount of medication available for bacterial kill.30 Cies and colleagues
Extracorporeal Membrane Oxygenation 223

reported that delivering meropenem via continuous infusion to an infant


resulted in serum and pulmonary concentrations above the minimum inhib-
itory concentration for an isolate of Pseudomonas aeruginosa for at least 40%
of the dosing interval. The result was clinical success.31
Oseltamivir. Given the use of ECMO to treat influenza in pediatric
patients, one group published pharmacokinetic data in three patients. This
demonstrated serum concentrations of oseltamivir were adequate while on
ECMO by doubling published age-specific dosing to mitigate the decreased
total plasma concentration.32

Sedatives
NICUs sometimes utilize benzodiazepines therapy when sedation is indicat-
ed and opioids do not provide sufficient clinical effect. The most common
agents are midazolam and lorazepam, with the majority of centers world-
wide using midazolam.
Midazolam. This drug is highly lipophilic and highly protein bound,
making it a challenge to use in ECMO because the circuit’s sequestration
compounds the issues created by an increased Vd. Additionally, midazolam
is metabolized by cytochrome P4503A4/5 to an active metabolite, and this
metabolic process is prolonged in critically ill children.33 Predictably, studies
in infants and young children on ECMO have demonstrated a three- to
four-fold increase in Vd with variable clearance of the parent drug and
metabolite.34 As a result, midazolam dosing on ECMO must be carefully
monitored with appropriate increases at initiation until binding sites are
saturated with a subsequent reduction as the medication moves through its
metabolic pathway.
Lorazepam. This drug is sometimes substituted due to the lack of
an active metabolite. However, solubility of lorazepam in water is poor,
requiring the parenteral formulation to contain polyethylene and propylene
glycol to solubilize the drug. This vehicle can be problematic in critically ill
infants and children, which causes a hyperosmolar anion gap acidosis as it
accumulates.35,36

Opioids
The most common opioids used in the NICU are fentanyl and morphine.
Fentanyl. Data collected from adult-size circuits primed for ECMO
show circuit sequestration of fentanyl occurs to such a degree that clinical
224 NICU Primer for Pharmacists

failure can occur.37 Fentanyl also presents a challenge in that patients develop
tachyphylaxis to its analgesic effects quickly, making dose escalation
throughout therapy necessary to maintain patient comfort.38
Morphine. Because circuit sequestration and tachyphylaxis are less
problematic than with fentanyl, morphine is the preferred opioid in
ECMO. However, morphine undergoes glucuronidation to an active metab-
olite. This presents a complication of accumulation during critical illness
and ECMO.

Conclusion
ECMO can be used in neonates to allow pulmonary healing or provide
bridge therapy until cardiac repair, depending on the modality employed.
Organ systems are affected by the presence of an exogenous, nonbiological
circuit so proactive management of physiologic processes is imperative.
Additionally, the disposition of medications is altered in the presence of an
ECMO circuit both with regard to how organ systems are affected by criti-
cal illness and extracorporeal support as well as the system’s physical barriers
of adherence to the circuit and Vd expansion. Clinicians must critically
evaluate literature to decide whether they can extrapolate the data to the
circuit type being used as well as the patient being treated.

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Extracorporeal Membrane Oxygenation 227

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Suggested Readings
See https://www.elso.org/ for more information.
Schaible T, Hermle D, Loersch F, et al. A 20-year experience on neonatal extracorporeal
membrane oxygenation in a referral center. Intensive Care Med. 2010;Jul 36(7):1229-34.
Shekar K, Fraser JF, Smith MT, et al. Pharmacokinetic changes in patients receiving extra-
corporeal membrane oxygenation. J Crit Care. 2012;27(6):9-18.
Index

A on respiratory syncytial virus, 158, 160


on sedation management, 112
Abortus, 4 on systemic corticosteroids, 88
Absolute neutrophil count, 146 on vaccinations, 187
Absorption, 17 on Vitamin K IM, 10-11
extravascular, 18 American College of Chest Physicians, 159
gastrointestinal, 18 American College of Emergency Physicians, 159
intramuscular, 18 American College of Obstetrics and Gynecology, 61
percutaneous, 19 American Congress of Obstetricians and
rectal, 19 Gynecologists, 145
Academy of Breastfeeding Medicine, 49, 61 American Society for Parenteral and Enteral
Acetaminophen, 21, 119, 127-128 Nutrition, 30, 34
PDA and, 103-104 American Society of Health-System Pharmacists
vaccination response and, 191-192 (ASHP), 34
Acid ionization constant, breast milk and, 47 American Thoracic Society, 159
Acid-base balance, 32 Amino acids, 30, 34-35
Activity, 5 Aminoglycoside(s), 19, 134, 172
Acute lung injury, 84-85 Aminophylline, 69
Acyclovir, 46 Aminosyn, 30
parenteral, 147-148 Amoxicillin-sulbactam, 172
Addiction, maternal, 61 Amphotericin B, 137
Adverse drug events, methylxanthine toxicity, 71 Ampicillin, 6, 134, 172
Adverse effects, neonatal abstinence treatment, 60 Ampicillin-sulbactam, 172
Airway patency maintenance, 68 Anaerobic antibiotic therapy, 172
Albuterol, 87, 161 Analgesia
Alcohol, 48 common agents for, 127-129
Alginate, 181 pharmacologic agents for, 118-119
Alpha agonists, 115-116 principles of, 116-117
Aluminum toxicity, 36-37 Analgesics, 123
American Academy of Pediatrics, 45 reversal of, 121
acyclovir shortage recommendations, 147 Angiotensin-converting enzyme inhibitors (ACEI),
alcohol and, 48 105
on apnea of prematurity, 65 Antacids, 181
on bronchiolitis, 161 Antenatal corticosteroids, 80, 101, 175
on neonatal abstinence syndrome, 56, 58
230 NICU Primer for Pharmacists

Antibiotic(s), 2, 6, 105, 134-135, 137 Bevacizumab (intravitreal), 11


administration risks of, 173-174 Biomarkers, 132-133, 175
empiric regimens for, 172 Blood culture(s), 132, 134-135
meningitis duration and, 135 Blood flow, 94, 95
scheduling of, 8 Blood volume, 7
sepsis duration and, 135 Body positioning, 180
Antiepileptic drugs, 211-212, 213 Bosentan, 206
Antifungal agent, 137 Brainstem maturity, 66
Anti-infectives, 222-223 Breastfeeding, 43
Antiretroviral dosing, neonatal, 152 alcohol and, 48
Antithrombin III infusions, 219 constipation and, 182, 183
Apgar, Dr. Virginia, 5 initiation of, 6
APGAR score, 5, 200 length of, 44
Apnea, 75, 192-193 neonatal abstinence syndrome and, 61
Apnea of prematurity (AOP), readings, 75 nicotine and, 48
causes of, 67 pain management and, 118
diagnosis of, 67-68 substance abuse and, 48-49
duration of treatment for, 71 Briggs, 51
epidemiology of, 65-66 Bronchiolitis management, 161
lab monitoring of, 67 Bronchodilators, 86-87
methylxanthines in, 69 Bronchopulmonary dysplasia, 83-84, 89-90, 96, 101
non-pharmacologic treatments for, 68-69 clinical presentation of, 85
pathophysiology of, 66 diagnosis of, 83-84
pharmacologic monitoring for, 70-71 epidemiology, risk factors of, 84
pharmacologic treatments for, 69-71 incidence of, 84
physical assessment of, 67 management of, 85
presentation of, 66-67 outcomes for, 89
therapeutic goals for, 68 pathophysiology of, 84-85
Appearance, 5 pharmacologic management of, 85-87
Appropriate for gestational age (AGA), 3 prevention strategies for, 87-89
Arachidonic acid pathway, 104 readings on, 92
Arginine, 30 Buffering agents, 181
Atelectasis, 78-79 Bumetanide, 213
Atracurium, 114, 126 Buprenorphine, 48, 57, 60

B C
Ballard, Dr. Jeanne, 5 Caffeine, 6, 21, 69, 174-175
Ballard scoring, 5 adverse drug events for, 71-72
Barbiturates, 113 IV, PO formulations for, 70
Barium enemas, 183 loading dose for, 70
Barotrauma, 79 maintenance dosing for, 70
Bartlett, Dr. Robert, 215 monitoring of, 70
Bell Stage I, suspected NEC, 169, 170 Calcium carbonate, 181
Bell Stage II, definite NEC, 169, 170, 174, 175 Calcium chloride, 37
Bell Stage III, advanced NEC, 169, 170-171, 174, Calcium gluconate, 32, 37
175 Calcium management, 220
Bell staging modification, 170-171 Calcium solubility, 36
Beneprotein, 45 Calfactant, 82
Benzathine penicillin, IM, 149 Caloric requirements, 28
Benzodiazepine(s), 20, 21, 56, 113, 121, 212-213, Canadian Paediatric Society, 88
223 Candida, 136
Beractant, 82 Candida spp., 36
Beta antagonists, 21 Carbamazepine, 213
Beta-agonists, 87 Carbapenem, 172
Betamethasone, 4, 80 Carbohydrates, 29
Bethanechol, 181 Cardiac support drips, 105
Index 231

Carnitine, 34 C-reactive protein, 132


Cefotaxime, 134, 222 CRIES scoring tool, 117
Cefoxitin, 172 Critically ill neonate, pharmacokinetic changes in,
Ceftriaxone, 9-10, 20 121-123
Centers for Disease Control and Prevention (CDC), Curosurf, 82
144, 145 Cyclopentolate, 11
immunization recommendations of, 189 Cysteine, 34
on hepatitis B infection, 188 Cytochromes, 20-21
on respiratory syncytial virus, 156 Cytomegalovirus (CMV), 144-145
on vaccinations, 187 prevention of, 145
Central apnea, 66 treatment for, 146
Central line access, 38, 136 Cytomegalovirus hyperimmune globulin, 145
Central line-associated blood stream infections
(CLABSIs), 36
Central nervous system changes, 219 D
Cephalosporin(s), 134, 172 DART, 88
Cerebral spinal fluid cultures, 132 Dexamethasone, 4, 8, 80, 88-89
Cesarean section birth, 4 Dexmedetomidine, 115-116, 127
Chest radiography, 200 Dextromethorphan, 21
Chickenpox, 143-144 Dextrose, 29
Chloramphenicol, 21 Dialysis, 221
Chlorothiazide, 86 Diazepam, 21, 212-213
Chorioamnionitis, 135 Diphtheria, tetanus and pertussis (DTaP), 189, 190,
Chorioretinitis, 142 193
Chromium, 33 Distribution, 17, 19-20
Chronic lung injury, 85 Diuretics, 85-86, 87, 104
Cimetidine, 46 Domperidone, 50
Cisatracurium, 115, 127 Donor milk, 45
Clindamycin, 172 Dopamine, 7, 8, 105
Clinical sepsis, 135 Dosing, 2
Clonic seizures, 211 Dosing error, 8
Clonidine, 60, 182 Drug dosing references, 14
Cluster care, 117-118 Drug transfer into milk, 46
CNS symptoms, NAS, 58 acid ionization constant for, 47
Coagulase-negative staphylococci (CoNS), 136 bioavailability of, 46
Cocaine, 56 labeling for, 51
ingestion, 48 milk-to-plasma ratio for, 47
Cochrane Review, 161 milk, molecular weight for, 46
Cocooning, 193 peak serum concentration of, 47
Code of Federal Regulations, 49 relative infant dose for, 47
Codeine, 57 risk-benefit statement for, 51
Colostrum, 44 volume of distribution and, 46-47
Congenital heart disease, 174 Drugs in lactation references, 14
Congenital syndromes, 95 Drugs in Pregnancy and Lactation, 51
Congenital varicella syndrome (CVS), 143-144 Ductus arteriole, 188
Conjugate vaccines, 189 Ductus arteriosus, 94-96
Constipation, 179
epidemiology of, 181-182
nonpharmacologic treatment for, 182-183 E
pharmacologic treatments for, 183
presentation of, 182 Early-onset infections, 132
Continuous positive airway pressure (CPAP), 68-69 common pathogens of, 133-134
Copper, 33 pharmacologic treatment for, 133-134
Corrected gestational age (CGA), 3 presentation, laboratory evaluation of, 132-133
Corticosteroids, 143, 188 Early-onset sepsis, 132
antenatal, 80, 175 Echocardiogram, 200-201
maternal, 4 Electrolyte(s), 31-32
systemic, 88 management of, 219
232 NICU Primer for Pharmacists

support for, 220 Fluid(s)


Elimination, 17, 22 goal for, 28
Emergency Nurses Association, 159 management, IV, 28
Empiric antibiotics, 172 nutrition and, 28
Endothelin receptor antagonists, 206 support, 222
Enoxaparin, 46 Flumazenil, 121, 122
Enteral feeding(s)/nutrition, 221 Fluoroquinolones, 9
bowel movements and, 182, 183 Food and Drug Administration (FDA), 143
gastroesophageal reflux and, 180-181 ceftriaxone warning by, 10
NSAID therapy and, 106-107 on aluminum exposure, 36
Enterobacteriaceae, 136 on drug passage into milk, 50-51
Enterococci, 36 sildenafil labeling requirements of, 204
Epinephrine, 105 Foramen ovale, 198
Erythromycin, 181 Formulary, 2
Erythromycin ophthalmic ointment, 6 Fosphenytoin, 212
Escherichia coli, 134 Furosemide, 86, 104
Ethanol locks, 36
Eutectic mixture of lidocaine and prilocaine
(EMLA), 192 G
Expiration dates, times, 9 GABA (gamma-aminobutyric acid) modulators,
Extracorporeal Life Support Organization, 216 113-114
Extracorporeal membrane oxygenation (ECMO), GABA/benzodiazepine receptor antagonist, 121
122, 202, 203, 205, 207, 215-216 Galactogogues, 48-50
anti-infectives and, 222-223 Ganciclovir, 146
central nervous system changes in, 219 Gastroesophageal reflux, 179
gastrointestinal, fluid, electrolytes, nutrition epidemiology of, 180
support in, 220 nonpharmacologic treatment for, 180-181
hematologic system changes in, 220 pharmacologic treatments for, 181
immune system changes in, 220-221 presentation of, 180
inclusion criteria, indications for, 217-218 Gastrointestinal contrast, 46
opioids and, 223-224 Gastrointestinal disorders, readings on, 186
organ system changes in, 218 Gastrointestinal support, 220
pharmacokinetic changes in, 221 Gentamicin, 6, 19-20, 134, 222
pharmacologic challenges of, 221-224 Gestational age (GA), 2
pulmonary system changes in, 218 GI symptoms, NAS, 58
readings on, 227 Glomerular filtration, 22
renal system changes in, 219-220 Glucocorticoids, 100
sedatives and, 223 indomethacin and, 12
veno-arterial, 216-217, 218, 219 Glucose infusion rates (GIR), 29-30
veno-venous, 216-217, 218 Glucuronidation, 21
Extravasation, 7 Glutathione, 34
Extremely low birth weight (ELBW), 3 Glycerin, 183
Extremely preterm (EPT), 3 Gravida, 3
Gravida/para (GP), 4
F Gray-baby syndrome, 21
Grimace, 5
Failure of optimal medical management, 217-218 Group B Streptococcus, 199
Famotidine, 34 Growth charts, 29
Fat emulsions, 31, 37
Fatty acid deficiency syndrome, 31
Fentanyl, 116, 120, 129, 223-224 H
Fenton growth charts, 29
Fenugreek, 49-50 H2-receptor antagonists, 34, 181
Fetal circulation, 198 Haemophilus influenza, 189, 190
Fick’s law, 216 Hale, Thomas, 51, 52
Fluconazole, 222 Hand washing, 145
Handbook on Injectable Drugs, 38
Index 233

Handbooks, 14-15 Inhaled nitric oxide, 202-203, 204 206, 207


Healthy People 2020 Goals, 44, 45 Institute of Medicine, 145
Hematologic system changes, 219 Insulin, 46
Heparin, 8, 34 Intestinal failure-associated liver disease, 31
Heparinization, systemic, 217 Intrauterine growth restriction (IUGR), 3
Heparinized fluids, 7 Intravenous admixtures, 8
Hepatic clearance, 123 Intravenous dextrose, 2
Hepatitis B immune globulin, 188 Intravenous fat emulsion (IVFE), 31, 220
Hepatitis B vaccine, 6, 188-189, 190 Intravenous fluid management, 28
Heroin, 57 Intraventricular hemorrhage (IVH), 12, 96-97, 99
Herpes simplex, 146-147 Iodine, 46
treatment for, 147-149 Ion trapping, 47
Herpes zoster, 144 Ipratropium MDI, 87
Hoffman elimination, 114-115 Iron supplementation, 45, 182
Human immunodeficiency virus, 149-153 Isoenzymes, 20
neonatal antiretroviral dosing for, 152
Human milk, 175
fortifier, 45 J
Hyaluronidase, 7, 32 Jitteriness, 210
Hydrocodone, 56
Hypercarbia, 79
Hyperglycemia, 29 K
Hyperoxia test, 200
Hypoglycemia, 30 Kangaroo care, 49
Hypothermia pain management and, 118
induction, 122 Kangaroo mother care (KMC), 6
rewarming, 122-123 Kernicterus, 10, 20
Hypoxemia, 66, 68, 79, 200, 201 Ketamine, 116, 127
King Guide to Parenteral Admixtures, 38
I
Iatrogenic opioid dependence, 120-121 L
Ibuprofen, 102, 103 Lactated Ringer’s solution, 10
contraindications for, 100 Lactation, 43
drug interactions with, 100 medications and, 53
PDA closure dosing for, 98-99 readings on, 54
vaccination response and, 191-192 risk categories for, 52
Ibuprofen lysine, 97-98 Lactic acidosis, 79
IFALD, 35 LactMed, 51
Iloprost, 206 Lactobacillus probiotics, 175
Inactivated polio virus, 189, 190 Lamotrigine, 213
Indomethacin, 5, 88, 96-97, 98, 102-103, 107 Lansoprazole, 181
antenatal, 174 Laparotomy, 173
contraindications for, 100 Large for gestational age (LGA), 3
drug interactions with, 100 Late-onset infections, 132
glucocorticoids and, 12 common pathogens for, 136
PDA closure dosing for, 98-99 pharmacologic treatment for, 136-137
side effects of, 99 presentation, laboratory evaluation of, 136
Indomethacin IV, 6 Late-onset sepsis, 132
Infant assessment, 5 Levetiracetam, 213
Infasurf, 82 Lidocaine, 119, 213
Infection risk, PN, 36 Lidocaine 4% cream, 192
Infectious disease references, 14 Lidocaine-prilocaine, 119
Infectious Diseases Society of America, 36 Line flushes, 8
Influenza vaccine, 193 Lipsitz tool, 58
Inhaled bronchodilators, 86-87 Local anesthetics, 119
Inhaled corticosteroids, 87 Loop diuretics, 86, 102
234 NICU Primer for Pharmacists

Lorazepam, 113, 126, 212-213, 223 donor milk and, 45


Low birth weight (LBW), 3 Moxifloxacin, 172
Lucinactant, 82 Multivitamins, 34
Luer lock oral syringes, 9 Muscarinic agents, 87
Myoclonic seizures, 211
focal, 211
M generalized, 211
Macrolides, 149 multi-focal, 211
Macronutrients, 29-30
Magnesium sulfate, 5 N
Maladaptation, 199
Maldevelopment, 199 Naloxone, 121
Manganese, 33 National Association of Neonatal Nurse
Manual stimulation, 68 Practitioners, 159
Marijuana, 56 National Association of Neonatal Nurses, 159
Maternal antibodies, 187-189 National Institute of Child Health and Human
Maternal history, 133 Development, 83-84, 200
Maturity rating, 5 National Institutes of Health, 51
Mechanical ventilation injury, 84 National Respiratory and Enteric Virus Surveillance
Meconium, 57, 182 System, 156
Medical induction of labor, 4 Nebulized saline, 161
Medication safety, 8 Necrotizing enterocolitis (NEC), 44, 96, 99, 101,
Medication standardization, 8 181, 183
Medication storage, 8-9 anaerobic antibiotics for, 172-173
Medications & Mothers’ Milk, 51 antibiotic therapy duration for, 173
Medications, to avoid in neonates, 9-10 Bell staging of, 169-171
Medium chain triglycerides oil, 45 congenital heart disease and, 174
Meningitis, 131, 136 diagnosis of, 169, 172
antibiotic therapy duration for, 135 empiric antibiotics for, 172
cefotaxime and, 134 epidemiology of, 167-168
CSF study values in bacterial, 136 medical treatment for, 172
readings on, 139 medications and, 174-175
Meropenem, 222-223 pathophysiology for, 168
Metabolism, 17, 20-22 presentation of, 169-170
Metered dose inhaler, 87 prevention of, 175
Methadone, 48, 56-58, 61, 120, 131 readings on, 177-179
Methemoglobinemia, 202-203 red blood cell transfusions for, 174
Methylxanthine(s), 21 surgical treatment of, 173
mechanism of action for, 69 treatment risks for, 173-174
toxicity of, 71-72 Neofax, 8, 147
Metoclopramide, 49, 50, 181 Neonatal Abstinence Scoring System, 59
Metronidazole, 172 Neonatal abstinence syndrome (NAS), 55, 121
Micronutrients, 31-32 breastfeeding and, 61
Midazolam, 8, 20, 113, 126, 212, 213, 223 family considerations in, 61
Milk-to-plasma ratio, 47 readings on, 63
Milrinone, 204-205 screening and scoring of, 57-58, 59
Mixed apnea, 66 symptoms of, 58
Moderate-to-late preterm (LPT), 3 treatment for, 58, 60
Modified Finnegan tool, 58, 59 Neonatal birth history, 133
Molybdenum, 33 Neonatal Research Network, 200
Morphine, 21, 57-58, 116, 119-120, 128, 224 Neonatal seizures, 209
Mother’s milk evaluation, diagnosis of, 211
additives to, 45 pathophysiology of, 210
benefits of, 44 presentation of, 210-211
breastfeeding length for, 44 readings on, 214
complications of, 45 treatment for, 211-213
composition of, 44 Neonatal sepsis, 139
Index 235

Neonatal Withdrawal Inventory, 58 P


Neonates, 2
NEOPAIN study, 119 Pain, 111
Neotrace, 33 analgesia principles for, 116-117
Neuromuscular blocking agents, 112, 114-115 assessment of, 117
Neutropenia, 146, 148 minimizing vaccination, 192
Nevirapine, 152 nonpharmacologic interventions for, 117-118
Newborn management, 6 pharmacologic agents for, 118-120
Nicardipine, 5 readings on, 125
Nicotine inhaler, 48 Palivizumab, 158-159, 162
Nicotine patch, gum, 48 usage guidelines, 159-161
Nifedipine, 5 Palo Alto Medical Foundation Toxoplasma Serology
NIPS scoring tool, 117 Laboratory, 142, 143
Nitric oxide, 202, 204 Pantoprazole, 181
Nitrofurantoin, 9 Para, 3
NMDA (N-methyl-D-aspartate) antagonists, 116 Paracetamol, 104
Nonopioids, 118-19 Parenteral nutrition, 7, 39, 136, 172, 220
Nonsteroidal anti-inflammatory drugs (NSAIDs), 3-in-1 vs. 2-in-1, 37
199 -associated liver disease, 31, 35
contraindications for, 100 complications of, 35-37
drug interactions with, 100 dextrose concentrations and, 29
oral options for, 100 light exposure on, 38
PDA closure and, 97-99 medication administration and, 38
PDA treatment and, 103-105, 106 medication compatibility and, 38
side effects of, 99 neonates and, 27-28
Nosocomial infections preparations of, 37
common pathogens of, 136 readings on, 42
pharmacologic treatment for, 136-137 with calcium, 10
presentation, laboratory evaluation of, 136 Patent ductus arteriosus, 93-94
N-PASS scale, 112 acetaminophen and, 103-104
Nutrition importance of, 96-97
fluids and, 28 incidence of, 94-95
management, 28-29 nonpharmacologic management for, 105-106
support, 222 NSAID therapy and, 97-100, 106-107
Pathophysiology of, 95-96
pharmacologic medical management for, 104
O pre-symptomatic treatment for, 101, 102
Oat cereal, 45 prophylactic management for, 101, 102-103
Obstructive apnea, 66 symptomatic management for, 101
Omegaven, 31, 35 readings on, 110
Omeprazole isomers, 181 treatment timing for, 100-101
Opiate maintenance therapy, 57 trials and, 103
Opiate replacement treatment, 60 Peak serum concentration, drug transfer into milk,
Opiate therapy, 58 47
Opiate withdrawal, 55-56 Pediarix, 189, 193
Opioids, 116, 119, 182, 183 Pediatric & Neonatal Dosage Handbook, 8
iatrogenic dependence on, 120-121 Pediatric Injectable Drugs: The Teddy Bear Book, 8
Organ systems changes, 218 Peditrace, 33
Oseltamivir, 223 Penicillin, 149
Oxidation, 38 Penicillin G, IV, 149
Oxycodone, 56, 57 Pentacel, 189
Oxygen concentration of supplemental oxygen, 201, Peripheral airway obstruction, 85
202 Peripheral line access, 38
Oxygen damage, 79 Peripherally inserted central catheter, 7
Oxygenation index, 201 Peritoneal drainage, 173
Peroxides, 38
Persistent pulmonary hypertension of newborn
clinical manifestations of, 200
236 NICU Primer for Pharmacists

diagnosis of, 200-201 Procaine penicillin, IM, 149


endothelin receptor antagonists and, 206 Procalcitonin concentrations, 132
extracorporeal membrane oxygenation and, 202, Prokinetic agents, 181
203, 205, 207 Proparacaine, 11
management of, 201 Prophylactic management, 101, 102-103
nitric oxide and, 202-203 Propofol, 113-114, 126
outcomes for, 206-207 Propranolol, 21
pathogenesis, causes of, 188-189 Prostacyclin I2, 206
phosphodiesterase type 3 inhibitors and, 204-205 Prostaglandin analogs, 206
phosphodiesterase type 5 inhibitors and, 203-204 Prostaglandin infusions, 174
prostaglandin analogs and, 206 Protein, 30
readings on, 208 binding, 20
risk factors for, 199 supplement, 45
severity determination for, 201 Proton pump inhibitors, 21, 181
surfactant therapy for, 205-206 Pulmonary surfactant deficiency, 78
transition from intrauterine to extrauterine Pulmonary system changes, 218
circulation in, 198 Pulmonary vascular resistance, 114, 197, 198, 199
Pertussis, 193 Pulmonary vasoconstriction, 79
Pharmacodynamics, 17 Pyrimethamine, sulfadiazine and folinic acid, 142-
readings on, 25 143
Pharmacokinetic(s), 17
changes in, 121-123
extracorporeal membrane oxygenation and, 221 R
readings on, 25 Ranitidine, 34
Phase I metabolism, 20 Rapid plasminogen reagent (RPR) screening, 148,
Phase II metabolism, 20, 21 150-151
Phenobarbital, 35, 60, 70, 113, 126, 212 Rectal stimulation, 182, 183
Phentolamine, 7 Red blood cell transfusions, 68, 174
Phenytoin, 20, 21, 212 RedBook (2015), 143
Phosphodiesterase type 3 inhibitors, 204 Relative infant dose, 47
Phosphodiesterase type 5 inhibitors, 203-204 Renal system changes, 219-220
Phosphorus solubility, 36 Respiratory distress syndrome (RDS), 4, 77-78, 94,
Phototherapy, 38 95
Physical dependence, 55-56 antenatal corticosteroids and, 80
Phytonadione, 10 clinical presentation of, 79
Piperacillin-tazobactam, 172 epidemiology, risk factors for, 78
PIPP scoring tool, 117 long-term complications of, 81
Platelet dysfunction, 99 management of, 79-80
Platelets, low, 96 pathophysiology of, 78-79
Pneumococcal conjugate, 189, 190 readings on, 92
Polysaccharide vaccines, 189 surfactant replacement therapy for, 80-83
Poractant alfa, 82 Respiratory syncytial virus, 155
Post-immunization apnea, 192-193 epidemiology of, 156
Post-menstrual age (PMA), 3 etiology, pathogenesis of, 156, 157, 158
Postnatal age (PNA), 2 neonatal, 158
Potassium, 38 prevention of, 158-159, 162
Premasol, 30 readings on, 165
Prematurity season duration of, 157
causes of birth in, 4 Respiratory systems, NAS, 58
risks of, 1-2 Respiratory ventilation support, 68-69
Pressor agents, 106 Retinopathy of prematurity, 11-12, 68
Pre-symptomatic treatment, 101, 102 Rice cereal, 45
Preterm, 3 Rocuronium, 114, 126
Preterm formula, 175 Rotarix, 190-191
Preterm labor RotaTeq, 190-191
management, 5 Rotavirus vaccine, 189-191
prevention, 4-5 Rubella, 143
Probiotics, 175
Index 237

S prevention of, 149


treatment for, 149
Salbutamol, 161 Syringes differentiation, 9
Sedation, 123 Systemic corticosteroids, 88
alpha agonists and, 115-116 Systemic vascular resistance, 198
assessment of, 112
common agents for, 126-127
GABA modulators and, 113-114 T
neuromuscular blocking agents and, 114-115 Taurine, 30, 34
NMDA antagonists and, 116 Terbutaline, 5
nonpharmacologic modalities for, 114 Term neonates, morphine metabolism by, 21
principles of, 111-112 Tetanus diphtheria and pertussis (TDaP), 189, 190,
readings on, 125 193
reversal of, 121 Tetracyclines, 9, 149
Seizures, 209 Text book references, 14
Selenium, 33 Theophylline, 21, 69
Sepsis, 131, 135 adverse drug events for, 71
Sepsis syndrome, 96 drug interactions for, 70
Serotonin discontinuation syndrome, 57 immediate release enteral solution, 69
Serotonin reuptake inhibitors (SSRIs), 57 IV premixed solutions, 69
17-alpha-hydroxyprogesteron caproate IM loading dose for, 69
(maternal), 5 maintenance dosing for, 69
Shingles, 144 monitoring of, 70-71
Sildenafil, 203-204 Thiazide diuretics, 86
Simultaneous pre-, postductal arterial blood gases, Thiazides with or without spironolactone, 102
200 Thickening feeds, 180-181
Small for gestational age (SGA), 3 TIPP trial, 102-103
Society of Hospital Medicine, 159 Tissue binding, 20
Sodium bicarbonate buffer, 119 Tocolytics (maternal), 5
Sodium phosphate, 37 Tonic neonatal seizures
Spasms, 211 focal, 211
Spiramycin, 142-143 generalized, 211
Spontaneous preterm labor, 3 Topical medication, 19
Staphylococcus aureus, 36 Topical nitroglycerin paste, 7
Steroids, 30 Topiramate, 213
Stooling frequency, 181-182 TORCH (Toxoplasmosis, Rubella, Cytomegalovirus,
Streptococcus agalactiae, 133-134 Herpes Simplex) infections, 153, 154
Substance abuse, maternal Toxoplasmosis gondii, 142
breastfeeding and, 48 prevention of, 142-143
screening and scoring of, 57-58 treatment for, 143
Substances of abuse, 56-57 Trace elements, 32-34
Subtle neonatal seizures, 211 Train-of-four, 112
Sucralfate, 181 Tramadol, 21
Sucrose, 118-119, 127, 192 Treponema pallidum, 148
Sulfation, 21 TrophAmine, 30, 37
Sulfonamides, 9-10, 20 Trophic feeding, 175
Supplemental oxygen, 68 Tubular excretion, 22
Suppressive therapy, 147-148 Tubular reabsorption, 22
Surfactant(s), 82, 95, 101 Tyrosine, 30
deficiency, 78
therapy, 80-83, 205-206
Surfaxin, 82 U
Surgical ligation, PDA, 104
Survanta, 82 Umbilical artery catheter, 7
Symptomatic management, 99 Umbilical venous catheter, 7
Synagis, 158-159 Underdevelopment abnormalities, 198-199
Syphilis, 148 Unfractionated heparin, 219
evaluation, treatment algorithm for, 150-51 Ursodiol, 35
238 NICU Primer for Pharmacists

V Vitamin K IM, 6, 10
Vitamin K1, 11
Vaccination(s), 187-188, 193-194 Vitamin K2, 11
administration of, 191 Vitamin K3, 11
adverse outcomes for, 192-193 VKDB classifications, 10-11
pain minimization of, 192 Volume of distribution (Vd), 19-20, 46-47, 221, 224
readings on, 195 Volutrauma, 79
Vaccination response
acetaminophen and, 191-192
ibuprofen and, 191-192 W
Valganciclovir, 146 Warfarin, 50
Valproate, 213 Website references, 15
Vancomycin, 172, 222 Weight gain goals, 28-29
Vancomycin plus aminoglycoside, 136 Wet nurses, 45
Vanilla PNs, 37 Withdrawal Assessment Tool-1, 121
Varicella zoster, 143-144 World Health Organization growth charts, 29
Varicella zoster immune globulin (VariZIG), 144
Vascular access, 6-7
Vecuronium, 114, 115, 126 Z
Veno-arterial ECMO, 216-217, 218, 219
Veno-venous ECMO, 216-217, 218 Zidovudine, 152, 153
Ventilator strategies, 106 Zinc, 33
Very low birth weight (VLBW), 3 Zoledronic acid, 47
Very preterm (VPT), 3 Zometa, 47
Vigabatrin, 215 Zonisamide, 213
Vitamin A, 89
Vitamin D, 45