PEDIATRIC

SELF-ASSESSMENT PROGRAM

2 0 1 6 B O OK 2

PEDIATRIC
CRITICAL CARE
Series Editors
Marcia L. Buck, Pharm.D., BCPPS, FCCP, FPPAG
Kalen B. Manasco, Pharm.D., BCPS

AMERICAN COLLEGE OF CLINICAL PHARMACY

 IMPORTANT INFORMATION ON THE RELEASE OF
PedSAP 2016 BOOK 2 Pediatric Critical Care
TESTING

BCPPS test deadline: 11:59 p.m. (Central) on January 17, 2017.

ACPE test deadline: 11:59 p.m. (Central) on September 14, 2019.

Online Errata: Follow this link to check for any changes or updates to this Pediatric Self-Assessment Program release. Be sure to
check the online errata before submitting a posttest.

You may complete one or all modules for credit. Tests may not be submitted more than one time. For information on passing lev-
els, assignment of credits, and credit reporting, see Continuing Pharmacy Education and Recertification Instructions page for
each module.

Important Notice on BCPPS Recertification: Submitting a required posttest for BCPPS recertification attests that you have com-
pleted the test as an individual effort and not in collaboration with any other individual or group. Failure to complete this test as
an individual effort may jeopardize your ability to use PedSAP for BCPPS recertification.

BOOK FORMAT AND CONTENT

E-Media Format: All purchasers of this PedSAP book also have access to the e-media version. Follow these instructions to load
the text and self-assessment questions in this book onto your e-reader, tablet, or Android phone.

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NOTE: To facilitate further learning and research, this publication incorporates live hyperlinks to websites administered by other
organizations. The URLs provided are those of third parties not affiliated in any way with ACCP. ACCP assumes no liability for
material downloaded from or accessed on these websites. It is the responsibility of the reader to examine the copyright and
licensing restrictions of linked pages and to secure all necessary permissions.

Abbreviations, Laboratory Values: This table, which is also reached by links at the beginning of each chapter, lists selected
abbreviations and reference ranges for common laboratory tests that can be used as a resource in completing the self-assess-
ment questions.

NOTE: The editors and publisher of PedSAP recognize that the development of this volume of material offers many opportunities
for error. Despite our best efforts, some errors may persist into publication. Drug dosage schedules are, we believe, accurate and
in accordance with current standards. Readers are advised, however, to check package inserts for the recommended dosages
and contraindications. This is especially important for new, infrequently used, and highly toxic drugs.
Director of Professional Development: Nancy M. Perrin, M.A., CAE
Associate Director of Professional Development: Wafa Y. Dahdal, Pharm.D., BCPS
Recertification Project Manager: Edward Alderman, B.S., B.A.
Medical Editor: Kimma Sheldon, Ph.D., M.A.
Information Technology Project Manager: Brent Paloutzian, A.A.S.

For ordering information or questions, write or call:

Pediatric Self-Assessment Program
American College of Clinical Pharmacy
13000 W. 87th St. Parkway
Lenexa, KS 66215-4530
Telephone: (913) 492-3311
Fax: (913) 492-4922
E-mail: accp@accp.com

Library of Congress Control Number: 2016947101

ISBN-13: 978-1-939862-35-8 (PedSAP 2016 Book 2, Pediatric Critical Care)

Copyright 2016 by the American College of Clinical Pharmacy. All rights reserved. This book is protected by copyright. No part
of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic or
mechanical, including photocopy, without prior written permission of the American College of Clinical Pharmacy.

To cite PedSAP properly:

Authors. Chapter name. In: Buck ML, Manasco KB, eds. Pediatric Self-Assessment Program, 2016 Book 2. Pediatric Critical Care.
Lenexa, KS: American College of Clinical Pharmacy, 2016:page range.

PedSAP is a registered trademark of the American College of Clinical Pharmacy.

Pediatric
Self-Assessment
Program
TABLE OF CONTENTS
Pediatric Critical Care I. . . . . . . . . . . . . . . . . . . . . . . . . . 1
Pediatric Critical Care I Panel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
ARDS and Ventilator-Associated Events
By Jennifer L. Morris, Pharm.D., FCCM, BCPS, BCPPS
LeMechanical Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Acute Lung Injury and PARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Toward Evidence-Based Pharmacotherapy Management
of ALI and ARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Ventilator-Associated Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Current Quality of Care Surveillance . . . . . . . . . . . . . . . . . . . . . . 22
Antibiotic Stewardship for IVAC Complications and VAP . . . . . 25
Strategies for Prevention of VAEs . . . . . . . . . . . . . . . . . . . . . . . . . 26
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Self-Assessment Questions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Hemodynamic Instability
By Regine L. Caruthers, Pharm.D.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Hypovolemic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Obstructive Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Cardiogenic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Distributive Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Hypertensive Urgency
and Emergency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Self-Assessment Questions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Pediatric Critical Care II. . . . . . . . . . . . . . . . . . . . . . . 49
Pediatric Critical Care II Panel. . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Extracorporeal Circuits in Children
By Elizabeth J. Beckman, Pharm.D., BCPS, BCPPS, BCCCP
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Extracorporeal Membrane Oxygenation . . . . . . . . . . . . . . . . . . 56
Continuous Renal Replacement Therapy . . . . . . . . . . . . . . . . . 63
Extracorporeal Liver Support . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Plasmapheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Self-Assessment Questions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
PedSAP 2016 Book 2 Pediatric Critical Care
Trauma
By Joseph M. LaRochelle, Pharm.D., BCPPS
Introduction to Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . 81
Cerebral Perfusion Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Other Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Emerging Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Introduction to Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Initial Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Hypermetabolic State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Self-Assessment Questions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Clinical and Practice Updates I. . . . . . . . . . . . . . 95
Clinical and Practice Updates I Panel. . . . . . . . . . . . . . . . . . . . . 97
Interactive Patient Case: Severe Acute
Asthma (Status Asthmaticus)
By Laura Lo Castro Bio, Pharm.D., BCPS
Interactive Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Self-Assessment Questions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Guideline Review: Diabetic Ketoacidosis and
Hyperglycemic Hyperosmolar State
By Elizabeth S. Goswami, Pharm.D., BCPS, BCPPS; and Susan Warrington,
Pharm.D., BCPPS
Guideline Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Self-Assessment Questions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Interactive Case: Status Epilepticus
By Christina Cox, Pharm.D., BCPS, BCPPS
Interactive Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Self-Assessment Questions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
iii Table of Contents
A MESSAGE FROM THE EDITORS
Welcome to the Pediatric Self-Assessment Program (Ped-
SAP), a new recertification component for the Board Certified
Pediatric Pharmacy Specialist (BCPPS). ACCP has a long tra-
dition of offering the best products for continuing pharmacy
education and pharmacotherapy specialist certification.
PedSAP continues that tradition by providing the latest in
evidence-based information for the practitioner or clinician
working with this special population.
In designing this series, the primary goal was to provide
updates that would improve clinical pharmacy practice and
patient outcomes. The process began with a careful review
of the content outline developed by the Board of Pharmacy
Specialties for the Pediatric Pharmacy Specialty Certification
Examination. The 20162018 PedSAP chapters will therefore
cover the domains of patient management; practice manage-
ment; information management and education; and public
health and patient advocacy. Specific content for individual
releases in this series was organized on the basis of the sys-
tems and patient-care problems that might be expected of the
BCPPS. Finally, calls went out to recruit faculty panel chairs,
authors, and reviewers committed to this new specialty and to
the board certification process.
The presentation of information, and its incorporation into
practice, was also given careful consideration. In a departure
PedSAP 2016 Book 2 Pediatric Critical Care
from ACCPs other self-assessment programs, PedSAP mod-
ules come in two formats: (1) the traditional review chapters;
and (2) Clinical and Practice Update modules that incorpo-
rate new learning formats such as recorded webinars and
HTML pages. These new learning formats are hoped to speed
the dissemination of new clinical information and satisfy the
learning preferences of a wider audience.
Some things have not changed: inside this PedSAP book
you will find user-friendly formatting as well as graphic ele-
ments such as patient-care scenarios (demonstrating the
application of concepts), treatment algorithms, descriptions
of pivotal studies that may change practice, and summative
practice points. All releases in this series are available elec-
tronically, enhancing the portability of this product. Prominent
in each chapter are hyperlinks to reference sources, assess-
ment tools, guidelines and resources, data compilers such as
PubMed, and even informational videos. Our hope is that this
depth of information, ease of access, and emphasis on clinical
application will have an immediate and positive impact on the
care of pediatric patients.
We very much appreciate the efforts of all the faculty panel
chairs, authors, and reviewers who lent their time, energy, and
expertise to this new series.
Marcia L. Buck and Kalen B. Manasco, series editors
iv Table of Contents
Pediatric Critical Care I
Pediatric Critical Care I Panel

Series Editors: Clinical Pharmacist

Department of Pharmacy
Marcia L. Buck, Pharm.D., BCPPS, FCCP, FPPAG
UC Health Northern Colorado-Poudre Valley Hospital
Clinical Coordinator
Fort Collins, Colorado
University of Virginia Childrens Hospital
Professor
Department of Pediatrics Hemodynamic Instability
University of Virginia School of Medicine
Clinical Professor Author
Virginia Commonwealth University School of Pharmacy
Regine L. Caruthers, Pharm.D.
Department of Pharmacy Services
Clinical Pharmacy Specialist, Pediatric Cardiology
University of Virginia Health System
Department of Pharmacy
Charlottesville, Virginia
Adjunct Clinical Assistant Professor of Pharmacy
Kalen B. Manasco, Pharm.D., BCPS College of Pharmacy
Clinical Associate Professor University of Michigan Hospital and Health Centers
Department of Clinical and Administrative Pharmacy Ann Arbor, Michigan
University of Georgia College of Pharmacy
Augusta, Georgia Reviewers
Ashley R. Schappell, Pharm.D., BCPS
Faculty Panel Chair:
Clinical & Unit Based Pharmacist
Joseph M. LaRochelle, Pharm. D., BCPPS Department of Pharmacy
Clinical Associate Professor Nemours/Alfred I. DuPont Hospital for Children
College of Pharmacy Wilmington, Delaware
Xavier University of Louisiana
Michael A. Maccia, Pharm.D, BCPS
Clinical Associate Professor of Pediatrics
Clinical Pharmacist
Louisiana State University Health Sciences
Pharmacy Department
Center School of Medicine
Moses H. Cone Memorial Hospital
New Orleans, Louisiana
Greensboro, North Carolina

ARDS and Ventilator-Associated Events The American College of Clinical Pharmacy and the authors
thank the following individuals for their careful review of the
Author Pediatric Critical Care I chapters:
Jennifer L. Morris, Pharm.D., FCCM, BCPS, BCPPS Ralph H. Raasch, Pharm.D., BCPS
Clinical Pharmacy Specialist, Pediatric Critical Care Associate Professor of Pharmacy (retired)
Department of Pharmacy Division of Practice Advancement and Clinical Education
Texas Childrens Hospital Eshelman School of Pharmacy
Houston, Texas The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Reviewers
Jeffrey T. Sherer, Pharm.D., MPH, BCPS
Kristine A. Parbuoni, Pharm.D., BCPPS Clinical Associate Professor
Assistant Professor Department of Clinical Sciences and Administration
Department of Pharmacy Practice University of Houston College of Pharmacy
Loma Linda University School of Pharmacy Houston, Texas
Loma Linda, California
Brandi L. Strauser, Pharm.D., BCPS, BCCCP
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Consultancies: Elizabeth J. Beckman (Lexi-Comp/Wolters/Kluwer Health); Regine L Caruthers (Lexi-Comp/Wolters Kluwer
Health); Joseph M. LaRochelle (ACCP); Lois F. Parker (ASHP/MSHP)

Stock Ownership:

Royalties:

Grants: Elizabeth J. Beckman (ASHP Foundation); Christina Cox (University of South Carolina);

Honoraria: Christina Cox (ACCP, Palmetto Health Richland Childrens Hospital); Jennifer L. Morris (ACCP, Society of Critical Care
Medicine, Pediatric Pharmacy Advocacy Group, Wolters Kluwer)

Other:

Nothing to disclose: Laura Lo Castro Bio, Joshua Caballero, Brooke Clark, Kyle Davis, Ifeyinwa D. Eboh, Elizabeth S. Goswami,
Aaron A. Harthan, Maha O. Kebir, Allison Lardieri, Michael A. Maccia, Kristine Parbuoni, Monica A. Puebla, Sara P. Rooney, Emily
L. Rowe, Ashley R. Schappell, Julie Pingel, Brandi L. Strauser, Andrea Joan Stumpe, Susan Warrington

ROLE OF BPS: The Board of Pharmacy Specialties (BPS) is an autonomous division of the American Pharmacists Association
(APhA). BPS is totally separate and distinct from ACCP. The Board, through its specialty councils, is responsible for specialty
examination content, administration, scoring, and all other aspects of its certification programs. PedSAP has been approved by
BPS for use in BCPPS recertification. Information about the BPS recertification process is available online.

Other questions regarding recertification should be directed to:

Board of Pharmacy Specialties

2215 Constitution Avenue NW
Washington, DC 20037
(202) 429-7591
CONTINUING PHARMACY EDUCATION AND
RECERTIFICATION INSTRUCTIONS
Continuing Pharmacy Education Credit: The American College of Clinical Pharmacy is accredited by the Accreditation
Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education (CPE).

PedSAP: Target Audience: The target audience for PedSAP 2016 Book 2(Pediatric Critical Care) is pediatric pharmacotherapy spe-
cialists and advanced-level clinical pharmacists caring for pediatric patients with several acute conditions and complications of
the pulmonary, cardiovascular, endocrine, and neurologic systems.

Available CPE credits: Purchasers who successfully complete all posttests for PedSAP 2016 Book 2 (Pediatric Critical Care) can
earn 13.0 contact hours of continuing pharmacy education credit. The universal activity numbers are as follows: Pediatric Critical
Care I 0217-0000-16-021-H01-P, 3.5 contact hours; Pediatric Critical Care II 0217-0000-16-022-H01-P, 4.5 contact hours; and
Clinical and Practice Updates 0217-0000-16-170-H01-P, 5.0 contact hours. You may complete one or all available modules for
credit. Tests may not be submitted more than once.

BCPPS test deadline: 11:59 p.m. (Central) on January 17, 2017.

ACPE test deadline: 11:59 p.m. (Central) on September 14, 2019.

Posttest access: Go to www.accp.com and sign in with your e-mail address and password. Technical support is available from
8 a.m. to 5 p.m. (Central) weekdays by calling (913) 492-3311. PedSAP products are listed under My Online Products on your My
Account page.

BCPPS Recertification Credit: To receive BCPPS recertification CPE credit, a PedSAP posttest must be submitted within the
4-month period after the books release. The first page of each print and online book lists the deadline to submit a required
posttest for BCPPS recertification credit. Only completed tests are eligible for credit; no partial or incomplete tests will be pro-
cessed. Tests may not be submitted more than once. The passing point for BCPPS recertification is based on an expert analysis
of the items in each posttest module.

ACPE CPE Credit: To receive ACPE CPE credit for a PedSAP module, a posttest must be submitted within the 3-year period after
the books release. The appropriate CPE credit will be awarded for test scores of 50% and greater.

Credit Assignment and Reporting: All required posttests that meet the 50% score standard will be immediately awarded the
appropriate ACPE CPE credit. Earned credits will be transmitted within 24 hours to www.mycpemonitor.net and should appear on
statements of credit within 3 business days.

Required posttests that are submitted before the BCPPS test deadline and that meet the passing point set by statistical analysis
will earn BCPPS recertification credits. These credits will be posted within 30 days after the BCPPS test deadline. For statements
of CPE credit, visit www.mycpemonitor.net.

All BCPPS recertification credits are forwarded by ACCP to the Board of Pharmacy Specialties (BPS). Questions regarding the
number of hours required for BCPPS recertification should be directed to BPS at (202) 429-7591 or www.bpsweb.org. The ACCP
Recertification Dashboard is a free online tool that can track recertification credits as they are earned through ACCP and schedule
new opportunities for credits from upcoming ACCP professional development programs.

Posttest Answers: The explained answers with rationale and supporting references will be posted 1 week after the BCPPS
test deadline and will be available to anyone who has either submitted a posttest or waived his or her right to receive credit (see
below) from a posttest. Go to www.accp.com and sign in with your e-mail address and password. Click the PedSAP book on your
My Account page and you will see a link to the explained answers.

Test Waivers: To access the explained answers without submitting a posttest, sign in to your My Account page, select the
PedSAP book, and click on the waiver link for that module. By completing the waiver form for a module, you waive the opportu-
nity to receive CPE credit for that module. After you submit a waiver, you will see a link to the PDF file that contains the answers
for the module you waived. Answers will be available starting 1 week after the BCPPS test deadline.

ACSAP 2016 Book 2 Pediatric Critical Care 6 Program Instructions

ARDS and Ventilator-Associated
Events
By Jennifer L. Morris, Pharm.D., FCCM, BCPS, BCPPS

Reviewed by Kristine A. Parbuoni, Pharm.D., BCPPS; and Brandi L. Strauser, Pharm.D., BCPS, BCCCP

LEARNING OBJECTIVES

1. Using the definitions for acute respiratory distress syndrome (ARDS), classify a patients pulmonary morbidity.
2. Analyze available data to design an appropriate pharmacotherapy plan, including exogenous pulmonary surfactant or the
use of corticosteroids, for pediatric patients with ARDS.
3. Analyze the current definition of ventilator-associated pneumonia to determine the need for surveillance, and measure
quality of care in pediatric ICU patients.
4. Evaluate deficiencies in current surveillance definitions and justify expanded surveillance in pediatric units to include
other ventilator-associated conditions.
5. For ventilator-associated infections in the pediatric ICU, design antimicrobial therapy plan that uses the narrowest-spec-
trum antibacterial agents for a duration that minimizes antibacterial exposure.
6. Justify a prevention strategy for ventilator-associated events in the pediatric ICU including, but not limited to, implemen-
tation of a ventilator-associated pneumonia bundle.

ABBREVIATIONS IN THIS CHAPTER
ALI Acute lung injury
ARDS Acute respiratory distress syndrome
IVAC Infection-related ventilator-associ-
ated condition
MDRGN Multidrug-resistant gram-negative
organisms
OI Oxygenation index
PALICC Pediatric Acute Lung Injury
Consensus Conference
PARDS Pediatric acute respiratory dis-
tress syndrome
PF ratio Ratio of Pao2 to Fio2
PVAP Possible ventilator-associated
pneumonia
SF ratio Ratio of saturation of arterial oxy-
gen to fraction of inspired oxygen
SRMD Stress-related mucosal disease
VAC Ventilator-associated condition
VAE Ventilator-associated event
VAP Ventilator-associated pneumonia
MECHANICAL VENTILATION
Invasive positive pressure ventilation is used in the treatment of crit-
ically ill pediatric patients for a variety of indications that may arise
from a pulmonary, cardiac, neurologic, or neuromuscular condition.
Respiratory failure, either from inadequate oxygenation or inade-
quate ventilation, may be caused by pulmonary or extrapulmonary
conditions. Patients with significant cardiovascular dysfunction may
benefit from mechanical ventilation, which may decrease both the
work of breathing and the myocardial oxygen demand. Neurologic
and neuromuscular disorders can result in loss of ventilatory drive,
ventilatory muscle weakness, loss of protective reflexes, and need
for induced hyperventilation, all of which may be supported by posi-
tive pressure ventilation (Venkataraman 2011).
Treatment of the Mechanically Ventilated Patient
One pharmacist role in the treatment of mechanically ventilated
patients is the management of pharmacotherapy used to facilitate
patient-ventilator synchrony and optimize patient comfort. Pediatric
patients requiring mechanical ventilation generally need some degree
of pain and sedation management. Agents such as benzodiazepines,
opioids, and dexmedetomidine may facilitate comfort, but their
use must be balanced with minimization of the associated adverse
events. This is usually achieved by identifying patient-specific goals

PedSAP 2016 Book 2 Pediatric Critical Care 7 ARDS and Ventilator-Associated Events
 In addition to facilitating patient comfort and the phar-
VAT Ventilator-associated tracheobronchitis
macologic management of the primary disorder resulting
VTE Venous thromboembolism
in the need for positive pressure ventilation, pharmacists
have a role in preventing health careassociated conditions.
Table of other common abbreviations.
This includes infection prevention as well as prevention of
stress-related mucosal disease (SRMD) and venous thrombo-
embolism (VTE).
and using a standardized approach to drug therapy that is
Stress-related mucosal disease may develop in acutely ill
based on the predefined goal. Although the only randomized
patients secondary to an inflammatory, erosive insult to the
controlled trial of protocolized sedation in mechanically ven-
upper GI tract. Of most concern is the development of overt,
tilated, critical care pediatric patients found no difference in
clinically significant GI bleeding, which may worsen patient
duration of mechanical ventilation, several secondary out-
outcomes. Box 1-1 lists risk factors for SRMD identified in
comes were improved with this approach, including fewer
adult and pediatric hospitalized patients.
episodes of skin breakdown, fewer days of opioid exposure,
fewer sedative class exposures, and more study days awake
and calm (Curley 2015). Although no guidelines exist for treat-
ing the pain, agitation, and delirium of pediatric patients, the Box 1-1. Risk Factors Associated with
tenets of the adult guidelines can be generally applied to the Upper GI bleeding
care of critically ill pediatric patients to optimize therapy with Independent Risk Factors
these agents (Barr 2013). Pediatric:
Coagulopathy a

PRISM score 10
Respiratory failureb

In mechanically ventilated pediatric patients:

High pressure ventilation (positive inspiratory
BASELINE KNOWLEDGE STATEMENTS pressure 25 cm H2O)
Organ failure
Readers of this chapter are presumed to be familiar
with the following: Adult:
Basic ventilator terminology, including settings and Coagulopathy
monitoring parameters
Respiratory failure
Shock
Concepts and management of pain, agitation, and Multiple trauma
delirium in the critically ill patient
Factors Contributing to Cumulative Riskc
Knowledge of the pharmacology of pulmonary
Acute hepatic failure
surfactants and corticosteroids Acute renal failure
Knowledge of the organisms commonly associated Anticoagulation
with health careassociated pneumonia and Burn injury (> 35% total body surface area)
ventilator-associated pneumonia and appropriate High-dose corticosteroids (> 250 mg/day of hydrocor-
empiric therapy tisone)
Knowledge of antibiotic therapy including spec- History of GI bleed
trum of activity and dose-optimization strategies Hypotension
Low intrinsic gastric pH
Knowledge of prophylactic strategies for both
Major surgery (> 4 hr)
stress-related mucosal bleeding and venous
Sepsis
thromboembolism
Severe head or spinal cord injury
Table of common pediatric laboratory reference values. a
Studies have used several definitions of coagulopathy, includ-
ing prolonged PTT, prolonged PT, INR > 1.5, and Plt < 100,000/
mm3.
ADDITIONAL READINGS b
Need for mechanical ventilation.
The following free resources have additional back-
c
Identified in adult and/or pediatric studies.
ground information on this topic: Information from: ASHP Commission on Therapeutics. ASHP
therapeutic guidelines on stress ulcer prophylaxis. Am J
CDC. National Healthcare Safety Network [homep- Health Syst Pharm 1999;56:347-79; Chaibou M, Tucci M, Duga
age on the Internet]. MA, et al. Clinically significant upper gastrointestinal bleed-
ing acquired in pediatric ICU: a prospective study. Pediatrics
Institute for Healthcare Improvement. How-to
1998;102:933-8; and Reveiz L, Guerrero-Lozano R, Camacho
Guide: Prevent Ventilator-Associated Pneumonia A, et al. Stress-ulcers, gastritis, and gastrointestinal bleed-
[homepage on the Internet]. ing prophylaxis in critically ill pediatric patients: a systematic
review. Pediatr Crit Care Med 2010;11:124-32.

PedSAP 2016 Book 2 Pediatric Critical Care 8 ARDS and Ventilator-Associated Events
 Guidelines for which pediatric ICU (PICU) patients should
receive pharmacologic prophylaxis are unavailable, and adult
guidelines were last published in 1999, although an update is
expected in the near future. Given the available data and the
adult guidelines, it is reasonable to recommend pharmaco-
logic prophylaxis to prevent upper GI bleeding from SRMD
in PICU patients who have one independent risk factor or at
least two cumulative risk factors (ASHP 1999). Prophylactic
strategies, including histamine-2 receptor antagonists and
proton pump inhibitors, have proved useful in maintaining a
gastric pH greater than 4 when compared with placebo or no
treatment. However, no effect on mortality or decreased risk
of clinically significant bleeding was seen in pediatric stud-
ies (Reveiz 2010). Therefore, it is important to balance the
benefits of SRMD prophylaxis with the potential risks (e.g.,
increased risk of infection, decreased bone mineral density).
The incidence of VTE, including deep venous thrombosis
and pulmonary embolism, has increased in hospitalized pedi-
atric patients (Sharathkumar 2012). This increase is postulated
to be caused by enhanced surveillance, as well as advanced
management of complex medical conditions leading to
improved mortality. There appears to be a bimodal distribu-
tion of pediatric age groups (i.e., infants and adolescents) at
higher risk of developing VTE. Other risk factors identified
in a hospitalized pediatric cohort include higher BMI, direct
admission to the ICU, bacteremia, central venous access,
immobilization, oral contraceptive exposure, length of stay
longer than 7 days, and mechanical ventilation. According to
a multiple regression analysis, the factors that continued to
be significantly associated with risk were direct admission to
the ICU, bacteremia, central venous access, immobilization,
oral contraceptive exposure, and length of stay longer than
7 days (Sharathkumar 2012).
In adult inpatients, use of pharmacologic thrombo-
prophylaxis with the low-molecular-weight heparins and
unfractionated heparin minimizes the risk of VTE and its asso-
ciated poor outcomes, and thromboprophylaxis is routinely
used. However, the same supporting data do not exist for pedi-
atric patients. Although broad-scale, systematic investigation
of these prophylactic strategies is needed, it is clinically appro-
priate to implement a risk assessment to identify high-risk
patients (Reiter 2012; Sharathkumar 2012). In most pediat-
ric patients identified as high risk, mechanical prophylaxis of
sequential compression devices can be implemented safely.
Pharmacologic prophylactic strategies can be implemented
according to institution-specific protocols for high-risk patients
with favorable risk-benefit for prophylactic anticoagulation.
As noted previously, the need for mechanical ventilation
may arise from either pulmonary or extrapulmonary condi-
tions. Pulmonary morbidities in critically ill pediatric patients
may result in the need for invasive mechanical ventilation or
may be caused by this invasive supportive therapy. Two such
conditions are pediatric acute respiratory distress syndrome
(PARDS) and ventilator-associated pneumonia (VAP).
PedSAP 2016 Book 2 Pediatric Critical Care
ACUTE LUNG INJURY AND PARDS
Pathophysiology
Acute respiratory distress syndrome (ARDS) is the clini-
cal syndrome that occurs secondary to the development of
noncardiogenic pulmonary edema. Pulmonary edema devel-
ops secondary to breakdown of the permeability barrier in
the alveoli, in the setting of inflammatory and coagulation
dysregulation. When functioning properly, the permeability
barrier maintains separation between the fluid (capillaries)
and the air (alveoli) compartments within the lung and allows
for appropriate gas exchange. With dysfunction, patients
develop the clinical symptoms of ARDS including hypoxemia,
changes on chest radiography, increase in physiologic dead
space, and decrease in functional residual capacity and lung
compliance. This pathophysiology usually results in the need
for respiratory support to improve both gas exchange and
work of breathing (Sapura 2015).
Two phases of the syndrome have been described, given
the pathologic findings during clinical progression and the
changes in pulmonary pathophysiology. The exudative phase,
or early phase, of the ARDS is a state of overwhelming expres-
sion of proinflammatory cytokines, neutrophil activation, and
coagulation dysregulation. The irreversible fibroproliferative
phase, or late phase, occurs around day 7 of illness in those
who do not clinically improve. This phase is characterized by
fibrosis and loss of alveolar structure (Deal 2008).
Prevalence in Pediatric Patients
Although less prevalent than in adults, ARDS and its asso-
ciated morbidity and mortality are regularly encountered in
the pediatric critical care population. The reported incidence
of ARDS in pediatric patients is 212.8 cases per 100,000
person-years compared with the 17.981 cases per 100,000
person-years reported in adults. From 21% to 74% of pediatric
patients are reported to have preexisting illness (commonly
immunodeficiency) before developing ARDS. Mortality rates
appears to be lower in pediatric patients (18%27%), although
some studies report mortality closer to the adult rate (27%
45%). Pediatric patient factors associated with an increased
risk of mortality from ARDS include immunodeficiency and
African American ethnicity. Although the risk of developing
ARDS appears to be higher in boys, the mortality risk is no
higher than in girls (Khemani 2015). The patients age may
alter long-term morbidity because of the potential impact of
ARDS on lung development in children (Sapura 2015).
Underlying causes for developing this syndrome may arise
from either direct injury to the alveolar epithelium or injury to the
capillary endothelium from conditions such as sepsis, pneumo-
nia, trauma, and submersion injury. In adult patients with ARDS,
the most commonly associated clinical condition is sepsis; in
pediatric patients it is respiratory infection. Respiratory viruses
are much more likely to result in ARDS in pediatric patients than
in adult; ARDS arising from this cause may have a histologic
9 ARDS and Ventilator-Associated Events
pattern of injury different from other causes. Recent evidence
suggests that the associated clinical cause alters outcomes
(Sapura 2015). There are few controlled trials in patients with
ARDS, and these are generally underpowered to be conclusive;
however, epidemiologic studies have shown improvement in
ARDS mortality rates (Bembea 2015; Randolph 2009).
Definition and Classification of PARDS
Initially reported in 1967, characterization of the adult respi-
ratory distress syndrome and subsequently renamed ARDS
has undergone several revisions. The American-European
Consensus Conference (AECC) published the first consen-
sus definition in 1994; it delineated requirements for defining
hypoxemia by the ratio of partial pressure of arterial oxygen to
fraction of inspired oxygen (Pao2/Fio2, or PF ratio), the onset
of hypoxemia, and chest radiographic findings. This definition
also established the umbrella category of acute lung injury
(ALI). Establishing a consensus definition was highly useful
in advancing ARDS clinical care and research; however, there
were areas for optimization within this definition.
The subsequent definition, called the Berlin definition, tried to
address these areas. In 2012, the European Society of Intensive
Care Medicine convened a task force to develop a subsequent
consensus definition. The Berlin definition expanded the ARDS
diagnostic criteria by clarifying the time interval for the onset
of hypoxemia and minimizing the effect of other ventilator
Table 1-1. ARDS Definition Criteria
Parameter AECC 1994
Timing Acute
Chest imaging Bilateral infiltrates seen on frontal
view
Pulmonary artery wedge 18 mm Hg
pressure If not measured, no clinical evidence
of left atrial hypertension
Presence of risk factors Not addressed
Origin of edema Not addressed
ALI category PF ratio < 300
Oxygenation PF ratio 200
ALI = acute lung injury; ARDS = acute respiratory distress syndrome; CPAP = continuous positive airway pressure; PEEP = positive
end-expiratory pressure; PF ratio = Pao2/Fio2.
Information from Ferguson ND, Fan E, Camporota L, et al. The Berlin definition of ARDS: an expanded rationale, justification, and sup-
plementary material. Intensive Care Med 2012;38:1573-82; and ESICM. ARDS Definition Task Force. Acute respiratory distress
syndrome: the Berlin definition. JAMA 2012;307:2526-33.
PedSAP 2016 Book 2 Pediatric Critical Care
parameters on the PF ratio by including positive end-expira-
tory pressure (PEEP) or continuous positive airway pressure in
the definition. Impaired oxygenation was further delineated as
mild, moderate, or severe. The term ALI was removed from the
definition and replaced by the mild category. In addition, in the
absence of common risk factors for ARDS, the Berlin definition
excludes hydrostatic pulmonary edema from causes such as
heart failure and fluid management.
Risk factors for ARDS include direct lung injury such as
pneumonia, aspiration, pulmonary contusions, inhalation
injury, pulmonary vasculitis, and submersion injury, as well as
indirect lung injury such as sepsis, major trauma, pancreati-
tis, transfusion-related, severe burn injury, and drug overdose
(ESICM 2012; Ferguson 2012). Table 1-1 details the AECC and
Berlin definitions of ARDS.
Although using the Berlin definition may be reasonable,
given the lack of pediatric-specific definitions, it may fail
to consider the pulmonary changes that occur throughout
development or how management strategies may be altered
(Sapura 2015; Yehya 2015; Cheifetz 2011). Because of the
potential issues with the adult-focused definition, the Pediatric
Acute Lung Injury Consensus Conference (PALICC) sought to
develop a pediatric-specific definition for PARDS (Figure 1-1).
This definition incorporates measures of hypoxemia including
oxygenation index (OI), oxygenation saturation index (OSI), and
ratio of saturation of arterial oxygen to fraction of inspired oxy-
gen (SF ratio) as markers of oxygenation impairment.
Berlin 2012
Onset within 1 wk of:
Known clinical insult OR
New/worsening respiratory symptoms
Bilateral opacities that are not fully explained by effusions, lobar/
lung collapse, or nodules
Removed from definition
Use to determine need to rule out hydrostatic edema
In the absence of risk factors, hydrostatic edema should be excluded
by objective assessment (e.g., echocardiography)
ALI term removed
Mild: PF ratio 201300 AND PEEP or CPAP 5 cm H2O
Moderate: PF ratio 101200 AND PEEP 5 cm H2O
Severe: PF ratio 100 AND PEEP 5 cm H2O
10 ARDS and Ventilator-Associated Events
 Findings consistent with a new infiltrate(s)
secondary to acute parenchymal lung disease
Chest imaging
criteria
Patient with CHD, CLD, or LV dysfunction:
- New infiltrate from baseline

Non-invasive ventilation:
Acute onset within
Full face-mask BiPAP or CPAP 5 cm H2O with
7 days and
a:
pulmonary edema
PF ratio 300 OR
not fully explained
SF ratio 264
by cardiac failure
fluid overloada
Invasive ventilation:
Mild OI 4 to < 8 OR OSI 5 to < 7.5
Moderate OI 8 to < 16 OR OSI 7.5 to < 12.3
Severe OI 16 OR OSI 12.3

Patient with CHD:

Oxygentation Acute deterioration that meets the oxygenation
criteria criteria not explained by underlying
cardiac disease

Patient with CLD:

Acute deterioration that meets the oxygenation
criteria that is not consistent with baseline
oxygenation requirement

Patient with LV Dysfunction:

Acute deterioration that meets the oxygenation
criteria not explained by left ventricular
dysfunction

Figure 1-1. Pediatric ARDS definition.

a
Excludes patients with lung disease unique to the perinatal period such as surfactant deficiency, meconium aspiration, and
congenital diaphragmatic hernia.
BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CHD = cyanotic heart disease; CLD = chronic
lung disease; LV = left ventricular; OI = oxygenation index [(FiO2 mean airway pressure 100)/PaO2]; OSI = oxygen saturation index
([FiO2 mean airway pressure (Paw) 100)/SpO2]; PARDS = pediatric ARDS; PEEP = positive end-expiratory pressure; PF ratio =
PaO2/FiO2; SF ratio = SaO2/FiO2.
Information from Khemani RG, Smith LS, Zimmerman JJ, et al. Pediatric acute respiratory distress syndrome: definition, incidence,
and epidemiology: proceedings from the pediatric acute lung injury consensus conference. Pediatr Crit Care Med 2015;16:S23-S40.

There are several reasons to use OI and OSI rather than
PEEP in the definition of PARDS. First, there is known vari-
ability in clinical ventilator management. Second, pediatric
intensivists may be less likely to use higher PEEP than their
adult colleagues. Third, PEEP is unavailable in high-fre-
quency oscillatory ventilation, which is commonly used in
PARDS. In addition, the OI may better delineate the mortal-
ity risk in pediatric patients than the PF ratio. The OSI and SF
ratio are offered as alternatives to the OI and PF ratio, respec-
tively, when pulse oximetry is available but an arterial blood
gas is not. There is no clearly defined upper age limit for when
the PARDS definition versus the Berlin definition should be
applied, but neither definition should be applied to patients
with perinatal-related respiratory failure (Khemani 2015).
TOWARD EVIDENCE-BASED
PHARMACOTHERAPY MANAGEMENT
OF ALI AND ARDS
Using an evidence-based approach to managing ARDS can be
difficult. Contradictory results among studies with small sam-
ple sizes for this heterogeneous syndrome make it difficult to
discern which pharmacologic therapies, if any, should be used
in these critically ill patients. Although the pathophysiology

PedSAP 2016 Book 2 Pediatric Critical Care 11 ARDS and Ventilator-Associated Events
of ARDS is likely similar between adults and children, there
are also likely subtle differences because of the developmen-
tal changes that occur in the lung parenchyma and immune
system. These differences may be behind the variability in
treatment outcomes between these two patient populations.
Many pulmonary-specific and nonpulmonary-specific ther-
apies for managing ARDS have been evaluated; this chapter
focuses on exogenous surfactant and corticosteroids. Much
clinical controversy exists concerning the use of these ther-
apies (Tamburro 2015). The proceedings from the PALICC,
convened in October 2012, address in further detail additional
pulmonary-specific and nonpulmonary-specific pharmacother-
apy, as well as ventilator management strategies. A complete
review of the PALICC is beyond the scope of this chapter. For
further details regarding the nonpharmacologic and pharma-
cologic management options (e.g., inhaled nitric oxide, inhaled
prostacyclins, bronchodilators, diuretics, neuromuscular block-
ing agents) see the published proceedings (PALICC 2015).
Exogenous Surfactant
Direct injury to the alveoli, together with the intrusion of fluid
into the alveolar airspace, is likely to result in pulmonary sur-
factant dysfunction or washout. The success of exogenous
pulmonary surfactant in respiratory distress syndrome of the
perinatal period has fueled interest in its use in ARDS. Many
studies have attempted to delineate surfactants benefit in
ARDS, with underwhelming results. Despite some positive
outcomes reported in the literature (Table 1-2; Table 1-3), sur-
factant investigations have varied greatly in surfactant product,
dose, routes of administration, population studied, and ARDS
definition used. In addition, although most studies have shown
improvements in oxygenation, improvements in clinical end
points have been inconsistent. Pharmacologic differences in
phospholipid and surfactant protein composition of the differ-
ent surfactant products make comparing the results between
studies difficult. The pulmonary-specific therapies group at
the PALICC reached strong agreement that routine use of sur-
factant therapy cannot be recommended (Tamburro 2015).
Future Directions and Ongoing Research
Much investigative effort has been placed into evaluating
exogenous surfactant in ARDS, with little identified benefit.
Potential reasons for failure to produce positive outcomes
include surfactant product, nonstandardized doses, prepara-
tion techniques, administration methods, and heterogeneity of
the ARDS population. Despite this extensive effort, the pulmo-
nary-specific therapy subgroup of the PALICC recommended
that future investigations focus on the populations most
likely to benefit from surfactant therapy, although the specific
groups this might include were not described (Tamburro 2015).
Secondary to the lack of identified survival benefit, a
pooled analysis of five multicenter investigations of recombi-
nant surfactant protein C (rSP-C) in adults sought to identify
which patient populations with ARDS to focus on in future
PedSAP 2016 Book 2 Pediatric Critical Care
investigations. Subgroups with decreased mortality included
those with direct lung injury, including lung injury secondary
to pneumonia or aspiration, and those with severe direct lung
injury, defined as having a mean baseline PF ratio of 100
29.4 (Taut 2008). Subsequent prospective clinical trials of
both adult and pediatric patients have failed to achieve mor-
tality benefit in patients with direct lung injury using either
rSP-C or calfactant, though the calfactant study was dis-
continued secondary to slow enrollment before reaching the
predetermined sample size (Willson 2015, 2013; Spragg 2011).
A review of clinicaltrials.gov shows no actively enrolling or
ongoing investigations into the use of pulmonary surfactant in
ARDS. One pediatric investigation of calfactant evaluated all-
cause mortality, duration of mechanical ventilation, PICU and
hospital length of stay, and effect on oxygenation in patients
with hematopoietic stem cell transplantation and acute leu-
kemia and lymphoma with ALI; this study is complete, but
results have not yet been reported (PSU 2015). Pending these
data, and using results from previous investigations, patients
with immunocompromise may be a reasonable group in
which to attempt pulmonary surfactant.
Pharmacoeconomic Considerations
To date, no pharmacoeconomic evaluations of surfactant
therapy in ARDS have been published, but cost must be con-
sidered when contemplating the use of this therapy for this
indication. Of the surfactants investigated for this use, only
beractant, calfactant, and poractant alfa are commercially
available in the United States. However, the calfactant prod-
uct used in the most recent adult and pediatric study is not
the commercially available product (Willson 2015, 2013).
Table 1-4 estimates the cost of this therapy using doses from
the published literature and a PICU patient of moderate size.
Even in the absence of a positive effect on mortality, the
additional drug cost may be justifiable if surfactant therapy
minimizes mechanical ventilation or length of stay. However,
because data to support clinical benefit are currently lacking,
it is difficult to justify the increased cost of therapy.
Corticosteroids
Inflammation, endothelial damage, and altered coagulation
caused by an uncontrolled innate defense response result in
the potentially reversible pathology of ARDS. However, in some
instances, this initial injury is followed by an irreversible fibro-
proliferative phase. Interest in corticosteroids arises from the
ability to protect patients from the uncontrolled inflammatory
response leading to ARDS and potentially irreversible fibrotic
changes. In addition, relative adrenal insufficiency can occur
in patients with ARDS (MacLaren 2002).
Evidence for Use, Dosing Regimen, and Timing
for Initiation
Investigations of corticosteroid use in adults with ARDS
span almost 30 years, a broad range of dosing strategies,
12 ARDS and Ventilator-Associated Events
 Table 1-2. Pediatric Evidence for Surfactant Use in Acute Hypoxemic Respiratory Failure
Reference Study Details End Point/Intervention
Willson 1996 Open-label, multicenter,
observational
n=29
Mean age 4.7 yr
Acute hypoxemic
respiratory failure
OI 7
PedSAP 2016 Book 2 Pediatric Critical Care
Luchetti 1998 Randomized, single center
n=10
PPV + surfactant
Mean age 10.4 mo
13
n=10
PPV only
Mean age 11.2 mo
Severe bronchiolitis
requiring:
PPV
PF ratio < 158 mm Hg
Willson 1999 Multicenter, prospective,
randomized, unblinded
n=21 surfactant group
n=21 control group
Acute hypoxemic
respiratory failure
OI 7
ARDS and Ventilator-Associated Events
25% improvement in OI
Calfactant 80 mL/m2;
endotracheal instillation in
four equal aliquots
Up to four doses, depending
on initial improvement,
followed by deterioration
Surfactant treatment effect
on gas exchange, PIP,
duration of PPV and PICU
stay
Poractant alfa 0.625 mL/kg
administered in two or three
aliquots
Surfactant treatment effect
on OI and clinical outcomes
Calfactant 80 mL/m2;
endotracheal instillation in
four equal aliquots
Up to four doses
retreatment criteria varied
Results Comments
25% improvement in OI Ventilator management algorithm used
First dose (n=29): 83% Improvement in oxygenation and ventilator
Second dose (n=17): 59% parameters in the 24 hr after surfactant
Third dose (n=10): 60% administration
Fourth dose (n=4): 50% Development of air leaks should be
4 of 29 patients died monitored for after administration
Complications: Effect on outcome cannot be assessed
Bronchospasm (1) because of lack of a control group
Pneumothoraces (2)
Pneumopericardium (1)
Unrelenting hypoxia (2)
Multiorgan failure (1)
Pneumopericardium (1)
No difference in baseline characteristics Viral etiology only known in four patients
or MV parameters (all RSV)
Surfactant vs. control: Gas exchange, pulmonary mechanics, and
PF ratio improved significantly at 1, 3, 12, clinical outcomes improved in surfactant
and 24 hr after surfactant group
Paco2 improved significantly at 12 and Other medications used in both groups
24 hr after surfactant including bronchodilators, corticosteroids,
PIP improved significantly at 3, 12, and and aminophylline, none of which
24 hr after surfactant is considered standard of care in
Duration of PPV and ICU length of stay bronchiolitis
decreased significantly
No adverse effects noted
No difference in baseline characteristics Ventilator management algorithm used
Surfactant vs. control Criteria for retreatment changed during
Acute sustained improvement of a 50% the study. Subsequent criterion was
decrease in OI from baseline at 24 hr retreatment in all patients unless a
after surfactant significant adverse event during previous
Duration of PPV and ICU length of stay administration or OI improved to < 7
decreased significantly With the exception of bronchospasm,
No significant difference in mortality complications in the surfactant group
Complications with surfactant were noted in a similar number of children
administration: in the control group
Bronchospasm (1)
Air leaks (1)
Pulmonary interstitial emphysema (1)
(continued)
 Table 1-2. Pediatric Evidence for Surfactant Use in Acute Hypoxemic Respiratory Failure (continued)

Reference Study Details End Point/Intervention Results Comments

Lopez-Herce Open-label, single-center, > 20% improvement in No significant difference in PF ratio Uncontrolled study
1999 observational PF ratio within 4 hr of improvement based on dose Heterogeneous population
n=20 administration Pulmonary or systemic pathology (n=13) High overall mortality
1 mo 16 yr Poractant alfa 0.625 mL/kg > 20% improvement in PF ratio in 10
Acute pulmonary (n=14) and 2.5 mL/kg (n=6) patients
disease with severe given in two equal aliquots 4 of 13 patients died
hypoxemia Number of repeat doses CCHD pathology (n=7)
PF ratio < 100 mm Hg (05) varied > 20% improvement in PF ratio in two
patients
Six of seven patients died

PedSAP 2016 Book 2 Pediatric Critical Care

Herting 2002 Retrospective report Poractant alfa given in two
n=8 equal aliquots. Dose not
1 mo 13 yr standardized (median dose
PF ratio < 100 mm Hg 1.625 mL/kg)
Pneumonia Repeat doses given,
depending on favorable
response
Significant improvement in PF ratio Rescue therapy
within 1 hr of first administration iNO or prostacyclin used in two patients
Repeat dose in seven of eight patients All patients had severe impairment of
Significant, but less pronounced oxygenation
improvement in PF ratio with second High overall mortality
administration
Four of eight patients died

14
Luchetti 2002 Multicenter, randomized
controlled
n=20
CMV + surfactant
Mean age 8.7 mo
n=20
CMV only
Mean age 7.4 mo
RSV-induced severe
respiratory failure:
PF ratio < 150 mm Hg
Surfactant treatment
effect on gas exchange,
respiratory mechanics, need
for retreatment, duration
of CMV, PICU stay, and
mortality
Poractant alfa 0.625 mL/kg
administered in two aliquots
Pneumothorax (2)
No difference in baseline characteristics Nasotracheal intubation used in all
or MV parameters patients associated with increased risk
Surfactant vs. control of VAP
PF ratio improved significantly at 1, 3, 6, Ventilator management algorithm used
12, 24, and 48 hr Prior treatment with 2-agonist,
Paco2 improved significantly at 1, 3, 6, corticosteroids, and epinephrine in all
12, 24, and 48 hr patients
PIP improved significantly at 1, 3, 6, 12, Unusually low mortality rate
24, and 48 hr
Duration of PPV and ICU length of stay
decreased significantly
No adverse effects noted
All patients survived

ARDS and Ventilator-Associated Events

 Willson 2005 Multicenter, randomized, Surfactant treatment effect No difference in baseline characteristics Ventilator guidelines
blinded on clinical outcomes Surfactant vs. control Eight patients (four in each group) were
Infants, children, and Calfactant administered in OI significantly improved at 12 hr protocol violations six did not meet
adolescents four equal aliquots Significantly lower CMV failure the OI criteria, and two received a non-
n=77 < 10 kg: 3 mL/kg Significantly lower mortality protocol surfactant
Surfactant 10 kg: 80 mL/m2 No difference in ventilator-free days High overall mortality likely because
Mean age 7.2 yr Two doses at 12-hr intervals Complications with surfactant of the number of immunocompromised
n=75 administration: patients
Placebo Significantly greater hypotension More immunocompromised patients in the
Mean age 6.7 yr Significantly greater transient hypoxia placebo group
Acute respiratory failure No difference in the development of air Mortality with placebo did not reach
OI < 7 leaks statistical significance when controlling
Enrollment within 48 hr for immune status

PedSAP 2016 Book 2 Pediatric Critical Care

of MV

Thomas 2012 Multinational, phase II,
double-blind, placebo-
controlled, randomized
Children 38 wk PMA to
2 yr
Duration of MV Lower baseline PEEP and tidal volume in Synthetic surfactant
Lucinactant 5.8 mL/kg in the placebo group No longer commercially available
four equal aliquots No other differences in baseline Ventilator management protocol
Repeat doses 1224 hr after characteristics Subset of patients with ALI shorter
initial allowed if patient still Surfactant vs. control duration of MV with lucinactant than with

15
n=84 met inclusion criteria No difference in duration of MV placebo
Surfactant No difference in improvement in PF ratio
Mean age 23.1 wk PNA Fewer repeat doses in the lucinactant
n=81 group
Placebo Complications with surfactant
Mean age 23.4 wk PNA administration:
Acute respiratory failure Transient bradycardia
Two consecutive PF Transient hypoxia
ratios 300 mm Hg (or
SF ratio 250)
MV 6 hr but 48 hr
on inclusion

(continued)

ARDS and Ventilator-Associated Events

 Table 1-2. Pediatric Evidence for Surfactant Use in Acute Hypoxemic Respiratory Failure (continued)

Reference Study Details End Point/Intervention Results Comments

Willson 2013 Multinational, randomized, Surfactant treatment effect No difference in baseline characteristics Combined adult and pediatric study (table
placebo-controlled, on clinical outcomes Surfactant vs. control 3 in: Willson 2015)
masked Calfactant in two equal No difference in mortality, ventilator-free Study terminated at planned interim
Infants, children, and aliquots days, or PICU-free days analysis for futility
adolescents < 10 kg: 1.7 mL/kg No improvement in oxygenation More homogeneous population direct
n=56 10 kg: 0.5 mL/cm Hospital-free days significantly less lung injury only
Surfactant Up to two repeat doses with Complications with surfactant Primarily infectious lung injury
Mean age 6.3 yr a 25% improvement in PF administration: Independent randomization of those
n=53 ratio (or SF ratio) within 12 Transient hypoxia with a PF ratio < 100 mm Hg, OI > 30, or
Placebo hr of the previous dose Transient bradycardia immunocompromised status to ensure

PedSAP 2016 Book 2 Pediatric Critical Care

Mean age 6 yr Pneumothorax equal distribution
ALI/ARDS secondary to Pneumomediastinum Calfactant product containing 60 mg/mL
direct lung injury of phospholipid
PF ratio 300 mm Hg
(or SF ratio 250)
Enrollment within 48 hr
of MV

16
CMV = conventional mechanical ventilation; CCHD = complex congenital heart disease; iNO = inhaled nitric oxide; MV = mechanical ventilation; PIP = positive inspiratory pressure;
PMA = postmenstrual age; PNA = postnatal age; PPV = positive pressure ventilations; RSV = respiratory syncytial virus; VAP = ventilator-associated pneumonia.
Information from: Willson DF, Jiao JH, Bauman LA, et al. Calfs lung surfactant extract in acute hypoxemic respiratory failure in children. Crit Care Med 1996;24:1316-22; Luchetti
M, Casiraghi G, Calsecchi R, et al. Porcine-derived surfactant treatment of severe bronchiolitis. Acta Anaesthesiol Scan 1998;42:805-10; Willson DF, Zartsky A, Bauman LA, et al.
Instillation of calf lung surfactant (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure. Crit Care Med 1999;27:188-95; Lopez-Herce J, de Lucas N, Carrillo A,
et al. Surfactant treatment for acute respiratory distress syndrome. Ach Dis Child 1999;80:248-52; Herting E, Moller O, Schiffmann JH, et al. Surfactant improves oxygenation in
infants and children with pneumonia and acute respiratory distress syndrome. Acta Paediatr 2002;91:1174-8; Luchetti M, Ferrero F, Gallini C, et al. Multicenter, randomized, con-
trolled study of porcine surfactant in severe respiratory syncytial virus-induced respiratory failure. Pediatr Crit Care Med 2002;3:261-8; Willson WF, Thomas NJ, Markovitz BP, et al.
Effect of exogenous surfactant (calfactant) in pediatric acute lung injury a randomized controlled trial. JAMA 2005;293:470-6; Thomas NJ, Guardia CG, Moya FR, et al. A pilot, ran-
domized, controlled trial of lucinactant, a peptide-containing synthetic surfactant, in infants with acute hypoxemic respiratory failure. Pediatr Crit Care Med 2012;13:646-53; Willson
WF, Thomas NJ, Tamburro R, et al. Pediatric calfactant in acute respiratory distress syndrome trial. Pediatr Crit Care Med 2013;14:657-65; and Willson DF, Truwit JD, Conaway MR,
et al. The adult calfactant in acute respiratory distress syndrome trial. Chest 2015;148:356-64.

ARDS and Ventilator-Associated Events

 Table 1-3. Adult Evidence for Surfactant Use in ARDS

Reference Study Details End Point/Intervention Results Comments

Weg 1994 Multicenter, double-blind, Safety of nebulized surfactant Numerically more females in the placebo group Synthetic surfactant, contains
placebo-controlled, Surfactant treatment effect No other differences in baseline characteristics no surfactant proteins
randomized, parallel on oxygenation and clinical Surfactant vs. placebo Product not manufactured
n=17 outcomes No safety issues for nebulization, intended for
12-hr nebulized Exosurf nebulized No significant differences in oxygenation endotracheal administration
surfactant 12-hr group: ~1.6 mL/kg per day improvements No longer commercially
n=17 24-hr group: ~3.2 mL/kg per day No significant differences in mortality or available
24-hr nebulized Administered for up to 5 days hospital days
surfactant
n=17

PedSAP 2016 Book 2 Pediatric Critical Care

12- or 24-hr nebulized
saline
Sepsis-induced ARDS
Within in 18 hr of onset

Anzueto 1996 Multicenter, double-blind, Surfactant treatment effect No differences in baseline characteristics Synthetic surfactant, contains
placebo-controlled, on oxygenation and clinical Surfactant vs. placebo no surfactant proteins
randomized outcomes Similar number completed 5 days of treatment Product not manufactured

17
n=364 Exosurf ~8.3 mL/kg per day No significant differences in oxygenation for nebulization, intended for
Nebulized surfactant Administered for up to 5 days improvements endotracheal administration
n=361 No significant differences in mortality or No longer commercially
Nebulized saline hospital days available
Sepsis-induced ARDS Complications with surfactant administration: Mean PF ratio for both groups
ARDS developed in the Worsening hypoxia < 150 mm Hg
preceding 48 hr Respiratory arrest
Increased PIP
Increased secretions
Hypotension (both groups)
Barotrauma (both groups)

(continued)

ARDS and Ventilator-Associated Events

 Table 1-3. Adult Evidence for Surfactant Use in ARDS (continued)

Reference Study Details End Point/Intervention Results Comments

Gregory 1997 Multicenter, open-label, Surfactant treatment effect Significant differences in baseline Included adolescent patients
randomized, controlled on oxygenation and clinical characteristics include: Large volumes of surfactant
n=43 outcomes Increased weight in the 4 mL/kg of LBW for up generally well tolerated
Surfactant Safety of endotracheally to four doses compared with control patients
n=16 administered surfactant More patients with risk factor for multiple

Control group Beractant in four equal aliquots transfusions in the 2 mL/kg of LBW for up
ARDS: 2 mL/kg of LBW for up to eight to eight doses and 4 mL/kg of LBW for up to
From trauma, doses (n=8) eight doses compared with control patients
multiple transfusions, 4 mL/kg of LBW for up to four Surfactant vs. control
aspiration of gastric doses (n=16) Significant reduction in Fio2 at 120 min in the 4

PedSAP 2016 Book 2 Pediatric Critical Care

contents, or sepsis 4 mL/kg of LBW for up to eight
Age 1570 yr doses (n=19)
AECC definition Assessment for retreatment
PEEP 5 cm H2O every 6 hr up to 96 hr
Retreatment criteria:
PF ratio > 60 to < 200 mm Hg
PEEP > 10 cm H O
2
PF ratio 200 but 250 mm
mL/kg of LBW for up to four doses group
Significant improvement in Fio2 and PEEP at 7
days 4 mL/kg of LBW for up to four doses group
Significantly increased length of stay in the 4
mL/kg of LBW for up to eight doses group
No difference in mortality
Complications with surfactant administration:
Oxygen desaturation

18
Hg AND PEEP 5 but 10 cm Air leak
H2 O Bronchospasm
Hypotension

Spragg 2004 Two clinical trials
Multicenter, randomized,
double-blind, controlled
n=224
Surfactant + standard
therapy
Surfactant treatment effect
on oxygenation and clinical
outcomes
rSP-C 1 mL/kg of LBW in
two aliquots intratracheal
administration
Percentage of patients with baseline APACHE Orphan drug status
II score > 23 was significantly higher in the Synthetic surfactant product
surfactant group Heterogeneous population of
All other baseline characteristics similar patients with ARDS
Surfactant vs. control Multivariate analysis showed:
91% received all four doses of surfactant Baseline PEEP and PIP

n=224 Up to three repeat doses Significant improvement in PF ratio at 424 hr associated with increased
Standard therapy only Assessment of retreatment from the first treatment relative risk of MV thus,
ARDS every 4 hr for 24 hr No difference in PF ratio at 48 hr from the first compromised lung function
AECC definition Retreatment criteria: treatment associated with fewer
PEEP 5 cm H2O PF ratio > 60 to < 200 mm Hg No difference in mortality or ventilator-free days ventilator-free days
Enrollment 48 hr AND Complications with surfactant administration: Enrollment in the European/

(North American sites) PEEP 5 cm H O

2
Significantly more adverse events in the South African arm, higher
to 72 hr (European/ surfactant group APACHE II, and older
South African sites) No significant difference in the number of patients had increased risk
from diagnosis serious adverse events of mortality
Most common events: hypoxemia, hypotension,
bradycardia

ARDS and Ventilator-Associated Events

 Spragg 2011 Multicenter, randomized,
controlled, blinded
n=419
Surfactant + standard
therapy
n=424
Standard therapy only
ARDS
Severe impairment
of gas exchange
Surfactant treatment effect
on oxygenation and clinical
outcomes
rSP-C 1 mL/kg of LBW in
two aliquots intratracheal
administration
Up to seven repeat doses at 6,
12, 24, 36, 48, 72, and 96 hr after Significantly more serious adverse events in the
the first dose
Retreatment criteria:
No differences in baseline characteristics Orphan drug status
Surfactant vs. control Synthetic surfactant product
No difference in mortality, gas exchange Fairly homogeneous patient
parameters, need for mechanical ventilation, or population
the number of non-pulmonary organ failure Because of alteration in
free days the surfactant suspending
Complications with surfactant administration: process and lack of expected
outcome, surfactant activity
surfactant group was performed post hoc
Adding shearing to the

from pneumonia or PF ratio > 60 to 170 mm Hg surfactant preparation

aspiration AND process may have
PF ratio 170 mm Hg PEEP 5 cm H O
2
impaired the function of

PedSAP 2016 Book 2 Pediatric Critical Care

Age 1285 yr the surfactant, which may
explain the deviation from
results of previous studies

Willson 2015 Multicenter, randomized, Surfactant treatment effect No differences in baseline characteristics Combined adult and pediatric
controlled, masked on oxygenation and clinical Surfactant vs. control: trial (table 3 in: Willson 2013)
n=151 outcomes No significant difference in mortality, ventilator- Study terminated at planned
Surfactant Calfactant 0.5 mL/cm in two free days, ICU-free days, or hospital-free days interim analysis for futility

19
n=157 aliquots No significant improvement in measures of More homogeneous
Placebo Up to two repeat doses oxygenation population direct lung injury
ARDS Retreatment criteria Complications with surfactant administration: only
AECC definition 25% improvement in PF ratio 116 adverse events possibly related to the Calfactant product containing
because of direct lung (or SF ratio) within 12 hr of the treatment intervention 60 mg/mL of phospholipid
injury previous dose Six events in the surfactant group were graded Ventilator algorithm used
Within 48 hr of as severe
initiating MV Most common adverse events were hypoxia and
Age 1885 hypotension

APACHE = Acute Physiology and Health Evaluation; LBW = lean body weight; rSP-C = recombinant surfactant protein C.
Information from: Weg JG, Balk, RA, Tharratt RS, et al. Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress. JAMA
1994;272:1433-8; Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized surfactant in adults with sepsis-induced adult respiratory distress. N Engl J Med 1996;334:1417-21;
Gregory TJ, Steinberg KP, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 1997;155:1309-15.
Spragg RG, Lewis JF, Walmrath HD, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med 2004;351:884-92;
Spragg RG, Taut FJH, Lewis JF, et al. Recombinant surfactant protein C-based surfactant for patients with severe direct lung injury. Am J Respir Crit Care Med 2011;183:1055-61;
Willson WF, Thomas NJ, Tamburro R, et al. Pediatric calfactant in acute respiratory distress syndrome trial. Pediatr Crit Care Med 2013;14:657-65; and Willson DF, Truwit JD,
Conaway MR, et al. The adult calfactant in acute respiratory distress syndrome trial. Chest 2015;148:356-64.

ARDS and Ventilator-Associated Events

 Table 1-4. Cost of Beractant, Calfactant, and Poractant Therapya
Beractant
WAC per vial 8-mL vial = $677.88
Cost of single dose 4 mL/kg 32 kg = 128 mL
Rounded to whole vial = 16
vials
Cost per dose = $10,846.08
Cost of studied 128 mL 4 doses = 512 mL
treatment course Rounded to whole vial = 64
vials 8 mL
Cost per treatment course =
$43,384.32
a
Calculated for a 10-yr-old boy with height 55 inches, weight 32 kg.
b
Equivalent dose based on phospholipid component; calfactant product studied contains 60 mg/mL of phospholipid; Infasurf con-
tains 35 mg/mL of phospholipid.
WAC = wholesale acquisition cost.
Information from: Willson WF, Thomas NJ, Tamburro R, et al. Pediatric calfactant in acute respiratory distress syndrome trial. Pediatr
Crit Care Med 2013;14:657-65; and Willson DF, Truwit JD, Conaway MR, et al. The adult calfactant in acute respiratory distress syn-
drome trial. Chest 2015;148:356-64.
and heterogeneous patient populations. Initial corticoste-
roid studies focused on prevention and used short courses of
high-dose corticosteroids (30 mg/kg of methylprednisolone
every 6 hours). These data did not support corticosteroid use
in the prevention of ARDS; rather, this treatment strategy may
increase the risk of developing ARDS (Deal 2008).
Subsequent investigations have used lower doses for more
prolonged courses, generally using methylprednisolone.
These investigations have sought to delineate the role of cor-
ticosteroids in both the early and late phases of the disease;
however, responses in clinical outcomes have been inconsis-
tent (Meduri 2007, 1998; Steinberg 2006). Table 1-5 compares
the treatment regimens, phase of ARDS, and outcomes.
Meta-analyses and systematic reviews have also had incon-
sistent or inconclusive results with respect to treatment effect
on mortality or resource use (Ruan 2014; Tang 2009; Peter
2008). Of interest, when evaluating the effect of steroids on
mortality in ARDS given the underlying etiology, there is an
increased risk of mortality with steroid administration in those
with influenza-related ARDS, but mortality is decreased in post-
operative patients with ARDS who receive steroids (Ruan 2014).
Data for pediatric patients are lacking. Published reports of
corticosteroid use in pediatric ARDS are limited to three case
reports and one case series of six patients. Similar to the data
available in adult patients, dosing regimens, time since onset
of the syndrome to initiation of corticosteroids, and underly-
ing cause of ARDS vary greatly. The combination of the lack
of data and variability prevents the ability to form conclusions
on the use of corticosteroids in pediatric patients with ARDS
PedSAP 2016 Book 2 Pediatric Critical Care
Calfactantb Poractant Alfa
6-mL vial = $671.11 3-mL vial = $764.40
~0.85 mL/cm 139 cm = 118 0.6252.5 mL/kg = 2080 mL
mL Rounded to whole vial = 7 27
Rounded to whole vial = 20 vials 3 mL
vials 6 mL Cost per dose =
Cost per dose = $13,422.20 $5350.8$20,638.80
118 mL 3 doses = 354 mL Cost not calculated secondary to
Rounded to whole vial = 60 repeat doses varied greatly
vials 6 mL
Cost per treatment course =
$40,266.60
using pediatric data (Guglani 2006; Haselton 2000; Goh 1999;
Martinot 1997).
Because of an overwhelming lack of evidence in pediat-
ric patients and inconsistent evidence in adult ARDS studies,
similar to surfactant therapy, the pulmonary-specific therapy
subgroup of the PALICC strongly agreed that corticosteroids
cannot be recommended as part of routine care in PARDS
(Tamburro 2015). According to adult data, if corticosteroids
are used in PARDS, moderate- to low-dose prolonged therapy
courses should be used. In addition, initiating this therapy is
likely most useful in the late phase, but initiation should occur
on or before day 13 of onset of the syndrome. Pending addi-
tional data, corticosteroids for ARDS should be avoided in
patients with influenza-related ARDS.
Consequences of Corticosteroid Use in the
Critically Ill Patient
Concerns with corticosteroid use in critically ill patients with
ARDS include risk of infection, hyperglycemia, and neuromus-
cular weakness. In randomized controlled trials, the risk of
infection has not been identified more commonly in the corti-
costeroid treatment group than in the control groups (Meduri
2007; Steinberg 2006; Meduri 1998). Both hyperglycemia and
neuromyopathy have been identified as occurring more com-
monly in methylprednisolone-treated patients (Steinberg 2006).
VENTILATOR-ASSOCIATED EVENTS
Enhancing the quality of medical care through prevent-
ing health careassociated infections is imperative in
20 ARDS and Ventilator-Associated Events
 Table 1-5. Randomized Controlled Trials of Methylprednisolone in Adult ARDS

Meduri 1998 Steinberg 2006 Meduri 2007

Number of subjects 24 180 91

Methylprednisolone (n=16) Methylprednisolone (n=89) Methylprednisolone (n=63)

Phase of ARDS Late Late Early

Time since onset of 7 days 728 days Within 72 hr

ARDS

Dosing regimen Day 1: 2 mg/kg loading
dose 1
(mg/kg PER dose) Days 114: 0.5 mg/kg q6hr
Days 1521: 0.25 mg/kg q6hr
Days 2228: 0.125 mg/kg q6hr
Days 2930: 0.063 mg/kg q6hr
Days 3132: 0.031 mg/kg q6hr
Note: Patients extubated
before day 14 were advanced
to day 15 and weaned
Day 1: 2 mg/kg loading
dose 1
Days 114: 0.5 mg/kg q6hr
Days 1521: 0.5 mg/kg q12hr
Note: Those still intubated
at day 21 were tapered over
4 days. If extubated by day
21, or developed infection
weaned over 2 days
Day 1: 1 mg/kg loading dose x 1
Days 114: 1 mg/kg
Days 1521: 0.5 mg/kg
Days 2225: 0.25 mg/kg
Days 2628: 0.125 mg/kg
Note: Patients extubated before day 14
were advanced to day 15 and weaned
Administered as continuous infusion,
transitioned to daily oral dose, once
possible

Oxygenation Significant improvement in PF Significant improvement in NR

ratio by day 5 PF ratio at days 3 and 14

LIS Significant improvement by NR Significantly more likely to have

day 5 improvement at day 7

Mortality Significantly higher in the No difference No difference

placebo group Higher risk of mortality in
methylprednisolone group
for those enrolled at > 14
days after ARDS onset

ICU length of stay NR Significantly shorter Significantly shorter

MV Significantly shorter duration Significantly shorter Significantly more likely to be extubated

duration by day 7

LIS = lung injury score; NR = not reported; q = every.

Information from: Meduri GU, Golden A, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized
controlled trial. Chest 2007;131:954-63; Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persis-
tent acute respiratory distress syndrome. N Engl J Med 2006;354:1671-84; and Meduri GU, Headley AS, Golden E, et al. Effect of
prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA
1998;280:159-65.

optimizing care for patients and minimizing resource use.
Ventilator-associated pneumonia is one such health care
associated infection that must be considered for surveillance
and prevention. At this time in PICUs, VAP is the only ventila-
tor-associated event (VAE) that is considered for surveillance.
However, this current state of quality surveillance is being
evaluated to ensure that an objective and outcomes-focused
definition is used.
Defining VAP in Pediatric Patients
Ventilator-associated pneumonia is a device-related, report-
able, health careassociated infection. Definitions of VAP
vary depending on the patients age. Figure 1-2 delineates
the current pediatric surveillance definition for the pneumo-
nia-reporting module (CDC 2016a). Applying this definition is
contingent on meeting the criteria for a health careassoci-
ated infection, which states that the date of occurrence must
be on or after the third calendar day of an inpatient admis-
sion. In patients receiving mechanical ventilation on the date
of the occurrence, the event must occur more than 2 calen-
dar days from the date of tracheal intubation to be considered
ventilator associated. In addition to these criteria, further lab-
oratory assessments primarily concerning lower respiratory
tract specimens can be used in determining VAP. Concerns

PedSAP 2016 Book 2 Pediatric Critical Care 21 ARDS and Ventilator-Associated Events
 Patients 1 yr
Chest imaging with one of the following:
1. New or progressive and persistent infiltrate
2. Consolidation
3. Cavitation
4. Pneumatoceles
Clinical signs and symptoms including:
Worsening gas exchange
PLUS three of the following:
1. Temperature instability
2. Leukocytosis, leukopenia, or left shift
3. Respiratory secretion findings: New-onset
purulent sputum, change in sputum
character, increase in respiratory secretions,
or increase in suctioning requirements
4. Apnea, tachypnea, nasal flaring with
retractions, or grunting
5. Wheezing, rales, or rhonchi
6. Cough
7. Bradycardia or tachycardia
Figure 1-2. Hospital-acquired/ventilator-associated pneumonia clinical criteria for infants and children.
Information from: CDC. CDC/NHSN Surveillance Device-Associated Module: Pneumonia (ventilator-associated and non-ventilator-
associate pneumonia) Event. 2016.
with the complexity and subjectivity of this definition are dis-
cussed later in this section.
Prevalence, Outcomes, and Associated Cost of
VAP in Pediatric Patients
Reported rates of VAP vary depending on the reference, likely
because of inter-reporter variability in data collection and
interpretation (Phongjitsiri 2015). Regardless, VAP is a com-
mon cause of health careassociated infections in pediatric
patients requiring mechanical ventilation. The most current
report of the device-associated module, which includes VAP,
from the National Healthcare Safety Network summarizes sur-
veillance data from January to December 2013. This report
provides VAP data from 134 pediatric locations including 14
cardiothoracic critical care units (CCUs), 10 medical CCUs, and
110-combined medical-surgical CCUs. The overall ventilator
use ratio, defined as the total number of ventilator-days to total
patient-days, was 0.37, with a VAP rate of 0.67 cases per 1000
ventilator-days (Dudeck 2015). This rate is less than the rates
reported in the literature. A recent multicenter, prospective
evaluation, which used the CDC surveillance definition current
PedSAP 2016 Book 2 Pediatric Critical Care
Patients > 1 yr to 12 yr
Chest imaging with one of the following:
1. New or progressive and persistent infiltrate
2. Consolidation
3. Cavitation
Clinical signs and symptoms including at
least three of the following:
1. Fever or hypothermia
2. Leukopenia or leukocytosis
3. Respiratory secretion findings such as:
New-onset purulent sputum, change in
sputum character, increase in respiratory
secretions, or increase in suctioning
requirements
4. New-onset worsening cough OR dyspnea,
apnea, or tachypnea
5. Rales or bronchial breath sounds
6. Worsening gas exchange
at the time of data collection, identified a VAP prevalence in the
PICU of 7.1 cases per 1000 ventilator-days (Gupta 2015).
Health careacquired infections, including VAP, can be
associated with worse outcomes and increased health care
costs. Ventilator-associated pneumonia in pediatric patients
has been associated with a significant increase in PICU length
of stay, duration of mechanical ventilation, and mortality
(Gupta 2015; Bigham 2009). Even when controlling for sever-
ity of illness, PICU patients who develop VAP are 3 times more
likely to die than are those who did not develop the infection
(Gupta 2015). In addition to these worse outcomes, increased
health care use results in increased health care cost. The
VAP-attributable cost in pediatric patients has been reported
at about $50,000 per incident (Brilli 2008).
CURRENT QUALITY OF CARE
SURVEILLANCE
Because of concerns with the complexity and subjectivity of
the surveillance definitions for VAP, surveillance in adult insti-
tutions was redirected in 2013. The goal was to develop a more
22 ARDS and Ventilator-Associated Events
objective and reliable approach, resulting in a refocus on VAEs
when the surveillance is prompted by worsening oxygenation
as opposed to chest radiograph changes (CDC VAE 2016).
Currently, pediatric units continue to report device-associ-
ated events according to the VAP definition (see Figure 1-2),
whereas adult units report VAEs. Pediatric reporting is only for
PICU areas. Neonatal ICUs can track VAP internally, but VAP is
no longer part of the surveillance plan option to be analyzed
by the National Healthcare Safety Network. The surveillance
definition used for reporting is determined by the location,
not the age, of the patient undergoing surveillance. Thus, a
patient 18 years or younger in an adult unit would report by the
VAE module, and a patient 18 years or older in a pediatric unit
would report by the pneumonia module (CDC 2016a, 2016b).
Differences in Adult vs. Pediatric Surveillance
The pediatric pneumonia surveillance definition is a single-tier
approach, initiated by changes in chest radiography. The adult
VAE surveillance definition is a three-tier approach that is initi-
ated secondary to indicators of worsening oxygenation after at
least 2 calendar days of respiratory improvement or stability.
Thus, the adult approach focuses on a change in respiratory
clinical status as opposed to less objective changes in chest
radiography. Streamlining and enhancing the objectivity of
the surveillance definition in pediatric patients will hopefully
allow for automation of surveillance in the future. In compari-
son, the pediatric VAP definition is far less objective. Table1-6
compares the current pediatric and adult unit surveillance
modules. For completeness, the table includes criteria that
were used to assess ventilator-associated tracheobronchitis
(VAT) in studies discussed later in the chapter.
Classification of VAEs
Ventilator-associated events are further delineated into
ventilator-associated conditions (VACs), infection-related
ventilator-associated conditions (IVACs), and possible ventila-
tor-associated pneumonia (PVAP). After initiating mechanical
ventilation, calendar day 3 is the earliest an event may occur
that can meet the criteria of a VAE on day 4 of mechanical
ventilation.

Table 1-6. Comparison of Ventilator-Associated Event Criteria

PedVAP VAT VAC IVACa PVAP

Worsening after Not considered Not considered Required Required Required

stability or
improvement

Chest imaging Change in chest No change in chest Not Not considered Not considered
imaging required imaging considered

Change in Fio2 No specific criteria Not considered Specific for Specific for Specific for worsening
but worsening gas worsening worsening oxygenation
exchange oxygenation oxygenation
1 yr: required
112 yr: optional

Change in PEEP No specific criteria Not considered Specific for Specific for Specific for worsening
but worsening gas worsening worsening oxygenation
exchange oxygenation oxygenation
1 yr: required
112 yr: optional

WBC Leukocytosis, 12 yr: 12 103 cells/ 12 103 cells/mm3 OR

leukopenia, or left- 15 103 cells/ mm3 OR < 4 103 cells/mm3
shift ( 1 yr) mm3 OR < 4 103 cells/
< 4 103 cells/mm3 mm3
> 12 yr:
12 103 cells/
mm3 OR
< 4 103 cells/mm3

Temperature 1 yr: instability > 38C OR > 38C OR > 38C OR

112 yr: fever or < 36C < 36C < 36C
hypothermia

(continued)

PedSAP 2016 Book 2 Pediatric Critical Care 23 ARDS and Ventilator-Associated Events
 Table 1-6. Comparison of Ventilator-Associated Event Criteria (continued)

PedVAP VAT VAC IVACa PVAP

New antimicrobial Not considered Not considered Started and Started and continued
continued for for 4 days
4 days

Sputum change New, changed, or Not considered Not considered

increased

Respiratory BAL: 100,000 CFU 10,000 CFU EA: 1,000,000 CFU

culture Lung tissue: BAL: 100,000 CFU
quantitationb 100,000 CFU Lung tissue: 100,000
PBS: 10,000 CFU CFU
PBS: 10,000 CFU

Sputum WBCc Not considered At least moderate 25 neutrophils AND

10 epithelial cells per
low-power field

Other positive Organism from N/A Organism from pleural

infectious pleural fluid fluid
testingd Lung histopathology Lung histopathology
showing: abscess showing: abscess
formation OR fungal formation OR fungal
infiltration infiltration
Positive Legionella Positive Legionella
Positive respiratory Positive respiratory
virus virus

Clinical symptoms Required N/A Not considered

of respiratory
distress

a
Require only that either WBC or temperature criteria be met.
b
Considered in criteria 1 and 2 for PVAP.
c
Considered in criterion 2 for PVAP.
d
Considered in criterion 3 for PVAP.
BAL = bronchoalveolar lavage; EA = endotracheal aspirate; IVAC = infection-related ventilator-associated condition; N/A = not appli-
cable; PBS = protected brush specimen; PedVAP = pneumonia criteria for pediatrics; PVAP = possible VAP; VAC = ventilator-associated
condition; VAT = ventilator-associated tracheobronchitis.
Information from: Beardsley AL, Nitu ME, Cox EG, et al. An evaluation of various ventilator-associated infection criteria in a PICU.
Pediatr Crit Care Med 2016;17:73-80; CDC. CDC/NHSN Surveillance Device-Associated Module: Pneumonia (ventilator-associated and
non-ventilator-associate pneumonia) Event; and CDC. CDC/NHSN Surveillance Device-Associated Module: Ventilator-Associated
Events. 2016.

Ventilator-Associated Conditions temperature or WBC count abnormalities plus initiation of a

After a period of stability or improvement on the ventilator,
an increase in the daily minimum Fio2 of at least 0.2 or an
increase in the daily minimum PEEP of at least 3 mm Hg is
defined as a VAC. These changes must be sustained for 2 or
more calendar days.
IVAC Complications
Patients presenting within 2 days before or after the onset
of the VAC are considered to have IVACs if they have either
new antimicrobial agent that is continued for at least 4 days.
Possible Ventilator-Associated Pneumonia
Categorization as PVAP occurs if one of three criteria is met
within 2 days before or after the onset of the VAC. The criteria
for PVAP incorporate information that may suggest an infec-
tious pathology. Concerning microbiologic data, one of three
criteria may be used to meet the definition of PVAP. Criterion
1 is a report of quantitative or semiquantitative growth from

PedSAP 2016 Book 2 Pediatric Critical Care 24 ARDS and Ventilator-Associated Events
endotracheal aspirates, bronchoalveolar lavage (BAL), lung
tissue, or protected brush specimen. Criterion 2 is purulent
respiratory secretions evaluated in combination with quanti-
tative or semiquantitative respiratory culture results that do
not meet specified quantitation thresholds. Criterion 3 are
identification of pathologic organisms from positive pleural
fluid culture, lung histology consistent with abscess or paren-
chymal invasion by fungi, Legionella, or viral testing positive
for respiratory viruses.
Utility of Surveillance Definitions
The paradigm shift in the need for a new surveillance method
in adult patients arose secondary to the fact that the cur-
rent definition used for surveillance of pneumonia is neither
sensitive nor specific. In a recent retrospective analysis, the
current pediatric VAP, IVAC, VAT, and lower respiratory tract
definitions were compared in 300 episodes of mechani-
cal ventilation in which there were 30 ventilator-associated
infections. Of the 30 infections, 9 met more than one of the
ventilator-associated infection criteria. Despite only moder-
ate overlap in the definitions with respect to diagnosis, the
risk factors for developing a ventilator-associated infection
and outcomes were similar, suggesting that each definition
has some validity (Beardsley 2016).
In adults, significant concern surrounded the use of a def-
inition in which surveillance was prompted by radiographic
findings, which may not accurately identify VAP. In addition,
the clinical signs and symptoms, although potentially useful
in diagnosis, may not consistently be documented, making
them poor surveillance features for quality improvement
endeavors. Optimizing surveillance definitions is important
in facilitating the development of optimal prevention strate-
gies (CDC 2016b).
Potential Transition of Pediatric Surveillance
Understanding that a new approach to surveillance would be
required for pediatric patients, a workgroup was convened to
explore the possibility of a new surveillance definition. This
workgroup agreed that the current surveillance definition had
room for optimization, but it was cautious about adopting the
adult definitions for VAE without further data.
A single-center, retrospective study applied the current
adult VAE definitions to a pediatric cohort. Rates of VACs
and IVACs per 1000 ventilator-days were 20.9 and 12.9
cases, respectively. Most of the patients classified as hav-
ing an IVAC were then further classified as having either
possible or probable pneumonia. Compared with those
without a VAC, patients with a VAC had a significantly lon-
ger duration of mechanical ventilation and duration of both
hospitalization and ICU length of stay, as well as a higher
risk of mortality. Immunocompromised status, tracheos-
tomy dependence, and chronic respiratory failure were
identified as independent risk factors for developing a VAC
(Phongjitsiri 2015).
PedSAP 2016 Book 2 Pediatric Critical Care
A multicenter, retrospective, matched cohort study of
PICU, cardiac ICU, and neonatal ICU was conducted to find
a pediatric VAC definition that would identify patients at risk
of worse outcomes. Worsening of oxygenation for at least 2
days after 2 days of stability or improvement was defined by
Fio2 daily increases of 0.2, 0.25, and 0.3 and mean airway pres-
sure (MAP) daily increases of 4, 5, 6, and 7 cm H2O. Patients
with a VAC were matched with patients without a VAC. Mean
airway pressure was used for this investigation because it
better reflects changes in lung compliance and allows for an
assessment of patients receiving high-frequency oscillatory
ventilation. The rate of VACs, according to these definitions,
including MAP in a multicenter approach, resulted in a sig-
nificantly lower rate of VACs of 2.93.2 cases per 1000
ventilator-days than in the 2015 single-center cohort study.
Each assessed increase in Fio2 and MAP was associated
with a greater risk of death and, among survivors, prolonged
hospitalization, time in the ICU, and duration of mechani-
cal ventilation. Outcomes assessment was consistent with
the earlier single-center cohort study (Cocoros 2016). Given
these results, the advisory committee recommended the use
of a daily minimum increase in Fio2 of 0.25 or a daily minimum
increase in MAP of 4 cm H2O for a pediatric VAC. This defini-
tion should be used in further studies to assess risk factors
and preventive measures.
Given these data and the overwhelming concern with the
current surveillance definition, it seems probable that there
will soon be a shift in the surveillance of pediatric VAP to
something consistent with the VAE surveillance now used
by adult institutions. The utility of a more objective surveil-
lance definition that identifies more than just VAP may help
enhance prevention strategies and better anticipate out-
comes in these patients.
ANTIBIOTIC STEWARDSHIP FOR IVAC
COMPLICATIONS AND VAP
While optimizing the surveillance and diagnostic criteria for
IVAC and VAP, pharmacists can focus on antimicrobial stew-
ardship for these health careassociated infections. The
primary goal is to enhance clinical outcomes while minimizing
any undue consequences (Dellit 2007). Antimicrobial stew-
ardship in IVAC and VAP can be achieved through several of
the standard strategies, including implementing institutional
guidelines or clinical pathways, minimizing combination ther-
apy when appropriate, de-escalating therapy, and optimizing
therapy duration, depending on the diagnosis and culture data.
Institutional guidelines and clinical pathways considering the
diagnostic criteria for IVAC and VAP, and an understanding of
institution and local bacterial resistance patterns, can help
facilitate the use of appropriate but not overly broad empiric
antimicrobial therapy, pending culture results.
Use of combination therapy for either empiric or targeted
therapy is a management strategy with more questions
25 ARDS and Ventilator-Associated Events
than answers. Use of combination therapy has long been
recommended as a method to prevent the emergence of
resistance, but evidence to support the routine use of this
strategy is lacking (Dellit 2007). However, use of combina-
tion therapy for empiric coverage may be appropriate in
certain instances.
At the time of publication, current guidelines for adults with
VAP recommend empiric combination therapy for patients at
risk of multidrug-resistant bacterial pathogens; however, this
set of guidelines is now more than 10 years old (ATS 2005).
Recently, two studies evaluated the outcomes for pediatric
patients with gram-negative bacteremia treated with combi-
nation antibiotics versus monotherapy. Neither study found
improved time to bacteremia resolution or mortality with
empiric combination therapy compared with monotherapy
(Berkowitz 2015; Sick 2014).
Survival benefit was identified in one study of patients
with multidrug-resistant gram-negative organisms (MDRGN),
leading the authors to conclude that in patients with risk
factors for MDRGN, empiric combination therapy may be
beneficial. Risk factors for MDRGN were a history of coloni-
zation or infection with MDRGN, exposure to broad-spectrum
antibiotic therapy in the past 30 days, prolonged current hos-
pitalization, or a high prevalence of MDRGN in the community
(Sick 2014). This list is much less extensive than that pro-
vided in the adult VAP guidelines.
An assessment of antibiotic duration in VAT in pediatric
patients identified an increased risk of subsequent develop-
ment of colonization or infection with a multidrug-resistant
organism in patients receiving combination therapy (Tamma
2011). Given these data, as well as the lack of pediatric VAP
guidelines, the outdated nature of the adult VAP guidelines,
and the risk of common combination agents (particularly ami-
noglycosides), it seems prudent for pharmacists and other
health care providers to judiciously consider which patients
should receive empiric combination therapy. Furthermore,
therapy de-escalation to the narrowest-spectrum agent(s)
should occur once culture and sensitivity data are available.
Therapy de-escalation is often hindered by the rate-limiting
step of culture speciation and susceptibility data. Progress
in developing rapid diagnostic testing that will provide both
organism and susceptibility for respiratory specimens will
facilitate earlier optimization of therapy.
Clarifying the IVAC being treated, especially when consid-
ering therapy for VAT versus VAP, can optimize the therapy
duration provided. A retrospective, cohort study of pedi-
atric patients with clinically diagnosed VAT compared the
outcome of progression with hospital-acquired pneumonia
(HAP) or VAP for prolonged ( 7 days) versus short (< 7 days)
courses of antibiotic therapy. Prolonged courses of antibiot-
ics did not provide a protective effect for progression to HAP
or VAP. Patients who received prolonged courses of antibiot-
ics were more likely to develop an infection or colonization
with a multidrug-resistant organism (Tamma 2011). These
PedSAP 2016 Book 2 Pediatric Critical Care
data support that courses of therapy less than 7 days may
be appropriate in patients with signs and symptoms consis-
tent with VAT.
Pharmacists can intervene to optimize duration of ther-
apy in patients with VAP. No pediatric data comparing
durations of antibiotics for VAP are available; however, one
randomized, prospective, double-blind study compared
treatment durations for VAP in adult patients. Patients were
randomized to receive 8 or 15 days of an antibiotic regi-
men chosen by the treating physician. No difference was
found in mortality, recurrent infections, ventilator-free days,
organ failurefree days, or length of ICU stay between the
two treatment groups. However, the 8-day group had signif-
icantly more antibiotic-free days, as would be expected. In
patients with nonfermenting gram-negative organisms (e.g.,
Pseudomonas, Acinetobacter), the risk of pulmonary infec-
tion recurrence was higher in the 8-day group; thus, for this
group, the noninferiority of 8 days could not be confirmed
(Chastre 2003).
Despite these data, it is reasonable to reassess patients
with nonfermenting gram-negative organisms at 8 days
of therapy to determine whether, given the patients clin-
ical improvement and status, the treatment duration is
appropriate. For all other patients with VAP having clinical
improvement, 8 days is a reasonable therapy duration.
STRATEGIES FOR PREVENTION
OF VAES
As with all health careassociated conditions, prevention is
key. To this point, prevention strategies for VAE are focused on
preventing infectious-related complications. As surveillance
shifts to include noninfectious VAE, expanded surveillance
will allow for the implementation of prevention strategies
for VAC. Improved surveillance may also help with determin-
ing methods to prevent progression to IVAC and VAP/PVAP.
Prevention includes a combination of reducing modifiable
risk factors (Box 1-2), when possible, and implementing pre-
vention bundles (Liu 2013; Foglia 2007).
Of the potentially modifiable risk factors that have been
identified, only the need for reintubation or self-extubation,
steroid administration, bloodstream infection, prior antibiotic
therapy, bronchoscopy, and presence of a genetic syndrome
were risk factors in a meta-analysis of VAP in the PICU (Lui
2013). Increased risk with the administration of acid-sup-
pressive therapy has been somewhat controversial. Although
there is a known increased risk of community-acquired
pneumonia with proton pump inhibitor therapy, data for
increased risk of VAP in adult patients have been inconsis-
tent (Plummer 2014). It is theorized that when the potentially
immune protective effects of gastric acid are neutralized
with acid-suppressive therapy, patients are at an increased
risk of bacterial growth in their gastric contents, which may
heighten the risk of pneumonia during periods of aspiration.
26 ARDS and Ventilator-Associated Events
 Patient Care Scenario
A 13-month-old boy born at 28 weeks gestation has
a medical history that includes chronic lung disease of
prematurity and pulmonary hypertension. He presents
to the PICU with respiratory failure secondary to respi-
ratory syncytial virus requiring mechanical ventilation.
He was discharged from the neonatal ICU at 3 months of
age and has not been readmitted; he has no recent anti-
biotic exposure. During the first 48 hours of admission,
he develops worsening respiratory status, and he is
given a diagnosis of severe ARDS. On day 6 of mechani-
cal ventilation, his temperature is 101.7F (38.7C), and
chest radiography reveals a new infiltrate. Because of
concern for developing VAP, a mini-BAL is obtained.
Considering the risk of potential drug-resistant organ-
isms and the tenets of antimicrobial stewardship, what
is the best empiric antibiotic coverage to initiate?
ANSWER
The best empiric antibiotic coverage in this patient
would be an antipseudomonal -lactam such as
cefepime or piperacillin/tazobactam plus vancomycin.
Given the duration of hospitalization, the patient would
potentially be at risk of resistant organisms. Although
duration of hospitalization may place the patient at
risk of resistant organisms, data do not support the
routine use of combination empiric therapy for gram-
negative organisms, most commonly the addition of
an aminoglycoside. Outcomes data in pediatric bacte-
remia support consideration of combination therapy in
patients with a history of colonization or infection with
MDRGN, exposure to broad-spectrum antibiotic therapy
in the past 30 days, prolonged current hospitalization,
or a high prevalence of MDRGN in the community. This
patient does not have these risk factors. As well, data do
not support that combination therapy is a strategy that
prevents the development of resistance.
1. Berkowitz NM, Spaeder MC, DeBiasi RL, et al.
Empiric monotherapy versus combination ther-
apy for Enterobacteriaceae bacteremia in children.
Pediatr Infect Dis J 2015;34:1203-6.
2. Sick AC, Tschudin-Sutter S, Turnbull AE, et al.
Empiric combination therapy for gram-negative
bacteremia. Pediatrics 2014;133:1-8.
3. Dellit TH, Owens RC, McGowan JE, et al. Infectious
Diseases Society of America and the Society of
Healthcare Epidemiology of America guidelines
for developing an institutional program to enhance
antimicrobial stewardship. CID 2007;44:159-77.
Administration of histamine-2 receptor antagonists or proton
pump inhibitors was not associated with an increased risk of
VAP in the aforementioned meta-analysis (Lui 2013).
The Institute for Healthcare Improvement (IHI) offers ven-
tilator bundle recommendations, including semirecumbent
positioning (elevating head of bed 3045 degrees), daily
sedation holidays and assessment of extubation readiness,
PedSAP 2016 Book 2 Pediatric Critical Care
Box 1-2. Potentially Modifiable Factors
That Increase VAP Riska
Acid-suppressive therapy
Bloodstream infectionb
Bronchoscopyb
Continuous enteral nutrition
Mechanical ventilation and duration > 3 days
Need for reintubation or self-extubationb
Neuromuscular blockade
Prior antibiotic therapyb
Steroid administrationb
Supine positioning
Transfusion
Transport out of PICU
Trauma
Uncuffed endotracheal tube
a
As identified in both adult and pediatric studies.
b
Identified as a risk factor in a meta-analysis of pediatric VAP
studies.
Box 1-3. Example of a Pediatric VAP
Prevention Bundle
Prevent colonization of the oropharynx, stomach, and
sinuses
Change ventilator circuit and in-line suction only when
visibly soiled
Drain condensation from the ventilator circuit every
24 hr
Rinse oral suction device after use; then store in a
nonsealed plastic bag
Use hand hygiene before and after ventilator circuit
contact
Wear gown when caring for patient if soiling from respi-
ratory secretions is expected
Provide mouth care every 24 hr
Prevent aspiration of contaminated secretions
Elevate head of bed 3045 degrees
Drain ventilator circuit before repositioning
In patients > 12 yr, use endotracheal tube with dorsal
lumen, when possible
Adapted from: Bigham MT, Amato R, Bondurrant P, et al.
Ventilator-associated pneumonia in the pediatric ICU: charac-
terizing the problem and implementing a sustainable solution.
J Pediatr 2009;154:582-7.
prophylaxis against SRMD, VTE prophylaxis, and oral hygiene
with chlorhexidine. Despite the potential increased risk of
VAP with acid-suppressive therapy, the IHI ventilator bun-
dle recommends that prophylaxis against SRMD be used in
mechanically ventilated patients when the benefits outweigh
the risks (IHI 2012). Ventilator-associated pneumonia bundles
decrease the risk of VAP in pediatric patients, and one such
27 ARDS and Ventilator-Associated Events
bundle reduced hospital cost by about $2.5 million over 2 fis-
cal years (Brilli 2008). One evaluated bundle (Box 1-3) reduced
the rate of VAP from 5.6 cases to 0.3 cases per 1000 ventila-
tor-days (Bigham 2009).
As with all prevention strategies, sustaining the use of the
prevention bundle is of utmost importance. Compliance with
the various components of the bundle described in the text that
follows waned to 78%100% 2 years after implementation, thus
delineating the need for continued follow-up and assessment of
compliance to ensure persistence with prevention strategies.
CONCLUSION
Pulmonary morbidities in pediatric patients are significant
and can lead to poor outcomes and death. Unfortunately, in
ARDS, pulmonary-specific pharmacotherapies have proven
less than successful at altering clinical outcomes. For cor-
ticosteroids, pediatric data are lacking, and the pediatric
pharmacist must have a working knowledge of adult data
to help discern corticosteroid use. Similarly, with VAE and
the shift in the surveillance process, which is likely to affect
pediatric patients in the near future, pharmacists must under-
stand the reasons for this shift as well as the new conditions
to be considered. Pharmacists should be actively involved
in VAP prevention strategies and in optimizing treatment in
patients who develop IVAC or VAP.
Practice Points
When designing evidence-based pharmacotherapy
regimens for ARDS, pharmacy practitioners should con-
sider the following:
Intensive assessment of exogenous surfactant products
has not resulted in significant improvements in patient
outcomes.
An ongoing study is assessing the effect of exogenous
surfactant on outcomes in the leukemia and stem cell
transplant populations. Previous studies have alluded to
the potential benefit in this population; thus, cautious con-
sideration and risk-benefit analysis may be considered.
In the absence of pediatric data, cautious consideration of
glucocorticoid use in both early and late phases of ARDS
may be evaluated on a patient-by-patient basis.
Pending further data, glucocorticoids should be avoided for
ARDS secondary to influenza or in those whose onset of
disease was more than 13 days before initiation of therapy.
The pharmacists role in the care of PICU patients
results in the need to:
Have an understanding of health careassociated infection
surveillance, including the concerns surrounding the cur-
rent VAP surveillance module
Use understanding of antibiotic pharmacotherapy, geo-
graphic resistance patterns, and tenets of antimicrobial
stewardship to apply the principles of judicious empiric and
targeted antibiotic use for VAP and VAT in this population
Participate in developing prevention strategies and pro-
grams for health careassociated conditions, including
VAP
PedSAP 2016 Book 2 Pediatric Critical Care
REFERENCES
ASHP Commission on Therapeutics. ASHP therapeutic
guidelines on stress ulcer prophylaxis. ASHP Commission
on Therapeutics and approved by the ASHP Board of
Directors on November 14, 1998. Am J Health Syst Pharm
1999;56:347-79.
American Thoracic Society (ATS), Infectious Diseases
Society of America. Guidelines for the management of
adults with hospital-acquired, ventilator-associated, and
healthcare-associated pneumonia. Am J Respir Crit Care
Med 2005;171:388-416.
Barr J, Fraser GL, Puntillo K, et al. Clinical practice guide-
lines for the management of pain, agitation, and delirium
in adult patients in the intensive care unit. Crit Care Med
2013;41:236-306.
Beardsley AL, Nitu ME, Cox EG, et al. An evaluation of various
ventilator-associated infection criteria in a PICU. Pediatr
Crit Care Med 2016;17:73-80.
Bembea MM, Jouvet P, Willson D, et al. Methodology of
the Pediatric Acute Lung Injury Consensus Conference.
Pediatr Crit Care Med 2015;16:S1-S5.
Berkowitz NM, Spaeder MC, DeBiasi RL, et al. Empiric
monotherapy versus combination therapy for
Enterobacteriaceae bacteremia in children. Pediatr Infect
Dis J 2015;34:1203-6.
Bigham MT, Amato R, Bondurrant P, et al. Ventilator-
associated pneumonia in the pediatric intensive care unit:
characterizing the problem and implementing a sustain-
able solution. J Pediatr 2009;154:582-7.
Brilli RJ, Sparkling KW, Lake MR, et al. The business case for
preventing ventilator-associated pneumonia in pediatric
intensive care unit patients. Jt Comm J Qual Patient Saf
2008;34:629-38.
CDC. CDC/NHSN Surveillance Device-Associated Module:
Pneumonia (ventilator-associated and non-ventilator-
associate pneumonia) Event. 2016a.
CDC. CDC/NHSN Surveillance Device-Associated Module:
Ventilator-Associated Events. 2016b.
Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs. 15
days of antibiotic therapy for ventilator-associated pneu-
monia in adults. JAMA 2003;290:2588-98.
Cheifetz IM. Pediatric acute respiratory distress syndrome.
Respir Care 2011;56:1589-99.
Cocoros NM, Kleinman K, Priebe GP, et al. Ventilator-
associated events in neonates and children a new
paradigm. Crit Care Med 2016;44:14-22.
Curley MA, Wypij D, Watson RS, et al. Protocolized sedation
vs usual care in pediatric patients mechanically ventilated
for acute respiratory failure: a randomized clinical trial.
JAMA 2015;313:379-89.
Deal EN, Hollands J, Schramm GE, et al. Role of corticoste-
roids in the management of acute respiratory distress
syndrome. Clin Ther 2008;30:787-99.
28 ARDS and Ventilator-Associated Events
Dellit TH, Owens RC, McGowan JE, et al. Infectious Diseases
Society of America and the Society of Healthcare
Epidemiology of America guidelines for developing an
institutional program to enhance antimicrobial steward-
ship. CID 2007;44:159-77.
Dudeck MA, Edwards JR, Allen-Bridson K, et al. National
Healthcare Safety Network report, data summary for
2013, device-associated module. Am J Infect Control
2015;43:206-21.
ESICM. ARDS Definition Task Force, Ranieri VM, Rubenfeld
GD, et al. Acute respiratory distress syndrome: the Berlin
definition. JAMA 2012;307:2526-33.
Ferguson ND, Fan E, Camporota L, et al. The Berlin definition
of ARDS: an expanded rationale, justification, and supple-
mentary material. Intensive Care Med 2012;38:1573-82.
Foglia E, Meier MD, Elward A. Ventilator-associated pneumo-
nia in neonatal and pediatric intensive care unit patients.
Clin Microbiol Rev 2007;20:409-25.
Goh AYT, Sekaran D, Roziah M. Corticosteroid rescue in
late paediatric acute respiratory distress syndrome.
Respirology 1999;4:295-7.
Guglani L, Jain S, Lodha R. Methylprednisolone ther-
apy in a child with unresolving ARDS. Indian Pediatr
2006;43:639-42.
Gupta S, Boville BM, Blanton R, et al. A multicentered pro-
spective analysis of diagnosis, risk factors, and outcomes
associated with pediatric ventilator-associated pneumo-
nia. Pediatr Crit Care Med 2015;16:e65-73.
Haselton DJ, Kiekamp JG, Christman BW, et al. Use of
high-dose corticosteroids and high-frequency oscil-
latory ventilation for treatment of a child with diffuse
alveolar hemorrhage after bone marrow transplantation:
case report and review of the literature. Crit Care Med
2000;28:245-8.
Institute for Healthcare Improvement (IHI). How-to Guide:
Prevent Ventilator-Associated Pneumonia. Cambridge,
MA: IHI, 2012.
Khemani RG, Smith LS, Zimmerman JJ, et al. Pediatric acute
respiratory distress syndrome: definition, incidence, and
epidemiology: proceedings from the Pediatric Acute
Lung Injury Consensus Conference. Pediatr Crit Care Med
2015;16:S23-S40.
Liu B, Li S, Zhang S, et al. Risk factors of ventilator-asso-
ciated pneumonia in pediatric intensive care unit: a
systematic review and meta-analysis. J Thorac Dis
2013;5:525-31.
MacLaren R, Jung R. Stress-dose corticosteroid therapy
for sepsis and acute lung injury or acute respiratory dis-
tress syndrome in critically ill adults. Pharmacotherapy
2002;22:1140-56.
Martinot A, Fourier C, Cremer R, et al. Short-course high-
dose corticosteroid treatment in six children with ARDS.
Pediatr Pulmonol 1997;23:314-6.
PedSAP 2016 Book 2 Pediatric Critical Care
Meduri GU, Golden A, Freire AX, et al. Methylprednisolone
infusion in early severe ARDS: results of a randomized
controlled trial. Chest 2007;131:954-63.
Meduri GU, Headley AS, Golden E, et al. Effect of prolonged
methylprednisolone therapy in unresolving acute respi-
ratory distress syndrome: a randomized controlled trial.
JAMA 1998;280:159-65.
Pediatric Acute Lung Injury Consensus Conference (PALICC),
Khemani RG, Smith LS, et al. Pediatric acute respiratory
distress syndrome: definition, incidence, and epide-
miology: proceedings from the Pediatric Acute Lung
Injury Consensus Conference. Pediatr Crit Care Med
2015;16:S1-S131.
Penn State University (PSU). CALIPSO: calfactant for pediat-
ric acute lung injury in pediatric stem cell transplantation
and oncology patients. In: ClinicalTrials.gov [Internet].
Bethesda, MD: U.S. National Library of Medicine, 2015.
Peter JV, John P, Graham PL, et al. Corticosteroids in the
prevention and treatment of acute respiratory distress syn-
drome (ARDS) in adults: meta-analysis. BMJ 2008;336:1006.
Phongjitsiri S, Coss-Bu J, Kennedy C, et al. The Centers
for Disease Control and Preventions new definitions for
complications of mechanical ventilation shift the focus
of quality surveillance and predict clinical outcome in a
PICU. Crit Care Med 2015;43:2446-51.
Plummer MP, Blaser AR, Deane AM. Stress ulceration: preva-
lence, pathology, and association with adverse outcomes.
Crit Care 2014;18:213-9.
Randolph AG. Management of acute lung injury and acute
respiratory distress syndrome in children. Crit Care Med
2009;37:2448-54.
Reiter PD, Wathen B, Valuck RJ, et al. Thrombosis risk factor
assessment and implications for prevention in critically ill
children. Pediatr Crit Care Med 2012;13:381-6.
Reveiz L, Guerrero-Lozano R, Camacho A, et al. Stress-
ulcers, gastritis, and gastrointestinal bleeding prophylaxis
in critically ill pediatric patients: a systematic review.
Pediatr Crit Care Med 2010;11:124-32.
Ruan AY, Lin HH, Huang CT, et al. Exploring the heterogeneity
of the effects of corticosteroids on the acute respiratory
distress syndrome: a systematic review and meta-analy-
sis. Crit Care 2014;18:R63.
Sapru A, Flori H, Quasney MW, et al. Pathobiology of acute
respiratory distress syndrome. Pediatr Crit Care Med
2015;16:S6-S22.
Sharathkumar AA, Mahajerin A, Heidt L, et al. Risk-prediction
tool for identifying hospitalized children with a predis-
position for development of venous thromboembolism:
Peds-Clot clinical decision rule. J Thromb Haemost
2012;10:1326-34.
Sick AC, Tschudin-Sutter S, Turnbull AE, et al. Empiric com-
bination therapy for gram-negative bacteremia. Pediatrics
2014;133:1-8.
29 ARDS and Ventilator-Associated Events
Spragg RG, Taut FJH, Lewis JF, et al. Recombinant sur-
factant protein C-based surfactant for patients with
severe direct lung injury. Am J Respir Crit Care Med
2011;183:1055-61.
Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and
safety of corticosteroids for persistent acute respiratory
distress syndrome. N Engl J Med 2006;354:1671-84.
Tamburro RF, Kneyber MCJ. Pulmonary specific ancil-
lary treatment for pediatric acute respiratory distress
syndrome: proceedings from the Pediatric Acute Lung
Injury Consensus Conference. Pediatr Crit Care Med
2015;16:S61-S72.
Tamma PD, Turnbull AE, Milstone AM, et al. Ventilator-
associated tracheitis in children: does antibiotic duration
matter? CID 2011;52:1324-31.
Tang BMP, Craig JC, Eslick GD, et al. Use of corticosteroids in
acute lung injury and acute respiratory distress syndrome:
a systematic review and meta-analysis. Crit Care Med
2009;37:1594-603.
PedSAP 2016 Book 2 Pediatric Critical Care
Taut FJH, Rippin G, Schenk P, et al. A search for subgroups
of patients with ARDS who may benefit from surfactant
therapy: a pooled analysis of five studies with recombi-
nant surfactant protein-C surfactant (Venticute). Chest
2008;134:724-32.
Venkataraman ST. Mechanical ventilation and respira-
tor care. In: Fuhrman BP, Zimmerman JJ, eds. Pediatric
Critical Care, 4th ed. Philadelphia: Elsevier, 2011.
Willson DF, Truwit JD, Conaway MR, et al. The adult calfac-
tant in acute respiratory distress syndrome trial. Chest
2015;148:356-64.
Willson WF, Thomas NJ, Tamburro R, et al. Pediatric calfac-
tant in acute respiratory distress syndrome trial. Pediatr
Crit Care Med 2013;14:657-65.
Yehya N, Servaes S, Thomas HJ. Characterizing the degree
of lung injury in pediatric acute respiratory distress syn-
drome. Crit Care Med 2015;43:937-46.
30 ARDS and Ventilator-Associated Events
Self-Assessment Questions
Questions 17 pertain to the following case. C. PF ratio less than 200 and PEEP of 5 cm H2O or
E.S. is a 5-year-old boy (height 42 inches, weight 31 kg) who greater, moderate PARDS
received a stem cell transplant for hemophagocytic lym- D. PF ratio less than 200 and PEEP of 5 cm H2O or
phohistiocytosis. However, despite initial engraftment, E.S. greater, severe PARDS
experienced graft rejection. He. is admitted to the PICU with
2. On day 2 of intubation and mechanical ventilation, E.S.s
signs and symptoms consistent with septic shock. His blood
oxygenation continues to worsen; his OI is now 18, and
cultures are positive for gram-negative rods, and he is initiated
the team is considering a transition to high-frequency
on meropenem and amikacin. On PICU day 1, despite bilevel
oscillatory ventilation (HFOV). Because of the patients
positive airway pressure (BiPAP), his respiratory status contin-
worsening clinical status, the PICU attending would like
ues to deteriorate. E.S. is intubated for impending respiratory
to discuss administering calfactant. Which one of the
failure. He is initiated on continuous infusion fentanyl and mid-
following best justifies administering a single dose of
azolam for pain and sedation management during mechanical
calfactant by endotracheal tube for E.S.?
ventilation. He is maintained NPO (nothing by mouth) and is ini-
tiated on intravenous pantoprazole for stress-related mucosal A. His oxygenation status is worsening, and surfactant
disease (SRMD) prophylaxis. Over the first 24 hours in the PICU, has consistently shown sustained improvements in
his oxygenation continues to worsen. Morning chest radiogra- oxygenation.
phy is consistent with new bilateral infiltrates. His ventilator B. With an immunocompromised host, surfactant has
settings and arterial blood gas are as follows: shown a potential improvement in clinical outcomes.
C. Because he developed acute respiratory distress
syndrome (ARDS) from an indirect lung injury,
Ventilator settings Arterial blood gas
surfactant is most likely to be beneficial.
SIMV-VC pH = 7.26 D. With the impending need for HFOV, surfactant may
Rate = 18 Pco2 = 61 be used as a strategy to prevent the need to escalate
Fio2 = 0.55 Pao2 = 99 mechanical ventilation support.
Ti = 0.8 Bicarbonate (calcu-
3. On day 8 of mechanical ventilation, E.S.s oxygenation
Positive inspiratory pressure (PIP) = lated) = 27
has not improved clinically, and his PARDS is still cate-
41 cm H2O Sao2 = 97
gorized as severe. Which one of the following drugs is
Set Vt = 200 mL
best to recommend for E.S.?
Positive end-expiratory pressure
(PEEP) = 10 cm H2O A. Calfactant 80 mL/m2 by endotracheal tube once
PS = 10 cm H2O B. Methylprednisolone 60 mg intravenously every 12
Paw = 18 cm H2O hours
C. Inhaled nitric oxide 20 ppm continuous
Blood culture data: Three of three sets of cultures are posi- D. Albuterol 2.5 mg nebulized every 4 hours
tive for Klebsiella pneumonia susceptibility data as follows:
4. Which one of the following strategies would best prevent
ventilator-associated pneumonia (VAP) in E.S.?
Susceptible Intermediate Resistant
A. Discontinue pantoprazole, assess safety of daily
Amikacin ( [MIC] Imipenem (MIC Cefepime (MIC 64) sedation awakening, elevate head of the bed to 30
= 16) = 2) Gentamicin (MIC 16) degrees, change ventilator circuit every 24 hours,
Tigecycline Levofloxacin (MIC 8) and provide routine oral care with chlorhexidine.
(MIC = 4) Meropenem (MIC = 8) B. Continue pantoprazole, assess safety of daily
Piperacillin/tazobac- sedation awakening, elevate head of the bed to 15
tam (MIC 128) degrees, change ventilator circuit every 24 hours,
Tobramycin (MIC 16) and provide routine oral care with chlorhexidine.
C. Continue pantoprazole, assess safety of daily
1. Given his clinical signs and symptoms and his clinical sedation awakening, elevate head of the bed to 30
and laboratory data, which one of the following best degrees, change ventilator circuit when visibly soiled,
describes E.S.s diagnosis? and provide routine oral care with chlorhexidine.
D. Discontinue pantoprazole, assess safety of daily
A. Oxygenation index (OI) = 10, moderate pediatric
sedation awakening, elevate head of the bed to 15
acute respiratory distress syndrome (PARDS)
degrees, change ventilator circuit when visibly soiled,
B. OI = 10, severe PARDS
and provide routine oral care with chlorhexidine.

PedSAP 2016 Book 2 Pediatric Critical Care 31 ARDS and Ventilator-Associated Events
5. On day 14 of mechanical ventilation, E.S. develops a
new consolidation on chest radiography. Despite previ-
ous improvements in oxygenation, his Fio2 requirement
is increasing this morning, and he is febrile (tempera-
ture 102.2F [39C]). His WBC is 1.57 x 103 cells/mm3. A
mini-BAL is obtained, and Gram stain shows few WBCs
and rare gram-negative rods. Which one of the following
best describes E.S.s clinical criteria for a diagnosis of
VAP?
A. New consolidation on chest radiography, worsening
gas exchange, febrile
B. Worsening gas exchange, febrile, leukopenia
C. New consolidation on chest radiograph, worsening
gas exchange, mini-BAL Gram stain positive for
gram-negative rods
D. Worsening gas exchange, febrile, mini-BAL Gram
stain positive for gram-negative rods
6. Given his historical data and the new information, which
one of the following regimens is most appropriate to rec-
ommend for E.S.?
A. Cefepime and amikacin
B. Imipenem/cilastatin and amikacin
C. Cefepime and tobramycin
D. Imipenem/cilastatin and tobramycin
7. On hospitalization day 16 for E.S., the culture results
from the mini-BAL done 2 days earlier return:
Mini-BAL: Many WBCs, no epithelial cells > 100,000 CFU/
mL Klebsiella pneumoniae Susceptibilities:
Susceptible: Amikacin (MIC = 2), cefepime (MIC = 1),
ciprofloxacin (MIC = 1), levofloxacin (MIC = 1), merope-
nem (MIC 0.25), piperacillin/tazobactam (MIC = 16)
Resistant: Ceftriaxone, gentamicin (MIC 16), tobramy-
cin (MIC 16)
During this period, E.S.s oxygenation has improved clin-
ically. Given his clinical status and culture data, which
one of the following is best to recommend for E.S.?
A. Ciprofloxacin, complete a total antibiotic course of 8
days
B. Ciprofloxacin, complete a total antibiotic course of
15 days
C. Cefepime, complete a total antibiotic course of 8
days
D. Cefepime, complete a total antibiotic course of 15
days
PedSAP 2016 Book 2 Pediatric Critical Care
Questions 810 pertain to the following case.
K.M. is a 2-year-old girl (weight 15 kg) with a medical his-
tory positive for trisomy 21, complete atrioventricular canal
after repair at 6 months, and mild pulmonary hypertension.
She presents to the PICU with respiratory distress requiring
full face mask BiPAP, for which she is receiving dexmedeto-
midine infusion to enhance tolerance of therapy. Her BiPAP
settings are 10 cm H2O/6 cm H2O with an Fio2 of 60%, and her
current Sao2 is 85%. K.M.s respiratory viral diagnostics are
positive for influenza A.
8. Which one of the following best describes K.M.s oxygen-
ation impairment?
A. PF ratio = 140
B. SF ratio = 140
C. PF ratio = 7
D. SF ratio = 7
9. K.M.s condition continues to worsen on BiPAP, and she
requires intubation for mechanical ventilation. Given her
OI, she is classified as having severe PARDS. The attend-
ing physician requests beractant administration for
PARDS secondary to pneumonia. Which one of the fol-
lowing responses to this request would be best for K.M.?
A. Beractant is not FDA labeled for this indication;
the medical team should submit an emergency
Investigational New Drug application before use.
B. Exogenous surfactant does not improve clinical
outcomes and is not recommended for use in
PARDS.
C. Calfactant is a better choice of surfactant product
than beractant to treat ARDS.
D. Exogenous surfactant cannot be used beyond the
neonatal period because of the excessive instillation
volume.
10. On intubation day 14, K.M. continues to require signifi-
cant ventilator support, and the team would like to initiate
methylprednisolone by the Meduri protocol. Which one
of the following is best to recommend for K.M.?
A. Do not use corticosteroids in this patient with ARDS.
B. Use an alternative dosing protocol that has been
reported in pediatric patients.
C. Use hydrocortisone at doses equivalent to the
methylprednisolone dosing protocol.
D. Provide frequent blood glucose monitoring.
11. Which one of the following statements best describes
the risk and benefits of using corticosteroids in adult
patients with ARDS?
A. High-dose methylprednisolone may be beneficial
in the prevention of ARDS, but patients should
be closely monitored for the development of new
infections.
32 ARDS and Ventilator-Associated Events
 B. Low- to moderate-dose methylprednisolone is
associated with a higher risk of death when used
in the late phase of ARDS and places patients at an
increased risk of infections.
C. High-dose methylprednisolone may be beneficial
in the prevention of ARDS, but patients should be
closely monitored for neuromuscular weakness.
D. Low- to moderate-dose methylprednisolone may
beneficial in the late phase of ARDS when initiated
before day 14 of illness, but patients should be
monitored closely for neuromuscular weakness.
12. A 15-year-old girl is admitted to an adult ICU after a coil-
ing arteriovenous malformation; she remains intubated.
Which one of the following is the best quality reporting
approach for this patient?
A. Given her age, reporting should occur by the device-
related pneumonia module. Surveillance reporting
begins on day 1 of mechanical ventilation.
B. Given her age, reporting should occur by the device-
related pneumonia module. Surveillance reporting
begins on day 3 of mechanical ventilation.
C. Given her location, reporting should occur by the
device-related ventilator-associated event (VAE)
module. Surveillance reporting begins on day 1 of
mechanical ventilation.
D. Given her location, reporting should occur by the
device-related VAE module. Surveillance reporting
begins on day 3 of mechanical ventilation.
13. Which one of the following statements best supports
reevaluating the current reporting structure for the
device-related pneumonia module used in pediatric
units?
A. Clinical criteria used for surveillance reporting are
consistently documented in the medical record.
B. Change in oxygenation after a period of stability is
an objective measure of clinical deterioration.
C. Chest radiography is likely to accurately identify
VAP.
D. Clinical criteria used for surveillance reporting are
objective.
Questions 1416 pertain to the following case.
K.N. is a 19-month-old boy (weight 8.3 kg) with a medical
history of very long-chain acyl-coenzyme A dehydrogenase
deficiency. He was admitted to the PICU for respiratory failure
secondary to respiratory syncytial virus (RSV) bronchiolitis.
He was subsequently intubated and placed on continuous
infusions of fentanyl and midazolam for pain and sedation
management. Before this hospitalization, K.N. had been rel-
atively healthy. His home acid suppression of ranitidine was
continued. He remained intubated for a prolonged course
because of weakness, and the care team planned to place a
PedSAP 2016 Book 2 Pediatric Critical Care
tracheostomy. Now, on day 16 of mechanical ventilation, 2
days before his scheduled tracheostomy, K.N. is febrile (tem-
perature 101.3F [38.5C]). The volume and thickness of his
secretions have not changed. A mini-BAL is sent. His chest
radiography is stable with no signs of new infiltrate. K.N.s
WBC is 10.5 103 cells/mm3. His ventilator parameters remain
stable, and K.N. continues to oxygenate well.
14. Given his clinical signs and symptoms, which one of the
following diagnoses is K.N. most likely to receive?
A. Ventilator-associated tracheobronchitis
B. Ventilator-associated condition (VAC)
C. VAP
D. Infection-related VAC (IVAC)
15. The Gram stain from K.N.s mini-BAL specimen shows
moderate WBC and gram-negative rods. The team wishes
to initiate antibiotic therapy, pending culture results. K.N.
has not received any antimicrobial therapy during this
hospitalization. Which one of the following is the most
appropriate empiric antibiotic regimen for K.N?
A. Ceftriaxone plus gentamicin
B. Ceftriaxone
C. Cefepime plus gentamicin
D. Cefepime
16. On day 2 of K.N.s antimicrobial therapy, the following
culture data become available:
Mini-BAL: Moderate WBCs, no epithelial cells
> 10,000 CFU/mL Pseudomonas aeruginosa
Pan-susceptible
K.N.s chest radiography continues to be without signs
of a pneumonia, and his oxygenation has not worsened.
Which one of the following therapy durations (in days) is
best to recommend for K.N.?
A. 5
B. 10
C. 15
D. 21
17. Empiric combination therapy for gram-negative organ-
isms may not be needed in all patients initiated on
antibiotic therapy for IVACs or VAP. Assuming a low risk
of MDRGN (multidrug-resistant gram-negative organ-
isms) from the community, in which one of the following
patients would combination empiric coverage best be
initiated?
A. A previously healthy 7-month-old boy, mechanically
ventilated 3 days for respiratory failure secondary to
RSV bronchiolitis
B. A previously healthy 14-year-old boy, mechanically
ventilated for 6 days secondary to a traumatic brain
injury
33 ARDS and Ventilator-Associated Events
 C. A 6-year-old girl receiving induction chemotherapy Second, you are asked to develop a plan to identify which
for acute lymphocytic leukemia, mechanically pediatric patients should receive venous thromboembolism
ventilated for 8 days secondary to septic shock (VTE) prophylaxis.
D. A 12-year-old girl with asthma, mechanically
19. In which one of the following Homefield patients would
ventilated for 2 days secondary to an acute asthma
it be most appropriate to discontinue SRMD prophylaxis
exacerbation
while the patient is receiving mechanical ventilation?
18. The new model of device-related event reporting for ven-
A. A patient who sustained multiple traumatic injuries,
tilated adult patients is a multi-tier approach for which
including a severe traumatic brain injury, who is
surveillance is initiated on the basis of changes in oxy-
receiving continuous jejunal feeding
genation versus change in chest radiography. A similar
B. A patient with chronic respiratory failure, receiving
set of surveillance definitions will likely be developed
gastric feeding, who has not received acid-
for pediatric patients, with the recommendation to use
suppressive therapy chronically
mean airway pressures (MAPs) instead of PEEP. Which
C. A patient with Guillain-Barr syndrome receiving
one of the following best justifies this change?
pulse dose steroids (methylprednisolone 1000 mg x
A. MAP allows the surveillance definition to be used in 3 doses) and gastric feeding
the evaluation of patients receiving HFOV. D. A patient with acute-on-chronic hepatic failure who
B. PEEP is a better marker of lung compliance. has now developed acute kidney injury, receiving
C. MAP is more affected by worsening gas exchange in jejunal feeding
pediatric patients.
20. Which one of the following responses is best to give the
D. PEEP use is inconsistent among pediatric
Homefield Hospital working group regarding the request
intensivists.
to identify patients who should receive VTE prophylaxis?
A. No patients; pediatric patients are not at an
Questions 19 and 20 pertain to the following case.
increased risk of VTE.
Homefield Childrens Hospital is part of a large health system.
B. No patients; although some might be at an
As the PICU pharmacist, you serve on a quality committee
increased risk of VTE, no data support that
responsible for developing a VAP prevention bundle. The
prophylaxis mitigates this risk in pediatric patients.
working groups plan is to incorporate bundle recommenda-
C. Adolescent patients with known risk factors for
tions from both IHI and the literature. You have been tasked
developing VTE and no contraindications: should
with two areas of the bundle. First, as a means of mitigat-
receive at least mechanical prophylaxis.
ing modifiable risk factors, you are asked to identify patients
D. All immobilized pediatric patients as long as they
in whom discontinuing SRMD prophylaxis is acceptable.
have a normal platelet count.

PedSAP 2016 Book 2 Pediatric Critical Care 34 ARDS and Ventilator-Associated Events
Learner Chapter Evaluation: ARDS and Ventilator-Associated Events.
As you take the posttest for this chapter, also evaluate the
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
1. The content of the chapter met my educational needs.
2. The content of the chapter satisfied my expectations.
3. The author presented the chapter content effectively.
4. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
5. The content of the chapter was objective and balanced.
6. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
7. The content of the chapter was useful to me.
8. The teaching and learning methods used in the chapter
were effective.
9. The active learning methods used in the chapter were
effective.
10. The learning assessment activities used in the chapter
were effective.
11. The chapter was effective overall.
PedSAP 2016 Book 2 Pediatric Critical Care
Use the 5-point scale to indicate whether this chapter pre-
pared you to accomplish the following learning objectives:
12. Using the definitions for acute respiratory distress syn-
drome (ARDS), classify a patients pulmonary morbidity.
13. Analyze available data to design an appropriate phar-
macotherapy plan, including exogenous pulmonary
surfactant or the use of corticosteroids, for pediatric
patients with ARDS.
14. Analyze the current definition of ventilator-associated
pneumonia to determine the need for surveillance, and
measure quality of care in pediatric ICU patients.
15. Evaluate deficiencies in current surveillance definitions
and justify expanded surveillance in pediatric units to
include other ventilator-associated conditions.
16. For ventilator-associated infections in the pediatric ICU,
design antimicrobial therapy plan that uses the narrow-
est-spectrum antibacterial agents for a duration that
minimizes antibacterial exposure.
17. Justify a prevention strategy for ventilator-associated
events in the pediatric ICU including, but not limited to,
implementation of a ventilator-associated pneumonia
bundle.
18. Please provide any specific comments related to any
perceptions of bias, promotion, or advertisement of
commercial products.
19. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
35 ARDS and Ventilator-Associated Events
Hemodynamic Instability

By Regine L. Caruthers, Pharm.D.

Reviewed by Ashley R. Schappell, Pharm.D., BCPS; and Michael A. Maccia, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Distinguish between the four types of shock using physical examination findings and laboratory measurements.
2. Classify the types of fluid used in resuscitating the patient with hypovolemic shock.
3. Justify the use of an inotrope or vasopressor in the treatment of circulatory shock.
4. Account for the mechanisms by which circulatory shock occurs.
5. Distinguish between hypertensive urgency and hypertensive emergency.

INTRODUCTION
ABBREVIATIONS IN THIS CHAPTER
Hemodynamic instability, also known as shock, reflects a state of
CO Cardiac output
inadequate perfusion and oxygenation (Kleinman 2010; Mitrovic
PE Pulmonary embolism
2010; Weil 2005). Although there are many causes of shock, they can
VAD Ventricular assist device
all be categorized under one of the following types: hypovolemic,
Table of other common abbreviations. obstructive, cardiogenic, or distributive (Weil 2005). Hypovolemic
shock is the most common type reported in children and is the lead-
ing cause of mortality in pediatric patients in the United States and
the world (Pasman 2015; Kleinman 2010). Early recognition and diag-
nosis of shock can significantly decrease morbidity and mortality
(Pasman 2015).
Signs and symptoms depend on the phase of shock, which can be
classified as compensated, decompensated, and/or irreversible. In
compensated shock, the body tries to maintain perfusion and oxy-
genation (i.e., cardiac output [CO] and perfusion pressure) and is
thus associated with tachycardia, increased systemic vascular resis-
tance, cool and pale extremities, prolonged capillary refill (greater
than 2 seconds), weak peripheral pulses, and normal blood pressures
(Kleinman 2010). Decompensated shock results when compensatory
mechanisms fail to maintain adequate CO and end-organ perfu-
sion, which ultimately leads to profound hypotension and the need
for pharmacologic treatment (Table 2-1) (Kleinman 2010). Signs of
this decompensated state include altered mental status, decreased
urine output, metabolic acidosis, tachypnea, weak central pulses,
weak-to-absent peripheral pulses, and skin mottling (Mtaweh 2013;
Kleinman 2010). Irreversible shock is a state beyond decompensated
shock in which death is inevitable, despite appropriate resuscitation
(McKiernan 2005).

PedSAP 2016 Book 2 Pediatric Critical Care 37 Hemodynamic Instability

HYPOVOLEMIC SHOCK renin, and aldosterone (Mitronvic 2005). Hypernatremia, hyper-
Hypovolemic shock results from a deficiency in intravascu- chloremia, increased BUN/SCr ratio, and an increase in base
lar blood volume and thus, an inability to maintain CO and deficit and lactate are also characteristics of hypovolemic
end-organ perfusion (Mitrovic 2010). Disease states associ- shock. Symptoms on presentation vary with the etiology and
ated with this specific type of shock include trauma, surgery, degree of hypovolemic shock but may include increased thirst,
GI bleeding, gastroenteritis, burns, diabetes insipidus, heat nausea, weakness, light-headedness, and dizziness.
stroke, and capillary leak with third spacing. The mainstay of treatment for hypovolemic shock is fluid
Signs of hypovolemic shock include hypotension, tachycar- resuscitation with crystalloid solutions, with sodium con-
dia, increased systemic vascular resistance (vasoconstriction), centrations approximating normal sodium values (i.e., 0.9%
tachypnea, and decreased urine output; the specific compen- sodium chloride) and lactated Ringer solution (DiPiro 2011).
satory mechanisms in the hypovolemic state can be attributed Selection of a sodium-containing intravenous fluid is based
to an increase in the secretion of catecholamines (epinephrine, solely on clinician preference. Because of the large amount
norepinephrine), vasopressin, angiotensin II, glucocorticoids, of fluid needed to correct the intravascular volume deficit,
smaller boluses repeated over time achieve hemodynamic
stability more safely and efficiently; this is therefore the rec-
ommended practice (McKiernan 2005). This recommendation
is especially pertinent when caring for patients with heart fail-
BASELINE KNOWLEDGE STATEMENTS
ure and those at risk of pulmonary edema. The clinician should
Readers of this chapter are presumed to be familiar consider administering several fluid boluses at 1020 mL/kg.
with the following: Colloid solutions (e.g., 5% and 25% albumin) and hydroxyethyl
Knowledge of normal ranges of vital signs in starch are safe and effective treatment options but have not
children been shown to be more advantageous than crystalloid solutions
Baseline knowledge of inotropes and vasopressors in the treatment of hypovolemic shock. Colloid solutions are not
Basic knowledge of anticoagulant and antiplatelet recommended as the preferred treatment option because of
therapies their higher cost and lack of additional benefits. Resuscitation
Understanding of prehypertension, stage 1 with blood products is no more effective than other colloid solu-
hypertension, and stage 2 hypertension for age, tions and, in fact, poses issues including an increase in blood
sex, and height percentile in pediatric patients
viscosity, immunomodulatory concerns, and infection risk.
Table of common pediatric laboratory reference values.
OBSTRUCTIVE SHOCK
ADDITIONAL READINGS Major impediments to pulmonary and systemic blood flow
ultimately impair CO and end-organ perfusion, resulting in
The following free resources are available for readers obstructive shock (Mitronic 2010; Weil 2005). Common causes
wishing additional background information on this
topic.
McKiernan CA, Lieberman SA. Circulatory shock in
Table 2-1. General Dosing of Vasopressor and
children: an overview. Pediatr Rev 2005;26:451-60.
Inotropic Agents
Monagle P, Chan AKC, Goldenberg NA, et al.
Antithrombotic therapy in neonates and children:
Initial Dose Dosing Range
antithrombotic therapy and prevention of thrombo-
sis: American College of Chest Physicians Dopamine 25 mcg/kg/min 220 mcg/
evidence-based clinical practice guidelines. Chest kg/min
2012;141(suppl 2):e737S-e801S.
Epinephrine 0.010.05 mcg/ 0.012 mcg/
National High Blood Pressure Education Program kg/min kg/min
(NHBPEP) Working Group on High Blood Pressure
in Children and Adolescents. The fourth report on Milrinone 0.25-0.3 mcg/ 0.25-0.75 mcg/
the diagnosis, evaluation, and treatment of high kg/min kg/min
blood pressure in children and adolescents.
Norepinephrine 0.020.05 mcg/ 0.022 mcg/
Pediatrics 2004;114(suppl 2):1-22.
kg/min kg/min
Overgaard CB, Dzavik V. Inotropes and vasopres-
sors: review of physiology and clinical use in Phenylephrine 0.050.1 mcg/ 0.050.5 mcg/
cardiovascular disease. Circulation kg/min kg/min
2008;118:1047-56.
Vasopressin 0.00010.0002 0.00010.002
unit/kg/min unit/kg/min

PedSAP 2016 Book 2 Pediatric Critical Care 38 Hemodynamic Instability

of obstructive shock include acute pulmonary embolism (PE),
tension pneumothorax, and cardiac tamponade (Pasman 2015;
Weil 2005). Signs and symptoms of obstructive shock depend
on the cause of obstruction. The following discussion focuses
on acute PE and the development of obstructive shock.
Pulmonary embolism is a rare but potentially fatal disease
in children (Van Ommen 2006). The nonspecific and often
masked symptoms of PE (e.g., shortness of breath, pleuritic
chest pain, hemoptysis, persistent tachypnea) make the diag-
nosis difficult and the disease easy to overlook (Patocka 2012;
Biss 2008; Van Ommen 2006). The definitive diagnosis of PE
can be made using several imaging modalities, including pul-
monary angiography, ventilation-perfusion lung scanning,
helical CT, MRI, and echocardiography (Patocka 2012).
Clinical manifestations of PE with hemodynamic instability
can occur when an acute thrombus occludes more than 50%
of the pulmonary circulation (Van Ommen 2006). An acute PE
negatively affects the integrity and function of the right and left
ventricles of the heart. Impaired ventricular function is a con-
sequence of the following cascade of events (Figure 2-1). Left
anticoagulants continue to have a place in treatment because
of the risks associated with thrombolytic therapy and embo-
lectomy. Unfractionated heparin is preferred because of
its pharmacokinetic profile (i.e., shorter half-life); however,
low-molecular-weight heparins can be used to stabilize
the thrombus and prevent enlargement, of which enoxa-
parin has the most pediatric clinical data (Monagle 2012).
Unfractionated heparin should be titrated to a goal activated
PTT correlating with an anti-factor Xa (anti-Xa) of 0.350.7
unit/mL. Subcutaneous enoxaparin doses should be adjusted
to obtain an anti-Xa of 0.51 unit/mL achieved 46 hours
after a dose is administered. Table 2-2 lists initial dose rec-
ommendations for heparin and enoxaparin.
Table 2-2. Initial Dosing Recommendation for
Heparin and Enoxaparin in the Treatment of Pulmonary
Embolism
Age Initial Dose

ventricular dysfunction alters CO and leads to systemic hypo- Heparin < 1 yr Bolus: 75 units/kg over 10 min
tension and inadequate perfusion to the periphery. Altered Continuous infusion: 28 units/kg/hr
coronary perfusion with subsequent myocardial ischemia
> 1 yr Bolus: 75 units/kg over 10 min
can occur in the setting of right-sided heart failure and hypo- Continuous infusion: 20 units/kg/hr
tension (Van Ommen 2006; Smulders 2000). Other signs of
Enoxaparin < 2 mo 1.5 mg/kg/dose SC q12hr
hemodynamic instability during an acute PE include cyanosis,
dysrhythmia, pallor, and syncope (Patocka 2012). > 2 mo 1 mg/kg/dose SC q12hr
Prompt dissolution using thrombolysis or removal by
embolectomy is the treatment of choice for PE with hemo- q = every; SC = subcutaneously.
dynamic instability (Van Ommen 2006). Despite this goal,

Acute increase in Increase in right

Dilation of the
right ventricular ventricular and
right ventricle
afterload pulmonary artery
systolic pressures

Abnormal filling of Leftward shift of Right-sided heart

the left ventricle the intraventricular failure and tricuspid
during diastole septum regurgitation

Hypotension and
Altered cardiac
inadequate
output
systemic perfusion

Figure 2-1. Pulmonary embolism and hemodynamic instability.

Information from Smulders YM. Pathophysiology and treatment of haemodynamic instability in acute pulmonary embolism: the
pivotal role of pulmonary vasoconstriction.Cardiovasc Res 2000;48:23-33; Van Ommen CH, Peters M. Acute pulmonary embolism in
childhood.Thromb Res2006;118:13-25; and Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the
golden hour of hemodynamically significant pulmonary embolism.CHEST 2002;121:877-905.

PedSAP 2016 Book 2 Pediatric Critical Care 39 Hemodynamic Instability

 When thrombolytic therapy is considered, alteplase is the
agent of choice for pediatric patients (Monagle 2012). Other
thrombolytic agents (i.e., urokinase and streptokinase) are
effective for clot resolution. However, previous concerns
about urokinases efficacy, as well as concerns about fibrin
specificity and immunogenicity of urokinase and streptoki-
nase, have made them second-line agents (Monagle 2012;
Gupta 2001; PHS 1999). Alteplase is the drug of choice in
pediatric patients; although optimal dosing of intravenous
alteplase has not been explained, 0.5 mg/kg/hour is the dose
most commonly reported (Monagle 2012; Wang 2003).
Data comparing low-dose alteplase (0.010.06 mg/kg/
hour) with standard-dose alteplase (0.10.5 mg/kg/hour)
are limited to small cohort studies and single-center expe-
riences. One of these studies evaluated and compared the
efficacy and safety of low- and standard-dose alteplase in the
treatment of arterial and venous thrombi. Thirty-five patients
were enrolled, and complete clot resolution occurred in 97%
of patients with acute thrombi (17 of 17 patients in the low-
dose group and 11 of 12 patients in the standard-dose group);
all six patients with chronic thrombi had partial resolution.
One patient had a major bleed (Wang 2003). The decision to
use low-dose versus standard-dose alteplase is based on
patient characteristics (e.g., age, symptoms, clot size), risks,
and benefits. Adult dosing (100 mg over 2 hours) should be
considered in larger pediatric patients.
CARDIOGENIC SHOCK
Cardiogenic shock occurs when impaired myocardial con-
tractility results in decreased stroke volume, CO, and systemic
hypoperfusion (Pasman 2015; Subramaniam 2012; Tobias
1996). Common causes of cardiogenic shock include arrhyth-
mias, cardiomyopathies, myocarditis, and congenital heart
disease (Pasman 2015; McKiernan 2005). Compensatory
mechanisms include activation of the renin-angiotensin-
aldosterone system to increase fluid retention, sympathetic
activation to increase contractility, and peripheral vaso-
constriction to perfuse only the vital organs (Long 2015).
Symptoms of compensated cardiogenic shock are tachycar-
dia, cool skin, decreased peripheral pulses, and deceased
urine output (Long 2015; Subramaniam 2015).
Treatment options include drugs to acutely improve con-
tractility of the heart, CO, and blood pressure. A combination
of milrinone and a vasopressor agent is the recommended
treatment. Milrinone increases myocardial contractility and
provides afterload reduction, improving CO without increas-
ing oxygen consumption (Kirk 2014; Bailey 1999; Chang
1995). The potential for hypotension exists but usually does
not outweigh the benefits of milrinone. Despite the paucity
of data in pediatric patients, dopamine and epinephrine are
routinely used to improve cardiac contractility and increase
systemic vascular resistance. In a subgroup analysis, dopa-
mine was associated with increased mortality at 28 days in
PedSAP 2016 Book 2 Pediatric Critical Care
adult patients with cardiogenic shock compared with norepi-
nephrine (De Backer 2010). In the absence of pediatric data,
clinicians have begun to consider the negative findings in the
adult population and to preferentially use epinephrine as the
first-line inotropic agent.
When drugs fail to stabilize blood pressure and restore
perfusion to the vital organs, mechanical circulatory support
with extracorporeal membrane oxygenation or an extracor-
poreal ventricular assist device (VAD) may be needed (Kirk
2014; Mitaweh 2013). These modalities help unload the ven-
tricles, decrease myocardial demand, improve coronary
perfusion, and stabilize hemodynamics to reestablish sys-
temic perfusion (Kirk 2014; Subramaniam 2012). Mechanical
circulatory support can be used as a bridge to transplanta-
tion, candidacy for transplantation, or recovery. It can also be
destination therapy (i.e., long-term support on a VAD when
candidacy for transplantation is limited or nonexistent); this
is becoming increasingly possible with improved VAD tech-
nologyis center-dependent and not routinely recommended
thearpy ng strategies (high and low dose). The previous state-
ment includes thi.
The advances in VAD technology and the use of VAD
in pediatric patients do not parallel the trend in adults
(VanderPluym 2014). Even so, six VADs are currently avail-
able for use in pediatric patients (Table 2-3). Anticoagulation
and antiplatelet therapies pose the most significant chal-
lenges for pharmacists caring for patients on a VAD. There is
a fine balance between clot formation and bleeding complica-
tions in this patient population, and the optimal approach has
yet to be explained. Anticoagulants of choice include hepa-
rin, low-molecular-weight heparins, and warfarin. Heparin is
most often used in the immediate postoperative period, with
eventual transition to warfarin for chronic anticoagulation.
The target for unfractionated heparin is an anti-Xa activity of
0.350.7 unit/mL and an INR of 23 for most VADs. The role of
low-molecular-weight heparins varies and is limited by renal
clearance and long half-life in the immediate postoperative
period. Scant pediatric data limit the use of other anticoag-
ulants, including fondaparinux, apixaban, and rivaroxaban.
Dual antiplatelet therapy with aspirin and dipyridamole or
clopidogrel is the standard of care. Monitoring with throm-
boelastography studies is center-dependent and has not yet
been incorporated into the clinical practice guidelines and
recommendations.
DISTRIBUTIVE SHOCK
Distributive shock is caused by inappropriate relaxation
of peripheral vascular tone and profound vasodilation that
results in increased venous capacitance, relative hypovole-
mia with no actual fluid loss, and decreased preload (Pasman
2015; Mitrovic 2010). A decrease in preload (i.e., filling vol-
umes) leads to a decrease in stroke volume, which ultimately
decreases CO and end-organ perfusion. Common causes
40 Hemodynamic Instability
 Table 2-3. VADs Used in Pediatric Patients

Ventricular Assist Device Population for Use Uses

Berlin Heart (EXCOR) Infants LVAD, RVAD, BiVADa

Smaller children

Thoratec VAD (IVAD/PVAD)b Children with BSA > 1.5 m2 LVAD, RVAD, BiVAD

HeartMate II Children with BSA 1.4 m2 LVAD

HeartWare HVAD Children with BSA 1.1 m2 LVAD

Total artificial heart Children with BSA 1.7 m2 Replaces both ventricles

HeartAssist 5 pediatric VAD (formerly the Children 516 yr with BSA 0.71.5 m 2
LVAD
DeBakey VAD Child)

a
Can support one or two ventricles in any anatomic arrangement
b
VAD not commonly used because of improved technology.
BiVAD = biventricular assist device; BSA = body surface area; LVAD = left ventricular assist device; RVAD = right ventricular assist
device; VAD = ventricular assist device.
Information from: Kirk R, Dipchand AI, Rosenthal DN. The International Society for Heart and Lung Transplantation Guidelines for
the management of pediatric heart failure. J Heart Lung Transplant 2014;33:888-909; and VanderPluym C, Urschel S, Buchholz H.
Advanced therapies for congenital heart disease: ventricular assist devices and heart transplantation. Can J Cardiol
2013;29:796-802.

include sepsis, drug intoxications, anaphylaxis, and neuro-
logic injury, including head and spinal injuries (Tobias 1996).
Sepsis and septic shock are the most common cause and
form of distributive shock and are associated with significant
morbidity and mortality.
Anaphylaxis describes a state in which the bodys
response to an allergic reaction is excessive. During anaphy-
laxis, the mast cells and basophils become unstable and leak
vasoactive mediators, including histamine, heparin, tryptase,
chymase, and tumor necrosis factor , into the smooth mus-
cles of the lung, heart, and systemic vasculature (Kirkpatrick
2008; Brown 2007; Fisher 1992). This can lead to wheezing,
shortness of breath, decreased tone of the blood vessels,
decreased blood pressure, skin flushing, hives, vomiting, diar-
rhea, decreased myocardial contractility, bradycardia, and
third spacing (Brown 2007; Heytman 2004; Adams 2001). Any
combination of these symptoms can decrease CO and oxy-
genation; however, the changes in vascular tone and cardiac
function are most often associated with the development of
anaphylactic shock (Brown 2007).
Treatment of anaphylactic shock differs from that of ana-
phylaxis (i.e., antihistamine, corticosteroids, intramuscular or
subcutaneous epinephrine). Treatment of anaphylactic shock
focuses on the symptomatic treatment of myocardial dys-
function and the hypovolemic state secondary to the change
in venous capacitance and third spacing. First-line treat-
ment options include continuous infusion epinephrine and
aggressive fluid resuscitation; second-line options include
norepinephrine or phenylephrine and atropine (Hussain 2008;
Brown 2007; Brown 2004; Fisher 1986). The inotropic effects
of continuous infusion epinephrine are more beneficial than
its vasopressor effects in anaphylactic shock.
Although the mechanism and pathophysiology of cardio-
vascular collapse are poorly understood, cardiac support and
stabilization with improvement in heart contractility and CO are
pivotal in minimizing lethal outcomes (Brown 2007). Aggressive
volume resuscitation with 20 mL/kg of normal saline increases
intravascular volume, preload, stroke volume, and ultimately
CO. On rare occasions, other agents have been needed to
completely normalize venous capacitance. In case reports,
phenylephrine and norepinephrine are second-line options
that have been used with variable outcomes. Vasopressin and
metaraminol (unavailable in the United States) have also been
effective in case reports (Heytman 2004; Kill 2004; Schummer
2004). Atropine can be used in sustained bradycardia, despite
treatment with inotropic and vasopressor agents.
Neurogenic shock is defined as the presence of hypoten-
sion and relative bradycardia after head and high-level spinal
cord injury (often at the cervical or high thoracic level); com-
pensatory tachycardia is not present in neurogenic shock
(Breslin 2012; Guly 2008; Cocchi 2007). Neurogenic shock
is a diagnosis of exclusion that results from the sudden loss
of sympathetic autonomic activity followed by vasodilation,
decreased venous capacitance, altered CO, hypotension,
and bradycardia (Summers 2013; Mitrovic 2010; ACS 2008).
Treatment options include intravenous fluids to improve CO
and vasopressors and inotropes to improve vascular tone
(Kirkpatrick 2008; Cocchi 2007). Use of vasopressors and
inotropes should be withheld until fluid resuscitation is com-
plete (Kirkpatrick 2008).

PedSAP 2016 Book 2 Pediatric Critical Care 41 Hemodynamic Instability

 Table 2-4. Intravenous Antihypertensive Agents

Bolus Dose Initial Dosing Dosing Range Additional Information

Enalaprilat None 0.05 mg/kg/dose 0.050.1 mg/kg q6hr Can cause acute renal failure and
as an IV bolus Max 1.25 mg/dose hyperkalemia

Esmolol 100500 mcg/kg 25-100 mcg/kg/min 100500 mcg/kg/min Monitor to avoid profound
Max 80 mg/dose bradycardia

Fenoldopam None 0.2 mcg/kg/min 0.20.8 mcg/kg/min Increases intracranial pressure

Hydralazine None 0.1 mg/kg/dose q46hr 0.10.2 mg/kg/dose

Max 20 mg/dose q46hr
Max 20 mg/dose

Labetalol 0.11.0 mg/kg 0.251 mg/kg/hr 0.253 mg/kg/hr Intermittent doses at 0.31 mg/kg/
Max 40 mg/dose dose can also be used

Nicardipine None 0.5-1 mcg/kg/min 13 mcg/kg/min Increases intracranial pressure

Nitroprusside None 0.3-0.5 mcg/kg/min 0.510 mcg/kg/min Monitor cyanide and thiocyanate
concentrations with doses greater
than 1.8 mcg/kg/min, prolonged
use or in renal failure to minimize
toxicity

Phentolamine None 0.1 mg/kg/dose 0.10.2 mg/kg/dose

Max 5 mg/dose

Information from: Lexicomp; Chandar J, Zilleruelo G. Hypertensive crisis in children. Pediatr Nephrol 2012;27:741-51; and National
High Blood Pressure Education Program (NHBPEP) Working Group on High Blood Pressure in Children and Adolescents. The fourth
report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114:1-22.

HYPERTENSIVE URGENCY hydralazine, labetalol, nicardipine, and sodium nitroprusside

AND EMERGENCY
Pediatric hypertensive urgency and emergency are defined
by an acute change in blood pressure well above the 99th
percentile for age, sex, and height. Hypertensive urgency
is usually associated with nausea and vomiting but poses
no risk to end-organ function (Chandar 2012). In contrast,
a hypertensive emergency is usually associated with more
severe symptoms, including encephalopathy and seizures,
and can lead to rapid end-organ damage. End-organ dam-
age can result in congestive heart failure, encephalopathy, or
renal failure (Patel 2012; NHBPEP 2004). Although pediatric
hypertension usually develops secondary to renal or cardiac
etiologies, a pediatric hypertensive emergency is angioten-
sin-dependent and has been associated with high vascular
reactivity, elevated concentrations of norepinephrine and
vasopressin, and decreased concentrations of vasodilating
hormones (Chandar 2012).
Only intravenous drugs should be used in the treatment of
a hypertensive emergency, unlike hypertensive urgencies, in
which intravenous or oral medications can be used (NHBPEP
2004). The most effective and commonly used treatment
options for a hypertensive emergency include esmolol,
(Chandar 2012; Patel 2012). Other treatment options include
phentolamine, fenoldopam, and enalaprilat (Chandar 2012).
Selection depends on the underlying cause of hypertension
and the clinicians comfort and preference (Table 2-4). Goals
of therapy include no more than a 25% reduction in blood
pressure within 8 hours of initiating treatment, followed by a
slower decrease in blood pressure over the next 2448 hours
(Chandar 2012; NHBPEP 2004).
Hypertensive urgency and emergency rarely occur in pedi-
atric patients. Prompt treatment with appropriate monitoring
is needed to minimize end-organ damage.
CONCLUSION
Hemodynamic instability reflects a complex of decreased
or inadequate perfusion and oxygenation. Causes of hemo-
dynamic instability include hypovolemia, primary cardiac
dysfunction, trauma with spinal cord injury, hyperacute
response to anaphylaxis, obstruction, and acute rise in blood
pressure. Early recognition and prompt treatment of the
underlying cause and supportive care are key in minimizing
morbidity and mortality in all forms of shock.

PedSAP 2016 Book 2 Pediatric Critical Care 42 Hemodynamic Instability


Practice Points
Hemodynamic instability is caused by a cascade of events
that ultimately result in decreased or inadequate perfusion
and oxygenation.
The four types of shock hypovolemic, cardiogenic, dis-
tributive, and obstructive have unique causes that result
in hemodynamic instability, namely hypotension.
Approaches to treatment differ for each type of shock;
prompt and appropriate treatment is key to minimizing
morbidity and mortality.
Hypertensive emergency is another form of hemodynamic
instability that requires immediate treatment with an intra-
venous antihypertensive agent.
REFERENCES
Adams HA, Baumann G, Gnsslen A, et al. Definition of shock
types. Anasthesiol Intensivmed Notfallmed Schmerzther
2001;36:S140-3.
American College of Surgeons (ACS); Committee on Trauma.
Shock: Advanced Trauma Life Support for Doctors,
Student Course Manual, 8th ed. Chicago: ACS, 2008.
Bailey JM, Miller BE, Lu W, et al. The pharmacokinetics
of milrinone in pediatric patients after cardiac surgery.
Anesthesiology 1999;90:1012-8.
Biss TT, Brendao LR, Kahr KW, et al. Clinical features
and outcome of pulmonary embolism in children. Br J
Haematol 2008;142:808-18.
Breslin K, Dewesh A. The use of methylprednisolone in
acute spinal cord injury: a review of the evidence, con-
troversies, and recommendations. Pediatr Emerg Care
2012;28:1238-45.
Brown SG. The pathophysiology of shock in anaphylaxis.
Immunol Allergy Clin North Am 2007;27:165-75.
Brown SG, Blackman KE, Stenlake V, et al. Insect sting
anaphylaxis; prospective evaluation of treatment with
intravenous adrenaline and volume resuscitation. Emerg
Med J 2004;21:149-54.
Chandar J, Zilleruelo G. Hypertensive crisis in children.
Pediatr Nephrol 2012;27:741-51.
Chang AC, Atz AM, Wernovsky G, et al. Milrinone: systemic
and pulmonary hemodynamic effects in neonates after
cardiac surgery. Crit Care Med 1995;23:1907-14.
Cocchi MN, Kimlin E, Walsh M, et al. Identification and resus-
citation of the trauma patient in shock. Emerg Med Clin
North Am 2007;25:623-42.
De Backer D, Biston P, Devriendt J, et al. Comparison of
dopamine and norepinephrine in the treatment of shock. N
Engl J Med 2010;362:779-89.
DiPiro JT, Talbert RL, Yee GC, et al. Hypovolemic shock. In:
Pharmacotherapy: A Pathophysiologic Approach, 8th ed.
New York: McGraw-Hill, 2011:chap 31.
PedSAP 2016 Book 2 Pediatric Critical Care
Fisher M. Treating anaphylaxis with sympathomimetic
drugs. BMJ 1992;305:1107-8.
Fisher MM. Clinical observations on the pathophysiology
and treatment of anaphylactic cardiovascular collapse.
Anaesth Intensive Care 1986;14:17-21.
Guly HR, Bouamra O, Lecky FE, et al. The incidence of neuro-
genic shock in patients with isolated spinal cord injury in
the emergency department. Resuscitation 2008;76:57-62.
Gupta AA, Leaker M, Andrew M, et al. Safety and outcomes
of thrombolysis with tissue plasminogen activator for
treatment of intravascular thrombosis in children. J
Pediatr 2001;139:682-8.
Heytman M, Rainbird A. Use of alphaagonists for manage-
ment of anaphylaxis occurring under anaesthesia: case
studies and review. Anaesthesia 2004;59:1210-5.
Hussain AM, Yousuf B, Khan MA, et al. Vasopressin for the
management of catecholamine-resistant anaphylactic
shock. Singapore Med J 2008;49:E225-8.
Kill C, Wranze E, Wulf H. Successful treatment of severe
anaphylactic shock with vasopressin. Int Arch Allergy
Immunol 2004;134:260-1.
Kirk R, Dipchand AI, Rosenthal DN. The International Society
for Heart and Lung Transplantation Guidelines for the
management of pediatric heart failure. J Heart Lung
Transplant 2014;33:888-909.
Kirkpatrick AW, Ball CG, DAmours SK, et al. Acute resus-
citation of the unstable adult trauma patient: bedside
diagnosis and therapy. Can J Surg 2008;51:57-69.
Kleinman ME, Chameides L, Schexnayder SM, et al. Pediatric
advanced life support: 2010 American Heart Association
guidelines for cardiopulmonary resuscitation and emer-
gency cardiovascular care. Pediatrics 2010;126:e1361-e99.
Long JD, Fairbrother HE. Pediatric Updates: Pediatric
Cardiogenic Shock. December 5, 2015.
McKiernan CA, Lieberman SA. Circulatory shock in children:
an overview. Pediatr Rev 2005;26:451-60.
Mitrovic I. Cardiovascular disorders: vascular disease. In:
McPhee SJ, Hammer GD, eds. Pathophysiology of Disease,
6th ed. New York: McGraw-Hill, 2010:chap 11.
Monagle P, Chan AKC, Goldenberg NA, et al. Antithrombotic
therapy in neonates and children: antithrombotic therapy
and prevention of thrombosis: American College of Chest
Physicians evidence-based clinical practice guidelines.
Chest 2012;141:e737S-e801S.
Mtaweh H, Trakas EV, Su E, et al. Advances in monitor-
ing and management of shock. Pediatr Clin North Am
2013;60:641-54.
National High Blood Pressure Education Program (NHBPEP)
Working Group on High Blood Pressure in Children and
Adolescents. The fourth report on the diagnosis, evalua-
tion, and treatment of high blood pressure in children and
adolescents. Pediatrics 2004;114(suppl 2):1-22.
43 Hemodynamic Instability
Pasman E. Shock in Pediatrics. 2015.
Patel NH, Romero SK, Kaelber DC. Evaluation and man-
agement of pediatric hypertensive crises: hypertensive
urgency and hypertensive emergencies. Open Access
Emerg Med 2012;4:85-92.
Patocka C, Nemeth J. Pulmonary embolism in pediatrics. J
Emerg Med 2012;42:105-16.
Public Health Service (PHS), FDA. Important Drug Warning:
Safety Information Regarding the Use of Abbokinase
(Urokinase). Rockville, MD: FDA, 1999.
Schummer W, Schummer C, Wipperman J. Anaphylactic
shock: is vasopressin the drug of choice? Anesthesiology
2004;101:1025-7.
Smulders YM. Pathophysiology and treatment of haemody-
namic instability in acute pulmonary embolism: the pivotal
role of pulmonary vasoconstriction. Cardiovasc Res
2000;48:23-33.
Subramaniam K, Boisen M, Shah PR, et al. Mechanical circu-
latory support for cardiogenic shock. Best Pract Res Clin
Anaesthesiol 2012;26:131-46.
PedSAP 2016 Book 2 Pediatric Critical Care
Subramaniam S, Rutman M. Cardiogenic shock. Pediatr Rev
2015;36:225-6.
Summers RL, Baker SD, Sterling SA, et al. Characterization of
the spectrum of hemodynamic profiles in trauma patients
with acute neurogenic shock. J Crit Care 2013;28:531.e1-5.
Tobias JD. Shock in children: the first 60 minutes. Pediatr
Ann 1996;25:330-8.
VanderPluym C, Urschel S, Buchholz H. Advanced therapies
for congenital heart disease: ventricular assist devices
and heart transplantation. Can J Cardiol 2013;29:796-802.
Van Ommen CH, Peters M. Acute pulmonary embolism in
childhood. Thromb Res 2006;118:13-25.
Weil MH. Defining hemodynamic instability. In: Pinsky MR,
Payen D, eds. Functional Hemodynamic Monitoring.
Berlin: Springer-Verlag, 2005:9-17.
44 Hemodynamic Instability
Self-Assessment Questions
Questions 2123 pertain to the following case.
E.B. is a 17-year-old female adolescent who has an atrial
septal defect after an Amplatzer device closure (6 months
ago). She was transferred to the ICU after having a cardiac
arrest at a friends house. The friend reports hearing E.B.
breathing abnormally but thought she was snoring. The
friend later found E.B. unresponsive and called paramedics,
who began CPR (cardiopulmonary resuscitation) and admin-
istered four shocks, four doses of epinephrine, and 2 g of
magnesium sulfate for torsades de pointes. E.B. was also
given one dose of naloxone. She had return of spontaneous
circulation and was intubated and transported to Childrens
Hospital. On arrival at the hospital, a non-contrast head
CT was negative. The cooling protocol was initiated. Chest
radiography revealed asymmetric opacities. Blood cul-
tures were obtained, and empiric antibiotics were initiated.
Toxicology screening was negative. An electroencephalo-
gram showed diffuse slowing. Echocardiography showed a
large thrombus versus vegetation on the right atrial side of
the Amplatzer device as well as two small thrombi versus
vegetations in the right ventricle. An ECG showed QTc 540
milliseconds. E.B. was not ill before the cardiac arrest and
had made no recent complaints of chest pain or shortness
of breath. Her vital signs on admission were blood pressure
70/45 mm Hg, heart rate 124 beats/minute, temperature
36.7C, respiratory rate 18 breaths/minute, and peripheral
capillary oxygen saturation (Sp O 2) 90%.
21. Which one of the following is the most likely cause of
E.B.s cardiac arrest?
A. Sepsis with progression to septic shock
B. Acute pulmonary embolism with progression to
obstructive shock
C. Heart failure with progression to cardiogenic shock
D. Arrhythmia with progression to cardiogenic shock
22. On presentation to the ICU, which one of the following is
best to immediately initiate to treat E.B.s hemodynamic
instability?
A. Alteplase
B. Milrinone
C. Amiodarone infusion
D. Norepinephrine
23. Which one of the following is most important to monitor
in E.B.?
A. Urine output and renal function
B. Heart rate and rhythm
C. Lactates
D. Cerebral perfusion pressure
PedSAP 2016 Book 2 Pediatric Critical Care
Questions 24 and 25 pertain to the following case.
S.S. is an 8-month-old boy referred to the ED by his pedia-
trician for further evaluation of his poor color and serum
sodium of 166 mEq/L. Three days earlier, his nasojejunal was
dislodged and found to be nasogastric (NG). As a result, S.S.
received NG feeds and had increased diarrhea. In addition,
S.S. did not receive any formula on the day of presentation to
the hospital. No recent history of fever, respiratory distress,
upper respiratory infection symptoms, vomiting, or edema
was noted. Vital signs for S.S. are Tmax 36.6C, heart rate 180
beats/minute, blood pressure 54/30 mm Hg, and Spo2 85%.
P.G.s laboratory test results include Na 164 mEq/L, K 5.1
mEq/L, Cl 131 mEq/L, CO2 24 mEq/L, SCr 0.73 mg/dL (base-
line 0.3 mg/dL), serum glucose 81 mg/dL, calcium 7.2 mg/
dL, albumin 4.4, magnesium 2.3 mEq/L, WBC 17.6 103 cells/
mm3, Hgb 14.8 g/dL, Hct 53.2%, and Plt 276,000/mm3.
24. Which one of the following best categorizes the type of
shock S.S. is experiencing?
A. Hypovolemic
B. Cardiogenic
C. Obstructive
D. Neurogenic
25. Which one of the following is best to recommend for S.S.?
A. Reinitiate his feeds at 1.5 times his normal rate
B. Fluid resuscitation with 5% albumin
C. Fluid resuscitation with 0.9% normal saline
D. Initiate dopamine
Questions 26 and 27 pertain to the following case.
J.C., a 12-year-old boy, sustains a head and neck injury after
diving into the shallow end of a swimming pool. He is taken by
emergency services to the nearest hospital.
26. Which one of the following forms of shock should the ED
staff be most concerned about in J.C.?
A. Neurogenic
B. Hypovolemic
C. Cardiogenic
D. Obstructive
27. On presentation, J.C.s vital signs are as follows: heart
rate 50 beats/minute, blood pressure 70/40 mm Hg,
respiratory rate 25 breaths/minute, and Sao2 95%. Which
one of the following is best to avoid in J.C.?
A. Fluid resuscitation
B. Phenylephrine
C. Norepinephrine
D. Milrinone
45 Hemodynamic Instability
Questions 2830 pertain to the following case.
P.J. is a 9-year-old boy who is recovering from aortic sur-
gery. His blood pressure readings have consistently been
greater than 180/90 mm Hg. P.J. is no longer responding to
commands.
28. Which one of the following best categorizes P.J.s blood
pressure?
A. Stage 1 hypertension
B. Stage 2 hypertension
C. Hypertensive urgency
D. Hypertensive emergency
29. Which one of the following is the best antihypertensive
agent to recommend for P.J.?
A. Isradipine
B. Esmolol
C. Nicardipine
D. Fenoldopam
30. Which one of the following best describes the goal of
therapy for P.J.?
A. Immediate blood pressure reduction to the normal
range
B. A 25% blood pressure reduction within 8 hours after
therapy initiation
C. Stabilization of blood pressure at the current level
D. Improvement in neurologic status
Questions 3133 pertain to the following case.
Q.T. is a 4-year-old girl who presents to the ED after consum-
ing a peanut butter and jelly sandwich at her day care center.
She has a known peanut allergy and has already received
two doses of intramuscular epinephrine. She is experiencing
respiratory distress and gasping for air; her lips are swollen,
and her body is covered with a rash. On admission, her vital
signs are Tmax 37.2C, heart rate 160 beats/minute, blood
pressure 55/45 mm Hg, and Spo2 80%.
31. Which one of the following best describes the type of
shock Q.T. is experiencing?
A. Cardiogenic
B. Anaphylactic
C. Obstructive
D. Neurogenic
32. Which one of the following is best to recommend for
immediate initiation in Q.T.?
A. Continuous infusion epinephrine
B. Dopamine
C. Intramuscular epinephrine
D. Norepinephrine
33. After receiving the recommended agent for 15 minutes,
Q.T.s vital signs are heart rate 180 beats/minute, blood
pressure 70/50 mm Hg, and respiratory rate 60 breaths/
PedSAP 2016 Book 2 Pediatric Critical Care
minute. On physical examination, Q.T. is peripherally vaso-
dilated, and wheezes can be heard on lung examination.
Which one of the following is best to recommend for Q.T.?
A. Dopamine
B. Phenylephrine
C. Intravenous fluids
D. Atropine
Questions 3436 pertain to the following case.
R.L., a 3-month-old girl, presents to the ED with projectile
vomiting. A workup for pyloric stenosis is in progress when
tachycardia is noted. Two doses of adenosine are given
without a response. An ECG and echocardiography reveal
fascicular ventricular tachycardia and a dilated left ventri-
cle with severely depressed left ventricular function. A dose
of intravenous verapamil is administered with conversion to
sinus tachycardia. R.L.s vital signs immediately afterward
are blood pressure 80/54 mm Hg, heart rate 207 beats/min-
ute, temperature 36.5C, respiratory rate 52 breaths/minute,
and Sao2 100%.
34. Which one of the following is best to initiate as a continu-
ous infusion for R.L.?
A. Milrinone
B. Enalaprilat
C. Dopamine
D. Epinephrine
35. Despite treating the arrhythmia and the echocardio-
graphic findings, R.L. continues to decompensate with
worsening heart function and more frequent runs of
fascicular ventricular tachycardia. Which one of the fol-
lowing best justifies placement of a ventricular assist
device for R.L.?
A. Bridge to recovery
B. Destination therapy
C. Bridge to transplantation
D. Bridge to determining the optimal treatment regimen
for arrhythmia
36. Which one of the following poses the greatest barrier for
dosing warfarin in R.L.?
A. Maturation of the CYP enzymes
B. Risk of bleeding
C. Formula diet
D. Lack of oral liquid formulation
Questions 37 and 38 pertain to the following case.
C.W. is a 15-year-old girl (weight 90 kg) who presents to the
pediatricians office with a 3-day history of headache and not
feeling herself. Her vital signs on presentation are tempera-
ture 37.8C, blood pressure 145/90 mm Hg, respiratory rate 20
breaths/minute, and heart rate 85 beats/minute. C.W.s medi-
cal history is significant for obesity.
46 Hemodynamic Instability
37. Which one of the following is the most likely cause of beats/minute, respiratory rate 25 breaths/minute, and Sao2
C.W.s headache? 98%. Laboratory test results are significant for the following:
Na 153 mEq/L, Cl 116 mEq/L, CO2 18 mEq/L, SCr 1.5 mg/dL
A. Tension migraine
(baseline 0.4 mg/dL), WBC 19 x 103 cells/mm3, Hct 45.2%, and
B. Elevated blood pressure
Plt 150,000/mm3.
C. Obesity
D. Viral infection 39. Which one of the following best describes the type of
shock T.C. is experiencing?
38. Which one of the following is best to recommend in the
pediatricians office to treat C.W.s headache? A. Hypovolemic
B. Cardiogenic
A. Isradipine
C. Distributive
B. Ibuprofen
E. Obstructive
C. Nicardipine
D. Diet and exercise 40. Which one of the following is best to recommend for T.C.?
A. Dopamine
Questions 39 and 40 pertain to the following case. B. Norepinephrine
T.C. is a 4-year-old boy with a medical history significant for C. Fluid resuscitation with a crystalloid solution
kidney transplantation. He presents to the ED and reports a D. Fluid resuscitation with a colloid solution
5-day history of bloody diarrhea. His vital signs are temper-
ature 39.1C, blood pressure 80/50 mm Hg, heart rate 150

PedSAP 2016 Book 2 Pediatric Critical Care 47 Hemodynamic Instability

Learner Chapter Evaluation: Hemodynamic Instability.

As you take the posttest for this chapter, also evaluate the
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
20. The content of the chapter met my educational needs.
21. The content of the chapter satisfied my expectations.
22. The author presented the chapter content effectively.
23. T
 he content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
24. The content of the chapter was objective and balanced.
25. T
 he content of the chapter is free of bias, promotion, or
advertisement of commercial products.
26. The content of the chapter was useful to me.
27. T
 he teaching and learning methods used in the chapter
were effective.
28. T
 he active learning methods used in the chapter were
effective.
29. T
 he learning assessment activities used in the chapter
were effective.
30. The chapter was effective overall.
Use the 5-point scale to indicate whether this chapter pre-
pared you to accomplish the following learning objectives:
31. D
 istinguish between the four types of shock using physi-
cal examination findings and laboratory measurements.
32. C
 lassify the types of fluid used in resuscitating the patient
with hypovolemic shock.
33. J
 ustify the use of an inotrope or vasopressor in the treat-
ment of circulatory shock.
34. A
 ccount for the mechanisms by which circulatory shock
occurs.
35. D
 istinguish between hypertensive urgency and hyperten-
sive emergency.
36. P
 lease provide any specific comments related to any
perceptions of bias, promotion, or advertisement of com-
mercial products.
37. P
 lease expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
Questions 3840 apply to the entire learning module.
38. How long did it take you to read the instructional materi-
als in this module?
39. How long did it take you to read and answer the assess-
ment questions in this module?
40. P
 lease provide any additional comments you may have
regarding this module:

PedSAP 2016 Book 2 Pediatric Critical Care 48 Hemodynamic Instability

Pediatric Critical Care II
Pediatric Critical Care II Panel

Series Editors: Joshua Caballero, Pharm.D., BCPP

Marcia L. Buck, Pharm.D., BCPPS, FCCP, FPPAG Associate Professor
Department of Pharmacy Practice
Clinical Coordinator
Nova Southeastern University, College of Pharmacy
University of Virginia Childrens Hospital
Fort Lauderdale, Florida
Professor
Department of Pediatrics Allison Lardieri, Pharm.D., BCPPS
University of Virginia School of Medicine Assistant Professor
Clinical Professor Department of Pharmacy Practice and Science
Virginia Commonwealth University School of Pharmacy University of Maryland School of Pharmacy
Department of Pharmacy Services Baltimore, Maryland
University of Virginia Health System
Charlottesville, Virginia
Kalen B. Manasco, Pharm.D., BCPS
Trauma
Clinical Associate Professor Author
Department of Clinical and Administrative Pharmacy
Joseph M. LaRochelle, Pharm. D., BCPPS
University of Georgia College of Pharmacy
Augusta, Georgia Clinical Associate Professor
College of Pharmacy
Faculty Panel Chair: Xavier University of Louisiana
Clinical Associate Professor of Pediatrics
Joseph M. LaRochelle, Pharm. D., BCPPS
Louisiana State University Health Sciences
Clinical Associate Professor Center School of Medicine
College of Pharmacy New Orleans, Louisiana
Xavier University of Louisiana
Clinical Associate Professor of Pediatrics Reviewers
Louisiana State University Health Sciences
Sara P. Rooney, Pharm.D., BCPS, BCPPS
Center School of Medicine
New Orleans, Louisiana Pediatric Intensive Care (PICU) Clinical Pharmacy Specialist
Department of Pharmacy
Childrens National Health System
Extracorporeal Circuits in Children Washington, District of Columbia
Andrea Joan Stumpe, Pharm.D., BCPS, BCPPS
Author
Clinical Pharmacist
Elizabeth J. Beckman, Pharm.D., BCPS, BCPPS, BCCCP Pharmacy Department
Clinical Pharmacy Specialist, Pediatric Critical Care Methodist Germantown Hospital
Department of Pharmacy Germantown, Tennessee
Riley Hospital for Children at Indiana University Health
Indianapolis, Indiana The American College of Clinical Pharmacy and the authors
thank the following individuals for their careful review of the
Reviewers Pediatric Critical Care II chapters:
Aaron A. Harthan, Pharm.D., BCPPS
Nicola G. Dahl, Pharm.D.
PGY-1 Residency Program Coordinator
Pediatric Critical Care Pharmacist Medical Writer
Department of Pharmacy Kanab, Utah
OSF Saint Francis Medical Center/
Childrens Hospital of Illinois
Peoria, Illinois
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Consultancies: Elizabeth J. Beckman (Lexi-Comp/Wolters/Kluwer Health); Regine L Caruthers (Lexi-Comp/Wolters Kluwer
Health); Joseph M. LaRochelle (ACCP); Lois F. Parker (ASHP/MSHP)

Stock Ownership:

Royalties:

Grants: Elizabeth J. Beckman (ASHP Foundation); Christina Cox (University of South Carolina);

Honoraria: Christina Cox (ACCP, Palmetto Health Richland Childrens Hospital); Jennifer L. Morris (ACCP, Society of Critical Care
Medicine, Pediatric Pharmacy Advocacy Group, Wolters Kluwer)

Other:

Nothing to disclose: Laura Lo Castro Bio, Joshua Caballero, Brooke Clark, Kyle Davis, Ifeyinwa D. Eboh, Elizabeth S. Goswami,
Aaron A. Harthan, Maha O. Kebir, Allison Lardieri, Michael A. Maccia, Kristine Parbuoni, Monica A. Puebla, Sara P. Rooney, Emily
L. Rowe, Ashley R. Schappell, Julie Pingel, Brandi L. Strauser, Andrea Joan Stumpe, Susan Warrington

ROLE OF BPS: The Board of Pharmacy Specialties (BPS) is an autonomous division of the American Pharmacists Association
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CONTINUING PHARMACY EDUCATION AND
RECERTIFICATION INSTRUCTIONS
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PedSAP: Target Audience: The target audience for PedSAP 2016 Book 2(Pediatric Critical Care) is pediatric pharmacotherapy spe-
cialists and advanced-level clinical pharmacists caring for pediatric patients with several acute conditions and complications of
the pulmonary, cardiovascular, endocrine, and neurologic systems.

Available CPE credits: Purchasers who successfully complete all posttests for PedSAP 2016 Book 2 (Pediatric Critical Care)
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ACSAP 2016 Book 2 Pediatric Critical Care 54 Program Instructions

Extracorporeal Circuits in Children
By Elizabeth J. Beckman, Pharm.D., BCPS, BCPPS, BCCCP

Reviewed by Aaron A. Harthan, Pharm.D., BCPPS; Joshua Caballero, Pharm.D., BCPP; and Allison Lardieri, Pharm.D., BCPPS

LEARNING OBJECTIVES

1. Account for the basic mechanics and components of extracorporeal therapies.

2. Develop a drug therapy regimen based on pharmacokinetic changes in extracorporeal therapies.
3. Design a therapeutic monitoring plan for patients receiving extracorporeal therapies.
4. Evaluate an anticoagulation strategy for patients receiving extracorporeal therapies.
5. Assess the attainment of therapeutic end points for patients receiving extracorporeal therapies.
6. Design a plan to treat common complications associated with extracorporeal therapies.

INTRODUCTION
ABBREVIATIONS IN THIS CHAPTER
Critically ill patients have pharmacokinetic and pharmacodynamic
ACT Activated clotting time
alterations that necessitate changes in medication regimens. These
AT Antithrombin
alterations include variations in medication absorption, increased
CRRT Continuous renal replacement
therapy volumes of distribution from fluid resuscitation or capillary leak, and
ECMO Extracorporeal membrane a decline in renal and hepatic function attributable to compromise of
oxygenation end-organ perfusion in shock states. Critically ill pediatric patients
FRF Filter replacement fluid require further pharmacotherapy modifications as they mature.
PMP Polymethylpentene Various extracorporeal technologies introduce an additional layer of
PVC Polyvinylchloride complexity to support critically ill children. There is often a lack of
SPAD Single-pass albumin dialysis or delay in pharmacokinetic studies using these technologies, and
TAMOF Thrombocytopenia-associated even less evidence with extracorporeal therapies in children. These
multiple organ failure supportive technologies are being modified at a rapid pace, antiquat-
TPE Therapeutic plasmapheresis ing the few pharmacokinetic data available and their application.
VA Veno-arterial The clinician must have an understanding of the pharmacokinetic
VV Veno-venous and pharmacodynamic changes in critically ill children on these sup-
portive modalities in order to provide safe, effective, and optimal
Table of other common abbreviations. medication management.
This chapter presents the basic mechanics and components
of extracorporeal membrane oxygenation (ECMO), continuous
renal replacement therapy (CRRT), and therapeutic plasmaphere-
sis (TPE) and discusses the pharmacokinetic changes that occur
with the introduction of this technology in children. In addition, liver
assist devices will be reviewed, although current clinical application
in pediatrics is absent because of the paucity of data surrounding
this novel therapy.

PedSAP 2016 Book 2 Pediatric Critical Care 55 Extracorporeal Circuits in Children

EXTRACORPOREAL MEMBRANE ECMO. One application of ECMO that is gaining traction is
OXYGENATION extracorporeal cardiopulmonary resuscitation for patients
Prevalence with cardiopulmonary arrest without return of spontane-
ous circulation for greater than 20 minutes. In addition, the
Extracorporeal membrane oxygenation is a life-sustaining
Institute of Medicine recommended in 2006 that ECMO be
modality that provides gas exchange and cardiac output
used to increase the number of viable organs for donation
in patients with cardiorespiratory failure. This device origi-
after cardiac death (Annich 2012).
nated in the 1930s with the work of Dr. John H. Gibbon, who
The continued expansion of technology and familiarity
used it in response to a patient who died of a pulmonary
with ECMO will decrease the number of relative contrain-
embolus. The modern-day ECMO circuit was pioneered by
dications to therapy. Absolute contraindications generally
adult surgeon Dr. Robert Bartlett, who was the first to use
consist of irreversible processes that evoke medical futility
ECMO support for neonates and children in 1972. Since
(e.g., lethal chromosomal abnormalities, severe neurologic
then, this technologys reach has continued to expand both
compromise, incurable malignancy). Other relative con-
domestically and internationally. As of January 2013, the
traindications (e.g., recent intracranial hemorrhage) and
Extracorporeal Life Support Organization registry listed
high-risk patients (e.g., severe multiorgan failure, coagulop-
53,000 ECMO cases with a hospital discharge survival rate of
athy) have been identified in the literature; the use of ECMO
61%. Almost 45,000 of these ECMO cases involved neonates
in these patients is often institution-dependent. Although
and children (Stang 2015).
the concern for medical futility will prohibit the use of ECMO,
exclusions will wane as the scope of extracorporeal support
Indications
expands.
Patients who receive ECMO often have a reversible cause or
a specific therapeutic destination that will alleviate the need
Circuit Characteristics
for further support. Acute respiratory failure (e.g., meconium
The ECMO circuit comprises a membrane oxygenator (arti-
aspiration syndrome, acute respiratory distress syndrome),
ficial lung), blood pump (artificial heart), heat exchanger,
acute cardiac failure (e.g., cardiomyopathy, inability to wean
and bladder/reservoir, all connected by a network of tubing
from cardiopulmonary bypass in the operating room), and
to the patient. Most of the circuit tubing consists of poly-
bridge to other destination therapies (i.e., ventricular-assist
vinylchloride (PVC) mixed with a plasticizer, di(2-ethylhexyl)
devices or solid organ transplantation) are common uses of
phthalate (DEHP), to provide flexibility. Leaching of DEHP
has been found in ECMO circuits but has been decreased
with biocompatible polymer-coated circuit elements
BASIC KNOWLEDGE STATEMENTS (Burkhart 2007). This system contains several access
points for blood product and drug infusions, as well many
Readers of the chapter are presumed to be familiar safety sensors that detect blood flow rates, pressure, and
with the following:
air in the system (Figure 1-1).
Pharmacokinetic and pharmacodynamic changes
in children
Vascular Access Points
Normal vital signs, weight and height for age, and
Extracorporeal membrane oxygenation support can be deliv-
laboratory values for children
ered using veno-arterial (VA) or veno-venous (VV) access.
Coagulation cascade and fibrinolytic system
Full cardiorespiratory support is provided by VA-ECMO,
constituents
whereas VV-ECMO provides respiratory support and allows
Table of common pediatric laboratory reference values. native cardiac output to participate. Veno-arterial access can
be transthoracic or extrathoracic. Transthoracic VA-ECMO
ADDITIONAL READINGS involves venous cannulation of the right atrium and arterial
cannulation of the ascending aorta. This type of cannula-
The following free resources have additional back- tion is used most commonly in postoperative cardiovascular
ground information on this topic:
surgery patients with sternotomy. Extrathoracic VA-ECMO
Extracorporeal Life Support Organization. ELSO involves venous cannulation through the femoral or internal
Guidelines [homepage on the Internet]
jugular vein and arterial cannulation through the femoral or
Kidney Disease Improving Global Outcomes. KDIGO
carotid artery. Veno-venous cannulation uses the internal jug-
Guidelines for Acute Kidney Injury. [homepage on
ular, femoral, or saphenous veins (Annich 2012).
the Internet]
University of Louisville Kidney Disease Program.
Circuit Priming
Drug Prescribing in Renal Failure. [homepage on
the Internet] The volume needed to prime the ECMO circuit is significant;
the neonatal circuits may need up 400500 mL to prime

PedSAP 2016 Book 2 Pediatric Critical Care 56 Extracorporeal Circuits in Children

 Oxygenated
Blood Return
(Arterial or Venous)
Heat
Exchanger
Pressure
Monitor
Membrane
Oxygenator
Heparin Venous
Infusion Blood
Port Sample
Port
Figure 1-1. Diagram of an extracorporeal membrane oxygenation (ECMO) circuit.
the tubing, membrane oxygenator, and blood pump. The
native circulating blood volume in neonates and infants is
7090mL/kg. Therefore, adding an ECMO circuit can dou-
ble or triple the total circulating volume in children weighing
less than 5 kg and increase the intravascular volume of
distribution. However, the ratio of ECMO circuit volume to
patient native blood volume generally decreases as patient
size increases.
The ECMO circuit can be primed on demand or wet pre-
primed and stored until needed. Wet pre-primed circuits are
typically primed first with CO 2 gas to displace the bubble-
inducing nitrogen, followed by normal saline to displace
CO 2 (Annich 2012). These sterile, wet-primed circuits can
be stored for up to 30 days (Walczak 2005). In general, all
ECMO circuits are initially primed with a balanced elec-
trolyte, isotonic solution that mimics extracellular fluid
composition and pH. Additional components may be added
to the circuit before ECMO initiation. For example, packed
red blood cells (PRBCs) may be added to create a circuit
hematocrit of 35%40%. Priming the circuit with blood
products requires adding heparin for anticoagulation and
calcium because of the citrated blood product. Albumin
can be added to create an oncotic load as well as to coat
PedSAP 2016 Book 2 Pediatric Critical Care
Patient Blood Drainage
(Venous)
Venous
Saturation
Bridge Sensor
Bladder/
Reservoir
Blood Pump
Pressure
Monitor
the plastic surfaces (Annich 2012). The recommended
priming solution is institution-specific and depends on the
type and size of circuit used. Neonates and smaller chil-
dren require a blood prime before ECMO initiation because
of the potential for hemodilution with the wet (bloodless)
prime solution.
Membrane Oxygenator
The membrane oxygenator functions as an extempo-
raneous lung by adding oxygen and removing CO 2 from
blood through diffusive gas exchange. Oxygen is blown
into the device and across the membrane to create a dif-
fusion gradient, in which CO 2 is passively removed across
the membrane. This oxygen gas delivery is termed sweep
and is titrated to maintain the desired Pco2. To increase CO2
clearance, the gas flow rate or sweep is increased, whereas
oxygen delivery is optimized by altering the blood flow rate
through the membrane oxygenator and hemoglobin concen-
tration (Annich 2012).
The ideal membrane is made of hydrophobic polymers
to prevent plasma leak and prolong the life of the mem-
brane. Initial membrane oxygenators were made of silicone
rubber, which afforded adequate gas exchange but had
57 Extracorporeal Circuits in Children
several disadvantages. These membrane oxygenators had
low mechanical strength and developed holes or cracks with
increased pressure or force. In addition, silicone rubber mem-
brane oxygenators had a large surface area, requiring large
priming volumes that caused an inflammatory response from
blood contact on the large surface area. Modern membrane
oxygenators are composed of polymethylpentene (PMP) hol-
low fibers coated with antithrombotic and anti-inflammatory
surfaces, which contribute to less plasma leak and improved
durability and flexibility (Stang 2015).
Blood Pump
The goal of the blood pump is to facilitate the movement of
blood throughout the extracorporeal system and the patient.
The circuit blood flow delivers oxygenated blood to the
patient and, depending on the cannulation access, may pro-
vide full cardiac output.
Two types of blood pumps are available: roller and cen-
trifugal pumps. Classically, the roller pump has been the
primary pump used to propel blood through the ECMO cir-
cuit. The roller ball is housed inside a curved raceway, which
passes over and compresses the blood tubing. This causes
an occlusion, pushes blood forward, and creates negative
pressure behind the occlusion. Most roller pump systems
use synchronized double rollers so that one roller is always
compressing the tubing, creating relatively nonpulsatile
flow. The roller pump is a reusable pumping mechanism
that can provide lower blood flow rates than centrifugal
pumps. The main disadvantage is the potential for tubing
fracture from the repeated compression, which can allow
air into the circuit.
The centrifugal pump is a newer alternative to the roller
pump and uses a spinning motor to create the rotation of the
pump with subsequent propulsion of blood. Like the roller
pump, it generates negative pressure entering the pump
and positive pressure exiting the pump. Historically, cen-
trifugal pumps have been avoided because of concern for
a higher risk of hemolysis. Recent literature suggests that
newer centrifugal pumps have similar rates of hemolysis
while decreasing the risk of air emboli compared with roller
pumps (Meyer 2012). However, a major downside of centrif-
ugal pumps is the cost because they are not reusable. Both
pumps create nonpulsatile flow in the ECMO circuit. This is an
important consideration for end-organ perfusion as well as
for the effects on drug absorption, metabolism, and elimina-
tion in the patient who lacks adequate native cardiac output,
as seen in VA-ECMO (Annich 2012).
Anticoagulation
The interaction of whole blood with the foreign surfaces
of the ECMO circuit stimulates an acute inflammatory
response, activation of platelets, and activation of the clot-
ting cascade with clot formation in the circuit and patient.
To prevent clot formation, anticoagulation therapy is
PedSAP 2016 Book 2 Pediatric Critical Care
initiated on cannulation and continued throughout ECMO.
Unfractionated heparin is the standard of practice in most
ECMO centers because of its short half-life, nonrenal elim-
ination, reversibility with protamine, and established use
in cardiopulmonary bypass (Annich 2015). Heparin binds
with antithrombin (AT) to form a complex that potenti-
ates the inhibition of activated factors IX, X, XI, XII, and II.
Antithrombin is produced in the liver and inhibits factor
Xa and thrombin. Deficiency in AT decreases unfraction-
ated heparin sensitivity, necessitating an escalation of
unfractionated heparin doses to meet therapeutic end
points. Infants younger than 1 year have decreased AT pro-
duction, which is likely the cause of the relative heparin
resistance reported (ELSO 2014). Antithrombin is found in
fresh frozen plasma (1 unit/mL) but is usually insufficient
to significantly change the AT activity level at standard
doses. Antithrombin concentrate products are available,
but expensive.
Exogenous AT supplementation has gained momentum for
the treatment of low AT activity in patients receiving ECMO.
One retrospective, multicenter study of children younger
than 18 years described a 5-fold increase in off-label AT use
(i.e., from 5% to 50%) over a 10-year period (Wong 2013).
Despite increasing use in pediatric ECMO, the results of AT
supplementation on clinical outcomes are mixed. One study
reported the AT supplementation experiences in 28 pediatric
patients receiving ECMO. This cohort had a mean age of 0.3
years and was a mixed group of primary cardiac failure and
primary respiratory failure. A statistically significant increase
in AT activity was noted at hours 8 and 24 after AT concen-
trate supplementation (baseline: 61.5 units/mL; hour 8, 96.8
units/mL; hour 24, 92 units/mL). However, there was no dif-
ference in the unfractionated heparin rate, activated clotting
time (ACT), chest tube output, or total volume of PRBC trans-
fusions (Niebler 2011).
Another center retrospectively investigated AT use in 64
children receiving ECMO. The AT supplementation group had
a mean AT activity level of 80%, but only 8% achieved the ther-
apeutic target activity of 120%. The AT cohort did show an
unfractionated heparin infusion rate drop by 10 units/kg/hour
for 12 hours after AT administration. However, both groups
had similar clot burden in the ECMO circuit and no identified
in vivo thrombosis. In addition, there was no difference in the
number of circuit changes, bleeding events, transfusions, or
ICU or hospital length of stay (Wong 2015).
In a similarly designed retrospective study of 40 pediat-
ric ECMO cases, no change in unfractionated heparin rate
with AT supplementation occurred, but the study detected
a decrease in unfractionated heparin anti-factor Xa (anti-
Xa) concentrations in the supplemented group (0.19 unit/
mL vs. 0.25 unit/mL; p<0.05). This center also reported a
greater frequency of ECMO circuit changes in the AT sup-
plementation cohort (HR 3.15; 95% CI, 1.218.16; p<0.05),
but the authors attributed the diminished circuit life to the
58 Extracorporeal Circuits in Children
subtherapeutic unfractionated heparin anti-Xa concentra-
tions (Byrnes 2014).
Instead of using a previously published bolus AT strat-
egy, one group of investigators reported their experience
with using continuous infusion AT. This observational study
compared AT dosing strategies in 11 postoperative, pediat-
ric cardiac patients receiving ECMO. Five patients received
intermittent boluses of AT to maintain an activity level greater
than 60%, and six patients received continuous infusion AT
to achieve an AT activity level above 100%. There were more
significant bleeding events in the AT bolus group than in the
continuous infusion group (3 of 5 vs. 0 of 6) (Agati 2006).
Controversy still exists regarding the role of AT supplemen-
tation in pediatric ECMO as the optimal target for AT activity,
and the ideal supplementation strategy to provide positive
clinical outcomes has not been described.
The ECMO experience with alternative parenteral antico-
agulants is not as well established as with unfractionated
heparin, but there are some theoretical advantages of using
direct thrombin inhibitors such as bivalirudin or argatroban.
These agents, without the need for AT, bind directly to both
free thrombin and clot-bound thrombin to inhibit further
clot formation. Unlike unfractionated heparin, these agents
are unaffected by fluctuations in other plasma proteins and
blood cells (ELSO 2014).
A comparative unfractionated heparin and bivaliru-
din study retrospectively investigated adult and pediatric
patients cannulated in a transthoracic fashion after cardiac
surgery and subsequently placed on VA-ECMO. Data points
were captured during the first 4 days of ECMO, even though
most had a duration beyond 96 hours (11 of 21 patients).
The patients in the bivalirudin group were older (bivalirudin
mean 36.5 19 years vs. heparin mean 13.9 29 years) but
Table 1-1. Anticoagulation Options for ECMO
Starting
Drug Initial Bolus Infusion
Unfractionated heparin 50100 units/kg 7.528.0 units/
kg/hr
Argatroban 100200 mcg/kg 0.20.75 mcg/
kg/min
Bivalirudin 0.040.14 mg/kg 0.050.3 mg/
kg/hr
ACT = activated clotting time; aPTT = activated PTT; AT = antithrombin; CRRT = continuous renal replacement therapy; ECMO =
extracorporeal membrane oxygenation.
PedSAP 2016 Book 2 Pediatric Critical Care
had statistically significant less mean blood loss (16 mL/
kg/day vs. 51 mL/kg/day) and fewer platelet transfusions
(3 mL/kg/day vs. 33 mL/kg/day) and plasma transfusions
(5.9 mL/kg/day vs. 12 mL/kg/day). Patients in the bivaliru-
din arm had a nonsignificant decline in PRBC transfusions
(15 mL/kg/day vs. 25 mL/kg/day; p=0.067). In addition, the
cost of anticoagulation (e.g., drug, blood product use, and
AT) favored bivalirudin, with an almost 50% cost reduc-
tion in both the adult and pediatric cohorts (Ranucci 2011).
Although this study had a small sample size and a hetero-
geneous age group and lacked generalizability, the results
are intriguing.
Argatroban has not been well studied in pediatric ECMO.
Case reports and small case series report relative success
with this agent in children receiving ECMO with confirmed or
suspected heparin-induced thrombocytopenia. The argatro-
ban dosing reported in these instances is wide and variable
(0.124 mcg/kg/minute) (Hursting 2006). A 2011 open-label
pediatric pharmacokinetic study reported a starting dose of
0.75 mcg/kg/minute in children younger than 16 years, with
a hepatic failure adjustment to 0.2 mcg/kg/minute (Young
2011). Adult literature suggests that doses even lower than
FDA-approved starting doses are necessary to avoid over-
anticoagulation in critically ill patients with multiorgan
dysfunction (Smythe 2009; Beiderlinden 2007).
Much is still unknown about the safety, efficacy, and ben-
efits of using direct thrombin inhibitors for anticoagulation
in pediatric ECMO. With the lack of a direct reversal antidote
and the high cost associated with these therapies, unfrac-
tionated heparin will likely remain the preferred anticoagulant
in pediatric ECMO for the immediate future. Direct thrombin
inhibitors will remain the drug of choice in heparin-induced
thrombocytopenia in ECMO (Table 1-1).
Monitoring Special Considerations
ACT, aPTT, anti-Xa Platelet administration, increased
urine output, and CRRT may
increase need; consider AT for
infusions > 35 units/kg/hr
ACT, aPTT Consider lower starting dose in
critically ill patients; lower doses
needed with hepatic dysfunction
ACT, aPTT Metabolized by blood proteases;
lower doses needed with renal
dysfunction
59 Extracorporeal Circuits in Children
 Several therapeutic monitoring avenues for ECMO anti-
coagulation are available. The ACT is a functional test of
hemostasis that measures the time in seconds needed for
whole blood to clot on exposure to an activator of the intrin-
sic pathway. This test can be performed at the bedside, with
the results provided within minutes. In addition, ACT testing
remains relatively inexpensive, providing an attractive option
for monitoring the various ECMO anticoagulation therapies.
Target ACT values of 180220 seconds are typical among
ECMO centers.
The anti-Xa concentration is a marker of anticoag-
ulation effect on factor Xa, which limits this test to
monitoring unfractionated heparin. Anti-Xa concentrations
for unfractionated heparin require a specific unfractionated
heparincalibrated assay, which is not synonymous with
the anti-Xa assay used with therapeutic drug monitoring of
low-molecular-weight heparins. The unfractionated hepa-
rin anti-Xa assay is not influenced by other coagulopathies,
hemodilution, or thrombocytopenia like ACTs. The down-
side to the anti-Xa assay is that it can be falsely lowered by
high plasma free hemoglobin, a marker of hemolysis that is
often present in ECMO. Hyperbilirubinemia, hyperlipidemia,
and AT deficiency can also affect the assay results. Goal
anti-Xa concentrations are typically 0.30.7 unit/mL for
unfractionated heparin.
Activated PTT (aPTT) is a plasma test that measures the
time to fibrin formation. It represents the activity of coagu-
lation factors XII, XI, X, IX, VIII, V, and II (prothrombin) and I
(fibrinogen). Because of alterations in the development of the
hemostatic system, infants often have a prolonged aPTT at
baseline. Therefore, the utility of using aPTT exclusively for
monitoring anticoagulation in infants receiving ECMO may be
less than ideal.
Thromboelastography (TEG) and thromboelastometry
(ROTEM) point-of-care testing are other tools that can help
characterize a patients bleeding and thrombosis risk. These
tests can measure platelet aggregation, clot strength and
stability, fibrin cross-linking time, and fibrinolysis time, all in
the presence of anticoagulants and procoagulants (Whiting
2014). This global look at a patients hemostatic system can
provide useful information, allowing the clinician to make
patient-specific therapy and monitoring plans. The out-
put is a series of tracings and numeric values that must be
interpreted in order to comprehend the coagulation and fibri-
nolysis process, which can be difficult for the novice user.
Another downside to this technology is that patient factors
(e.g., age, sex) or technical factors (e.g., sample hemodilution,
blood collection site) have been reported to influence results
(Ganter 2008; Luddington 2005). As clinicians become more
familiar with this technology, TEG and ROTEM use will likely
continue to expand outside its historical use within the oper-
ating room.
Anticoagulation monitoring in ECMO is complex and ever-
changing. The Extracorporeal Life Support Organization
PedSAP 2016 Book 2 Pediatric Critical Care
has not accepted any one therapeutic monitoring strat-
egy as the standard of practice, but rather, leaves this to
the discretion of each ECMO program. No single monitor-
ing strategy is error free; thus, a combination monitoring
strategy should be considered and tailored to the individual
patient receiving ECMO.
Antimicrobial Prophylaxis
The infection rate in neonatal and pediatric ECMO is 10.1
infections and 20.8 infections per 1000 ECMO-days, respec-
tively. Coagulase-negative Staphylococcus is the most
commonly identified bacterial organism (15.9%), followed by
Pseudomonas aeruginosa (10.5%) and Staphylococcus aureus
(9.4%). Candida infections were the most common fungal
infections reported (12.7%). Infection rates increased after 14
days of ECMO (Bizzarro 2011). The most common infection
sites are the bloodstream, followed by surgical sites, urinary
tract, and respiratory tract (OHoro 2016).
The risk of infection with percutaneous ECMO cannulation
is comparable with the risk associated with central intrave-
nous catheter placement. After sterile intravenous catheter
placement procedures, using central lineassociated blood-
stream infection tool kits and care bundles is recommended.
If surgical cutdown for cannula placement is needed, pre-
operative antimicrobial prophylaxis with a first-generation
cephalosporin to cover staphylococci and streptococci skin
flora is warranted. Patients who are cannulated by open ster-
notomy may benefit from skin flora prophylaxis to decrease
the risk of mediastinitis (Annich 2012).
At this time, the literature does not support routine anti-
biotic prophylaxis as a means to reduce the transmission of
nosocomial infections during ECMO (OHoro 2016). Similarly,
data are lacking to support infectious surveillance by daily
blood and respiratory cultures in patients receiving ECMO
(Annich 2012). Standards of care for infection control should
be used to prevent catheter-, ventilator-, and health care
associated infections.
Complications
As previously discussed, a profound inflammatory response,
hemolysis, thrombosis, and infections are all potential com-
plications of ECMO. In addition, the systemic anticoagulation
necessary in ECMO may lead to bleeding events, such as
surgical site, intracranial, GI, or mucous membrane bleed-
ing. Using subcutaneous and intramuscular administration
routes is not recommended for risk of injection-site bleeding
and hematoma.
Administration of blood products to maintain an insti-
tution-specific threshold concentration of hemoglobin,
hematocrit, platelets, and fibrinogen is commonplace in
ECMO. The antifibrinolytic agents aminocaproic acid and
tranexamic acid have been used to manage surgical site
bleeding and oozing in ECMO (ELSO 2014). These agents
work by inhibiting fibrin degradation through activity on
60 Extracorporeal Circuits in Children
plasminogen. Aminocaproic acid decreased surgical site
bleeding (from 12% to 7%) in patients receiving ECMO, with
the most profound drop in bleeding in the pediatric car-
diac surgery population (from 30% to 10%) (Downard 2003).
However, no benefit was found in using aminocaproic acid
to decrease the rate of intracranial hemorrhage in neonates
receiving ECMO (Horwitz 1998).
In another study, aminocaproic acid was associated with
thrombotic complications and an increase in the number
of ECMO circuit changes in the treatment group (p=0.02)
(Downard 2003). Tranexamic acid has shown benefit in
decreasing blood transfusion (tranexamic acid group: 1.13
mL/kg/hour; no antifibrinolytic group: 2.96 mL/kg/hour;
p=0.03) and surgical site bleeding (tranexamic acid group:
0.49 mL/kg/hour; no antifibrinolytic: 2.26 mL/kg/hour;
p=0.02) in neonates with congenital diaphragmatic hernia
repair while receiving ECMO. In addition, thrombotic com-
plications occurred at the same rate in both groups (van der
Staak 1997).
Use of activated recombinant factor VII to control refrac-
tory bleeding in ECMO remains controversial. It has been
found to reduce chest tube output and decrease blood prod-
uct transfusions in children receiving ECMO (Niebler 2010).
Conversely, both non-catastrophic and fatal thrombotic com-
plications have been reported in children and adults receiving
ECMO after activated recombinant factor VII administra-
tion (Long 2014; Syburra 2010; Chalwin 2008). The decision
to administer activated recombinant factor VII should be
entered into cautiously, weighing the risks versus benefits.
Prothrombin complex concentrates may be a viable option
to alleviate active bleeding and decrease the need for blood
transfusions. These products contain inactivated vitamin
Kdependent factors II, VII, IX, and X and protein C and S at
various concentrations, depending on the product chosen.
However, these agents are contraindicated in disseminated
intravascular coagulation and have been associated with one
adult ECMO death (Bui 2002).
Aside from hematologic complications in ECMO, envi-
ronmental complications may be prevalent. Because of the
size of the ECMO circuit and the amount of blood circulating
outside the patient in an ambient temperature environment,
heat loss can be substantial and lead to hypothermia.
Active warming of the ECMO circuit blood almost always
takes place in neonatal and pediatric patients via a heat
exchanger (see Figure 1-1). Topical warming strategies (e.g.,
heating blankets) can be effective in smaller patients, but
larger patients often require a heat exchanger that warms
the circuit blood before returning it to the patient. The goal
temperature in ECMO is normothermia (36C37.5C), unless
otherwise indicated.
Pharmacokinetic Changes
Clinical pharmacokinetic studies of ECMO are limited by small
sample sizes, variations in ECMO circuits, and complexity
PedSAP 2016 Book 2 Pediatric Critical Care
and heterogeneity of this patient population. A critically ill
child has alterations in organ function, disturbances in end-
organ perfusion, and fluctuation in fluid status. Adding ECMO
support to a critically ill child creates a new pharmacokinetic
challenge to provide optimal yet safe drug therapies.
Adsorption
Drug loss and sequestration in the ECMO circuit are well
documented and can contribute to significantly lower drug
exposures than expected. Most data on drug adsorption in the
ECMO circuit are from ex vivo studies and pharmacokinetic
modeling. To truly understand the impact of drug sequestra-
tion in the ECMO circuit, the circuit contribution and the drug
properties must be appreciated.
Most adsorption data are from silicone membrane oxy-
genators and non-coated PVC tubing, which are assumed
to sequester drug to a greater extent than present-day
materials. The presence of PVC and other plastics in the
extracorporeal circuit provides a hydrophobic site for the
migration of water-insoluble drugs. In a comparative study
of a centrifugal pump with PMP membrane oxygenator ver-
sus a roller pump with silicone membrane oxygenator, drug
recovery of fentanyl and midazolam was significantly lower
in the roller pump/silicone oxygenator circuit (fentanyl 24%
vs. 0.4% midazolam; 63% vs. 0.6%; p<0.05) (Wildschut 2010).
The authors did not explain this difference, but given other
published experiences, the silicone membrane oxygenator
may be a contributor.
In 2007, investigators reported that the PMP membrane
oxygenator did not significantly contribute to the loss of
fentanyl (around 5%); rather, the PVC tubing alone was asso-
ciated with almost 80% of fentanyl sequestration. Morphine
had similar loss in both of the circuit models (with and with-
out PMP membrane oxygenator) in this study, suggesting
that the membrane oxygenator is not the site of drug seques-
tration (Preston 2007). Coated PVC tubing tested for drug
adsorption showed no difference in the amount of mor-
phine and fentanyl lost compared with uncoated PVC tubing.
However, the rate of drug loss was different. Morphine was
sequestered to its saturation point within 5 minutes of admin-
istration, whereas fentanyl never reached a saturation point
for the duration of the 6-hour study (Preston 2010).
As the ECMO circuit ages, the surfaces may become sat-
urated, and drug loss may not be as extreme. This principle
was assessed in a newly primed circuit and a circuit that was
used on a patient for at least 48 hours. In this study, recovery
of fentanyl, morphine, and midazolam did not differ signifi-
cantly between the new and used circuit after a 180-minute
run in each (Wildschut 2010).
Drugs that are basic, nonpolar, and lipophilic tend to bind
to the ECMO circuit components and contribute to drug loss.
The logP represents the octanol-water coefficient in which
higher values denote lipophilicity and lower and negative val-
ues indicate hydrophilicity (Table 1-2).
61 Extracorporeal Circuits in Children
 Table 1-2. Drug Characteristics and Adsorption in ECMO

Drug LogPa Protein Binding (%) Drug Loss (%)

Sedatives/Analgesics
Dexmedetomidine 2.8 94 1173
Diazepam 2.82 98 88
Fentanyl 4.05 8085 70100
Hydromorphone 0.9 20 NT
Lorazepam 2.39 8591 3040
Midazolam 3.89 97 6887
Morphine 0.89 3040 2040
Propofol 3.79 9599 98
Antibiotics
Ampicillin 1.35 1018 1538
Cefazolin -0.58 7486 1548
Ceftriaxone -1.7 95 20
Ciprofloxacin 0.28 2040 4
Gentamicin -3.1 < 30 10
Meropenem -0.6 2 20
Piperacillin/tazobactam 0.3/-1.8 2633/3132 NT
Tobramycin -5.8 < 30 0
Vancomycin -3.1 55 936

a
LogP is the octanol-water coefficient. The higher the number, the higher the lipophilicity; negative logP implies hydrophilicity.
NT = not tested, no published information available for circuit adsorption of drug.

A drug with a high logP value and thus a high lipophilicity
has been associated with greater adsorption into the ECMO
circuit (Shekar 2015b). Some commonly used lipophilic drugs
in critically ill children receiving ECMO include fentanyl, ben-
zodiazepines, and other sedatives. Literature has described
fentanyl sequestration of 70%100% in ECMO circuits
(Wildschut 2010; Mehta 2007; Preston 2007). Similarly, there
are reports of significant sequestration in the ECMO circuit of
sedatives such as lorazepam, midazolam, diazepam, and pro-
pofol (Mulla 2000). The obstacle with applying these data to
present-day practice is that many of these studies were not
conducted on contemporary ECMO circuits with PMP hollow-
fiber membrane oxygenators and coated PVC tubing.
Some investigators have been funded to a complete a
multiphase pharmacokinetic study of antibiotics, seda-
tives, and analgesics in a series of modern ECMO models:
in vitro, in animals, and the final phase in adults. The first
phase, which tested 80 samples for each drug, was con-
ducted in four contemporary ECMO circuits and four control
PVC jars over a 24-hour sampling period. As expected, the
lipophilic drugs such as fentanyl and midazolam were
significantly sequestered by the ECMO circuits compared
with the PVC controls (recovered fentanyl: 3% vs. 82%; recov-
ered midazolam: 13% vs. 100%; p<0.05). Morphine recovery
in the circuit and control samples was similar, which is likely
because of its more hydrophilic properties (Shekar 2012b).
Of the antimicrobials tested ceftriaxone, caspofungin,
ciprofloxacin, fluconazole, linezolid, meropenem, and van-
comycin only meropenem showed a difference in drug
recovery between the control and circuit samples (42% vs.
20%; p<0.05) (Shekar 2015b). The authors concluded that
meropenem was not stable at the physiologic temperature
of the ECMO circuit and thus was degraded and sequestered,
leading to drug loss (Shekar 2012b). To combat adsorption
drug loss, higher doses should be considered to achieve
desired results. In addition, infusing the drug into the patient
rather than the circuit exposes the patient to the drug first
before it can be sequestered (Hoie 1993).
One additional factor to consider is the effect of ECMO on
total parenteral nutrition, specifically the lipid component. Fat
emulsions may cause issues within the ECMO circuit because
of their hydrophobic properties, including layering out of the

PedSAP 2016 Book 2 Pediatric Critical Care 62 Extracorporeal Circuits in Children

emulsion, agglutination, and clot formation. Toavoid these
complications, fat emulsions or a 3:1 total parenteral nutrition
should be administered to the patient instead of through an
ECMO circuit access point (Buck 2005).
Distribution
Volume of distribution of medication is increased in ECMO
for several reasons. Drug sequestration, as described pre-
viously, can result in increased distribution of lipophilic
compounds (Shekar 2012a). In a series of ovine ECMO mod-
els, lipophilic drugs were associated with an increased
volume of distribution at steady state (p<0.05) (Shekar
2015a). Temperature or pH fluctuations within the ECMO
system may affect the binding affinities for protein-bound
medications. An association with higher protein binding
and increased volume of distribution has occurred in ovine
models (p=0.05) (Shekar 2015a). The additional volume
of the ECMO circuit and the administration of blood prod-
ucts and other volume expanders can lead to hemodilution,
thus increasing the volume of distribution of certain drugs,
especially hydrophilic medications (Shekar 2012a). This
expanded volume for drug distribution can be significant for
achieving the desired pharmacodynamic end points. Special
attention should be paid to these medications because they
may need dosage adjustments to meet the pharmacody-
namic target (Buck 2003).
Metabolism
The liver receives pulsatile blood flow from the left side of the
heart, which produces perfusion pressure. In VA-ECMO, blood
flow is altered, causing changes in end-organ perfusion pres-
sure, which can affect the function and capacity of the organ.
Hepatic metabolism may be altered by the nonpulsatile flow
to the liver that occurs during ECMO; however, this effect has
not been quantified. Moreover, the liver end-organ perfusion
status may change if the liver was injured in the events lead-
ing up to cannulation.
Elimination
Changes in renal elimination during ECMO are likely multi-
factorial. Renal hypoxia and hemodynamic instability with
alterations in renal blood flow, injury mediated by poor per-
fusion, and inflammation can reduce renal clearance of
medications. The impact of nonpulsatile blood flow to the
kidney with VA-ECMO has been theorized to contribute to
decreased renal clearance (Buck 2003). Renal dysfunction
has also been described with VV-ECMO, which allows the
native cardiac output to provide end-organ perfusion pres-
sure (Buck 2003). Therefore, the presence of pulsatile versus
nonpulsatile blood flow may not be as contributory as previ-
ously thought. Because of the many inciting factors stated
earlier, renal clearance of medications in patients receiving
ECMO can be delayed from the patients baseline. Delayed
clearance of drugs removed by the kidney (e.g., gentami-
cin, vancomycin) has been described in neonatal patients
PedSAP 2016 Book 2 Pediatric Critical Care
receiving ECMO, leading to recommendations to extend the
administration interval (Mulla 2005; Buck 2003). The stan-
dard practice of routine serum creatinine and urine output
monitoring can provide the information necessary to guide
renal dosing adjustments in children receiving ECMO.
Management of medication therapy in patients receiving
ECMO is complex. Balancing the pharmacokinetic changes
in the critically ill child together with the effects of ECMO on
the patient and drug therapy is not easy. Specific drug dosing
recommendations for patients receiving ECMO are scarce.
Monitoring serum drug concentrations to avoid organ toxicity
and optimize therapeutic end points is prudent. When serum
drug concentrations are unavailable, titrating the drug to the
desired effect while avoiding adverse effects is a reasonable
approach.
Future Direction
The technology allowing for ECMO support continues to
evolve and bring new and exciting discoveries that will
improve outcomes. As technologies are introduced into prac-
tice, the pharmacist will be challenged to provide optimal
medication therapy with the paucity of data. An understand-
ing of how ECMO technologies interact and influence drug
adsorption, distribution, metabolism, and elimination within
the circuit and within the patient will be pivotal to providing
exceptional pharmaceutical care.
CONTINUOUS RENAL REPLACEMENT
THERAPY
Indication
Historically, the indications for hemodialysis were sum-
marized using the acronym AEIOU acidosis, electrolyte
imbalances (e.g., hyperkalemia, hyperphosphatemia,
hypercalcemia), intoxications, fluid overload, and uremia.
Continuous renal replacement therapy has been used in
acute kidney injury and in patients with chronic kidney dis-
ease who cannot tolerate intermittent hemodialysis because
of hemodynamic compromise. Treatment of fluid overload
has become a topic of discussion, given that the adult lit-
erature suggests increased mortality with fluid overload in
septic shock (Boyd 2011). Pediatric literature states that fluid
overload greater than 10% leads to increased mortality, and
the addition of hemofiltration may increase survival (Gillespie
2004; Goldstein 2001).
In recent years, there has been a shift toward using
CRRT for nonrenal indications such as systemic inflamma-
tory response syndrome and sepsis. Profound systemic
inflammatory responses create capillary leak and endothe-
lial damage from many cytokines and complement proteins
and can lead to death without adequate support. Continuous
renal replacement therapy has been evaluated for filtration
of the blood of these pro- and anti-inflammatory mediators
(Honore 2013). Mixed results have been documented with
conventional use of CRRT, and research has moved toward
63 Extracorporeal Circuits in Children
creating more adsorbent filters and columns to remove
these mediators (Honore 2013; Schetz 1999). Therefore, an
increase in CRRT use earlier in the treatment course for ill-
nesses such as septic shock or acute respiratory distress
syndrome may become more common (Schetz 1999).
Circuit Characteristics
The advantages of CRRT are providing continuous solute
and/or fluid removal in hemodynamically unstable patients.
This stems from the slower solute and fluid removal rate,
which allows CRRT use in patients who cannot tolerate fluid
shifts or the high blood flow rate of intermittent hemodialysis.
The standard of care for CRRT circuits in the United States
includes an integrated machine with pumps that control the
blood flow rate, fluid rates, and safety mechanisms (e.g., air
detectors, pressure monitors) and a balancing system that
manages fluid removal. The continuous and complex nature
of this modality requires close monitoring and nursing care to
support, thus necessitating ICU-level care.
Vascular Access
All CRRTs discussed in this chapter are VV systems. A
mechanical pump moves the patients blood forward through
the VV system. Often, the limiting step to initiating CRRT is the
availability and placement of the appropriate-sized venous
cannula. Infants weighing less than 6 kg generally have the
most difficulty with placement and maintenance of venous
access at low blood flow rates (Sutherland 2012). The site
of placement may also influence the longevity of the circuit
and success of providing CRRT. Femoral venous lines have
the most complications related to patient movement and
also carry the highest infection risk. Subclavian and internal
jugular venous cannula placement is associated with longer
circuit survival because these catheters are not as sensitive
to patient movement (Sutherland 2012).
Circuit Filter
Many hemofilters and biocompatible membranes are avail-
able for use with CRRT. These filters come in a variety of
pore sizes, but most of the high-flux membranes used in
CRRT have pore sizes of 20,00030,000 Da (Bhler 1999).
Pore size is an important attribute when considering the
passage of drugs across the dialysis membrane. Similar to
ECMO, the CRRT circuit requires blood priming for infants if
the circuit volume exceeds 15% of the patients estimated
blood volume (Sutherland 2012). This can be particularly
problematic when using an acrylonitrile-69 (AN-69) filter,
which is associated with bradykinin release syndrome. In
bradykinin release syndrome, blood encounters the AN-69
filter, ultimately leading to the release of bradykinin, a potent
vasodilator, which results in profound hypotension shortly
after initiation. Strategies have been published to mitigate
this reaction and provide a safer initiation process for these
PedSAP 2016 Book 2 Pediatric Critical Care
patients (Hackbarth 2005; Pasko 2003). Other marketed fil-
ters are composed of polyarylethersulfone or polysulfone
derivatives. Although these products boast lower bradyki-
nin release on CRRT initiation, they are unavailable in the
range of sizes necessary to meet the needs of all pediatric
patients.
Dialysate and Replacement Fluids
Dialysate and replacement fluids typically contain sodium,
potassium, chloride, bicarbonate, dextrose, calcium, mag-
nesium, phosphate, and lactate. Only small amounts of
lactate are available in the solutions, given that previous
studies have shown that lactate onlybuffered fluids con-
tribute to lactic acidosis and hemodynamic instability and
are inferior to bicarbonate-buffered solutions (Sutherland
2012). Calcium-containing fluids do not include phosphorus
because of precipitation, and similarly, calcium-contain-
ing fluids are not usually used with citrate anticoagulation.
The dialysate composition may require several adjustments
throughout the CRRT run to maintain desired electrolyte con-
centrations in the patient. Many commercially available fluids
are in varying electrolyte concentrations (e.g., potassium, cal-
cium, bicarbonate), which can meet the needs of the patient
with little to no additional electrolyte manipulation. Fluids
can be compounded in the pharmacy if alternative electrolyte
concentrations are required (e.g., greater than 140 mEq/L of
sodium). Patient-specific dialysis fluids introduce many ave-
nues for error, from prescribing to compounding. Because of
the risks involved, the Institute for Safe Medication Practices
has placed dialysis solution on the high-alert medication list
for acute care centers.
Dialysate runs countercurrent to the patients blood and
remains separated by the semipermeable membrane in the
hemofilter. The goal of the dialysate is to create a diffusion
gradient across the membrane in order to return the blood
to normal physiologic electrolyte composition. The counter-
current flow optimizes the concentration gradient across the
length of the filter. Titration of blood flow rate is more effec-
tive at optimizing diffusion than titration of dialysate rate.
After passage through the hemofilter, the dialysate fluid is
routed to an effluent bag, which will be wasted.
Filter replacement fluid (FRF) is deposited into the hemofil-
ter either before or after the patients blood enters the chamber
(Figure 1-2). Pre-FRF is used to dilute the blood entering the
filter to decrease hemofilter clotting and enhance convection.
Post-FRF is added to reverse hemoconcentration after solute
and plasma water removal that occurred within the hemofil-
ter. Whether pre- or post-FRF, the solution will be infused into
the bloodstream. Therefore, the electrolyte composition of
the FRF should be conducive to the ongoing treatment of the
patient. When concurrent dialysate and FRF are used, using
the same solution composition for both greatly decreases the
risk of medication errors (Sutherland 2012).
64 Extracorporeal Circuits in Children
 Venous outlet
(to patient)

Calcium infusion Hemofilter

(to patient)

Venous inlet
(from patient)

Blood
Blood
Pump
Pump

Effluent Infusiona Dialysate FRF

Figure 1-2. Continuous renal replacement therapy (CRRT) circuit arrangement.

a
Infusion can be pre-blood pump anticoagulation, such as trisodium citrate.
FRF = filter replacement fluid (can be pre- and/or post-hemofilter).

CRRT Comparison transmembrane pressure, or convection. Diffusion allows the

Continuous renal replacement therapy can be continuous
hemodialysis, hemofiltration, or both (Table 1-3). Hemodialysis
is accomplished through diffusion across a semipermeable
membrane from an area of high concentration to low con-
centration, whereas hemofiltration is the movement of solute
with fluid across the semipermeable membrane because of
passage of smaller molecules, whereas convection moves
both small- and middle-weight molecules across the mem-
brane (Sutherland 2012).
The prescription for CRRT depends on the modality used. The
blood flow rate is ultimately determined by the size of the cath-
eter but is usually 215 mL/kg/minute (50200 mL/minute).

Table 1-3. Differences Between Continuous Renal Replacement Modalities

Abbreviation Continuous Modality Clearance Mechanism FRF Needed? Influences Drug Removal

CVVHD Hemodialysis Diffusion No Dialysis flow rate

CVVH Hemofiltration Convection Yes Ultrafiltration rate
SCUF Hemofiltration Convection No Ultrafiltration rate
CVVHDF Hemodiafiltration Diffusion, convection Yes Dialysis flow rate, ultrafiltration rate

CVVH = continuous veno-venous filtration; CVVHD = continuous veno-venous hemodialysis; CVVHDF = continuous veno-venous
hemodiafiltration; FRF = filter replacement fluid; SCUF = slow continuous ultrafiltration.

PedSAP 2016 Book 2 Pediatric Critical Care 65 Extracorporeal Circuits in Children


Box 1-1. Example of a CRRT Prescription
CRRT Parametersa:
1. Type: CVVHDF
Filter: M60
Catheter: Central, right internal jugular
Initiation procedure: Blood bypass
2. Blood flow: 50 mL/min
Post-FRF: 50 mL/hr
Pre-FRF: 0 mL/hr
Dialysis rate: 800 mL/hr
Fluid balance: 0 mL/hr
3. Anticoagulation: Anticoagulant Citrate Dextrose
Pre-pump citrate: 40 mL/hr
a
Typically, a CRRT prescription has three parts (1) circuit/
access information and mode of CRRT, (2) dialysis and ultrafil-
tration information, and (3) anticoagulation information.
CRRT = continuous renal replacement therapy; CVVHDF = con-
tinuous veno-venous hemodialysis; FRF = filter replacement
fluid.
Dialysis rates range from 20 mL/kg/hour to a maximum of 40
mL/kg/hour (Sutherland 2012). The FRF rate is determined by
the intended use. Ultrafiltration is set as an hourly net loss or net
gain or to remain net even, according to total hourly input that
includes the FRF rate as well as intravenous medications given.
Accumulated excess extracellular fluid is not directly removed
through CRRT, and hemodynamic instability may occur with over-
zealous intravascular fluid removal via ultrafiltration (Box 1-1).
Anticoagulation
Much like the ECMO circuit, the CRRT circuit stimulates an
acute inflammatory response, the activation of platelets, and
the clotting cascade, leading to clot formation because of the
interaction of whole blood with foreign surfaces. Similar to
ECMO, systemic anticoagulation with unfractionated heparin
has been used for anticoagulation of CRRT circuit; however,
regional anticoagulation with trisodium citrate, also known as
anticoagulant citrate dextrose, is an alternative.
Anticoagulation practices vary by institution and modal-
ity. Given the intermittent hemodialysis experience,
unfractionated heparin has been the mainstay for CRRT
anticoagulation for many years. The unfractionated hepa-
rin infusion is administered into the CRRT circuit pre-filter
and titrated to achieve a post-filter aPTT of 1.52 times nor-
mal values or an ACT of 180220 seconds (Sutherland 2012).
Other parenteral anticoagulants such as argatroban and
bivalirudin do not have much utility, even in heparin-induced
thrombocytopenia, since the introduction of citrate regional
anticoagulation.
Citrate binds to ionized calcium, which is a cofactor for
activation of the intrinsic pathway of the clotting cascade.
Removing available calcium halts the forward progression
of the cascade. Trisodium citrate is delivered pre-filter to
chelate calcium within the filter to achieve an intra-circuit
PedSAP 2016 Book 2 Pediatric Critical Care
ionized calcium of 12 mg/dL (0.250.5 mmol/L). Because
of the risk of hypocalcemia, patients should receive a con-
tinuous calcium chloride or calcium gluconate infusion to
correct their ionized calcium to normal physiologic con-
centrations (4.45.2 mg/dL or 1.11.3 mmol/L) (Brophy
2005). The calcium infusion is administered to the patient
to replete the ionized calcium deficit hence, the term
regional anticoagulation. Citrate is metabolized to bicarbon-
ate in the liver and skeletal muscle, which can contribute
to elevated bicarbonate concentrations and a subsequent
metabolic alkalosis. Citrate clearance may be impaired
in patients with liver dysfunction, resulting in an accu-
mulation of citrate, which potentiates hypocalcemia
(ionized) and hypotension (Sutherland 2012; Fleming 2011).
Monitoring ionized calcium in the circuit and ionized and
total calcium concentration in the patient is imperative for
successful CRRT regional anticoagulation. Rapid bedside
point-of-care devices that perform ionized calcium con-
centrations have made regional citrate anticoagulation a
feasible option.
Trisodium citrate and unfractionated heparin have been
compared as anticoagulation strategies in pediatric CRRT.
Both agents have equal efficacy with respect to circuit anti-
coagulation, but unfractionated heparin is associated with
an increased risk of bleeding. This is not surprising because
unfractionated heparin produces systemic anticoagulation in
the patient in addition to the circuit (Brophy 2005).
Complications
Technical complications of the CRRT circuit include clot for-
mation and obstructed vascular access, resulting in inlet or
outlet pressure concerns. Patient-specific complications
such as bleeding from heparinization, metabolic alkalo-
sis from citrate overload, electrolyte abnormalities from
aggressive dialysis, or hypotension from ultrafiltration have
previously been discussed.
With aggressive dialysis and ultrafiltration, the loss of
amino acids and water-soluble vitamins, with the exception
of B12, can be significant. Critically ill patients including chil-
dren are often hypermetabolic and hypercatabolic because
of the increased energy expenditures of the stressed state.
Furthermore, the clinician must consider the energy needed
for normal growth and development or at least maintenance
of the nutritional status during critical illness in a child.
Therefore, a positive nitrogen balance should be maintained,
even in the presence of renal failure.
Adult studies suggest that 5%21% of amino acids admin-
istered in the CRRT circuit can be lost (Btiache 2008). Amino
acid loss in children receiving CRRT has been cited as up to
12% (Maxvold 2000). Therefore, giving more than 2 g/kg/day
of protein is recommended (Maursetter 2011; Btiache 2008).
Water-soluble vitamins can be replaced with a standard
enteral childrens multivitamin or an intravenous multivita-
min added to total parental nutrition. Patients receiving high
66 Extracorporeal Circuits in Children
ultrafiltration rates may need additional thiamine because
stores of this water-soluble vitamin can be exhausted in
as quickly as 1 week (Berger 2004). The trace elements
selenium, copper, manganese, chromium, and zinc are not
extensively removed by CRRT in children (Pasko 2009).
Daily supplementation of these trace elements above nor-
mal recommended daily values is not recommended unless
a deficiency is identified.
Environmental complications are possible with CRRT
like with ECMO. Administration of large volumes of fluid
at ambient temperature can result in hypothermia in these
patients. A blood warmer attached to the return line of the
patient may alleviate this issue, but using warming strate-
gies directly to the patient may also be of benefit. Warming
the dialysis fluid or FRF is not recommended because
uniform heating of these fluid bags is difficult and may com-
promise stability.
Pharmacokinetic Changes
The pharmacokinetic properties most influenced by the
addition of a CRRT circuit are drug distribution and elim-
ination. Metabolism is not likely affected by CRRT, but it is
assumed altered by the critical illness of the child. Few stud-
ies describe the extent of drug adsorption in CRRT. The filter
and tubing of the CRRT circuit are made of plastic polymers
that are assumed to adsorb drugs much like in ECMO, but the
clinical significance at this time is unknown.
supplemental dosing, as used in intermittent hemodialysis.
However, predicting the elimination rate and magnitude at
which a drug is removed is difficult. Much of the drug loss
depends on the physiochemical properties of the medication,
the type and rate of CRRT modality (hemodialysis or hemo-
filtration), and even the residual renal function of the patient.
Physiochemical properties that can influence medica-
tion elimination by CRRT include molecular size, charge,
hydrophilicity, volume of distribution, and protein binding.
Smaller molecules are more likely to cross than larger com-
pounds. Small molecules (less than 500 Da) typically move
across the dialysis membrane by diffusion, whereas middle
molecules (5005000 Da) usually cross with the convec-
tive forces of ultrafiltration (Veltri 2004). Larger compounds
above 5000 Da such as albumin seldom pass across the
membrane (Box 1-2).
Molecular charge will limit the passage of molecules
across the semipermeable membrane. As with most mem-
brane scenarios, polar molecules become trapped on one
side of a membrane, whereas neutral molecules pass more
readily. However, this can be complicated by the surface
charge of the semipermeable membrane, making it difficult
to predict molecular movement.
Medication solubility also affects movement across the
membrane. Water-soluble drugs tend to have smaller vol-
umes of distribution than their lipophilic counterparts.
Drugs with smaller volumes of distribution are concentrated

Distribution
Critical illness and acute renal failure can increase the volume
of distribution, regardless of the addition of dialysis modali- Box 1-2. Molecular Size of
ties. The same volume of distribution increase seen with the Common Drugs
ECMO circuit occurs with CRRT because of the additional vol- Small (< 500 Da)
ume necessary to prime and run the circuit. The CRRT circuit Amino acids
is a network of tubing and a filter that requires a fluid volume Ampicillin
of 40200 mL, depending on the filter set chosen. Therefore, Barbiturates
drugs that distribute predominantly in the extracellular space
Benzodiazepines
Carbapenems
will have an increase in volume of distribution. Volume of dis- Catecholamines
tribution also plays a role in the ability of the CRRT circuit Electrolytes
to remove the medication. Medication with a volume distri- Fluoroquinolones
bution over 0.7 L/kg likely will not be significantly removed Levocarnitine
(Veltri 2004). Because of the continuous nature of the modal-
Linezolid
Nafcillin
ity, it is possible to have removal of drugs with larger volumes Opioids
of distribution, but the rate of this removal depends on the Thiamine
intercompartment equilibration rate as well as other phys- Zinc
iochemical properties discussed in the text that follows Medium (5005000 Da)
(Veltri 2004). Protein binding is unlikely to be affected by the Aminoglycosides
addition of the CRRT circuit, but protein binding does influ- Cephalosporins
ence drug elimination across the filter membrane.
Daptomycin
Piperacillin/tazobactam
Elimination
Vancomycin
Large (> 5000 Da)
The most significant role of CRRT is clearance of solute and Albumin
removal of fluid, but often at the expense of drug removal. Immune globulin
The continuous nature of CRRT eliminates the need for Monoclonal antibodies

PedSAP 2016 Book 2 Pediatric Critical Care 67 Extracorporeal Circuits in Children

in the extracellular compartment and available in the circula-
tion for removal. Larger volume of distribution medications
(e.g., digoxin, amiodarone) are widely distributed in tissues,
allowing for minimal impact of dialysis on drug removal.
Drugs that are 80% or greater protein bound are unlikely
to be removed by hemodialysis and hemofiltration (Veltri
2004). Unbound or free drug is more efficiently removed by
either mechanism of CRRT (Joy 1998). The nature of criti-
cally illness and variability in protein production throughout
normal growth and development of children provides addi-
tional complexity in predicting pharmacokinetic changes
with protein binding (Veltri 2004).
Drug clearance may be enhanced if the native kidney
maintains some residual function or if other nonrenal elimi-
nation pathways are present. If the native kidney has some
residual filtration and secretion capacity, it will contribute
to drug clearance. It is difficult to quantify residual renal
function on CRRT because the modality removes urea and
creatinine. Therefore, using serum creatinine as a marker
for calculating creatinine clearance is unreliable. Urine
output may be an indicator of residual renal function, but
it is difficult to interpret and quantify the urine clearance
of creatinine without additional testing. Nonrenal routes
of elimination may arise in the setting of renal failure. For
example, imipenem clearance in patients with acute kidney
failure is higher than in patients with chronic renal failure
(95 mL/minute vs. 10.5 mL/minute, p<0.02), likely because
of hepatic elimination compensation for the acute change
in renal clearance (Mueller 1993).
Many strategies are used to estimate drug clearance in
CRRT. Some methods are more difficult because they require
the use of information that is difficult to retrieve such as
the sieving coefficient, saturation coefficient, and drug con-
centrations in effluent fluids (Joy 1998). It is estimated that
continuous veno-venous filtration (CVVH) corresponds to
a creatinine clearance rate of 1030 mL/minute/1.73 m2,
whereas continuous veno-venous hemodialysis (CVVHD)
estimates a clearance of 1520 mL/minute/1.73 m2. When
convection and diffusion clearance are combined in continu-
ous veno-venous hemodiafiltration (CVVHDF), the estimated
drug clearance rate is 1050 mL/minute/1.73 m2. When CRRT
dosing information is unavailable, using these creatinine
clearance estimations is a reasonable starting point in mak-
ing drug dosing adjustments in CRRT. Because CRRT doses
in children vary greatly with patient size and CRRT modality,
creatinine clearance estimations should be normalized for an
adult body surface area (1.73 m2) (Aronoff 2007) (Box 1-3).
An optimal medication therapy regimen must be created
for a patient receiving CRRT. Reports suggest that cur-
rent recommendations for dosing in CRRT are inadequate
in meeting therapeutic end points. Variable clearance and
PedSAP 2016 Book 2 Pediatric Critical Care
Box 1-3. Equations for Estimating
Clearance in CRRT
Estimating Specific Medication Clearance
Sieving coefficient
SC = 1 fraction bound of drug
CVVH
Qr SC
a
If pre-FRF prescribed: Qr SC (QL/[QL + Qrf])
If post-FRF prescribed: Qr SC
CVVHD
Qd Sd or Qd SC
Sd is not always available and has been clinically ap-
plied as SC
CVVHDF
(Qr + Qd) SC
Adjustment for the pediatric patient:
Clearance (mL/min)/BSA (m ) 2
Clearance (mL/min)/kg
Estimating CrCl for any CRRT modality
([Qd + Qr] 1.73 )/(BSA 60 )
b c
a
The ultrafiltration rate is the sum of pre- and post-FRF rate
less the hourly net loss or net gain.
b
This factor (1.73) reflects the standard adult BSA that the
childs BSA is normalized against.
c
This factor reflects changing the units from milliliters per hour
to milliliters per minute.
BSA = body surface area; CVVH = continuous veno-venous fil-
tration; CVVHDF = continuous veno-venous hemodiafiltration;
Qd = dialysate rate (milliliters per hour); QL = blood flow rate
(milliliters per minute); Qr = ultrafiltration rate (milliliters per
hour); Qrf = pre-replacement fluid rate (milliliters per hour); SC
= sieving coefficient; Sd = saturation coefficient.
potential underdosing of -lactam antibiotics have been
reported in adult patients receiving CRRT (Roberts 2015;
Ulldemolins 2014; Seyler 2011). For example, the recom-
mended dosing of meropenem in children receiving CRRT
is 2040 mg/kg every 12 hours; however, a pediatric phar-
macokinetic modeling study suggested a dosing interval
of 8 hours in children younger than 5 years (Nehus 2014).
To further complicate matters, an in vivo study of children
older than 5 years confirmed the dosing of meropenem 20
mg/kg every 12 hours in CRRT (Nehus 2016). It is import-
ant to evaluate the literature that addresses individual drug
therapy behavior within the CRRT circuit. Data from the
primary literature, coupled with the clinical scenario and
knowledge of the interactions with the extracorporeal cir-
cuit, should form the basis to provide optimal drug therapy
for these patients. Monitoring drug concentrations when
clinically feasible is recommended to ensure attainment of
therapeutic targets.
68 Extracorporeal Circuits in Children
 Patient Care Scenario
J.R. is a 4-year-old boy (height 39 inches [100 cm],
weight 15 kg) with febrile neutropenia admitted to the
pediatric ICU for gram-negative septic shock. He was ini-
tiated on CVVHDF for fluid overload and an acute kidney
injury that was precipitated by the infection. He remains
anuric. His current BUN is 12 mg/dL and SCr is 0.3 mg/dL.
His CVVHDF prescription is written as follows:
ANSWER
This patients CrCl on CVVHDF is estimated as 54 mL/
min/1.73 m2.
Body surface area (BSA) = (weight in kilograms
height in centimeters/3600)
(15 kg 100 cm/3600) = 0.645 m2
Qr = Pre-FRF + Post-FRF (fluid balance)
Qr = 0 + 200 (-10) = 210 mL/hr
CrCl = ([Qd + Qr] 1.73)/(BSA 60)
([1000 + 210)] 1.73)/(0.645 60) = 54 mL/min/1.73 m2
1. Bhler, J, Donauer J, Keller F. Pharmacokinetic principles during continuous renal replacement therapy: drugs and doses. Kidney
International. 1999;56:S24-8.
2. Veltri MA, Neu AM, Fivush BA, et al. Drug dosing during intermittent hemodialysis and continuous renal replacement therapy: special
considerations in pediatric patients. Paediatr Drugs 2004;6:45-65.
Future Direction
As with ECMO, renal replacement therapies continue to
evolve. Currently, a CRRT circuit is used in Europe for pre- and
full-term neonates and infants weighing 210 kg. This circuit,
the Cardio-Renal Pediatric Dialysis Emergency Machine or
CARPEDIEM, touts efficiency with smaller vascular access
points (4 French), a smaller priming volume (30 mL), and more
sensitive scales (within 1 g) to allow for lower blood flow, dial-
ysis rates, and ultrafiltration rates (Ronco 2014). This fills a
necessary gap in current CRRT management for the small-
est patients.
More attention on conducting quality pharmacokinetic
studies in CRRT is needed. Current literature features dif-
ferent modes of CRRT, differing doses of hemodialysis and
hemofiltration, and differing medication doses tested both in
vitro and in vivo. A standardized approach may help clarify
the magnitude of drug clearance in differing CRRT modalities
(Vaara 2012).
EXTRACORPOREAL LIVER SUPPORT
Indication
Fulminant hepatic failure is an egregious and relentless dis-
ease process with few therapeutic modalities to reverse it,
and subsequently, a high mortality rate. Acute liver fail-
ure manifests as life-threatening complications such as
PedSAP 2016 Book 2 Pediatric Critical Care
Blood flow: 80 mL/min
Dialysis rate: 1000 mL/hr
Post-FRF: 200 mL/hr
Ultrafiltration: Net loss 10 mL/hr
What is this patients estimated CrCl on CVVHDF?
Using SCr to estimate the CrCl would not be accurate
because most of the SCr is being eliminated by the CRRT
circuit. It is unlikely that J.R. has any residual renal func-
tion that would contribute to CrCl, as suggested by his
anuria. Therefore, it is assumed that CrCl is performed by
the CRRT circuit, and this calculation can be used as a
surrogate to help dosing medication in this scenario.
coagulopathy, hepatic encephalopathy, cerebral edema,
hypotension, and renal failure. Because of the nature of
this disease and the lack of therapeutic options, interest in
extracorporeal liver support has grown. The first artificial liv-
ers were constructed in Italy and Japan in the 1950s. Over
the next several decades, machines were designed with
advances in membrane technology and improved compre-
hension of the functionality of the liver.
Both biologic and non-biologic liver support systems
have been explored. Biologic liver support systems integrate
a mechanical device with human or porcine hepatocytes
that have synthetic, metabolic, and excretory functions
(Hassanein 2011). These biologic extracorporeal liver circuits
are only available in the investigational setting at this time.
Non-biologic systems mimic hemodialysis with albumin and
other artificial membranes to detoxify the blood, similar to a
functional liver. Historically, non-biologic systems have been
used as a bridge to liver transplantation or until organ recov-
ery. Only one system (MARS; Gambro, Stockholm, Sweden)
has FDA approval for hepatic encephalopathy, drug overdose,
or poisoning.
Current evidence is limited, and improvement in sur-
vival has not been established. However, small studies with
liver assist devices have reported improvement in hepatic
encephalopathy (p=0.003) and decreases in bilirubin concen-
trations (p=0.005) (Tsipotis 2015). In addition, improvements
69 Extracorporeal Circuits in Children
in the hemodynamic dysregulation seen in liver failure have
occurred with albumin dialysis devices (Stange 2011). In chil-
dren, a single-pass albumin dialysis (SPAD) study bridged
7 of the 9 enrolled patients to liver recovery or transplanta-
tion, reduced hepatic encephalopathy scores in 6 patients,
improved bilirubin concentrations (baseline: 22.6 mg/dL; 24
hours: 8.2 mg/dL), and resulted in a 50% decline in ammonia
concentrations (Ringe 2011).
Circuit Characteristics
All non-biologic extracorporeal liver support systems use the
principles of adsorption and filtration. These systems may be
run continuously like CRRT or intermittently for 48 hours a
day. The circuits have a configuration similar to a standard
dialysis circuit. Venous blood is removed from the patient,
passes through a special membrane filter with countercur-
rent albumin, and is then returned. The main variance within
non-biologic artificial liver support systems is the manage-
ment of the toxin-bound albumin.
The SPAD system is the simplest extracorporeal liver sys-
tem. This circuit can be likened to continuous veno-venous
hemodiafiltration (CVVHDF) with an albumin-containing dialy-
sate solution. The high-flux filter in this circuit features much
larger pores (50,000 Da) than the typical CRRT filter. This larger
pore size is necessary to move albumin-bound and other large
toxins across the membrane and out of the blood, but it does
not remove immunoglobulins, complement, or clotting pro-
teins. The albumin and protein-bound toxins empty into an
effluent bag and are discarded after one pass through the
hemofilter. The disadvantage of this modality is that it does
not recycle the albumin, which increases the cost. However,
the ability to use this modality on a conventional CRRT
machine with albumin dialysate and the appropriate filter pro-
vides a distinct advantage. In addition, SPAD is a continuous
removal system like CRRT and has lower blood flow rate, which
is advantageous in the hemodynamically unstable patient.
Another extracorporeal support system, the fraction-
ated plasma separation and adsorption hemodialysis
Table 1-4. Extracorporeal Liver Assist Device Differences
Liver Assist High-Flux Low-Flux Adsorbent
Device Dialyzer Dialyzer Columns
SPAD Yes No No
MARS Yes Yes Yes (2)
Prometheus Yes No Yes (2)
MARS = molecular adsorbent recirculating system; SPAD = single-pass adsorption dialysis.
PedSAP 2016 Book 2 Pediatric Critical Care 70
system (Prometheus; Fresenius Medical Care, Bad Homburg,
Germany), features a high-flux hemofilter as well as direct
albumin adsorption. First, the venous blood flows through
a specialized filter that extracts albumin-rich plasma; this
is then is transferred to a neutral resin and then to an anion
exchanger. The filtered plasma passes through an absor-
bent circuit and is reunited with the patients blood; finally,
it is passed through a high-flux dialyzer before returning
to the patient. The first step in this process removes the
toxin-carrying albumin from the blood, and the second step
removes ammonia and urea, as expected in hemodialysis.
This entire process takes place within one circuit specific to
the Prometheus system. This modality is prescribed intermit-
tently with 4- to 8-hour run times once daily, as used in recent
studies (Tsipotis 2015).
The final and most complex artificial liver system cur-
rently available is the molecular adsorbent recirculating
system (MARS). It is composed of a blood circuit and an albu-
min circuit. Venous blood is pumped into the biocompatible
high-flux dialyzer, where blood is dialyzed against albumin
dialysate. This high-flux dialysis filter features a pore size of
50,000 Da to allow the passage of protein-bound molecules
across the semipermeable membrane. The albumin dialy-
sate is regenerated in a closed-loop circuit. It passes through
a low-flux dialysis filter against standard dialysis fluid to
remove water-soluble toxins and then travels to two differ-
ent adsorption columns to remove the protein-bound toxins.
One adsorptive column contains charcoal, and the other con-
tains an anion-exchange resin. After passing through the
columns, the albumin is restored and travels through the
high-flux dialyzer again. The filtered blood is then returned
to the patient. This complex system can be executed with
a standard CRRT machine for the blood separation and an
additional closed-loop circuit for the albumin detoxification.
Like the Prometheus system, MARS is typically administered
intermittently each day for 68 hours. Because of this device
setup, it is an easier transition back to CRRT when the albu-
min dialysis run is complete (Table 1-4).
Albumin Prescribed
Recycled Interval Machine Used
No Continuous CRRT
Yes Over 48 hr, CRRT +
daily proprietary
circuit
Yes Over 68 hr, Proprietary
daily circuit
Extracorporeal Circuits in Children
Anticoagulation
Use of anticoagulation in these systems is controversial.
Inherently, patients with fulminant liver failure are coagulo-
pathic because of the decreased production of coagulation
factors and platelet dysfunction. As a further complication,
critically ill patients may present with systemic inflamma-
tion or disseminated intravascular coagulation. Therefore,
providing therapy that blocks the coagulation cascade may
be excessive and increase the risk of bleeding. Low-dose
unfractionated heparin and regional citrate anticoagulation
have been used successfully in the MARS and Prometheus
systems (Tsipotis 2015). The SPAD circuit has success-
fully used heparin (Ringe 2011). With the short-course,
intermittent daily use of some of these devices (MARS and
Prometheus), the exposure to anticoagulation is limited
(Stange 2011).
Complications
Most published complications consist of catheter-related
bleeding, hematomas, and infections. One adult MARS
study found no significant difference in bleeding rate in the
study population compared with the standard medical ther-
apy group (17.8% vs. 9.5%; p=0.14) (Baares 2013). Similarly,
a large Prometheus randomized controlled trial reported
a bleeding rate of 43% in the study group and 49% in the
standard medical therapy group (p=0.79) (Kribben 2012).
Bleeding rates were not routinely reported in the SPAD trials,
although a nonsignificant decline in platelets was reported
compared with standard medical therapy (mean difference
15,840 per microliter [95% CI, 24,000 to 55,960]; p=0.44)
(Tsipotis 2015). The pediatric SPAD study reported a decline
in platelets within the first 24 hours before returning to or
exceeding baseline values (Ringe 2011). In a comparative
trial of MARS therapy versus SPAD in adult patients, a sig-
nificant platelet drop occurred in the MARS group compared
with the SPAD group (8000 vs. 2000, p=0.032) (Sponholz
2016). Although the infection rates reached 50% or above
in both groups, there was no difference between standard
therapy and the MARS or the Prometheus systems (Baares
2013; Kribben 2012).
Pharmacokinetic Changes
Although development of artificial liver support systems
started over 50 years ago, literature pertaining to pharmaco-
kinetic and pharmacodynamic alterations is lacking. Biologic
liver support systems may have intrinsic metabolic and excre-
tory functions that would affect drug dosing. Understanding
the technology will facilitate comprehension of how medica-
tions interact with the liver support devices.
Because the MARS and Prometheus circuits contain
adsorbent columns (charcoal and anion-exchange resin), a
drug may be lost through adsorption. Charcoal is a porous,
high-surface-area carbon resin that binds well to many sub-
stances. However, polar molecules such as alcohols or
PedSAP 2016 Book 2 Pediatric Critical Care
highly ionic metals and minerals such as sodium, iron, lead,
and iodine are not extensively bound. The anion-exchange
resin compound binds bile acids and other organic anions.
Drug loss would vary, depending on the placement of these
adsorbent columns and the protein binding of the drug. For
example, in the MARS system, the drug would have to pass
across the first semipermeable membrane and into the albu-
min circuit to come in contact with the adsorbent columns.
Highly protein-bound drugs are more likely to be sequestered
in the albumin dialysis systems. Even with protein-bound drug
sequestration in these extracorporeal devices, the overall
systemic exposure may not be influenced, especially if there
is a high volume of distribution into the tissues. No literature
exists currently to quantify the amount of drug adsorption
with these modalities.
It is unknown whether distribution and metabolism are
directly affected by the artificial liver assist devices. The
SPAD system, which is similar to CVVHDF, could be postu-
lated to have effects on distribution similar to that mode of
CRRT. Hepatic failure will induce changes in drug distribution
from fluid overload, ascites, and low protein stores, as well as
decreased hepatic metabolism and clearance of drugs.
With the high-flux dialysis filter featured in each of these
non-biologic liver support devices, drug elimination is likely
affected. The pore size on these filters is quite large; thus,
many drugs used in the critical care setting are likely to
move across that membrane. The MARS or Prometheus
circuit may be used intermittently with corresponding
alterations in elimination during these periods. The SPAD
circuit should behave similarly to CVVHDF drug elimination,
given the similarities in configuration with the addition of a
larger-pore filter.
PLASMAPHERESIS
Plasmapheresis and its intention, in some form, have been
around for centuries. The ancient humors of blood, phlegm,
black bile, and yellow bile were proposed by Hippocrates,
and Claudius Galen later emphasized the need to keep these
humors in balance (Fortenberry 2006). The humor imbal-
ances described in ancient medicine are now recognized as
the autoantibodies seen in autoimmune diseases such as
Guillain-Barr syndrome, antigen-antibody complexes, allo-
proteins responsible for transplant rejection and transfusion
reactions, endogenous toxins seen in liver failure, and anti- and
proinflammatory mediators seen in sepsis. Plasmapheresis,
or TPE, is the practice of separating plasma from whole blood
and returning to the body plasma-poor blood with exoge-
nously supplemented fresh frozen plasma, albumin, and other
physiologic fluids. Historically, whole blood was manually
removed from the patient in aliquots and spun down by a cen-
trifuge to separate the plasma from the blood cells, and blood
cells were returned to the patient. This process is now mod-
ernized and administered by mobile machines.
71 Extracorporeal Circuits in Children
Indication
Plasmapheresis indications have grown lengthy over the
decades. The American Society for Apheresis maintains an
exhaustive list of diseases that may benefit from TPE, which
are also graded according to potential benefit. The indications
are extensive: from autoimmune to infectious to inflammatory
processes (Schwartz 2013). Plasmapheresis has gained inter-
est for managing sepsis with multiorgan failure, especially
with the scarcity of options to remove excessive anti- and pro-
inflammatory mediators to restore homeostasis (Fortenberry
2006). The massive systemic inflammatory response is
caused by cytokines such as tumor necrosis factor alpha,
interleukins, prostaglandins, and other mediators. An imbal-
ance in pro- and anti-inflammatory systems leads to tissue
injury, multiorgan dysfunction syndrome, disseminated intra-
vascular coagulation, and relative immunosuppression.
The goal of TPE in fulminant sepsis is to remove cytotoxins
and return to the body anti-inflammatory mediators, immu-
noglobulins, and pro- and anti-inflammatory proteins (Kawai
2015). Both adults and children have reported benefit with this
intervention in sepsis and thrombocytopenia-associated mul-
tiple organ failure (TAMOF). In 1999, one of the first groups to
report that TPE was associated with a slight improvement in
the number of organs that failed in sepsis (plasmapheresis
2.57 vs. standard therapy 2.94; p=0.37) found no difference in
mortality (57% vs. 50%; p=0.73) (Reeves 1999). In a larger ran-
domized controlled study of adults with septic shock, 28-day
all-cause mortality was decreased in the TPE group compared
with the standard therapy group (33% vs. 53%; p=0.05) (Busund
2002). A retrospective pediatric study found similar results,
with 28-day mortality favoring the TPE group over the stan-
dard therapy group in children with TAMOF (26.6% vs. 70.3%;
p=0.006) (Sevketoglu 2014). Plasmapheresis has even been
investigated in children with TAMOF receiving other extracor-
poreal therapies (e.g., ECMO with or without CRRT), where it
was found to have a 5-fold lower vasopressor infusion score
and improved organ function after treatment (Kawai 2015).
Circuit Characteristics
The configuration for TPE is similar to that for other extra-
corporeal therapies. Plasmapheresis can be administered
through two large-bore peripheral intravenous lines; a central
venous line is not necessary for every patient. Whole blood
is extracted from the venous system of the patient and then
separated by plasma filtration or continuous flow centrifuga-
tion. The cells are returned to the patient through a venous
access port with a replacement fluid of 4%5% albumin, fresh
frozen plasma, normal saline, or a combination, depending on
the clinical scenario. Plasma filtration takes place in a large-
bore polymer membrane plasma separator accomplished
using modern-day CRRT circuits with the appropriate-sized
filter and necessary replacement fluids. Centrifugal plasma
exchange requires a dedicated machine with a spinning cham-
ber that relies on gravity to separate blood components and
PedSAP 2016 Book 2 Pediatric Critical Care
plasma by densities. Plasmapheresis is typically prescribed
for 34 hours a day, often for several days in a row (35 days).
Anticoagulation
Trisodium citrate regional anticoagulation has been a suc-
cessful anticoagulant in centrifugal TPE circuits. Heparin
can be used for either exchange modality and is preferred for
plasma filtration. The risks and benefits of heparin or triso-
dium citrate anticoagulation are similar to those discussed in
previous sections.
Complications
Loss of plasma components can create unnecessary com-
plications. Proteins such as immune globulins, albumin, and
coagulation factors are removed, with significant losses
occurring with repeated exchanges. After a single pass of
plasma volume exchange, patient immunoglobulin G (IgG)
concentrations may drop by 28%. If the exchange volume is
increased to 1.5 times the total body plasma volume, the loss
increases to 35% of total body IgG (Annich 2012). Albumin is
typically monitored before and after each exchange to help
guide the replacement fluid plan. Monitoring of IgG after
completion of the multiday therapy is warranted. Exogenous
replacement of IgG, albumin, and fresh frozen plasma can
combat deficiencies and potential complications.
With unfractionated heparin anticoagulation, there is
always a remote risk of bleeding. Paresthesias caused by
hypocalcemia from citrate exposure have also been reported
(Winters 2012). Because of its intermittent nature and use
in hemodynamically unstable patients, hypotension may
manifest from fluid shifts. Heat loss from the circuit and
the addition of large volumes of colloids and crystalloids in
replacement fluids stored at ambient temperature contribute
to hypothermia (Annich 2012).
Pharmacokinetic Changes
The pharmacokinetic changes associated with TPE are not
well described. Many case reports describe the magnitude of
drug removal but do not address changes in adsorption, dis-
tribution, and metabolism.
Drug sequestration possibly occurs in the TPE circuit
because of adsorption to the filter and tubing similar to the other
extracorporeal circuits previously described. Drug adsorption
has not yet been quantified in the published literature for this
modality. Distribution may be intermittently affected with the
removal of plasma and protein binding sources and the addi-
tion of replacement fluids that would dilute the serum; however,
this change is likely transient. Alterations in hepatic metabo-
lism have not been studied, but plasma esterase metabolism
may decrease because of the depletion of pseudocholin-
esterases by TPE, which could ultimately lead to prolonged
neuromuscular blockade (Naik 2002).
Drug elimination is the best-described pharmacokinetic
alteration in TPE. Typically, TPE is prescribed for 11.5 times
72 Extracorporeal Circuits in Children
 Table 1-5. Pharmacokinetic Changes in Extracorporeal Therapies
Modality Adsorption Distribution
ECMO
CRRT NC or NC or
Liver assist devices Unknown NC or
TPE Unknown NC or
a
Elimination rate depends on dialysis and ultrafiltration rates.
Liver failure contributes to changes and likely a decrease in hepatic metabolism.
b
Increased elimination of protein-bound drugs only.
c
NC = no change; TPE = therapeutic plasmapheresis.
the patients circulating plasma volume, which can remove
up to 63%72% of circulating plasma components (Ibrahim
2012). Plasmapheresis is the most effective modality of drug
removal in intoxications in highly protein-bound (greater than
80%) medications or those with a small distribution (volume
of distribution 0.2 L/kg or less) (Ibrahim 2007). Drugs with
higher free fraction available are not likely removed by TPE.
Removal also depends on the serum concentration at the
time of the exchange. Medication administration may need
to be held until after TPE because removal increases with
higher concentrations such as those during peak concen-
trations (Ibrahim 2012). Therapeutic drug monitoring should
be delayed for at least 2 hours after termination of the daily
exchange to account for redistribution and equilibration.
CONCLUSION
Caring for the critically ill child is becomingly increasingly
complicated with the addition of various extracorporeal ther-
apies. Alterations in pharmacokinetics and the interaction of
medications within the extracorporeal systems constantly
challenge the pediatric pharmacist because of the lack of
clinical data to guide recommendations. When extracorpo-
real therapies are used in combination, a greater degree of
complexity is added. Even fewer data exist on the interactions
of medications within concurrent extracorporeal circuits.
Additive therapies create a challenge in designing safe medi-
cation regimens as well as in optimizing pharmacodynamic
targets. The pharmacists recommendations regarding
extracorporeal circuits should account for known drug prop-
erties and any available literature. Apractical monitoring plan
should be in place to ensure the attainment of therapeutic
end points and avoid toxicities in all cases (Table 1-5).
REFERENCES
Agati S, Ciccarello G, Salvo D, et al. Use of a novel antico-
agulation strategy during ECMO in a pediatric population:
single-center experience. ASAIO J 2006;52:513-6.
PedSAP 2016 Book 2 Pediatric Critical Care 73
Metabolism Elimination
NC to
NC or a
b c
Unknown
Practice Points
ECMO
Because of the large network of polymer tubing, drug
adsorption and sequestration may be significant, neces-
sitating higher-than-usual doses of highly adsorbed
medications.
End-organ perfusion changes caused by an inciting
event may adversely affect hepatic and renal clearance.
Recommend serum concentration monitoring, when
possible; otherwise, follow clinically and titrate to
desired effect.
CRRT
The different CRRT modalities may use diffusion, con-
vection, or both with subsequent changes in clearance
properties.
Drug removal by the CRRT circuit depends on drug phys-
iochemical properties (e.g., ionization, molecular size,
volume of distribution) and CRRT flow rates.
Residual renal function can contribute to additional drug
clearance, but this is difficult to quantify.
Estimating circuit clearance by dialysate and replace-
ment fluid rates can be helpful for designing medication
therapy plans.
Extracorporeal Liver Support
Large filter pores allow passage of components that are
50,000 Da or less, which includes many protein-bound
drugs.
The magnitude of drug removal likely depends on
protein binding and therapy duration, although no stud-
ies or case reports have quantified the extent of drug
removal with these therapies.
Plasmapheresis
Medications with high protein binding (80%) and small
volumes of distribution (0.2 L/kg or less) are effectively
removed by TPE.
If possible, schedule drug administration after TPE to
decrease drug extraction.
Annich GM. Extracorporeal life support: the precarious bal-
ance of hemostasis. J Thromb Haemost 2015;13(suppl
5):336-42.
Extracorporeal Circuits in Children
Annich GM, Lynch WR, MacLaren G, et al, eds. ECMO
Extracorporeal Cardiopulmonary Support in Critical Care,
4th ed. Ann Arbor, MI: ELSO, 2012.
Aronoff GR, Bennett WM, Berns JS, et al., eds. American
College of Physicians. Drug Prescribing in Renal Failure:
Dosing Guidelines for Adults and Children, 5th ed.
Philadelphia: Versa Press, 2007.
Baares R, Nevens F, Larsen FS, et al; RELIEF study group.
Extracorporeal albumin dialysis with the molecular adsor-
bent recirculating system in acute-on-chronic liver failure:
the RELIEF trial. Hepatology 2013;57:1153-62.
Beiderlinden M, Treschan T, Grlinger K, et al. Argatroban
in extracorporeal membrane oxygenation. Artif Organs
2007;31:461-5.
Berger MM, Shenkin A, Revelly JP, et al. Copper, selenium,
zinc, and thiamine balances during continuous venove-
nous hemodiafiltration in critically ill patients. Am J Clin
Nutr 2004;80:410-6.
Bizzarro MJ, Conrad SA, Kaufman DA, et al. Extracorporeal
Life Support Organization Task Force on Infections,
Extracorporeal Membrane Oxygenation. Infections acquired
during extracorporeal membrane oxygenation in neonates,
children, and adults. Pediatr Crit Care Med 2011;12:277-81.
Bhler J, Donauer J, Keller F. Pharmacokinetic principles
during continuous renal replacement therapy: drugs and
dosage. Kidney Int 1999;56:S24-8.
Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in
septic shock: a positive fluid balance and elevated central
venous pressure are associated with increased mortality.
Crit Care Med 2011;39:259-65.
Brophy PD, Somers MJ, Baum MA, et al. Multi-centre evalu-
ation of anticoagulation in patients receiving continuous
renal replacement therapy. Nephrol Dial Transplant
2005;20:1416-21.
Buck ML. Pharmacokinetic changes during extracorporeal
membrane oxygenation: implications for drug therapy of
neonates. Clin Pharmacokinet 2003;42:403-17.
Buck ML, Wooldridge P, Ksenich RA. Comparison of methods
for intravenous infusion of fat emulsion during extra-
corporeal membrane oxygenation. Pharmacotherapy
2005;25:1536-40.
Bui JD, Despotis GD, Trulock EP, et al. Fatal thrombosis after
administration of activated prothrombin complex concen-
trates in a patient supported by extracorporeal membrane
oxygenation who had received activated recombinant fac-
tor VII. J Thorac Cardiovasc Surg 2002;124:852-4.
Burkhart HM, Joyner N, Niles S, et al. Presence of plasticizer
di-2(ethylhexyl)phthalate in primed extracorporeal circula-
tion circuits. ASAIO J 2007;53:365-7.
Busund R, Koukline V, Utrobin U, et al. Plasmapheresis in
severe sepsis and septic shock: a prospective, randomised,
controlled trial. Intensive Care Med 2002;28:1434-9.
PedSAP 2016 Book 2 Pediatric Critical Care
Byrnes JW, Swearingen CJ, Prodhan P, et al. Antithrombin
III supplementation on extracorporeal membrane oxygen-
ation: impact on heparin dose and circuit life. ASAIO J
2014;60:57-62.
Chalwin RP, Tiruvoipati R, Peek GJ. Fatal thrombosis with
activated factor VII in a paediatric patient on extracor-
poreal membrane oxygenation. Eur J Cardiothorac Surg
2008;34:685-6.
Downard CD, Betit P, Chang RW, et al. Impact of AMICAR on
hemorrhagic complications of ECMO: a ten-year review.
JPediatr Surg 2003;38:1212-6.
Extracorporeal Life Support Organization (ELSO). ELSO
Anticoagulation Guidelines. 2014.
Fleming GM. Renal replacement therapy review.
Organogenesis 2011;7:2-12.
Fortenberry JD, Paden ML. Extracorporeal therapies in
the treatment of sepsis: experience and promise. Semin
Pediatr Infect Dis 2006;17:72-9.
Ganter MT, Hofer CK. Coagulation monitoring: current tech-
niques and clinical use of viscoelastic point-of-care
coagulation devices. Anesth Analg 2008;106:1366-75.
Gillespie RS, Seidel K, Symons JM. Effect of fluid overload
and dose of replacement fluid on survival in hemofiltra-
tion. Pediatr Nephrol 2004;19:1394-9.
Goldstein SL, Currier H, Graf JM. Outcome in children receiv-
ing venovenous hemofiltration. Pediatrics 2001;107:1309-12.
Hackbarth RM, Eding D, Gianoli C, et al. Zero balance ultra-
filtration (Z-BUF) in blood-primed CRRT circuits achieves
electrolyte and acid-base homeostasis prior to patient
connection. Pediatr Nephrol 2005;20:1328-33.
Hassanein TI, Schade RR, Hepburn IS. Acute-on-chronic liver
failure: extracorporeal liver assist devices. Curr Opin Crit
Care 2011;17:195-203.
Hoie EB, Hall MC, Schaaf LJ. Effects of injection site and
flow rate on the distribution of injected solutions in an
extracorporeal membrane oxygenation circuit. Am J Hosp
Pharm 1993;50:1902-6.
Honore PM, Jacobs R, Joannes-Boyau O, et al. Newly
designed CRRT membranes for sepsis and SIRS a prag-
matic approach for bedside intensivists summarizing the
more recent advances: a systematic structured review.
ASAIO J 2013;59:99-106.
Horwitz JR, Cofer BR, Warner BW, et al. A multicenter trial of
6-aminocaproic acid (Amicar) in the prevention of bleed-
ing in infants on ECMO. J Pediatr Surg 1998;33:1610-3.
Hursting MJ, Dubb J, Verme-Gibboney CN. Argatroban anti-
coagulation in pediatric patients: a literature analysis.
JPediatr Hematol Oncol 2006;28:4-10.
Ibrahim RB, Balogun RA. Medications in patients treated
with therapeutic plasma exchange: prescription dosage,
timing, and drug overdose. Semin Dial 2012;25:176-89.
74 Extracorporeal Circuits in Children
Ibrahim RB, Liu C, Cronin SM, et al. Drug removal by plasma-
pheresis: an evidence-based review. Pharmacotherapy
2007;27:1529-49.
Joy MS, Matzke GR, Armstrong DK, et al. A primer on con-
tinuous renal replacement therapy for critically ill patients.
Ann Pharmacother 1998;32:362-75.
Kawai Y, Cornell TT, Cooley EG, et al. Therapeutic plasma
exchange may improve hemodynamics and organ failure
among children with sepsis-induced multiple organ dys-
function syndrome receiving extracorporeal life support.
Pediatr Crit Care Med 2015;16:366-74.
Kribben A, Gerken G, Haag S, et al; HELIOS Study Group.
Effects of fractionated plasma separation and adsorption
on survival in patients with acute-on-chronic liver failure.
Gastroenterology 2012;142:782-9.
Long MT, Wagner D, Maslach-Hubbard A, et al. Safety and
efficacy of recombinant activated factor VII for refrac-
tory hemorrhage in pediatric patients on extracorporeal
membrane oxygenation: a single center review. Perfusion
2014;29:163-70.
Luddington RJ. Thrombelastography/thromboelastometry.
Clin Lab Haematol 2005;27:81-90.
Maursetter L, Kight CE, Mennig J, et al. Review of the
mechanism and nutrition recommendations for patients
undergoing continuous renal replacement therapy. Nutr
Clin Pract 2011;26:382-90.
Maxvold NJ, Smoyer WE, Custer JR, et al. Amino acid loss
and nitrogen balance in critically ill children with acute
renal failure: a prospective comparison between classic
hemofiltration and hemofiltration with dialysis. Crit Care
Med 2000;28:1161-5.
Mehta NM, Halwick DR, Dodson BL, et al. Potential drug
sequestration during extracorporeal membrane oxygen-
ation: results from an ex vivo experiment. Intensive Care
Med 2007;33:1018-24.
Meyer AD, Wiles AA, Riveria O, et al. Hemolytic and throm-
bocytopathic characteristics of extracorporeal membrane
oxygenation systems at simulated flow rates for neonates.
Pediatr Crit Care Med 2012;13:e255-61.
Mueller BA, Scarim SK, Macias ML. Comparison of imipe-
nem pharmacokinetics in patients with acute or chronic
renal failure treated with continuous hemofiltration. Am J
Kidney Dis 1993;21:172-9.
Mulla H, Lawson G, von Anrep C, et al. In vitro evaluation of
sedative drug losses during extracorporeal membrane
oxygenation. Perfusion 2000;15:21-6.
Mulla H, Pooboni S. Population pharmacokinetics of van-
comycin in patients receiving extracorporeal membrane
oxygenation. Br J Clin Pharmacol 2005;60:265-75.
Naik B, Hirshhorn S, Dharnidharka VR. Prolonged neu-
romuscular block due to cholinesterase depletion by
plasmapheresis. J Clin Anesth 2002;14:381-4.
PedSAP 2016 Book 2 Pediatric Critical Care
Nehus EJ, Mizuno T, Cox S, et al. Pharmacokinetics of
meropenem in children receiving continuous renal
replacement therapy: validation of clinical trial simula-
tions. J Clin Pharmacol 2016;56:291-7.
Nehus EJ, Mouksassi S, Vinks AA, et al. Meropenem in chil-
dren receiving continuous renal replacement therapy:
clinical trial simulations using realistic covariates. J Clin
Pharmacol 2014;54:1421-8.
Niebler RA, Christensen M, Berens R, et al. Antithrombin
replacement during extracorporeal membrane oxygen-
ation. Artif Organs 2011;35:1024-8.
Niebler RA, Punzalan RC, Marchan M, et al. Activated
recombinant factor VII for refractory bleeding during
extracorporeal membrane oxygenation. Pediatr Crit Care
Med 2010;11:98-102.
OHoro JC, Cawcutt KA, De Moraes AG, et al. The evidence
base for prophylactic antibiotics in patients receiving extra-
corporeal membrane oxygenation. ASAIO J 2016;62:6-10.
Pasko DA, Churchwell IF, Jain JC, et al. Continuous venove-
nous hemodiafiltration trace element clearance in pediatric
patients: a case series. Pediatr Nephrol 2009;24:807-13.
Pasko DA, Mottes TA, Mueller BA. Pre-dialysis of blood prime
in continuous hemodialysis normalizes pH and electro-
lytes. Pediatr Nephrol 2003;18:1177-83.
Preston TJ, Hodge AB, Riley JB, et al. In vitro drug adsorp-
tion and plasma free hemoglobin levels associated with
hollow fiber oxygenators in the extracorporeal life support
(ECLS) circuit. J Extra Corpor Technol 2007;39:234-7.
Preston TJ, Ratliff TM, Gomez D, et al. Modified surface
coatings and their effect on drug adsorption within the
extracorporeal life support circuit. J Extra Corpor Technol
2010;42:199-202.
Ranucci M, Ballotta A, Kandil H, et al; Surgical and Clinical
Outcome Research Group. Bivalirudin-based versus
conventional heparin anticoagulation for postcardiot-
omy extracorporeal membrane oxygenation. Crit Care
2011;15:R275.
Reeves JH, Butt WW, Shann F, et al. Continuous plasmafiltra-
tion in sepsis syndrome. Plasmafiltration in Sepsis Study
Group. Crit Care Med 1999;27:2096-104.
Ringe H, Varnholt V, Zimmering M, et al. Continuous
veno-venous single-pass albumin hemodiafiltration in
children with acute liver failure. Pediatr Crit Care Med
2011;12:257-64.
Roberts DM, Liu X, Roberts JA, et al; RENAL Replacement
Therapy Study Investigators. A multicenter study on the
effect of continuous hemodiafiltration intensity on anti-
biotic pharmacokinetics. Crit Care 2015;19:84.
Ronco C, Garzotto F, Brendolan A, et al. Continuous renal
replacement therapy in neonates and small infants: devel-
opment and first-in-human use of a miniaturised machine
(CARPEDIEM). Lancet 2014;383:1807-13.
75 Extracorporeal Circuits in Children
Schetz M. Non-renal indications for continuous renal
replacement therapy. Kidney Int 1999;56(suppl 72):S88-94.
Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on
the use of therapeutic apheresis in clinical practice-evi-
dence-based approach from the Writing Committee of the
American Society for Apheresis: the sixth special issue. J
Clin Apher 2013;28:145-284.
Sevketoglu E, Yildizdas D, Horoz OO, et al. Use of therapeutic
plasma exchange in children with thrombocytope-
nia-associated multiple organ failure in the Turkish
thrombocytopenia-associated multiple organ failure net-
work. Pediatr Crit Care Med 2014;15:e354-9.
Seyler L, Cotton F, Taccone FS, et al. Recommended -lactam
regimens are inadequate in septic patients treated with con-
tinuous renal replacement therapy. Crit Care 2011;15:R137.
Shekar K, Fraser JF, Smith MT, et al. Pharmacokinetic
changes in patients receiving extracorporeal membrane
oxygenation. J Crit Care 2012a;27:741.e9-18.
Shekar K, Roberts JA, Barnett AG, et al. Can physicochemi-
cal properties of antimicrobials be used to predict their
pharmacokinetics during extracorporeal membrane oxy-
genation? Illustrative data from ovine models. Crit Care
2015a;19:437.
Shekar K, Roberts JA, Mcdonald CI, et al. Protein-bound
drugs are prone to sequestration in the extracorporeal
membrane oxygenation circuit: results from an ex vivo
study. Crit Care 2015b;19:164.
Shekar K, Roberts JA, Mcdonald CI, et al. Sequestration of
drugs in the circuit may lead to therapeutic failure dur-
ing extracorporeal membrane oxygenation. Crit Care
2012b;16:R194.
Shekar K, Roberts JA, Smith MT, et al. The ECMO PK Project:
an incremental research approach to advance understand-
ing of the pharmacokinetic alterations and improve patient
outcomes during extracorporeal membrane oxygenation.
BMC Anesthesiol 2013;13:7.
Shekar K, Roberts JA, Welch S, et al. ASAP ECMO: Antibiotic,
Sedative and Analgesic Pharmacokinetics during
Extracorporeal Membrane Oxygenation: a multi-cen-
tre study to optimise drug therapy during ECMO. BMC
Anesthesiol 2012c;12:29.
Smythe MA, Koerber JM, Forsyth LL, et al. Argatroban
dosage requirements and outcomes in intensive care
versus non-intensive care patients. Pharmacotherapy
2009;29:1073-81.
Sponholz C, Matthes K, Rupp D, et al. Molecular adsorbent
recirculating system and single-pass albumin dialysis in
liver failure a prospective, randomised crossover study.
Crit Care 2016;20:2.
Stange J. Extracorporeal liver support. Organogenesis
2011;7:64-73.
PedSAP 2016 Book 2 Pediatric Critical Care
Sutherland SM, Alexander SR. Continuous renal replacement
therapy in children. Pediatr Nephrol 2012;27:2007-16.
Syburra T, Lachat M, Genoni M, et al. Fatal outcome of
recombinant factor VIIa in heart transplantation with
extracorporeal membrane oxygenation. Ann Thorac Surg
2010;89:1643-5.
Tsipotis E, Shuja A, Jaber BL. Albumin dialysis for liver
failure: a systematic review. Adv Chronic Kidney Dis
2015;22:382-90.
Ulldemolins M, Vaquer S, Llaurad-Serra M, et al. Beta-
lactam dosing in critically ill patients with septic shock
and continuous renal replacement therapy. Crit Care
2014;18:227.
Vaara S, Pettila V, Kaukonen KM. Quality of pharmacoki-
netic studies in critically ill patients receiving continuous
renal replacement therapy. Acta Anaesthesiol Scand
2012;56:147-57.
van der Staak FH, de Haan AF, Geven WB, et al. Surgical
repair of congenital diaphragmatic hernia during
extracorporeal membrane oxygenation: hemorrhagic com-
plications and the effect of tranexamic acid. J Pediatr
Surg 1997;32:594-9.
Veltri MA, Neu AM, Fivush BA, et al. Drug dosing during
intermittent hemodialysis and continuous renal replace-
ment therapy: special considerations in pediatric patients.
Paediatr Drugs 2004;6:45-65.
Walczak R, Lawson D, Kaemmer D, et al. Evaluation of a
preprimed microporous hollow-fiber membrane for rapid
response neonatal extracorporeal membrane oxygen-
ation. Perfusion 2005;20:269-75.
Whiting D, Dinardo J. TEG and ROTEM: technology and clini-
cal applications. Am J Hematol 2014;89:228-32.
Wildschut ED, Ahsman MJ, Allegaert K, et al. Determinants
of drug absorption in different ECMO circuits. Intensive
Care Med 2010;36:2109-16.
Winters JL. Plasma exchange: concepts, mechanisms,
and an overview of the American Society for Apheresis
guidelines. Hematology Am Soc Hematol Educ Program
2012;2012:7-12.
Wong TE, Delaney M, Gernsheimer T, et al. Antithrombin con-
centrates use in children on extracorporeal membrane
oxygenation: a retrospective cohort study. Pediatr Crit
Care Med 2015;16:264-9.
Wong TE, Huang YS, Weiser J, et al. Antithrombin concen-
trate use in children: a multicenter cohort study. J Pediatr
2013;163:1329-34.
Young G, Boshkov LK, Sullivan JE, et al. Argatroban therapy
in pediatric patients requiring nonheparin anticoagulation:
an open-label, safety, efficacy, and pharmacokinetic study.
Pediatr Blood Cancer 2011;56:1103-9.
76 Extracorporeal Circuits in Children
Self-Assessment Questions
Questions 1 and 2 pertain to the following case.
T.M. is an 18-month-old girl (weight 15 kg) admitted to the
pediatric ICU for acute respiratory failure caused by influ-
enza A infection and complex parapneumonic effusions from
methicillin-resistant S. aureus. T.M. is placed on VV-ECMO
support. She is currently sedated with fentanyl at 5 mcg/
kg/hour and midazolam 0.3 mg/kg/hour, which have been
aggressively titrated over the past 24 hours.
1. Which one of the following best justifies rapidly escalat-
ing infusions for T.M.?
A. Enhanced renal elimination of fentanyl and
midazolam
B. Elevated CYP metabolism of fentanyl and
midazolam
C. Decreased volume of distribution of fentanyl and
midazolam
D. Increased adsorption to the circuit of fentanyl and
midazolam
2. Which one of the following would best optimize sedation
in T.M.?
A. Discontinue fentanyl and change to morphine
infusion.
B. Discontinue midazolam and change to pentobarbital
infusion.
C. Give intravenous bolus fentanyl dose and increase
fentanyl infusion by 20%.
D. Give intravenous bolus of midazolam and increase
midazolam infusion by 20%.
3. A 4-year-old boy (weight 16 kg) is on day 9 of VA-ECMO
because of viral myocarditis. He has been on a con-
tinuous infusion of opioid and benzodiazepine for the
duration and is experiencing profound constipation,
despite best efforts with enteral stimulants and osmotic
agents. The medical team is asking whether subcutane-
ous methylnaltrexone would be a good option for this
patient to promote a bowel movement. Which one of the
following best justifies avoiding subcutaneous methyln-
altrexone administration in this patient?
A. Increased volume of distribution in the patient
B. Decreased renal elimination of methylnaltrexone
C. Bleeding risk due to systemic anticoagulation
D. High lipophilicity of methylnaltrexone
Questions 46 pertain to the following case.
G.V. is a 4-month-old boy (weight 5.5 kg) with known bron-
chomalacia, now admitted with respiratory syncytial virus
bronchiolitis and complicated Streptococcus pneumoniae
PedSAP 2016 Book 2 Pediatric Critical Care
pneumonia. He has been receiving VV-ECMO for 2 days and
is anticoagulated with unfractionated heparin. G.V.s current
infusion rate is 50 units/kg/hour, and the most recent acti-
vated clotting time is 140 seconds. His urine output is 1.2 mL/
kg/hour without diuretics.
4. Which one of the following best explains G.V.s clinical
picture in regard to anticoagulation?
A. Increase in hepatic metabolism of heparin
B. Increase in heparin volume of distribution
C. Decreased antithrombin (AT) levels
D. Decreased clotting factor production
5. G.V.s left chest tube starts to ooze blood around the site.
Which one of the following is best to recommend for G.V.?
A. Decrease heparin infusion
B. Change to bivalirudin infusion
C. Consider AT administration
D. Add aminocaproic acid infusion
6. G.V.s chest tube continues to ooze and is requiring daily
blood transfusions to manage his declining hemoglobin
and hematocrit. No other sources of bleeding have been
identified (e.g., intracranial, mucosal), but the ECMO
circuit has visible fibrin strands developing post-mem-
brane oxygenator. The team is considering administering
recombinant activated factor VII. Which one of the fol-
lowing is best to recommend for G.V.?
A. Consider administration because the patient is not
bleeding from any other source.
B. Consider administration because the blood product
requirement is rising.
C. Avoid administration because the optimal dose has
not been established.
D. Avoid administration because thrombosis risk
outweighs the benefit.
Questions 7 and 8 pertain to the following case.
R.W. is a 16-day-old, full-term girl (weight 3.3 kg) now immedi-
ately postoperative from a Norwood procedure. She returned
with her sternum open. R.W. decompensated overnight and
was placed on VA-ECMO support.
7. The team caring for R.W. wants to continue antibiotic pro-
phylaxis for the open sternotomy cannulation site. Which
one of the following is best to recommend for R.W.?
A. Ampicillin
B. Cefazolin
C. Cefepime
D. Gentamicin
77 Extracorporeal Circuits in Children
8. R.W. is now on day 4 of VA-ECMO and continues to have
intermittent hemodynamic instability. Her WBC rises
significantly. Which one of the following is best to rec-
ommend for R.W.?
A. Add fluconazole to current skin flora prophylaxis.
B. Add vancomycin to current skin flora prophylaxis.
C. Expand to piperacillin/tazobactam and vancomycin.
D. Expand to cefuroxime and clindamycin.
Questions 911 pertain to the following case.
H.L. is a 17-year-old female adolescent (height 65 inches,
weight 102 kg) now 20 days after a bone marrow transplant
for refractory acute lymphoblastic leukemia. She is receiving
CVVH for acute kidney injury and fluid overload. Her SCr is 0.5
mg/dL, and she remains anuric. H.L.s CVVH prescription is
pre-filter replacement rate 1000 mL/hour, post-filter replace-
ment rate 3000 mL/hour, and ultrafiltration rate 0 mL/hour
(net even). The team wants to initiate piperacillin/tazobactam
and vancomycin to rule out sepsis.
9. Which one of the following piperacillin/tazobactam regi-
mens is best to recommend for H.L.?
A. 4.5 g intravenously every 8 hours
B. 4.5 g intravenously every 12 hours
C. 3.375 g intravenously every 8 hours
D. 3.375 g intravenously every 12 hours
10. Which one of the following vancomycin doses, adminis-
tered intravenously, is best to recommend for H.L.?
A. 500 mg
B. 750 mg
C. 1000 mg
D. 2000 mg
11. Which one of the following is the best time after the first
dose to obtain a vancomycin serum concentration in
order to redose vancomycin for H.L.?
A. 6 hours
B. 12 hours
C. 24 hours
D. 48 hours
Questions 1214 pertain to the following case.
R.S. is a 2-month-old boy (length 22 inches [57 cm], weight
6kg) with a new diagnosis of hemophagocytic lymphohistio-
cytosis. He is receiving VV-ECMO for acute respiratory failure
and CVVHDF for acute kidney injury and fluid overload. His
laboratory results include SCr 0.2 mg/dL, BUN 20 mg/dL, total
bilirubin 1.2 mg/dL, and direct bilirubin 0.8 mg/dL. R.S.s urine
output is 220 mL in 24 hours. His CVVHDF prescription is as
follows: dialysis rate 800 mL/hour, pre-filter fluid replacement
100 mL/hour, post-filter fluid replacement 50 mL/hour, and
ultra-filtration rate 0 mL/hour.
PedSAP 2016 Book 2 Pediatric Critical Care
12. The oncology group wants to initiate R.S.s weekly eto-
poside therapy as soon as possible. Which one of the
following pharmacokinetic concepts is most important
to consider in designing a dosing recommendation for
R.S.?
A. Adsorption of etoposide to CRRT circuit
B. Distribution of etoposide in a critically ill infant
C. Metabolism of etoposide in a critically ill infant
D. Elimination of etoposide through CRRT and residual
renal function
13. R.S. is having issues with hypothermia and temperature
control while receiving both ECMO and CRRT. The heat
exchanger on the ECMO circuit is at maximal capacity.
Which one of the following would be best to keep R.S.
warm?
A. Add external heating blanket.
B. Place dialysis bags in warmer.
C. Increase the room temperature.
D. Add blood warmer to CRRT return line.
14. R.S. has been stable on vancomycin 90 mg intravenously
every 6 hours for several days for the treatment of coag-
ulase-negative Staphylococcus bacteremia, with troughs
within the goal range. This morning, the nephrology team
is adjusting his CRRT ultrafiltration rate to a net loss of
10 mL/hour. Which one of the following is best to recom-
mend for R.S.s vancomycin therapy?
A. Decrease vancomycin interval to every 8 hours.
B. Increase dose to vancomycin 120 mg intravenously
every 6 hours.
C. Recheck a vancomycin trough before the next
dose.
D. No change is necessary.
15. A 4-year-old boy with acute on chronic renal failure
has been receiving CVVHDF for solute clearance and
optimization of nutrition for 17 days. Which one of the
following laboratory values is best to measure in this
patient?
A. Copper
B. Thiamine
C. Manganese
D. IgG
Questions 16 and 17 pertain to the following case.
V.T. is a 16-year-old girl (weight 45 kg) given a diagnosis of
myasthenia gravis 2 months ago. She presented for admission
to the pediatric ICU 5 days ago with progressing weakness
that necessitated mechanical ventilation support. Yesterday,
V.T. completed her last dose of intravenous immunoglobulin.
She has made little progress, so V.T.s team is considering ini-
tiating plasmapheresis today.
78 Extracorporeal Circuits in Children
16. The neurology team would like to know whether V.T.s pyr- Which one of the following is best to recommend for
idostigmine therapy will be affected by plasmapheresis. B.T.s dosing adjustment?
Which one of the following best answers this question
A. Make no change in recommended dose.
from V.T.s team?
B. Decrease by 25% of recommended dose.
A. No protein binding will allow for elimination by C. Decrease by 50% of recommended dose.
plasmapheresis. D. Avoid giving rituximab while patient is receiving
B. Hepatic metabolism precludes plasmapheresis CRRT.
elimination.
19. B.T.s serum calcium has increased to 13.4 mg/dL, but his
C. Volume of distribution of 0.5 L/kg is too large for
ionized serum calcium is low at 3.4 mg/dL. He remains
elimination.
on trisodium citrate regional anticoagulation and is
D. Poor oral absorption inhibits plasmapheresis
receiving a calcium chloride infusion. Which one of the
elimination.
following best explains the reason for these abnormali-
17. Which one of the following laboratory values is best to ties in B.T.s calcium?
obtain after V.T. completes her multiday plasmapheresis
A. Excessive infusion rate of calcium chloride
course?
B. Underdosing of trisodium citrate infusion
A. Platelets C. Delayed citrate clearance by the liver
B. IgG D. Underdosing of calcium chloride infusion
C. Albumin
20. A 6-month-old girl with hypoplastic left heart syndrome
D. Hepatic enzymes
presents after hemi-Fontan surgery. She remains on VA-
ECMO postoperatively, cannulated through her sternum.
Questions 18 and 19 pertain to the following case. Nutrition is to be initiated in the form of 3-in-1 total par-
B.T. is a 12-year-old boy (height 63 inches [160 cm], weight enteral nutrition. Which one of the following is the best
61 kg) with newly diagnosed Burkitt lymphoma. He is now access point for this patients administration of intrave-
receiving CVVHDF for tumor lysis syndrome. B.T. is receiving nous nutrition?
regional citrate anticoagulation. He remains anuric, and his
A. Internal jugular venous catheter
SCr is 0.4 mg/dL. Current CRRT orders are as follows: dialy-
B. Peripheral venous catheter
sis rate 2000 mL/hour, pre-filter rate 2000 mL/hour, post-filter
C. Post-roller pump stopcock
rate 1000 mL/hour, and ultrafiltration rate 0 mL/hour.
D. Pre-membrane oxygenator stopcock
18. The oncology team wants to continue with B.T.s treat-
ment and scheduled chemotherapy next with rituximab.
Learner Chapter Evaluation: Extracorporeal Circuits in Children.
As you take the posttest for this chapter, also evaluate the
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
1. The content of the chapter met my educational needs.
2. The content of the chapter satisfied my expectations.
3. The author presented the chapter content effectively.
4. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
5. The content of the chapter was objective and balanced.
6. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
7. The content of the chapter was useful to me.
8. The teaching and learning methods used in the chapter
were effective.
9. The active learning methods used in the chapter were
effective.
10. The learning assessment activities used in the chapter
were effective.
11. The chapter was effective overall.
PedSAP 2016 Book 2 Pediatric Critical Care
Use the 5-point scale to indicate whether this chapter pre-
pared you to accomplish the following learning objectives:
12. Account for the basic mechanics and components of
extracorporeal therapies.
13. Develop a drug therapy regimen based on pharmacoki-
netic changes in extracorporeal therapies.
14. Design a therapeutic monitoring plan for patients receiv-
ing extracorporeal therapies.
15. Evaluate an anticoagulation strategy for patients receiv-
ing extracorporeal therapies.
16. Assess the attainment of therapeutic end points for
patients receiving extracorporeal therapies.
17. Design a plan to treat common complications associ-
ated with extracorporeal therapies.
18. Please provide any specific comments related to any
perceptions of bias, promotion, or advertisement of
commercial products.
19. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
80 Extracorporeal Circuits in Children
Trauma
By Joseph M. LaRochelle, Pharm.D., BCPPS

Reviewed by Sara P. Rooney, Pharm.D., BCPS, BCPPS; and Andrea Joan Stumpe, Pharm.D., BCPS, BCPPS

LEARNING OBJECTIVES

1. Develop strategies to optimize a patients mean arterial pressure.

2. Assess strategies to decrease or prevent increased intracranial pressure.
3. Demonstrate appropriate sedation management strategies, as well as appropriate glucose control and seizure
prophylaxis, for the patient with traumatic brain injury.
4. Design appropriate fluid management and treatment approach to increase lean body mass in a patient with burns.
5. Compose strategies to optimize pain control and treat infections in a patient with burns.

ABBREVIATIONS IN THIS CHAPTER
CPP Cerebral perfusion pressure
GCS Glasgow Coma Scale
ICP Intracranial pressure
MAP Mean arterial pressure
TBI Traumatic brain injury
TBSA Total body surface area
Table of other common abbreviations.
INTRODUCTION TO TRAUMATIC
BRAIN INJURY
One of four pediatric patients will have a traumatic injury, which is the
leading cause of death in children (Osterman 2015). Traumatic brain
injury (TBI) accounts for 500,000 incidents, 35,000 hospitalizations,
and 2000 deaths each year (Faul 2010). Severe TBI is usually defined
as a Glasgow Coma Scale (GCS) score less than 8 or the need for
mechanical ventilation (Piatt 2012; Stanley 2012); this type of injury
is the focus of this chapter.
In a retrospective study of 236 pediatric patients with severe TBI,
the average age was 8 years, most patients were boys, and abu-
sive head trauma was the most common injury (Vavilala 2014). The
pathophysiology of TBI is complex and includes both primary and
secondary injuries. In the primary injury, rapid acceleration, decelera-
tion, and/or rotational forces move the brain against the cranium, or
a direct insult to the brain (e.g., penetrating trauma) can produce the
injury. This causes hemorrhage, hematoma, or diffuse axonal injury
(Greve 2009). Diffuse axonal injury is a global phenomenon that can
lead to poor neurologic outcomes (Bhalla 2012). Secondary injury
occurs because of an increase in tumor necrosis factor alpha (TNF-)
and interleukin (IL)-1, causing inflammation, neuronal death, and
edema. Glutamate and other excitatory neurotransmitters increase
calcium influx into the cell through N-methyl-d-aspartate (NMDA)
receptors, releasing oxygen-free radicals and nitric oxide, leading to
lipid peroxidation and cell death (Greve 2009).

CEREBRAL PERFUSION PRESSURE

In TBI, the focus of treatment should be on increasing cerebral perfu-
sion pressure (CPP). Cerebral perfusion pressure is the mean arterial
pressure (MAP) minus the intracranial pressure (ICP). Therefore, the

PedSAP 2016 Book 2 Pediatric Critical Care 81 Trauma

perfusion into the brain depends on blood pressure and the
force that the head is pushing back on the blood flow.
Mean Arterial Pressure
Much controversy exists regarding the optimal MAP for pedi-
atric patients with TBI. The consensus is to maintain a MAP
at a level about normal for age, with a minimum goal of 4050
mm Hg. Adult studies avoid MAP goals greater than 70 mm
Hg. Hypotension should be avoided because poor neuro-
logic outcomes are associated with hypotensive episodes.
As in other aspects of critical care, hypotension should ini-
tially be managed with fluid resuscitation. The fluid of choice
for fluid resuscitation in pediatric TBI is 0.9% sodium chlo-
ride because other fluids are less osmolar or lack the needed
sodium content (Kochanek 2012).
After appropriate fluid resuscitation, vasoactive agents
may be needed to increase MAP. Although no specific vaso-
pressor has proved superior in pediatric TBI, dopamine,
phenylephrine, and norepinephrine have been studied.
Although all positively affect MAP, phenylephrine and nor-
epinephrine have larger and more sustained effects because
of their greater selectivity for 1-adrenergic receptors
(Sookplung 2011). In some animal models of TBI, vasopressin
can alter the blood-brain barrier and increase cerebral edema
by activating vasopressin receptor 1a (Zink 2010). However,
because clinical data are lacking to support its use and alter-
native agents are available, vasopressin should be avoided in
pediatric TBI.
BASELINE KNOWLEDGE STATEMENTS
Readers of this chapter are presumed to be familiar
with the following:
General knowledge of general critical care manage-
ment of patients
Basic drug knowledge of sedation strategies
Pharmacology of vasopressor agents
Table of common pediatric laboratory reference values.
ADDITIONAL READINGS
The following free resources have additional back-
ground information on this topic:
Kochanek PM, Carney N, Ashwal S, et al. Guidelines
for the acute medical management of severe
traumatic brain injury in infants, children, and
adolescents-second edition. Pediatr Crit Care Med
2012;13:S1-S82.
Jeschke MG, Herndon DN. Burns in children:
standard and new treatments. Lancet
2014;383:1168-78.
PedSAP 2016 Book 2 Pediatric Critical Care
Hyperosmolar Agents
Hypertonic Saline
Increases in ICP cause a decrease in the CPP, resulting in fur-
ther injury to brain tissue as a result of secondary injury. An
ICP of 20 mm Hg or greater for 5 minutes or more will require
active interventions to decrease the pressure and secondary
injury. A cutoff of 15 mm Hg or greater can be used for infants
and small children for ICP intervention because of their lower
physiologic MAP (Kochanek 2012).
Hypertonic saline (3%) is the preferred agent in pediatric
TBI to lower ICP; it changes the osmolar gradient, cell volume,
and cell membrane resting potential, leading to its positive
therapeutic benefit of lowering ICP. In addition, hypertonic
saline may release atrial natriuretic peptide, enhance car-
diac output, and decrease inflammation (Kochanek 2012). A
bolus dose of 6.510 mL/kg, followed by a continuous infu-
sion of 0.11 mL/kg/hour, should be initiated and titrated to
a maximum serum osmolarity of 360 mOsm/L and a sodium
concentration of 170180 mEq/L (LaRochelle 2015; Kochanek
2012). Central pontine myelinolysis, hyperchloremic meta-
bolic acidosis, and renal insufficiency can occur with sodium
chloride therapy.
Although 3% saline is the mainstay of TBI therapy, evi-
dence is emerging to support higher concentrations in
the management of increased ICP. A 2012 case report
describes two cases of successful use of 23.4% saline. In
the first case, a 23-month-old child (weight 12 kg) had an
initial GCS score of 3 after sustaining a closed-head injury.
A transthoracic echocardiogram revealed left systolic dys-
function with an estimated ejection fraction of 10%15%.
Because of elevated ICP (44 mm Hg), the patient was given
six boluses of 3% saline 50 mL, a norepinephrine contin-
uous infusion to maintain MAP, two boluses of mannitol,
sedation, paralytics, phenobarbital, CSF drain, and bilateral
decompressive craniectomies. Because of the concern for
fluid overload together with decreased myocardial func-
tion, the 3% saline was changed to 23.4% saline; the patient
received 15 boluses of 23.4% saline (10 mL each) over 7
days. After each dose of 23.4% saline, the ICP decreased
more (7.9 mm Hg average) than with the 3% doses. No
adverse effects were observed with the 23.4% saline, and
the maximal serum sodium reached was 170 mEq/L. In the
second case, a 4-year-old child (weight 14 kg) had a two-
story fall. Initially, her ICP was managed by sedation and a
craniotomy for a skull fracture. The patients ICP increased
to 44 mm Hg, and she was given 12 boluses of 23.4% saline
(810 mL) over 9 days. The only strength of hypertonic
saline used was 23.4%. Similar to the first case, significant
decreases in ICP occurred (up to 19 mm Hg), with a maxi-
mum sodium concentration of 146 mEq/L, with no adverse
effects detected (Nakagawa 2012). The 23.4% saline solu-
tion used in the two cases was administered through a
central venous catheter; if 23.4% saline is used, peripheral
intravenous administration is not advised.
82 Trauma
 A retrospective cohort study in Australia evaluated 23.4%
saline administration in 32 pediatric patients with severe TBI
over 8 years (20032011). The standard hospital protocol was
0.5 mL/kg to a maximum of 30 mL given over 10 minutes. The
hospital protocol for increased ICP used similar treatment
modalities of standard care, including sedation, neuromuscu-
lar blocking agents, normothermia, and inotropic support for
hypotension. Three patients received only one dose of 23.4%
saline; however, most received several doses (up to 28 in one
patient) because of the inability to maintain a hypernatremic
state. The average ICP decrease was 10.2 mm Hg, and mean
sodium was 139 mEq/L with a maximum of 161 mEq/L. No
major adverse effects, including renal failure, were noted.
Seventy-four percent of the patients had outcomes that
would allow them to have independent functioning, and the
mortality rate was low (6%) (Piper 2015).
Although data for using 23.4% saline are limited to retro-
spective studies and case reports, it may be considered in
pediatric patients with TBI. This modality may be most ben-
eficial in patients with fluid overload or decreased cardiac
function. Further randomized prospective trials are needed to
establish its role in pediatric patients.
Mannitol
Mannitol has been used for years to reduce ICP in TBI. It
decreases blood viscosity and maintains blood flow in low blood
volume states. This mechanism of action takes effect rapidly
and lasts about 1 hour (Kochanek 2012). Its second mechanism
of action is that of an osmolar agent, which changes the gradi-
ent decreasing ICP. This mechanism of action has an onset of
about 15 minutes but lasts for up to 6 hours. The dose is 0.25
0.5 g/kg intravenously every 6 hours; however, doses of 1 g/kg
can be used clinically (Taketomo 2015). In light of increasing
use of hypertonic saline, the use of mannitol is falling out of
favor because of its propensity to accumulate in injured sec-
tions of the brain. This causes a reverse osmotic gradient that
can lead to an increase in ICP (Kochanek 2012).
Barbiturates
Barbiturates lower ICP by changing vascular tone, causing met-
abolic suppression and decreasing oxygen free radicals, which
will decrease lipid peroxidation. Therapy, usually limited by
hypotension, should only be used in hemodynamically stable
patients after other treatment modalities have failed (Kochanek
2012). Although thiopental has been studied, pentobarbital is
used most commonly. Bolus dosing of 510 mg/kg followed by
a continuous infusion of 12 mg/kg/hour should be used to tar-
get burst suppression on electroencephalogram and not dosed
to a particular drug concentration (Taketomo 2015).
SEDATION
Because of the extensive injuries and cerebral dysfunc-
tion associated with severe TBI, the patient will probably
be intubated and placed on mechanical ventilation. Thus,
PedSAP 2016 Book 2 Pediatric Critical Care
proper sedation will be required, as in most intubated criti-
cal care patients. The effect of the sedative agents used can
decrease ICP through overall metabolic suppression, blunt
the response to painful stimuli and procedures, and have anti-
epileptic properties (Kochanek 2012). Sedation in critical care
is overall a controversial topic, given that a consensus on the
optimal agents and protocols has yet to be shown. In gen-
eral, patients with TBI will require pain control with an opioid
analgesic such as a fentanyl continuous infusion starting at 1
mcg/kg/hour and an anxiolytic such as a midazolam continu-
ous infusion starting at 0.1 mg/kg/hour (Taketomo 2015). All
of the standard agents used for sedation can cause hypoten-
sion, which will decrease CPP. In hemodynamically unstable
patients, adequate blood pressure should be ensured before
initiating these agents, either using a fluid bolus or initiating
a vasopressor agent until the MAP increases.
Use of sedatives such as ketamine, dexmedetomidine,
and propofol as adjunctive agents has been described in TBI.
Ketamine works by blocking glutamate, one of the excitatory
neurotransmitters released in TBI, through antagonizing the
NMDA receptor, which leads to a decrease in ICP (Bar-Joseph
2009). In addition, ketamine releases catecholamines, which
can help increase MAP, a critical determinant in CPP. Use
of ketamine in TBI has been met with resistance because
of 1970s reports indicating its potential to increase ICP.
The mechanisms behind this concern are that an increase
in Pco2 in nonventilated patients leads to vasodilation and
ketamines ability to block nitric oxide synthase, which can
increase oxygen extraction in the brain. In a recent review,
seven articles evaluated ketamine in severe TBI in 55 pediatric
patients and 101 adult patients. Four studies used continu-
ous infusion ketamine as sedation, with no increases in ICP
in these patients. In the three studies that used bolus dosing
(two pediatric studies), none showed increases in ICP, and
there were even some decreases in ICP (Zeiler 2014). From
the limited data, the initial concern surrounding ketamine
use in TBI appears not to apply to mechanically ventilated
patients. In pediatric patients, ketamine in severe TBI could
be considered for procedural sedation as a bolus dose. Until
reports of continuous infusion ketamine in pediatric patients
are available, it should be avoided for continuous sedation.
Randomized control trials are needed to establish ketamines
role in pediatric severe TBI.
Propofol is a general anesthetic agent that works through
-aminobutyric acid activation and blocking NMDA recep-
tors (Taketomo 2015). Because of its short half-life, propofol
is used in TBI to assist in the neurologic examination. Its
use, however, is limited to less than 24 hours because of
the increased risk of propofol-related infusion syndrome
(Sabsovich 2007).
Dexmedetomidine is a centrally acting 2-agonist used for
sedation in various critical care patients, including those with
TBI. It also activates the extracellular signal-regulated protein
kinase 1 and 2 pathways, which may have neuroprotective
83 Trauma
effects (Schoeler 2012). Dexmedetomidine can cause hypo-
tension through decreased conduction in the AV node and
should be used with caution because of the potential decrease
in MAP (Buck 2010). This agent is dosed as a bolus of 0.51
mcg/kg, followed by a continuous infusion of 0.20.7 mcg/
kg/hour, with higher doses used clinically (Taketomo 2015).
Etomidate is a short-acting benzylimidazole with anes-
thetic properties (Taketomo 2015). It has been used in
single-dose administration in patients with TBI with a reduc-
tion in ICP (Bramwell 2006). The TBI guidelines recommend
against its global use for sedation in TBI; however, it may be
considered an option (Kochanek 2012). Etomidate causes
adrenal suppression, so caution must be used. In addition,
it contains propylene glycol, which could lead to toxicity with
prolonged infusion.
After effective and adequate sedation has been achieved,
another option to help decrease ICP is the use of neuromus-
cular blocking agents. They decrease intrathoracic pressure,
which is likely increased secondary to mechanical ventila-
tion. This decrease in pressure allows for an increase in brain
venous outflow and a decrease in ICP. These agents paralyze
the skeletal muscle, which can decrease metabolic oxygen
demand, decreasing ICP (Kochanek 2012). Succinylcholine
is the only neuromuscular blocking that can increase ICP; it
should be used only if other agents are not available.
OTHER THERAPIES
Hypothermia
Hypothermia decreases metabolic oxygen demand, excitotox-
icity, inflammation, cell death, and seizures (Kochanek 2012).
Although studies of pediatric patients with TBI have been
somewhat inconclusive, most show no improved outcomes
when therapeutic hypothermia strategies are used. A retro-
spective study of 190 pediatric patients showed an increased
mortality when hypothermia was present at admission
(Sundberg 2011). In a phase III multicenter trial of hypo-
thermia in TBI, an interim analysis showed futility, and the
study was terminated early (Adelson 2012). In a multicenter
study conducted in Australia, New Zealand, and Canada, 50
patients with severe TBI were randomized to hypothermia
(32C33C) or normothermia. This study, which followed the
children 12 months postinjury, showed no difference in length
of stay, mortality, or pediatric cerebral performance category
score (Beca 2015). This further adds to the evidence that
therapeutic hypothermia should be avoided in pediatric TBI.
Hyperthermia, however, should also be avoided and treated
aggressively because of its potential to increase ICP.
Glycemic Control
The debate over optimal glucose control in the adult and pedi-
atric critical care populations is ongoing (Brunkhorst 2008;
Yung 2008; van den Berghe 2001). Hyperglycemia can pro-
duce oxygen free radicals and metabolic acidosis in the brain,
PedSAP 2016 Book 2 Pediatric Critical Care
potentially leading to poor neurologic outcomes (Kochanek
2012). Hypoglycemia in children is detrimental because of
the risk of decreased neurologic functioning (Wayne 1990).
In a study of 57 children, hyperglycemia 48 hours after injury
was associated with poor outcomes, especially when blood
glucose concentrations were greater than 200 mg/dL (Smith
2012). In a retrospective study of 271 mechanically ven-
tilated patients with TBI in which glucose measurements
were obtained, patients were stratified into mild, moderate,
and severe hyperglycemia categories. Patients in the severe
hyperglycemia group (greater than 200 mg/dL) had a signif-
icantly greater risk of death and poorer outcomes than the
other two blood glucose groups. The severe hyperglycemia
group had a 3.5-fold increase in poor outcomes over the mild
hyperglycemia group (110160 mg/dL) (Elkon 2014). From the
limited available data, it appears that glucose should be kept
in a normal range of 80180 mg/dL while avoiding both hypo-
glycemia (less than 60 mg/dL) and hyperglycemia (greater
than 200 mg/dL).
Seizure Prophylaxis
About 10%20% of pediatric patients with TBI have an early
post-TBI seizure (Arango 2012; Liesemer 2011). Loss of
consciousness at the scene, focal neurologic deficits, hema-
toma, bone or metal fragments, penetrating injury, GSC less
than 10, and age younger than 2 years are risk factors for sei-
zures in TBI (Liesemer 2011). Routine antiseizure prophylaxis
in patients with TBI is under debate. In a multicenter study
of 477 children, those who received an antiseizure drug had
decreased mortality (Tilford 2001). In contrast, another study
of 300 patients showed no difference (Liesemer 2011).
According to the available evidence, it seems prudent to
use prophylactic agents for seizures if the patient has risk
factors because of the injury. Phenytoin is most commonly
used for seizure prophylaxis. A loading dose of 1520 mg/
kg, followed by 5 mg/kg/day divided every 812 hours, of phe-
nytoin or fosphenytoin is recommended (Taketomo 2015).
Pharmacokinetic parameters and especially albumin bind-
ing are altered in critical care and especially in patients with
TBI. It is recommended to obtain free phenytoin concentra-
tions when initiating therapy and every 23 days thereafter,
with a goal of 12 mcg/mL. During a hypothermia trial, inves-
tigators found that phenytoin elimination was decreased by
about half during cooling protocol procedures, necessitating
a phenytoin dose reduction (Empey 2013).
Another, newer agent for TBI seizure prophylaxis that
has gained increased use in pediatric patients is levetirace-
tam (Jones 2008). A pilot phase II study evaluated the use
of levetiracetam in preventing late posttraumatic epilepsy.
The patients (618 years of age) were administered 55 mg/
kg/day divided twice daily orally (intravenously if NPO [noth-
ing by mouth]) within the first 8 hours of injury and until day
30 postinjury. Twenty patients were included in the treatment
group and were matched to 20 control patients. Headache,
84 Trauma
fatigue, and somnolence were common adverse effects in
the levetiracetam-treated patients. A patient in the levetirace-
tam group had a seizure, the only patient in the 40-sample
size. Although this study included patients with a GCS score
greater than 6, levetiracetam appears to be safe to use in
pediatric patients with TBI (Pearl 2013).
EMERGING THERAPIES
Bone marrow mononuclear cells can change regional inflam-
mation, enhance angiogenesis, and reduce growth factor
(Walker 2010; Qu 2007). In a phase I trial of 10 children, organ
function returned after autologous bone marrow cells were
administered (Cox 2011). In a follow-up study, these 10 patients
were compared with an age- and severity-matched control
group. The treated patients had a significantly decreased
intensity level of therapy score, logistic organ dysfunction
score, and duration of ICP monitoring (Liao 2015). Although
this was done in only 10 patients, the results seem promising
and may be a treatment option for patients with severe TBI.
Progesterone can reduce cerebral edema, inflammation,
oxidative damage, excitation, and apoptosis. It up-regulates
P-glycoprotein, which increases the efflux pumps in the blood-
brain barrier, thus decreasing cerebral edema. Aquaporin 4
is a water membrane channel that becomes up-regulated
in injured sections of the brain. Progesterone can decrease
the amount of Aquaporin 4, which leads to decreased cere-
bral edema. Progesterone decreases inflammation through
decreasing proinflammatory cytokines (TNF, IL-1, and IL-6),
an important aspect in the neuroinflammation that occurs
after TBI. In addition, it inhibits nitric oxide synthase, which
reduces the production of nitric oxide. It also up-regulates
superoxide dismutase, which reduces lipid peroxidation. In
studies of adult patients, decreased mortality and less dis-
ability 30 days postinjury occurred in patients who received
progesterone. One large trial of adults with TBI who were
treated with progesterone was terminated because of a lack
of better outcomes. Other large multicenter trials evaluat-
ing the role of progesterone in adults with TBI are under way.
Because there are developmental changes in the brain and its
response to progesterone, this may become an option in pedi-
atric TBI (Robertson 2015).
INTRODUCTION TO BURNS
Burns account for 400,000 injuries each year in the United
States, with 4000 deaths (WHO 2015; Jeschke 2014b). Burns
over a greater than 30% total body surface area (TBSA) con-
stitute a risk factor for mortality in children. Causes of death
from burn injury are usually sepsis, multiorgan system failure,
and anoxic brain injury (Jeschke 2014b).
The pathophysiology of burns involves a complex cas-
cade that occurs not only in the burned tissue but also in the
healthy tissue. Changes in ATPase activity increase sodium
inside the cell. This leads to cellular edema and hypervolemia.
PedSAP 2016 Book 2 Pediatric Critical Care
Cytokines, histamine, prostaglandins, substance P, and oxy-
gen free radicals are released, causing systemic vasodilation
and regional vasoconstriction (Pham 2008; Scott 2005). In
severe burns (greater than 20% TBSA), catecholamines and
cortisol are released, resulting in an increased metabolic
state. This can subsequently cause hyperglycemia and lipol-
ysis in addition to muscle wasting (Jeschke 2008).
Treatment occurs in three phases. The first phase, initial
care, occurs at the scene and hospital and consists of rapid
assessment, resuscitation, and admission to a burn center.
The second phase occurs while the child is in the hospital and
consists of infection control, surgical procedures, and main-
taining adequate organ function. The last phase occurs after
discharge and consists of reconstruction and rehabilitation.
INITIAL MANAGEMENT
Initial therapy goals focus on salvaging limbs, organs, and life.
Initial fluid resuscitation should be initiated according to the
Parkland formula, which is about 4 mL/kg/%TBSA burned of
crystalloid over the first 24 hours (Jeschke 2014b). However,
in children, this may be an underestimate, and up to 6 mL/
kg/%TBSA burned can be used to prevent burn shock (Pham
2008). The general strategy follows that of typical dehydration
management, in which half of the fluid is given over the first
8 hours and the second half is given over the next 16 hours.
Consequences of fluid under resuscitation include death and
multiorgan system dysfunction. Administration of excessive
fluids increases the risk of respiratory distress syndrome,
pneumonia, multiple organ dysfunction, and death, neces-
sitating an adequate but not excessive fluid administration.
Urine output and MAP should be monitored for successful
resuscitation with goals of greater than 0.51 mL/kg/hour
and greater than 65 mm Hg, respectively (Jeschke 2014b). No
large trials assessing the optimal fluid in these populations
have been conducted, but lactated Ringer solution is used
most often (Jeschke 2014b). In patients with 10%20% TBSA
burned (moderate burns), lower fluid resuscitation volumes
may be considered. A study of 88 patients showed that 2 mL/
kg/%TBSA resulted in a shorter length of stay (Walker 2014).
Until further data are available, aggressive and adequate
fluid resuscitation up to 6 mL/kg/%TBSA should be used in
severely burned (greater than 20% TBSA) pediatric patients.
Inhalation injury from fires confers significant mortality
because of pulmonary edema and ventilation-perfusion mis-
match with subsequent respiratory failure (Jeschke 2014b).
If needed, mechanical ventilation should be used to support
oxygen delivery, as well as standard ventilator strategies and
medications.
HYPERMETABOLIC STATE
Glycemic Control
The hypermetabolic state that occurs because of burn injury
results in hyperglycemia and the inability to use lipids and
85 Trauma
amino acids. This extensive catabolism leads to protein
breakdown within the body and can lead to poor outcomes,
including death. The hyperglycemia that results is an inde-
pendent risk factor for sepsis and mortality.
In a small study of 29 patients, those who maintained a
tight glucose control (80110 mg/dL) had improved muscle
oxidative capacity and less resting energy expenditure than
those whose glucose was maintained at less than 215 mg/dL
(Fram 2010). In a larger study of 239 patients, those whose
serum glucose was maintained in the 80110 mg/dL range
had lower mortality than those whose serum glucose was
maintained in the 140180 mg/dL range (Jeschke 2010). In
a study of 106 severely burned children, investigators found
that children with glucose concentrations greater than 150
mg/dL had a higher incidence of sepsis and longer duration
of mechanical ventilation because of bacterial pneumonia
than those with serum glucose concentrations below 150
mg/dL (Kraft 2014).
A study of 660 severely burned patients investigated
episodes of hypoglycemia on several clinical end points.
Of these, 568 patients were never hypoglycemic, and 198
patients had hypoglycemia (less than 60 mg/dL). A signifi-
cantly higher percentage of patients in the hypoglycemia
group died, developed sepsis, and had longer hospital stays
(Jeschke 2014a). The ideal glucose value in critically ill
burned patients appears to be elusive, but both hypoglycemia
and hyperglycemia should be avoided. Euglycemia should be
targeted with a serum glucose of 80130 mg/dL.
Nutritional Support
Adequate and early nutritional support is essential for the
critical care patient (Mehta 2009). In a study of 688 pediat-
ric burn patients, those who received early enteral therapy
had decreased mortality (Khorasani 2010). In pediatric burn
patients, no specific enteral or parenteral formulation has
proved more successful than another. Experts recommend
high-protein, high-glucose, and low-fat formulations (Jeschke
2014b). In a trial of 27 severely burned pediatric patients using
amino acid supplementations with Travasol and phenylala-
nine, patients were followed to discharge, 6 months postburn,
and 1 year postburn. No difference occurred in skeletal mus-
cle fractional synthesis rate, showing that additional amino
acid supplementation did not improve muscle protein syn-
thesis (Porter 2013). In addition, trace elements and vitamins
are usually decreased in burn patients and should be supple-
mented (Jeschke 2014b).
Hormones
The overall catabolic state that results from severe burns
causes protein and muscle wasting. Oxandrolone is a hormone
medication with a structure similar to testosterone; taken
orally, it can enhance protein synthesis in skeletal muscle
through its action as a synthetic androgen receptor hormone
(Hart 2011; Tuvdendorj 2011). Studies using oxandrolone
PedSAP 2016 Book 2 Pediatric Critical Care
have reported increased overall muscle mass, increased
wound healing, and decreased hospital stay (Jeschke 2014b).
A study of 12 severe burn patients showed increased muscle
proteins in those who received oxandrolone 0.1 mg/kg twice
daily for 6 months (Tuvdendorj 2011). In a larger and longer
study of 70 patients who were given oxandrolone for 1 year,
there was a significant decrease in the hypermetabolic state
compared with controls (Porro 2012). Although the data are
limited and the long-term survival effects are unknown, use of
oxandrolone may help increase lean muscle mass.
Studies have shown that growth hormone decreases
catabolism and increases regeneration of the skin through
cellular mechanisms (Branski 2009; Pereira 2005). In a
study of 86 children treated with growth hormone, a slightly
shorter healing time in skin grafts occurred, but no difference
in major outcomes of hospital stay or mortality was found
(Breederveld 2012). Other studies have shown no difference;
thus, growth hormone is usually not used in the treatment of
burn patients (Jeschke 2014b).
Bisphosphonates
Pediatric burn patients can be afflicted with resorptive bone
loss because of the increase in glucocorticoids second-
ary to the stress response and overall inflammatory process
(Borsheim 2014). Pamidronate is a bisphosphonate that
inhibits bone resorption and decreases osteoclast activity
(Taketomo 2015). In a study of 17 patients, 10 received pami-
dronate and 7 received placebo. The authors found that the
control group had a greater muscle breakdown rate and a nega-
tive nitrogen balance, both of which were significantly different
from the pamidronate group (Borsheim 2014). Further studies
are needed to determine their true role in pediatric burns, but
bisphosphonates may be a future option in these patients.
-Blockers
During the hypermetabolic response, catecholamines are
released; this, in turn, causes increases in heart rate and blood
pressure. Propranolol, a nonselective -blocker, decreases
both the hypermetabolic and the hyperglycemic response
and increases lean body mass. In a study of 174 patients who
received 4 mg/kg/day for 1 year, patients had lower heart rate,
lower resting energy expenditure, and increased lean muscle
mass (Herndon 2012). Another larger study of 340 patients
had similar findings with propranolol doses up to 6 mg/kg/
day (Williams 2011). Propranolol can be considered in pediat-
ric burn patients, especially if there is an extensive metabolic
response. Further trials should help determine the long-term
outcomes of propranolol use in pediatric burn patients.
INFECTIONS
Because of the extent of injuries, the severely burned pediat-
ric patient is at increased risk of infections, including sepsis.
Prompt recognition and adequate treatment are essential for
patient survival. Infection is generally a late complication in
86 Trauma
burn patients, usually occurring after 72 hours postinjury.
Fever in burn patients can occur because of the inflamma-
tory processes associated with the burn or because of an
infection. In a retrospective analysis of 353 patients admit-
ted for a burn injury (all severity levels), only 30.6% had a
fever. In general, patients with a fever had higher TBSA burns,
more hospital days, and higher mortality. In the patients with
a fever, almost half had a bacterial infection. The common
organisms included Escherichia coli, Staphylococcus aureus,
and Enterococcus faecium. All patients with a fever should be
evaluated, but it appears that greater TBSA burned, as well as
the presence of indwelling catheters, are risks for bacterial
infections, including sepsis (Vyles 2014).
In another retrospective analysis of 92 ventilated burn
patients admitted to a single burn center, about 40% had a
ventilator-associated pneumonia, which correlated with a
statistically significantly longer hospital stay. Organisms
responsible for the pneumonia included Streptococcus pneu-
moniae, S. aureus, Pseudomonas aeruginosa, and Acinetobacter
baumannii. Half of the deaths in the cohort were attributed
to pneumonia (Rogers 2014). Similar to other critically ill
patients, early recognition and treatment of infections are
important for ventilated burn patients.
Secondary to their hypermetabolic state and need for
aggressive fluid management, burn patients may have
altered pharmacokinetics. In 70 patients administered ami-
kacin together with piperacillin/tazobactam and vancomycin
for presumed or actual sepsis, a pharmacokinetic model was
used to evaluate standard dosing of amikacin applied to the
burn patients. Clearance of amikacin increased, but peak
concentrations remained similar to those of other critically ill
children. Given the mechanism of action of aminoglycosides,
this increased clearance may not affect the efficacy of the
antibiotic in burn patients (Sherwin 2014).
In a small study evaluating vancomycin pharmacokinetics
in 13 severe burn patients, patients were administered a 10- to
15-mg/kg/dose four times a day infused over 1 hour. On ini-
tial dosing, a target vancomycin trough plasma concentration
greater than 10 mcg/mL was achieved in only 15% of patients.
An increase in the daily dose to an average of 98 mg/kg/day
produced an average trough concentration of 13 mcg/mL.
With this vancomycin dose, an AUC/MIC ratio greater than
400 was achieved in 93% of patients, assuming an S. aureus
MIC of 0.5 mg/L (Gomez 2013). Given these results from this
small number of patients, together with the dosage strate-
gies used in critical care in general, doses of 80100 mg/kg/
day divided every 6 hours should be used for vancomycin in
pediatric burn patients to achieve optimal vancomycin trough
targets of 1520 mcg/mL.
PAIN MANAGEMENT
The pain associated with burns and the procedures asso-
ciated with treatment must be treated adequately and
aggressively. General treatment strategies involve opioids and
PedSAP 2016 Book 2 Pediatric Critical Care
benzodiazepines with adjunctive use of ketamine, NSAIDs,
dexmedetomidine, and gabapentin if neuropathic pain
persists.
In one study of 500 burn patients; almost all patients
received an opioid, 75% received a benzodiazepine; and
about 50% received propofol or ketamine (Stoddard 2011).
A retrospective study of 147 patients observed the effects
of opioids administered early in burn treatment. Opioid dos-
ing within the first 7 days of injury correlated with decreased
Child Stress Disorders Checklist scores, signifying less post-
traumatic stress disorder. The authors also found that the
effect was long lasting (up to 4 years after discharge) and
dose related (Sheridan 2014). In a study that evaluated dex-
medetomidine (average dose 0.57 mcg/kg/hour for 40 hours)
as a sedative in 11 mechanically ventilated severely burned
patients, the patients had better sedation and fewer episodes
of hypotension (Lin 2011).
In a study of 8 severely burned patients, the children were
given escalating doses of morphine (average 0.45 mg/kg/
hour) and midazolam (average 0.44 mg/kg/hour) until dexme-
detomidine was added at a bolus of 1 mcg/kg over 10 minutes
followed by a continuous infusion of 0.752.5 mcg/kg/hour.
Three of the patients had a drop in MAP below 50 mm Hg;
thus, the continuous infusion was held. In general, the aver-
age decrease in MAP was 37%, and heart rate decreased
by almost 20%. During burn injury, there is a hypermeta-
bolic state with increased catecholamines, which can lead
to hypertension. Administration of dexmedetomidine can
decrease this, but a significant drop in blood pressure also
can be observed (Shank 2013). According to this small study,
bolus dosing likely should not be used or given over 30 min-
utes in burn patients.
Studies evaluating the proper pain management and
sedation strategies in burn patients have been inadequate,
but opioids and benzodiazepines should be the mainstay of
therapy, with opioids administered early to these children.
Dexmedetomidine can be used as an adjunct or agent for
sedation in patients with severe burns, using normal hospital
sedation protocols.
CONCLUSION
Treatment of TBI in the pediatric patient is complex and con-
sists of various treatment modalities. Initial management of
MAP includes aggressive fluid resuscitation with 0.9% saline
and vasopressors. Management of elevated ICP includes
hypertonic saline, adequate sedation with benzodiazepines,
and opioids with adjunctive sedative agents as needed.
Neuromuscular blockage, seizure prophylaxis, normothermia,
and euglycemia should also be used in the patient with TBI.
Burn pathophysiology is complex with a generalized hyper-
metabolic state. Early and adequate fluid resuscitation with
lactated Ringer solution at up to 6 mL/kg/%TBSA should
be used. Strategies such as euglycemia, early nutritional
support, oxandrolone, and -blockers potentially improve
87 Trauma
outcomes. Burn patients are at an increased risk of infec-
tions, including sepsis and ventilator-associated pneumonia.
Early and aggressive antibiotic management should be used
to decrease infectious complications. Pain, a significant
comorbidity of burn injuries, should be managed with opioids
and adjunctive agents as needed.
Practice Points
Traumatic Brain Injury:
CPP = MAP ICP
Optimize MAP using 0.9% saline and vasopressors
Decrease ICP:
Sedation (watching for hypotension)
3% saline
23.4% saline in certain situations (e.g., fluid over-
load or cardiac dysfunction)
Barbiturates
Mannitol (but falling out of favor)
Avoid hypothermia and hyperthermia
Keep patient euglycemic
Seizure prophylaxis with fosphenytoin if focal neurologic
deficits, bone or metal fragments, young age, penetrating
injury
Burns
Initial fluid management with lactated Ringer at up to
6mL/kg/%TBSA
Keep patient euglycemic
Start nutrition early
Oxandrolone and -blockers for hypermetabolic state
Watch for infections and treat aggressively
Adequate pain control
REFERENCES
Adelson PD. Hypothermia in Children After Trauma. 2012.
Clinical Trials.gov:NCT00222742.
Arango JI, Deibert CP, Brown D, et al. Posttraumatic seizures
in children with severe traumatic brain injury. Childs Nerv
Syst 2012;28:1925-9.
Bar-Joseph G, Guilburd Y, Tamir A, et al. Effectiveness of
ketamine in decreasing intracranial pressure in chil-
dren with intracranial hypertension. J Neurosurg Pediatr
2009;4:40-6.
Beca J, McSharry B, Erickson S, et al. Hypothermia for trau-
matic brain injury in children a phase II randomized
controlled trial. Crit Care Med 2015;43:1458-66.
Bhalla T, Dewhirst E, Sawardekar A, et al. Perioperative man-
agement of the pediatric patient with traumatic brain
injury. Pediatr Anaesth 2012;22:627-40.
Borsheim E, Herndon DN, Hawkins HK, et al. Pamidronate
attenuates muscle loss following pediatric burn injury. J
Bone Miner Res 2014;29:1369-72.
Bramwell KJ, Haizlip J, Pribble C, et al. The effect of etomi-
date on intracranial pressure and systemic blood pressure
PedSAP 2016 Book 2 Pediatric Critical Care
in pediatric patients with severe traumatic brain injury.
Pediatr Emerg Care 2006;22:90-3.
Branski LK, Herndon DN, Barrow RE, et al. Randomized con-
trolled trial to determine the efficacy of long-term growth
hormone treatment in severely burned children. Ann Surg
2009;250:514-23.
Breederveld RS, Tuinebreijer WE. Recombinant human
growth hormone for treating burns and donor sites.
Cochrane Database Syst Rev 2012;12:CD008990.
Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin ther-
apy and pentastarch resuscitation in severe sepsis. N Engl
J Med 2008;358:125-39.
Buck ML. Dexmedetomidine use in pediatric intensive
care and procedural sedation. J Pediatr Pharmacol Ther
2010;15:17-29.
Cox CS, Baumgartner JE, Harting MT, et al. Autologous bone
marrow mononuclear cell therapy for severe traumatic
brain injury in children. Neurosurgery 2011;68:588-600.
Elkon B, Riva Cambrin J, Hirshberg E, et al. Hyperglycemia:
an independent risk factor for poor outcome in chil-
dren with traumatic brain injury. Pediatr Crit Care Med
2014;15:623-31.
Empey PE, Velez de Mendizabal N, Bell MJ, et al. Therapeutic
hypothermia decreases phenytoin elimination in children
with traumatic brain injury. Crit Care Med 2013;41:2379-87.
Faul M, Xu L, Wald MM, et al. Traumatic brain injury in the
United States: emergency department visits, hospitaliza-
tions and deaths 2002-2006. Atlanta: CDC, National Center
for Injury Prevention and Control, 2010.
Fram RY, Cree MG, Wolfe RR, et al. Intensive insulin therapy
improves insulin sensitivity and mitochondrial function in
severely burned children. Crit Care Med 2010;38:1475-83.
Gomez DS, Campos EV, de Azevedo RP, et al. Individualised
vancomycin doses for paediatric burn patients to achieve
PK/PD targets. Burns 2013;39:445-50.
Greve MW, Zink BJ. Pathophysiology of traumatic brain
injury. Mt Sinai J Med 2009;76:97-104.
Hart DW, Wolf SE, Ramzy PI, et al. Anabolic effects of oxan-
drolone after severe burn. Ann Surg 2001;233:556-64.
Herndon DN, Rodriguez NA, Diaz EC, et al. Long-term pro-
pranolol use in severely burned pediatric patients: a
randomized controlled study. Ann Surg 2012;256:402-11.
Jeschke MG, Chinkes DL, Finnerty CC, et al.
Pathophysiologic response to severe burn injury. Ann Surg
2008;248:387-401.
Jeschke MG, Kulp GA, Kraft R, et al. Intensive insulin therapy
in severely burned pediatric patients: a prospective ran-
domized trial. Am J Respir Crit Care Med 2010;182:351-59.
Jeschke MG, Pinto R, Herndon DN, et al. Hypoglycemia is
associated with increased postburn morbidity and mortal-
ity in pediatric patients. Crit Care Med 2014a;42:1221-31.
88 Trauma
Jeschke MG, Herndon DN. Burns in children: standard and
new treatments. Lancet 2014b;383:1168-78.
Jones KE, Puccio AM, Harshman KJ, et al. Levetiracetam ver-
sus phenytoin for seizure prophylaxis in severe traumatic
brain injury. Neurosurg Focus 2008;25:E3-E3.
Khorasani EN, Mansouri F. Effect of early enteral nutrition
on morbidity and mortality in children with burns. Burns
2010;36:1067-71.
Kochanek PM, Carney N, Ashwal S, et al. Guidelines for the
acute medical management of severe traumatic brain
injury in infants, children, and adolescents-second edition.
Pediatr Crit Care Med 2012;13:S1-S82.
Kraft R, Herndon DN, Mlcak RP, et al. Bacterial respiratory
tract infections are promoted by systemic hyperglyce-
mia after severe burn injury in pediatric patients. Burns
2014;40:428-35.
LaRochelle JM. Trauma. In: Eiland LS, Todd TJ, eds.
Advanced Pediatric Therapeutics. Memphis: Pediatric
Pharmacy Advocacy Group, 2015:chap 23.
Liao GP, Harting MT, Hetz RA, et al. Autologous bone marrow
mononuclear cells reduce therapeutic intensity for severe
traumatic brain injury in children. Pediatr Crit Care Med
2015;16:245-55.
Liesemer K, Bratton SL, Zebrack CM, et al. Early post-trau-
matic seizures in moderate to severe pediatric traumatic
brain injury: rates, risk factors, and clinical features. J
Neurotrauma 2011;28:755-62.
Lin H, Faraklas I, Sampson C, et al. Use of dexmedetomidine
for sedation in critically ill mechanically ventilated pediat-
ric burn patients. J Burn Care Res 2011;32:98-103.
Mehta NM, Compher C; ASPEN Board of Directors. ASPEN
clinical guidelines: nutrition support of the critically ill
child. JPEN J Parenter Enteral Nutr 2009;33:260-76.
Nakagawa K, Chang CWJ, Koenig MA, et al. Treatment of
refractory intracranial hypertension with 23.4% saline
in children with traumatic brain injury. J Clin Anesth
2012;24:318-23.
Osterman MJK, Kochanek KD, MacDorman MF. Annual
summary of vital statistics: 2012-2013. Pediatr
2015;135:1115-25.
Pearl PL, McCarter R, McGavin CL, et al. Results of phase
II levetiracetam trial following acute head injury in
children at risk for posttraumatic epilepsy. Epilepsia
2013;54:e135-37.
Pereira CT, Murphy KD, Herndon DN. Altering metabolism. J
Burn Care Rehabil 2005;26:194-9.
Pham TN, Cancio LC, Gibran NS. American Burn Association
practice guidelines burn shock resuscitation. J Burn Care
Res 2008;29:257-66.
Piatt JH, Neff DA. Hospital care of childhood traumatic brain
injury in the United States, 1997-2009: a neurosurgical per-
spective. J Neurosurg Pediatr 2012;10:257-67.
PedSAP 2016 Book 2 Pediatric Critical Care
Piper BJ, Harrigan PW. Hypertonic saline in paediatric trau-
matic brain injury: a review of nine years experience with
23.4% hypertonic saline as standard hyperosmolar ther-
apy. Anaesth Intensive Care 2015;43:204-10.
Porro LJ, Herndon DN, Rodriguez NA, et al. Five-year out-
comes after oxandrolone administration in severely
burned children: a randomized clinical trial of safety and
efficacy. J Am Coll Surg 2012;214:489-502.
Porter C, Cotter M, Diaz EC, et al. Amino acid infusion fails to
stimulate skeletal muscle protein synthesis up to 1 year
after injury in children with severe burns. J Trauma Acute
Care Surg 2013;74:1480-84.
Qu R, Li Y, Gao Q, et al. Neurotrophic and growth factor gene
expression profiling of mouse bone marrow stromal cells
induced by ischemic brain extracts. Neuropathology
2007;27:355-63.
Robertson CL, Fidan E, Stanley RM, et al. Progesterone for
neuroprotection in pediatric traumatic brain injury. Pediatr
Crit Care Med 2015;16:236-44.
Rogers DA, Deal C, Argent AC, et al. Ventilator associ-
ated pneumonia in major paediatric burns. Burns
2014;40:1141-8.
Sabsovich I, Rehman Z, Yunen J, et al. Propofol infusion syn-
drome: a case of increasing morbidity with traumatic brain
injury. Am J Crit Care 2007;16:82-5.
Schoeler M, Loetscher PD, Rossaint R, et al.
Dexmedetomidine is neuroprotective in an in vitro model
for traumatic brain injury. BMC Neurol 2012;12:20.
Scott JR, Muangman PR, Tamura RN, et al. Substance P
levels and neutral endopeptidase activity in acute burn
wounds and hypertrophic scar. Plast Reconst Surg
2005;115:1095-102.
Shank ES, Sheridan RL, Ryan CM, et al. Hemodynamix
responses to dexmedetomidine in critically injured intu-
bated pediatric burned patients: a preliminary study. J
Burn Care Res 2013;34:311-7.
Sheridan RL, Stoddard FJ, Kazis LE, et al. Long-term post-
traumatic stress symptoms vary inversely with early
opiate dosing in children recovering from serious burns:
effects durable at 4 years. J Trauma Acute Care Surg
2014;76:828-32.
Sherwin CMT, Wead S, Stockmann C, et al. Amikacin popu-
lation pharmacokinetics among paediatric burn patients.
Burns 2014;40:311-8.
Smith RL, Lin JC, Adelson PD, et al. Relationship between
hyperglycemia and outcome in children with severe trau-
matic brain injury. Pediatr Crit Care Med 2012;13:85-91.
Sookplung P, Siriussawakul A, Malakouti A, et al.
Vasopressor use and effect on blood pressure after severe
adult traumatic brain injury. Neurocrit Care 2011;15:46-54.
Stanley RM, Bonsu BK, Zhao W, et al. US estimates of hos-
pitalized children with severe traumatic brain injury:
implications for clinical trials. Pediatrics 2012;129:e24-30.
89 Trauma
Stoddard FJ, White GW, Kazis LE, et al. Patterns of medica-
tion administration from 2001 to 2009 in the treatment of
children with acute burn injuries: a multicenter study. J
Burn Care Res 2011;32:519-28.
Sundberg J, Estrada C, Jenkins C, et al. Hypothermia is asso-
ciated with poor outcome in pediatric trauma patients. Am
J Emerg Med 2011;29:1019-22.
Taketomo CK, Hodding JH, Kraus DM. Pediatric and
Neonatal Dosage Handbook, 22nd ed. Hudson, OH: Lexi-
Comp, 2015.
Tilford JM, Simpson PM, Yeh TS, et al. Variation in therapy
and outcome for pediatric head trauma patients. Crit Care
Med 2001;29:1056-61.
Tuvdendorj D, Chinkes DL, Zhang XJ, et al. Long-term oxan-
drolone treatment increases muscle protein net deposition
via improving amino acid utilization in pediatric patients 6
months after burn injury. Surgery 2011;149:645-53.
van den Berghe G, Wouters P, Weekers F, et al. Intensive
insulin therapy in critically ill patients. N Engl J Med
2001;345:1359-67.
Vavilala MS, Kernic MA, Wang J, et al. Acute care clinical
indicators associated with discharge outcomes in chil-
dren with severe traumatic brain injury. Crit Care Med
2014;42:2258-66.
Vyles D, Sinha M, Rosenberg DI, et al. Predictors of serious
bacterial infections in pediatric burn patients with fever. J
Burn Care Res 2014;35:291-95.
PedSAP 2016 Book 2 Pediatric Critical Care
Walker PA, Harting MT, Jimenez F, et al. Direct intrathe-
cal implantation of mesenchymal stromal cells leads to
enhanced neuroprotection via an NFkappaB-mediated
increase in interleukin-6 production. Stem Cells Dev
2010;19:867-76.
Walker TLJ, Urriza Rodriguez D, Coy K. Impact of reduced
resuscitation fluid on outcomes of children with 10-20%
body surface area scalds. Burns 2014;40:1581-86.
Wayne EA, Dean HJ, Booth F, et al. Focal neurologic deficits
associated with hypoglycemia in children with diabetes. J
Pediatr 1990;117:575-7.
Williams FN, Herndon DN, Kulp GA, et al. Propranolol
decreases cardiac work in a dose-dependent manner in
severely burned children. Surgery 2011;149:231-9.
WHO. Media Center. Burns. 2016.
Yung M, Wilkins B, Norton L, et al. Glucose control, organ fail-
ure, and mortality in pediatric intensive care. Pediatr Crit
Care Med 2008;9:147-52.
Zeiler FA, Teitelbaum J, West M, et al. The ketamine
effect on ICP in traumatic brain injury. Neurocrit Care
2014;21:163-73.
Zink BJ, Szmydynger-Chodobska J, Chodobski A. Emerging
concepts in the pathophysiology of traumatic brain injury.
Psychiatr Clin North Am 2010;33:741-56.
90 Trauma
Self-Assessment Questions
Questions 2124 pertain to the following case.
L.T. is a 10-year-old boy (weight 30 kg) who was an unre-
strained passenger in a motor vehicle crash. At the scene, his
Glasgow Coma Scale (GSC) score is 4, and he is intubated.
Initial vital signs include blood pressure 40/20 mm Hg and
heart rate 140 beats/minute.
21. Which one of the following is best to recommend for
L.T.s initial treatment?
A. Normal saline 20 mL/kg bolus
B. Albumin 5% 20 mL/kg bolus
C. Dextrose 5% 20 mL/kg/bolus
D. 3% normal saline 10 mL/kg
22. L.T. begins to have rales on physical examination; how-
ever, his blood pressure is 50/25 mm Hg. Which one of
the following is best to recommend for L.T.?
A. Albumin 5% 20 mL/kg bolus
B. Norepinephrine 0.1 mcg/kg/minute
C. Milrinone 0.5 mcg/kg/minute
D. Vasopressin 1 milliunit/kg/minute
23. On transfer to your hospital, L.T. still has a GCS score of 7
and is becoming hypertensive. The interventions in the pre-
vious questions are discontinued, and L.T.s blood pressure
is now stable at 120/80 mm Hg. Rales are now absent from
the lung fields. No other drugs have been given. The neu-
rosurgery team has begun placing an intracranial pressure
(ICP) monitor and drain when L.T.s blood pressure becomes
150/100 mm Hg with a heart rate of 150 beats/minute.
Which one of the following is the best intervention for L.T.?
A. Therapeutic hypothermia
B. 3% hypertonic saline
C. Sedation with fentanyl and midazolam bolus
D. A neuromuscular blocking agent
24. L.T.s ICP monitor is placed without incident, and his
blood pressure and heart rate are normal and stable.
Laboratory values are normal. Initial ICP is 35 mm Hg.
Which one of the following is best to initiate for L.T.?
A. Fosphenytoin
B. Normal saline bolus
C. Pentobarbital
D. 3% saline
25. A 3-year-old child who sustains a traumatic brain injury
(TBI) after a motor vehicle collision is admitted to the
pediatric ICU. Five 5 hours after the injury, her temper-
ature is 101.9F. Which one of the following is the best
course of action for this patient?
A. Acetaminophen
B. Therapeutic hypothermia
PedSAP 2016 Book 2 Pediatric Critical Care
C. Cultures and broad-spectrum antibiotics
D. No treatment needed
26. A 9-year-old girl was admitted to the ICU after a severe
TBI. She has been stabilized and has normal blood pres-
sure and adequate sedation. The patients ICP has been
10 mm Hg for the past several hours. Laboratory val-
ues are as follows: Na 160 mEq/L, K 4.1 mEq/L, Cl 100
mEq/L, HCO3 25 mEq/L, BUN 20 mg/dL, and SCr 0.6 mg/
dL. The patients osmolarity is 340 mOsm/L. Her perti-
nent drugs include fentanyl 1 mcg/kg/hour, midazolam
0.1 mg/kg/hour, 3% saline at 0.3 mL/kg/hour, and man-
nitol 0.25 g/kg every 6 hours. Her ICP suddenly increases
to 35 mm Hg for 6 minutes, with no changes to her vital
signs. Which one of the following is most appropriate in
this patients ICP management?
A. Increase mannitol to 0.5 g/kg every 6 hours.
B. Increase fentanyl and midazolam.
C. Administer 3% saline bolus 7 mL/kg.
D. Administer pentobarbital 5 mg/kg.
Questions 27 and 28 pertain to the following case.
V.R. is a 6-year-old girl who sustains a TBI from a motor vehi-
cle crash. She is intubated for a GCS score of 6. All of her
laboratory values are normal except for Na 170 mEq/L and
serum osmolarity 355 mOsm/L. V.R.s heart rate is 150 beats/
minute, and her blood pressure is 170/100 mm Hg. Her per-
tinent drugs include fentanyl 1 mcg/kg/hour, midazolam
0.1 mg/kg/hour, 3% saline at 0.3 mL/kg/hour, and mannitol
0.25 g/kg every 6 hours. Her ICP is 30 mm Hg.
27. Which one of the following is best to recommend for V.R.?
A. Increase mannitol to 0.5 g/kg every 6 hours.
B. Give fentanyl and midazolam bolus.
C. Administer 3% saline bolus 7 mL/kg.
D. Administer pentobarbital 5 mg/kg.
28. V.R. receives the intervention described earlier, and her
vital signs remain normal. The team will insert a central
and arterial line on the patient. Which one of the follow-
ing would be best to prevent ICP spikes in V.R.?
A. 23.4% saline bolus
B. 3% saline bolus
C. Mannitol 0.25 g/kg intravenous bolus
D. Propofol bolus
29. A 4-year-old girl sustains a TBI and is intubated for a
GCS score of 5. All of her laboratory values and vital
signs are normal except for Na 170 mEq/L and serum
osmolarity 355 mOsm/L. Her pertinent drugs include
fentanyl 2 mcg/kg/hour, midazolam 0.2 mg/kg/hour,
vecuronium 0.1 mg/kg/hour, 3% saline at 0.3 mL/kg/hour,
91 Trauma
and mannitol 0.25 mg/kg every 6 hours. Sedation and Questions 3340 pertain to the following case.

paralysis are adequate. The patients ICP is now 30 mm Q.V. is a 3-year-old boy (weight 10 kg) who sustained a 50%
Hg. Which one of the following is best for this patients total body surface area burn in a house fire. Q.V. is intubated
treatment? and brought to your burn center. On admission, a central line
is placed.
A. Increase fentanyl to 3 mcg/kg/hour.
B. Increase 3% saline to 0.4 mL/kg/hour. 33. Which one of the following would best provide fluid
C. Give mannitol 0.5 mg/kg intravenous bolus. resuscitation in Q.V.?
D. Give pentobarbital 5 mg/kg bolus, followed by A. 5% albumin
continuous infusion. B. Lactated Ringer
C. 0.9% saline
Questions 3032 pertain to the following case.
D. 3% saline

T.F. is a 1-year-old girl who arrives to the pediatric ICU intu-
bated after a TBI. On CT, there is diffuse axonal injury (DAI)
as well as bone fragments in the brain. Echocardiography
reveals an ejection fraction of 10% after the injury. On
day 2 of admission, T.F.s drug therapy includes fentanyl,
midazolam, mannitol, vecuronium, pentobarbital, and
3% saline. Her vital signs and laboratory values are nor-
mal. Her serum sodium is 145 mEq/L, and osmolarity is
300mOsm/L. Sedation is adequate. Rales are auscultated
bilaterally in both lungs. T.F.s ICP rises to 40 mm Hg for
7minutes.
30. Which one of the following is best for T.F.?
A. Give 23.4% saline 0.5 mL/kg.
B. Increase fentanyl and midazolam.
C. Give 3% saline bolus 10 mL/kg.
D. Give mannitol 0.5 g/kg intravenous bolus.
31. T.F.s attending physician asks your opinion about sei-
zure prophylaxis. Which one of the following is best to
recommend for T.F.?
A. Seizure prophylaxis is discouraged in the TBI
guidelines.
B. The patient has risk factors of DAI, young age,
andbone fragments; thus, prophylaxis should be
given.
C. The patient has risk factors of mannitol
administration, a decreased ejection fraction, and
rales; thus, prophylaxis should be given.
D. The patient has no risk factors for seizures; thus,
prophylaxis is not indicated.
32. T.F.s care team decides to initiate seizure prophylaxis.
Which one of the following is the best agent and monitor-
ing to recommend for T.F.?
A. Fosphenytoin and total phenytoin concentration
B. Fosphenytoin and free phenytoin concentration
C. Phenobarbital and phenobarbital trough
concentration
D. Valproic acid and valproic acid trough
concentration
34. Which one of the following represents the optimal
administration of intravenous fluids for resuscitation
inQ.V.?
A. 188 mL/hour for 8 hours; then 93 mL/hour for 16
hours
B. 125 mL/hour for 8 hours; then 63 mL/hour for 16
hours
C. 125 mL/hour for 24 hours
D. 83 mL/hour for 24 hours
35. Which one of the following glycemic ranges would be
optimal for Q.V.?
A. 6080 mg/dL
B. 80130 mg/dL
C. 140180 mg/dL
D. 170215 mg/dL
36. Q.V. is intubated and requires sedative agents. Which one
of the following is best to recommend for Q.V.?
A. Midazolam
B. Dexmedetomidine
C. Ketamine and clonidine
D. Fentanyl and midazolam
37. On day 3 of admission, Q.V. spikes a fever (temperature
102.5F). Which one of the following is best to recom-
mend for Q.V.?
A. This is a post-burn fever, and antibiotics are
unnecessary.
B. This is viral related, and supportive care is
indicated.
C. Give piperacillin/tazobactam and vancomycin.
D. Give ampicillin and gentamicin.
38. Q.V.s team decided to initiate vancomycin, independent
of your suggestion. Which one of the following is the best
dosing strategy for Q.V.?
A. 150 mg intravenously every 8 hours
B. 150 mg intravenously every 6 hours
C. 200 mg intravenously every 8 hours
D. 200 mg intravenously every 6 hours

PedSAP 2016 Book 2 Pediatric Critical Care 92 Trauma

39. After 1 week, Q.V. has signs of a hypermetabolic state.
Which one of the following is best for Q.V.?
A. Oxandrolone
B. Growth hormone
C. Pamidronate
D. Clonidine
40. The intervention you recommended for Q.V. was partly
successful. However, he still has signs of tachycardia
and hypertension. Which one of the following is best to
recommend for Q.V.?
A. Esmolol
B. Lisinopril
C. Verapamil
D. Propranolol

PedSAP 2016 Book 2 Pediatric Critical Care 93 Trauma

Learner Chapter Evaluation: Trauma.
As you take the posttest for this chapter, also evaluate the
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
20. The content of the chapter met my educational needs.
21. The content of the chapter satisfied my expectations.
22. The author presented the chapter content effectively.
23. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
24. The content of the chapter was objective and balanced.
25. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
26. The content of the chapter was useful to me.
27. The teaching and learning methods used in the chapter
were effective.
28. The active learning methods used in the chapter were
effective.
29. The learning assessment activities used in the chapter
were effective.
30. The chapter was effective overall.
PedSAP 2016 Book 2 Pediatric Critical Care
Use the 5-point scale to indicate whether this chapter pre-
pared you to accomplish the following learning objectives:
31. Develop strategies to optimize a patients mean arterial
pressure.
32. Assess strategies to decrease or prevent increased intra-
cranial pressure.
33. Demonstrate appropriate sedation management strate-
gies, as well as appropriate glucose control and seizure
prophylaxis, for the patient with traumatic brain injury.
34. Design appropriate fluid management and treatment
approach to increase lean body mass in a patient with burns.
35. Compose strategies to optimize pain control and treat
infections in a patient with burns.
36. Please provide any specific comments related to any
perceptions of bias, promotion, or advertisement of
commercial products.
37. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
Questions 3840 apply to the entire learning module.
38. How long did it take you to read the instructional materi-
als in this module?
39. How long did it take you to read and answer the assess-
ment questions in this module?
4 0. Please provide any additional comments you may have
regarding this module:
94 Trauma
Clinical and Practice Updates I
Clinical and Practice Updates I Panel

Series Editors: Kyle Davis, Pharm.D., BCPS

Marcia L. Buck, Pharm.D., BCPPS, FCCP, FPPAG Clinical Pharmacy Specialist-Internal Medicine
Department of Pharmacy and Internal Medicine
Clinical Coordinator
Ochsner Medical Center
University of Virginia Childrens Hospital
New Orleans, Louisiana
Professor
Department of Pediatrics
University of Virginia School of Medicine
Guideline Review: Diabetic
Clinical Professor
Virginia Commonwealth University School of Pharmacy Ketoacidosis and Hyperglycemic
Department of Pharmacy Services Hyperosmolar State
University of Virginia Health System
Authors
Charlottesville, Virginia
Elizabeth S. Goswami, Pharm.D., BCPS, BCPPS
Kalen B. Manasco, Pharm.D., BCPS
Clinical Pharmacy Specialist
Clinical Associate Professor
Department of Pharmacy
Department of Clinical and Administrative Pharmacy
The Johns Hopkins Hospital
University of Georgia College of Pharmacy
Baltimore, Maryland
Augusta, Georgia
Susan Warrington, Pharm.D., BCPPS
Faculty Panel Chair: Clinical Pharmacist, Pediatric Critical Care
Joseph M. LaRochelle, Pharm. D., BCPPS Department of Pharmacy
The Childrens Hospital of Philadelphia
Clinical Associate Professor
Philadelphia, Pennsylvania
College of Pharmacy
Xavier University of Louisiana
Reviewers
Clinical Associate Professor of Pediatrics
Louisiana State University Health Sciences Julie Pingel, Pharm.D.
Center School of Medicine Pediatric Critical Care Clinical Pharmacist
New Orleans, Louisiana Pediatric Pharmacy
Monroe Carell Jr. Childrens Hospital at Vanderbilt
Nashville, Tennessee
Interactive Case: Severe Acute Asthma Ifeyinwa D. Eboh, Pharm.D., MPH, BCPS
(Status Asthmaticus) Clinical Pharmacist
Pharmacy Department
Author
Texas Health Presbyterian Hospital
Laura Lo Castro Bio, Pharm.D., BCPS Allen, Texas
Clinical Pharmacist
Monica A. Puebla, Pharm.D., MBA, MHA, BCPS
Department of Pharmacy
Medication Safety-Healthcare Professional Reviewer
Lucile Packard Childrens Hospital Stanford
Med-ERRS, Inc.
Palo Alto, California
Horsham, Pennsylvania
Reviewers
Lois F. Parker, BSPharm, FASHP Interactive Case: Status Epilepticus
Clinical Pharmacist
Department of Pharmacy Author
Massachusetts Eye and Ear Christina Cox, Pharm.D., BCPS, BCPPS
Boston, Massachusetts
Assistant Professor
Brooke Clark, Pharm.D., BCPS Clinical Pharmacy and Outcomes Sciences
Clinical Pharmacy Program Manager South Carolina College of Pharmacy,
Banner Health University of South Carolina
Phoenix, Arizona Columbia, South Carolina
Reviewers The American College of Clinical Pharmacy and the authors
Emily L. Rowe, Pharm.D., BCPS, BCPPS, MS-PREP thank the following individuals for their careful review of the
Senior Clinical Pharmacy Specialist, Pediatrics Clinical and Practice Updates I features:
Department of Pharmacy
Nicola G. Dahl, Pharm.D.
The Floating Hospital for Children at Tufts Medical Center
Medical Writer
Boston, Massachusetts
Kanab, Utah
Maha O. Kebir, Pharm.D., MS, BCPS, CPHQ
Clinical Pharmacist
Department of Pharmacy
Christiana Care Health System
Newark, Delaware
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Consultancies: Elizabeth J. Beckman (Lexi-Comp/Wolters/Kluwer Health); Regine L Caruthers (Lexi-Comp/Wolters Kluwer
Health); Joseph M. LaRochelle (ACCP); Lois F. Parker (ASHP/MSHP)

Stock Ownership:

Royalties:

Grants: Elizabeth J. Beckman (ASHP Foundation); Christina Cox (University of South Carolina);

Honoraria: Christina Cox (ACCP, Palmetto Health Richland Childrens Hospital); Jennifer L. Morris (ACCP, Society of Critical Care
Medicine, Pediatric Pharmacy Advocacy Group, Wolters Kluwer)

Other:

Nothing to disclose: Laura Lo Castro Bio, Joshua Caballero, Brooke Clark, Kyle Davis, Ifeyinwa D. Eboh, Elizabeth S. Goswami,
Aaron A. Harthan, Maha O. Kebir, Allison Lardieri, Michael A. Maccia, Kristine Parbuoni, Monica A. Puebla, Sara P. Rooney, Emily
L. Rowe, Ashley R. Schappell, Julie Pingel, Brandi L. Strauser, Andrea Joan Stumpe, Susan Warrington

ROLE OF BPS: The Board of Pharmacy Specialties (BPS) is an autonomous division of the American Pharmacists Association
(APhA). BPS is totally separate and distinct from ACCP. The Board, through its specialty councils, is responsible for specialty
examination content, administration, scoring, and all other aspects of its certification programs. PedSAP has been approved by
BPS for use in BCPPS recertification. Information about the BPS recertification process is available online.

Other questions regarding recertification should be directed to:

Board of Pharmacy Specialties

2215 Constitution Avenue NW
Washington, DC 20037
(202) 429-7591
CONTINUING PHARMACY EDUCATION AND
RECERTIFICATION INSTRUCTIONS
Continuing Pharmacy Education Credit: The American College of Clinical Pharmacy is accredited by the Accreditation
Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education (CPE).

PedSAP: Target Audience: The target audience for PedSAP 2016 Book 2(Pediatric Critical Care) is pediatric pharmacotherapy spe-
cialists and advanced-level clinical pharmacists caring for pediatric patients with several acute conditions and complications of
the pulmonary, cardiovascular, endocrine, and neurologic systems.

Available CPE credits: Purchasers who successfully complete all posttests for PedSAP 2016 Book 2 (Pediatric Critical Care)
can earn 13.0 contact hours of continuing pharmacy education credit. The universal activity numbers are as follows: Pediatric
Critical Care I 0217-0000-16-021-H01-P, 3.5 contact hours; Pediatric Critical Care II 0217-0000-16-022-H01-P, 4.5 contact
hours; and Clinical and Practice Updates 0217-0000-16-170-H01-P, 5.0 contact hours. You may complete one or all available mod-
ules for credit. Tests may not be submitted more than once.

BCPPS test deadline: 11:59 p.m. (Central) on January 17, 2017.

ACPE test deadline: 11:59 p.m. (Central) on September 14, 2019.

Posttest access: Go to www.accp.com and sign in with your e-mail address and password. Technical support is available from
8 a.m. to 5 p.m. (Central) weekdays by calling (913) 492-3311. PedSAP products are listed under My Online Products on your My
Account page.

BCPPS Recertification Credit: To receive BCPPS recertification CPE credit, a PedSAP posttest must be submitted within the
4-month period after the books release. The first page of each print and online book lists the deadline to submit a required
posttest for BCPPS recertification credit. Only completed tests are eligible for credit; no partial or incomplete tests will be pro-
cessed. Tests may not be submitted more than once. The passing point for BCPPS recertification is based on an expert analysis of
the items in each posttest module.

ACPE CPE Credit: To receive ACPE CPE credit for a PedSAP module, a posttest must be submitted within the 3-year period after
the books release. The appropriate CPE credit will be awarded for test scores of 50% and greater.

Credit Assignment and Reporting: All required posttests that meet the 50% score standard will be immediately awarded the
appropriate ACPE CPE credit. Earned credits will be transmitted within 24 hours to www.mycpemonitor.net and should appear on
statements of credit within 3 business days.

Required posttests that are submitted before the BCPPS test deadline and that meet the passing point set by statistical analysis
will earn BCPPS recertification credits. These credits will be posted within 30 days after the BCPPS test deadline. For statements
of CPE credit, visit www.mycpemonitor.net.

All BCPPS recertification credits are forwarded by ACCP to the Board of Pharmacy Specialties (BPS). Questions regarding the
number of hours required for BCPPS recertification should be directed to BPS at (202) 429-7591 or www.bpsweb.org. The ACCP
Recertification Dashboard is a free online tool that can track recertification credits as they are earned through ACCP and schedule
new opportunities for credits from upcoming ACCP professional development programs.

Posttest Answers: The explained answers with rationale and supporting references will be posted 1 week after the BCPPS
test deadline and will be available to anyone who has either submitted a posttest or waived his or her right to receive credit (see
below) from a posttest. Go to www.accp.com and sign in with your e-mail address and password. Click the PedSAP book on your
My Account page and you will see a link to the explained answers.

Test Waivers: To access the explained answers without submitting a posttest, sign in to your My Account page, select the
PedSAP book, and click on the waiver link for that module. By completing the waiver form for a module, you waive the opportu-
nity to receive CPE credit for that module. After you submit a waiver, you will see a link to the PDF file that contains the answers
for the module you waived. Answers will be available starting 1 week after the BCPPS test deadline.

ACSAP 2016 Book 2 Pediatric Critical Care 100 Program Instructions

Interactive Patient Case: Severe
Acute Asthma (Status Asthmaticus)
By Laura Lo Castro Bio, Pharm.D., BCPS

Reviewed by Lois F. Parker, BSPharm, FASHP; Brooke Clark, Pharm.D., BCPS; and Kyle Davis, Pharm.D., BCPS

LEARNING OBJECTIVES

1. Devise an appropriate -agonist regimen based on presentation of a pediatric patient with severe acute asthma.
2. Justify the use of ipratropium as adjunct therapy for pediatric patients with severe acute asthma.
3. Identify the most appropriate magnesium sulfate regimen for severe acute asthma in pediatric patients.
4. Evaluate the benefits and limitations of various treatment modalities for severe acute asthma management in pediatric patients.
5. Design a stepwise approach to escalate therapy for a child with severe acute asthma refractory to standard of care.

INTERACTIVE CASE
ABBREVIATIONS IN THIS CHAPTER
Click here to begin this PedSAP activity.
CRS Clinical Respiratory Score
DBP Diastolic blood pressure
ICS Inhaled corticosteroids
IQR Interquartile range BASELINE KNOWLEDGE STATEMENTS
IVF Intravenous fluids
LOS Length of stay Readers of this chapter are presumed to be familiar
with the following:
MAP Mean arterial pressure
Physiology of the respiratory tract and immune
PAS Pediatric asthma score
system
PASS Pediatric asthma severity score
Drug delivery systems including metered-dose
PRAM Pediatric respiratory assessment
inhalers, nebulizers, and injectables
measure
Weight-based dose calculations
PS Pulmonary score
Fluid and electrolyte management for non-critically
RAD Respiratory rate, accessory mus-
cle use, decreased breath sounds ill patients
SABA Short-acting -agonist Normal vital signs for children
SCS Systemic corticosteroids
ADDITIONAL READINGS

The following free resources have additional back-

ground information on this topic:
AboutKidsHealth. Appropriate administration
technique for an MDI with spacer [homepage on
the Internet].
Web MD. Asthma Health Center. Patient education
on severe acute asthma [homepage on the
Internet].

PedSAP 2016 Book 2 Pediatric Critical Care 101 Interactive Patient Case: Severe Acute Asthma
REFERENCES
Allen JY, Macias CG. The efficacy of ketamine in pediatric
emergency department patients who present with acute
severe asthma. Ann Emerg Med 2005;46:43-50.
FDA Over-The-Counter Drugs Advisory Committee. Panel
recommends limits on alcohol content of nonprescription
products. Am J Hosp Pharm 1993;50:400.
Arnold DH, Gebretsadik T, Abramo TJ, et al. The RAD score:
a simple acute asthma severity score compares favorably
to more complex scores. Ann Allergy Asthma Immunol
2011;107:22-8.
Barnes PJ, Adcock I. Anti-inflammatory actions of ste-
roids: molecular mechanisms. Trends Pharmacol Sci
1993;14:436-41.
Berlinski A, Willis JR, Leisenring T. In-vitro comparison of 4
large-volume nebulizers in 8 hours of continuous nebuliza-
tion. Respir Care 2010;55:1671-9.
Bhogal SK, McGillivray D, Bourbeau J, et al. Early admin-
istration of systemic corticosteroids reduces hospital
admission rates for children with moderate and severe
asthma exacerbation. Ann Emerg Med 2012;60:84-91.
Bigham MT, Jacobs BR, Monaco MA, et al. Helium/oxy-
gen-driven albuterol nebulization in the management
of children with status asthmaticus: a random-
ized, placebo-controlled trial. Pediatr Crit Care Med
2010;11:356-61.
Bio LL, Willey VJ, Poon CY. Comparison of levalbuterol and
racemic albuterol based on cardiac adverse effects. J
Pediatr Pharmacol Ther 2011;16:191-8.
Bogie AL, Towne D, Luckett PM, et al. Comparison of intrave-
nous terbutaline versus normal saline in pediatric patients
on continuous high-dose nebulized albuterol for status
asthmaticus. Pediatr Emerg Care 2007;23:355-61.
Browne GJ, Lam LT. Single-dose intravenous salbutamol
bolus for managing children with acute severe asthma in
the emergency department: reanalysis of data. Pediatr Crit
Care Med 2002;3:117-23.
Carrie S, Anderson TA. Volatile anesthetics for status asth-
maticus in pediatric patients: a comprehensive review and
case series. Paediatr Anaesth 2015;25:460-7.
Castro-Rodriguez JA, J Rodrigo G, E Rodrguez-Martnez C.
Principal findings of systematic reviews of acute asthma
treatment in childhood. J Asthma 2015;52:1038-45.
Charmandari E, Kino T, Chrousos GP. Glucocorticoids.
In: Yaffe SJ, Aranda JV, eds. Neonatal and Pediatric
Pharmacology. Philadelphia: Wolters Kluwer,
2011:760-72.
Childrens Hospital of Philadelphia (CHOP). Acute Asthma
Emergent Care. CHOP Clinical Pathway. Updated
September 2015.
Dahmani S, Delivet H, Hilly J. Emergence delirium in children:
an update. Curr Opin Anaesthesiol 2014;27:309-15.
PedSAP 2016 Book 2 Pediatric Critical Care
Dalabih AR, Bondi SA, Harris ZL, et al. Aminophylline infu-
sion for status asthmaticus in the pediatric critical care
unit setting is independently associated with increased
length of stay and time for symptom improvement. Pulm
Pharmacol Ther 2014;27:57-61.
Denmark TK, Crane HA, Brown L. Ketamine to avoid mechan-
ical ventilation in severe pediatric asthma. J Emerg Med
2006;30:163-6.
DiPiro CV. Electrolyte homeostasis. In: Wells BG, DiPiro
JT, Schwinghammer TL, et al., eds. Pharmacotherapy
Handbook. New York: McGraw-Hill, 2015:798-812.
Doymaz A, Schneider J, Sagy M. Early administration of ter-
butaline in severe pediatric asthma may reduce incidence
of acute respiratory failure. Ann Allergy Asthma Immunol
2014;112:207-10.
Ducharme FM, Chalut D, Plotnick L, et al. The Pediatric
Respiratory Assessment Measure: a valid clinical score for
assessing acute asthma severity from toddlers to teenag-
ers. J Pediatr 2008;152:476-80.
Egelund TA, Wassil SK, Edwards EM, et al. High-dose mag-
nesium sulfate infusion protocol for status asthmaticus: a
safety and pharmacokinetics cohort study. Intensive Care
Med 2013;39:117-22.
Gorelick MH, Stevens MW, Schultz T, et al. Difficulty in
obtaining peak expiratory flow measurements in children
with acute asthma. Pediatr Emerg Care 2004;20:22-6.
Green SM, Roback MG, Kennedy RM, et al. Clinical practice
guideline for emergency department ketamine disso-
ciative sedation: 2011 update. Ann Emerg Med. 2011
May;57(5):449-61.
Griffiths B, Ducharme FM. Combined inhaled anticholiner-
gics and short-acting beta2-agonists for initial treatment
of acute asthma in children. Cochrane Database Syst Rev
2013;8:CD000060.
Hames H, Seabrook JA, Matsui D, et al. A palatability study
of a flavored dexamethasone preparation versus predniso-
lone liquid in children. Can J Clin Pharmacol 2008;15:e95-8.
Hendeles L. Selecting a systemic corticosteroid for acute
asthma in young children. J Pediatr 2003;142:S40-4.
Institute for Safe Medication Practices (ISMP). Safety Brief:
Questionable Safety with Continuous Inhalation Albuterol
Infusion Set-up. ISMP Medication Safety Alert! Acute Care
Newsletter. June 3, 2010.
Keeney GE, Gray MP, Morrison AK, et al. Dexamethasone for
acute asthma exacerbations in children: a meta-analysis.
Pediatrics 2014;133:493-9.
Kelly CS, Littleman CA, Pestian JP, et al. Improved outcomes
for hospitalized asthmatic children using a clinical path-
way. Ann Allergy Asthma Immunol 2000;84:509-16.
Kenyon CC, Fieldston ES, Luan X, et al. Safety and effec-
tiveness of continuous aerosolized albuterol in the
non-intensive care setting. Pediatrics 2014;134:e976-82.
102 Interactive Patient Case: Severe Acute Asthma
Kim MK, Yen K, Redman RL, et al. Vomiting of liquid corti-
costeroids in children with asthma. Pediatr Emerg Care
2006;22:397-401.
Koninckx M, Buysse C, de Hoog M. Management of status
asthmaticus in children. Paediatr Respir Rev 2013;14:78-85.
Koumbourlis AC, Mastropietro C. Continuous inhalation
of ipratropium bromide for acute asthma refractory
to 2-agonist treatment. J Pediatr Pharmacol Ther
2015;20:66-9.
Liu LL, Gallaher MM, Davis RL, et al. Use of a respiratory clini-
cal score among different providers. Pediatr Pulmonol
2004;37:243-8.
McMahon AW, Levenson MS, McEvoy BW, et al. Age and risks
of FDA-approved long-acting beta2-adrenergic receptor
agonists. Pediatrics 2011;128:e1147-54.
Miller AG, Breslin ME, Pineda LC, et al. An asthma proto-
col improved adherence to evidence-based guidelines for
pediatric subjects with status asthmaticus in the emer-
gency department. Respir Care 2015;60:1759-64.
National Asthma Education and Prevention Program
(NAEPP). Expert Panel Report 3 (EPR-3): Guidelines for the
Diagnosis and Management of Asthma. Clinical Practice
Guidelines. National Institutes of Health, National Health,
Lung, and Blood Institute. NIH Publication No. 08-4051,
2007.
Nievas IF, Anand KJ. Severe acute asthma exacerbation in
children: a stepwise approach for escalating therapy in
a pediatric intensive care unit. J Pediatr Pharmacol Ther
2013;18:88-104.
Nuorti JP, Whitney CG. Prevention of pneumococcal disease
among infants and children use of 13-valent pneumo-
coccal conjugate vaccine and 23-valent pneumococcal
polysaccharide vaccine: recommendations of the advisory
committee on immunization practices (ACIP). Morb Mortal
Wkly Rep 2010;59(RR11):1-18.
Papiris SA, Manali ED, Kolilekas L, et al. Acute severe
asthma: new approaches to assessment and treatment.
Drugs 2009;69:2363-91.
Phumeetham S, Bahk TJ, Abd-Allah S, et al. Effect of high-
dose continuous albuterol nebulization on clinical
variables in children with status asthmaticus. Pediatr Crit
Care Med 2015;16:e41-6.
Powell C, Dwan K, Milan SJ, et al. Inhaled magnesium sulfate
in the treatment of acute asthma. Cochrane Database Syst
Rev 2012;12:CD003898.
PedSAP 2016 Book 2 Pediatric Critical Care
Powell C, Kolamunnage-Dona R, Lowe J, et al. Magnesium
sulphate in acute severe asthma in children (MAGNETIC):
a randomised, placebo-controlled trial. Lancet Respir Med
2013;1:301-8.
Raissy HH, Kelly HW, Szefler AJ. Antiasthmatics. In: Yaffe
SJ, Aranda JV, eds. Neonatal and Pediatric Pharmacology.
Philadelphia: Wolters Kluwer, 2011:574-97.
Rampa S, Allareddy V, Asad R, et al. Outcomes of invasive
mechanical ventilation in children and adolescents hos-
pitalized due to status asthmaticus in United States: a
population based study. J Asthma 2015;52:423-30.
Shankar V, Churchwell KB, Deshpande JK. Isoflurane ther-
apy for severe refractory status asthmaticus in children.
Intensive Care Med 2006;32:927-33.
Smith SR, Baty JD, Hodge D. Validation of the pulmonary
score: an asthma severity score for children. Acad Emerg
Med 2002;9:99-104.
Soltsz S, Mencke T, Stunz M, et al. Attenuation of a
rocuronium-induced neuromuscular block in patients
receiving prednisolone. Acta Anaesthesiol Scand
2009;53:443-8.
Stoicea N, Versteeg G, Florescu D, et al. Ketamine-based
anesthetic protocols and evoked potential monitoring: a
risk/benefit overview. Front Neurosci 2016;10:37.
Tobias JD. Inhalational anesthesia: basic pharmacology, end
organ effects, and applications in the treatment of status
asthmaticus. J Intensive Care Med 2009;24:361-71.
Torres S, Sticco N, Bosch JJ, et al. Effectiveness of magne-
sium sulfate as initial treatment of acute severe asthma
in children. A randomized, controlled trial. Arch Argent
Pediatr 2012;110:291-7.
Wheeler DS, Jacobs BR, Kenreigh CA, et al. Theophylline ver-
sus terbutaline in treating critically ill children with status
asthmaticus: a prospective, randomized, controlled trial.
Pediatr Crit Care Med 2005;6:142-7.
Wong JJ, Lee JH, Turner DA, et al. A review of the use of
adjunctive therapies in severe acute asthma exacerbation in
critically ill children. Expert Rev Respir Med 2014;8:423-41.
Wyatt EL, Borland ML, Doyle SK, et al. Metered-dose inhaler
ipratropium bromide in moderate acute asthma in chil-
dren: a single-blinded randomised controlled trial. J
Paediatr Child Health 2015;51:192-8.
103 Interactive Patient Case: Severe Acute Asthma
Self-Assessment Questions
1. A 5-year-old boy (weight 16 kg) with a 1-year history
of mild intermittent asthma 1 presents to his pediatri-
cians clinic with his mother because of increased work
of breathing and lack of response to three doses of alb-
uterol nebulizations administered at home. Physical
examination reveals expiratory wheezing, accessory
muscle use, decreased breath sounds at the bases bilat-
erally, and SaO2 91% on room air. The pediatrician is
concerned about the severity of this acute asthma epi-
sode and arranges transport to the hospital for further
evaluation and management. As the clinic pharmacist,
which one of the following is best to recommend as this
patient awaits transport?
A. Continuous albuterol nebulization 5 mg/hour
B. Intubation
C. Ipratropium nebulization 2.5 mg/3 mL once
D. Prednisolone 16 mg by mouth once
2. In the pediatric ED triage, a 3-year-old girl is evaluated
for severe acute asthma. Vital signs and physical exam-
ination findings include heart rate 90 beats/minute,
respiratory rate 55 breaths/minute, positive intercos-
tal retractions, inspiratory and expiratory wheezing,
decreased breath sounds bilaterally, and positive nasal
congestion. The patient received three doses of nebulized
albuterol/ipratropium inhalation separated by 20 minutes,
but her symptoms persist. Prednisone 1 mg/kg/dose for
oral administration is ordered immediately. Which one of
the following is best to recommend for this patient?
A. Continuous albuterol nebulization
B. Intubation
C. Magnesium sulfate intravenously
D. Methylprednisolone intravenously
3. A 32-month-old boy is admitted to the inpatient pediatric
unit for the management of a moderate asthma exacer-
bation. On hospital day 2, he is receiving the following
drugs: continuous albuterol nebulization, prednisone
1 mg/kg/dose by mouth twice daily, and dextrose 5% and
sodium chloride 0.45% at maintenance rate. He is NPO
status (nothing by mouth). Which one of the following is
best to monitor for potential adverse effects from this
patients therapy?
A. WBC
B. Serum potassium concentration
C. Platelet count
D. Serum sodium concentration
4. A 4-year-old girl (weight 14.7 kg) with a medical history of
mild persistent asthma presents to the ED in acute respi-
ratory distress (increased work of breathing, shortness of
breath, respirations 48 breaths/minute, Sao2 93% on room
PedSAP 2016 Book 2 Pediatric Critical Care
air). She has received three doses of albuterol and ipratro-
pium by nebulization without clinical response. Which one
of the following is best to recommend for this patient?
A. Repeat her albuterol nebulization.
B. Initiate magnesium sulfate intravenous intermittent
dose.
C. Initiate continuous albuterol nebulization.
D. Initiate terbutaline intravenous infusion.
5. A 26-month old boy (weight 14.2 kg) requires continuous
albuterol nebulization. Which one of the following doses
is best to recommend for this patient?
A. 5 mg/hour
B. 7.5 mg/hour
C. 15 mg/hour
D. 20 mg/hour
6. Although ipratropium nebulization is commonly used
in the treatment of children with acute asthma present-
ing in the ED, which one of the following degrees of
asthma exacerbation severity is most supported by the
evidence?
A. Mild persistent
B. Moderate persistent
C. Severe persistent
D. Mild intermittent
7. A 6-year-old girl (weight 29.6 kg) with a medical history
of moderate persistent asthma is being admitted to the
pediatric unit from the ED after her severe acute asthma
failed to respond to standard therapy. She received alb-
uterol with ipratropium nebulization for three doses and
dexamethasone 1 mg/kg/dose by mouth, and continu-
ous albuterol 15 mg/hr was initiated. Laboratory values
are within normal limits. Her home drugs include alb-
uterol metered-dose inhaler (MDI) 2 puffs as needed for
wheezing, fluticasone/salmeterol dry powder inhaler 250
mcg/50 mcg inhaled twice daily, and a multivitamin. She
has no known drug allergies. Her asthma scores con-
tinue to indicate severe work of breathing, according
to the examination. Which one of the following orders
would be best to place for this patient before the admis-
sion order?
A. Magnesium 1 g intravenously over 30 minutes
before transfer
B. Dextrose 5% and sodium chloride 0.9% with
potassium chloride 20 mEq/L at 70 mL/hour
C. Increase continuous albuterol nebulization to
30 mg/hour
D. Methylprednisolone 30 mg intravenously every
12 hours
104 Interactive Patient Case: Severe Acute Asthma
Questions 8 and 9 pertain to the following case.
T.R. is an 8-year-old boy (weight 36 kg) with a medical his-
tory of mild persistent asthma. He is admitted for lack of
response to severe acute asthma standard therapy in the
ED. He received albuterol with ipratropium nebulization
for three doses, prednisone 30 mg by mouth once, contin-
uous albuterol nebulization at a dose of 15 mg/hour, and
magnesium sulfate intravenously 1 g over 30 minutes. He
has no known drug allergies. T.R.s home regimen includes
albuterol MDI 24 puffs as needed for wheezing and beclo-
methasone 40-mcg inhalation twice daily. Results of the
laboratory tests obtained on his arrival to the inpatient unit
are as follows:
145 | 102 | 12 / 145
2.9 | 18 | 0.67 \ calcium 8.9 mg/dL, magnesium 2.3 mg/dL
T.R.s physical examination on admission revealed a heart
rate of 128 beats/minute, blood pressure 98/68 mm Hg, respi-
ratory rate 36 breaths/minute, temperature 98.2F (36.8C),
and Sao2 91% on 100% fraction of inspired oxygen (Fio2)
delivered at 2 L/minute with albuterol by a large-volume neb-
ulizer. Wheezing persisted during the prolonged expiratory
phase, and accessory muscles are in use. Breath sounds are
decreased at the bases, and he speaks in phrases when he
takes off the mask. T.R.s asthma score placed him in mod-
erate severity.
8. On arrival at the inpatient unit, which one of the follow-
ing is best to recommend for T.R.s fluid and electrolyte
management?
A. Dextrose 5% and sodium chloride 0.9% with
potassium chloride 20 mEq/L continuous infusion at
76 mL/hour
B. Potassium chloride 20 mEq/100 mL intravenous
rider over 2 hours
C. Sodium chloride 0.9% continuous infusion at 76 mL/
hour
D. Dextrose 5% with potassium chloride 20 mEq/L
continuous infusion at 76 mL/hour
9. T.R.s attending physician asks whether the magnesium
sulfate intravenous dose should be repeated because
the serum concentration after the initial infusion is 2.3
mg/dL and symptoms persist. Which one of the following
is the best response to give T.R.s physician?
A. Continuous magnesium intravenous infusion can
achieve higher serum concentrations and has
proved more effective than intermittent magnesium
dosing in improving clinical asthma scores.
B. Use of intravenous magnesium sulfate for severe
acute asthma management improves clinical
asthma scores in all health care settings.
PedSAP 2016 Book 2 Pediatric Critical Care
C. Children with severe acute asthma who were treated
with intravenous magnesium sulfate in the ED had
reduced admission rates but did not have clinical
asthma scores in the inpatient setting consistently.
D. The dose was below the recommended weight-
based dose and should be repeated regardless of
the treatment setting to improve clinical asthma
scores.
10. Which one of the following best describes the role of neb-
ulized magnesium therapy in severe acute asthma?
A. Nebulized magnesium can replace nebulization of
albuterol and ipratropium.
B. A nebulized dosage form of magnesium is
commercially available.
C. Clinical asthma score may improve with nebulized
magnesium when administered with standard
therapy.
D. Nebulized magnesium reduces hospital admission
rates when used in children with severe acute
asthma.
11. A 7-year-old girl (weight 34 kg) with a medical history
of mild persistent asthma, seasonal allergies, eczema,
and gastroesophageal disease was hospitalized 1 year
ago for an asthma exacerbation caused by viral pneu-
monia. She was admitted to the pediatric ICU for the
management of severe acute asthma after an inade-
quate response to standard therapy and magnesium
intravenously 1 g in the ED. She received two doses of
terbutaline subcutaneously and a continuous albuterol
nebulization and was switched to terbutaline intravenous
continuous infusion at 1 mcg/kg/minute. The patient is
now receiving BiPAP (bilevel positive airway pressure)
100% Fio2 delivered by a non-rebreather mask. Her most
recent evaluation classifies her asthma as severe. The
attending physician is considering intubation and is will-
ing to discuss options to avoid intubation. Which one of
the following is best to share with this patients attend-
ing physician?
A. Isoflurane has been used with success in a few
children with severe refractory asthma and is an
option for this patient.
B. Ketamine has been used to avoid intubation in a few
case reports and is an option for this patient.
C. Heliox has improved the delivery of albuterol
nebulization and is an option for this patient.
D. Proceed with intubation because no other
intervention is beneficial at this time.
12. Which one of the following best describes the role of ami-
nophylline in the treatment of severe acute asthma?
105 Interactive Patient Case: Severe Acute Asthma
 A. Recent literature concluded aminophylline provides
no benefit in the treatment of severe acute asthma
in children.
B. When initiating aminophylline intravenously in a
patient receiving theophylline, the dose should be
80% of the oral theophylline dose.
C. The Expert Panel Review 3 recommends
aminophylline for severe acute asthma but only
in the ICU setting and only in intubated pediatric
patients.
D. Aminophylline delays improvement in clinical
asthma scores and lengthens hospital admission
when used for severe acute asthma in children.

PedSAP 2016 Book 2 Pediatric Critical Care 106 Interactive Patient Case: Severe Acute Asthma
Learner Evaluation: Interactive Case: Severe Acute Asthma (Status Asthmaticus).
As you take the posttest for this chapter, also evaluate the
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
1. The content of the chapter met my educational needs.
2. The content of the chapter satisfied my expectations.
3. The author presented the chapter content effectively.
4. The content of the chapter was relevant to my practice and
presented at the appropriate depth and scope.
5. The content of the chapter was objective and balanced.
6. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
7. The content of the chapter was useful to me.
8. The teaching and learning methods used in the chapter
were effective.
9. 
The active learning methods used in the chapter were
effective.
PedSAP 2016 Book 2 Pediatric Critical Care
10. The learning assessment activities used in the chapter
were effective.
11. The chapter was effective overall.
Use the 5-point scale to indicate whether this chapter pre-
pared you to accomplish the following learning objectives:
12. Devise an appropriate -agonist regimen based on pre-
sentation of a pediatric patient with severe acute asthma.
13. Justify the use of ipratropium as adjunct therapy for pedi-
atric patients with severe acute asthma.
14. Identify the most appropriate magnesium sulfate regimen
for severe acute asthma in pediatric patients.
15. Evaluate the benefits and limitations of various treatment
modalities for severe acute asthma management in pedi-
atric patients.
16. Design a stepwise approach to escalate therapy for a child
with severe acute asthma refractory to standard of care.
17. Please provide any specific comments related to any
perceptions of bias, promotion, or advertisement of com-
mercial products.
18. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
107 Interactive Patient Case: Severe Acute Asthma
Guideline Review: Diabetic
Ketoacidosis and Hyperglycemic
Hyperosmolar State
By Elizabeth S. Goswami, Pharm.D., BCPS, BCPPS; and Susan Warrington, Pharm.D., BCPPS

Reviewed by Julie Pingel, Pharm.D.; Ifeyinwa D. Eboh, Pharm.D., MPH, BCPS; and Monica A. Puebla, Pharm.D., MBA, MHA, BCPS

LEARNING OBJECTIVES

1. Classify the severity of diabetic ketoacidosis (DKA) using patient-specific biochemical data.
2. Distinguish between DKA and hyperosmolar hyperglycemic state (HHS) with regard to pathophysiology and presentation.
3. Devise a strategy for fluid and electrolyte management in a pediatric patient with DKA.
4. Develop a plan for insulin therapy in a pediatric patient with DKA.
5. Evaluate a pediatric patient with DKA for risk factors and clinical signs or symptoms of cerebral edema and recommend
appropriate therapy.
6. Construct an argument against controversial, ineffective, or harmful therapies for DKA.

GUIDELINE REVIEW
ABBREVIATIONS IN THIS FEATURE
Topic Article
BOHB -hydroxybutyrate
CVC Central venous catheter Wolfsdorf JI, Allgrove J, Craig ME, et al. ISPAD Clinical Practice
Consensus Guidelines 2014 Compendium. Diabetic ketoacidosis
DKA Diabetic ketoacidosis
and hyperglycemic hyperosmolar state. Ped Diab 2014:15(Suppl.
HHS Hyperglycemic hyperosmolar 20):154-79.
state
ISPAD International Society for Pediatric
and Adolescent Diabetes On-demand Webcast
VTE Venous thromboembolism Click here to begin this PedSAP activity.
Click here to view a transcription of this recorded webcast.
Table of other common abbreviations.

BASELINE KNOWLEDGE STATEMENTS

Readers of this chapter are presumed to be familiar

with the following:
General knowledge of pathophysiology and treat-
ment of both type 1 and type 2 diabetes mellitus.
Normal-for-age laboratory reference ranges and
vital signs for pediatric patients
Pharmacokinetics and pharmacodynamics of
various insulin products.
Fluid and electrolyte management for pediatric patients.

Table of common pediatric laboratory reference values.

PedSAP 2016 Book 2 Pediatric Critical Care 109 Guideline Review: Diabetic Ketoacidosis

ADDITIONAL READINGS
The following free resources have additional back-
ground information on this topic:
American Diabetes Association. Standards of
medical care in diabetes 2016: 11. Children and
adolescents. Diabetes Care
2016;39(suppl1):S86-S93.
Danne T, Bangstad H, Deeb L, et al. ISPAD Clinical
Practice Consensus Guidelines 2014. Insulin
treatment in children and adolescents with
diabetes. Pediatric Diabetes
2014;15(suppl20):115-34.
Springer SC, Silverstein J, Copeland K, et al.
Management of type 2 diabetes mellitus in children
and adolescents. Pediatrics 2013;131:e648-e664.
Chafe R, Albrechtsons D, Hagerty D, et al. Reducing
episodes of diabetic ketoacidosis within a youth
population: a focus group study with patients and
families. BMC Res Notes 2015;8:395.
Practice Points
DKA
DKA results from an absolute or relative insulin deficiency.
The severity of DKA varies, depending on the degree of
acidosis.
Patients with DKA have a 5%10% fluid deficit and require
fluid replacement.
Insulin at 0.050.1 unit/kg/hr is needed to reverse ketosis.
Patients will require replacement of potassium and may
require phosphate replacement.
Patients with DKA should not be administered these
therapies: insulin boluses, rapid fluid boluses (except
in hemodynamic instability), and bicarbonate (except in
life-threatening hyperkalemia).
HHS
HHS is rare in pediatric patients, but it is increasing in oc-
currence.
HHS presents as extreme hyperglycemia and hyperosmo-
lality without ketosis.
Patients with HHS are extremely dehydrated (1215%)
from osmotic diuresis and require significant fluid and
electrolyte supplementation.
Insulin should not be administered to patients with HHS
until the rate of blood glucose decline becomes inadequate
with fluid administration alone.
PedSAP 2016 Book 2 Pediatric Critical Care
REFERENCES
Bagdure D, Rewers A, Campagna E, et al. Epidemiology of
hyperosmolar hyperglycemic syndrome in children hospi-
talized in USA. Pediatr Diabetes 2013;14:18-24.
Carlotti AP, St George-Hyslop C, Bohn D, et al. Hypokalemia
during treatment of diabetic ketoacidosis: clinical evi-
dence for an aldosterone-like action of insulin. J Pediatr
2013;163:201-12.e1.
Chua H, Venkatesh B, Stachowski E, et al. Plasma-Lyte 148
vs 0.9% saline for fluid resuscitation in diabetic ketoacido-
sis. J Crit Care 2012;27:138-45.
Decourcey DD, Steil GM, Wypij D, et al. Increasing use of
hypertonic saline over mannitol in the treatment of symp-
tomatic cerebral edema in pediatric diabetic ketoacidosis:
an 11-year retrospective analysis of mortality. Pediatr Crit
Care Med 2013;14:694-700.
Fiordalisi I, Novotny WE, Holbert D, et al. An 18-yr prospec-
tive study of pediatric diabetic ketoacidosis: an approach
to minimizing the risk of brain herniation during treatment.
Pediatr Diabetes 2007;8:142-9.
Glaser NS, Ghetti S, Casper TC, et al. Pediatric diabetic keto-
acidosis, fluid therapy and cerebral injury: the design of
a factorial randomized controlled trial. Pediatr Diabetes
2013;14:435-46.
Glaser NS, Wooton-Gorges WL, Buonocore MH, et al.
Subclinical cerebral edema in children with diabetic keto-
acidosis randomized to 2 different rehydration protocols.
Pediatrics 2013;131:e73-80.
Grimberg A, Cerri RW, Satin-Smith M, et al. The two bag
system for variable intravenous dextrose and fluid admin-
istration: benefits in diabetic ketoacidosis management. J
Pediatr 1999;134:376-8.
Nallasamy K, Jayashree M, Singhi S, et al. Low-dose vs stan-
dard-dose insulin in pediatric diabetic ketoacidosis. JAMA
Pediatr 2014;168:999-1005.
Rosenbloom AL. The management of diabetic ketoacidosis
in children. Diabetes Ther 2010;1:103-20.
So T, Gruenwalder E. Evaluation of the two-bag system for
fluid management in pediatric patients with diabetic keto-
acidosis. J Pediatr Pharmacol Ther 2009;14:100-5.
Sottosanti M, Morrison GC, Singh RN, et al. Dehydration in
children with diabetic ketoacidosis: a prospective study.
Arch Dis Child Ed 2012;97:96-100.
Ugale J, Mata A, Meert KL, et al. Measured degree of dehy-
dration in children and adolescents with type 1 diabetic
ketoacidosis. Pediatr Crit Care Med 2012;13:e103-7.
Watts W, Edge JA. How can cerebral edema during treatment
of diabetic ketoacidosis be avoided. Pediatr Diabetes
2014;15:271-6.
110 Guideline Review: Diabetic Ketoacidosis
Wolfsdorf JI. The International Society of Pediatric and Wolfsdorf JI, Allgrove J, Craig ME, et al. ISPAD Clinical
Adolescent Diabetes guidelines for management of dia- Practice Consensus Guidelines 2014. Diabetic ketoac-
betic ketoacidosis: do the guidelines need to be modified? idosis and hyperglycemic hyperosmolar state. Pediatr
Pediatr Diabetes 2014;15:277-86. Diabetes 2014;15(suppl 20):154-79.

Wolfsdorf J, Glaser N, Sperling MA. Diabetic ketoacidosis in Zeitler J, Haqq A, Rosenbloom A, et al. Hyperglycemic
infants, children, and adolescents. A consensus statement hyperosmolar syndrome in children: pathophysiological
from the American Diabetes Association. Diabetes Care considerations and suggested guidelines for treatment. J
2006;29:1150-9. Pediatr 2011;158:9-14.

PedSAP 2016 Book 2 Pediatric Critical Care 111 Guideline Review: Diabetic Ketoacidosis
Self-Assessment Questions
Questions 1315 pertain to the following case. 17. You are the pediatric clinical pharmacist at a community
K.C. is an 11-year-old boy (weight 34 kg) with a history of hospital that cares for both adult and pediatric patients;
type 1 diabetes and asthma. He presents to the ED with it has 25 pediatric acute care beds and a level III neo-
a 2-day history of increased thirst and urination. K.C. has natal ICU. Your hospital is undergoing an expansion that
vomited five times today. He has no fever and no history will include an eight-bed pediatric ICU. Your hospital pre-
of recent illness. His insulin is administered by an insulin viously referred patients with DKA to a nearby tertiary
pump. At presentation, the following laboratory values are pediatric hospital in the same health system. However,
obtained: after the expansion, the hospital plans to accept these
patients into the pediatric ICU and will have pediatric
Venous pH Na K Cl Bicarbonate SCr Glucose endocrinologists available to consult. Which one of the
6.98 128 5.1 97 4 mEq/L 1.02 435 following would best ensure the safe and appropriate
mEq/L mEq/L mEq/L mg/dL mg/dL care of pediatric patients with DKA at your institution?
A. Assist in developing an educational inservice for the
Urinalysis shows 3+ ketones, and point-of-care -hydroxybu-
staff pharmacists verifying orders for the pediatric
tyrate (BOHB) is 7.5 mmol/L.
ICU.
13. Which one of the following is most likely the cause of B. Assist in developing institutional guidelines for the
K.C.s osmotic diuresis? care of children with DKA.
C. Ensure that intravenous fluids are administered by a
A. Glucosuria
two-bag system instead of a one-bag system.
B. Glucosuria and ketonuria
D. Reach out to the pediatric ICU pharmacist at
C. Ketonuria
the tertiary pediatric hospital as a resource for
D. Antidiuretic hormone deficiency
complicated clinical questions.
14. Given the available laboratory data, which one of the
18. A 6-year-old boy (weight 25 kg) presents to the ED with
following best classifies the severity of K.C.s diabetic
new diagnosis of type 1 diabetes and moderate DKA. He
ketoacidosis (DKA)?
is alert and oriented with vomiting and signs of dehydra-
A. Mild tion. His capillary refill is 3 seconds and blood pressure
B. Moderate is 96/52. Venous pH is 7.13. He was urinating frequently
C. Severe for the past 4 days, but has only urinated twice in the
D. Ultra-severe past 12 hours. Which one of the following is best to rec-
15. Which one of the following best describes K.C.s acid- ommend for initial fluid resuscitation in this patient?
base status and its most likely cause? A. Administer 20 mL/kg 0.9% NaCl as rapidly as
A. Anion gap metabolic acidosis; hyperglycemia possible and reassess hemodynamic status.
B. Anion gap metabolic acidosis; ketonemia B. Administer 40 mL/kg 0.9% NaCl over 2 hours and
C. Non-anion gap metabolic acidosis; ketonemia reassess hemodynamic status.
D. Anion gap respiratory acidosis; hyperglycemia C. Administer 10 mL/kg 0.9% NaCl as rapidly as
possible and reassess hemodynamic status.
16. A 3-year-old girl presents with mild DKA and new-onset
D. Administer 20 mL/kg 0.9% NaCl over 2 hours and
type 1 diabetes. On physical examination, her capillary
reassess hemodynamic status.
refill is 4 seconds, and she shows tenting when her skin
turgor is examined. Her respiratory rate is 57 breaths/ Questions 19 and 20 pertain to the following case.
minute. Both her central and peripheral pulses are pal-
T.E. is an 8-year-old girl (height 51 inches [130 cm], weight
pable, and her blood pressure is normal for age. She
27 kg) who is admitted to the pediatric ICU with moderate
has had frequent urination for the past 3 days, and she
DKA. The ED staff estimates her fluid deficit at 5% and orders
just had a 3-mL/kg urine void before the physical exam-
a 10-mL/kg bolus of NaCl 0.9% over 2 hours. T.E. is quickly
ination. Which one of the following best estimates this
transferred to the pediatric ICU. After the fluid bolus, she
patients fluid deficit?
is initiated on intravenous fluids using the two-bag system
A. 5% and continuous insulin infusion. At presentation, her blood
B. 10% glucose was 550 mg/dL; this decreased to 489 mg/dL after
C. 12% 1 hour of the fluid bolus, and is now 402 mg/dL at the end of
D. 15% the 2-hour fluid bolus.

PedSAP 2016 Book 2 Pediatric Critical Care 112 Guideline Review: Diabetic Ketoacidosis
19. Which one of the following best represents an appropri-
ate total hourly intravenous fluid rate for T.E.?
A. 23 mL/hr
B. 67 mL/hr
C. 90 mL/hr
D. 180 mL/hr
20. Which one of the following maintenance intravenous
solutions is best for T.E. for the first 4 hours after fluid
resuscitation?
A. NaCl 0.45%
B. NaCl 0.9%
C. Dextrose 5%, NaCl 0.45%
D. Dextrose 5%, NaCl 0.9%
21. You work in an ED at a small community hospital that
admits both adult and pediatric patients. A 2-year-old
boy (weight 14 kg) presents with DKA and new-onset dia-
betes. Urinalysis is positive for large ketones, and initial
laboratory results are as follows.
Venous pH Na K Cl Bicarbonate SCr Glucose
7.04 134 3.2 97 4 mEq/L 0.5 700
mEq/L mEq/L mEq/L mg/dL mg/dL
The physician orders a bolus of regular insulin 0.1 unit/
kg intravenously 1 after initial fluid resuscitation.
Which one of the following is best to recommend for this
patient?
A. Prepare a 10-unit/mL dilution of insulin so that
the dose can be accurately measured in a 1-mL
intravenous syringe.
B. Recommend 0.05 unit/kg as an appropriate
intravenous insulin bolus for a patient with DKA, and
ask the physician to change the order.
C. Refuse to dispense the insulin dose because
intravenous insulin boluses increase the risk of
cerebral edema, and ask the physician to change the
order.
D. Refuse to dispense the insulin dose until potassium
is above 3.5 mEq/L, and ask the physician to change
the order.
22. You are the clinical pharmacist in the pediatric ICU at
an institution that uses the two-bag system. Your proto-
col includes lactated Ringer solution with 40 mEq/L of
potassium chloride for fluid A and dextrose 10% lactated
Ringer solution with 40 mEq/L of potassium chloride
for fluid B. You are caring for a 4-year-old girl (weight 23
kg) with a history of diabetes who was admitted over-
night with DKA. Her glucose is currently 90 mg/dL. Her
blood glucose 1 hour earlier was 210 mg/dL. She is cur-
rently receiving fluid A at a rate of 47 mL/hr and fluid B
at 47 mL/hr. Given her new blood glucose concentration,
PedSAP 2016 Book 2 Pediatric Critical Care
which one of the following is the optimal fluid regimen
adjustment for this patient?
A. Reduce both fluid A and fluid B to 31 mL/hr.
B. Reduce fluid A to 31 mL/hr, and keep fluid B at
47 mL/hr.
C. Discontinue fluid A, and increase fluid B to 94 mL/hr.
D. Increase fluid A to 94 mL/hr, and discontinue fluid B.
23. Eighteen hours ago, a 7-year-old boy (weight 25 kg) with a
history of type 1 diabetes and asthma was admitted to the
pediatric ICU with DKA. His current medications include:
Dextrose 12.5% plus NaCl 0.45% plus 40 mEq/L of potas-
sium acetate at 110 mL/hr; regular insulin infusion at 0.1
unit/kg/hr; and fluticasone (100 mcg/puff) 2 puffs twice
daily. His most recent laboratory values are as follows:
Venous pH Na K Cl Bicarbonate Glucose BOHB
7.27 137 3.2 110 11 mEq/L 55 mg/ 4.2
mEq/L mEq/L mEq/L dL mmol/L
Which one of the following is best to recommend for this
patient?
A. Change fluids to dextrose 15% plus NaCl 0.45% plus
40 mEq/L of potassium acetate at 110 mL/hr.
B. Keep the same fluids, but change the rate to
165 mL/hr.
C. Change the insulin rate to 0.05 unit/kg/hr.
D. Transition to subcutaneous insulin and enteral diet.
24. The clinical pharmacy manager at your institution has
assigned you to provide clinical management of a potas-
sium phosphate drug shortage. Currently, the DKA order
set has a two-bag system with the following fluids:
Fluid A: NaCl 0.9% plus 20 mEq/L of potassium chloride
plus 15 mmol/L of potassium phosphate
Fluid B: dextrose 10% plus NaCl 0.9% plus 20 mEq/L
of potassium chloride plus 15 mmol/L of potassium
phosphate
Which one of the following would you recommend as the
best option for conserving potassium phosphate?
A. Make no changes, and prioritize potassium
phosphate supply to use for DKA intravenous fluids.
B. Remove potassium phosphate from intravenous
fluids on the DKA order set, and make no additional
changes.
C. Remove potassium phosphate from intravenous
fluids on the DKA order set, and replace with an
additional 20 mEq/L of potassium chloride.
D. Remove potassium phosphate from intravenous
fluids on the DKA order set, and replace with 20
mEq/L of potassium acetate.
113 Guideline Review: Diabetic Ketoacidosis
25. You are working in the ED at a community hospital that Questions 2831 pertain to the following case.

admits both pediatric and adult patients. An 8-year-old R.T. is a 15-year-old boy (weight 90 kg) with a history of type
girl (weight 46 kg) presents in severe DKA. Results of her 2 diabetes who presents to the ED with the following labora-
laboratory tests are as follows: tory data:

Venous pH Na K Cl Bicarbonate Glucose BOHB Venous pH Na K

6.99 132 2.1 98 4 mEq/L 609 8.2 7.31 150 mEq/L 1.3 mEq/L
mEq/L mEq/L mEq/L mg/dL mmol/L
Phosphorus Magnesium Serum
Lactate osmolality
2.1 mmol/L 1.2 mg/dL 1.1 mEq/L 361 mOsm/
kg
The physician asks for your recommendation regarding
Cl Bicarbonate Glucose BOHB
bicarbonate administration for this patient. Which one of
the following is best to recommend for this patient? 122 28 mEq/L 988 mg/ < 0.3
mEq/L dL mmol/L
A. Do not administer bicarbonate because of the risk of
cerebral edema. R.T. states that he has been urinating more over the past
B. Do not administer bicarbonate because of the risk of week or two. His blood pressure is 74/56 mm Hg.
hyperkalemia.
C. Administer bicarbonate to reverse severe 28. Which one of the following best represents R.T.s fluid
ketoacidosis. deficit?
D. Administer bicarbonate to reverse severe lactic
A. 5L
acidosis.
B. 9L
26. You are reviewing patients for inclusion in a retrospective C. 12 L
quality improvement project for patients with cere- D. 20 L
bral edema and DKA. The projects definition for DKA
29. After initial fluid resuscitation, R.T.s blood pressure has
matches the criteria for clinical diagnosis referenced by
improved to 98/68 mm Hg. He has ongoing osmotic
the DKA guidelines. Which one of the following patients
diuresis. Which one of the following is best to rec-
would be best to include in the study?
ommend regarding the management of R.T.s urinary
A. A 3-year-old girl with fluctuating mentation and replacement?
vomiting
A. Do not replace urinary losses
B. A 10-year-old boy with fluctuating mentation and
B. Replace urinary losses with NaCl 0.225%
lethargy
C. Replace urinary losses with NaCl 0.45%
C. An 8-year-old girl with fluctuating mentation and
D. Replace urinary losses with NaCl 0.9%
headache
D. A 6-year-old boy with fluctuating mentation and 30. Fluid administration is initiated for R.T. One hour later,
diastolic blood pressure 92 mm Hg you are asked to recommend a dose for R.T.s insulin infu-
sion. Which one of the following is best to recommend
27. Six hours after starting therapy for DKA, a 12-year-old
regarding insulin therapy for R.T.?
boy with known type 1 diabetes begins to have decorti-
cate posturing. There is immediate concern for cerebral A. Initiate insulin at 0.1 unit/kg/hr when blood glucose
edema. Which one of the following is best to recommend decline is less than 50 mg/dL/hr with fluid therapy.
for this patient? B. Initiate insulin at 0.05 unit/kg/hr when blood
glucose decline is less than 50 mg/dL/hr with fluid
A. Infuse 5 mL/kg of NaCl 3% IV immediately after head
therapy.
CT results return
C. Initiate insulin at 0.1 unit/kg/hr at this time.
B. Infuse 1 g/kg of mannitol IV immediately after
D. Initiate insulin at 0.05 unit/kg/hr at this time.
stopping continuous fluid replacement
C. Infuse 2.5 mL/kg of NaCl 3% IV immediately after 31. Which one of the following is best to recommend for the
continuous replacement fluids are decreased to 1 to treatment of R.T.s hypophosphatemia?
1.3x maintenance A. Administer 0.3 mmol/kg of potassium phosphate
D. No interventions are required at this time. Continue to intravenously now.
monitor the patient and treat only if enough major and B. Administer 0.3 mmol/kg of potassium phosphate
minor criteria for diagnosis of cerebral edema are met intravenously when R.T. becomes symptomatic from
hypophosphatemia.

PedSAP 2016 Book 2 Pediatric Critical Care 114 Guideline Review: Diabetic Ketoacidosis
 C. Use replacement fluids containing 20 mEq/L of
potassium chloride and 15 mmol/L of potassium
phosphate now.
D. Use replacement fluids containing 20 mEq/L of
potassium chloride and 15 mmol/L of potassium
phosphate when R.T. becomes symptomatic from
hypophosphatemia.
32. A 13-year-old girl (weight 38 kg) has a history of type 1 dia-
betes diagnosed at age 5. She presents to the ED with a
1-day history of abdominal pain, increased urination, and
vomiting. She has no history of diarrhea or fever. Her labora-
tory values are consistent with moderate DKA. Her parents
state they have recently been concerned that she has devel-
oped an eating disorder because she is not gaining weight
and has been very selective in what she eats. They have
scheduled an appointment with her regular pediatrician
next week. The patients home insulin regimen includes
insulin glargine at bedtime and insulin lispro for correction
and at mealtimes. She administers insulin on her own with-
out supervision. This is her third DKA episode in 12 months.
The patients family is in a high socioeconomic class, and
she has not missed any scheduled appointments. The fam-
ily has private insurance. There are no concerns for abuse
or unstable home situation. Which one of the following is
most likely contributing to this patients recurrent DKA?
A. Insulin pump failure
B. Lack of access to medical care
C. Gastroenteritis
D. Insulin omission

PedSAP 2016 Book 2 Pediatric Critical Care 115 Guideline Review: Diabetic Ketoacidosis
Learner Evaluation: Guideline Review: Diabetic Ketoacidosis and Hyperglycemic
Hyperosmolar State.
As you take the posttest for this chapter, also evaluate the
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
19. The content of the chapter met my educational needs.
20. The content of the chapter satisfied my expectations.
21. The author presented the chapter content effectively.
22. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
23. The content of the chapter was objective and balanced.
24. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
25. The content of the chapter was useful to me.
26. The teaching and learning methods used in the chapter
were effective.
27. The active learning methods used in the chapter were
effective.
28. The learning assessment activities used in the chapter
were effective.
29. The chapter was effective overall.
PedSAP 2016 Book 2 Pediatric Critical Care
Use the 5-point scale to indicate whether this chapter pre-
pared you to accomplish the following learning objectives:
30. Classify the severity of diabetic ketoacidosis (DKA) using
patient-specific biochemical data.
31. 
Distinguish between DKA and hyperosmolar hypergly-
cemic state (HHS) with regard to pathophysiology and
presentation.
32. Devise a strategy for fluid and electrolyte management in
a pediatric patient with DKA.
33. Develop a plan for insulin therapy in a pediatric patient
with DKA.
34. Evaluate a pediatric patient with DKA for risk factors and
clinical signs or symptoms of cerebral edema and recom-
mend appropriate therapy.
35. Construct an argument against controversial, ineffective,
or harmful therapies for DKA.
36. Please provide any specific comments related to any
perceptions of bias, promotion, or advertisement of com-
mercial products.
37. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
116 Guideline Review: Diabetic Ketoacidosis
Interactive Case: Status Epilepticus

By Christina Cox, Pharm.D., BCPS, BCPPS

Reviewed by Emily L. Rowe, Pharm.D., BCPS, BCPPS, MS-PREP; and Maha O. Kebir, Pharm.D., MS, BCPS, CPHQ

LEARNING OBJECTIVES

1. Distinguish the cause of status epilepticus (SE) in neonates, infants, children, and adolescents.
2. Design an appropriate treatment plan for the pediatric patient with SE or refractory SE.
3. Design a treatment strategy for the patient with complications of SE, including hypoxemia and acidosis.
4. Evaluate the patient with SE for the development of long-term sequelae of prolonged seizure activity and/or treatment
of SE.

INTERACTIVE CASE
ABBREVIATIONS IN THIS FEATURE
Click here to begin this PedSAP activity.
AES American Epilepsy Society
BMP Basic metabolic panel
CSE Convulsive status epilepticus
REFERENCES
EEG Electroencephalograph
Abend NS, Monk HM, Licht DJ, et al. Intravenous levetiracetam in
HSV Herpes simplex virus critically ill children with status epilepticus or acute repetitive sei-
ICP Intracranial pressure zures. Pediatr Crit Care Med. 2009;10(4):505-10.
LP Lumbar puncture
Abend NS, Dlugos DJ. Treatment of refractory status epilepti-
NCSE Non-convulsive status
cus: literature review and a proposed protocol. Pediatr Neurol
epilepticus
2008;38:377-90.
NMDA N-methyl-d-aspartate
RSE Refractory status epilepticus American Academy of Pediatrics Committee on Drugs. Inactive
SE Status epilepticus ingredients in pharmaceutical products: update (subject review).
American Academy of Pediatrics Committee on Drugs. Pediatrics
1997;99:268-78.
Table of other common abbreviations.
Appleton R, Macleod S, Martland T. Drug management for acute ton-
ic-clonic convulsions including convulsive status epilepticus in
children. Cochrane Database Syst Rev. 2008;16;(3): CD001905.

Argawal P, Kumar N, Chandra R, et al. Randomized study of intra-

venous valproate and phenytoin in status epilepticus. Seizure
2007;16:527-32.

Babl FE, Sheriff N, Borland M, et al. Emergency management of pae-

diatric status epilepticus in Australia and New Zealand: practice
patterns in the context of clinical practice guidelines. J Paediatr
Child Health. 2009;45:541-6.

Barberio M, Reiter PD, Kaufman J, et al. Continuous infusion pen-

tobarbital for refractory status epilepticus in children. J Child
Neurol 2012;27:721-6.

PedSAP 2016 Book 2 Pediatric Critical Care 117 Interactive Case: Status Epilepticus
Bleck TP. Management approaches to prolonged sei-
zures and status epilepticus. Epilepsia 1999;40(suppl
1):S59-S63.
Brevoord JC, Joosten KF, Arts WF, et al. Status epilepticus:
clinical analysis of a treatment protocol based on midaz-
olam and phenytoin. J Child Neurol 2005;20:476-81.
Brophy GM, Bell R, Claassen J, et al. Guidelines for the evalu-
ation and management of status epilepticus. Neurocritical
Care 2012;17:3-23.
Chamberlain JM, Okada P, Holsti M, et al. Lorazepam vs
diazepam for pediatric status epilepticus: a randomized
clinical trial. JAMA 2014;311:1652-60.
Chin RF, Neville BG, Peckham C, et al. Treatment of com-
munity-onset, childhood convulsive status epilepticus:
a prospective, population-based study. Lancet Neurol
2008;7(8):696-703.
Chin RF, Neville BG, Peckham C, NLSTEPSS Collaborative
Group, et al. Incidence, cause, and short-term outcome of
convulsive status epilepticus in childhood: prospective
population-based study. Lancet 2006;368:222-9.
Claassen J, Hirsch LJ, Emerson RG, et al. Treatment
of refractory status epilepticus with pentobarbital,
propofol, or midazolam: a systemic review. Epilepsia
2001;43:146-53.
Claassen J, Hirsch LJ, Mayer SA. Treatment of status
epilepticus: a survey of neurologists. J Neurol Sci.
2003;211:37-41
DeLorenzo R, Hauser WA, Towne AR, et al. A prospective,
population-based epidemiologic study of status epilepti-
cus in Richmond, Virginia. Neurology 1996;46:1029-35.
Eriksson K, Metsaranta P, Huhtala H, et al. Treatment delay
and the risk of prolonged status epilepticus. Neurology
2005;65:1316-8.
Fang Y, Wang X. Ketamine for the treatment of refractory sta-
tus epilepticus. Seizure 2015;30:14-20.
Gallagher RC, Van Hove JL, Scharer G, et al. Folinic acid-re-
sponsive seizures are identical to pyridoxine-dependent
epilepsy. Ann Neurol 2009;65:550-6.
Gallentine WB, Hunnicutt AS, Husain AM. Levetiracetam
in children with refractory status epilepticus. Epilepsy
Behav. 2009;14(1):215-8.
Glass HC, Kan J, Bonifacio SL et al. Neonatal seizures: treat-
ment practices among term and preterm infants. Pediatr
Neurol 2012;46:111-5.
Glauser T, Shinnar S, Gloss D, et al. Evidence-Based
Guideline: Treatment of Convulsive Status Epilepticus in
Children and Adults: Report of the Guideline Committee
of the American Epilepsy Society. Epilepsy Currents 2016;
16(1):48-61.
Grosso S, Zamponi N, Bartocci A, et al. Lacosamide in chil-
dren with refractory status epilepticus. A multicenter
Italian experience. Eur J Paediatr Neurol 2014;18:604-8.
PedSAP 2016 Book 2 Pediatric Critical Care
Hanhan UA, Fiallos MR, Orlowski JP. Status epilepticus.
Pediatr Clin North Am 2001;48:683-94.
Harbord MG, Kyrkou NE, Kyrkou MR, et al. Use of intranasal
midazolam to treat acute seizures in paediatric commu-
nity settings. J Paediatr Child Health 2004;40:556-8.
Harrison AM, Lugo RA, Schunk JE. Treatment of convul-
sive status epilepticus with propofol: case report. Pediatr
Emerg Care 1997;13:420-2.
Haut SR, Shinnar S , Moshe SL, et al. The association
between seizure clustering and convulsive status epilep-
ticus in patients with intractable complex partial seizures.
Epilepsia 1999;40:1832-4.
Hayashi K, Osawa M, Aihara M, Research Committee
on Clinical Evidence of Medical Treatment for Status
Epilepticus in Childhood, et al. Efficacy of intravenous mid-
azolam for status epilepticus in childhood. Pediatr Neurol
2007;36:366-72.
Hellstrm-Westas L, Boylan G, Agren J. Systematic review
of neonatal seizure management strategies provides
guidance on anti-epileptic treatment. Acta Paediatr
2015;104:123-9.
Hofler J, Trinka E. Lacosamide as a new treatment option in
status epilepticus. Epilepsia 2013;54:393-404.
Holsti M, Sill BL, Firth SD, et al. Prehospital intranasal mid-
azolam for the treatment of pediatric seizures. Pediatr
Emerg Care 2007;23:148-53.
Igartua J, Silver P, Maytal J, et al. Midazolam coma for
refractory status epilepticus in children. Crit Care Med
1999;27:1982-5.
Ilvento L, Rosati A, Marini C, et al. Ketamine in refractory
convulsive status epilepticus in children avoids endotra-
cheal intubation. Epilepsy Behav 2015;49:343-6.
Kim JS, Lee JH, Ryu HW, et al. Effectiveness of intravenous
levetiracetam as an adjunctive treatment in pediat-
ric refractory status epilepticus. Pediatr Emerg Care
2014;30(8):525-528.
Kim SJ, Lee DY, Kim JS. Neurologic outcomes of pediatric
epileptic patients with pentobarbital coma. Pedi Neurol
2001;25:217-20.
Koul R, Chacko A, Javed H, et al. Eight-year study of child-
hood status epilepticus; midazolam infusion management
and outcome. J Child Neurol 2002;17:908-10.
Koul RL, Raj Aithala G, Chacko A, et al. Continuous midaz-
olam infusion as treatment of status epilepticus. Arch Dis
Child 1997;76:445-8.
Kravljanac R, Jovic N, Djuric M, et al. Outcome of status epi-
lepticus in children treated in the intensive care unit: a
study of 302 cases. Epilepsia 2011;52:358.
Lacroix J, Deal C, Gauthier M, et al. Admissions to a pediatric
intensive care unit for status epilepticus: a 10-year experi-
ence. Crit Care Med 1994;22:827-32.
118 Interactive Case: Status Epilepticus
Lambrechtsen FA, Buchhalter JR. Aborted and refractory
status epilepticus in children: a comparative analysis.
Epilepsia 2008;49:615-25.
Maytal J, Shinnar S, Moshe SL, et al. Low morbidity and
mortality of status epilepticus in children. Pediatrics
1989;83:323-31.
Mehta V, Singhi P, Singhi S. Intravenous sodium valproate
versus diazepam infusion for the control of refractory sta-
tus epilepticus in children: a randomized controlled trial. J
Child Neurol 2007;22:1191-7.
Morrison G, Gibbons E, Whitehouse WP. High-dose midaz-
olam therapy for refractory status epilepticus in children.
Intensive Care Med 2006;32:2070-6.
Nicolai J, van Kranen-Mastenbroek VH, Wevers RA, et al.
Folinic acid-responsive seizures initially responsive to pyr-
idoxine. Pediatr Neurol 2006;34:164-7.
Novak G, Maytal J, Alshansky A, et al. Risk factors for sta-
tus epilepticus in children with symptomatic epilepsy.
Neurology 1997;49:533-7.
Ozdemir D, Gulez P, Uran N, et al. Efficacy of continuous
midazolam infusion and mortality in childhood refrac-
tory generalized convulsive status epilepticus. Seizure
2005;14:129-32.
Patten W, Naqvi SZ, Raszynski A, et al. Complications during
the management of pediatric refractory status epilepticus
with benzodiazepine and pentobarbital infusions. Indian J
Crit Care Med 2015;19:275-7.
Prasad A, Worrall BB, Bertram EH, et al. Propofol and mid-
azolam in the treatment of refractory status epilepticus.
Epilepsia 2001;42:380-6.
Ram D, Martland T. Management of convulsive status epilep-
ticus in children. Paediatr Child Health 2015;25:522-7.
Raspall-Chaure M, Chin RF, Neville BG, et al. Outcome of pae-
diatric convulsive status epilepticus: a systematic review.
Lancet Neurol 2006;5:769-79.
Redecker J, Wittstock M, Benecke R, et al. Comparison of the
effectiveness of four antiepileptic drugs in the treatment
of status epilepticus according to four different efficacy
criteria. Epilepsy Behav 2015;49:351-3.
Reiter PD, Huff AD, Knupp KG, et al. Intravenous levetirac-
etam in the management of acute seizures in children.
Pediatr Neurol. 2010 Aug;43(2):117-21.
Rivera R, Segnini M, Baltodano A, et al. Midazolam in the
treatment of status epilepticus in children. Crit Care Med
1993;21:991-4.
Riviello JJ, Ashwal, S, Hirtz D, et al. Practice parameter: diag-
nostic assessment of the child with status epilepticus (an
evidence-based review): report of the Quality Standards
Subcommittee of the American Academy of Neurology
and the Practice Committee of the Child Neurology
Society. Neurology 2006;67:1542-50.
PedSAP 2016 Book 2 Pediatric Critical Care
Rosati A, LErario M, Ilvento L, et al. Efficacy and safety of
ketamine in refractory status epilepticus in children.
Neurology 2012;79:2355-8.
Sahin M, Menache CC, Holmes GL, et al. Outcome of severe refrac-
tory status epilepticus in children. Epilepsia 2001;42:1461-7.
Saz EU, Karapinar B, Ozcetin M, et al. Convulsive status
epilepticus in children: etiology, treatment protocol and
outcome. Seizure 2011;20:115-8.
Shehab N, Lewis CL, Streetman DD, et al. Exposure to the
pharmaceutical excipients benzyl alcohol and propylene
glycol among critically ill neonates. Pediatr Crit Care Med
2009;20:115-8.
Shiloh-Malawsky Y, Fan Z, Greenwood R, et al. Successful
treatment of childhood prolonged refractory status epilep-
ticus with lacosamide. Seizure 2011;20:586-8.
Shinnar S, Berg AT, Moshe SL, et al. The risk of seizure recur-
rence after a first unprovoked afebrile seizure in childhood:
an extended follow-up. Pediatrics 1996;98(pt 1):216-25.
Shinnar S, Pellock JM, Berg AT, et al. Short-term outcomes
of children with febrile status epilepticus. Epilepsia
2001;42:47-53.
Shorvon S. Super-refractory status epilepticus: an approach
to therapy in this difficult clinical situation. Epilepsia
2011;52(suppl 8):53-6.
Shorvon SD. Status Epilepticus: Its Clinical Features and
Treatment in Children and Adults. Cambridge: Cambridge
University Press, 1987.
Sillanpaa M, Shinnar S. Status epilepticus in a popula-
tion-based cohort with childhood-onset epilepsy in
Finland. Ann Neurol 2002;52:303-10.
Singh RK, Stephens S, Berl MM, et al. Prospective study of
new-onset seizures presenting as status epilepticus in
childhood. Neurology 2010;74:636-42.
Singhi S, Murthy A, Singhi P, et al. Continuous midazolam
versus diazepam infusion for refractory convulsive status
epilepticus. J Child Neurol 2002;17:106-10.
Sofou K, Kristjansdorrir R, Papachatzakis NE, et al. Management
of prolonged seizures and status epilepticus in childhood: a
systematic review. J Child Neurol 2009;24:918-26.
Stockler S, Plecko B, Gospe SM, et al. Pyridoxine dependent
epilepsy and antiquitin deficiency: clinical and molecular
characteristics and recommendations for diagnosis, treat-
ment and follow-up. Mol Genet Metab 2011;104:48-60.
Synowiec AS, Singh DS, Yenugadhati V, et al. Ketamine use
in the treatment of refractory status epilepticus. Epilepsy
Res 2013;105:183-8.
Tobias JD. Tolerance, withdrawal, and physical dependency
after long-term sedation and analgesia of children Tobias
JD. Tolerance, withdrawal, and physical dependency after
long-term sedation and analgesia of children in the pedi-
atric in the pediatric intensive care unit. Crit Care Med
2000;23:2122-32.
119 Interactive Case: Status Epilepticus
Tobias JD. The use of propofol to treat status epilepticus
in a nine-month-old female patient. Pediatr Emerg Care
1998;14:248-9.
Trinka E, Cock H, Hesdorffer D, et al. A definition and clas-
sification of status epilepticus - report of the ILAE Task
Force on Classification of Status Epilepticus. Epilepsia
2015;56:1515-23.
Uberall MA, Trollmann R, Wunsiedler U, et al. Intravenous val-
proate in pediatric epilepsy patients with refractory status
epilepticus. Neurology 2000;54:2188-9.
Wada T, Takase M, Fukushima Y. Diamox acetazolamide in
treatment of the epileptics with frequent seizures or sta-
tus epilepticus. Folia Psychiatr Neurol Jpn 1961;15:98-109.
PedSAP 2016 Book 2 Pediatric Critical Care
White JR, Santos CS. Intravenous valproate associated with
significant hypotension in the treatment of status epilepti-
cus. J Child Neurol 1999;14:822-3.
Wilkes R, Tasker RC. Intensive care treatment of uncontrolled
status epilepticus in children: systematic literature search
of midazolam and anesthetic therapies. Pediatr Crit Care
Med 2014;15:632-9.
Wu YW, Shek DW, Garcia PA, et al. Incidence and mortality
of generalized convulsive status epilepticus in California.
Neurology 2002;58:1070-6.
Yu KT, Mills S, Thompson N, et al. Safety and efficacy of
intravenous valproate in pediatric status epilepticus and
acute repetitive seizures. Epilepsia 2003;44:724-6.
120 Interactive Case: Status Epilepticus
Self-Assessment Questions
Questions 3335 pertain to the following case.
L.N. is a 5-year-old girl (weight 18 kg) who is being transferred
to the pediatric ICU from the ED for seizure activity at home
(duration about 5 minutes per caregiver). While being trans-
ferred to the unit, LN begins seizing again.
33. Which one of the following best describes L.N.s seizure
activity and need for pharmacologic therapy?
A. She is in status epilepticus, defined as a seizure
duration longer than 5 minutes, and therapy should
be initiated.
B. She is in status epilepticus, defined as a seizure
duration longer than 30 minutes, and therapy should
be initiated.
C. She is not in status epilepticus because she has
had multiple seizures with a duration of 5 minutes
with return to baseline function, and should not
receive therapy.
D. She is not in status epilepticus, defined as multiple
seizures with a duration of 30 minutes and return
to baseline function, and should not receive
therapy.
34. L.N. receives two doses of lorazepam 0.1 mg/kg/dose,
and the team is preparing to give a second-line agent at
the 15-minute period. On further investigation of L.N.s
home drugs and laboratory results, you confirm that she
is taking phenytoin suspension 8 mg/kg/day divided
every 12 hours and levetiracetam solution 30 mg/kg/
day divided every 12 hours. Laboratory tests, including
levetiracetam and phenytoin concentrations, are sent for
evaluation. Which one of the following is best to recom-
mend for L.N.?
A. Phenytoin 20 mg/kg intravenously 1 dose over 30
minutes.
B. Fosphenytoin 20 mg/PE/kg intravenously 1 dose
over 10 minutes.
C. Levetiracetam 20 mg/kg intravenously 1 dose over
15 minutes.
D. Phenobarbital 20 mg/kg intravenously 1 dose over
20 minutes.
35. L.N.s laboratory values show a levetiracetam concentra-
tion of 15 mcg/mL and a total phenytoin concentration of
21 mcg/mL. She was loaded with levetiracetam, and her
seizure ceased. After observing the patient and ensur-
ing return to baseline behavior and function, the patient
is to be discharged. The team is discussing potential
causes of this episode. Which one of the following best
describes the rationale for a supratherapeutic phenytoin
concentration, assuming the patient had a normal albu-
min concentration?
PedSAP 2016 Book 2 Pediatric Critical Care
A. Drug-drug interaction between levetiracetam and
phenytoin
B. Phenytoin binding to enteral tubing
C. Not shaking the suspension
D. Inappropriate home dose of phenytoin
Questions 3638 pertain to the following case.
A.B. is a 10-day-old girl born at 29 weeks gestation (birth weight
1100 g). She has new-onset seizure activity. Maternal history is
positive for preeclampsia and premature rupture of membranes.
Since birth, A.B. has been weaned from continuous positive
airway pressure (CPAP) and is currently receiving 1/2 L nasal
cannula since seizure activity began. She has had increased
apneic events requiring stimulation and decreased activity.
Her current drugs include caffeine 5 mg/kg/dose intravenously
every 24 hours and parenteral nutrition with lipids (dextrose 10%,
protein 4 g/kg, and lipids 2 g/kg). Results of physical examina-
tion and laboratory tests include the following: current weight
1160 g, sodium 131 mEq/L, urine output 3.4 mL/kg/hour, potas-
sium 5.5 mEq/L, chloride 99 mmol/L, CO2 25 mmol/L, WBC 2.4
103 cells/mm3, BUN 10 mg/dL, Hgb 8 g/dL, SCr 0.2 mg/dL, Hct
40 g/dL, glucose 67 mg/dL, platelets 340,000/mm3, and calcium
9.7 mg/dL. Differential shows increased bands.
36. Based on these data, which one of the following is the
most likely etiology of A.B.s seizure activity?
A. Apnea of prematurity
B. Hypoglycemia
C. Hyponatremia
D. Late-onset sepsis
37. A.B. has antibiotics initiated (ampicillin 100 mg/kg/dose
intravenously every 12 hours and gentamicin 4.5 mg/
kg/dose intravenously every 36 hours), but her seizure
activity progresses from lasting 30 seconds to more pro-
longed durations. The nurse alerts the team that A.B. has
been seizing now for 3 minutes. After 5 minutes, which
one of the following is the most appropriate pharmaco-
logic therapy to recommend for A.B.s seizures?
A. Levetiracetam 40 mg/kg intravenously 1 dose
B. Lorazepam 0.1 mg/kg intravenously 1 dose
C. Midazolam 0.05 mg/kg intravenously 1 dose
D. Phenobarbital 20 mg/kg intravenously 1 dose
38. Which one of the following is best to recommend to the
care team to prevent long-term complications from phe-
nobarbital therapy in A.B.?
A. Phenobarbital has not been associated with long-
term adverse effects in neonates.
B. Monitor for chronic lung disease from increased
respiratory depression and advanced ventilation
requirements.
121 Interactive Case: Status Epilepticus
 C. Monitor for vitamin D deficiency and decreased
cognitive development.
D. Monitor for development of necrotizing enterocolitis.
Questions 3944 pertain to the following case.
V.V. is a 3-year-old boy (weight 14 kg) who presents to the
pediatric ICU with new-onset seizures of unknown etiology.
Toxic exposure is not suspected, and the following laboratory
results are available: pH on blood gas 7.3, sodium 139 mEq/L,
lactate 5 mmol/L, potassium 3.5 mEq/L, AST 44 IU/L, chlo-
ride 104 mmol/L, ALT 52 IU/L, CO2 15 mmol/L, BUN 30 mg/
dL, SCr 0.7 mg/dL, glucose 134 mg/dL, magnesium 2 mEq/L,
and calcium 10 mg/dL. V.V.s acetaminophen and salicylate
concentrations are undetectable, and the urine drug screen
is negative. He has no sick contacts. Although V.V. has had
no previous seizure activity, he has a positive family history
of seizures (paternal grandfather). The resident examines V.V.
while the boy is sleeping and notices seizure activity. After
about 3 minutes, V.V.s seizure activity has not subsided. He
does not currently have intravenous access.
39. Which one of the following is best to initiate for V.V.s
seizures?
A. Intramuscular phenytoin 20 mg/kg 1 dose
B. Intranasal midazolam 0.2 mg/kg 1 dose
C. Oral lorazepam 0.1 mg/kg 1 dose
D. Rectal diazepam 0.3 mg/kg 1 dose
40. Intravenous access has been obtained for V.V., and a
second dose of a benzodiazepine (lorazepam 0.1 mg/kg
intravenously 1 dose) is administered. The boy contin-
ues to seize for 10 minutes without cessation. The team
decides to administer fosphenytoin. Which one of the
following best justifies the use of fosphenytoin versus
phenytoin in V.V.?
A. Fosphenytoin can be administered faster and will
have a quicker onset of action.
B. Fosphenytoin has a decreased extravasation risk
because of a lower pH.
C. Fosphenytoin contains more propylene glycol for
solubility and can be administered over a shorter
period.
D. Fosphenytoin does not need therapeutic drug
monitoring.
41. V.V. is still seizing after 15 minutes, despite fosphenyt-
oin administration. He is given levetiracetam 20 mg/
kg intravenously 1 dose, and at 30 minutes, the deci-
sion is made to intubate. He is intubated with fentanyl
1 mcg/kg intravenously 1 dose, midazolam 0.1 mg/kg
intravenously 1 dose, and vecuronium 0.1 mg/kg intra-
venously 1 dose. On intubation, he is continued on
fentanyl 1 mcg/kg/hour and midazolam 0.1 mg/kg/hour
continuous infusions for pain and sedation. A continu-
ous EEG has been initiated on V.V., and continued seizure
PedSAP 2016 Book 2 Pediatric Critical Care
activity is present. His blood pressure has remained sta-
ble but lower since initiation of continuous infusion of
midazolam 0.1 mg/kg/hour and fentanyl 1 mcg/kg/hour.
Fentanyl has been decreased to 0.5 mcg/kg/hour, and
blood pressure monitoring continues. Which one of the
following is best to initiate for V.V.?
A. Lacosamide 1 mg/kg/day divided twice daily
B. Pentobarbital 5-mg/kg bolus followed by 1 mg/kg/
hour continuous infusion
C. Propofol 3-mg/kg bolus followed by 100 mcg/kg/
minute continuous infusion
D. Acetazolamide 10 mg/kg/day divided twice daily by
nasogastric tube
42. Seven days after therapy initiation, burst suppression is
apparent on the EEG, but V.V. has had persistent hypo-
tension requiring 10 mcg/kg/minute of dopamine. His
updated laboratory values, which have been consistent
over the past few days, include the following: sodium
143 mEq/L, potassium 4.5 mEq/L, chloride 109 mmol/L,
CO2 15 mmol/L, BUN 32 mg/dL, SCr 0.5 mg/dL, glucose
110 mg/dL, and calcium 10 mg/dL. Given V.V.s current
clinical status, which one of the following best justifies
discontinuing V.V.s pentobarbital?
A. The potential for hypotension
B. The potential for propylene glycol toxicity
C. The lack of correlation between burst suppression
and cessation of seizures in refractory SE
D. The lack of data on prolonged continuous infusions
43. V.V. has now been receiving pentobarbital for 8 days, and
the neurologist wishes to discontinue this therapy. V.V. can
tolerate a wean to 2 mg/kg/hour. Which one of the following
is the best strategy for discontinuing V.V.s pentobarbital?
A. Decrease pentobarbital by 10% every day until off.
B. Convert to pentobarbital intermittent dosing by
dividing the total daily dose into an every-6-hour
interval.
C. Give a loading dose of phenobarbital, and initiate
maintenance dosing at one-third the loading dose.
D. Do not wean the patient from therapy until additional
agents are added for seizure control.
44. Despite the above actions, V.V. continues to have sei-
zures. He is becoming hypotensive despite a fluid bolus
of NS 20 mL/kg and decreasing his pain and sedation
medications. The team initiates epinephrine continuous
infusion at 0.1 mcg/kg/min (titrate to goal systolic and
diastolic blood pressure). Which of the following is best
to recommend for V.V.s continued SE?
A. Acetazolamide 5 mg/kg/dose IV every 8 hours
B. Ketamine 1 mg/kg/hr continuous infusion
C. Lacosamide 3 mg/kg/dose IV every 12 hours
D. Propofol 10 mg/kg/hr continuous infusion
122 Interactive Case: Status Epilepticus
Learner Evaluation: Interactive Case: Status Epilepticus.
As you take the posttest for this chapter, also evaluate the
materials quality and usefulness, as well as the achievement
of learning objectives. Rate each item using this 5-point scale:
Strongly agree
Agree
Neutral
Disagree
Strongly disagree
38. The content of the chapter met my educational needs.
39. The content of the chapter satisfied my expectations.
40. The author presented the chapter content effectively.
41. The content of the chapter was relevant to my practice
and presented at the appropriate depth and scope.
42. The content of the chapter was objective and balanced.
43. The content of the chapter is free of bias, promotion, or
advertisement of commercial products.
44. T
 he content of the chapter was useful to me.
45. The teaching and learning methods used in the chapter
were effective.
46. The active learning methods used in the chapter were
effective.
47. The learning assessment activities used in the chapter
were effective.
48. The chapter was effective overall.
PedSAP 2016 Book 2 Pediatric Critical Care
Use the 5-point scale to indicate whether this chapter pre-
pared you to accomplish the following learning objectives:
49. Distinguish the cause of status epilepticus (SE) in neo-
nates, infants, children, and adolescents.
50. Design an appropriate treatment plan for the pediatric
patient with SE or refractory SE.
51. Design a treatment strategy for the patient with complica-
tions of SE, including hypoxemia and acidosis.
52. 
Evaluate the patient with SE for the development of
long-term sequelae of prolonged seizure activity and/or
treatment of SE.
53. P
 lease provide any specific comments related to any
perceptions of bias, promotion, or advertisement of com-
mercial products.
54. Please expand on any of your above responses, and/or
provide any additional comments regarding this chapter:
Questions 5557 apply to the entire learning module.
55. How long did it take you to read the instructional materi-
als in this module?
56. How long did it take you to read and answer the assess-
ment questions in this module?
57. Please provide any additional comments you may have
regarding this module:
123 Interactive Case: Status Epilepticus
PedSAP 2016-2018 Releases

Title Release Date BCPPS Test Deadline ACPE Test Deadline

Immunology May 16, 2016 September 15, 2016 May 14, 2019

Pediatric Critical Care September 15, 2016 January 17, 2017 September 14, 2019

Research Ethics/
January 17, 2017 May 15, 2017 January 14, 2020
Study Design

Pediatric Emergencies May 15, 2017 September 15, 2017 May 14, 2020

Sedation and
September 15, 2017 January 16, 2018 September 14, 2020
Analgesia

Pediatric Oncology January 16, 2018 May 15, 2018 January 14, 2021

Fluids/Electrolytes/ May 15, 2018 September 17, 2018 May 14, 2021
Nutrition

Neonatal and Pediatric September 17, 2018 January 15, 2019 September 14, 2021
Sepsis

PedSAP Pricing ACCP Members Nonmembers

Single Book $65 $90

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Full Series
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(eight books)

*Appropriate shipping charges will apply.

This book is one release from the American College of Clinical Pharmacys 2016-2018 Pediatric Self-Assessment Program (PedSAP).

Releases are available singly or as an eight-book series over 3 years. Topics for the series are designed to cover the content outline

for the Board Certified Pediatric Pharmacy Specialist examination administered by the Board of Pharmacy Specialties.

For specific faculty, chapter titles, and available continuing pharmacy education contact hours, go to www.accp.com/bookstore.

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