NICU Primer for Pharmacists [1 ed.] 1585284750, 9781585284757, 2015024504, 1585284769, 9781585284764

Citation preview

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 HealthSystem 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. Director, Special Publishing: Jack Bruggeman Acquisitions Editor: Robin Coleman Editorial Project Manager: Ruth Bloom Production Manager: Johnna Hershey 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 understanding; 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 concurrent 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 administration 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 correcting 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 available 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 assignments 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, BCPS

Megan Lunberry, PharmD Novant Health Forsyth Medical Center Winston Salem, North Carolina

Women & Children’s Pharmacy Specialist Fairview Hospital/Cleveland Clinic Children’s Hospital Strongsville, Ohio

Ashley McCallister, PharmD Candidate Advance, North Carolina

John Brock Harris, PharmD, BCPS

Ying-Tang Ng, PharmD

Pharmacy Assistant Professor— Pediatrics Pediatric Clinical Pharmacy Specialist Presbyterian Medical Center Hemby Children’s Hospital Matthews, North Carolina

Assistant Professor Husson University School of Pharmacy Bangor, Maine

Michelle F. F. Poole, PharmD PGY1 Clinical Pharmacy Resident Fairview Hospital Cleveland, Ohio

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

Miyuki Nakayama Shouse, RPh, MS Clinical Staff Pharmacist Winston Salem, North Carolina

Wyn Wheeler, PharmD, FCCM Clinical Pharmacy Specialist, Neonatal and Pediatric Critical Care Levine Children’s Hospital at Carolinas Medical Center Charlotte, North Carolina

Julia Lau, PharmD, BCPS Novant Health Presbyterian Medical Center 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 AAP: American Academy of Pediatrics ABG: Arterial blood gas ACEI: Angiotensin-converting enzyme inhibitor ACOG: American College of Obstetricians and Gynecologists AED: Antiepileptic drugs AEDF: Absent end diastolic flow AGA: Appropriate for gestational age AMPA: α-amino-3-hydroxyl-5-methyl-4isoxazolepropionic acid ANC: Absolute neutrophil count AOP: Apnea of prematurity APAP: Acetaminophen APGAR: Appearance, Pulse, Grimace, Activity, and Respiration ART: Antiretroviral treatment ASHP: American Society of HealthSystem Pharmacists

A.S.P.E.N.: American Society for Parenteral and Enteral Nutrition BBT: Baby’s blood type BIO: Binocular indirect ophthalmoscope BPD: Bronchopulmonary dysplasia BSA: Body surface area BUN: Blood urea nitrogen cAMP: Cyclic adenosine monophosphate CBC: Complete blood count CDC: Centers for Disease Control and Prevention CDH: Congenital diaphragmatic hernia CGA: Corrected gestational age cGMP: Cyclic guanosine monophosphate CI: Confidence interval CLABSI: Central line-associated blood stream infection CLD: Chronic lung disease xv

xvi

NICU Primer for Pharmacists

CMV: Cytomegalovirus CMV HIG: Cytomegalovirus hyperimmune globulin CNS: Central nervous system CoNS: Coagulase-negative staphylococci CPAP: Continuous positive airway pressure CPS: Canadian Paediatric Society CRIES: Crying, Requires O2 for SaO2 90th percentile). ❖❖ Small for gestational age (SGA)—babies who weigh less than expected for their gestational age (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 sildenafil 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 communication 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 receiving 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 peripheral 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 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, electrolyte disturbance, abnormal liver function test or coagulation profile, thrombocytopenia, 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 recommended 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 recommended 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 decreasing 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 treatment options are limited. Survivors of severe PPHN and/or ECMO treatment are at an increased risk for developmental delay, feeding problems, short-term respiratory morbidities, motor disability, and hearing deficit. These infants should have neurodevelopmental 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 treatment 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, doublemasked, 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 respiratory 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 Database 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 hypertension 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 neonates 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 newborn. 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 hyperexcitability 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-4isoxazolepropionic acid glutamate receptors, metabotropic glutamate receptors, gamma-aminobutyric acid (GABA) transporters, and corticotropinreleasing 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 treatments 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 movement. 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. 2. 3. 4. 5.

clonic myoclonic spasms subtle 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 association 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 examination. 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 abnormality is suspected, clinicians should obtain inborn errors of metabolism panel (to assess for disorders relating to metabolic process of amino acids, carbohydrates, 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 increasing 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 administration.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 phenobarbital 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 administered 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 recommendations are less stringent. Moreover, fosphenytoin may be administered with dextrose-containing fluids, easing use in neonatal populations requiring 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 phenobarbital, 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. Lorazepam 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, changing 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 neonatal 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 midazolam 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 extracorporeal membrane oxygenation (ECMO) in neonates.1 As methodology improved to form the backbone of ECMO practices today, many more studies and publications were written. Advancements in pump technology from roller to centrifugal 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 abnormalities of pulmonary circulation. Coupled with the limitations of conventional 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 methodology 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 coagulopathy, or major intracranial hemorrhage

Gestational age limits are often based on the required systemic heparinization required during ECMO and the reported rates of intracerebral hemorrhage and mortality related to premature infants.8 However, a retrospective review of these early ECMO patients concluded that with further improvements in technique, lowering the gestational age requirement may be possible.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 inclusion 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 diaphragmatic 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 evaluation of neurologic status. Serial cranial ultrasounds can offer assistance too. Neurologic complications result in increased mortality, with risks correlating 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 infarction.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. Mitigating reductions in hemoglobin levels and platelet counts with frequent transfusions are critical to maintenance of oxygen-carrying capacity and hemostasis, 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 management 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 expansion 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 gastrointestinal 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 aforementioned 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 reduction 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 specialists 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 impossible 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 modalities 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 neonatal 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 echinocandins, making it a reasonable option for antifungal therapy during ECMO.29 Meropenem. Its use during ECMO is complex in that it seems challenging 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 inhibitory 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 indicated and opioids do not provide sufficient clinical effect. The most common agents are midazolam and lorazepam, with the majority of centers worldwide 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 metabolite. 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 critical 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.

References 1. Bartlett RH, Gazzaniga AB, Jeffries MR, et al. Extracorporeal membrane oxygenation (ECMO) cardiopulmonary support in infancy. Trans Am Soc Artif Intern Organs. 1976;22:80-93. 2. Extracorporeal Life Support Organization. ELSO guidelines for ECMO centers. Feb 2010 v1.7:1-7. http://www.elso.med.umich.edu/WordForms/ELSO%20Guidelines%20For%20ECMO%20Centers.pdf. 3. Bartlett RH, Gazzaniga AB, Toomasian J, et al. Extracorporeal membrane oxygenation (ECMO) in neonatal respiratory failure. Ann Surg. 1986 Sep;204(3):236-45. 4. Jeewa A, Manlhiot C, McCrindle BW, et al. Outcomes with ventricular assist device versus extracorporeal membrane oxygenation as a bridge to pediatric heart transplantation. Artif Organs. 2010;34:1087-91. 5. Almond CS, Gauvreau K, Canter CE, et al. A risk-prediction model for in-hospital mortality after heart transplantation in US children. Am J Transplant. 2012;30:10951103.

Extracorporeal Membrane Oxygenation 225 6. MacLaren G, Combes A, Barlett RH. Contemporary extracorporeal membrane oxygenation for adult respiratory failure: life support in the new era. Intensive Care Med. 2012;38:210-20. 7. Kenner C, Wright Lott J. Newborn or infant transplant patient. Comprehensive Neonatal Care: An Interdisciplinary Approach. St Louis, MO: Elsevier Health Sciences; 2007:395. 8. Cilley RE, Zwischenberger JB, Andrews AF, et al. Intracranial hemorrhage during extracorporeal membrane oxygenation in neonates. Pediatrics. 1986;78(4):699-704. 9. Bui KC, LaClair P, Vanderkerhove J, et al. ECMO in premature infants: review of factors associated with mortality. ASAIO Trans. 1991;37:54-9. 10. Lazar DA, Cass DL, Olutoye OO, et al. Venovenous cannulation for extracorporeal membrane oxygenation using a bicaval dual-lumen catheter in neonates. J Pediatr Surg. 2012;47(2):430-4. 11. Lequier L, Horton SB, McMullan DM, et al. Extracorporeal membrane oxygenation circuitry. Ped Crit Care Med. 2013 Jun;14(5 Suppl 1):S7-12. 12. Hermon M, Golej J, Mostafa G, et al. Veno-venous two-site cannulation versus venovenous double lumen ECMO: complications and survival in infants with respiratory failure. Signa Vitae. 2012;7(2):40-6. 13. Wung JT, James LS, Kilchevsky E, et al. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics. 1985;76(4):488-94. 14. Hintz ST, Suttner DM, Sheehan AM, et al. Decreased use of neonatal extracorporeal membrane oxygenation (ECMO): how new treatment modalities have affected ECMO utilization. Pediatrics. 2000;106(6):1339-43. 15. 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. 16. Wolf GK, Arnold JH. Extracorporeal membrane oxygenation. In: Cloherty JP, ed. Manual of Neonatal Care. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. 17. Polito A, Barrett CS, Wypij D, et al. Neurologic complications in neonates supported with extracorporeal membrane oxygenation: an analysis of ELSO registry data. Int Care Med. 2013;39(9):1594-601. 18. Hardart GE, Fackler JC. Predictors of intracranial hemorrhage during neonatal extracorporeal membrane oxygenation. J Pediatr. 1999;134:156–9. 19. Mehta A, Ibsen LM. Neurologic complications and neurodevelopmental outcome with extracorporeal life support. World J Crit Care. 2013;2(4):40-7. 20. Hines MH, Berkowitz I, Bizzarro M, et al. Infection control and extracorporeal life support. ELSO Infectious Disease Task Force. 1-25. https://www.elso.org/Portals/0/ Files/Infection-Control-and-Extracorporeal-Life-Support.pdf

226 NICU Primer for Pharmacists 21. Buck ML, Wooldridge P, Ksenich RA. Comparison of methods for intravenous infusion of fat emulsion during extracorporeal membrane oxygenation. Pharmacotherapy. 2005;25(11):1536-40. 22. Steiner CK, Stewart DL, Bond SJ, et al. Predictors of acquiring a nosocomial bloodstream infection on extracorporeal membrane oxygenation. J Pediatr Surg. 2001; Mar 36(3):487-92. 23. Elerian LF, Sparks JW, Meyer TA, et al. Usefulness of surveillance cultures in neonatal extracorporeal membrane oxygenation. ASAIO Journal. 2001;47:220-3. 24. Shekar K, Fraser JF, Smith MT, et al. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care. 2012;27(6):9-18. 25. Wildschut ED, Ahsman MJ, Allegaert K, et al. Determinants of drug absorption in different ECMO circuits. Intensive Care Med. 2010;36:2109-16. 26. Dagan O, Klein J, Gruenwald C, et al. Preliminary studies of the effects of extracorporeal membrane oxygenation on the disposition of common pediatric drugs. Ther Drug Monit. 1993;15(4):263-6. 27. Mulla H, Pooboni S. Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation. Brit J Clin Pharm. 2005;60(3):265-75. 28. Ahsman MJ, Wildschut ED, Tibboel D, et al. Pharmacokinetics of cefotaxime and desacetylcefotaxime in infants during extracorporeal membrane oxygenation. Antimicrob Agents Chemother. 2010;54(5):1734-41. 29. Watt KW, Benjamin DK, Cheifetz IM, et al. Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation. Ped Inf Dis J. 2012;31(10):1042-6. 30. Shekar K, Roberts JA, Ghassabian S, et al. Altered antibiotic pharmacokinetics during extracorporeal membrane oxygenation: cause for concern? J Antimicrob Chem. 2012; 12:29. 31. Cies JJ, Moore WS, Dickerman MJ, et al. Pharmacokinetics of continuous-infusion meropenem in a pediatric patient receiving extracorporeal life support. Pharmacotherapy. 2014;34(10):e175-9. 32. Wildschut ED, deHoog M, Ahsman MJ, et al. Plasma concentrations of oseltamivir and oseltamivir carboxylate in critically ill children on extracorporeal membrane oxygenation support. PLoS ONE. 2010;June 5(6):e10938. 33. Vet NJ, deHoog M, Tibboel D, et al. The effect of critical illness and inflammation on midazolam therapy in children. Pediatr Crit Care Med. 2012;13(1):e48-50. 34. Ahsman MJ, Hanekamp M, Wildschut ED, et al. Population pharmacokinetics of midazolam and its metabolites during venoarterial extracorporeal membrane oxygenation in neonates. Clin Pharmacokinet. 2010;49(6):407-19.

Extracorporeal Membrane Oxygenation 227 35. Arroliga AC, Shehab N, McCarthy K, et al. Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults. Crit Care Med. 2004;32(8):1709-14. 36. Lim TY, Poole RL, Pageler NM. Propylene glycol toxicity in children. J Pediatr Pharmacol Ther. 2014;19(4):277-82. 37. Shekar K, Roberts JA, McDonald CI, et al. Sequestration of drug in the circuit may lead to therapeutic failure during extracorporeal membrane oxygenation. Crit Care. 2012;16(5):r194. 38. Arnold JH, Truog RD, Orav EJ, et al. Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology. 1990;73(6):1136-40.

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 extracorporeal membrane oxygenation. J Crit Care. 2012;27(6):9-18.

Index A Abortus, 4 Absolute neutrophil count, 146 Absorption, 17 extravascular, 18 gastrointestinal, 18 intramuscular, 18 percutaneous, 19 rectal, 19 Academy of Breastfeeding Medicine, 49, 61 Acetaminophen, 21, 119, 127-128 PDA and, 103-104 vaccination response and, 191-192 Acid ionization constant, breast milk and, 47 Acid-base balance, 32 Activity, 5 Acute lung injury, 84-85 Acyclovir, 46 parenteral, 147-148 Addiction, maternal, 61 Adverse drug events, methylxanthine toxicity, 71 Adverse effects, neonatal abstinence treatment, 60 Airway patency maintenance, 68 Albuterol, 87, 161 Alcohol, 48 Alginate, 181 Alpha agonists, 115-116 Aluminum toxicity, 36-37 American Academy of Pediatrics, 45 acyclovir shortage recommendations, 147 alcohol and, 48 on apnea of prematurity, 65 on bronchiolitis, 161 on neonatal abstinence syndrome, 56, 58

on respiratory syncytial virus, 158, 160 on sedation management, 112 on systemic corticosteroids, 88 on vaccinations, 187 on Vitamin K IM, 10-11 American College of Chest Physicians, 159 American College of Emergency Physicians, 159 American College of Obstetrics and Gynecology, 61 American Congress of Obstetricians and Gynecologists, 145 American Society for Parenteral and Enteral Nutrition, 30, 34 American Society of Health-System Pharmacists (ASHP), 34 American Thoracic Society, 159 Amino acids, 30, 34-35 Aminoglycoside(s), 19, 134, 172 Aminophylline, 69 Aminosyn, 30 Amoxicillin-sulbactam, 172 Amphotericin B, 137 Ampicillin, 6, 134, 172 Ampicillin-sulbactam, 172 Anaerobic antibiotic therapy, 172 Analgesia common agents for, 127-129 pharmacologic agents for, 118-119 principles of, 116-117 Analgesics, 123 reversal of, 121 Angiotensin-converting enzyme inhibitors (ACEI), 105 Antacids, 181 Antenatal corticosteroids, 80, 101, 175

230 NICU Primer for Pharmacists Antibiotic(s), 2, 6, 105, 134-135, 137 administration risks of, 173-174 empiric regimens for, 172 meningitis duration and, 135 scheduling of, 8 sepsis duration and, 135 Antiepileptic drugs, 211-212, 213 Antifungal agent, 137 Anti-infectives, 222-223 Antiretroviral dosing, neonatal, 152 Antithrombin III infusions, 219 Apgar, Dr. Virginia, 5 APGAR score, 5, 200 Apnea, 75, 192-193 Apnea of prematurity (AOP), readings, 75 causes of, 67 diagnosis of, 67-68 duration of treatment for, 71 epidemiology of, 65-66 lab monitoring of, 67 methylxanthines in, 69 non-pharmacologic treatments for, 68-69 pathophysiology of, 66 pharmacologic monitoring for, 70-71 pharmacologic treatments for, 69-71 physical assessment of, 67 presentation of, 66-67 therapeutic goals for, 68 Appearance, 5 Appropriate for gestational age (AGA), 3 Arachidonic acid pathway, 104 Arginine, 30 Atelectasis, 78-79 Atracurium, 114, 126

Bevacizumab (intravitreal), 11 Biomarkers, 132-133, 175 Blood culture(s), 132, 134-135 Blood flow, 94, 95 Blood volume, 7 Body positioning, 180 Bosentan, 206 Brainstem maturity, 66 Breastfeeding, 43 alcohol and, 48 constipation and, 182, 183 initiation of, 6 length of, 44 neonatal abstinence syndrome and, 61 nicotine and, 48 pain management and, 118 substance abuse and, 48-49 Briggs, 51 Bronchiolitis management, 161 Bronchodilators, 86-87 Bronchopulmonary dysplasia, 83-84, 89-90, 96, 101 clinical presentation of, 85 diagnosis of, 83-84 epidemiology, risk factors of, 84 incidence of, 84 management of, 85 outcomes for, 89 pathophysiology of, 84-85 pharmacologic management of, 85-87 prevention strategies for, 87-89 readings on, 92 Buffering agents, 181 Bumetanide, 213 Buprenorphine, 48, 57, 60

B

C

Ballard, Dr. Jeanne, 5 Ballard scoring, 5 Barbiturates, 113 Barium enemas, 183 Barotrauma, 79 Bartlett, Dr. Robert, 215 Bell Stage I, suspected NEC, 169, 170 Bell Stage II, definite NEC, 169, 170, 174, 175 Bell Stage III, advanced NEC, 169, 170-171, 174, 175 Bell staging modification, 170-171 Beneprotein, 45 Benzathine penicillin, IM, 149 Benzodiazepine(s), 20, 21, 56, 113, 121, 212-213, 223 Beractant, 82 Beta antagonists, 21 Beta-agonists, 87 Betamethasone, 4, 80 Bethanechol, 181

Caffeine, 6, 21, 69, 174-175 adverse drug events for, 71-72 IV, PO formulations for, 70 loading dose for, 70 maintenance dosing for, 70 monitoring of, 70 Calcium carbonate, 181 Calcium chloride, 37 Calcium gluconate, 32, 37 Calcium management, 220 Calcium solubility, 36 Calfactant, 82 Caloric requirements, 28 Canadian Paediatric Society, 88 Candida, 136 Candida spp., 36 Carbamazepine, 213 Carbapenem, 172 Carbohydrates, 29 Cardiac support drips, 105

Index 231 Carnitine, 34 Cefotaxime, 134, 222 Cefoxitin, 172 Ceftriaxone, 9-10, 20 Centers for Disease Control and Prevention (CDC), 144, 145 immunization recommendations of, 189 on hepatitis B infection, 188 on respiratory syncytial virus, 156 on vaccinations, 187 Central apnea, 66 Central line access, 38, 136 Central line-associated blood stream infections (CLABSIs), 36 Central nervous system changes, 219 Cephalosporin(s), 134, 172 Cerebral spinal fluid cultures, 132 Cesarean section birth, 4 Chest radiography, 200 Chickenpox, 143-144 Chloramphenicol, 21 Chlorothiazide, 86 Chorioamnionitis, 135 Chorioretinitis, 142 Chromium, 33 Chronic lung injury, 85 Cimetidine, 46 Cisatracurium, 115, 127 Clindamycin, 172 Clinical sepsis, 135 Clonic seizures, 211 Clonidine, 60, 182 Cluster care, 117-118 CNS symptoms, NAS, 58 Coagulase-negative staphylococci (CoNS), 136 Cocaine, 56 ingestion, 48 Cochrane Review, 161 Cocooning, 193 Code of Federal Regulations, 49 Codeine, 57 Colostrum, 44 Congenital heart disease, 174 Congenital syndromes, 95 Congenital varicella syndrome (CVS), 143-144 Conjugate vaccines, 189 Constipation, 179 epidemiology of, 181-182 nonpharmacologic treatment for, 182-183 pharmacologic treatments for, 183 presentation of, 182 Continuous positive airway pressure (CPAP), 68-69 Copper, 33 Corrected gestational age (CGA), 3 Corticosteroids, 143, 188 antenatal, 80, 175 maternal, 4 systemic, 88

C-reactive protein, 132 CRIES scoring tool, 117 Critically ill neonate, pharmacokinetic changes in, 121-123 Curosurf, 82 Cyclopentolate, 11 Cysteine, 34 Cytochromes, 20-21 Cytomegalovirus (CMV), 144-145 prevention of, 145 treatment for, 146 Cytomegalovirus hyperimmune globulin, 145

D DART, 88 Dexamethasone, 4, 8, 80, 88-89 Dexmedetomidine, 115-116, 127 Dextromethorphan, 21 Dextrose, 29 Dialysis, 221 Diazepam, 21, 212-213 Diphtheria, tetanus and pertussis (DTaP), 189, 190, 193 Distribution, 17, 19-20 Diuretics, 85-86, 87, 104 Domperidone, 50 Donor milk, 45 Dopamine, 7, 8, 105 Dosing, 2 Dosing error, 8 Drug dosing references, 14 Drug transfer into milk, 46 acid ionization constant for, 47 bioavailability of, 46 labeling for, 51 milk-to-plasma ratio for, 47 milk, molecular weight for, 46 peak serum concentration of, 47 relative infant dose for, 47 risk-benefit statement for, 51 volume of distribution and, 46-47 Drugs in lactation references, 14 Drugs in Pregnancy and Lactation, 51 Ductus arteriole, 188 Ductus arteriosus, 94-96

E Early-onset infections, 132 common pathogens of, 133-134 pharmacologic treatment for, 133-134 presentation, laboratory evaluation of, 132-133 Early-onset sepsis, 132 Echocardiogram, 200-201 Electrolyte(s), 31-32 management of, 219

232 NICU Primer for Pharmacists support for, 220 Elimination, 17, 22 Emergency Nurses Association, 159 Empiric antibiotics, 172 Endothelin receptor antagonists, 206 Enoxaparin, 46 Enteral feeding(s)/nutrition, 221 bowel movements and, 182, 183 gastroesophageal reflux and, 180-181 NSAID therapy and, 106-107 Enterobacteriaceae, 136 Enterococci, 36 Epinephrine, 105 Erythromycin, 181 Erythromycin ophthalmic ointment, 6 Escherichia coli, 134 Ethanol locks, 36 Eutectic mixture of lidocaine and prilocaine (EMLA), 192 Expiration dates, times, 9 Extracorporeal Life Support Organization, 216 Extracorporeal membrane oxygenation (ECMO), 122, 202, 203, 205, 207, 215-216 anti-infectives and, 222-223 central nervous system changes in, 219 gastrointestinal, fluid, electrolytes, nutrition support in, 220 hematologic system changes in, 220 immune system changes in, 220-221 inclusion criteria, indications for, 217-218 opioids and, 223-224 organ system changes in, 218 pharmacokinetic changes in, 221 pharmacologic challenges of, 221-224 pulmonary system changes in, 218 readings on, 227 renal system changes in, 219-220 sedatives and, 223 veno-arterial, 216-217, 218, 219 veno-venous, 216-217, 218 Extravasation, 7 Extremely low birth weight (ELBW), 3 Extremely preterm (EPT), 3

F Failure of optimal medical management, 217-218 Famotidine, 34 Fat emulsions, 31, 37 Fatty acid deficiency syndrome, 31 Fentanyl, 116, 120, 129, 223-224 Fenton growth charts, 29 Fenugreek, 49-50 Fetal circulation, 198 Fick’s law, 216 Fluconazole, 222

Fluid(s) goal for, 28 management, IV, 28 nutrition and, 28 support, 222 Flumazenil, 121, 122 Fluoroquinolones, 9 Food and Drug Administration (FDA), 143 ceftriaxone warning by, 10 on aluminum exposure, 36 on drug passage into milk, 50-51 sildenafil labeling requirements of, 204 Foramen ovale, 198 Formulary, 2 Fosphenytoin, 212 Furosemide, 86, 104

G GABA (gamma-aminobutyric acid) modulators, 113-114 GABA/benzodiazepine receptor antagonist, 121 Galactogogues, 48-50 Ganciclovir, 146 Gastroesophageal reflux, 179 epidemiology of, 180 nonpharmacologic treatment for, 180-181 pharmacologic treatments for, 181 presentation of, 180 Gastrointestinal contrast, 46 Gastrointestinal disorders, readings on, 186 Gastrointestinal support, 220 Gentamicin, 6, 19-20, 134, 222 Gestational age (GA), 2 GI symptoms, NAS, 58 Glomerular filtration, 22 Glucocorticoids, 100 indomethacin and, 12 Glucose infusion rates (GIR), 29-30 Glucuronidation, 21 Glutathione, 34 Glycerin, 183 Gravida, 3 Gravida/para (GP), 4 Gray-baby syndrome, 21 Grimace, 5 Group B Streptococcus, 199 Growth charts, 29

H H2-receptor antagonists, 34, 181 Haemophilus influenza, 189, 190 Hale, Thomas, 51, 52 Hand washing, 145 Handbook on Injectable Drugs, 38

Index 233 Handbooks, 14-15 Healthy People 2020 Goals, 44, 45 Hematologic system changes, 219 Heparin, 8, 34 Heparinization, systemic, 217 Heparinized fluids, 7 Hepatic clearance, 123 Hepatitis B immune globulin, 188 Hepatitis B vaccine, 6, 188-189, 190 Heroin, 57 Herpes simplex, 146-147 treatment for, 147-149 Herpes zoster, 144 Hoffman elimination, 114-115 Human immunodeficiency virus, 149-153 neonatal antiretroviral dosing for, 152 Human milk, 175 fortifier, 45 Hyaluronidase, 7, 32 Hydrocodone, 56 Hypercarbia, 79 Hyperglycemia, 29 Hyperoxia test, 200 Hypoglycemia, 30 Hypothermia induction, 122 rewarming, 122-123 Hypoxemia, 66, 68, 79, 200, 201

I Iatrogenic opioid dependence, 120-121 Ibuprofen, 102, 103 contraindications for, 100 drug interactions with, 100 PDA closure dosing for, 98-99 vaccination response and, 191-192 Ibuprofen lysine, 97-98 IFALD, 35 Iloprost, 206 Inactivated polio virus, 189, 190 Indomethacin, 5, 88, 96-97, 98, 102-103, 107 antenatal, 174 contraindications for, 100 drug interactions with, 100 glucocorticoids and, 12 PDA closure dosing for, 98-99 side effects of, 99 Indomethacin IV, 6 Infant assessment, 5 Infasurf, 82 Infection risk, PN, 36 Infectious disease references, 14 Infectious Diseases Society of America, 36 Influenza vaccine, 193 Inhaled bronchodilators, 86-87 Inhaled corticosteroids, 87

Inhaled nitric oxide, 202-203, 204 206, 207 Institute of Medicine, 145 Insulin, 46 Intestinal failure-associated liver disease, 31 Intrauterine growth restriction (IUGR), 3 Intravenous admixtures, 8 Intravenous dextrose, 2 Intravenous fat emulsion (IVFE), 31, 220 Intravenous fluid management, 28 Intraventricular hemorrhage (IVH), 12, 96-97, 99 Iodine, 46 Ion trapping, 47 Ipratropium MDI, 87 Iron supplementation, 45, 182 Isoenzymes, 20

J Jitteriness, 210

K Kangaroo care, 49 pain management and, 118 Kangaroo mother care (KMC), 6 Kernicterus, 10, 20 Ketamine, 116, 127 King Guide to Parenteral Admixtures,

38

L Lactated Ringer’s solution, 10 Lactation, 43 medications and, 53 readings on, 54 risk categories for, 52 Lactic acidosis, 79 LactMed, 51 Lactobacillus probiotics, 175 Lamotrigine, 213 Lansoprazole, 181 Laparotomy, 173 Large for gestational age (LGA), 3 Late-onset infections, 132 common pathogens for, 136 pharmacologic treatment for, 136-137 presentation, laboratory evaluation of, 136 Late-onset sepsis, 132 Levetiracetam, 213 Lidocaine, 119, 213 Lidocaine 4% cream, 192 Lidocaine-prilocaine, 119 Line flushes, 8 Lipsitz tool, 58 Local anesthetics, 119 Loop diuretics, 86, 102

234 NICU Primer for Pharmacists Lorazepam, 113, 126, 212-213, 223 Low birth weight (LBW), 3 Lucinactant, 82 Luer lock oral syringes, 9

M Macrolides, 149 Macronutrients, 29-30 Magnesium sulfate, 5 Maladaptation, 199 Maldevelopment, 199 Manganese, 33 Manual stimulation, 68 Marijuana, 56 Maternal antibodies, 187-189 Maternal history, 133 Maturity rating, 5 Mechanical ventilation injury, 84 Meconium, 57, 182 Medical induction of labor, 4 Medication safety, 8 Medication standardization, 8 Medication storage, 8-9 Medications & Mothers’ Milk, 51 Medications, to avoid in neonates, 9-10 Medium chain triglycerides oil, 45 Meningitis, 131, 136 antibiotic therapy duration for, 135 cefotaxime and, 134 CSF study values in bacterial, 136 readings on, 139 Meropenem, 222-223 Metabolism, 17, 20-22 Metered dose inhaler, 87 Methadone, 48, 56-58, 61, 120, 131 Methemoglobinemia, 202-203 Methylxanthine(s), 21 mechanism of action for, 69 toxicity of, 71-72 Metoclopramide, 49, 50, 181 Metronidazole, 172 Micronutrients, 31-32 Midazolam, 8, 20, 113, 126, 212, 213, 223 Milk-to-plasma ratio, 47 Milrinone, 204-205 Mixed apnea, 66 Moderate-to-late preterm (LPT), 3 Modified Finnegan tool, 58, 59 Molybdenum, 33 Morphine, 21, 57-58, 116, 119-120, 128, 224 Mother’s milk additives to, 45 benefits of, 44 breastfeeding length for, 44 complications of, 45 composition of, 44

donor milk and, 45 Moxifloxacin, 172 Multivitamins, 34 Muscarinic agents, 87 Myoclonic seizures, 211 focal, 211 generalized, 211 multi-focal, 211

N Naloxone, 121 National Association of Neonatal Nurse Practitioners, 159 National Association of Neonatal Nurses, 159 National Institute of Child Health and Human Development, 83-84, 200 National Institutes of Health, 51 National Respiratory and Enteric Virus Surveillance System, 156 Nebulized saline, 161 Necrotizing enterocolitis (NEC), 44, 96, 99, 101, 181, 183 anaerobic antibiotics for, 172-173 antibiotic therapy duration for, 173 Bell staging of, 169-171 congenital heart disease and, 174 diagnosis of, 169, 172 empiric antibiotics for, 172 epidemiology of, 167-168 medical treatment for, 172 medications and, 174-175 pathophysiology for, 168 presentation of, 169-170 prevention of, 175 readings on, 177-179 red blood cell transfusions for, 174 surgical treatment of, 173 treatment risks for, 173-174 Neofax, 8, 147 Neonatal Abstinence Scoring System, 59 Neonatal abstinence syndrome (NAS), 55, 121 breastfeeding and, 61 family considerations in, 61 readings on, 63 screening and scoring of, 57-58, 59 symptoms of, 58 treatment for, 58, 60 Neonatal birth history, 133 Neonatal Research Network, 200 Neonatal seizures, 209 evaluation, diagnosis of, 211 pathophysiology of, 210 presentation of, 210-211 readings on, 214 treatment for, 211-213 Neonatal sepsis, 139

Index 235 Neonatal Withdrawal Inventory, 58 Neonates, 2 NEOPAIN study, 119 Neotrace, 33 Neuromuscular blocking agents, 112, 114-115 Neutropenia, 146, 148 Nevirapine, 152 Newborn management, 6 Nicardipine, 5 Nicotine inhaler, 48 Nicotine patch, gum, 48 Nifedipine, 5 NIPS scoring tool, 117 Nitric oxide, 202, 204 Nitrofurantoin, 9 NMDA (N-methyl-D-aspartate) antagonists, 116 Nonopioids, 118-19 Nonsteroidal anti-inflammatory drugs (NSAIDs), 199 contraindications for, 100 drug interactions with, 100 oral options for, 100 PDA closure and, 97-99 PDA treatment and, 103-105, 106 side effects of, 99 Nosocomial infections common pathogens of, 136 pharmacologic treatment for, 136-137 presentation, laboratory evaluation of, 136 N-PASS scale, 112 Nutrition fluids and, 28 management, 28-29 support, 222

O Oat cereal, 45 Obstructive apnea, 66 Omegaven, 31, 35 Omeprazole isomers, 181 Opiate maintenance therapy, 57 Opiate replacement treatment, 60 Opiate therapy, 58 Opiate withdrawal, 55-56 Opioids, 116, 119, 182, 183 iatrogenic dependence on, 120-121 Organ systems changes, 218 Oseltamivir, 223 Oxidation, 38 Oxycodone, 56, 57 Oxygen concentration of supplemental oxygen, 201, 202 Oxygen damage, 79 Oxygenation index, 201

P Pain, 111 analgesia principles for, 116-117 assessment of, 117 minimizing vaccination, 192 nonpharmacologic interventions for, 117-118 pharmacologic agents for, 118-120 readings on, 125 Palivizumab, 158-159, 162 usage guidelines, 159-161 Palo Alto Medical Foundation Toxoplasma Serology Laboratory, 142, 143 Pantoprazole, 181 Para, 3 Paracetamol, 104 Parenteral nutrition, 7, 39, 136, 172, 220 3-in-1 vs. 2-in-1, 37 -associated liver disease, 31, 35 complications of, 35-37 dextrose concentrations and, 29 light exposure on, 38 medication administration and, 38 medication compatibility and, 38 neonates and, 27-28 preparations of, 37 readings on, 42 with calcium, 10 Patent ductus arteriosus, 93-94 acetaminophen and, 103-104 importance of, 96-97 incidence of, 94-95 nonpharmacologic management for, 105-106 NSAID therapy and, 97-100, 106-107 Pathophysiology of, 95-96 pharmacologic medical management for, 104 pre-symptomatic treatment for, 101, 102 prophylactic management for, 101, 102-103 symptomatic management for, 101 readings on, 110 treatment timing for, 100-101 trials and, 103 Peak serum concentration, drug transfer into milk, 47 Pediarix, 189, 193 Pediatric & Neonatal Dosage Handbook, 8 Pediatric Injectable Drugs: The Teddy Bear Book, 8 Peditrace, 33 Penicillin, 149 Penicillin G, IV, 149 Pentacel, 189 Peripheral airway obstruction, 85 Peripheral line access, 38 Peripherally inserted central catheter, 7 Peritoneal drainage, 173 Peroxides, 38 Persistent pulmonary hypertension of newborn clinical manifestations of, 200

236 NICU Primer for Pharmacists diagnosis of, 200-201 endothelin receptor antagonists and, 206 extracorporeal membrane oxygenation and, 202, 203, 205, 207 management of, 201 nitric oxide and, 202-203 outcomes for, 206-207 pathogenesis, causes of, 188-189 phosphodiesterase type 3 inhibitors and, 204-205 phosphodiesterase type 5 inhibitors and, 203-204 prostaglandin analogs and, 206 readings on, 208 risk factors for, 199 severity determination for, 201 surfactant therapy for, 205-206 transition from intrauterine to extrauterine circulation in, 198 Pertussis, 193 Pharmacodynamics, 17 readings on, 25 Pharmacokinetic(s), 17 changes in, 121-123 extracorporeal membrane oxygenation and, 221 readings on, 25 Phase I metabolism, 20 Phase II metabolism, 20, 21 Phenobarbital, 35, 60, 70, 113, 126, 212 Phentolamine, 7 Phenytoin, 20, 21, 212 Phosphodiesterase type 3 inhibitors, 204 Phosphodiesterase type 5 inhibitors, 203-204 Phosphorus solubility, 36 Phototherapy, 38 Physical dependence, 55-56 Phytonadione, 10 Piperacillin-tazobactam, 172 PIPP scoring tool, 117 Platelet dysfunction, 99 Platelets, low, 96 Pneumococcal conjugate, 189, 190 Polysaccharide vaccines, 189 Poractant alfa, 82 Post-immunization apnea, 192-193 Post-menstrual age (PMA), 3 Postnatal age (PNA), 2 Potassium, 38 Premasol, 30 Prematurity causes of birth in, 4 risks of, 1-2 Pressor agents, 106 Pre-symptomatic treatment, 101, 102 Preterm, 3 Preterm formula, 175 Preterm labor management, 5 prevention, 4-5 Probiotics, 175

Procaine penicillin, IM, 149 Procalcitonin concentrations, 132 Prokinetic agents, 181 Proparacaine, 11 Prophylactic management, 101, 102-103 Propofol, 113-114, 126 Propranolol, 21 Prostacyclin I2, 206 Prostaglandin analogs, 206 Prostaglandin infusions, 174 Protein, 30 binding, 20 supplement, 45 Proton pump inhibitors, 21, 181 Pulmonary surfactant deficiency, 78 Pulmonary system changes, 218 Pulmonary vascular resistance, 114, 197, 198, 199 Pulmonary vasoconstriction, 79 Pyrimethamine, sulfadiazine and folinic acid, 142143

R Ranitidine, 34 Rapid plasminogen reagent (RPR) screening, 148, 150-151 Rectal stimulation, 182, 183 Red blood cell transfusions, 68, 174 RedBook (2015), 143 Relative infant dose, 47 Renal system changes, 219-220 Respiratory distress syndrome (RDS), 4, 77-78, 94, 95 antenatal corticosteroids and, 80 clinical presentation of, 79 epidemiology, risk factors for, 78 long-term complications of, 81 management of, 79-80 pathophysiology of, 78-79 readings on, 92 surfactant replacement therapy for, 80-83 Respiratory syncytial virus, 155 epidemiology of, 156 etiology, pathogenesis of, 156, 157, 158 neonatal, 158 prevention of, 158-159, 162 readings on, 165 season duration of, 157 Respiratory systems, NAS, 58 Respiratory ventilation support, 68-69 Retinopathy of prematurity, 11-12, 68 Rice cereal, 45 Rocuronium, 114, 126 Rotarix, 190-191 RotaTeq, 190-191 Rotavirus vaccine, 189-191 Rubella, 143

Index 237

S Salbutamol, 161 Sedation, 123 alpha agonists and, 115-116 assessment of, 112 common agents for, 126-127 GABA modulators and, 113-114 neuromuscular blocking agents and, 114-115 NMDA antagonists and, 116 nonpharmacologic modalities for, 114 principles of, 111-112 readings on, 125 reversal of, 121 Seizures, 209 Selenium, 33 Sepsis, 131, 135 Sepsis syndrome, 96 Serotonin discontinuation syndrome, 57 Serotonin reuptake inhibitors (SSRIs), 57 17-alpha-hydroxyprogesteron caproate IM (maternal), 5 Shingles, 144 Sildenafil, 203-204 Simultaneous pre-, postductal arterial blood gases, 200 Small for gestational age (SGA), 3 Society of Hospital Medicine, 159 Sodium bicarbonate buffer, 119 Sodium phosphate, 37 Spasms, 211 Spiramycin, 142-143 Spontaneous preterm labor, 3 Staphylococcus aureus, 36 Steroids, 30 Stooling frequency, 181-182 Streptococcus agalactiae, 133-134 Substance abuse, maternal breastfeeding and, 48 screening and scoring of, 57-58 Substances of abuse, 56-57 Subtle neonatal seizures, 211 Sucralfate, 181 Sucrose, 118-119, 127, 192 Sulfation, 21 Sulfonamides, 9-10, 20 Supplemental oxygen, 68 Suppressive therapy, 147-148 Surfactant(s), 82, 95, 101 deficiency, 78 therapy, 80-83, 205-206 Surfaxin, 82 Surgical ligation, PDA, 104 Survanta, 82 Symptomatic management, 99 Synagis, 158-159 Syphilis, 148 evaluation, treatment algorithm for, 150-51

prevention of, 149 treatment for, 149 Syringes differentiation, 9 Systemic corticosteroids, 88 Systemic vascular resistance, 198

T Taurine, 30, 34 Terbutaline, 5 Term neonates, morphine metabolism by, 21 Tetanus diphtheria and pertussis (TDaP), 189, 190, 193 Tetracyclines, 9, 149 Text book references, 14 Theophylline, 21, 69 adverse drug events for, 71 drug interactions for, 70 immediate release enteral solution, 69 IV premixed solutions, 69 loading dose for, 69 maintenance dosing for, 69 monitoring of, 70-71 Thiazide diuretics, 86 Thiazides with or without spironolactone, 102 Thickening feeds, 180-181 TIPP trial, 102-103 Tissue binding, 20 Tocolytics (maternal), 5 Tonic neonatal seizures focal, 211 generalized, 211 Topical medication, 19 Topical nitroglycerin paste, 7 Topiramate, 213 TORCH (Toxoplasmosis, Rubella, Cytomegalovirus, Herpes Simplex) infections, 153, 154 Toxoplasmosis gondii, 142 prevention of, 142-143 treatment for, 143 Trace elements, 32-34 Train-of-four, 112 Tramadol, 21 Treponema pallidum, 148 TrophAmine, 30, 37 Trophic feeding, 175 Tubular excretion, 22 Tubular reabsorption, 22 Tyrosine, 30

U Umbilical artery catheter, 7 Umbilical venous catheter, 7 Underdevelopment abnormalities, 198-199 Unfractionated heparin, 219 Ursodiol, 35

238 NICU Primer for Pharmacists

V Vaccination(s), 187-188, 193-194 administration of, 191 adverse outcomes for, 192-193 pain minimization of, 192 readings on, 195 Vaccination response acetaminophen and, 191-192 ibuprofen and, 191-192 Valganciclovir, 146 Valproate, 213 Vancomycin, 172, 222 Vancomycin plus aminoglycoside, 136 Vanilla PNs, 37 Varicella zoster, 143-144 Varicella zoster immune globulin (VariZIG), 144 Vascular access, 6-7 Vecuronium, 114, 115, 126 Veno-arterial ECMO, 216-217, 218, 219 Veno-venous ECMO, 216-217, 218 Ventilator strategies, 106 Very low birth weight (VLBW), 3 Very preterm (VPT), 3 Vigabatrin, 215 Vitamin A, 89 Vitamin D, 45

Vitamin K IM, 6, 10 Vitamin K1, 11 Vitamin K2, 11 Vitamin K3, 11 VKDB classifications, 10-11 Volume of distribution (Vd), 19-20, 46-47, 221, 224 Volutrauma, 79

W Warfarin, 50 Website references, 15 Weight gain goals, 28-29 Wet nurses, 45 Withdrawal Assessment Tool-1, 121 World Health Organization growth charts, 29

Z Zidovudine, 152, 153 Zinc, 33 Zoledronic acid, 47 Zometa, 47 Zonisamide, 213