Critical Care Pharmacotherapy (Jan 1, 2018)_(1939862205)_(American College of Clinical Pharmacy) 9781939862204

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A M E R I C A N COLLEGE O F CLINICAL P H A R M A C Y

CRITICAL CARE PHARMACOTHERAPY

B R I A N E R S T A D , P H A R M . D . , F C C P, B C P S , E O I T O R

“IP

Critical Care Pharmacotherapy

Director of Professional Development: Nancy M. Perrin, M.A., CAE Associate Director of Professional Development: Wafa Dahdal, Pharm.D., BCPS Publications Project Manager: David Shaw, M.B.A. Desktop Publisher/Graphic Designer: Mary Ann Kuchta; Steve Brooker Medical Editor: Kimma Sheldon, Ph.D., M.A.

For order information or questions, contact: American College of Clinical Pharmacy 13000 W. 87th Street Parkway, Suite 100 Lenexa, KS 66215 (913) 492-3311 (913) 492-0088 (fax) [email protected]

Copyright © 2016 by the American College of Clinical Pharmacy. 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. 16 17 18 EBM 10 9 8 7 6 5 4 3 2 1 Printed in the United States of America. ISBN: 978-1-939862-20-4 Library of Congress Control Number: 2015953696

DEDICATION To my son, Alex, my wife, Sue, and my mother, Donna, for their unwavering support. B. Erstad

CONTENTS Preface Brian L. Erstad, Pharm.D., FCCP, BCPS Foreword Joseph F. Dasta, M.S., FCCP; Curtis N. Sessler, M.D., FCCP, FCCM; Ashlee Dauenhauer, Pharm.D.;and Ohoud A. Aljuhani, Pharm.D. Letter from ACCP Judith Jacobi, FCCP, MCCM, BCPS, BCCCP, ACCP President 2014– 2015

SECTION 1: SUPPORTIVE CARE Chapter 1: Acid-Base Disorders Curtis E. Haas, Pharm.D.; David C. Kaufman, M.D.; and Brian L. Erstad, Pharm.D., FCCP, BCPS Chapter 2: Fluid Therapy in the Critically Ill Patient Brian L. Erstad, Pharm.D., FCCP, BCPS Chapter 3: Electrolyte Disorders in the Critically Ill Population Jeffrey J. Bruno, Pharm.D., BCPS, BCNSP; and Todd W. Canada, Pharm.D., FASHP, FTSHP, BCNSP Chapter 4: Nutrition Support Therapy in Critically Ill Patients Amber Verdell, Pharm.D., BCPS, BCNSP; and Carol J. Rollins, M.S., RD, Pharm.D., FASHP,FASPEN, BCNSP Chapter 5: Glucose Management in the Critically Ill Population

Paul M. Szumita, Pharm.D., FCCM, BCCCP, BCPS; and James F. Gilmore, Pharm.D., BCCCP, BCPS Chapter 6: Analgesia Asad E. Patanwala, Pharm.D. Chapter 7: Agitation and Comfort in the Intensive Care Unit David J. Gagnon, Pharm.D.; Nicole Kovacic, Pharm.D.; and Gilles L. Fraser, Pharm.D., MCCM Chapter 8: Delirium in Critically Ill Adults John W. Devlin, Pharm.D., FCCP, FCCM Chapter 9: Neuromuscular Blocking Agents M. Claire McManus, Pharm.D., BS(Pharm) Chapter 10: Shock Syndromes Ishaq Lat, Pharm.D., FCCP, FCCM, BCPS; and Sajni Patel, Pharm.D., BCPS

SECTION 2: INFECTIOUS DISEASES Chapter 11: Appropriate Use of Antimicrobials Scott T. Micek, Pharm.D.; and Marin H. Kollef, M.D. Chapter 12: Pharmacokinetic and Pharmacodynamic Considerations for Antimicrobial Use in Critically Ill Patients Douglas N. Fish, Pharm.D., FCCP, FCCM, BCPS-AQ ID Chapter 13: Laboratory Testing Considerations Kali Martin, Pharm.D.; Shanna Cole, Pharm.D.; and Michael Klepser, Pharm.D. Chapter 14: Antimicrobial Resistance in the Critical Care Environment

Andrew M. Roecker, Pharm.D.; and Steven J. Martin, Pharm.D. Chapter 15: Severe Sepsis and Septic Shock Seth R. Bauer, Pharm.D., FCCM, BCPS; Simon W. Lam, Pharm.D., FCCM, BCPS; and Lance J. Oyen, Pharm.D., FCCM, FCCP, BCPS Chapter 16: Invasive Fungal Infections Kathryn R. Matthias, Pharm.D., BCPS-AQ ID Chapter 17: Invasive Viral Infections in the Intensive Care Unit P. Brandon Bookstaver, Pharm.D., FCCP, BCPS-AQ ID, AAHIVP; and Caroline B. Derrick,Pharm.D., BCPS Chapter 18: Antimicrobial Prophylaxis Keith M. Olsen, Pharm.D., FCCP, FCCM; and Gregory Peitz, Pharm.D., BCPS

SECTION 3: NEUROCRITICAL CARE Chapter 19: Status Epilepticus and Acute Seizure Management Eljim P. Tesoro, Pharm.D., BCPS; Karen Berger, Pharm.D., BCPS; and Gretchen M. Brophy,Pharm.D., FCCP, FCCM, FNCS, BCPS Chapter 20: Traumatic Brain Injury and Acute Spinal Cord Injury A. Shaun Rowe, Pharm.D., BCPS; and Bradley A. Boucher, Pharm.D., BCPS Chapter 21: Acute Management of Stroke Martina Holder, Pharm.D., BCPS; and Stacy Voils, Pharm.D., M.Sc., BCPS Chapter 22: Critical Care Management of Aneurysmal Subarachnoid Hemorrhage Denise H. Rhoney, Pharm.D., FCCP, FCCM, FNCS; Kathryn Morbitzer,

Pharm.D.; and J. Dedrick Jordan, M.D., Ph.D.

SECTION 4: HEMATOLOGY Chapter 23: Prevention and Treatment of Venous Thromboembolism William E. Dager, Pharm.D., FCCP, FCCM, FCSHP, FASHP, MCCM, BCPS; and A. Josh Roberts, Pharm.D., BCPS Chapter 24: Hemostatic Agents for the Prevention and Management of Hemorrhage in the ICU Robert MacLaren, Pharm.D., MPH, FCCP, FCCM; Bradley A. Boucher, Pharm.D.,FCCP, FCCM; and Laura Baumgartner, Pharm.D. Chapter 25: Laboratory Testing with Anticoagulation Tyree H. Kiser, Pharm.D., FCCP, FCCM, BCPS

SECTION 5: ACUTE KIDNEY INJURY Chapter 26: Acute Kidney Injury—Prevention and Management Curtis L. Smith, Pharm.D., BCPS; and Thomas C. Dowling, Pharm.D., Ph.D., FCCP, FCP Chapter 27: Drug Dosing in Acute Kidney Injury and Extracorporeal Therapies Melanie S. Joy, Pharm.D., Ph.D., FCCP, FASN; Michael L. Bentley, Pharm.D.; and Katja M. Gist, D.O., M.A., MSCS

SECTION 6: Liver/GASTROINTESTINAL

Chapter 28: Management and Drug Dosing in Acute Liver Failure Andrew C. Fritschle Hilliard, Pharm.D., BCPS, BCCCP; and David R. Foster, Pharm.D., FCCP Chapter 29: Acute Gastrointestinal Bleeding: Prophylaxis and Treatment Salmaan Kanji, Bsc. Pharm, Pharm.D.; and David Williamson, B. Pharm, M.Sc., Ph.D., BCPS

SECTION 7: ACUTE PULMONARY DISEASE Chapter 30: Pulmonary Arterial Hypertension Steven E. Pass, Pharm.D., FCCP, FCCM, FASHP, BCPS; and Joseph E. Mazur, Pharm.D., BCPS Chapter 31: Critical Care Management of Asthma and Chronic Obstructive Pulmonary Disease Amanda Zomp, Pharm.D., BCPS; Katherine Bidwell, Pharm.D., BCPS; and Stephanie Mallow Corbett, Pharm.D., FCCM

SECTION 8: CARDIOVASCULAR CRITICAL CARE Chapter 32: Acute Decompensated Heart Failure Jo E. Rodgers, Pharm.D., FCCP, BCPS-AQ Cardiology; and Brent N. Reed, Pharm.D.,FAHA, BCPS-AQ Cardiology Chapter 33: Management of Acute Coronary Syndrome Zachary A. Stacy, Pharm.D., M.S., FCCP, BCPS; and Paul P. Dobesh, Pharm.D., FCCP,BCPS-AQ Cardiology Chapter 34: Management of Cardiac Arrest Toby C. Trujillo, Pharm.D., FCCP, FAHA, BCPS-AQ Cardiology

Chapter 35: Acute Management of Arrhythmias James E. Tisdale, Pharm.D., FCCP, FAPhA, FAHA, BCPS Chapter 36: Pharmacologic Challenges During Mechanical Circulatory Support in Adults Amy L. Dzierba, Pharm.D., FCCM, BCPS; and Erik Abel, Pharm.D., BCPS

SECTION 9: OTHER URGENCIES AND EMERGENCIES Chapter 37: Hypertensive Crisis Jeremy Flynn, Pharm.D., FCCP, FCCM; Melissa Nestor, Pharm.D., BCPS; and Komal Pandya,Pharm.D., BCPS Chapter 38: Medication Withdrawal in the Intensive Care Unit Colgan T. Sloan, Pharm.D., BCPS; Robert French, M.D., MPH; Nicholas B. Hurst, M.D., M.S.;Stephen R. Karpen, Pharm.D.; and Mazda Shirazi, M.D., Ph.D. Chapter 39: Endocrine Disorders Robert L. Talbert, Pharm.D. Chapter 40: Oncologic Emergencies Ali McBride, Pharm.D., M.S., BCPS, BCOP; Michelle Nadeau, Pharm.D., BCPS; and Cory M. Vela, Pharm.D.

SECTION 10: MISCELLANEOUS Chapter 41: Drug Dosing in Special Intensive Care Unit Populations Jeffrey F. Barletta, Pharm.D., FCCM Chapter 42: Management of the Critically Ill Burn Patient

Claire V. Murphy, Pharm.D., BCPS; and Kate Oltrogge Pape, Pharm.D., BCPS Chapter 43: The Role of Pharmacotherapy in the Treatment of the Multiple Trauma Patient Rita Gayed, Pharm.D.; Prasad Abraham, Pharm.D., FCCM, BCPS; and David V. Feliciano,M.D., FACS Chapter 44: Pediatric Critical Care Elizabeth Farrington, Pharm.D., FCCP, FCCM, FPPAG, BCPS Chapter 45: Drug Shortages: An Overview of Causes, Impact, and Management Strategies Samuel E. Culli, Pharm.D., MPH; and John J. Lewin III, Pharm.D., MBA, FASHP,FCCM, FNCS Chapter 46: Drug Interactions in the Intensive Care Unit Cristian Merchan, Pharm.D.; and John Papadopoulos, Pharm.D., B.S., FCCM, BCNSP Chapter 47: Acute Illness Scoring Systems Thomas J. Johnson, Pharm.D., MBA, FASHP, FCCM, BCPS Chapter 48: Leading and Managing Intensive Care Unit Pharmacy Services Robert J. Weber, Pharm.D., M.S., FASHP, BCPS Chapter 49: Medication Safety and Active Surveillance Sandra L. Kane-Gill, Pharm.D., M.Sc., FCCP, FCCM; and Mitchell S. Buckley, Pharm.D.,FCCP, FASHP, FCCM, BCPS Chapter 50: Care of the Immunocompromised Patient Heather Personett, Pharm.D., BCPS; and Simon W. Lam, Pharm.D., FCCM, BCPS Chapter 51: Clinically Applied Pharmacogenomics in Critical Care Settings

Samuel G. Johnson, Pharm.D., FCCP; and Christina L. Aquilante, Pharm.D., FCCP Contributors Reviewers Index Disclosure of Potential Conflicts of Interest

PREFACE Brian L. Erstad, Pharm.D., FCCP, BCPS The origin of critical care as a specialty is open to debate. Critically ill patients have received care in groups near battlefields ever since organized large-scale fighting first occurred. In hospital settings,isolated postoperative units dedicated to critically ill patients have been reported since the early 1900s.However, the widespread need for mechanical ventilation (commonly called respirators at the time) of patients with polio during the epidemics of the 1940s and 1950s led to a tipping point in the formation of critical care specialization. One of the first papers describing the care of patients with polio referred to care “by a team” of clinicians, although pharmacists were not among the health professionals listed.1 In addition to ventilators, other technologies that began to have more widespread use in critically ill patients by the 1950s included rudimentary dialysis machines,AC electrical defibrillators, and transvenous cardiac pacing equipment.2 More invasive respiratory and hemodynamic monitoring tools were also increasingly used in the early intensive care units (ICUs) of the 1950s and 1960s. These developments in the care of critically ill patients necessitated specialization by physicians in areas such as internal medicine, trauma,and anesthesiology. Other specialized personnel such as nurses, respiratory therapists, and eventually pharmacists (circa 1970s–1980s) were needed to complement the increasing number of critical care physicians in more modern critical care units. Today, a multidisciplinary or interdisciplinary patient care team that includes pharmacists has become the practice mantra and is now the norm in many ICU settings. The term intensivist is now used to describe physicians with critical care specialty training following primary residency training in areas like

internal medicine, surgery, anesthesiology, emergency medicine, pediatrics, and obstetrics and gynecology.The first certification examination for critical care specialization by physicians was offered within internal medicine in 1987 by the American Board of Medical Specialties. Board certification for intensivists is now available from several specialty boards. For pharmacists,critical care has been recognized as a unique specialty by the Board of Pharmacy Specialties, with the first examination offered in the fall of 2015; widespread support for this certification within the profession of pharmacy is evidenced by the petition for specialty recognition that was jointly submitted by the American College of Clinical Pharmacy (ACCP), the American Pharmacists Association, and the American Society of Health-System Pharmacists. In addition to specialty recognition, there are many other indicators of the growth and advancement of critical care pharmacy practice. The number of unit-based (i.e., clinical) critical care pharmacists increases in each new survey of critical care pharmacy practice.Similarly, the number of accredited PGY2 critical care residencies continues to increase. Fellowships in critical care have been developed, albeit in smaller numbers. Critical care pharmacists have their own recognized specialty groups in professional pharmacy organizations, such as the ACCP Critical Care Practice-Related Network (PRN). Position and opinion papers have been published that discuss the scope, level (i.e., fundamental, desirable, optimal), and justification of critical care pharmacy services and the credentialing of critical care pharmacists.3,4 But perhaps the best testimonial to the advancement and success of critical care pharmacists is their own substantial involvement in interprofessional critical care societies,organizations, and associations. The four largest professional groups in the United States with critical care practitioner membership are the American Thoracic Society, the American College of Chest Physicians, the American Association of Critical-Care Nurses, and the Society of Critical Care Medicine (SCCM). Together, these groups formed a loose association known as the Critical Care Societies Collaborative (CCSC), which was established in 2009 to work on common core critical issues. Of the

organizations that constitute the CCSC,the first to recognize critical care pharmacists in a meaningful way was SCCM, established in 1970 —as evidenced by its involvement in governance and committee work. Since 1998, critical care pharmacists have had a recognized section (Clinical Pharmacy and Pharmacology) within the administrative structure of SCCM. Furthermore, critical care pharmacists have widespread involvement in governance and other aspects of SCCM, as evidenced by the pharmacists who have served in numerous high-level positions (including president), the highly respected awards and honors bestowed on critical care pharmacist members (e.g., Fellow of the American College of Critical Care Medicine, Master Critical Care Medicine, Shubin-Weil Master Clinician/Teacher: Excellence in Bedside Teaching Award), the number of pharmacists involved in SCCM educational programming and guideline development efforts, and the long-standing practice models that have recognized pharmacists as integral members of the critical care team.5 Moreover, pharmacists continue to make inroads in other national critical care organizations that have traditionally been more physician-centric; for example, the Neurocritical Care Society recently placed a pharmacist in the governance line leading to the presidency. The preceding overview of the evolution of critical care pharmacy practice serves as the backdrop for this first edition of Critical Care Pharmacotherapy. A cursory look at the authors of the chapters in this textbook reveals many of the pioneers and thought leaders in critical care pharmacy practice. Several of these authors were the first pharmacists to establish decentralized, unit-based critical care pharmacy services in their institutions. Many of the authors have held high-level positions in organizations with critical care membership, and most have active educational training and research programs. I am honored to be part of this collective effort. The choice of chapters for this text was not an easy one, and I am indebted to many colleagues for their helpful suggestions. Chapters in general medical and pharmacy textbooks are often compiled on the basis of disease states or organ systems, but neither of these approaches was deemed appropriate for a critical care text focusing

on pharmacotherapy. A pharmacologic approach to the chapters based on drug class was excluded because it would not integrate the diseasemedication decision-making process that is reflective of actual practice. Ultimately, a combination approach was decided on. Many of the chapters are listed under an organ system section, but most of the specific chapters in each section use a medication-focused approach. Another large section of chapters pertains to supportive care because this reflects so many of the medications that are used in critical care practice. Finally, several miscellaneous topics, some of which involve special ICU populations, did not fit neatly into either the organ system or supportive care sections but were deemed necessary to present a complete picture of critical care pharmacy practice. Although this text is primarily aimed at a critical care pharmacist audience, we hope that it will provide valuable information for other pharmacists who must periodically care for critically ill patients, as well as for other health professionals who care for critically ill patients and desire a pharmacotherapy-focused resource. Ultimately, the intent of this text is to better educate pharmacists and other health professionals on issues pertaining to critical care pharmacotherapy so that they can provide optimal care for our patients in an efficient and cost-effective manner.

References 1. Ibsen B. The anaesthetist’s viewpoint on the treatment of respiratory complications in poliomyelitis during the epidemic in Copenhagen, 1952. Proc R Soc Med 1954;47:72-4. 2. Weil MH, Tang W. From intensive care to critical care medicine. Am J Respir Crit Care Med 2011;183:1451-3. 3. Rudis MI, Brandl KM. Society of Critical Care Medicine and American College of Clinical Pharmacy Task Force on Critical Care Pharmacy Services. Position paper on critical care pharmacy services. Crit Care Med 2000;28:3746-50. 4. Dager W, Bolesta S, Brophy G, et al. An opinion paper outlining

recommendations for training, credentialing, and documenting and justifying critical care pharmacy services. Pharmacotherapy 2011;31:135e-175e. 5. Brilli RJ, Spevetz A, Branson RD, et al. Critical care delivery in the intensive care unit: defining clinical roles and the best practice mode. Crit Care Med 2001;29:2007-19.

FOREWORD

Joseph F. Dasta, M.S., FCCP When I began to establish my clinical practice in 1979 in the medical intensive care unit (MICU) at The Ohio State University Hospital (now Wexner Medical Center), I knew of only two pharmacists in the United States who were critical care specialists. The first was David Angaran, M.S., at the University of Wisconsin trauma ICU. During my hospital pharmacy residency at Ohio State, we visited the University of Wisconsin in 1975 and toured the ICU, where I met David. He had been in that role since 1972. I was so impressed with his level of involvement in the care of the ICU patient that I recall saying to myself, “I want to be like him someday.” The second was Thomas Majerus,Pharm.D., who had been practicing in the trauma ICU since 1977 at the Maryland Institute of Emergency Medical Services. He was also very involved with direct patient care. Clearly, both of these pharmacists filled an unmet need in pharmacotherapy, and they were practicing at a high level of clinical involvement,even in today’s terms. They were the true pioneers of critical care pharmacy.1 My initial practice area in 1977 was pulmonary medicine, and my clinical responsibility at the college of pharmacy was to develop a practice site at the hospital for pharmacy students (B.S. program) to gain clinical experience. Please note that I was employed full-time by the college of pharmacy, not the hospital pharmacy, although I had a good relationship with the pharmacy department because I was a graduate of their residency. I decided to change my practice site in 1979 from pulmonary medicine to the MICU because the pulmonary medicine division became administratively responsible for establishing an ICU team with a pulmonologist as the attending physician. It sounded like an interesting area for a pharmacist. It may be of interest to know that I had no idea that critical care pharmacy would develop

into what it is today. I had not considered the future potential of critical care; I was primarily interested in developing a site for pharmacy students to fulfill their clinical rotation requirements.As the adage goes, “I’d rather be lucky than good.” Even in 1979, Ohio State had a relatively well-established clinical pharmacy program whereby “floor pharmacists” were assigned to certain nursing units to evaluate the appropriateness of drug orders and to verify these orders before sending them to the central pharmacy for dispensing. As such, a floor pharmacist was assigned to the MICU; however, floor pharmacists usually did not attend daily ICU rounds because they had duties in other nursing units in the hospital. As such, I was the first pharmacist to consistently attend daily MICU rounds. I had not completed a formal training in the area of critical care pharmacy because no formal training programs yet existed; therefore, this practice setting posed many learning opportunities for me. I learned on my own by reading as much as I could and asking a lot of questions of the critical care nurses and physicians. During one visit to the health sciences library, I went to the stacks under the letter “C.” I found several textbooks on critical care and a journal called Critical Care Medicine. I leafed through its pages and realized that it was the official journal of the Society of Critical Care Medicine (SCCM). I recall thinking “Wow, they even have a specialty society.” A few days later, I called the society to inquire about membership.After I provided a brief explanation of my activities,a staff member said that it sounded like I was part of the critical care team and said, “Of course you can join … we’d love to have you as part of this society.” I was flattered…. It seemed to me that critical care would be a natural specialty for pharmacists. Patients are often hemodynamically unstable, they receive many drugs,and the data on therapies pertaining to the critically ill patient were scant to nonexistent. I hoped someday there would be many pharmacists specializing in critical care. In 1981, I switched my practice to the surgical ICU (SICU). This unit was very different because there was no floor pharmacist. The pharmacy department sent drugs for the nurses to prepare (i.e., reconstitute vials and make an intravenous admixture) and administer.I heard rumors about this unit, which appeared in desperate need of a

clinical pharmacist. I later discovered that the main interaction of the nurse with a pharmacist was for nurses to frequently call the pharmacy and say something like “my gentamicin was late.” This was a ripe area for the total scope of pharmacy services, both distributional and clinical. I decided to introduce myself to the physician director, Dr. Tom Reilley, an anesthesiologist. After I told him who I was, I’ll never forget his words to me: “Where have you been … I’ve been looking for a clinical pharmacologist since arriving here several years ago.” He told me to meet him the next day at 9 a.m. in the SICU. Honestly, I was scared to death that someone would ask me a question that I could not answer. On rounds, one of the first patients we encountered was shaving his beard; of course, he did not have a razor. Apparently, this elderly man was hallucinating. A review of his medication list revealed that he was receiving intravenous cimetidine 300 mg every 6 hours, and his serum creatinine was about 3–4 mg/dL. I sheepishly pointed this out on rounds and suggested that his altered mental status could be from excess cimetidine. Dr. Reilley turned to me and asked me the dreaded question, “How do we fix this?” Although I was prepared to speculate and provide theories, it dawned on me that he wanted an action plan. I said to hold the dose for 24 hours and reinitiate cimetidine 300 mg every 12 hours. The order was changed according to my suggestion. A few days later, his mental status was better. Little did I know that, years later, I would be part of the SCCM clinical practice guideline on pain, agitation, and delirium! The care of the critically ill patient in the early 1980s was much different from today. For example, most mechanically ventilated patients were heavily sedated. It was believed that ICU patients are best served if they don’t participate in their care and have no memory of their critical illness. There is an observation made by Dr. Tom Petty at the University of Colorado, in mid-1998, where he reflects on seeing patients in the ICU motionless, sedated, paralyzed, and appearing to be dead, except for the monitors that told him otherwise.2 I suspect that if I had suggested early mobility, it would have sounded like heresy.

Many patients in the ICU, particularly the SICU, had pulmonary artery catheters. As such, several hemodynamic monitoring variables were generated,often many times per day. All of this information plus laboratory results, drugs, and so forth was on paper-based flow sheets. It was difficult to make sense of the volume of data. Regarding the paper medication administration record, at least at Ohio State, the scheduled drugs were on the front page, and the as-needed drugs were on the reverse side. As I recall, we often ignored the as-needed drugs like analgesics and sedatives because that was considered a “nursing issue.” Common orders included morphine 2–8 mg every 1–4 hours as needed, lorazepam 1–4 mg every 4–8 hours as needed, haloperidol 2.5–10 mg every 8–12 hours as needed, and diphenhydramine 25–50 mg intravenously every night at bedtime as needed for sleep. When I reviewed this page, I recall concluding that it appeared to be the nurse who was selecting the drug, the dose, how often to administer, and what parameter to monitor. In addition to clinical practice and precepting B.S. pharmacy students, I initiated some clinical research studies. I quickly learned how difficult it was to conduct research in such an unstable population. After about 15 years of performing these functions, the pharmacy department opened an SICU/perioperative satellite pharmacy and later hired a Pharm.D. specifically for the SICU. My role changed to more of a clinical consultant, educator, and clinical researcher. Myinteraction with the SICU clinical pharmacist served as a model for optimal collaboration between hospital- and college-paid faculty. We coprecepted Pharm.D.students and collaborated on several clinical research studies. During this time, I established one of the nation’s first residencies in critical care pharmacy. My first resident was a woman who had just completed her Pharm.D. degree. She was passionate about the care of the critically ill patient. I soon realized that she was a very talented person; beyond being smart, hard-working, and an excellent communicator, she was able to step back and examine the big picture in ways that I could not have imagined. Of course, I’m referring to Judi Jacobi, Pharm.D., who became the first pharmacist president of SCCM in 2010 and is the 2015 president of ACCP.

During my tenure at Ohio State, I was fortunate to train 11 residents and 9 fellows. My first fellow was Robert Weber, whose program was funded by an ASHP grant in 1980. Bob is now administrator of pharmacy services at Ohio State. I am very proud of all the accomplishments of my 20 residents and fellows. There have been many changes in pharmacy and health care since I first established my clinical practice in the late 1970s. The pharmacy department has evolved from a revenue-generating center to a cost center after capitated reimbursement was initiated. This generated numerous initiatives focused on cost reduction of pharmaceuticals. In the area of professional organizations, the Critical Care Practice Research Network of the American College of Clinical Pharmacy (ACCP) is consistently one of the largest PRNs within ACCP. Regarding SCCM, the Clinical Pharmacy and Pharmacy (CPP) section was formed in 1989 and currently has more than 2,000 members.It is a very active section, with pharmacists serving on key committees of the section and within the SCCM organization. Furthermore, there is a designed CPP seat on the council. There are usually four or five pharmacists on the editorial board of Critical Care Medicine, many pharmacists have been members of clinical practice guidelines and a few have been chair,and a pharmacist was recently selected as program cochair for the annual congress. In 2015, the Board of Pharmacy Specialties (BPS) recognized critical care pharmacy as the seventh BPS specialty. There usually are 70–80 critical care residencies,and many ICUs have pharmacist preceptors actively involved with direct patient care. However, the number of fellowships has dropped dramatically. It is of concern that so few critical care pharmacists are being trained for research-oriented academic positions. In addition,some critical care pharmacists are being diverted to other areas of the hospital, or they are being redirected to reduce drug costs. These changes are occurring despite data showing the important role of the critical care pharmacist.3,4 Clearly, the critical care pharmacist should focus on providing cost-effective, quality care. In summary, critical care pharmacy is a well-established specialty in

the field of clinical pharmacy,which now has a board certification process.Thousands of ICU patients have benefited from critical care pharmacists providing excellence in patient care,leadership roles in professional societies, and clinical research resulting in improved outcomes. The future is bright. However, it will be important for pharmacists to be paid for their services and for organizations like the Joint Commission, Leapfrog, and the Centers for Medicare & Medicaid Services to endorse the critical care pharmacist as a crucial element in the provision of optimum care to the critically ill patient.

References 1. Dasta JF. Critical care. Ann Pharmacother 2006;40:736-7. 2. Petty T. Suspended life or extending death? Chest 1998;114:3601. 3. Kane SL, Weber RJ, Dasta JF. The impact of critical care pharmacists on enhancing patient outcomes. Intensive Care Med 2003;29:691-8. 4. MacLaren R, Devlin JW, Martin SJ, et al. A national survey characterizing the practice of critical care pharmacists. Ann Pharmacother 2006;40:612-7.

Curtis N. Sessler, M.D., FCCP, FCCM I recently celebrated my 30-year anniversary as an attending physician in the intensive care unit (ICU) setting and was thrilled when Brian Erstad invited me to reflect on the journey of critical care pharmacotherapy.I have long been an enthusiastic believer that by getting the right people with the right skills in the right seats on the bus, one can be confident of achieving the best possible outcomes. This is certainly true in critical care medicine, where the sickest patients have the most complex management, often proceeding at the fastest pace. Although I am confident that we have been providing the best care possible for many years, I personally count the addition of the clinical

pharmacist as a regular member of the ICU team as a sentinel moment in the quest to deliver high-quality patient care. I have had the very good fortune of working with some spectacular clinical pharmacists in a wide variety of settings—a reflection of the many roles that clinical pharmacists play and the different hats I’ve worn over the years. These roles have evolved to the point that,unquestionably, clinical pharmacists are essential for the optimal care of the individual ICU patient, as well as the safe, effective, and cost-conscious critical care delivered throughout hospitals around the world. As is true for many clinicians, my most consistent appreciation for the clinical pharmacist is of the value added on a daily basis in their direct patient-centric role. The instances in which one of our clinical pharmacists has identified and corrected a potentially life-threatening drug interaction or adverse drug effect are too numerous to count. I recall one patient who had suffered a small stroke at another hospital but arrived to our ICU manifesting severe neurocognitive deficits.Our clinical pharmacist noted that the patient had been receiving an amiodarone infusion and recommended discontinuation as a potential cause of neurotoxicity.This patient rapidly improved and was eventually discharged home with good functional abilities. Important roles our clinical pharmacists play in the daily management of ICU patients include participating in pharmacotherapy decision-making,providing pharmacokinetic consultation, identifying and mitigating potential drug interactions, taking steps to avoid or quickly recognize adverse drug effects, monitoring drug dosing and administration,and avoiding administration of costly or unnecessary medications. Widespread organ dysfunction, extensive lists of medications, and rapidly changing medical illnesses contribute to a fertile setting for the emergence of medication misadventure. In fact, among all patient groups, critically ill patients present perhaps the greatest challenges and therefore the greatest needs for the skills of a good clinical pharmacist. Although many ICU patients benefit from direct clinical pharmacist involvement, I consider the clinical pharmacistphysician partnership to be among the most powerful patient-care tools in the intensivist’s armamentarium.In fact, one might consider this partnership to reflect the collective expertise as the therapeutic

strategists who design and implement the pharmacologic therapeutic plan, as well as therapeutic tacticians who make fine adjustments to medications in the heat of medical battle. Together with ICU nurses, clinical pharmacists and physicians establish the core of the ICU team that provides patient-centered care. My experiences as medical director for our medical ICU, as well as other leadership roles in the critical care community throughout our institution, have broadened my appreciation for the many important contributions by, and the unique expertise of, clinical pharmacists with respect to tackling important system-wide issues.Our clinical pharmacists are at the forefront of a wide variety of educational, administrative, and local policy-making activities. Many important activities focus on traditional pharmacy-based issues, but typically with an eye to educating and assisting other members of the health care team. For example, like many hospitals, we have experienced shortages of critical medications including vasopressors, sedative and opioid medications,and others. Our clinical pharmacists’ action plans have included detailed and evidence-based guidelines for substitution medications with matching educational programs for all affected clinicians. In addition, our clinical pharmacists routinely serve as key members of multiprofessional taskforces that create order sets,checklists, treatment algorithms, and other tools and documents. As an academician, I am delighted that we have a strong culture of scientific inquiry in our critical care community. Our clinical pharmacists are highly engaged and often lead the way in the process of addressing clinically relevant questions through clinical research and scholarly analysis. I’m proud of our clinical pharmacists who routinely present posters at national meetings and publish important original investigations and reviews. One of the more noteworthy accomplishments from the ICUs at our institution—developing and validating the Richmond Agitation-Sedation Scale (RASS)—initially emerged from a bedside conversation several clinical pharmacists and I were having about adjusting sedative medications.We concluded, let’s make a better patient assessmenttool and build one that includes the viewpoints of all the key stakeholders—nurses, pharmacists, and physicians—for this important and common problem.

For the past decade or so, I have had increasingly frequent collaboration with clinical pharmacy colleagues on several national projects, including serving on work groups addressing critical care workforce shortages, clinical practice guideline writing committees, and expert panels to address important problems like managing pain in the ICU. It is clear that clinical pharmacy is a discipline at the heart of critical care practice, research, and education and that clinical pharmacists provide the unique expertise that complements that of nurses, physicians, and other individuals, all striving to provide superlative patient care. I conclude by applauding Dr. Erstad for leading a distinguished group of contributors in creating an outstanding textbook of critical care pharmacotherapy.I am grateful for the opportunity to contribute and,in doing so, to help celebrate the tremendous work performed by my clinical pharmacy colleagues.

Ashlee Dauenhauer, Pharm.D. As a new practitioner in the field of critical care, I was ready to take my 8+ years of higher education and make a difference in patients’ lives. What I quickly found is that the reality of daily patient care is much more complex than what is taught during those fruitful years of training. Even after a rigorous 2-year residency program, where I was seemingly exposed and prepared for every situation, I realized how much untapped knowledge exists in medicine. Nevertheless, some of the most indispensable information I have gained in the field of health care resulted from my daily experiences in the intensive care unit (ICU). As I reflect on my years of training and the first year of my career as an ICU pharmacist, I am exceptionally pleased with my decision to pursue the area of critical care. I was first exposed to the acute care setting as a fourth-year pharmacy student during clinical rotations. At that time, I had a limited preconceived notion of what clinical pharmacists actually did on a daily basis. However, after observing my preceptors, I acknowledged the potential impact that pharmacists have on patient care through diligent

patient and physician interaction. When I began my pharmacy residency, I was fortunate enough to train in a program that already had well-established clinical pharmacist positions. Pharmacists and pharmacy residents at the University of Arizona Medical Center have a recognized and respected relationship with other members of the health care profession. Training at an institution with a valued pharmacy presence has allowed me to grow exponentially in medical knowledge, workload efficiency, and team communication. As a clinical pharmacy resident, I was much more involved with direct patient care than I had originally perceived. I was available at the patient’s bedside to provide real-time medication-related recommendations and assistance for complex treatment plans. This decentralized pharmacy model allowed me to resolve medicationrelated issues immediately, creating more time for other health care professions such as physicians and nurses to provide excellent patient care.This pharmacist-physician collaboration also provided the patient with a multidisciplinary crafted treatment plan, consisting of the most evidence-based, cost-effective, and accessible medications. Although there has been substantial growth in clinical pharmacist positions among institutions, many are still without this multidisciplinary model. A focus of expanding this position to include a pharmacist on every unit is a current objective at my own institution, which will hopefully continue to improve health care collaboration and optimize patient care. After accepting a position as a critical care pharmacist, I was placed mainly in the cardiothoracic ICU. Experiencing this specific unit made me recognize the importance of having specialty-trained pharmacists in all capacities of health care. Much like other areas of medicine, having the wealth of knowledge and experience with every single medication and interacting disease state is difficult because of the dynamic parameters that change with different patient populations. Being proficiently trained in medication pharmacodynamics, pharmacokinetics, and pharmacoeconomics specifically in the cardiothoracic population has given me comprehensive knowledge for the medications and disease states observed in this specialty area. This foundation includes acute decompensated heart failure requiring mechanical circulatory support and valve replacements as well as

initiation, regulation, and monitoring of anticoagulation for cardiac device patients such as left ventricular assist devices, total artificial hearts, and extracorporeal membrane oxygenation. After completing the first full year of my career, I find that being a new clinician has made me realize how far health care still needs to progress in the future.The proverb that “medicine is not black and white” could not be truer in the critical care setting. Many health care professionals practicing in this area can verify that the textbook patients included in medical studies simply do not exist in the ICU because of a perpetually aging population surrounded by many comorbidities. Therefore, providing optimal patient care established by evidence-based medicine becomes increasingly challenging in many cases. I believe that continuing to observe modern medical practice outcomes through research in every patient population will undoubtedly benefit the progression of health care. This past year, I have begun to direct my focus in clinical studies occurring at my institution, specifically in the cardiothoracic ICU setting. I hope to continue participating in research to further advance medical practice in cardiothoracic devices, all while providing my services to both patients and other health care professionals to make a difference in patients’ lives.

Ohoud A. Aljuhani, Pharm.D. Where I stand today is at the culmination of a journey that began 5 years ago when I took the first steps toward becoming a specialist in critical care pharmacy. As a pharmacist with a stable career at one of the largest universities and academic medical centers in Saudi Arabia, I found the decision to go back to school, travel to the United States, and start all over again to be a difficult one. I look back on my journey with no regrets. In 2007, I began practicing as a clinical pharmacist in the medical intensive care unit (ICU) at King Abdul-Aziz University (KAU) Medical Center in Jeddah,Saudi Arabia. I remember my first day on the job seeing how excited the medical ICU team was to have a clinical pharmacist working with them. Even though the pharmacy profession

had been well established in my country for more than 50 years, clinical pharmacy practice was still in its infancy. Although some specialty health care centers were practicing clinical pharmacy, most government-run hospitals, including KAU Medical Center, had yet to establish services,despite a growing patient population. A major step toward initiating these services was establishing the first Pharm.D.granting institution in the country at KAU. Among the first group of graduates from this school, I was honored to participate in such a new and unique program. After graduation, with the passion and energy of a young practitioner, I accepted a shared position with the School of Pharmacy and KAU Medical Center. This position provided mentors and guidance that helped me throughout my career. Initiating clinical pharmacy services in the ICU of a hospital with 500 beds was certainly a challenge. To meet this challenge,I sought advice from experienced clinical pharmacists,actively participated in the implementation of ICU pharmacotherapy protocols, participated in several hospital committees, made rounds with medical ICU teams, provided daily recommendations about therapies, and assisted with the training of pharmacy students at the hospital. While practicing clinical pharmacy in the ICU’s trauma/surgical and medical departments, I became aware of the need for well-trained clinical pharmacists in these areas. This moment of realization was the principal force driving me to make one of the important decisions in my life—to seek professional training in critical care pharmacotherapy. Unfortunately, the only available residency program in Saudi Arabia at that time was for general pharmacy training. Therefore, I made the decision to travel to the United States and receive specialized training in critical care pharmacotherapy at one of the country’s top academic medical centers. What I have learned and practiced in this program during the past few years has lit a candle of hope that I will carry back to my country. My postgraduate education has helped me become a well-trained and capable critical care pharmacist and researcher and will allow me to actively participate in the development of clinical pharmacy services in Saudi Arabia. If you are reading this book and hoping to play an active

role in improving clinical pharmacy practice in your country,this foreword is dedicated for you.

LETTER FROM ACCP Judith Jacobi, FCCP, MCCM, BCPS, BCCCP, ACCP President 2014–2015 When I consider the literature of critical care pharmacotherapy, I recall with fondness the text edited by Bart Chernow, M.D., FCCM, Master FCCP,initially published in 1983, titled The Pharmacologic Approach to the Critically Ill Patient. However, it was the third edition that embraced the role of the critical care team and included a large number of pharmacist authors.1 This version blended pharmacology with the clinical nuance of critical care therapeutics. This “antique” remains in my library as an important reminder of both a simpler time and the tremendous progress we have made—and still how much we need to learn to optimally care for these patients. For those of us with long careers in critical care, books like this lend an important perspective on current practices and their foundation. Much time has passed, and many other publications have come and gone from my critical care library. Critical care journals and other periodicals are generating data at a dizzying rate. One might ask how another textbook could contribute to the training and effectiveness of critical care clinicians.However, that is easy to answer with a publication of the quality of Critical Care Pharmacotherapy, which compiles key information in a format that illustrates our current understanding of pertinent therapeutic and pharmacologic topics. Indeed, this book will establish a new basis for future research and knowledge development and will hopefully become a foundational text for new practitioners and the growing number of Board Certified Critical Care Pharmacists. Brian Erstad has assembled an impressive group of authors, many of whom are friends and colleagues in critical care pharmacy and have done the cutting-edge research that contributes to this expansive

work.Many other talented and dedicated clinicians and researchers will be cited, but most contributors will remain in relative obscurity as our specialty continues to mature. As a past president of ACCP, I want to thank the efforts of the growing number of critical care clinicians who make such a difference in the care of our patients and who have contributed to the Critical Care Practice and Research Network and to this text. I anticipate that we will all use this text for our own education and as a teaching tool for future generations.

References 1. Chernow B. The Pharmacologic Approach to the Critically Ill Patient. Baltimore: Williams & Wilkins, 1994.

Section 1 Supportive Care

Chapter 1 Acid-Base Disorders Curtis E. Haas, Pharm.D.; David C. Kaufman, M.D.; and Brian L. Erstad, Pharm.D., FCCP, BCPS

LEARNING OBJECTIVES 1. Explain the common contributors to and potential clinical consequences of acid-base disorders in the critically ill patient. 2. Appreciate the differences between the traditional physiologic (carbonic acid-bicarbonate), standard base excess, and physiochemical (Stewart) models of acid-base physiology. 3. Complete the stepwise approach to assessment and reach a correct conclusion concerning the acid-base status of a critically ill patient. 4. Define the independent and dependent variables in acid-base physiology and their relevance to understanding the mechanisms and treatments for common acid-base disturbances. 5. Summarize the common causes, presentations, complications, and treatments for acid-base disorders commonly observed in critically ill patients. 6. Explain the relationship between fluid and electrolyte therapy and acid-base disturbances in critically ill patients, and explain how choice of fluids used during resuscitation can influence acid-base balance.

ABBREVIATIONS IN THIS CHAPTER

[x]

Denotes concentration of x

ABG

Arterial blood gas

ACAG

Albumin-corrected anion gap

ALCAG

Albumin and lactate corrected anion gap

AG

Anion gap

ATOT

Total weak acid concentration

BE

Base excess

BEUA

Base excess caused by unmeasured anions

DKA

Diabetic ketoacidosis

ICU

Intensive care unit

SBE

Standard base excess

SID

Strong ion difference

SIDa

Apparent strong ion difference

SIDe

Effective strong ion difference

SIG

Strong ion gap

UAG

Urinary anion gap

INTRODUCTION Acid-base disorders are common findings in critically ill patients, are often complicated and multifactorial in nature, and are associated with significant morbidity and mortality. The diagnosis of the underlying causes of an acid-base disorder in critically ill patients is further complicated by concomitant and dynamic abnormalities in plasma protein concentrations, electrolyte profiles, free water or overall extracellular volume status, and ventilatory status. Given the often-

complicated nature of the presentation, a simplistic or casual approach to evaluating acid-base disorders is inadequate for the intensive care unit (ICU) environment and may lead to a missed diagnosis or a complication that needs treatment. Although the mainstay for managing an acid-base disorder remains treatment of the underlying processes, a full understanding of the contributors to the acid-base status may identify a need for specific therapeutic interventions. This chapter is focused on an understandable and practical, but comprehensive, approach to assessing and managing the acid-base disorders commonly encountered in critically ill patients. Several studies that have evaluated diagnostic approaches to metabolic acidosis provide some insights into the frequency of this disorder in different ICU settings. Cusack and coworkers reported on 100 consecutive adult patients admitted to a mixed medical-surgical ICU. Standard base excess (SBE) was abnormal in 57% of patients, corrected base excess (BE) was decreased in 86%, and corrected anion gap (AG) was elevated in 100%, indicating that laboratory evidence of metabolic acidosis was very common.1 Of 427 patients admitted to an adult trauma ICU, hyperlactatemia was present in 18%, hyper-chloremia in 21%, and an elevated strong ion gap (SIG) in 92%, consistent with evidence of metabolic acidosis.2 Dubin et al. reported results from 935 patients admitted to a mixed medical-surgical ICU. The SIG and corrected AG were elevated in 71% and 74% of patients, respectively, and hyperlactatemia was evident in 34%, with 6% of patients having a lactate concentration greater than 5 mEq/L.3 Chawla et al. reported on 143 patients admitted to a medical-surgical ICU. The mean albumin-corrected AG was 14.1 plus or minus 3.8 mEq/L, and 16.3% of patients had hyperlactatemia, despite the exclusion of patients with ketoacidosis, serum creatinine (SCr) greater than 6 mg/dL, or a history consistent with toxic ingestions.4 Although most series have reported on evidence of metabolic acidosis, Liborio and coworkers evaluated serum bicarbonate concentrations from a database of 18,982 ICU patients for evidence of metabolic alkalosis, excluding patients with evidence of pure respiratory acidosis. During their ICU stay, 5,655 patients (29.3%) had a serum bicarbonate

concentration greater than 30 mEq/L for at least 1 day, with most patients (86.6%) experiencing metabolic alkalosis within 72 hours of admission to the ICU. In addition, 17.9% of patients included in this database had evidence of a persistent metabolic acidosis. Most patients with an elevated serum bicarbonate concentration also had a metabolic acidosis at some point in their ICU stay. Only 11.4% had serum bicarbonate concentrations in the reference range throughout their ICU admission.5 Although several of these reports may overestimate the overall prevalence of acid-base disorders in critically ill patients, because of the inclusion of only patients who underwent arterial blood gas (ABG) measurements, it is abundantly clear that metabolic acid-base abnormalities are common in the ICU. When the picture also includes all ICU patients with predominantly respiratory acid-base disorders, the argument is further strengthened that acidbase abnormalities are one of the most ubiquitous and heterogeneous disorders requiring assessment, monitoring, and treatment in critically ill patients. The many potential contributing factors to acid-base abnormalities in critically ill patients will be discussed in much greater detail later. The major organ systems responsible for regulation of acid-base homeostasis are the respiratory and renal systems, with a lesser contribution from the liver.6 Therefore, dysfunction or failure of any of these systems, not uncommon in the critically ill patient, is expected to be associated with acid-base disorders. Although the gastrointestinal (GI) system does not regulate acid-base balance, dysfunction or diseases of the GI tract including vomiting, high nasogastric tube output, diarrhea, ileostomy losses, villous adenoma of the colon, and high-volume pancreatic/biliary fluid drainage can contribute to metabolic acid-base imbalances.7 Sepsis, shock, hypoxemia, trauma, microvascular dysfunction, dysregulation of cellular metabolism, hypoalbuminemia, renal replacement therapy, and many electrolyte disorders can also contribute to metabolic acid-base abnormalities. A variety of toxic ingestions may be associated with metabolic acidosis (e.g., alcohols, glycols, salicylates, iron). Iatrogenic factors in the ICU that can contribute to abnormal acid-base status include fluid

resuscitation with high-chloride fluids (e.g., 0.9% sodium chloride solution), drugs (e.g., propofol, lorazepam, CNS depressants), over- or under-ventilation during mechanical ventilation, and total parenteral nutrition.6,8,9 It is important to appreciate that acid-base disorders are not only a result of the underlying illness leading to ICU admission, but can also adversely be affected by the management of those illnesses and general supportive care.10 Although disorders of acid-base balance have been associated with increased ICU length of stay and increased mortality,2,5,11,12 the findings are not universal.1,13 The direct impact or attributable morbidity or mortality from metabolic acid-base disorders is controversial and difficult to separate from the contributions of the underlying illness.8 Persistent severe acidemia (pH less than 7) or alkalemia (pH greater than 7.6) is considered incompatible with life; however, the cause-andeffect relationship with poor outcomes for more transient and moderate derangements of acid-base status is not conclusively shown. Elevated blood lactate concentrations, regardless of the cause, have been associated with increased mortality, especially with sustained elevations or very high concentrations of lactate.14 In a randomized, multicenter trial, early lactate-directed resuscitation led to a significant decline in risk-adjusted mortality (hazard ratio 0.61; 95% confidence interval, 0.43–0.87).15 There is also growing evidence that using chloride-rich crystalloid therapy compared with a more balanced fluid after major surgery or after an ICU admission is associated with a greater frequency of acute kidney injury, more need for renal replacement therapy,16,17 and higher in-hospital mortality.16 Although these lines of evidence do not validate that treatment of acid-base disorders improves outcome independently of treating the underlying disease state, they do suggest that therapeutic approaches to the underlying problem that either improve or do not induce or exacerbate preexisting acid-base abnormalities are associated with better outcomes.

TERMINOLOGY AND CONCEPTS

In discussing acid-base analysis and the common abnormalities of acid-base status, the following terms and concepts are important to understand.

Acid and Base For this chapter, we will use the definitions of an acid and base offered by Stewart.18,19 An acid is a substance that increases the oxonium (formerly called hydronium ion) concentration ([H3O+]) of a solution, and a base is a substance that decreases the [H3O+] of a solution. A decrease in [H3O+] is equivalent to an increase in [OH−]. Water is amphoteric and can therefore act as an acid or base. Remember that a solution is neutral when the [H3O+] is equal to the hydroxyl ion concentration ([OH−]).

Analysis of -emia vs. -osis The usually accepted normal range for blood pH is 7.35–7.45, and throughout this chapter, we will use 7.4 as normal in all analyses. A blood pH of less than 7.35 represents an acidemia, whereas a blood pH of greater than 7.45 is an alkalemia. The terms acidosis and alkalosis define the underlying processes that lead to an acid-base disorder, but they should not be used to describe an abnormal blood pH value. For example, a patient may have a metabolic alkalosis and a respiratory acidosis or a metabolic acidosis and a respiratory alkalosis but a blood pH of 7.35–7.45.

Analysis of pH vs. [H3O+] The pH value was adopted more than 100 years ago to express blood [H3O+] in clinical medicine. The pH is the inverse log10 [H3O+] and is therefore an unfortunate, dimensionless, non-linear, and non-intuitive expression of the [H3O+]. Because of its nonlinear nature, a greater change in [H3O+] is needed to decrease the pH to the acidemic range than the change in [H3O+] resulting in an alkalemia. Although it is

possible to manage acid-base disorders while working with the [H3O+] in the physiologically and pathologically relevant pH range of 6.8–7.6 ([H3O+] range of 160 nmol/L to 25 nmol/L, respectively), it is highly unlikely that [H3O+] will supplant the use of pH in clinical medicine in the near future.

Strong vs. Weak Ions Strong ions are essentially fully dissociated in solution; therefore, there is no dissociation equilibrium applicable to these electrolytes (e.g., Na+ and Cl−). Because they are fully dissociated at all times, they do not participate in any reactions within the solution. Weak ions, which are by definition only partly dissociated in solution, are defined by the following equilibrium expression:

where HA is a weak acid, H+ and A− are the dissociated proton and anion, and KA is the weak acid dissociation constant.

Electroneutrality In any aqueous solution, the sum of all positively charged and all negatively charged ions must be equal, resulting in an electrically neutral solution. It requires excess energy to maintain a charged solution, so an electrically neutral solution is naturally energetically favored. In vivo, any macroscopic fluid volume (e.g., plasma, extracellular fluid) will be electrically neutral, creating a link between the nonreactive strong ions and the equilibrating weak ions.

Conservation of Mass The amount of substance in solution will change only if it is added, removed, generated, or destroyed. The relevance relative to clinical acid-base status is that strong ions like Na+ and Cl− only change

quantitatively if they are added or removed, whereas organic acids like lactate and pyruvate can be generated or metabolized. For partly dissociated substances, the total concentration is the sum of the dissociated and undissociated forms, which will equilibrate depending on the presence of other constituents in the solution.

Anion Gap The AG is widely used in the diagnostic workup of metabolic acidosis. It represents the difference between the concentration of commonly measured and most abundant serum cations (Na+ and K+) and anions (Cl− and HCO3−). The equation for the AG is as follows:

where the concentration of each electrolyte is expressed as milliequivalents per liter. Because of the greater concentration of total unmeasured anions compared with unmeasured cations in equation 1, the normal range for the AG is usually quoted as 12 plus or minus 4 mEq/L. The actual value depends on the normal ranges for the reporting laboratory, which will vary depending on analytic methodology.9,20,21 Because of the relatively narrow and tightly controlled range of serum [K+], the equation is often simplified in clinical practice:

For this simplified equation, the normal range is 8 plus or minus 6 mEq/L. However, in the critically ill population, there is often greater variability in serum [K+], and some authorities recommend not ignoring potassium’s contribution to the AG.9,22 The major contributor (about 80%) to the serum AG is albumin, which is consistently low in critically ill patients. Hypoalbuminemia results in a falsely low serum AG and poor diagnostic performance; therefore, the AG must be corrected for the albumin concentration for all critically ill patients. For every 1-g/dL change in serum albumin, there is a directional change in the AG by 2.3–2.5 mEq/L.21,22 A widely used

equation for calculating the albumin-corrected AG (ACAG) is as follows:

The albumin concentrations are in grams per deciliter, and the normal albumin concentration should be the local laboratory normal value.

ACID-BASE MODELS: ANALYSIS AND INTERPRETATION Traditional, Physiologic, or Bicarbonate-Centered Model This model is based on the work of Henderson and Hasselbalch from more than 100 years ago and remains the most commonly used model for describing and interpreting acid-base disturbances.23–25 This model is based on the assumption that the carbonic acid-bicarbonate buffer system is the major determinant of acid-base balance and is described by the Henderson-Hasselbalch equation:

where pK is the dissociation constant for carbonic acid (6.1), Paco2 is the arterial blood partial pressure of carbon dioxide (CO2) in millimeters of mercury, [HCO3−] is the plasma bicarbonate concentration (measured as total CO2 content) expressed as milliequivalents per liter, and 0.03 represents the solubility of CO2 in plasma. From this model followed the concept that the major determinants of [H3O+] are changes in Paco2 and [HCO3−] and that these parameters are adjusted in vivo as a control system to regulate alterations in acid-base balance. Disorders that are predominantly associated with alterations in Paco2 are respiratory disorders, whereas those that are primarily associated with alterations in [HCO3−] are metabolic disorders. This model is based on the equation describing CO2/HCO3− equilibrium with carbonic

acid:

Assuming that this reaction will equilibrate (Le Châtelier’s principle), metabolic acidosis has therefore been explained by either the addition of H+ to the system, shifting the reaction to the left with a reduction in [HCO3−], or the loss of bicarbonate from the body, shifting the reaction to the right to replace lost bicarbonate and increasing [H+].25 It has also been taught that metabolic alkalosis is attributable to factors that can either increase the [HCO3−] (e.g., bicarbonate generation and reabsorption by the kidney or contraction of the extracellular volume), which will shift the reaction to the left with a decrease in the [H+], or cause the loss of H+ (e.g., vomiting), which will shift the reaction to the right, leading to an increase in [HCO3−]. Carbon dioxide is the primary volatile acid produced through normal cellular metabolism, accounting for around 15,000 mmol/day of hydrogen ion equivalents for an average adult. The CO2 is expired by the lungs. Sensitive receptors in the medulla and carotid and aortic bodies respond to alterations in [CO2] in the cerebrospinal fluid and the Paco2 and [H3O+] in plasma, respectively, leading to changes in minute ventilation to maintain Paco2 and pH within tight ranges. Changes in ventilation to regulate acid-base disturbances are relatively rapid, with a new equilibrium achieved in minutes to hours, meaning that changes in minute ventilation and Paco2 can rapidly compensate for a metabolic acid-base disorder. In contrast, with a persistent abnormality in ventilation leading to a chronic respiratory acid-base disorder, a metabolic compensation develops slowly over 2–5 days.23,24 Organic and inorganic non-volatile acids are produced to a lesser extent than the volatile acid CO2. Organic acids are predominantly lactate and ketones, with about 1500 mmol/day being metabolized by the liver and kidney. The two most important inorganic acids are sulfate and phosphate, generated from dietary protein and amino acid metabolism and contributing about 1.5 mmol/kg/day. Most lactate undergoes hepatic metabolism either by an oxidative pathway to

generate water and CO2 (and subsequently HCO3−) or by gluconeogenesis to glucose, with both pathways consuming protons and therefore contributing to the maintenance of acid-base balance. The traditional teaching is that the free protons (H+) from organic and inorganic acids are rapidly buffered by the bicarbonate-carbonate buffer system with consumption of HCO3−. The ability of the kidney to reclaim and regenerate HCO3− prevents the rapid depletion of the available buffer by continued acid production.20,23,24 In normal homeostasis, two major mechanisms have been implicated in the generation and reclamation of HCO3− by the kidney. The proximal tubular cell secretes free protons (by the NHE3 sodiumhydrogen exchanger) into the glomerular lumen, which combines with filtered HCO3− to form H2CO3. In the presence of luminal carbonic anhydrase, H2CO3 is converted to CO2 and water, with the CO2 freely back diffusing into the proximal tubular cell along its concentration gradient. Intracellular carbonic anhydrase then catalyzes the conversion of CO2 and water to HCO3− and H+ with the bicarbonate transported to the blood by the serosal NBC (sodium-bicarbonate) transporter, and the H+ is secreted into the lumen to “reclaim” more bicarbonate. The regeneration of bicarbonate can also result from the conversion of CO2 produced through normal tubular cell metabolism into HCO3− and H+. The HCO3− is transported into the blood, and the H+ passes into the tubular lumen, where it combines with a non-bicarbonate anion like ammonium or phosphate and is excreted in the urine, leading to a net increase in plasma HCO3− content and loss of H+.20,24,25 Given these mechanisms, it is estimated that the kidney filters and re-absorbs 4,500 mmol/day of bicarbonate. The relationship between the liver and the kidney in renal ammoniagenesis and acid-base balance is also important to recognize. Nitrogen metabolism by the liver results in the production of glutamine, urea, and ammonium (NH4+). The liver normally releases only a very small amount of NH4+, but it incorporates this nitrogen into urea and glutamine, which are released into the systemic circulation. Renal

ammoniagenesis involves the metabolism of glutamine to generate NH4+ and increases the renal excretion of H+, leading to an alkalinizing effect on plasma. Acidosis stimulates hepatic glutaminogenesis and inhibits ureagenesis, therefore shifting the balance of nitrogen metabolism toward greater production of glutamine. This greater presentation of glutamine to the kidney increases renal ammoniagenesis, facilitating a greater renal alkalinizing effect.6,24 This relationship between liver nitrogen metabolism and renal ammonium excretion appears to be an important mechanism in regulating the metabolic response to acid-base disorders. Although the traditional physiologic model of acid-base analysis can be useful clinically to identify and diagnose acid-base disorders, viewing it as a mechanistic explanation for the underlying physiology of acid-base disturbances is problematic. The Henderson-Hasselbalch equation, although permitting a quantification of the severity of a respiratory disorder, cannot quantitatively represent the severity of a metabolic acid-base disturbance. It also tells the clinician nothing about the acids contributing to a metabolic disorder other than carbonic acid. Traditional teaching using the physiologic model implies that HCO3− is independently regulated in response to acid-base disorders; however, HCO3− cannot be regulated independently of Paco2. The [HCO3−] in plasma is always increased as the Paco2 increases, but this does not represent a metabolic alkalosis. It is clear that bicarbonate is a dependent parameter in acid-base equilibrium and therefore cannot be presented as a variable that can be manipulated to independently regulate acid-base homeostasis. It is also important to recognize that at a normal plasma pH, the [H3O+] is in the nanomolar range, whereas most acids and strong ions are in the millimolar range. That means that H3O+ values are about one-millionth the concentration of other contributors classically attributed to acid-base homeostasis, suggesting that something else must be primarily responsible for acid-base balance.6,20 Stated another way, blaming the metabolic acidosis on the finding of a decreased [HCO3−] is analogous to blaming the bacterial pneumonia on the abnormal chest radiograph. This may be a useful

diagnostic test, but it is not the cause of the disorder.

BE Model To overcome the inability of the Henderson-Hasselbalch equation to quantify the metabolic component of an acid-base disturbance, several methods have been developed, with BE being most widely used. Base excess is defined as the amount of acid or base that must be added to a sample of blood in vitro to restore the pH to 7.40 while the Paco2 is held constant at 40 mm Hg at 37°C. Because of inaccuracies of this approach in vivo given the variability in Paco2, the equation was empirically modified to account for an average hemoglobin content across extracellular fluid space, resulting in the SBE. An SBE less than –5 mmol/L is considered to represent a metabolic acidosis, whereas an SBE greater than 5 mmol/L represents a metabolic alkalosis. A negative SBE is often called a base deficit. Although the SBE is able to quantify the change in metabolic acid-base status in vivo, SBE is not regulated by the body and still does not tell the clinician anything about the underlying mechanism of a metabolic acid-base disturbance.6,20 The SBE fails as a measure of metabolic acidosis in the patient with hypoalbuminemia, which is almost universal in critically ill patients.4,26 The BE can be corrected for changes in albumin, chloride, free water, and Paco2 to derive a calculation of the BE caused by unmeasured anions (BEUA); however, the calculations are complex for use at the bedside. The BEUA has been found to be superior at identifying lactic acidosis in critically ill patients compared with SBE or uncorrected AG1,27,28 and is more closely associated with mortality in some studies.2,27 However, the BEUA is not superior to ACAG at detecting unmeasured anions or predicting mortality,2,13 is more complex to apply, and is therefore not recommended for routine clinical use in the ICU.

The Physiochemical or Stewart Model This model requires the application of two physical-chemical principles

discussed previously in the analysis of acid-base physiology: electroneutrality and conservation of mass. In addition, all relevant biologic solutions are aqueous and alkaline ([OH−] is greater than [H3O+]). The physical-chemical properties of water that are relevant to acid-base physiology include a high dielectric constant, very slight dissociation into H+ and OH−, and extraordinarily high molar concentration (around 55.5 M). An aqueous solution provides an almost limitless supply of H+, because of the dissociation of water, and electrolytes and CO2 present in biologic solutions impart strong electrochemical forces that affect the dissociation of water. Stewart has hypothesized that three independent factors affect acid-base status in vivo: strong ion difference (SID), total weak acid concentration (ATOT), and CO2 content (Paco2) of plasma. Changes in one or more of these three independent variables will result in changes in the dependent variables [H3O+] (or pH) and [HCO3−]. That is, contrary to the physiologic or traditional model, alterations in acid-base status are not caused by changes in [H3O+] or [HCO3−], and these variables are not regulated to maintain homeostasis but are instead dependent on changes in SID, ATOT, or Paco2. In addition, acid-base homeostasis can be explained by mechanisms that regulate SID (metabolic disorders) and Paco2 (respiratory disorders).6,18,19 Consistent with the traditional model, CO2 content is an independent predictor of pH and is closely regulated by the respiratory center by influencing minute ventilation. In the ICU setting, fluctuations in minute ventilation may also result from the provision of mechanical ventilation with the possibility of iatrogenic respiratory acid-base disorders. Changes in CO2 expiration that either exceed or fail to meet CO2 production rates will result in a primary respiratory alkalosis or acidosis, respectively. A well-controlled and precise match of alveolar ventilation and metabolic CO2 production will result in a normal Paco2 of 40 mm Hg (35–45 mm Hg). Several signals may influence the respiratory center regulation of minute ventilation, including Paco2, arterial pH, and arterial oxygenation. These variables may be influenced by exercise, anxiety, and wakefulness. This provides a

relatively rapid regulatory mechanism for the regulation of acid-base balance in patients with adequate ventilatory reserve. In the setting of metabolic acidosis or alkalosis, the Paco2 is adjusted in a predictable way, which is called respiratory compensation. In the setting of a persistent alteration in Paco2 caused by an underlying respiratory, neurologic, or other disease process leading to a respiratory acidosis or alkalosis, the body will try to correct the acid-base disorder by regulating the independent variable SID, called metabolic compensation.6,9,18,25 The SID refers to the difference between the plasma concentrations of fully dissociated cations (Na+, K+, Mg2+, Ca2+) and anions (Cl− and lactate). Plasma lactate is included because it is almost completely dissociated at a physiologically relevant pH range; it therefore acts as a strong anion. Urate plasma concentration has also been included in the SID calculation; however, it is often unavailable and is quantitatively a small contributor, so it is typically excluded from the calculation. This calculation of SID is also called the apparent SID (SIDa) because it does not consider weak acids, which are important physiologic buffers to SID:

Concentrations are expressed as milliequivalents per liter, with calcium included as the ionized concentration (calculated or measured). Under normal conditions, the SIDa is about 40 mEq/L, the positive value consistent with the alkaline state of human plasma, which would be even more alkaline were it not for the presence of dissolved CO2 in blood. The SIDa is often much lower than 40 mEq/L in critically ill patients because of alterations in albumin (reducing ATOT).6,9,18,29 The SID has a strong effect on the dissociation of water and therefore the [H3O+] and pH. An increasingly positive SID results in a progressive decrease in the weak cation H3O+ (increasing pH) to maintain electroneutrality. Likewise, a reduction in SID will lead to an increase in H3O+ (decreasing pH). The mechanisms underlying the

regulation of SID are discussed in the paragraphs that follow. A more complicated calculation developed by Figge et al.30 incorporates the role of weak acids (albumin, phosphate) and Paco2 to the electrical charge equilibrium to derive what is called the effective SID (SIDe). The SIG is the difference between SIDa and SIDe and represents the contribution of unmeasured anions to the SID (e.g., sulfates, ketones, citrate, pyruvate, acetate, and gluconate).9,28–30 The recognition of the presence of unmeasured anions has diagnostic relevance for mixed acid-base disorders, and the presence of unmeasured anions has been correlated with increased mortality of critically ill patients.2,11,27 The equations for SIDe and SIG are as follows:

In this equation, [albumin] is expressed in grams per deciliter, Paco2 is expressed in millimeters of mercury, and [PO4] is the concentration of plasma phosphates in millimoles per liter.

Under normal conditions, the SIG is essentially zero. In the presence of unmeasured strong anions, the SIG is positive, and with accumulation of unmeasured strong cations, the value is negative. A positive SIG is analogous to an elevated ACAG or BEUA because all three are affected by the presence of unmeasured strong anions like ketones, sulfates, and other exogenous acids associated with the ingestion of toxins.6,24,28,29 The SID is regulated by changes in the relative plasma concentrations of strong cations and strong anions, with the kidney being the primary organ responsible for adjustments in the SID through the regulation of Cl− balance. A relative loss of Cl− in the urine leads to an increase in the SID and alkalization of the plasma. Although renal

regulation of Na+ and K+ could also affect SID and acid-base balance, Na+ transport is prioritized to maintain intravascular volume and plasma osmolality, and K+ homeostasis is essential to cardiac and neuromuscular function, so Cl− regulation appears to be the predominant renal mechanism to alter SID and maintain acid-base balance without affecting other homeostatic mechanisms.6,24 The traditional explanation of H+ excretion being affected by renal ammoniagenesis may not be the true regulatory mechanism because water provides an unlimited source of H+ on both sides of the renal tubular cell membrane through dissociation of water affected by the composition of the respective aqueous solutions. The importance of renal ammoniagenesis (and hepatic shift to glutaminogenesis described previously) is to increase the excretion of Cl− without concomitant losses in Na+ and K+ by providing a weak cation (NH4+) to be excreted with Cl−, emphasizing the importance of electroneutrality as an explanation for many of the factors leading to normalcies and abnormalities in acid-base. The regulation of Cl− excretion results in relatively small quantitative changes over time; therefore, subsequent changes in the plasma SID involves a slow process, consistent with the known delayed metabolic compensation in the presence of a persistent respiratory acid-base disorder.6 Several acid-base disorders that are common in the ICU can be used to show the important role of alterations of SID on [H3O+] and explain how the Stewart model provides a much more rational understanding of acid-base pathophysiology than the traditional, bicarbonate-based model. The infusion of a large volume of 0.9% sodium chloride for injection (normal saline) during the resuscitation of critically ill or injured patients can lead to a hyperchloremic metabolic acidosis. Under the traditional model, this has been called a dilutional metabolic acidosis, based on an explanation that dilution of bicarbonate in the extracellular fluid shifts the bicarbonate-carbonate equilibrium to the right, increasing [H3O+] and leading to an acidemia. According to the Stewart model, both [HCO3−] and [H3O+] are dependent variables in an aqueous biologic fluid; therefore, the dilutional mechanism is

inadequate to explain the acid-base abnormality. Normal saline provides equal concentrations of Na+ and Cl− (154 mEq/L); however, because of the higher concentration of Na+ relative to Cl− in plasma, the infusion of normal saline leads to a greater relative accumulation of Cl− and a reduction in the SID. The electrochemical force of a decreasing SID leads to an increase in [H3O+] to maintain electroneutrality and therefore the onset of acidemia. An alternative way to consider this is that for normal saline, the SID is zero (equal concentration of strong cations and strong anions). Therefore, infusing large volumes of a SID 0-mEq/L solution into moderately alkaline plasma (SID approximately equal to 40 mEq/L) will lead to a reduction in the plasma SID and a metabolic acidosis.6 Alterations in normal GI function are a common cause of metabolic acid-base disorders in critically ill patients. Under normal conditions, the stomach pumps out large amounts of Cl−, leading to a decrease of the SID in the lumen and reducing the pH of gastric contents. The loss of the Cl− from plasma raises the plasma SID and is consistent with the alkaline tide observed at the start of a meal. The Cl− is rapidly reabsorbed at the duodenum, quickly restoring plasma SID and pH. However, if the gastric secretions are lost because of either vomiting or nasogastric suctioning, the plasma SID is persistently increased, leading to a reduction in [H3O+] and a metabolic alkalosis. The traditional explanation of gastric H+ loss leading to a metabolic alkalosis is not plausible given that 1 L of gastric secretions with a pH between 1 and 2 would result in the loss of more total H+ content than is normally present in all of the extracellular fluid and should therefore lead to a profoundly fatal metabolic alkalosis. In actuality, this modest amount lost from 1 L of vomitus will have a mild effect on acid-base balance, showing that the loss of H+ cannot be the mechanistic explanation. In addition to the initial increase in SID secondary to Cl− loss, the loss of intravascular volume leads to the need to conserve Na+ and water and maintain K+ balance. This combination of metabolic alkalosis and intravascular volume loss is commonly termed a contraction alkalosis. Activation of the renin-angiotensin-aldosterone

axis increases sodium reabsorption at the proximal tubular Na-H exchanger (NHE3) and collecting duct Na channels, and activation of hydrogen-ATPase (type B intercalated cells) and K+-hydrogen ATPase (type A intercalated cells). The overall effect is to reduce urinary SID, leading to acidification of the urine and maintenance of the metabolic alkalosis. To correct the metabolic alkalosis, it is necessary to replace Na+ and Cl− while restoring intravascular volume, replace lost K+, and decrease plasma SID. Administering normal saline with supplemental potassium chloride will achieve these goals. This example shows the important interaction between fluid and electrolyte balance and acidbase disorders. In traditional teaching, this is called a chlorideresponsive metabolic alkalosis.6,18,25 The third independent variable determining acid-base status in the Stewart model is ATOT, the total concentration of weak acids and their conjugate bases.

The weak acids represented by ATOT are mostly plasma proteins, with albumin being quantitatively most important, and phosphates. Some have suggested that given the independent role of ATOT on acid-base balance, there should be six defined acid-base categories, adding protein-aceous alkalosis and acidosis to the traditional respiratory and metabolic disorders. Although the loss of albumin is associated with an alkalemia and the rapid infusion of albumin will cause a decrease in arterial pH,31 there is no evidence that the active regulation of ATOT is physiologically relevant in the maintenance of acid-base balance, so expanding the categories of acid-base disorders is not clinically relevant. Given that hypoalbuminemia is common in the critically ill patient, the ATOT is reduced and is associated with a concomitant reduction in SID to maintain acid-base balance. This apparent compensatory SID response to hypoalbuminemia results in a new normal SID in critically ill patients of about 30–32 mEq/L.6 From the perspective of the Stewart model, the regulation of Paco2 and SID is the major determinant and therapeutic target of acid-base balance. The

ATOT should be considered an independent variable influencing acidbase status that is not actively regulated, or manipulated clinically to treat acid-base disorders.18 Although we believe that the physiochemical model provides a rational explanation of acid-base physiology and mechanistic explanations for common acid-base disorders and their treatments, other experts disagree that there is adequate evidence to accept Stewart’s theories. Kurtz and colleagues provide a comprehensive and sophisticated critique of the issue and conclude that the Stewart and bicarbonate-based approaches provide quantitatively identical results and that the Stewart model provides no diagnostic or prognostic advantage to an approach using the Henderson-Hasselbalch equation. In addition, they argue that the underlying premise that the [H+] in any given fluid compartment is dependent on SID lacks an experimental basis.32 Thus, although we favor the physio-chemical model proposed by Stewart and others for teaching and clinical purposes, it is important to realize that it remains a controversial and unsettled area of debate.

DIAGNOSIS OF ACID-BASE DISORDERS (STEPWISE APPROACH) The physiochemical or Stewart model provides a thorough diagnostic approach to acid-base balance that is also consistent with the mechanisms of acid-base abnormalities in clinical medicine. This understanding of the underlying mechanisms of metabolic disorders leads to a more rational therapeutic approach when intervention is warranted. However, the comprehensive analysis of acid-base status using the Figge-Stewart approach in a critically ill patient requires variables that are often not routinely measured in a simultaneous manner and requires rather complex computations that limit the practical utility of this approach at the bedside. The SBE approach, which accurately quantifies the extent of a metabolic acid-base abnormality, is routinely reported with blood gas results, but SBE is not effective at identifying mixed acid-base disorders without the use of complex corrections of the SBE, which are challenging during routine

clinical care in the ICU. Several investigators have shown that the traditional bicarbonate approach with appropriate adjustment of the AG for hypoalbuminemia, with or without adjustment for lactate, has a diagnostic and prognostic value similar to that obtained with the more complex Figge-Stewart and corrected SBE methods2–4,13,26,28,33 and may represent the most practical and easily performed diagnostic approach.23,25,29 An organized, consistent, stepwise approach to the diagnosis of acid-base disorders in critically ill patients is recommended to improve the identification of mixed acid-base disorders, reduce the potential for missing clinically important concomitant problems, and best inform the therapeutic approach to the patient. Although several stepwise approaches have been recommended,23 the following approach is recommended for the critically ill patient with a suspected acid-base disturbance (also see Table 1.1). Step 1 – Provide a careful clinical evaluation of the patient. Clinical assessment of the patient must include medical history, history of present illness, vital signs, level of consciousness, physical assessment, and medication history. Given this assessment, the expected acid-base abnormalities can be predicted (Table 1.2), and results of the stepwise approach that differ from these expected findings should be suspect and warrant reinvestigation of the patient history and presentation. Step 2 – Determine the -emia. This is the easiest step in the process. For practical purposes, if the ABG pH is less than 7.38, the patient can be considered to have an acidemia. If the pH is greater than 7.42, the patient can be considered to have an alkalemia. Step 3 – Determine the principal -osis. According to an evaluation of the ABG results, the principal or predominant disorder can normally be determined (Table 1.3). If the patient has a pH in the normal range of 7.35–7.45, the principal disorder will usually be associated with the relative direction of the pH above or below 7.40. An acidemia should be associated with either a decreased [HCO3−] (metabolic acidosis) or an elevated Paco2 (respiratory acidosis). An alkalemia will be associated with either an increased [HCO3−] (metabolic alkalosis) or a decreased

Paco2 (respiratory alkalosis). The secondary or compensatory change in a simple acid-base disorder should be in the same direction as the principal change. For example, a principal metabolic acidosis should be associated with a decrease in [HCO3−], and a compensatory decrease in Paco2 (Table 1.3). In a complex ICU patient who may have an underlying chronic disorder (e.g., chronic obstructive lung disease), determining the principal disorder may be more challenging because the change from the patient’s normal baseline values is what is relevant to diagnosing an acute change in acid-base status. Without specific data concerning the patient’s baseline status, assumptions based on history and initial serum chemistry results will often need to be made.

Table 1.1 Stepwise Approach to Diagnosis of Acid-Base Status Step 1

Careful clinical evaluation of the patient

Step 2

Determine the -emia

Step 3

Determine the primary -osis

Step 4

If the primary disorder is respiratory, is it acute or chronic?

Step 5

Is compensation for the primary disorder appropriate?

Step 6

Calculate the anion gap, corrected for albumin

Step 7

If corrected anion gap is elevated, calculate the delta ratio

Step 8

If normal anion gap and unknown cause, calculate the urinary anion gap

Step 4 – If the principal disorder is respiratory, is it acute or chronic? The metabolic regulation of acid-base balance in response to a respiratory disorder takes 2–5 days to reach a new steady state; therefore, a respiratory disorder of less than 2–3 days’ duration is

considered an acute respiratory disorder, whereas a disorder of longer duration is considered chronic from the perspective of metabolic secondary response or compensation. Acute, smaller changes in metabolic status are considered primarily the result of cellular electrolyte shifts, whereas the later and quantitatively greater changes are the result of renal regulation of Cl− excretion, leading to compensatory changes in plasma SID. Differentiating acute from chronic classification of respiratory acid-base disorders is necessary to determine whether the degree of compensation is appropriate and therefore determine the presence of simple or mixed acid-base disorders. Step 5 – Is the secondary or compensatory response appropriate? There are highly conserved patterns between the changes that occur between Paco2 and [HCO3−] for various principal acid-base disorders that permit the creation of rules to define the secondary or compensatory response to a primary disorder.6 These compensatory changes in either Paco2 or [HCO3−] should be considered the patient’s new normal, and values that differ from the new normal are therefore abnormal and represent evidence of a second or concomitant acidbase disorder. Although several different estimations of appropriate compensation for the primary acid-base disorders have been published, Table 1.4 presents the estimations most commonly used in clinical medicine.23 Step 6 – Calculate the AG, corrected for albumin. See earlier text for the calculation of AG and ACAG. In critically ill patients, the AG is a poor estimate of unmeasured anions because of the very common presence of hypoalbuminemia; however, the correction for plasma [albumin] greatly improves the ability of the ACAG to detect the presence of “gap” anions.2–4,26,33 Given the near-universal availability of plasma [lactate] in the diagnostic evaluation of metabolic acidosis, the AG can be further corrected for both albumin and lactate (ALCAG):

where albumin concentrations are expressed in grams per deciliter and

lactate concentration in millimoles per liter or milliequivalents per liter. An elevated ALCAG provides evidence of unmeasured anions, which may include toxins (e.g., salicylate, toxic alcohol, and glycols), ketones, sulfates, phosphate, citrate, and d-lactate, among many others. This may provide diagnostic clues toward combined causes of a metabolic acidosis in a critically ill patient.9 Unmeasured anions are important contributors to metabolic acidosis in critically ill patients and, in some studies, have been correlated with increased mortality.2,11,27 Although some stepwise approaches recommend only calculating the AG when the principal disorder is a metabolic acidosis, failure to calculate the ACAG in the complex critically ill patient may lead to missing the presence of a concomitant elevated AG metabolic acidosis; therefore, routine calculation of the ACAG in critically ill patients is recommended regardless of the principal disorder.

Table 1.2 Acid-Base Disorders Associated with Common Clinical Findings Metabolic Acidosis

Respiratory Alkalosis

Elevated Anion Gap

Chronic

Shock

Chronic obstructive lung disease

Hypoxia or ischemic injury

Neuromuscular diseases (hypoventilation)

Sepsis Type 1 diabetes Crush injury (rhabdomyolysis) Renal disease Liver failure Alcoholism Starvation/cachexia Toxic ingestions (salicylate, alcohols, glycols) Medications (metformin, propofol, NNRTI) Seizures

Restrictive lung diseases Acute CNS depression – disease- or druginduced Acute exacerbation of asthma Pneumonia Pulmonary edema Pulmonary embolism (massive)

Normal Anion Gap Resuscitation with normal saline Diarrhea Biliary or pancreatic drainage History of renal tubular acidosis

Metabolic Alkalosis

Respiratory Alkalosis

Diuretic use

Chronic

Vomiting

Pregnancy

NG tube losses

Hyperthyroidism

Mineralocorticoid use

Liver disease

Excessive alkali ingestion

Pulmonary embolism Acute: Pain or anxiety Fever Neurologic injury (stroke, trauma, meningitis) Salicylate toxicity Pneumonia Pulmonary edema Pulmonary embolism Sepsis

NG = nasogastric; NNRTI = nonnucleoside reverse transcriptase inhibitor.

Table 1.3 Principal Acid-Base Disorders Principal Disorder

Initial Laboratory Change

Compensatory Change

Metabolic acidosis

↓[HCO3−]

↓Paco2

Metabolic alkalosis

↑[HCO3−]

↑Paco2

Respiratory acidosis

↑Paco2

↑[HCO3−]

Respiratory alkalosis

↓Paco2

↓[HCO3−]

[HCO3−] = plasma bicarbonate concentration (mEq/L); Paco2 = arterial partial pressure of carbon dioxide (mm Hg).

Step 7 – If the ACAG is elevated, calculate the delta ratio. The delta ratio (also called the delta-delta) is a comparison of the magnitude of the abnormality of the ACAG (delta ACAG) with the change in the [HCO3−] (delta bicarbonate). When calculated as a ratio, the equation is as follows:

where all variables have been previously defined and are expressed as milliequivalents per liter. A delta ratio of 1–2 is consistent with a pure elevated AG metabolic acidosis. A ratio less than 1 is predictive of a concomitant normal AG metabolic acidosis, and a ratio greater than 2 provides evidence of either a concomitant metabolic alkalosis or an appropriately compensated chronic respiratory acidosis. These estimates may be inaccurate in critically ill patients who may have abnormal baseline values because of other underlying processes, and some have raised serious concerns about the accuracy of relying on a single calculation to detect a mixed acid-base disorder. This should be used in the context of a complete understanding of the clinical presentation and history of the patient, together with continued monitoring of changes in the patient status. The delta ratio is just one piece of evidence that needs to be considered with other evidence in a complex ICU patient.34

Table 1.4 Normal Secondary or Compensatory Responses Principal Disorder

Secondary Response Rule

Metabolic acidosis

Paco2 = 1.5 × [HCO3−] + 8 ± 2

Metabolic alkalosis

Paco2 = 0.7 × [HCO3−] + 20

Respiratory acidosis Acute

[HCO3−] increases 1 mEq/L for each Paco2 increase of 10 mm Hg above 40 mm Hg

Chronic

[HCO3−] increases 4–5 mEq/L for each Paco2 increase of 10 mm Hg above 40 mm Hg

Respiratory alkalosis Acute

[HCO3−] decreases 2 mEq/L for each Paco2 decrease of 10 mm Hg below 40 mm Hg

Chronic

[HCO3−] decreases 4–5 mEq/L for each Paco2 decrease of 10 mm Hg below 40 mm Hg

Step 8 – If the ACAG is normal in the presence of a metabolic acidosis and the cause is unknown, calculate the urinary anion gap (UAG). Of note, it is uncommon for the critical care clinician to use the UAG or the urinary osmolal gap to evaluate a normal AG metabolic acidosis because the likely causes are typically already known. The UAG is calculated using measured urinary electrolytes:

UAG m

+

\ K \ - \ Cl

|

where all urinary electrolyte concentrations are expressed in milliequivalents per liter. The most common causes of normal AG metabolic acidosis with a negative UAG are infusion of large volumes of normal saline and diarrhea. Proximal renal tubular acidosis (RTA) is also associated with a negative UAG; however, new-onset proximal RTA is not a common cause of acidosis in critically ill patients with no history of RTA. A normal AG metabolic acidosis with a positive UAG may be seen with renal failure, distal RTA, and hypoaldosteronism because of an impaired ability to excrete NH4+ as NH4Cl. When the UAG may be unreliable (polyuria, urine pH greater than 6.5, and the presence of other urinary anions [e.g., ketones]), the urinary osmolal gap may be used in place of the UAG. A urinary osmolal gap less than 40 mmol/L is equivalent to a positive UAG.23 Following this stepwise approach to evaluate an acid-base disturbance in the critically ill patient will normally result in an accurate and complete diagnosis of the acid-base disorders present. A more casual review of the blood gas and chemistry results will often lead to a missed concomitant disorder that may have important diagnostic and therapeutic implications. With practice, this stepwise approach will become routine and can be completed in just a few minutes using simple math and laboratory values commonly available at the bedside. Because of the inherent variability in the measurement of the relevant analytes and the dynamic status of critically ill patients, acid-base analysis is best conducted using results from samples obtained simultaneously.

CLINICAL SYNDROMES The most common acid-base abnormality observed in critically ill patients is an acidosis (metabolic or respiratory). Common reasons for admission to an ICU including sepsis, shock, trauma, renal failure, toxic ingestion, surgical catastrophe, and endocrinologic emergency are associated with a metabolic acidosis, and initial resuscitation or intraoperative management of critically ill patients may lead to

iatrogenic metabolic acidosis, predominantly because of large volumes of intravenous chloride-rich fluids. In addition, respiratory failure secondary to exacerbations of underlying lung disease, neurologic disorders, or toxic drug or substance exposures is associated with an acute respiratory acidosis. The complex nature of critically ill patients and their acute management commonly results in mixed acid-base disorders.20 Although much of the critical care literature has focused on the recognition, risks, and management of an acidosis in the critically ill patient, recent evidence suggests that metabolic alkalosis is also a common finding during a critical care stay, with most episodes occurring within the first 72 hours of admission to the ICU.5

Metabolic Acidosis As discussed previously, many of the medical and surgical reasons for admission to the ICU and treatments administered in the ICU can be associated with a metabolic acidosis. As shown in Table 1.3, the expected principal finding on an ABG result is a decreased [HCO3−], with a secondary response of decreased Paco2. Metabolic acidoses have historically been divided into those with an elevated AG and those with a normal AG. As discussed previously, it is critically important that the AG be corrected for serum albumin concentration (ACAG) in ICU patients to improve diagnostic value. An elevated ACAG is analogous to an elevated SIG or BEUA for the Stewart and BE acid-base models, respectively. For diagnostic purposes, this is a valuable way to categorize metabolic acidosis, given that the elevated AG represents traditionally unmeasured anions that are weak or strong acids responsible for the acidosis and provides valuable clues to the underlying cause and therapeutic approach. Table 1.1 provides a list of common conditions associated with an elevated AG metabolic acidosis. Several acronyms have been used over the years to aid clinicians in remembering the common sources of unmeasured anions when presented with an elevated AG metabolic acidosis, with MUDPILES, GOLD MARRK, and the much simpler KULT being the most popular. Table 1.5 provides the detail of the components of these acronyms.

Lactic acidosis is one of the most common metabolic acidoses presenting in critically ill patients, with the most common causes being shock of any cause, sepsis, severe heart failure, and severe trauma.14 The accumulation of lactate, which serves as a strong anion, leads to a reduction in the plasma SID, increasing [H3O+], and resulting metabolic acidosis. An elevated lactate concentration has a quantitative relationship, both peak lactate and duration of hyperlactatemia, with the risk of mortality in critically ill patients,14 and resuscitative measures leading to a reduction in blood lactate levels have been associated with improved clinical outcomes.15 The l-isomer of lactate, as primarily the byproduct of anaerobic cellular metabolism, is the physiologically relevant form of lactate. However, d-lactate accumulation can be clinically important in the ICU setting after intravenous propylene glycol administration (e.g., lorazepam infusions), toxic ingestions of propylene glycol,35,36 and ischemic bowel.8 Routine clinical laboratory assays detect and report only l-lactate concentrations, so the presence of dlactate represents an unmeasured anion that can contribute to a metabolic acidosis.

Table 1.5 Elevated Anion Gap Metabolic Acidosis Acronyms MUDPILESa:

GOLD MARRK

Methanol

Glycols (ethylene and propylene)

Uremia

5-Oxoproline (pyroglutamic acid)

Diabetic ketoacidosis

L-Lactate

Paraldehyde (historically), or Propylene Glycol

D-Lactate

Isoniazid (INH), or Iron, or Infection

Methanol

Lactate

Aspirin

Ethylene glycol

Renal Failure

Salicylate

Rhabdomyolysis Ketoacids

KULT

Ketoacidosis Uremia Lactate Toxins

aRevised

by some to MUDPILERS, with the “R” representing rhabdomyolysis.

Pyruvate is generated primarily by cellular anaerobic glycolysis under hypoxic conditions and is reversibly converted to lactate by the following reaction:

An adult human generates about 20 mmol/kg of lactate daily. Lactate is normally reconverted to pyruvate, which is then metabolized by mitochondrial oxidation within LDH-rich tissues including the liver (70%), kidneys, and skeletal muscle. Metabolism through the Cori cycle leads to the formation of glucose (gluconeogenesis). The tricarboxylic acid cycle and oxidative phosphorylation leads to the generation of CO2 and water, which can lead to bicarbonate generation. Normal equilibrium of production and metabolism of lactate-pyruvate leads to low steadystate plasma concentrations of lactate; however, rapid increases in lactate production during various causes of tissue hypoxia can lead to sharp increases in blood lactate concentrations. The combination of decreased mitochondrial oxidative phosphorylation secondary to tissue hypoxia, microcirculatory failure, and tissue acidemia will also decrease lactate clearance, contributing to the increase in blood lactate. Other potential contributors to hyper-lactatemia in critically ill patients may include underlying chronic liver disease, fulminant hepatic failure, renal failure, drugs that impair normal oxidative phosphorylation (e.g., antiretroviral agents, propofol, and metformin), and physiologic stress (e.g., severe trauma, pheochromocytoma) or drugs (e.g., epinephrine, albuterol) that cause β2-adrenoceptor stimulation, leading to increased aerobic glycolysis independent of tissue hypoxia.8,14 High-dose catecholamine infusions during treatment of shock can aggravate

hyperlactatemia by β2-adrenoceptor stimulation; this has especially been true with the use of epinephrine vasopressor therapy.27,37–39 Traditionally, lactic acidosis has been categorized into type A and type B; however, in a complex critically ill patient, differentiating type A from type B is difficult, artificial, and probably clinically irrelevant.8,14 An elevated serum AG, even with correction for plasma [albumin], lacks adequate sensitivity and specificity for the diagnosis of lactic acidosis.4,33 In the setting of sepsis and other clinical conditions potentially associated with lactic acidosis, the current recommendation is to directly measure blood lactate concentrations rather than rely on a calculation of unmeasured anions like the AG or ACAG.14,40 It is also important to recognize that in cases of metabolic acidosis with confirmed hyperlactatemia, there is often a significant contribution to the acidemia by other unmeasured anions, with studies showing that lactate contributes only a portion of the increased AG.2,27,28,33 An elevation in unmeasured anions other than lactate has been associated with increased mortality,11,27,28,33,41 but the finding has not been consistent.1–3,13 Gunnerson et al.41 reported the results of a retrospective study of 851 ICU patients, of which 584 had evidence of a metabolic acidosis. The patients were classified according to the primary anion contributing to metabolic acidosis as lactate, chloride, or other unmeasured anions (elevated SIG). To be classified as lactic or SIG acidosis, at least 50% of the contribution had to be from that factor, with many patients having a combined lactate and SIG contribution to the metabolic acidosis. The mortality rate for lactic acidosis was 56%, for hyperchloremic acidosis 29%, and for SIG acidosis 39% (p 5.5 mEq/ L)

1 Serum Potassium 5.5 - 5.9 mEq / L PLUS Normal ECG

Source Control DiscontinueExogenous Potassium (e g , IVF, PN) Hold Contributing Medications ( e.g. ACE inhibitors )

..

Serum Potassium 6 mEq/L OR AbnormalECG

.

Consider Calcium Gluconate 1gram IVPB over 1hour

Calcium Gluconatelgram IV push over 5 min STAT

Furosemide 40 mg IV push

Ifcathe ter already present, Dialysisimmediately

OR OTHERWISE

SPS 15 grams PO/30 grams PR

Consider: Regular Insulin + Dextrose 50%

Metabolic Acidosis: Consider SodiumBicarbonate

Regular Insulin 10 units IV push STAT, immediatelyfollowed byDextrose 50% 25 grams IV push (lf metabolic acidosis present administer Sodium Bicarbonate 50 - 100 mEqlVpush in addition to Insulin /Dextrose

PLUS

Furosemide 40 mg IV push Recheck Serum Potassium every 4 hours until < 5 mEq /L

Recheck Serum Potassium every 2 hours until < 5 mEq/ L

Consider Dialysis if minimal /no response

Figure 3.3 Algorithm for the management of hyperkalemia. ACE = Angiotensin converting enzyme; ECG = Electrocardiogram; IVF = Intravenous fluids; IVPB = Intravenous piggyback; PO = By mouth; PN = Parenteral nutrition; PR = Per rectum; SPS = Sodium polystyrene sulfonate

Symptomatic patients (i.e., those with ECG abnormalities) regardless of the degree of hyperkalemia require emergent

intervention. Intravenous calcium should be administered to stabilize the cardiac membrane (i.e., to restore resting membrane potential and thereby increase the threshold for generating a cardiac action potential). The amount of calcium necessary to achieve this goal is unknown, but use of either calcium gluconate 1–2 g intravenously or calcium chloride 1 g intravenously is acceptable. Calcium chloride may be preferred because of a theorized faster dissociation of calcium from the chloride salt and thus more immediate impact, but superiority has never been shown. Overall, calcium should be administered to all symptomatic patients with the exception of hyperkalemia in the setting of digoxin toxicity because calcium can propagate such toxicity.59 In addition, regular insulin (10 units) and dextrose (25–50 g) should be administered because this intervention has been shown to rapidly (within 15 minutes) and reliably shift potassium intracellularly (0.5- to 1.5-mEq/L reduction in serum potassium that can last 2–3 hours).77 Intravenous sodium bicarbonate (e.g., 50 mEq by intravenous push) can also cause modest intracellular shifts in potassium (about 0.5 mEq/L reduction in serum potassium), but this is only effective in the setting of a non-anion gap metabolic acidosis and should be reserved as adjunctive therapy in such cases.57,77 Granted that shifting of potassium intracellularly is a temporizing measure, interventions to eliminate excess potassium should be implemented as well, such as administration of loop diuretics (e.g., furosemide 20–40 mg intravenously). Hemodialysis is the most predictable and effective method for rapidly reducing serum potassium; however, in the absence of an existing dialysis catheter, this intervention may not be the most practical or efficient. Regardless, a nephrologist should be contacted early, should the patient not respond to pharmacologic methods.

MAGNESIUM Magnesium is the second most abundant intracellular cation. Normal body stores of magnesium are 23–25 g with about 99% in the intracellular space, located predominantly in bone (50%–60%), skeletal muscle (20%–30%), and soft tissues (20%). Only about 0.3% of total

body magnesium is located in the serum.81,82 As such, normal serum magnesium concentrations range from 1.8 to 2.4 mg/dL (1.5–2 mEq/L) and are not reflective of total body stores.81 Most magnesium in the ECF is in the ionized (active) form, with 20% bound to serum proteins.83 Results vary regarding whether total and ionized serum magnesium concentrations correlate in critically ill patients, with some studies showing a strong84 and others a poor correlation.85,86 There have also been investigations regarding whether ionized serum magnesium concentrations are better predictors of clinical outcomes and response to magnesium supplementation, but similarly, conflicting results exist.82 The magnesium tolerance test may be the most accurate method of determining magnesium deficiency87; however, the requirement for “normal” renal function, influence of diuretic therapy, and cumbersome procedure lead to little utility in critically ill patients.82 At this time, assessment of total serum magnesium concentrations remains the most widely available and accepted method of evaluation in critically ill patients. Magnesium is an essential cofactor in hundreds of enzymatic reactions, including the formation of ATP, replication and transcription of DNA, and translation of messenger RNA.81,82 Magnesium is essential to mitochondrial function, cell membrane function, neuromuscular transmission, parathyroid hormone (PTH) secretion, and glucose metabolism.83 As mentioned earlier under hypokalemia, the NaKATPase enzyme is dependent on magnesium for proper functioning; thus, magnesium helps regulate the transcellular gradient as well as renal excretion of potassium. Magnesium also plays a role in smooth muscle tone by regulating intra-cellular calcium concentrations.82 Specifically, magnesium decreases activation of inositol triphosphate, decreasing calcium release from the sarcoplasmic reticulum, and also activates calcium ATPase, facilitating the movement of calcium back into the sarcoplasmic reticulum and from the ICF to the ECF. Magnesium deficiency has been proposed to cause coronary vasospasm, hypertension, bronchial airway constriction, and seizures.82 Magnesium homeostasis is regulated by the small bowel and the

kidneys.81-83 Overall, 30%–50% of dietary magnesium is absorbed under normal conditions, primarily in the jejunum and ileum. Gastrointestinal absorption of magnesium is saturable and inversely proportional to intake. The kidneys play the most important role in magnesium homeostasis, with about 95% of all filtered magnesium reabsorbed into the systemic circulation. Most reabsorption occurs in the thick ascending limb of the loop of Henle (65%–75%), followed by the proximal tubule (15%–20%) and the distal tubule (5%–10%).83 The serum magnesium concentration is the primary regulator of magnesium reabsorption because calcium and magnesium receptors located on the capillary side of the thick ascending limb of the loop of Henle sense serum magnesium concentrations and enhance or reduce reabsorption accordingly.81 There are no hormonal mediators of magnesium homeostasis; thus, serum magnesium concentrations can profoundly be affected by changes in intake and/or renal function (including use of diuretics).

HYPOMAGNESEMIA Hypomagnesemia is defined as a serum magnesium concentration less than 1.8 mg/dL (less than 1.5 mEq/L). The incidence of hypomagnesemia on ICU admission ranges from 20% to 61%,87-92 with the large variation likely attributable to different diagnostic thresholds and patient populations. The incidence of ICU-acquired hypomagnesemia is not well reported.

Pathophysiology The predominant causes of hypomagnesemia can be divided into two categories: GI and renal-related losses. The content of magnesium in upper GI fluids (i.e., stomach) is about 1 mEq/L, which is in contrast to the 15 mEq/L found in the lower intestines.82 Hypomagnesemia from GI loss of magnesium can be observed with frequent vomiting, high NG tube output, diarrhea (including excessive use of cathartic agents), high ileostomy or colostomy output, and enterocutaneous fistulae. Damage

to the bowel can lead to decreased magnesium absorption (i.e., increased output by feces) such as that seen with radiation enteritis, Crohn disease, or ulcerative colitis. In addition, physical manipulation of the bowel may limit the surface area for magnesium absorption, such as that seen with extensive small bowel resections.81,82 Renal loss of magnesium in critically ill patients may often be iatrogenic and associated with medications provided to treat their acute illness. Loop diuretics are a prominent cause, given their activity at the thick ascending limb of the loop of Henle.82 Aminoglycosides, amphotericin B products, and foscarnet have been associated with renal magnesium wasting, as have cyclosporine and tacrolimus. For critically ill oncology patients, prior use of a platinum-based chemotherapeutic agent (e.g., cisplatin, carboplatin, oxaliplatin) will predictably result in renal magnesium wasting.81,82 Renal magnesium wasting can also be seen with hyperglycemia (secondary to an osmotic diuresis), in the diuretic phase of acute kidney injury, and in those with chronic alcohol abuse.81,82 Other less common causes of hypomagnesemia (e.g., hungry bone syndrome) have also been reported in the literature.81

Clinical Manifestations Hypomagnesemia can be considered an “excitatory” state, and potential clinical manifestations are listed in Table 3.7. Cardiac complications are a prominent concern for clinicians, particularly development of atrial fibrillation, supraventricular tachycardia, or ventricular arrhythmias, such as torsades de pointes.82 Electrocardiographic abnormalities that can be seen include a prolonged PR interval, widening of the QRS complex, and peaked (mild hypomagnesemia) or flattened (severe hypomagnesemia) T waves.82,83 Given that hypomagnesemia and hypokalemia often coexist,93 it is difficult to attribute such cardiac abnormalities to hypomagnesemia alone. Neuromuscular hyperexcit-ability, including spontaneous carpal-pedal spasms and seizures, may develop.82 Seizures should be of particular concern in patients with

hypomagnesemia and a history of epilepsy or those considered at high risk (e.g., neuro-surgical intervention, alcoholism). Refractory hypokalemia can be observed in the presence of hypomagnesemia for reasons mentioned earlier. Finally, through inhibition of PTH release and/or activity, hypomagnesemia can also contribute to the development of hypocalcemia, which may exacerbate neuromuscular excitability.82

Table 3.7 Clinical Manifestations of Magnesium Disorders83,a Organ System

Neurologic

Cardiac

Neuromuscular

Electrolyte disorders

aTo

Hypomagnesemia (serum < 1.8 mg/dL)

Hypermagnesemia (serum > 3.5 mg/dL)

Nystagmus Ataxia Seizures

Sedation (> 6 mg/dL) Coma (> 12 mg/dL)

Atrial fibrillation Ventricular arrhythmias Torsades de pointes Digitalis toxicity

Hypotension (> 3.5 mg/dL) Bradycardia (> 4.5–5 mg/dL) Bundle branch block (> 6 mg/dL) Asystole (> 18 mg/dL)

Hyperreflexia Muscle twitching/tremors (+) Chvostek/Trousseau sign

Hyporeflexia (> 8 mg/dL) Muscle paralysis (> 13 mg/dL) Respiratory depression (> 14.5 mg/dL)

Refractory hypokalemia Refractory hypocalcemia

N/A

convert magnesium in mg/dL to mEq/L, divide by 1.2.

Morbidity and Mortality With respect to clinical outcomes, observational trials have shown a significantly higher mortality among patients with versus without hypomagnesemia on ICU admission.88-90,94 In addition, reports have

associated hypomagnesemia with increased ICU and hospital length of stay,94 lack of recovery from acute kidney injury,91 and lactic acidosis.92 Of note, in none of these reports can causality be determined.

Management Overall, there are few data regarding the treatment of patients with severely symptomatic hypomagnesemia. Intravenous administration of magnesium is plausible for the treatment of such patients, and magnesium sulfate or chloride are the only intravenous formulations currently available in the United States. For patients with torsades de pointes, magnesium sulfate is the drug of choice according to the American Heart Association guidelines, with a recommended dose of 2 g administered by intravenous push over 1–2 minutes (with 10–20 mL of 0.9% sodium chloride flush to ensure systemic delivery).95 If the response is inadequate, a second intravenous bolus of 2 g can be administered within 5 minutes.96 This recommendation is primarily based on a case series of 12 patients with torsades de pointes successfully treated with this regimen.96 It is unclear whether this dosing regimen for magnesium sulfate could also be considered in patients who are hypomagnesemic presenting with other atrial or ventricular arrhythmias, as well as those with refractory status epilepticus. After the initial bolus, a continuous intravenous infusion should be provided to sustain the serum magnesium concentrations, yet data are lacking for the specifics of such therapy in these clinical scenarios. When reviewing the protocols for magnesium sulfate evaluated in clinical trials for AMI and stroke, dosages of up to 160 mEq have been infused intravenously over 24 hours and safely used in patients with a serum creatinine concentration of less than 2.3 mg/dL.97-101 Intravenous recommendations for continuous magnesium sulfate in the treatment of symptomatic patients are provided in Table 3.8. As a safety measure with such high doses, patients’ respiratory rate, deep tendon reflexes, and urine output should be monitored often. Clinicians should expect serum magnesium concentrations to be elevated during the infusion, but concentrations up to 3.5 mg/dL may be

tolerated. After the first 24 hours of magnesium treatment, an additional 0.5 mEq/kg/day intravenously is recommended on days 2–5 to account for potential total body magnesium deficits.102 Magnesium replacement should be continued until hypocalcemia or hypokalemia unresponsive to conventional supplementation resolves. Administration of large doses of magnesium sulfate as described in Table 3.8 should be avoided in patients with hypotension, bradycardia, or heart block because hypermagnesemia may exacerbate these conditions. In asymptomatic patients, magnesium supplementation is often provided in a preventive manner to maintain normal serum concentrations. As mentioned earlier, poor outcomes have been observed in patients admitted to the ICU with hypomagnesemia; however, the ability of magnesium supplementation to prevent such outcomes remains unknown, as does the ideal serum magnesium concentration in asymptomatic critically ill patients. Conventionally, many ICU clinicians target a serum magnesium concentration of about 2 mg/dL; however, no data support that this practice is more beneficial than simply maintaining normomagnesemia (i.e., 1.8 mg/dL or more). Table 3.4 lists some of the available enteral magnesium products. These products can be considered for maintenance therapy, but they often have a limited role because of their low bioavailability and potential cathartic effect. As a result, intravenous magnesium is often used. In general, for every 1 g of magnesium sulfate administered, the serum magnesium concentration is expected to increase by 0.1 mg/dL.98,99 Considerations regarding intravenous magnesium sulfate administration are provided in Table 3.5, including a recommended infusion rate. Although an infusion rate of 32 mEq/hour has been reported in the literature, using conservative infusion rates of 4–16 mEq/hour is recommended because renal elimination of magnesium is directly correlated with serum concentrations. In the presence of normal serum magnesium concentrations, renal elimination of magnesium is increased103; therefore, an unnecessarily rapid rise in serum magnesium concentration may lead to a greater portion of the administered dose being eliminated by the kidneys, ultimately impairing the ability to replete total body stores. In addition, a minimum of 2 g of

intravenous magnesium sul-fate is recommended in order to observe any significant change in the serum magnesium concentration. Serum magnesium concentrations should be rechecked 2 hours after completion of each intravenous infusion. If consistent replacement is needed, clinicians are encouraged to add magnesium to the patient’s maintenance intravenous fluids to avoid serum concentration oscillations (similar to that recommended for potassium).

HYPERMAGNESEMIA Technically, hypermagnesemia is defined as a serum magnesium concentration greater than 2.4 mg/dL (2 mEq/L); however, symptoms of hypermagnesemia typically do not develop until serum concentrations reach or surpass 3.5 mg/dL.83 The incidence of hypermagnesemia on ICU admission is relatively low (5%–7%),88-90 and no data are available regarding ICU-acquired hypermagnesemia. Hypotension is usually the first clinical manifestation of hypermagnesemia, followed by bradycardia, sedation, and hyporeflexia. If serum magnesium concentrations rise drastically (8.5 mg/dL or higher), patients can have somnolence, coma, respiratory depression, and even asystole (Table 3.7).83 In critically ill patients, hypermagnesemia can be iatrogenic (i.e., overcorrection of hypomagnesemia) or a result of acute renal failure. Other potential, less likely causes of hypermagnesemia in the critically ill population include drug induced (i.e., magnesium-containing cathartics), hypothyroidism, Addison disease, and diabetic ketoacidosis.83 Management of hypermagnesemia revolves around reversing the symptoms (if present) and lowering the serum magnesium concentration in addition to correcting the underlying etiology. In the presence of cardiac or neuromuscular symptoms, administration of 100–200 mg of intravenous elemental calcium (i.e., calcium gluconate 1–2 g or calcium chloride 500 mg to 1 g) is recommended because calcium antagonizes the activity of magnesium. In addition, cardiac support (e.g., vasopressor therapy, trans-cutaneous pacing) and/or respiratory support (e.g., endotracheal intubation) may be needed for

severe hypermagnesemia. In patients with preserved renal function, serum magnesium concentrations may be lowered using loop diuretics (e.g., furosemide 20–40 mg intravenous push) in addition to intravenous hydration with an isotonic fluid.83 Finally, immediate hemodialysis may be needed, particularly in patients with chronic kidney disease or those who are acutely oliguric or anuric.81,83

Table 3.8 Suggestions for the Treatment of Symptomatic Hypomagnesemiaa,b Degree of Deficiency Mild hypomagnesemia Moderate hypomagnesemia Severe hypomagnesemia

Serum Magnesium Range (mg/dL)

Treatment in First 24 hr (IV infusion) (mEq/kg)c

1.6–1.8

0.5

1.2–1.5

1

< 1.2

2

aSubsequent

therapy after 2 g (16 mEq) IV push of magnesium sulfate for patients with severe symptoms. bTo

convert magnesium in mg/dL to mEq/L, divide by 1.2.

cBased

on ideal body weight and provided as a continuous infusion over 24 hr; only suggested for use in patients with urine output > 0.5 mL/kg/hr and estimated creatinine clearance > 50 mL/minute/1.73 m 2; in the setting of renal insufficiency, consider 25%– 50% of suggested dose and reevaluate serum magnesium concentration every 12 hr.

PHOSPHORUS Phosphorus is the body’s primary intracellular anion and is present as both organic (i.e., bound) and inorganic (i.e., free) phosphate. Most intracellular phosphate consists of organic phosphate esters, including 2,3-diphosphoglycerate, adenosine, and guanosine triphosphate. Most

inorganic phosphate is contained within the ECF.104 Phosphate is essential in the development of phospholipid cell membranes, nucleic acids, phosphoproteins, and ATP, the main energy source for most cellular functions.104 On average, the human body contains only 250 g of ATP and turns over its own body weight equivalent in ATP each day. Phosphate also regulates several enzymatic reactions, including glycolysis, ammoniagenesis, and the 1hydroxylation of 25-hydroxyvitamin D. In addition, phosphate is required for the production of 2,3-diphosphoglycerate in RBCs, a compound necessary for proper oxygen delivery to tissues.104 Finally, phosphate serves as the primary buffer in the urine. The normal serum phosphorus concentration in adults is 2.5–4.5 mg/dL.81,104 During the day, serum phosphorus concentrations can oscillate by as much as 2 mg/dL, reflecting acute changes in transcellular distribution secondary to carbohydrate intake and insulin secretion.104 1,25-Dihydroxycholecalciferol (i.e., activated vitamin D) and PTH are the primary mediators of phosphorus homeostasis (Figure 3.4). Around 60%–80% of ingested phosphorus is absorbed in the GI tract, primarily in the jejunum, through both active and passive processes. Gastrointestinal absorption of phosphorus by active transport is directly facilitated by 1,25-dihydroxycholecalciferol and indirectly by PTH (through activation of vitamin D).104,105 Parathyroid hormone also increases serum phosphorus concentrations by stimulating the release of phosphorus from bones.105 However, PTH prevents renal tubular reabsorption of phosphorus after glomerular filtration, ultimately reducing serum phosphorus concentrations because this effect overshadows PTH-mediated GI absorption and release from bone.105

Figure 3.4 Overview of phosphorus homeostasis. aPTH

mediated inhibition of phosphorus reabsorption by the kidneys overshadows phosphorus resorption from bone and absorption from the gastrointestinal tract, ultimately resulting in hypophosphatemia GI = Gastrointestinal; PTH = Parathyroid hormone Information obtained from: Kelly A, et al. J Intensive Care Med 2013;28:166-177

HYPOPHOSPHATEMIA Hypophosphatemia is defined as a serum phosphorus concentration less than 2.5 mg/dL, with severe hypophosphatemia characterized by a concentration of less than 1 mg/dL. The prevalence of hypophosphatemia in critically ill patients varies widely (10%–80%).106 A recent large, single-center retrospective study involving 2,730 adult critically ill patients showed a 20% prevalence of hypophosphatemia.107

Pathophysiology

Hypophosphatemia can develop as a result of decreased intake/absorption, increased renal excretion, and/or internal redistribution. Internal redistribution of phosphorus (i.e., from the ECF to the ICF) is considered the most common cause of hypophosphatemia and can be seen with hyperventilation/respiratory alkalosis, insulin secretion/provision (e.g., management of diabetic ketoacidosis), hungry bone syndrome after parathyroidectomy, and refeeding syndrome.81 Refeeding syndrome is typically observed when glucose (either enterally or parenterally) is provided to patients after periods of prolonged (e.g., 7–10 days) starvation or inadequate nutrition, resulting in rapid intracellular shifts of potassium, magnesium, and phosphorus.108 Patients who have insufficient phosphorus stores because of preexisting malnutrition, such as in those who abuse alcohol and patients with cancer cachexia, may be particularly prone to refeeding-induced hypophosphatemia. In addition, in the setting of extensive burns and prolonged hyperventilation, phosphate stores may be quickly exhausted through the building of new cells and maintenance of ATP quantities sufficient for diaphragmatic contractions.104 Decreased GI absorption of phosphate may occur as a result of vitamin D deficiency, excessive administration of phosphate-binding agents (e.g., sevelamer, calcium carbonate), or use of other enteral medications that inadvertently bind phosphate in the GI tract (e.g., sucralfate). Increased urinary excretion of phosphate can be seen with primary and secondary hyperparathyroidism, osmotic diuresis, volume resuscitation, and Fanconi syndrome.81

Clinical Manifestations Given the many roles of phosphate in the body, it is not surprising that hypophosphatemia can affect many organ systems. Clinical manifestations of hypophosphatemia are thought to be primarily related to the depletion of ATP (e.g., myalgia, respiratory failure, heart failure) and reduced RBC concentrations of 2,3-diphosphoglycerate (e.g., metabolic encephalopathy syndrome from tissue hypoxia).104 Significant neuromuscular and cardiac sequelae can be seen with

severe hypophosphatemia (i.e., less than 1 mg/dL).109 However, moderate hypophosphatemia (i.e., 1–2 mg/dL) can also result in significant clinical manifestations, including impaired diaphragmatic contractility, intermittent ventricular tachycardia, and insulin resistance.109

Morbidity and Mortality Despite the wide array of organ systems affected, hypophosphatemia does not appear to be associated with an overall increased risk of mortality. In a recent single-center observational study including 2,730 adult critically ill patients (34% surgical, baseline APACHE II of 18), multivariate logistic regression failed to reveal an independent association of hypophosphatemia with ICU mortality (OR 0.86; 95% CI, 0.66–1.10) or hospital mortality (OR 0.89; 95% CI, 0.73–1.07).107 The lack of statistical significance was observed regardless of the hypophosphatemia threshold evaluated (1.9 or less, 1.5 or less, 1.2 or less, 0.9 or less, 0.6 mg/dL or less), although the small number of patients with a serum phosphorus concentration of 0.9 mg/dL or less (n=55) may have influenced the results for this subset.107 In contrast, critically ill patients undergoing intermittent hemodialysis and experiencing hypophosphatemia had an increased incidence of inhospital and 1-year mortality, as well as prolonged dialysis dependency, delayed recovery of complete renal function, and a higher prevalence of chronic kidney disease at 1 year.110 Overall, the impact of hypophosphatemia on mortality in critically ill patients, irrespective of renal function, deserves evaluation in prospective trials. The potential impact of hypophosphatemia on vital organ function (e.g., reduced cardiac contractility and impaired diaphragmatic contraction) demands daily serum phosphorus evaluation and prompt supplementation in the critically ill population.

Management Hypophosphatemia can be corrected with oral or intravenous

phosphate supplementation. In general, oral phosphate replacement should be reserved for patients who are asymptomatic and may be considered when the serum phosphorus concentration is greater than or equal to 2 mg/dL. Some of the more commonly used enteral replacement options for phosphate are presented in Table 3.4. Clinicians must be cognizant that oral phosphate administration can result in a cathartic effect, and some preparations contain significant amounts of potassium. Intravenous administration of phosphate is the recommended route for managing symptomatic hypophosphatemia and is typically recommended for critically ill patients with a serum phosphorus concentration less than 2 mg/dL, even in the absence of symptoms. Intravenous phosphate is available as both a sodium and potassium salt. The management of hypophosphatemia may be the most widely studied electrolyte derangement in the critically ill population other than hyponatremia. Table 3.9 provides a summary of the available data regarding intravenous phosphate replacement.106,109,111-118 Overall, studies vary widely in many respects including, but not limited to, the patient population (e.g., trauma, mixed medical-surgical), classification of hypophosphatemia, phosphate replacement regimen (e.g., fixed vs. weight-based dosing), infusion rate, and assessment of efficacy. In general, patients with renal dysfunction (e.g., urine output less than 30 mL/hour), hypo- or hypercalcemia, and conditions associated with phosphaturia (e.g., Fanconi syndrome) were excluded from most trials. When the larger and more recent trials evaluating intravenous phosphate replacement are viewed together,114,117,118 it appears that doses of 0.16–0.32 mmol/kg, 0.32–0.64 mmol/kg, and 0.64–1 mmol/kg are required to correct mild (i.e., 2.2–2.9 mg/dL), moderate (1.6–2.2 mg/dL), and severe (1.5 mg/dL or less) hypophosphatemia, respectively, in most critically ill patients. As shown by Brown and colleagues, it may be prudent to use the upper limit of such recommendations in trauma patients, particularly those with traumatic brain injury.118 The dose of intravenous phosphate should be rounded to the nearest 3-mmol interval (e.g., 21 mmol vs. 20 mmol) to ease compounding because both intravenous sodium and potassium

phosphate include 3 mmol of phosphate per milliliter. In addition, it is imperative to repeat serum phosphate concentrations 2–6 hours postinfusion and daily because serum phosphorus may undergo rapid redistribution, and additional supplementation may be necessary in the setting of a total body deficit. Serum calcium and magnesium should be monitored concurrently. With respect to the ideal infusion rate of intravenous phosphate, a study that compared 7.5 mmol/hour with 15 mmol/hour showed a greater urinary fractional excretion of phosphorus with 15 mmol/hour and no difference in serum phosphorus concentrations between the groups at the end of infusion.116 This suggests that 15 mmol/hour exceeds the renal threshold for phosphorus reabsorption (and may also contribute to hyperkalemia if potassium phosphate is administered). Bech and colleagues showed impaired tubular reabsorption of phosphorus with an infusion rate of 10 mmol/hour.106 Accordingly, a standard infusion rate for intravenous phosphate of 7.5 mmol/hour is recommended, with a maximum of 15 mmol/hour in patients having severe symptoms (i.e., respiratory failure) for which rapid correction is needed.

Table 3.9 Trials Evaluating Intravenous Phosphate Replacement106,109,111-118

Citation / Design Vannatta J, et al. 1981

”

SC, P, OL trial

Study Population

-

Adult patients (n 10)

• Serum phosphorus < 1mg /dL • Urine output > 30 mL /hr

Intervention / Infusion Rate

Comments

Outcomes

Potassium phosphate 9 mmol IV over 12 hr

Mean Serum Phosphorus

• Couldrepeatasneededevery 12 hr for 48 hr

• Baseline: 0.81mg/dL

Concentration*

• At 12 hr;127 mg /dL

• Overall,supplementation dose inadequate forsevere hypophosphatemia, as evidenced by 40% with peak conc < 1mg/dL and 100% with peak conc < 2 mg /dL after first dose • According to body weight, phosphorus dose ra nge 0.1-0.17 mmol/kg

-

Diluent • 0.45% NaCI (volume not prov ided)

Phosphorus > 1mg/ dL at 12 hr: 60%

.

Phosphorus 2.5-4 S mg /dL at 48 hr: 60%

Infusion rate

• 0.75 mmol/hr

• Nomentionofnumberof repeatdoses

• Limited information regarding study population; 60% with alcoholism • No incident of hyperkalemia

-

• Serum calcium 6.3 mg /dL (n 1), asymptomatic

-

• Serum phosphorus 5.2 mg/dL (n 1), asymptomatic

-

Vannatta J, et al. 1983

Adult patients (n 10)

SC, P, OL trial

• Urine output > 30 mL /hr • Twoormorereasonsfor

”

• Serum phosphorus < 1mg /dL

hypophosphatemia

Potassium phosphate 0.32 mmol /kglVoverl2 hr

Patients with Serum Phosphorus > 2 mg /dL

• Criteria forescalation midinfusion to 0.48 mmol/kg

By 6 hr: lot 10

• Repeat dose until serum phosphorus > 2 mg /dL

By 12 hr: 4 of 10 By 24 hr: 7 of 10 By 36 hr: 9 of 10 By 48 hr: 10 of 10

Diluent

• 0.45% NaCI (“volume determined for each patient individually*)

Patients Needing Repeat Doses of Phosphorus

At 12 hr: 6 of 9

Infusion rate

At 24 hr: 3 of 6

• 0.03-0.04 mmol/ kg/hr

At 36 hr:1of 3

• Follow-up study to that published in 1981 • Increased dose appears more adequate • Dose escalation to 0.48 mmol/kg conducted in one patient (although two met the criteria

for escalation)

• Body weight not provided;unable to determine absolute dose or infusion rate (estimate for 70-kg patient, 22-34 mmol and 2.1-2.8 mmol/hr) • No patients with serum calcium < 7 mg/dL • No patients had hyperphosphatemia; however, monitoring stopped on attainment of phosphorus > 2 mg/dL • Limited information regarding study population; 60% with alcoholism

At 48 hr: 0 ofl

.

Kingston M etal. 1985

.

”

SC, P OL trial

Adult, “seriously ill’patients with hypophosphatemia ( n 31)

—

- -

Sodium phosphate (n 17) or potassium phosphate (n 14)

• Dose not standardired

Mean Serum Phosphorus'

• 16 patients (52%) malnourished

Baseline: 0.88 ± 0.4 mg /dL

• One patient with hyperphosphatemia (peak

End infusion: 2.3 ± 0.9 mg/dL

Diluent ( 250 mL each )

Correlation Between Delta Phosphorus and mg / kg Dose

• 0.9% NaCI or 5% dextrose

r 0.74

Infusion rate

• Over 4 hr (2.5-3.75 mmol /hr)

conc of 5.3 mg/dL) • No change in mean serum calcium

• Most (28/31) received 10-15 mmol

-

Rosen G, et al. 1995 os

'

Adult, surgical and trauma patients with phosphorus < 2 mg/dL (n 11)

-

Sodium phosphate 15 mmol ( or potassium phosphate if serum potassium 3.5 mEq/ L)

• Baseline 16-15 mg /dL Diluent

Serum Phosphorus 2 mg /dL

-

6 hr Post infusion: 9 of 10

Total of three patients required additional doses to achieve / maintain serum phosphorus 2 2 mg / dL within 24 hr

• All patients critically III, but severity of illness

notprovided

-

• PN patients ( n 3) received 12 mmol of phosphorus / L in addltion to study amount • Incidence of peak ( immediately postinfusion) serum phosphorus > 6 mg/dL: 0%

• 0.9% NaCI 100 mL

• Corrected calcium: 8.5-97 mg/ dL during

Infusion rate

• One patient with serum potassium of 5.1 mEq /L

study

• 7.5 mmol/hr

• Given baseline serum phosphorus of 16-19 mg /dL,high success of achieving 2 2 mg /dL can be expected

If phosphorus remained < 2 mg/ dL at 6 hr post-infusion oronroutinefollow-up, administration of 15 mmol was repeated ( max 45 mmol /24 hr)

Clark C, et al. 1995

.

“

SC, P OLtrial

Consecutive, adult patients co-managed by nutrition support service with serum phosphorus < 3 mg/ dL, divided into three groups ( n 67)

-

One dose of sodium phosphate ( or potassium phosphate if serum potassium < 4 mEq /L)

pergraduateddosing scheme

• Mild ( 0.16 mmol /kg)

• Mild (23-3 mg/dL); n 31

• Moderate (0.32 mmol/kg)

• Moderate (16-2.2 mg / dL); n 22

Diluent

-

—

• Severe (s 15 mg/dL); n 14

-

• Severe (0.64 mmol /kg) • 0.9% NaClor 5% dextrose • 100 mL (mild /moderate) • 150 mL (severe)

Mean Rise in Serum Phosphorus from Baseline

• Mild: 0.7 ± 0.6 mg /dLs • Moderate: 0.8 ± 0.6 mg/dLb • Severe:1± 0.8 mg/dL° Phosphorus (> 2.5 mg /dL) on day lor 2

Mild: 81%/ 97% Moderate: 68%/73% Severe: 21%/50%

• Patient population: trauma (73%); general surgery (12%), bum (10.5%), medicine (4.5%)

• Excluded patients » 130% IBW • Patients received EN (76%; 23 mmol of phosphate/ L), PN (18%;15 mmol of phosphate/ L), ora combination ( 6%) • Patients followed for 48 hr after study dose

• Additional doses of phosphate could be provided as needed; percentage of patients given additional doses • Mild - Day 1(32%) /day 2 (13%) • Moderate - Dayl(50%) /day 2 (45%)

Infusion rate

• Severe - Day 1(50%) /day 2 (64%)

• 4-6 hr (mild /moderate group)

• No decrease in mean serum calcium

• 8-12 hr (severe group) Perreault M, et al.

1997

“

.

SC, P OLtrial

Adult surgical, trauma, or medical ICU patients with serum phosphorus < 2.48 mg /dL and central line

Potassium phosphate • Group 1: 15 mmol • Group 2: 30 mmol

Serum Phosphorus ( 2.48-4.19 mg / dL) 3 hr Post -infusion

• Group1: 81.5% • Group 2: 30%

Diluent ( both groups) Hypophosphatemia episodes (n 37)

-

• Group 1(127-2.48 mg / dL; n 270

—

• 0.9% NaCI, 5% dextrose, or 5% dextrose-0.9% NaCI • 250 mL

—

n 10)

Group 1*

Infusion rate (both groups )

• Post-infusion: 2.82 ± 0.50

• Over 3 hr (5-10 mmol/hr)

Group 2‘

• Baseline 0.83 ± 0.40 If phosphorus < 2.48 mg / dL after initial dose, repeat IVdoseperprotocolor oral supplementation per physician

• Excluded patients with serum potassium > 4.8 mEq/ L • Baseline APACHEII ~20;85% MV

Mean Rise in Phosphorus ( mg/ dL) from Baseline

• Baseline 2.0210.28

• Group 2 (s 1.24 mg /dL;

• Total of 27 patients with 37 episodes of hypophosphatemia; reenrollment possible if episodes separated by 272 hr

• Post-infusion: 2.17 ± 0.81

• Nutrition: EN ( 63%), PN ( 22%), both (8%); none (8%). PN with 15 mmol of phosphate/ L

• Nosignificant decrease in serum calcium • Maximum serum potassium increase of 0.6 and 11mEq/ L in groups 1and 2, respectively; no episodes of hyperkalemia • Recurrent hypophosphatemia seen in 47% of patients in group1on study days 2-3 • In group 2, mean total dose of phosphate on day1was 38 ± 11mmol (30-60 mmol)

ChatTon T, et al.

“

2003

SC, R

Adult medicaland surgical ICU patients with serum phosphorus < 0.64 mmol /L (n 47)

Moderate ( 0.4-0.64 mmol / L)

• Moderate (0.4 0.64 mmol/ L); n 37

• Groupl: 30 mmolin 50 mL over 2 hr (n 19)

• Severe (< 0.4 mmol/L) n 10

• Group 2; 30 mmolinl00 mL over 4hr (n 18)

-

— -

-

Potassium phosphate

—

-

Serum Phosphorus > 0.65 mmol/ L at End of Infusion:

98% (all except 1patient in group 2)

Mean Serum Phosphate at End of Infusion/ at 24 hr

Group 1:1.28/ 0.86 mmol/ L

Patients in each category ofhypophosphatemia were randomizedto oneof twoarms

Severe ( < 0.4 mmol /L)

Group 2:1.20 /0.89 mmol/ L

• Group 3: 45 mmolinlOOmL over 3 hr (n 5)

Group 3: 1.32 /0.83 mmol / L

-

• Intervention effective at achieving serum phosphorus > 0.65 mmol /L (> 2 mg/dL) • 15 mmol/hr infusion (groups1and 3) resulted in absolute increase in FePO compared with 7.5 mmol /hr

(

• Maximum study drugconcentration (potassium 900 mEq/ L) not recommended in clinical practice • Transient (mid-infusion) hyperphosphatemia and hyperkalemia seen infive and eight patients, respectively

Group 4: 1.07/0.61mmol /L

• Group 2: 45 mmolinlOOmL over 6 hr (n 5)

—

Diluent (both groups ) • 0.9% NaCI, 50-100 mL

Urinary Fractional Excretion of Phosphate (FePOJ

Group 1: 46 ± 18% Group 2: 36 ± 29% Group 3: 54 ± 31%

Infusion rate

Group 4: 22 ± 26%

• 7.5-15 mmol /hr Taylor B, et al. 2004

“

SC, 2 -phase

Adult, surgical ICU patients with serum phosphorus 2.2 mg/ dLorwhoreceived phosphate despite normal concentrations (n 158)

—

-

• Pre-intervention (n 47) • Post-intervention (n 111)

-

Intervention Period

• Graduateddosingscheme (three tier) based on both phosphorus concentration and patient weight

..

Treatment Success (i e , serum phosphorus > 2.2 mg /dL within 18-24 hr)'

• Pre: 47%

• Post: 76%

• Sodium phosphate ( or

potassium phosphate if serum potassium < 4 mEq /L), range 10-50 mmol

• No patients had hyperphosphatemia in either pre- or post-intervention groups • Protocol implementationreduced percentage of patients not receiving supplementation when indicated

• Over 6 hr (1.7—8.3 mmol/hr )

.

SC, R OLtrial

-

Graduated dosing scheme

• Mild (032 mmol/kg ) • Moderate ( 0.64 mmol/kg) • Severe (1mmol /kg)

-

n 34

-

• Severe ( s 1.5 mg /dL);

-

• Mild: 2.57/2.66/2.97 • Moderate:1.98/238*/2.881

Diluent

• Moderate (1.6-2.2 mg/ dL);n 30

n 15

Mean Serum Phosphorus ( mg / dL) on Study Days 1/ 2 / 3

• Severe: 1.18/ 2.88V2.663

• Mild ( 2.3-3 mg/dL);

• 0.9% NaClor 5% dextrose

Normal Serum Phosphorus ( > 2.5 mg / dL) on Day 2 /3

• 100 mL (mild/moderate group)

• Mild: 59%/59%

• 250 mL (severe group)

• Moderate: 50%/70% • Severe: 53%/ 60%

Infusion rate

• 75 mmol /hr

-

supplementation in patients with moderate (1.5-2.2 mg/dL) and severe hypophosphatemia (< 1.5 mg /dL)

Infusion rate:

Adult trauma patients, followed by the nutrition support service with aserum phosphorus 3 mg /dL (n 79)

• Dosing tier essentially 0.16-0.25 mmol/kg (for phosphorus 1.8 2.2 mg/dL), 0.3-0.5 mmol /kg (for phosphorus 1-1.7 mg /dL), and 0.42-0.75 mmol/kg (for phosphorus < • Protocol improved successful

• 250 mL, 5% dextrose

“

• 39% trauma patients

1mg/dL)

Diluent

Brown KA, et al. 2006

• Excluded patients:> 120 kg, < 40 kg, receiving phosphate-containing PN

• 78% of patients with traumatic brain injury, likely contributing to high phosphate requirements • Adjusted BW used if > 130% IBW; patients

with BMI > 40 kg/m2 excluded

• All patients received EN (93.5%; 26-39 mmol phosphate /L), PN ( 2.5%;15 mmol phosphate/L), or a combination (4%) • If indicated, additional doses could be provided on days 2 or 3 according to the protocol or according to the discretion of the trauma team; percentage of patients given additional doses on study day 2: mild 71%, moderate 80%, severe 73% • 3.4% incidence of serum phosphorus > 4.5 mg/dL • 5% of patients with hypocalcemia

Bech A, et al. 2013

Adult general medicalsurgical ICU patients with serum phosphorus < 1.8 mg /dL (n 50)

“'

-

SC, R, OL trial

Calculated phosphate dose

Mean Serum Phosphorus1

• BW (kg) * 0.5 L/ kg (1.25

• Baseline: 0.46 ± 0.01mmol/ L

mmol /L - serum phosphate mmol /L)

• End infusion:108 ± 0.03 mmol/L • Sodium-potassium-phosphate Next morning: 0.78 ± 0.04 • ( NaKP; Netherlands ) mmol/L Standard preparation

• 30 mLof 0.9% NaCI + 20 mL NaKP

Tubular Maximum Phosphate ReabsorptionperGFR (n =7)

•

< 0.6 mmol/Lin 6 of 7

• Onlytwo patients with severe hypophosphatemia, limiting applicability to this subset

• Phosphate replacement based on Vd of 0.5 L / kg • NaKP - Sodium-potassium-phosphate contains 1.5 mmol/mL phosphate, 0.75 mEq/ mL sodium,125 mEq/mL potassium

• Study drug concentration (potassium 0.5 mEq /mL) not recommended • Infusion rate of 10 mmol/ hr led to phosphaturia

Infusion rate • 17 mL /hr (10 mmol/hr) by syringe pump

ap0.05

between study groups.

APACHE = Acute Physiology and Chronic Health Evaluation; BMI = body mass index; BW = body weight; conc = concentration; EN = enteral nutrition; GFR = glomerular filtration rate; IBW = ideal body weight; MV = mechanical ventilation; OL = open label; P = prospective; PN = parenteral nutrition; R = randomized; SC = single center; Vd = volume of distribution.

HYPERPHOSPHATEMIA Hyperphosphatemia is defined as a serum phosphorus concentration greater than 4.5 mg/dL. In one report of 2,730 critically ill patients and more than 10,000 serum phosphorus measurements, 45% of all serum phosphorus measurements were indicative of hyperphosphatemia107; however, the prevalence of hyperphosphatemia in the critically ill population is not well defined. Hyperphosphatemia is predominantly an electrolyte derangement of those who are dialysis-dependent and has been associated with an increased risk of all-cause119,120 and cardiovascular120 mortality in this population.

Pathophysiology Hyperphosphatemia is usually a complication of renal dysfunction in which filtration of phosphorus is impaired.81 This can be seen in both acute kidney injury and chronic kidney disease, often leading to the use of phosphate-binding agents in patients with dialysis dependence.104

Other causes of hyperphosphatemia in the critically ill population include iatrogenic administration of large phosphate loads, cell destruction (e.g., tumor lysis syndrome, trauma, rhabdomyolysis, hemolysis), lactic or diabetic ketoacidosis, and 81,104 hypoparathyroidism. Clinicians should be cognizant of the large amounts of phosphorus contained in rectal cathartic products. For example, adult phosphate cathartic enemas contain about 180 mmol per dose. Caution should be exercised with use of these products in older adults, patients with impaired renal function, and patients taking other medications that may affect renal function (e.g., ketorolac). Tumor lysis syndrome is of concern in the critically ill oncologic population, particularly those with a highly proliferative malignancy (e.g., non-Hodgkin lymphoma) or severe leukocytosis, especially in the presence of concomitant chronic kidney disease. Spontaneous or treatment-induced cell lysis will result in the release of intra-cellular phosphate stores into the ECF compartment.121,122 Cellular damage and release of intracellular phosphorus is also the pathophysiology of hyperphosphatemia in the setting of trauma, rhabdomyolysis, and hemolysis.81 Lactic and diabetic ketoacidosis can result in the shifting of phosphorus from the ICF to the ECF, raising serum phosphorus concentrations. This shift is temporary, and clinicians should be aware of the potential for hypophosphatemia after correction of the underlying acidosis.104 Finally, in the setting of hypoparathyroidism, serum phosphorus concentrations will increase primarily because of decreased renal elimination (i.e., increased renal tubular reabsorption from decreased PTH).

Clinical Manifestations Serum phosphorus can complex with serum calcium, leading to the development of calcium-phosphate precipitates. These precipitates can deposit in the lungs (impairing respiratory function possibly resulting in death),123 kidneys (impairing filtration), bladder (resulting in nephrolithiasis), and/or ureters (causing obstructive uropathy). Other potential acute manifestations include nausea, vomiting, diarrhea,

lethargy, and/or seizures. Long-term complications include accumulation of calcium-phosphate precipitates in the soft tissues and vasculature of the body, as well as complications from associated hypocalcemia.104

Management In general, emergency treatment of hyperphosphatemia is only needed if a patient is having severe symptoms from associated hypocalcemia (e.g., tetany). In such cases, intravenous calcium gluconate or calcium chloride may be administered cautiously until symptoms resolve at the lowest possible dose of calcium. Although this increases the risk of calcium-phosphate precipitation, correction of tetany is of primary importance.104 Dialysis could be considered first to correct severe hyperphosphatemia. Continuous dialysis may be needed in cases of continued release of intracellular phosphorus from ongoing damage (e.g., tumor lysis syndrome).124 For non-emergent hyperphosphatemia, reduction in phosphate administration (e.g., phosphate-restricted diet or use of enteral nutrition appropriate for chronic kidney disease) should occur. In addition, use of phosphate-binding agents, such as calcium carbonate or sevelamer, can be considered, particularly in patients with chronic kidney disease. Chronic administration of aluminum-containing antacids to facilitate phosphate binding is not recommended because of the potential to elicit anemia, bone disease, and altered mental status from aluminum accumulation.104

CALCIUM Calcium is predominantly an extracellular cation, with an extracellular to intracellular gradient of about 10,000:1 mmol.125 Most (99%) total body calcium is stored in the bones.105 In the serum, calcium circulates in three forms: ionized (50% of total serum calcium), protein bound (40%, predominantly to albumin), and as a complex with organic and inorganic acids, such as citrate and phosphate (about 10%).105 Ionized calcium is the only biologically active form and has several vital roles within the

body.105,125 These include the propagation of neuromuscular activity, mediation of action potential in cardiac and smooth muscles, excitation/contraction coupling in skeletal muscle, regulation of endocrine and exocrine secretory functions, blood coagulation and platelet adhesion, cell membrane stability and for the structural integrity of bones.104,105,125 Thus, alterations in serum calcium can result in several clinical manifestations including muscle weakness, tetany, convulsions, hypotension, systolic dysfunction, and potentially cardiac arrest. Calcium homeostasis is primarily maintained through the activity of PTH and vitamin D, with other hormones (e.g., calcitonin) playing only a minor role (Figure 3.5).105,125 In general, PTH secretion is stimulated by low serum ionized calcium concentrations and inhibited by elevated concentrations. Parathyroid hormone increases serum ionized calcium by directly stimulating the release of calcium from bone and reabsorption by the kidneys. Parathyroid hormone also stimulates 1-βhydroxylase, the enzyme responsible for the rate-limiting step of vitamin D activation (i.e., conversion of 25-hydroxyvitamin D to 1,25dihydroxyvitamin D or calcitriol). Calcitriol directly increases ionized calcium concentrations by facilitating the absorption of ingested calcium in the small intestine by active transport.105,125 Under normal conditions, 30%–35% of dietary calcium is absorbed by both passive and vitamin D–mediated active transport.125 As calcitriol concentrations rise with subsequent elevations in ionized calcium, PTH secretion is suppressed. Calcitonin works the opposite of PTH, impairing calcium release from bone and reabsorption in the renal tubules, ultimately decreasing serum calcium. However, endogenous production of calcitonin has little overall impact on serum calcium homeostasis because PTH activity predominates.105 Reference ranges for total serum calcium and ionized calcium are 8.5–10.5 mg/dL and 1.12–1.33 mmol/L, respectively.125 In critically ill patients, it is recommended to evaluate ionized in contrast to total serum calcium. This recommendation is made because of the following: (1) ionized calcium is the biologically active form (as mentioned previously); (2) changes in serum albumin are commonly seen in

critically ill patients, and such changes can profoundly affect total calcium concentrations; and (3) use of equations to adjust total serum calcium for changes in serum albumin do not correlate well with measured ionized calcium. In general, as serum albumin falls, so does the measured total calcium. The modified Orrell method (equation 3.4) is commonly used for adjusting total serum calcium 126,127 concentrations.

Trials evaluating the utility of the modified Orrell equation against measured ionized calcium show that the formula overestimates hypercalcemia128 or normocalcemia129 and underestimates129 or fails to identify hypocalcemia.128 In a study of 100 critically ill trauma patients receiving nutrition support, 22 different formulas (7 to estimate ionized calcium and 15 to correct total calcium) were evaluated against measured ionized calcium.130 In this trial, 21% of patients were hypocalcemic (measured ionized calcium of 1.12 mmol/L or less), and 6% were hypercalcemic (measured ionized calcium of 1.33 mmol/L or greater). Overall, for the 22 methods, the mean sensitivity for predicting hypocalcemia was 25%, specificity 90%, false-positive rate 10%, and false-negative rate 75%; for predicting hypercalcemia, the sensitivity was 15%, specificity 83%, false-positive rate 17%, and false-negative rate 85%. Although some formulas performed better than others, none of the formulas had a sensitivity and specificity above 80% for predicting both hypo- and hypercalcemia.130 If only a total serum calcium concentration is available, a concentration less than 7 mg/dL has been associated with a higher rate of ionized hypocalcemia, whereas concentrations of 7–7.9 mg/dL have not.131

Figure 3.5 Overview of calcium homeostasis. Essentially, serum calcium levels are increased by parathyroid hormone and activated Vitamin D (1, 25-dihydroxycholecalciferol); whereas calcitonin reduces serum calcium levels. GI = gastrointestinal; PTH = parathyroid hormone. Information obtained from: Zaloga G. Crit Care Med 1992;20:251-262 and Kelly A, et al. J Intensive Care Med 2013;28:166-177

HYPOCALCEMIA Hypocalcemia is defined as an ionized calcium concentration of 1.12 mmol/L or less (or total serum calcium less than 8.5 mg/dL, although this method of assessment is not recommended because of the reasons discussed previously). The incidence of hypocalcemia in the critically ill population varies widely secondary to differences in definition (i.e., use of ionized vs. total calcium, variations in threshold) and study population (e.g., trauma, surgical). Ionized hypocalcemia is reported to occur in 15%–88% of critically ill patients.125,129,131-134

Pathophysiology The etiology of hypocalcemia in critically ill patients is likely multifactorial. Proposed factors include secondary hypoparathyroidism or relative PTH deficiency, impaired activation of vitamin D, calcium chelation, acid-base abnormalities, hyperphosphatemia, and iatrogenic causes.125,131 Patients with liver and/or renal dysfunction may be predisposed to hypocalcemia because of impaired hydroxylation of vitamin D to 25-hydroxyvitamin D and subsequently to 1,25dihydroxyvitamin, respectively.125 In addition, frequent packed RBC transfusion may contribute to hypocalcemia by chelation of calcium by citrate.135 Citrate-mediated chelation is also of concern with continuous renal replacement therapy, necessitating frequent assessment of ionized calcium.136 Development of alkalosis facilitates protein binding of calcium and can therefore decrease ionized calcium concentrations. In general, for every 0.1-unit increase in serum pH above 7.4, ionized calcium is expected to decrease by about 0.05 mmol/L.131 In the setting of chronic kidney disease, hyperphosphatemia can cause hypocalcemia by the complexing of calcium and phosphate, as mentioned earlier. Secondary hypoparathyroidism can be seen after head and neck surgical intervention with excision or damage to the parathyroid gland (e.g., thyroidectomy). In addition, hypomagnesemia can lead to both decreased PTH secretion and PTH resistance.125 Hypocalcemia can also be a complication of acute pancreatitis secondary to saponification of calcium with free fatty acids.125,131 Finally, medications should also be considered in the differential diagnosis that result in unintended calcium wasting in the urine, such as foscarnet and loop diuretics, as well as therapeutic measures to treat hypercalcemia, such as calcitonin or bisphosphonates.125

Clinical Manifestations Clinical findings of hypocalcemia are associated with the neuromuscular, cardiovascular, respiratory, and central nervous systems. Some experts consider neuromuscular irritability the hallmark of hypocalcemia, manifesting as tetany (characterized by circumoral

numbness, distal extremity paresthesia, and muscle cramps). Other potential neuromuscular findings include Trousseau sign, Chvostek sign, and hyperactive reflexes. Such findings are a result of a lower resting membrane potential, allowing more frequent nerve signal generation.105 Cardiovascular compromise, including decreased systolic function, hypotension, and arrhythmias, can be seen with hypocalcemia.125 In critically ill patients, cardiovascular findings are likely the most often seen because of continuous telemetry monitoring. Central nervous system manifestations of hypocalcemia are usually vague and include symptoms such as anxiety, irritability, depression, psychosis, and confusion.105,125

Morbidity and Mortality Many reports detail increased mortality among critically ill patients with hypocalcemia.132,133,137-139 A multicenter retrospective epidemiological study of 7,024 critically ill patients with 177,578 ionized calcium measurements (corrected to a pH of 7.4) showed a progressive increase in hospital and ICU mortality with worsening degrees of hypocalcemia. Multivariate logistic regression revealed that an ionized calcium concentration of 0.8 mmol/L or less using the lowest recorded value during the ICU stay was significantly associated with ICU and hospital mortality (similar findings were observed for a maximum ionized calcium concentration greater than 1.4 mmol/L).134 The potential influence of hypocalcemia on mortality deserves further investigation in prospective studies.

Management Management of hypocalcemia in the critically ill population has not been well studied. In fact, no trials have evaluated the impact of parenteral calcium supplementation on outcomes or complications in critically ill patients.140 This is of particular concern, given that animal models with sepsis and trauma show increased mortality and end-organ dysfunction with calcium administration and potential protective effects of

hypocalcemia and/or calcium antagonism.140 Regardless, clinicians must make decisions every day regarding calcium supplementation. Although an agreement that intravenous calcium should be provided to patients who are hypocalcemic with symptoms can be assumed, particularly in cardiovascular compromise, many other questions remain. These include the proper threshold for supplementation among asymptomatic patients, method of calcium replacement (i.e., intermittent vs. continuous intravenous infusion), choice of calcium salt (gluconate vs. chloride), and amount of calcium to administer. With respect to treatment threshold in asymptomatic patients, some experts recommend reserving treatment unless the ionized calcium is 0.8 mmol/L125 or less, whereas others suggest a more conservative threshold of 1 mmol/L131,141 or less in an attempt to prevent the development of cardiac sequelae. Trials have not been conducted to compare these two recommended thresholds. However, one small trial evaluating hemodynamic changes associated with calcium supplementation in hemodynamically compromised patients with hypocalcemia may assist clinicians in identifying a treatment threshold.142 In a prospective observational trial, Vincent and colleagues administered calcium chloride 1 g intravenously over 10 minutes to 17 consecutive ICU patients with hypocalcemia (ionized serum calcium less than 1.05 mmol/L) who were undergoing invasive cardiac monitoring. The mean baseline ionized calcium was 0.91 ± 0.12 mmol/L, which rose to 1.11 and 1.09 mmol/L at 30 and 60 minutes post-infusion. In addition, at 30 and 60 minutes post-infusion, a statistically significant rise in mean arterial pressure (from 77.2 mm Hg to 89.9 and 88 mm Hg, respectively) and left ventricular stroke work index was observed, showing improved vascular tone and myocardial contractility compared with baseline. A non-significant rise in cardiac index was observed as well, whereas no other changes were made in hemodynamic management (i.e., vasopressor escalation) during the time of intravenous calcium administration and evaluation.142 In light of these findings, and those of select case reports, an ionized calcium target of greater than 1 mmol/L may be considered in patients who are hypocalcemic with systolic dysfunction and/or hypotension. Currently,

no data are available to suggest that targeting a normal ionized calcium concentration (1.12–1.33 mmol/L) is more beneficial than a concentration greater than 1 mmol/L.131 Two intravenous calcium products are currently available in the United States, calcium gluconate and calcium chloride, both 10% solutions (i.e., 1 g per 10 mL). Calcium gluconate contains 4.65 mEq of elemental calcium per gram, whereas calcium chloride contains 13.6 mEq of elemental calcium per gram. Therefore, calcium chloride is about 3 times more potent than calcium gluconate, and there are no direct trials comparing these two agents for calcium supplementation. Because calcium is a vesicant, both agents should be administered by a central venous access device. Dosing recommendations for intravenous calcium supplementation have been provided in several publications,105,143-145 but such recommendations appear to be based primarily on opinion rather than available data. In many cases, calcium administration by continuous or prolonged intravenous infusion is recommended. However, continuous administration may not be practical in most critically ill patients because of incompatibility with other infusions (e.g., medications, phosphate replacement, parenteral nutrition) and subsequent need for a dedicated or additional central venous access device. In the absence of data confirming the superiority of continuous to intermittent intravenous infusion, no ideal strategy is recommended for critically ill patients. Intermittent intravenous calcium administration appears to be the most practical; limited available data to support this strategy are provided in Table 3.10.146,147 In accordance with targeting an ionized calcium concentration of 1 mmol/L or greater (in contrast to normalization), supplementation with 2 g of calcium gluconate intravenously over 2 hours through a central venous access device for critically ill patients with an ionized calcium of less than 1 mmol/L, regardless of the presence or absence of symptoms, appears safe. In patients who are hypertensive, it is recommended to withhold calcium supplementation unless the ionized calcium is less than 0.8 mmol/L or the patient is symptomatic. Repeat laboratory assessment should be conducted 2–12 hours post-infusion,

with further supplementation if indicated. In addition, management should include interventions for correctable underlying etiologies, such as hyperphosphatemia. Further research is needed to delineate the impact of intravenous calcium administration on outcomes in critically ill patients.

HYPERCALCEMIA Hypercalcemia is defined as an ionized calcium concentration greater than 1.33 mmol/L (or a total serum calcium greater than 10.5 mg/dL). In general, hypercalcemia is not a disorder commonly associated with critical illness, and thus, the incidence among critically ill patients is relatively low (3.4–15%),129,130,133,148 although one large study showed an incidence of 23%.134 Clinical manifestations vary widely, are associated with reduced activity or slowing of the affected organ systems (in contrast to an excitatory state associated with hypocalcemia), and progress in severity as the calcium concentration rises. Hypercalcemia can affect the CNS (resulting in apathy, somnolence, and/or coma), cardiovascular system (hypertension, bradycardia, and cardiac arrest), GI system (nausea/vomiting, constipation, and ileus), muscular system (fatigue, bone pain, and/or fractures), and genitourinary system (polyuria, nephrolithiasis, and oliguria). As mentioned earlier, an ionized calcium greater than 1.4 mmol/L was independently associated with increased ICU and hospital mortality in a large, multicenter retrospective study; however, this has yet to be confirmed prospectively.134 Hypercalcemia may be a result of excessive vitamin D or calcium intake, may be medication-induced (e.g., thiazide diuretics), or may be the result of granulomatous diseases (e.g., tuberculosis), excessive immobility, Paget disease, or familial hypocalciuric hypercalcemia. Most often, hypercalcemia is a result of malignancy and/or primary hyperparathyroidism. As such, readers are encouraged to visit the chapters related to oncologic and endocrine emergencies for details regarding the management of hypercalcemia.

ELECTROLYTE PROTOCOLS Protocol-driven, in contrast to prescriber-driven, electrolyte replacement appears to have become rather common in daily practice. Although variations exist, protocol-driven electrolyte replacement entails the use of a standing order-set executed by a prescriber that provides the bedside nurse the authority to administer electrolyte replacement doses as needed on the basis of observed laboratory results (and may also provide standing orders for follow-up monitoring post-replacement). The utility of protocol-driven electrolyte replacement has been evaluated in several single-center before-andafter investigations.149-152 Overall, protocol-driven electrolyte replacement has been shown to reduce the time to electrolyte administration149,150 as well as the number of missed electrolyte replacement doses.149-151 Certain studies also report increased efficacy by way of a higher percentage of “normalized” serum concentrations post-replacement with protocol versus prescriber-driven dosing, particularly with respect to potassium.151,152 In addition, physicians and nurses report high satisfaction with protocol-driven electrolyte replacement.150 Figure 3.6 provides an example of protocoldriven electrolyte replacement for a critically ill patient with a central venous access device.

CONCLUSION Electrolyte disorders are prevalent among critically ill patients and confer the risk of adverse sequelae. Patients with severe symptoms require prompt evaluation and intervention. Unfortunately, limited primary literature exists to guide decisions regarding the management of electrolyte disorders in the critically ill population, and as such, clinicians are often left with only their clinical judgment and little formal training. In particular, well-designed, prospective trials are needed to determine the ideal management strategy for severely symptomatic hyponatremia. Finally, and perhaps of greatest importance, critical care clinicians should focus their efforts on identifying risk factors and appropriately intervening before development of electrolyte disorders

or associated clinical manifestations. Use of protocol-directed electrolyte replacement appears to be a step in the right direction.

Table 3.10 Trials Evaluating Intermittent Intravenous Calcium Replacement in the Critically Ill Patient146,147

Ca = calcium; iCa = ionized calcium; OL = open label; P = prospective; PRBC = packed red blood cell; PTH = parathyroid hormone; SC = single center.

ICU Adult Electrolyte Replacement Protocol Via CVC OT PICC (For Use in Critical Care Unit Only) [+] Attending Physician:

Allergies:

Height:

cm Weight:

Kg

Notify physician if: 1. Patient initiated on dialysis (IHD or CRRT). 2. Serum creatinine greater than 1.5 mg/dL or increased by 0.3 mg/dL since last value reported 3. Urine output less than 500 mL in past 24 hrs. 4. Patienfs body weight is less than 30 kg. 5. No CVC or PICC access. LABS

Recheck serum electrolyte(s) 2 hours after the end of an electrolyte replacement infusion and with AM labs • Only recheck serum electrolyte(s) that were replaced per protocol. • If potassium phosphate is administered, both serum phosphate and potassium levels must be rechecked. MAGNESIUM Serum magnesium 1.8 2 mg/ dL • Magnesium Sulfate 16 mEq (2 grams) in 50 mL of sterile water IVPB (PYXIS premix) infused over 4 hours. Serum magnesium less than 1.8 mg/dL • Magnesium Sulfate 32 mEq (4 grams) in 100 mL of sterile water IVPB (PYXIS premix) infused over 6 hours. Contact ICU physician if serum magnesium is less than 1.5 mg/dL.

-

POTASSIUM Serum potassium 3.3 - 4 mEq/L • Potassium Chloride 40 mEq in 100 mL of sterile water IVPB (PYXIS premix) infused via CVC or PICC over 4 hours. Serum potassium less than 3.3 mEq/L • Potassium Chloride 40 mEq in 100 mL of sterile water IVPB (PYXIS premix) infused via CVC or PICC over 2 hours for 2 doses (total dose 80 mEq over 4 hours).

Contact ICU physician if serum potassium is less than 2.5 mEq/ L. PHOSPHATE Serum phosphate less than 2.5 mg/ dL (replacement is dependent on serum potassium and/ or sodium levels) If phosphate less than 2.5 mg/dL, potassium less than or eoual to 4 mEq/ L, and Potassium Chlonde not administered: • Potassium Phosphate 30 mmol in 100 mL of 0.9% NaCI IVPB infused via CVC or PICC over 6 hours (Thirty mmol of potassium phosphate equals 45 mEq of potassium)

If phosphate less than 2.5 mg/dL, potassium greater than 4 mEq/L and sodium less than 145 mEq/ L: • Sodium Phosphate 30 mmol in 250 ml of D5W IVPB infused over 6 hours Contact ICU physician if serum phosphorus is less than 1 mg/ dL.

ELECTROLYTE GUIDELINE REMINDERS • All electrolytes must be infused via pump • When both serum magnesium and serum potassium are low, replace magnesium unless otherwise instructed • Calcium replacement to be determined per ICU physician based on ionized calcium results. • Do NOT infuse calcium (including Lactated Ringers) and phosphate together.

.

Figure 3.6 Example of protocol-driven electrolyte replacement.

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Chapter 4 Nutrition Support

Therapy in Critically Ill Patients Amber Verdell, Pharm.D., BCPS, BCNSP; and Carol J. Rollins, M.S., RD, Pharm.D., FASHP, FASPEN, BCNSP

LEARNING OBJECTIVES 1. Evaluate the applicability of a given predictive equation for determining caloric requirements in a critical care population based on factors such as age and weight. 2. Discuss the appropriateness of permissive underfeeding in a given patient scenario based on the route of feeding and patient characteristics, including malnutrition. 3. Evaluate the role of individual nutrients, such as glutamine, arginine, antioxidants, and omega-3 fatty acids, in the nutritional regimen for critically ill patients. 4. Discuss the impact of various dialysis procedures (hemodialysis, continuous venovenous hemofiltration, continuous venovenous hemodialysis, hemodiafiltration) on nutritional goals of the critically ill patient. 5. Evaluate a protocol for pancreatic enzyme administration with enteral nutrition.

ABBREVIATIONS IN THIS CHAPTER

AKI

Acute kidney injury

ALI

Acute lung injury

ARDS

Acute respiratory distress syndrome

ASPEN American Society for Parenteral and Enteral Nutrition BCAA

Brained chain amino acid

BMI

Body mass index

CKD

Chronic kidney disease

CRRT

Continuous renal replacement therapy

DRI

Dietary reference intake

EN

Enteral nutrition

ESPEN European Society for Parenteral and Enteral Nutrition ICU

Intensive care unit

LOS

Length of stay

PN

Parenteral nutrition

RDA

Recommended dietary allowance

SCCM

Society of Critical Care Medicine

SGA

Subjective global assessment

INTRODUCTION Depriving the human body of adequate calories and nutrients results in death within 6–12 weeks in young, healthy men only consuming water to avoid dehydration.1 Altered metabolism in critically ill patients is associated with more rapid nutritional deterioration than expected from reports in healthy individuals or those having famine, and poor

outcomes are correlated with malnutrition in the critically ill patient.2 Providing full nutrient requirements to the critically ill patient as soon as possible would, therefore, seem rational. Unfortunately, despite ongoing research and many randomized controlled trials during the past 2 decades, there are no decisive answers regarding the best time to feed, where or how to feed, and what to feed the critically ill patient. What seems like an answer from early studies is often of no benefit— or worse, is harmful to some patients—after further data analysis or more rigorous studies. This chapter explores available information and the many controversies related to nutrition support for critically ill patients in intensive care unit (ICU) settings.

MALNUTRITION IN THE ICU Malnutrition has a prevalence of 20%–60% in hospitalized patients, depending on the criteria used.3-5 Most studies do not use rigorous criteria to define malnutrition, do not clearly delineate criteria for critical illness, and often depend on parameters negatively influenced by nonnutritional factors. Simply defined, malnutrition is abnormal nutrition related to macronutrients or micronutrients. As commonly used, malnutrition refers to undernutrition, although obesity also presents nutritional challenges, especially when metabolic alterations associated with critical illness are present. Critically ill patients are at particular risk of malnutrition because of increased nutritional demands and altered metabolism that result in far different clinical consequences than simple starvation. The hallmark of the stress response in critical illness as related to nutrition is failure to adapt energy and protein use to restore homeostasis, which would otherwise occur in simple starvation. Neuroendocrine and inflammatory components of the stress response culminate in hyperglycemia, insulin resistance, accelerated protein catabolism, diminished efficiency of protein use, loss of skeletal muscle, and reduced lean muscle tissue.6-10 Activation of the sympathetic nervous system occurs within minutes of a stress event, followed within hours by activation of the hypothalamus-pituitary axis

and release of thyroid-stimulating hormone, growth hormone, adrenocorticotropic hormone, and others. Growth hormone, catecholamines, and cortisol serve as cell mediators acting in conjunction with various hormones to drive the inflammatory response and increase the conversion of protein to glucose through the process of gluconeogenesis. Excessive glucose production by the liver is a major contributor to stress hyperglycemia. Peripheral resistance to the effects of insulin, thyroid hormone, growth hormone, and cortisol affects the metabolism of glucose, protein, and fat through the postinjury phase. Cytokines released as part of the inflammatory component cause weight loss, protein breakdown, and lipolysis, in addition to triggering anorexia.

Assessment of Nutritional Status Longer length of stay (LOS), increased complications, and higher mortality have been associated with hospitalized patients identified as being at nutrition risk or mal-nourished.11 Nutrition screening is intended to identify patients who would benefit from a more comprehensive nutrition evaluation, yet some nutrition factors are used in both screening and assessment. Nutrition assessment, as defined by the American Society for Parenteral and Enteral Nutrition (ASPEN), is “a comprehensive approach to diagnosing nutrition problems that uses a combination of the following: medical, nutrition, and medication histories; physical examination; anthropometric measurements; and laboratory data.”12 In addition, from a practice or research perspective, nutrition assessment results should correlate with outcomes. In a systematic review of studies including construct or criterion validity versus a reference method, or predictive validity related to outcomes such as mortality, LOS, or complications, 32 nutrition screening or assessment tools used in hospitalized patients were identified.13 The tools included individual parameters and scoring systems using a combination of factors. A few tools performed fair to good for determining nutrition status or predicting outcomes in specific non-ICU patient populations; however, none performed well across all

populations, and none was designed specifically to assess critically ill patients. Most anthropometric, biochemical (laboratory), and clinical parameters used for nutrition screening and assessment have significant limitations in the critical care setting because of fluid changes, effects of inflammation, sedation, and loss of consciousness, limiting ability to obtain data requiring patient participation (weight and dietary histories, previous gastrointestinal [GI] symptoms, functional parameters), and effects of medications commonly used in ICUs. Recorded weight has been found in less than 20% of charts during quality audits of hospitalized patients.14 Acute-phase proteins, including serum albumin, transthyretin (prealbumin), and transferrin, are not valid in critically ill patients as markers of nutritional status and do not predict outcome in this population.15,16 Physical assessment and anthropometric measures commonly used to evaluate critically ill patients enrolled in clinical research should be applicable in the non-research setting and show clinical utility to allow better alignment of practice with research results. An analytic observational study evaluated the performance of individual bedside measures used in clinical research to determine clinical usefulness for identifying malnourished critically ill patients and ability to predict outcomes, primarily increased risk of mortality.17 Measures evaluated did not require patient participation and were collected by trained assessors for 1,363 patients in 31 hospitals from 31 ICUs in Australia and New Zealand. Five measures, including mid-upper-arm circumference, mid-arm muscle circumference, subcutaneous muscle wasting and fat loss (both assessed by physical assessment using subjective global assessment [SGA] criteria18), and body mass index (BMI) analyzed as a continuous variable, showed statistically significant clinical usefulness and predictive ability. However, the strength of clinical utility was poor for any individual measurement. The area under the receiver operating characteristic curves (aROCs) ranged from 0.52 to 0.56, and the 95% confidence interval (CI) did not exceed 0.60. An aROC under 0.70 is considered a poor test; acceptable performance in sensitivity and specificity is typically based on a minimum performance

threshold of 0.70 (aROC 0.70).19 Multivariate analysis identified the best combination of factors showing independent clinical usefulness and predictive ability to be mid-arm-muscle-circumference and subcutaneous fat loss assessed by SGA criteria.17,18 Triceps skinfold thickness and BMI categorized by World Health Organization (WHO)20 breakpoints failed to show a significant predictive ability for mortality at hospital discharge. The statement on malnutrition by the Academy of Nutrition and Dietetics and ASPEN, called the Consensus Statement on Malnutrition, uses an etiology-based construct incorporating inflammation as a primary factor distinguishing starvation-related malnutrition (inflammation not present) from disease- or injury-related malnutrition with inflammation present.21 Chronic disease–related malnutrition is characterized by mild to moderate inflammation, as occurs in organ failure and sarcopenic obesity; acute disease– or injury-related malnutrition is associated with marked inflammation, as noted with major infections, trauma, and burns. Critically ill patients may develop acute on top of chronic disease–related or starvation-related malnutrition; however, pure starvation-related malnutrition is rare in this population. Recognizing the importance of inflammation in disease- or injury-related malnutrition is a starting point for assessing nutrition status in critically ill patients; however, other measures or combinations of factors are also necessary. The Consensus Statement on Malnutrition requires two of six characteristics—weight loss, reduced nutrition intake, edema, muscle wasting, fat loss, and impaired functional status—to be present for the diagnosis of malnutrition.21 Assessment of muscle wasting and fat loss is required when using either the Consensus Statement on Malnutrition or SGA.18,21 Conducting a nutrition-focused physical examination to assess muscle and fat can be difficult in critically ill patients because of the effects of edema, fluid overload, presence of lines and tubes, distortion of facial tissue from oxygen masks or mechanical ventilation tubes, and body tissue alterations related to lying in bed and fluid redistribution. The quadriceps region is an area where skeletal muscle wasting can be identified in critically ill patients.22,23 The deltoids and temporalis

muscles are other important areas to assess for muscle wasting, although guidelines for evaluating and rating of seven muscle regions (temple, clavicle bone, shoulder and acromion bone, scapula and upper back, anterior thigh, patella, and posterior calf ) and 12 muscle groups typically included in a complete nutrition-focused physical examination are available.18,22 Loss of subcutaneous fat can be assessed by physical examination in three regions using guidelines for nutritionfocused physical examination; however, the upper arm region overlying the triceps may be the most readily assessed and least likely to be altered by non-nutritional factors in critically ill patients. Promising areas of research for assessing muscle and fat changes in critically ill patients include use of computed tomography (CT) and ultrasound techniques.23,24 A small study of 56 mechanically ventilated patients suggests that CT also detects sarcopenia more readily than SGA.25 Patients classified as normal nourished by SGA were misclassified 50% or more of the time according to detection of sarcopenia using CT. Patients more likely to be misclassified in this study were male, minority, and overweight or obese. Despite its apparent limitations in identifying sarcopenia and need for patient participation, SGA has been shown to be an independent predictor of length of hospital stay in several patient populations and for LOS, readmission to the ICU, and probability of death in critically ill patients.5,11,26-28 The Nutrition Risk in the Critically Ill (NUTRIC) score was developed specifically to identify the critically ill patients most likely to benefit from nutritional therapy and is calculated from age, Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA), number of comorbidities, and days from hospital to ICU admission.29 Interleukin-6 is included in the NUTRIC calculation when available. A modified NUTRIC score without interleukin-6 has been validated in 1,199 critically ill patients with multi-organ failure.30 Nutritional adequacy has a high positive association with 28-day and 6month survival in patients with high modified NUTRIC scores. The modified NUTRIC score, however, identifies different patients than does SGA.31 Calculation of the modified NUTRIC score and SGA in the same patients identified 26% (36 of 139) and 80% (111 of 139),

respectively, as candidates for nutrition support or as malnourished. Using these two methods plus the institution’s routine screening method, only 6.7% of patients were determined to be at nutrition risk and malnourished by all three methods. In this small study of 294 patients admitted to the ICU with 139 deemed at nutrition risk or malnourished by at least one of the three methods, the modified NUTRIC score identified patients with the longest hospital and ICU LOSs, whereas SGA identified patients more likely to be discharged to a rehabilitation facility. Determining nutrition status in critically ill patients is difficult; limitations exist for all available assessment methods. However, assessing nutrition status is necessary to appropriately apply available research results and clinical guidelines. Using a combination of methods may therefore be rational. The modified NUTRIC score should be considered as one of the combination of methods because it was specifically developed and validated for critically ill patients.29,30 However, compared with other assessment methods, modified NUTRIC identifies a relatively small percentage of patients as most likely to benefit from nutritional therapy; other patients who would conceivably benefit are not identified.31 The Consensus Statement on Malnutrition is a second method to consider as part of a combination of assessment methods because it is one of the few methods to incorporate inflammation as a factor in defining the type and severity of malnutrition.21 Use of SGA in combination with the other two methods could also be considered. It is unclear whether combining assessment using the Consensus Statement on Malnutrition criteria and SGA would provide any added benefit for clinical utility or predictive ability regarding outcomes in critically ill patients compared with one of the methods alone. Several components of SGA are incorporated into the Consensus Statement on Malnutrition; however, SGA includes specific areas for assessment of fat and muscle, as well as assessment of GI symptoms and metabolic stress.18 Patients likely to require discharge to a rehabilitation facility are identified by SGA; the Consensus Statement on Malnutrition has not been evaluated in this context, although inclusion of functional status makes it reasonable to expect

the Consensus Statement on Malnutrition to perform similarly to SGA in this respect.21,31 No studies comparing the Consensus Statement on Malnutrition criteria and SGA are available, including none in critically ill patients and none evaluating the ability to predict patient outcomes. Nor has routine use of both the NUTRIC or modified NUTRIC score and the Consensus Statement on Malnutrition criteria in critically ill patients been evaluated, despite an apparent rationale for the combination.

Timing and Route of Nutrition Support When to feed critically ill patients remains controversial. The route of feeding (enteral vs. parenteral), volume of feeding (trophic or partial feeding vs. full goal), and patient characteristics, including disease severity, comorbidities, and degree of malnutrition, all influence when to feed. The debate over when feeding should start is significantly influenced by the route of feeding. Four major clinical guidelines addressing the care of critically ill patients, including joint guidelines of the Society of Critical Care Medicine (SCCM) and ASPEN, Canadian Clinical Practice Guidelines, European Society for Parenteral and Enteral Nutrition (ESPEN) guidelines on enteral nutrition (EN), and the Surviving Sepsis Campaign, recommend initiating EN within 24 or 48 hours of ICU admission when patients cannot tolerate oral intake and are expected to remain in the ICU.32-35 The recommendation for early EN is repeated in the ESPEN guidelines on parenteral nutrition (PN).36 No new studies with significantly different results were available for the 2015 update to the Canadian Clinical Practice Guidelines, and the recommendation was continued without change.37 The strength of the recommendation is not strong; the Canadian Clinical Practice Guidelines reported only a trend toward a reduction in mortality and infectious complications with early EN. There are no randomized studies showing a survival benefit with early EN in critically ill patients, with or without sepsis. Statistically significant reductions in mortality (odds ratio [OR] 0.34; 95% confidence interval [CI], 0.14–0.85) and pneumonia (OR 0.31; 95% CI, 0.12–0.78) were noted with EN initiated within 24 hours of ICU

admission in a meta-analysis of six randomized controlled trials.38 A total of 234 patients were analyzed for the meta-analysis; 117 were trauma patients, and only 28 patients were mechanically ventilated. Despite inclusion criteria intended to select only trials with sound methodology, several risks of bias were present.39 Bene-fits in secondary outcomes attributed to early EN include preservation of GI integrity, decreased LOS in the hospital and ICU, lower risk of infection, and reduced time on mechanical ventilation.40-43 When randomized trials reporting clinical outcomes with early EN versus delayed EN or no nutrition were evaluated for the presence of methodological bias, all 15 trials meeting rigorous inclusion criteria showed substantial heterogeneity, and none were low risk of bias.39 An early review of 111 studies also found substantial methodologic limitations in trials evaluating nutrition support in critically ill patients.44 Two trials encompassing 87 total patients were classified as “more robust” and assessed alone versus 10 “less robust” trials with 632 total patients evaluated for mortality and 11 trials with 580 total patients for infectious morbidity; neither mortality nor infectious morbidity was significantly different.39 Only one of the trials identified as more robust was of critically ill patients.45 Overall, less robust trials were the only ones to show a clinically significant mortality benefit for early EN. The same is true for infectious morbidity; however, there was little difference in the size of the estimated effect of bias between more robust and less robust studies in this group. Pneumonia, days on mechanical ventilation, and ICU LOS were not different between more and less robust trials in this evaluation, and no data were reported for non-infectious morbidity, adverse events, hospital LOS, and cost in more robust trials. The authors concluded that randomized controlled trials with low bias are needed before early EN can be considered beneficial compared with late EN or no nutrition. Conversely, there is no evidence that early EN is harmful when initiated in appropriate patients, defined as after adequate fluid resuscitation has been completed and the patient is hemodynamically stable with no contraindication to EN.32,33 Guidance for early EN in patients who require vasoactive agents is

limited because of a lack of adequate studies. The Canadian Clinical Practice Guidelines and the ESPEN guidelines indicate uncertainty regarding this patient population.33,34 The SCCM/ASPEN guidelines clearly state that small bowel EN should be held in patients with a mean arterial blood pressure under 60 mm Hg and when high doses or escalating doses of vasoactive agents are required to maintain perfusion.32 Cautious use of EN with close clinical monitoring for any signs of intolerance is supported at that lowest level of evidence for patients receiving “stable low doses of vasopressor agents,” but low dose is not defined. Reports of nonocclusive mesenteric ischemia and bowel necrosis in hemodynamically unstable patients receiving EN fuel the caution and uncertainty of early EN in this population.46-48 Administration of EN is postulated to cause inadequate intestinal perfusion resulting in necrosis as further compromise of splanchnic blood flow on top of that caused by hypotension and the underlying disease process occurs. Although cases of ischemia and necrosis have occurred in hemodynamically unstable patients receiving EN, no studies have adequately evaluated the premise related to perfusion and EN administration. In addition, individual vasoactive agents, and sometimes different doses of the same agent, exert different GI effects and may produce different responses with early EN.47 Changes in hemodynamic parameters, including decreased mean arterial pressure and systemic vascular resistance in addition to increased cardiac index and stoke volume, have been shown with early EN in patients receiving vasopressor agents after cardiac surgery.49 Patients in this prospective study required cardiopulmonary bypass during surgery the previous day and were receiving stable doses of dobutamine or dobutamine plus norepinephrine; EN was administered by a postpyloric tube. The study collected baseline data during 2 hours of fasting, followed by data collection during 3 hours of EN. Study limitations, including an extremely small sample size of only nine patients, none with evidence of bowel ischemia, and the short duration of EN make it problematic to extrapolate the data to patient care. Another small prospective study of patients who were post-cardiac

surgery compared 23 patients receiving dopamine, dobutamine, norepinephrine, or a combination of these medications at doses well below maximum clinical doses with 16 patients not requiring vasoactive therapy.50 Splanchnic blood flow increased with EN, as indicated by increased indocyanine green clearance after EN compared with before EN. Patients receiving vasopressor support tolerated EN but averaged about half of the 25-calorie/kg/day goal. A larger retrospective study using information in a multi-institution ICU database evaluated 1,174 patients requiring mechanical ventilation for over 2 days and requiring vasopressor agents (norepinephrine, epinephrine, dopamine, or phenylephrine).51 The early enteral group was composed of 707 patients receiving EN within 48 hours of starting mechanical ventilation; the remaining 467 patients constituted the late enteral group. Results showed a benefit of early EN on both ICU and hospital mortality, with the patients receiving several vasopressor agents during the first 2 days of ventilatory support benefiting the most (OR 0.36; 95% CI, 0.15–0.85). Patients requiring vasopressor support for more than 2 days also had greater benefit with early EN (OR 0.59; 95% CI, 0.39– 0.90). After correcting for confounders, early EN was associated with a 30%–35% decreased risk of death according to Cox proportional hazards analyses. Ventilator-associated pneumonia, ICU LOS, and ventilator-free days were not statistically different, and no evidence of harm was found with early EN. Assessment at 28 days indicated no significant change in results. Slight differences did exist between groups, with patients in the early EN group being slightly older but also having a lower severity of illness with two of the three methods assessed. A respiratory diagnosis was also more likely at ICU admission in the early EN group. These results support the cautious use of early EN in patients requiring vasopressor agents. A large randomized trial is now needed to confirm the retrospective data. Until more definitive answers are available, several factors should be considered when deciding whether a patient requiring vasopressor support is appropriate for a trial of early EN. Patients already at risk of nonocclusive mesenteric ischemia are likely to be at higher risk when starting EN. This includes patients with a history of sepsis, major

infection, diabetes mellitus, smoking, or critical stenosis in the mesenteric vasculature, and older adult patients with cardiovascular disease or arrhythmia.48,52 Conditions present at the time of evaluation that suggest not proceeding with EN include low mean arterial blood pressure (consistently less than 60 mm Hg), increasing doses of vasoactive agents, cardiac failure resulting in a low flow state, active bleeding requiring ongoing transfusions, and requirement for massive fluid resuscitation. The vasoactive agent being administered and its dose also need to be considered. One recommended classification of a high-dose vasopressor agent indicating greater caution for initiation of EN is as follows: dopamine over 10 mcg/kg/minute, epinephrine or norepinephrine over 5 mcg/minute, vasopressin above 0.04 unit/minute, and milrinone above 0.375 mcg/kg/minute.48 Phenylephrine has been associated with nonocclusive mesenteric ischemia and may be more risky than other pharmacologic agents when EN is provided.52 In addition, partial enteral support may be more appropriate than full support, at least when EN is first initiated. Close clinical monitoring for any signs of intolerance is essential.32,48 Optimal timing for initiation of PN has not been determined; research has produced mixed results. From a practice standpoint, knowing the most appropriate time to initiate PN often becomes a question of nutrition versus no nutrition in the first few days of ICU admission because early EN is often not achievable in patients either with or without prior malnutrition. In a retrospective observational study evaluating actual practices for early EN in critically ill patients, 60.8% of patients met a goal of EN within 48 hours of ICU admission; 13.3% received EN within 24 hours.53 The study was international in scope and included 2,946 patients from 158 ICUs, indicating that the problem of delay in initiating EN is widespread in ICUs. Initiating PN within 24–48 hours of ICU admission if the GI tract cannot be used within 3 days is recommended by the ESPEN guidelines, whereas the SCCM/ASPEN guidelines recommend not initiating PN until after 7 days.32,36 The initial 2003 Canadian Clinical Practice Guidelines recommended against the routine use of PN in patients with an intact GI tract, and subsequent updates, including the

2015 update, have continued this recommendation.33,37 However, the 2015 update included an additional statement to consider PN when a relative contraindication to early EN existed in patients with high nutritional risk.37 The American Thoracic Society, together with four other professional societies, included not using PN within the first 7 days of ICU admission in adequately nourished patients as the third of five recommendations for its Choosing Wisely Top 5 list in critical care medicine.54 All recommendations or guidelines assume no preexisting malnutrition. The SCCM/ASPEN guidelines rely heavily on two meta-analyses comparing no nutrition support with use of PN for their recommendations. The first meta-analysis reported significantly lower infectious morbidity with no nutrition support (relative risk [RR] 0.77; 95% CI, 0.65– 0.91) in critically ill patients without preexisting malnutrition than in patients receiving PN.55 The difference in complications was not statistically significant, although a trend toward lower overall complications was reported. A significant increase in mortality with PN (RR 1.78; 95% CI, 1.11–2.85) was noted in the second meta-analysis.56 A trend toward more complications was found with PN compared with no nutrition support. The impact of adequate glucose management on outcome was not yet recognized when the studies in these two meta-analyses were completed; therefore, it is unclear whether inadequate glucose control contributed to worse outcomes with PN. The eventual risk of harm from not feeding was recognized when determining the point at which PN would be better than no nutrition in the guidelines. Data indicated that after 14 days with no nutrition compared with providing PN, mortality and hospital LOS increased in hospitalized patients.57 The SCCM/ASPEN guidelines selected over 7 days as their recommendation for initiating PN.32 Guide-lines from ESPEN were swayed by a meta-analysis of 11 trials, which included both elective surgery and critically ill patients when early EN was not feasible.36,58 Better survival was shown when PN was initiated within 24 hours of ICU admission than when EN was initiated late (OR 0.29; 95% CI, 0.12–0.70). No subanalysis was conducted to separate effects on critically ill patients compared with elective surgery

patients, despite the heterogeneity between these two populations. Studies available after both the ESPEN and the SCCM/ASPEN guidelines were published in 2009 have shown variable outcomes related to initiating PN in ICU patients, as shown in Table 4.1. Trials as a whole define early nutrition support, either EN or PN, as starting within 48 hours of ICU admission and late as starting after 48 hours. The term delayed PN is sometimes used to define the initiation of PN specifically after ICU day 7. These definitions are used here unless otherwise specified. An observational study of 703 critically ill patients with a medical diagnosis and remaining in the ICU over 72 hours found that early PN better met goals for calories (74.1% ± 21.2%) and protein (71.5% ± 24.9%) than either late PN (57.4% ± 22.7% calories, 53.2% ± 22.7% protein) or late EN (42.9% ± 21.2% calories, 38.7% ± 21.6% protein).59 Although the 83 patients initiated on early PN received more of their goal calories and protein than the 79 patients receiving late PN or the 541 patients receiving late EN, there was no statistically significant difference in mortality or hospital and ICU LOS. The trial known as Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients, or EPaNIC, compared early PN, as recommended by ESPEN, with PN initiated after 7 days in the ICU (delayed PN), as recommended in the SCCM/ASPEN guidelines.32,60 The early PN group had 2,312 patients, and the delayed PN group had 2,328 patients; all patients were at nutritional risk. Hospital, ICU, and 90-day mortality did not differ between early and delayed PN. Overall, delayed initiation of PN was associated with better outcomes than was early PN, including a greater likelihood of live discharge from the ICU at day 8, earlier ICU discharge by a median of 1 day (HR 1.06; 95% CI, 1.00–1.13), earlier hospital discharge by a median of 2 days (HR 1.06; 95% CI, 1.00–1.13), fewer new infections, a lower percentage of patients requiring mechanical ventilation for more than 2 days, and a shorter duration of renal replacement therapy. Inflammation measured by C-reactive protein was higher, and more patients had hypoglycemia with delayed PN. Functional status was not different at discharge. The EPaNIC study design was different from that of previous

studies evaluating the timing for PN initiation because patients were randomized to early versus late PN as a supplement to inadequate EN initiated early; the goal for PN was to meet calorie requirements with PN plus EN.60 Patient demographics were different from those in many studies evaluating nutrition support in ICU patients; enrolled patients were about 90% surgery patients, and more than 50% appeared to be elective admissions. Cardiac surgery patients represented about 60% of each group. However, outcomes in cardiac surgery patients were no different from those in the entire study population. Severity of illness appeared to be relatively low, given that most patients had a short ICU LOS and under 10% ICU mortality. A predefined post hoc subgroup analysis was performed in the 517 patients at high nutritional risk, based on complex surgery with a contraindication to early EN and no nutrition by ICU day 7. In the high-risk group, patients receiving delayed PN had a lower infection rate (29.9% vs. 40.2%) and were more likely to be discharged alive from the ICU sooner (HR 1.20; 95% CI, 1.00– 1.44) than were patients in the early PN group. Early PN, with or without concomitant EN, was detrimental compared with delayed PN in the patient population studied, including patients at nutritional risk.

Table 4.1 Studies on Initiating PN in Critically Ill Patients Published Since ESPEN and SCCM/ASPEN Guidelines in 2009

Study Cahilletal.

”

Type of Study

Patient Number and Characteristics

Comments

Observational

703, medical diagnosis

Prospective RCT, multicenter; predefined post hoc analysis

2,312 eariy PN; 2,328 delayed PN; 90% surgery patients with > 50% elective admissions; about 60% cardiac patients

EN initiated in all patients without contraindication (4,123)

Post hoc analysis of 517

Contraindication to eariy EN and no nutrition by ICU day 7

Outcome:Infection

Outcome: LOS

Outcome: Mortality ND

Eariy PN hetter at meeting calorie and protein goals

ND ICU or hospital

ND , ICU, hospital, 90

Eariy PN ± concomitant EN, was

Eariy PN vs . late PN or late EN

Casaer etal.

“

EPaNIC ,

eariy PN vs. delayed PN

Casaer et al.61

EPaNIC post hoc analysis

Kutsogiannis et al.°

AdditionofPNtoENvs. EN

Post hoc analysis for severity ofillness

Total EPaNIC population (4,640) dividedinto quartiles by APACHEII score

Observational, multicenter

2,920 total, 188 with eariy PN and 170 with late PN

alone

Heidegger et al.64

RCT, two centers

Supplemental PN or SPN

PN added to supplement EN on ICU days 4-8 vs. EN alone

305,mixed medical and surgical; patients receiving < 60% goal calories by EN enrolled on ICU day 3

“

RCT

1372, relative contraindication to EN

Eariy PN vs . standard care ( EN, PN no nutrition per attending physician)

.

Harvey et al.66

RCT,

CALORIES,

multicenter

eariy PN vs. eariy EN

2,388,> 90 % well-nourished before ICUbased on BMI and weight loss; moderate severity of illness

day

detrimental, including less likelihood of live discharge by ICU day 8 and M V > 2 days was required in more patients

Detrimental effect of eariy PN ± concomitant EN, was not related to severity of illness

Increased for both ICU and hospital with PN. Later discharge alive with PN

Subgroup analysis of patients with eariy or persistent Gl intolerance and Gl admitting diagnosis

Calories by indirectcalorimetry or set at 25/kg for women, 30 /kg for men using IBW Achieved 103% goal with PN vs. 77% with EN only Evaluated days 9-28 and full 28 days

Doig etal.

More new infections with eariy PN ( 26.2% vs . 22.8%, p=0.008)

Outcome: Overall

ND ICUor hospital

Increased

Did not change for subgroup analysis

Fewer patients developed nosocomial infection with PNvs. EN alone ( 27% vs . 38%,

ND for full 28 days but statistical difference in nosocomial infection for day 9-28 evaluation; difference in "other" infection, not in typical ICU (pneumonia , bloodstream, urogenital, or abdominal) infections

p= 0.0338) days 9-28; ND full 28 days

40.8% in standard care arm received no nutrition, 43.7% received EN at sometimein ICU

ND

No contraindication to either PN or EN; fed for 5 days in ICU

ND in treated infections

Worse outcomes with addition of PN, either eariy or late, to EN. Longer MV

ND

ND , 60 day

ND, including organ failure

ND , 30 and 90

ND

day

Protein < 1g / kg /day, calorie goals not reached in either group

APACHE = Acute Physiology and Chronic Health Evaluation; ASPEN = American Society for Parenteral and Enteral Nutrition; EN = enteral nutrition; ESPEN = European Society for Parenteral and Enteral Nutrition; IBW = ideal body weight; ICU = intensive care unit; LOS = length of stay; MV = mechanical ventilation; ND = no difference; PN = parenteral nutrition; RCT = randomized controlled trial; SCCM = Society of Critical Care Medicine.

Because of criticism of the original EPaNIC trial, a post hoc analysis was conducted to determine whether severity of illness influences the results.61 The total EPaNIC population was divided into quartiles according to severity of illness as defined by the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. The APACHE II quartiles in order of increasing severity of illness were 10–13, 16–18, 22–30, and 35–41. No quartile showed a benefit from early PN with respect to live discharge from the ICU at day 8. Delayed PN remained a benefit across all quartiles when evaluating the percentage of patients developing a new infection; quartiles for APACHE II of 16–18 and 22–39 showed a decrease in the percentage of patients developing new infection. Adverse effects of early PN initiation were not related to the severity of illness in this post hoc analysis.

A small preplanned substudy of EPaNIC evaluated changes in muscle and adipose tissue in 15 patients admitted to the ICU with intracranial bleed, isolated brain trauma, or subarachnoid hemorrhage.62 Inclusion criteria required a clinical indication for CT scanning within 48 hours of ICU admission and repeat CT scanning scheduled at ICU admission for 1 week later. Six demographically matched healthy volunteers served as controls and underwent repeat CT scanning at an interval of 7 days. Repeat quantitative CT images, both mid-femur and abdominal, were used to estimate muscle and adipose tissue volume. Ten patients were in the early PN group of EPaNIC and five in the delayed PN group. Muscle wasting occurred with both early and delayed PN. Early PN was associated with increased lipid and water content of muscles. According to this small study, early PN does not prevent muscle wasting better than delayed initiation of PN and may result in more accumulation of water and fat in the muscles. The EPaNIC study primarily evaluated the addition of PN, either early or late, in patients receiving early EN to bring the total caloric intake to 100% of estimated requirements. An observational study of 2,920 patients from 226 ICUs compared both early and late addition of PN to EN with early EN alone.63 This study design allows a better comparison of PN effects with EN than does the EPaNIC design because there was a group randomly assigned to early EN alone. A diligent attempt to use the GI tract in study patients is suggested by only a small percentage of the total study population in the two PN groups: 188 patients (6.4%) with PN added early and 170 patients (5.8%) with PN added late. Both PN groups of patients were more likely to have early and persistent GI dysfunction than were patients receiving only early EN, and the late PN group of patients had more persistent GI dysfunction than did patients with PN added early. Outcomes were worse with the addition of PN than with EN alone. Either early or late PN was associated with higher mortality and longer time on mechanical ventilation, and both ICU and hospital LOS were longer. Patients receiving early PN had a later discharge alive (HR 0.75; 95% CI, 0.59–0.96), as did patients receiving late PN (HR 0.64;

95% CI, 0.51–0.81). Subgroup analysis was conducted on high nutritional risk categories, including patients with EN intolerance, either early (258 patients) or persistent (379 patients), and those with a GI admitting diagnosis (178 patients). No benefit to early or late addition of PN was found in patients with either early or late GI intolerance. Compared with patients in the subgroup receiving EN alone, time to discharge alive was longer for patients with an admitting GI diagnosis for either early PN (HR 0.35; 95% CI, 0.19–0.63) or late PN (HR 0.62; 95% CI, 0.41–0.94). In contrast to these and EPaNIC’s results, a much smaller study reported better outcomes when PN was added to inadequate EN for critically ill patients.64 The trial, often called the Supplemental Parenteral Nutrition trial, included 305 ICU patients from two centers and enrolled patients on ICU day 3. By default, this relatively late enrollment indicated that patients were at higher risk nutritionally, as did attention to patients with GI intolerance. Patients receiving less than 60% of goal calories from EN were randomized to supplemental PN (153 patients) on ICU days 4–8 or continued EN alone (152 patients). Calorie requirements were determined on ICU day 3 by indirect calorimetry or, if not available, set at 25 or 30 calories per kilogram per day using ideal body weight for women and men, respectively. Between days 4 and 8, patients receiving supplemental PN achieved their calorie goal; the EN group received 77% ± 27% of goal. The primary outcome was nosocomial infection rate after the intervention and was measured from day 9 to day 28. The supplemental PN group had a reduced nosocomial infection rate (HR 0.65; 95% CI, 0.43–0.97) together with fewer total infections per patient. The major discrepancy was in “other” infections post-intervention (4% in supplemental PN; 18% in EN group); most infections typically identified as problematic in critically ill patients (pneumonia, bloodstream, urogenital, and abdominal infections) appeared in a similar percentage of patients in the two groups. There was no definition of “other” infections. Evaluation of 1,372 critically ill patients with a relative contraindication to EN showed no difference in the primary outcome of 60-day mortality between the half randomized to PN starting within 24

hours of ICU admission and those receiving standard care, including EN, PN, or no nutrition as determined by the attending physician.65 Nutrition support was initiated in standard care patients at a mean of 2.8 days after study randomization, which occurred within the first 24 hours of ICU stay. Neither EN nor PN was administered to 40.8% of standard care patients; at some time during their ICU stay, 43.7% received EN. Mechanical ventilation was required for about 1 less day with early PN, and coagulation failure averaged about ½ day less. Infection rates did not differ between groups, nor did organ failure (renal, pulmonary, hepatic, cardiovascular, and multisystem failure). A randomized comparison of early PN with early EN, called the CALORIES trial, was conducted in 2,388 patients admitted to one of 33 participating ICUs.66 Inclusion criteria required no contraindications to either PN or EN. Nutrition was administered by the assigned route for 5 days (120 hours) unless the patient transitioned to a complete oral diet, was discharged from the ICU, or died before this time. No difference between PN and EN was found in the primary outcome of 30-day mortality (RR for PN 0.97; 95% CI, 0.86–1.08) or secondary outcome of mean number of treated infectious complications (0.22 vs. 0.21). Rates of hypoglycemia and vomiting were significantly less with PN, and increased liver function tests occurred more commonly. Other secondary outcomes did not differ between EN and PN, including days alive and free of organ support at 30 days, abdominal distention, ICU and hospital LOS, and death in the ICU, hospital, or at 90 days. The CALORIES trial showed that early PN was not associated with worse outcomes than early EN.65 Mortality was not increased, nor was morbidity, including infectious risk. However, the patient population studied must be considered before widely extrapolating these data to critically ill patients, especially those at nutritional risk. Given the BMI and percentage of weight loss in the previous 6 months, more than 90% of the patients in the CALORIES trial were well nourished before ICU admission. Severity-of-illness scores were moderately high; the APACHE II score was slightly under 20, and the SOFA score was slightly below 10 in both groups. Vasoactive agents were required in 80%–85% and mechanical ventilation in 83%–84% of patients in both

groups. Protein provision was very low at 0.6–0.7 g/kg/day in both groups, and the calorie goal of 25 calories per kilogram per day was not reached in either group. Taken as a whole, trials published since the ESPEN and SCCM/ASPEN guidelines became available in 2009 have added to the controversy regarding the best practice for nutrition support in critically ill patients. Early EN continues to be recognized as the best practice; however, many patients do not meet the goal of early EN.32-36,53 A concerted effort to initiate early EN should be made; however, PN now appears to be a more viable option for some patients than continued inadequate nutrition. Studies must be evaluated carefully to determine the study population, including severity of illness and nutritional status, and applicability of results to an individual patient. Patients with the greatest severity of illness and high nutritional risk are most likely to benefit from, and not be harmed by, early PN. The 2015 Canadian Clinical Practice Guidelines recommend consideration of early PN in patients at high nutritional risk with a relative contraindication to EN.37

NUTRITIONAL GOALS—MACRONUTRIENTS Paralleling the question of timing for nutrition support is the question of how much to feed the critically ill patient. Various methods are used to determine calorie goals, including measurement of metabolic substrates and products, predictive equations ranging from simple to complex, and fixed caloric targets based on weight. The doubly labeled water method is the gold standard for establishing caloric requirements, although clinical use is limited by the 1-week or more delay in obtaining results.67 Indirect calorimetry is the standard to which other methods for determining the resting energy expenditure are compared in the clinical setting. Nonetheless, the Canadian Clinical Practice Guidelines committee found insufficient data to make a recommendation on the use of indirect calorimetry compared with predictive equations during its initial guidelines development or for any subsequent updates.33,37,68,69 Limitations to indirect calorimetry include availability, cost, and decreased accuracy in the presence of several

commonly encountered ICU conditions including high oxygen requirements; leaks in the airway circuit from endotracheal cuffs, chest tubes, or bronchial-pleural fistulas; and removal of carbon dioxide by renal replacement therapy or extracorporeal systems. Determining an activity factor to account for energy expenditure above the resting state can also be problematic in the critical care setting, especially when patients are not comatose or heavily sedated. Predictive equations use anthropometric data and other variables developed from regression analysis to predict caloric requirements of a specified population. Only a few predictive equations among the hundreds published were designed for use in critically ill patients. Many predictive equations used in the ICU were not developed or validated in this setting and are not accurate across the full range of ages and body habitus encountered in the critically ill population. Compared with indirect calorimetry in 202 ventilated patients, overall accuracy of various predictive equations ranged from 18% to 67%.70 Among the predictive equations tested, the Penn State equations incorporating Mifflin equations to account for demographic data (weight, height, age, sex) were the most accurate, had the lowest percentage of estimates over 15% different from measured, and were not biased overall or in any subgroups (young nonobese or obese, older adult nonobese or obese).70,71 The Mifflin equations themselves are supported by considerable evidence and widely used; however, in the critically ill population, the equations lack precision, have a 25% accuracy rate, and are consistently biased toward underestimating energy requirements.70-73 Harris-Benedict equations are widely used in the original form and various permutations; however, they are not recommended for use in critical care.73 Because of inaccuracies in the older adult group with obesity using almost all predictive equations, modified Penn State equations were developed for this population.74 Table 4.2 summarizes guideline recommendations for calorie goals and predictive equations commonly in use or designed specifically to estimate the resting energy expenditure for critically ill patients.32,33,34,37,68,69,72,74-79 The question of how much to feed the critically ill patient is not

answered by determining energy expenditure. The effect of underfeeding versus full feeding on outcomes remains an area of investigation and ongoing discussion. Major guidelines do not agree on the best strategy, especially regarding the dose for PN, as shown in Table 4.3.32-34,37,68,69 As with the timing of nutrition support, the answer may depend on many factors, including the route of nutrition support and patient characteristics. The Canadian Clinical Practice Guidelines show the progression in recommendations for underfeeding versus full feeding as well as some of the uncertainties in definitions and need for clarifications. When the initial Canadian Clinical Practice Guidelines were developed, data were insufficient to make a recommendation on achieving the target dose of EN except in patients with severe head injuries, where one trial indicated less infections and more rapid recovery but no difference in mortality when closer to goal calories and protein were fed.33 At the same time, the guidelines indicated that hypocaloric PN should be considered in specific patients, but there was no consensus on the definition of hypocaloric because of the inconsistency among studies. By the 2009 Canadian Clinical Practice Guidelines, the recommendation for EN implied that the target dose of EN should be considered for all critically ill patients rather than any specific subgroup.68 Starting in 2013, patients with acute lung injury (ALI) were identified as a group in whom trophic feeds should not be considered.37,69 Guidelines have not changed regarding hypocaloric PN since the 2007 clarification regarding insufficient data in specific populations (malnourished, obese patients, PN more than 10 days).37,68,69 Studies evaluating hypocaloric feeding versus full nutrition have produced varied results. Hypocaloric feeding is not a standardized term with a defined caloric intake but varies from study to study and encompasses other terms used to categorize the degree of underfeeding. Trickle feeding is often defined by a rate of 10 or 15 mL per hour and trophic feeding as 25% or less of estimated requirements. These feeding amounts are intended to maintain gut integrity. The term permissive underfeeding is sometimes used to

signify about one-half of estimated requirements with a range of onethird to two-thirds of requirements typically used. Table 4.4 summarizes studies evaluating hypocaloric feeding versus goal or full feeding published after the guidelines from SCCM/ASPEN, ESPEN, and the Canadian Clinical Practice Guidelines committee in 2009.32,34,41,68,80-89 Interpretation and comparison of these studies is difficult because of differences in patient populations and nutrient provision. Inadequate differences between underfeeding and full feeding may confound the results in some studies (e.g., 59% vs. 71% of goal calories).87 Severity of illness appeared to vary between studies when assessing several parameters, such as the percentage of patients with sepsis enrolled, time on the ventilator, and average ICU LOS. In several studies, the average age was in the low to mid-50s range, a relatively young critically ill population, whereas the average age was in the lower 60s for other studies. Nutritional status was not always clarified or considered for study enrollment; thus, it is unclear whether patients at lower nutritional risk may have skewed results in some studies. Most studies included BMI when comparing patient characteristics, which provides some indication of adequate calorie stores. The BMI could also signal the likelihood of response to varied nutrient provision. In an observational cohort study including 167 ICUs and 2,772 patients, mortality was unaffected by increased calorie provision in patients with a BMI of 25 kg/m2 to less than 35 kg/m2, whereas mortality was lower with increased calories on either side of this BMI range.90 Two studies with lower average BMI (26–28 kg/m2) and higher average age (61–63 years) showed a benefit to increased calorie and protein provision.41,82 However, in a study comparing early EN alone with the addition of either early or late PN, the early EN plus early PN group had a low BMI (24.5 kg/m2) and average age of 62.3 years versus 27.2 kg/m2 and 58.4 years for the group receiving early EN alone.63 The early EN plus early PN group received the most adequate calories (81.2% of goal) and protein (80.1%) but had worse outcomes than the early EN alone group, where calorie and protein provision were considerably less (63.4% and 59.3%, respectively). The percentage of patients in either group with a respiratory diagnosis or sepsis (33.2% and 9.3% EN;

28.2% and 3.7% EN plus early PN, respectively) at ICU admission was much lower than in the study by Elke et al., where all patients had either sepsis (45%) or pneumonia (55%).41,63 Two striking features when evaluating studies comparing underfeeding with full feeding are the nutrition goals and the actual nutrition provided with full feeding. Caloric goals are determined by various methods in the studies; none of the studies uses indirect calorimetry exclusively; some studies use methods with poor performance in critically ill patients, such as Harris-Benedict equations. This raises the question of whether appropriate calorie goals were established. Most studies were conducted during the acute phase of illness when exogenous calorie requirements are lower because of endogenous glucose production, which again raises the question of appropriate calorie goals. With calorie goals set at 30 calories per kilogram per day, or 25–30 nonprotein calories per kilogram per day, it is probable that full feeding was actually overfeeding and may have contributed to worse outcomes.84,85

Table 4.2 Guidelines and Predictive Equations for Determining Energy Expenditure in Critically Ill Patients

Critical Care Source SCCM/ASPEN Guidelines

Subgroup Critically ill patients

Grade or Accuracy Recommended Calorie Goal EN: Calculate energy requirements using indirect calorimetry, published predictive equations, or simplistic formulas ( 25-30 kcal/ kg/day). For individual patients, predictive equations are less accurate than indirect calorimetry

and Errors1

Overall Biasb

Specific Biasb

Grade E

PN: 80% of calculated energy requirement After patient stabilizes, increase to meet energy requirement

Grade C Grade E

SCCM/ ASPEN Guidelines

Patients with obesity ( BMI 2= 30 kg/m2)

EN and PN: Do not exceed 60%-70% of goal kcal or 11-14 kcal /

Grade D

kg actual BW/ day or

22-25 kcal/kg IBW/day Canadian Clinical Practice Guidelines

Critically ill patients

No recommendation is made for calorie goals or the use of indirect calorimetry vs. predictive equations because of insufficient evidence

ESPEN

Patients in acuteor initial phase of illness

EN: No more than 20-25 kcal /kg BW/day

Patients in recovery ( anabolic) phase of illness

ENorPN:

ESPEN

Se verely undemourished patients

EN: Up to 25-30 kcal/kg BW/day

Grade C

American College of Chest

Critically ill patients

25 kcal/kg usual BW/day

35% overall accuracy; range 12% in older adult obese to 50 % in older adult nonobese

ESPEN

PN: 25 kcal/kg BW/day when indirect calorimetry is not available

Grade C

Grade C Grade C

25-30 kcal/ kg BW /day

Physicians (ACCP)

Over-estimate

Over-estimates in othergroups ( young obese, older adult obese ornonobese)

Consensus statement

Errors: 51%, highest in older adult obese (78%) Penn State equations, original Harris-Benedict equations modified with addition of Tmaxand Vefactors plus a new constant

Penn State equations, modified

Ventilated patients, mixed ICU population; developed from 169 patients

Ventilated patients

Mifflin St. Jeor equations modified by addition of Tmax and Ve factors plus a new constant Penn State equations, modified for obesity and age

Men: (13.75 ( Wt) + 5 (Ht) - 6.8 ( A ) + 66] (0.85) + [175 ( Tmax) + 33 ( Ve) ] - 6344 Women: [9.6 ( Wt) + 1.8 (Ht) - 4.7 (A ) + 655] ( 0.85) + [175 ( Tmax) + 33 ( Ve) ] - 6344

Men: [10 ( Wt) + 625 (Ht) - 5 ( A) + 5 ] ( 0.96) + [167 ( Tmax) + 31( Ve) ] - 6212 Women: [10 ( Wt) + 625 (Ht) - 5 ( A ) - 161] ( 0.96) + [167 ( Tmax) + 31( Ve ) ] - 6212

Ventilated, 51patients with BMI 30 kg/m2 and age 60 yr

Men: [10 ( Wt) + 625 (Ht) - 5 ( A) + 5] (0.71) + [85 (Tmax) + 64 ( Ve)] - 3085 Women: [10 ( Wt) + 625 (Ht) - 5 ( A ) - 161] ( 0.71) + [85 ( Tmax) + 64 ( Ve)] - 3085

64% overall accuracy; range 46% in older adult obese to 77 % in older adult nonobese

Not biased

Errors: 19%, highest in older adult obese (33%)

74% accuracy in obese older adult

Not biased in obese,

young, and older adult or nonobese older adult

Errors: 20%, highest in older adult obese (37%) 67% overall accuracy; range 53% older adult obese to 77% older adult nonobese

Under-estimates in young nonobese

Under-estimates in young nonobese Not biased

Not biased in anygroup ( young, older adult, obese, nonobese )

Ireton- Jones

Spontaneous breathing, acutely ill patients; developed from 65 patients, half being patients with burns

5 ( Wt) - 10 (A ) + 281 ( Male ) + 292 (Trauma) + 851 (Burn)

Male, trauma, and burn are replaced by 1if present, 0 if abs ent

46 % overall accuracy;range 33% young nonobese to 51% older adultobese

Not biased

Not biased in older

adultobese

Under-estimation in young obese

Errors: 39%, highest in young obese ( 58%)

Over-estimation in nonobese, young, and older adult

Swinamer

Critically ill patients, mixed medicalsurgicallCU

941(BSA ) - 6.3 (A ) + 104 (T) + 24 (RR) + 804 ( tidal volume in liters) - 4243

population; developed from 112 patients

Mifflin St. Jeor

Developed from 498 healthy people

54% overall accuracy; range 43% older adult obese to 61% young nonobese

Over-estimate

Over-estimates in all groups ( young, older adult,

obese, nonobese)

Errors: 30%, highest in older adult obese (47%)

Men:10 (Wt) + 6.25 (Ht) - 5 ( A) + 5 Women: 10 ( Wt) + 6.25 (Ht) - 5 (A ) - 161

25% overall accuracy; range 21% young obese and older adult nonobese to 35% older

Under-estimate

Under-estimates in all groups

Not biased

Over-estimates in obese, young, and older adult

adultobese Errors: 60%, highest in nonobese, young, and older adult ( 67%)

Brandi

Critically ill trauma patients; developed from 26 patients

Modified Harris-Benedict equations withaddition ofHRand Ve factors plus

Men: [13.75 ( Wt ) + 5 (Ht ) - 6.8 ( A) + 66 ](0.96) + [7 (HR) + 48 ( Ve) ] - 702

Women: [ 9.6 ( Wt) + 1.8 (Ht) - 4.7 ( A) + 655] ( 0.96) + [7 ( HR) + 48 ( Ve) ] - 702

Not biased in nonobese, young, or older adult

Errors: 33%, highest in older adult obese ( 51%)

anewconstant

Faisy

55% overall accuracy; range 41% older adult obese to 61% nonobese, older adult, andyoung

Critically ill medical patients; developed from 70 patients

8 ( Wt) + 14 (Ht ) + 32 ( Ve) + 94 (T) - 4834

53% overall accuracy; range 37% older adult nonobese to 72% young obese

Errors: 36%, highest in older adult nonobese (56%)

Not biased

Over-estimates in older adult, obese and nonobese

Not biased in young, obese, ornonobese

aGrade

is based on the level of evidence as described in McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr 2009;33:277-316; and Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 2013;39:165-228. Accuracy based on percentage of calculated energy expenditure estimates with 10% of measured by indirect calorimetry. Errors based on overall incidence of estimates more than 15% different between calculated and measured energy expenditure. bBias

based on difference between resting energy expenditure calculated from the equation and measured by indirect calorimetry, 95% coefficient of variation. A = age in years; BSA = body surface area in m 2; BW = body weight; HR = heart rate in beats/minute; Ht = height in cm; IC = indirect calorimetry; RR = respiratory rate in breaths/minute; T = temperature in degrees Celsius; Tmax = maximum body temperature in previous 24 hours in degrees Celsius; Wt = weight in kg; Ve = minute ventilation read from ventilator at time of measurement.

The low amount of nutrients actually provided with full feeding is alarming in some studies and raises the question of whether both groups were being underfed.41,80 A retrospective analysis of prospectively collected data for 475 patients requiring mechanical ventilation indicated that almost 40% of patients received no more than 50% of estimated nutritional requirements during the first 8 days in the ICU, and less than 15% received 80% or more of estimated requirements.81 In a study with 523 patients analyzing data for up to 7 days in the ICU, almost 33% of the patients received less than 33% of estimated requirements, and 67% received no more than 65%.89 Protein delivery, when evaluated, also tends to be poor; average protein intake of 0.7 g/kg/day has been reported.41,80 This is less than the 0.8 g/kg/day recommended for healthy adults and may be a contributing factor to poor outcomes.82,91 However, a 12-month followup of 510 surviving patients from the EDEN study found no difference in functional status for those receiving trophic feeding versus those receiving full feeding.85,92 All survivors showed significant impairments in physical, cognitive, and psychosocial functioning compared with population norms matched for age and sex; the physical function score at 12 months was 55 compared with 82 (p 10 days

2013: Same as 2009 with the addition of patients with acute lung injury should NOT be considered for trophic feeds ESPEN34,36

100% measured or estimated calories

100% measured or estimated calories

Poor performance in meeting nutritional goals with EN alone resulted in attempts to meet nutritional goals by adding supplemental PN when EN alone was inadequate. As reviewed earlier in this chapter, the benefit of added PN versus the risks does not have a definitive answer. It is unclear whether adding PN has adverse effects that counter the positive effects of more adequate nutrition in some patients but not others. There is almost certainly a complex interplay between several factors that determines which patients benefit from increased calorie provision and which do not. Unfortunately, available data are insufficient to devise a predictive algorithm or equation to assist the practitioner in identifying the patients who will benefit from aggressive nutrition.

NUTRITION SUPPORT—MICRONUTRIENTS Vitamins and Trace Elements There are no current guidelines for vitamin or mineral requirements in critically ill patients. Although evidence suggests that some vitamins

and minerals have increased requirements in critical illness because of increased metabolic demands, evidence is lacking to suggest that vitamins and minerals should be supplemented above physiologic amounts in critically ill patients. Enteral formulas supply the dietary reference intakes (DRIs), which includes recommended dietary allowances (RDAs) where these have been determined, at a certain volume, typically 1,000 mL.91 The DRI/RDA applies only to oral or enteral vitamins and minerals. If less than this amount is delivered to a patient daily, the patient will require additional vitamin and mineral supplementation. The parenteral multivitamins that are available in the United States provide fat-soluble vitamins at about the same dose as the DRI/RDA, even though there is a difference in oral and parenteral bio-availability. Water-soluble vitamins are provided at about 2.5–5 times the RDA in these multivitamin products. These doses have been used for 3 decades without reports of toxicity and allow for adequate dosing despite limited stability of some vitamins in PN. The increased doses provided parenterally will be enough to replete deficiencies or accommodate increased metabolic demands.93 Vitamin D Vitamin D deficiency is an emerging area of research in the ICU. Observational studies of non-ICU patients suggest that vitamin D has pleiotropic effects; hypovitaminosis D is implicated in musculoskeletal disorders, falls, altered immunity, infections, glucose intolerance, and cardiovascular disease.94 Serum 25-hydroxyvitamin D (25(OH)D) is typically ordered to assess vitamin D status, although specific guidelines for monitoring are still controversial. Although some sources recommend thresholds for vitamin D deficiency and insufficiency as less than 50 and 75 nmol/L, respectively,94 the IOM defines vitamin D deficiency and insufficiency as 30 and 50 nmol/L, respectively.95 The difficulty in monitoring vitamin D status during critical illness is caused by the effect of the systemic inflammatory response on serum or plasma concentrations. A prospective study from 2012 evaluated baseline vitamin D concentrations and followed subsequent daily vitamin D concentrations through 10 days after ICU admission. The

authors found that baseline levels decreased 3 days after admission and remained low while patients were in the ICU.96 Index of suspicion for deficiency is likely as good as 25(OH)D serum concentrations and more cost-effective when determining the need for supplemental vitamin D in critically ill patients.

Table 4.4 Studies Published After 2009 Comparing Underfeeding with Full Feeding

Study PERMIT trial80 Permissive underfeeding or standard EN with same protein

Study Design RCT, non-blinded with data collection up to 14 days;

seven centers enrolled patients

Patient Population 894 patients, 75% medicaland 21% nonoperative trauma admissions, 35% severe sepsis

Feeding Characteristics Permissive underfeeding: avcragcd 46 % of calculated requirements Standard EN averaged 71% of goal calories

Similar protein intakefor both groups ( averaged 0.7 g /kg/day)

Outcomes No difference in 90-day all -cause mortality, ICU or hospital LOS, or nosocomial ICU infect ions

There was no difference in diarrhea or feeding intolerance

Meanage 51 yr. BMIabout 29 kg/m2

Weietal

“

Nutritional adequacy and long- term outcomes

Retrospective analysis of prospectively collected data, observational cohort study; multicenter

475 patients on MV > 8 days and hå ving at least two organ failures

Low ( < 50%) or moderate (50 % to < 80%) nutritional adequacy vs. close to goal (80 % to < 110%)

Higher mortality at 6 mo with low (HR 1.7; 95% Cl,1.1-2.6) and moderate (HR 1.3; 95% Cl, 0.7-23) vs. near-goal nutrition Improved function at 3 mo with each 25% increase in nutritional adequacy but no longer significant at 6 mo

Mean age 62 yr, BMI 30 kg /m2

Yeh et al.82

Prospective observational cohort study; single center

213 patients, surgical ICU receiving EN > 72 hr; data collected up to 14 days

Adequate nutrition may getyouhome

Mean age 63 yr ; BMI 26.5 kg/m2

Categorized by cumulative nutrient deficit in the ICU:

Low if < 6,000 calories or < 300 g of protein (averaged 80% of goal calories and protein )

More ventilator-free days, lower ICU and hospital LOS, and lower hospital and 30 -day mortality in low deficit group (i.e., more adequate nutrition). Discharge home was more likely in the low deficit group

High if 6,000 calories or 300 g of protein (averaged 54% and 60% of goal calories and protein, respectively)

Goals set using actual body weight ( IBW when BMI was > 30 kg/m2); 25-30 calories/kg/ day and protein 13-2 g/kg /day

Eike et al.41 Close to goal calorie and protein by EN

Secondary analysis of pooled data, collected prospectively from international nutrition studies for up to 12 days (351 ICUs )

2,270 patients, MV with diagnosis of sepsis (45%) or pneumonia (55%)

ENwasreceived Mean age 61.7 yr; BMI 27.6 kg/m2

Nicolo et al.®

Clinical outcomes related to protein delivery

Retrospective analysis of data from an international pragmatic observational study

2,828 patients in the 4-day analysis;1,584 in the 12-day analysis

Mean age 60 yr, BMI 27 kg/m2

INTACT study84

Prospective RCT; single center

Goal calories set by each site,most commonly with weight-based calculation ( 53.7%), rarely with IC (0.6%); overall 61% of prescribed

78 patients, medical and surgical ICU; ALI diagnosis

Mean calories 14.5 calories /kg /day; mean protein intake 0.7 g/kg /day

Goal calories and protein set by each site Mean energy in 4-day group was 1,100 calories ( 64% of goal) and protein 51 g ( 61% of goal);1,200 calories (70.7% of goal) and 57 g ( 66.7% of goal) for the 12-day group

Intensive therapy provided 84.7% of estimated energy requirements vs. 55.4% for standard therapy

Intensive medical nutrition therapy vs. standard nutrition therapy

Mean age 52-59 yr; BMI about 30 kg/m2

Goal calories set at 30 calories /kg admission weight or adjusted for obesity. The overall percentage of calories from PN was < 10 % in each group

60-day mortality was decreased with each additional 1,000 calories /day ( OR 0.61; 95% Cl, 0.48-0.77, pMIC for 100% of the dosing interval is desirable for optimal outcome.5,7,11 These studies have also suggested that both the AUC0-24/MIC and the f T>MIC are important predictors of clinical efficacy and the risk of developing microbial resistance.5,7,8,10,11 Because patients in the ICU are often infected with serious

nosocomial pathogens that have decreased susceptibilities to antimicrobials and are prone to developing resistance with inadequate therapy, failure to properly dose antimicrobial agents predisposes patients to clinical and microbiological failure. The appropriate consideration of PD principles in the treatment of infection in critically ill patients enables clinicians to select dosing regimens that will maximize the potential effectiveness of the specific agent. However, the ability to adequately achieve desired PD targets for key parameters (Cmax/MIC, AUC0-24/MIC, and f T>MIC) is obviously highly dependent on the PK properties of the drugs and the ability to anticipate or compensate for potential PK alterations in individual patients.

PK ALTERATIONS IN CRITICAL ILLNESS Pharmacokinetic properties that should be specifically considered in critically ill patients include distribution to various tissues and fluids, and routes of metabolism and excretion.12 The ability of a drug to penetrate to the infection site in sufficient quantities to have activity against a pathogen is crucial for achieving clinical and microbiological efficacy. Although the distributional characteristics of antimicrobials are often only specifically considered in the treatment of central nervous system or bone infections, good penetration to tissues and fluids present at the infection site is a necessary consideration when selecting agents for any infection in ICU patients. Routes of drug metabolism and elimination are also important PK properties because of the prevalence of acute and chronic organ failures in most critically ill populations. Antimicrobials are not titrated to a desired response in the same way as sedatives, analgesics, and vasopressors, and there is often a prolonged lag time between initiation of an antimicrobial regimen and occurrence of an observable or measurable response to therapy. Practitioners must therefore be familiar with the PK properties of commonly used antimicrobials as well as sources of potential PK alterations in order to use them in an efficacious and safe manner.12 Several studies have shown that the PK of antimicrobials is often significantly altered in critical illness and that a high degree of

interpatient (and also intrapatient) variability exists in this population.1320 Alterations to the PK properties of antimicrobials in critically ill patients are driven by both drug- and disease-related factors. Physicochemical properties of the molecule such as hydrophilicity and lipophilicity, molecular weight, and protein binding will influence the types of PK alterations that may be seen in the presence of pathophysiological changes in critically ill patients. Table 12.1 summarizes the relationship between hydrophilicity and lipophilicity and general PK characteristics of commonly used antimicrobials. Although the relative hydrophilicity and lipophilicity of drugs is an often imprecise predictor of PK characteristics, such information is readily available to clinicians and does offer a useful starting point for predicting the significance of potential PK alterations within individual patients.

Changes in Drug Absorption Although oral administration of antimicrobials is not as common as intravenous administration in critically ill patients, factors that may affect the absorption of orally administered drugs are nevertheless worth discussing. The rate and extent of drug absorption after oral administration is dependent on several physiochemical properties of the drug, including molecular weight; solubility in aqueous fluids; relative lipophilicity, which will govern the ability of the drug to cross membranes of the gastrointestinal (GI) tract; net ionization state of the drug; and chemical stability of the drug at pHs found in the GI tract. Physiological factors affecting drug absorption from the GI tract include pH, blood flow to organs and tissues of the GI tract, surface area of membranes across which the drug is absorbed, and GI motility. Because many of these physiological factors are disrupted during critical illness, especially early in ICU stays when patients are not yet stable, both the rate and the extent (bioavailability) of absorption of orally administered drugs may be significantly and adversely altered. Perfusion abnormalities in patients with shock states are associated with redistribution and shunting of blood to more vital organs at the frequent expense of the GI tract. The use of vasoactive drugs often results in further reductions in regional blood flow to abdominal

organs.21 This decreased perfusion of the GI tract and the attendant dysfunction adversely affect the absorption of drugs in shock states.22 In addition to hypoperfusion of the gut, the use of opiates in patients requiring analgesia may contribute to decreased GI motility and impaired oral absorption.23,24 Finally, patients in an unfed state (i.e., not receiving enterally administered nutrition) have been shown to rapidly develop intestinal atrophy, loss of intestinal surface area, and impaired cellular function.25,26 In light of these many causes of GI dysfunction and impaired absorption, intravenous administration is often the preferred route of drug administration in critically ill patients. This is particularly true for antimicrobials in patients with severe infections where rapid, more reliable achievement of therapeutic drug concentrations is required.

Changes in Volume of Distribution at Steady State The volume of distribution at steady state (Vss) of an antimicrobial can be mathematically expressed as C0 = dose/Vss, where C0 is the initial concentration of a drug after administration of an intravenous bolus dose and Vss is the volume of distribution. Distribution of drugs throughout various fluids and tissues is dependent on several factors including blood flow, lipid solubility of the drug, degree of protein binding, permeability of the tissues, and pH of the fluid or tissue in relation to the net ionization state of the drug. Drugs with relatively small Vss values (less than 0.1–0.8 L/kg) are assumed to have low passive diffusion through plasma membranes and to be primarily distributed into body water, particularly intravascular and interstitial fluids. Drugs with larger Vss values (greater than 0.8 L/kg) are assumed to more freely diffuse through cell membranes and to achieve relatively greater penetration into and concentration within tissues, including adipose tissue. During critical illness, many factors related to disease states or therapeutic interventions can alter drug distribution. Distribution of antimicrobials to infected tissues may also be affected by hemodynamic instability and regional or local changes in perfusion of various organs and tissues. Hepatic disease, renal disease or injury,

administration of large volumes of fluid such as during resuscitation regimens, and malnutrition are examples of factors that may lead to the increased Vss values of hydrophilic drugs through increased total body water and increased intravascular and interstitial fluid volumes (Table 12.2). Infections themselves are also often associated with altered Vss values. Microbial endotoxins and proteins may stimulate the production of proinflammatory mediators that may affect the vascular endothelium, resulting in vasoconstriction or vasodilatation with maldistribution of blood flow, endothelial damage, increased capillary permeability, and decreased plasma oncotic pressure.27-29 The resulting capillary leak syndrome results in fluid shifts from the intravascular compartment to the interstitial space and other anatomical spaces (i.e., third spacing)30,31; this in turn has the potential to increase the Vss of hydrophilic drugs and decrease tissue and plasma drug concentrations. The Vss of hydrophilic drugs may also be increased by the presence of other proinflammatory states such as trauma, burn injuries, mediastinitis, peritonitis, and mechanical ventilation.13-17,19,20,32-34 Such shifts in body fluid as described previously have been implicated as a major cause of alterations in Vss in critical illness. Aggressive administration of crystalloids or colloids to maintain intravascular volumes in patients with sepsis, trauma, or burns also contributes to significant third spacing and alterations in Vss. Fluid collections such as pleural effusions, ascites, peritoneal exudates, mediastinitis, and edema serve as additional reservoirs where hydrophilic drugs such as the aminoglycosides and β-lactams may be distributed, further increasing their Vss.13,14,16,32,35-47

Table 12.1 Relationship Between Hydrophilicity and Lipophilicity of Antimicrobials and Potential for PK Alterations in Critically Ill Patients Hydrophilic Drugs Example

Penicillins

Lipophilic Drugs (Fluoroquinolones)a

antimicrobials

General PK characteristics

Cephalosporins Carbapenems Monobactams (Fluoroquinolones)a Aminoglycosides Vancomycin Daptomycin Linezolid Colistin Fluconazole Acyclovir Low Vss (≤ 0.8 L/kg) Low degree of intracellular penetration, primarily distributed to intravascular, interstitial, and other extracellular fluids Primarily eliminated through renal clearance of unmetabolized drug

Potential PK alterations in critically ill patients

Potential for highly variable PK disposition: ↑↑ Vss associated with many factors ↑ or ↓ clearance depending on renal function, presence of ARC, other factors ↓ Protein binding in many patients, may affect both Vss and clearance ↑ or ↓ T1/2 depending on relative changes in Vss and clearance

General dosing considerations in critically ill patients

Macrolides Clindamycin Tigecycline Rifampin Voriconazole Posaconazole Itraconazole Amphotericin B

Higher Vss (> 0.8 L/kg) Higher degree of intracellular penetration, distributed into adipose tissues Primarily eliminated through hepatic metabolism and clearance followed by renal elimination of metabolites Usually less variability in PK disposition: ↔/↑ Vss, largely unchanged for most drugs ↑ or ↓ clearance depending on hepatic function ↓ Protein binding in many patients, not usually clinically relevant ↔/↑ t1/2 depending primarily on changes in clearance

↑ Dose may be required for loading doses, intermittent doses of concentrationdependent drugs

↑ Doses may be required in obesity; otherwise, loading and intermittent doses not usually affected

↑ or ↓ in total daily doses may be required depending on net

↑ or ↓ in total daily doses may be required depending on

changes in clearance, t1/2

net changes in clearance, t1/2

aFluoroquinolones

do not clearly fit into one specific category as being either hydrophilic or lipophilic. Fluoroquinolones are zwitterionic compounds; although often characterized as hydrophilic, they also have PK characteristics of more lipophilic compounds. ARC = augmented renal clearance; PK = pharmacokinetic; t1/2 = half-life; Vss = volume of distribution at steady state.

Decreased plasma albumin concentrations occur commonly in a wide variety of critically ill patients. Hypoalbuminemia may be the result of capillary leak syndrome, fluid overload, malnutrition, or hypercatabolic states.13 Reductions in plasma oncotic pressure as a result of hypoalbuminemia may result in increased fluid extravasation and third spacing, which in turn contributes to increased Vss for hydrophilic antimicrobials. Protein binding of antimicrobials that bind primarily to albumin may also be significantly altered. In the setting of hypoalbuminemia, drugs that are normally highly bound to albumin have increased proportions of unbound drug (free fraction, or fu); this unbound drug is free to distribute to tissues to which the albumin-bound drug was not previously accessible.48,49 A notable example is ceftriaxone (95% bound to albumin), which has Vss values increased by as much as 90% in critically ill patients.49 Several drugs have been shown to have increased Vss, and sometimes increased drug clearance as well, because of altered protein binding in patients with hypoalbuminemia and increased fluid extravasation.13 Although antimicrobial fu is often increased in hypoalbuminemia, the actual unbound concentration of drug (Cu) is not necessarily increased because the reduced protein binding also causes an increased clearance of this free drug. For hydrophilic drugs, this increased clearance is often because of increased renal elimination of unbound drug through the glomerulus; any increases in Cu are thus transient as the unbound drug is rapidly eliminated. As a rule, the Vss of hydrophilic drugs is likely to be greater than

normal in critically ill patients, and peak drug concentrations are likely to be correspondingly lower after any given dose. Thus, the ability of concentration-dependent antimicrobials to meet desired PK/PD targets such as the Cmax/MIC ratio is more likely to be adversely affected by changes in Vss. Lipophilic drugs tend to be less affected by these types of changes in body water and pathophysiological changes. However, changes in Vss are highly variable and may actually be decreased in certain patients. In addition, fluid shifts alone do not completely explain changes in antimicrobial Vss because other factors (e.g., protein binding) may also be responsible for Vss alterations in critically ill patients. Obesity represents a major challenge for accurate drug dosing in the critically ill. The clinical significance of obesity in the dosing of antimicrobials is represented by data suggesting associations between obesity and subtherapeutic antibiotic concentrations or antibiotic treatment failure.50-52 Because data are currently sparse, particularly in the critical care setting, it is difficult to make specific recommendations regarding the dosing of most antimicrobials in obesity. Obesity is known to increase the Vss of both hydrophilic and lipophilic drugs and may also be associated with increased clearance of certain drugs, particularly through enhanced clearance mechanisms.53,54 The presence of obesity should be carefully evaluated in formulating antimicrobial dosing recommendations and potential PK changes accounted for as appropriate. Although beyond the scope of this chapter, useful recommendations for dosing of antimicrobials in obesity have been published elsewhere.55-57

Changes in Drug Clearance Clearance, generally described as the intrinsic ability of the body to remove drug, is also significantly affected by the many disease processes that occur in critically ill patients. Although metabolism and excretion are two separate processes in a strictly PK sense, with respect to PK alterations in the critically ill, it is most useful to consider these processes together. Lipophilic drugs usually undergo clearance through hepatic metabolism followed by excretion of inactive

metabolites through urine, bile, or feces. Although the formation of active metabolites through hepatic metabolic pathways is common for other classes of drugs, it is unusual and largely insignificant for most antimicrobials. Hydrophilic drugs, in contrast, do not usually undergo significant metabolism and are largely eliminated through renal excretion, with the kidneys serving as the organ of clearance. Changes in drug clearance are therefore usually because of either alterations in hepatic metabolism or alterations in renal function, or both.

Table 12.2 Selected Clinical Factors Associated with Alterations in Antimicrobial Pharmacokinetics in Critically Ill Patients

Increased

Absorption

Decreased

Shock states Vasopressors

Lack of enteral nutrition Drugs that decrease Gl motility ( e.g., opiates)

Volume of distribution

Hydrophilic drugs

Acid-base disturbances

Dehydration

Aggressive volume resuscitation

Ascites Cachexia, muscle mass depletion

Capillaryleaksyndromes Chronic fluid overload Edema

Heart failure Hypoalbuminemia Large TBSA burn injury

Large pleural effusions

Malnutrition Mechanical ventilation Mediastinitis Peritonitis, peritoneal exudates Thirdspacing Trauma

Clearance

Lipophilic drugs

Obesity

Renally eliminated drugs

Augmented renal clearance

Hepatic disease or injury

Burn injuries (> 30%-40% TBSA )

Hemodynamic instability or failure

Hypoalbuminemia

Protein malnutrition

Postsurgical drains with high drainage volumes

Renal disease or injury

Vasopressors1

Sepsis Shock states

Vasopressors1 Hepatically eliminated drugs

Drug-drug interactions ( e.g., hepatic enzyme inducers )

Drug- drug interactions ( e.g., hepatic enzyme inhibitors )

Vasopressors1

Hepatic disease or injury Sepsis Shock states Vasopressors1

Protein binding

Burn injury Trauma

Hepatic disease Hypoalbuminemia

Malnutrition

aEffects

are dependent on net effects on renal and hepatic perfusion.

TBSA = total body surface area.

Hepatic Metabolism and Hepatic Drug Clearance Hepatic metabolism of drugs is primarily dependent on three separate physiological processes: hepatic blood flow, intrinsic activity of metabolic enzymes, and protein binding of drugs. Models of hepatic drug metabolism include an important factor, the hepatic extraction ratio (EH), which generally describes the efficiency with which a particular drug is removed (i.e., cleared) from the blood during a single pass through the liver. Although detailed descriptions of hepatic extraction ratios are beyond the scope of this chapter, it is important to recognize that drugs may be broadly classified on the basis of their hepatic metabolism as either high extraction ratio or low extraction ratio. Drugs classified as high extraction ratio (EH greater than 0.70) are metabolized by the liver with very high efficiency; their rate of metabolism and thus of drug clearance will be highly dependent on hepatic blood flow. Relatively minor changes in intrinsic enzyme activity (e.g., drug interactions involving weak to moderate inhibition of hepatic enzymes and protein binding alterations) are unlikely to cause significant changes in hepatic clearance. In contrast, the hepatic metabolism and clearance of low extraction ratio drugs (EH less than 0.30) will be highly dependent on both protein binding and the intrinsic activity of specific enzymes involved in the metabolism of those drugs. Given known or predicted changes in blood flow, intrinsic enzyme activity, and/or protein binding in a critically ill patient, characterizing a particular drug as either high or low EH is useful in predicting corresponding alterations in drug metabolism, clearance, and potential need for changes in dosing regimens. Alterations in blood flow to the liver may commonly be seen in critically ill patients. Conditions in which significantly reduced hepatic perfusion may occur include severe sepsis and septic shock in which organ malperfusion is present, other shock states (hemorrhagic, hypovolemic, cardiogenic, anaphylactic), myocardial infarction, acute heart failure, thrombotic disorders involving the hepatic circulation, and therapeutic hypothermia. All of these various disorders are potentially associated with reduced clearance of drugs.58,59 Mechanical ventilation with or without the administration of PEEP (positive end-expiratory

pressure) has also been associated with decreased hepatic perfusion,60 as well as the administration of α-adrenergic agents such as epinephrine, norepinephrine, phenylephrine, vasopressin, and highdose dopamine.61-63 Conversely, inotropic agents such as dobutamine and dopamine and vasodilators such as nitroglycerin may increase hepatic perfusion through improved hemodynamics and increasing cardiac output. Regarding the intrinsic activity of metabolic enzymes, the induction or suppression of the metabolizing enzymes by disease state–related mechanisms or drug-drug interactions may also have significant effects on drug metabolism. Several mediators commonly present in critically ill patients have been associated with significant inhibition of both phase I oxidative metabolism involving the cytochrome P450 (CYP) system and phase II conjugative metabolism, which includes acetylation, glucuronidation, and sulfation pathways. These inhibitory mediators include stress hormones such as cortisol, epinephrine, and norepinephrine and proinflamma-tory cytokines including interleukin-1b, interleukin-6, and tumor necrosis factor-α.58,64 Conversely, hepatic metabolism has been shown to increase for selected medications in patients with traumatic brain injury. Both phase I and phase II metabolism has been shown to be increased in this population, raising the potential for subtherapeutic concentrations of drugs that are dependent on these metabolic pathways.65 Nutritional supplementation with increased amounts of dietary protein has also been shown to increase hepatic metabolism and drug clearance.66 Alterations in protein binding may have important effects on the hepatic metabolism of low extraction ratio drugs. Critically ill patients commonly have alterations in plasma proteins as a result of physiological stress, including decreased concentrations of plasma albumin and increased concentrations of α1-acid glycoprotein (AAG). Albumin concentrations are often decreased in response to hepatic processes and catabolic states, whereas AAG concentrations are known to increase in many inflammatory processes such as severe thermal injuries. Albumin binds acidic drugs, and decreased albumin concentrations potentially result in increased fu, whereas increased

concentrations of AAG result in decreased fu of basic drugs. Such changes in protein binding tend to produce temporary, offsetting changes in hepatic metabolism so that the net changes in free drug concentrations are minimal. The activity of CYP may be unchanged, increased, or decreased because of hepatocellular loss, enzyme induction, or inhibition. The net effect of these many changes in protein binding, hepatic blood flow, effects of critical illness, or drug-drug interactions on liver function and drug clearance is extremely complex and difficult to predict in the clinical setting. Fortunately, the overall number of agents for which protein-binding alterations significantly affect drug exposure has been proposed to be relatively limited.67 In addition, for most antimicrobials, hepatic metabolism is limited, and protein binding is low enough to make little difference to their effectiveness. Specific antimicrobials for which lowering of doses in patients with severe hepatic disease would be advisable include clindamycin, metronidazole, nafcillin, erythromycin, and certain antifungals such as voriconazole, posaconazole, and the echinocandins. Renal Clearance of Drugs Renal elimination of parent drugs or their metabolites is the primary route of excretion for most pharmacologic agents, including most antimicrobial agents (Table 12.3). In critically ill patients, renal failure may occur because of several pathophysiological processes including severe sepsis and septic shock, multiple organ failure syndrome, extensive burns, trauma, hypovolemic shock, heart failure, and cardiogenic shock.13 Acute kidney injury may also be caused by drug toxicities as well as therapeutic use of vasopressors, which may cause reduced renal blood flow and decreased renal clearance of drugs.39 Because preexisting renal impairment related to underlying illnesses and acute kidney injury are common among critically ill patients of all types, decreased clearance of renally eliminated drugs is of major importance in the ICU setting. Severe renal impairment requiring renal replacement therapy is also common and presents special challenges to clinicians related to appropriate drug dosing. Although methods for

assessing renal function such as the Cockcroft-Gault (CG) and MDRD (Modified Diet in Renal Disease) equations are commonly used in the ICU because they are familiar to clinicians and simple,68,69 it must be remembered that they are also known to be relatively inaccurate in critically ill patients and do not always provide reliable measures of drug clearance.70-76

Table 12.3 Selected Pharmacokinetic Parameters for Antimicrobials Commonly Used in Critically Ill Patients

Volumeof Distributionat Steady State (L /kg )

Protein Binding (% )

Metabolism?

( % as unchangeddrug)

Plasma Half -life ( hours )

Aminoglycosides ( gentamicin, tobramycin, amikacin)

0.30

< 10

None

95

2-3

Nafcillin

0.30

90

Hepatic

30

0.5-1

Piperacillin

0.25

26

Moderate hepatic

50-70

0.7-1.2

Antimicrobial

Renal Clearance

Cefazolin

0.30

75-85

Minimal hepatic

> 80-90

2

Ceftriaxone

0.14

90

Moderate hepatic

60

6-9

Ceftazidime

0.25

17

None

90

1-2

Cefepime

0.30

20

Minimal

85

2

Imipenem/cilastatin

0.26

20

No hepatic

70

1

Meropenem

0.30

2

Minimal

75

1

Aztreonam

0.25

56

Minimal

60-70

1.5-2

Vancomycin

0.70

50

None

100

4-6

0.5-0.6

31

Hepatic

30

4-5

0.10

Minor

80

9-10

Biliary excretion

6

70-80

Moderate hepatic

50

3-4

Linezolid Daptomycin Azithromycin

31.1

90 30-40

Ciprofloxacin

2.1-2.7

40

Levofloxacin

1.0—1.5

30

None

60-80

6-10

Clindamyein

0.6-1.2

90

Hepatic

10

1.5-5

Metronidazole

0.80

20

Hepatic

20

8

Fluconazole

0.60

10

Minor hepatic

90

31

1.8-2.0

> 95

Minimal hepatic

3-20

100-160

0.80

> 95

Minimal hepatic

5

100-153

Amphotericin B deoxycholate

LiposomalamphotericinB Caspofungin

0.40

97

Hepatic

MIC) depends on being able to adequately estimate the PK disposition of antimicrobials in individual patients. Beyond PK considerations, the other important variable in PD targets is the pathogen MIC. As bacterial pathogens encountered in the ICU continue to become less susceptible with higher MICs,107-112 the use of aggressive initial dosing regimens becomes even more important because the selected dosing regimens have to allow for the elevated MICs as well as variability in PK parameters.107 Given the extreme variability of PK parameters such as Vss and clearance and the inability to precisely assess renal function, hepatic function, protein binding, and tissue penetration of antimicrobials in critically ill patients, clinicians should err on the side of aggressive dosing in order to avoid being too conservative with administered regimens.16,20,76,113 However, use of high doses also places patients at higher risk of drug-related adverse effects and toxicities, again partly owing to PK variability in drug Vss and clearance. Although drug dosing should be aggressive, it

must also be based on appropriate clinical considerations involving relevant issues such as appropriate PK/PD goals, careful clinical assessment for the presence of renal or hepatic dysfunction that may lead to drug accumulation, presence of obesity, the presumed infection site and the ability of the drug to achieve adequate concentrations in that site, susceptibilities of presumed or documented pathogens to the drugs in question, and potential drug toxicities. Because achieving appropriate PK/PD targets for antimicrobials is an important predictor of clinical efficacy and the risk of developing microbial resistance, clinicians must take care not to underdose antimicrobials in critically ill patients. Given the known inaccuracies in estimating creatinine clearance on the basis of serum creatinine, clinicians should not rely on estimated creatinine clearance as a sole consideration for choosing drug dosing regimens in patients with renal impairment. Apparently, “proper” dosing adjustments on the basis of estimated creatinine and published recommendations for dose adjustment (e.g., product package inserts) may effectively reduce total drug use and drug cost and potentially also reduce adverse effects of some drugs. However, given the need to achieve PD targets in the setting of variable PK parameters and difficult pathogens, even high doses of many drugs are already marginal, and alternative dosing strategies are sometimes necessary.113-117 Because serum creatinine– based methods of assessing renal function are notoriously inaccurate for predicting drug clearance in ICU patients,70-76 clinicians should not try to “fine-tune” dose adjustments because doing so may place some patients at risk of treatment failure. For example, in a severely infected patient with a creatinine clearance estimated at 48 mL/minute by the CG method, antimicrobial doses should not necessarily be reduced just because the product labeling specifies dose reduction at calculated creatinine clearances less than 50 mL/minute. Rather, clinicians must consider potential risks to the patient (drug toxicities, etc.) versus the potential benefits to be gained by administering higher doses than those recommended, at least until the patient starts having a response to antimicrobial therapy.20,116 Given the apparently high prevalence of ARC and the potential for

patients to be underdosed in this setting, clinicians should be alert to patients who fit the currently recognized risk factors for ARC (young, male, trauma, low severity of illness, etc.) and be prepared to administer higher-than-normal doses to such patients. Recognition of ARC also depends on accurate assessment of renal function. Because serum creatinine–based methods are not reliably accurate, including among patients with ARC,71 the use of timed urinary creatinine measurements should be standard practice when more accurate assessment of renal function is needed.15,84,118-120 Although timed urinary creatinine measurements are also not completely accurate, this method is generally recognized as providing somewhat more accurate estimates of GFR (glomerular filtration rate) in critically ill patients. Because U.S. Food and Drug Administration (FDA)-labeled dosing of antimicrobials does not specifically address recommended doses in patients with a creatinine clearance greater than 130–150 mL/minute and no other formal dosing recommendations exist for patients with ARC, clinicians will need to exercise their best judgment in determining appropriate doses. One recent study found that 55% of patients in a medical/surgical ICU receiving standard doses of meropenem (1 g every 8 hours) or piperacillin/tazobactam (4.5 g every 6 hours) did not meet the PK/PD targets intended to treat Pseudomonas aeruginosa infections, even when 3-hour extended infusions were used for drug administration.90 Therapeutic drug monitoring (TDM) of aminoglycosides and vancomycin is common in current practice and is considered a standard of care for patients receiving these agents. Because of the extreme PK variability of β-lactam agents in ICU patients, routine TDM has been suggested for these drugs as well.121-123 The ability to routinely measure and adjust β-lactam concentrations could be very advantageous in detecting patients with significant alterations in PK parameters and adjusting doses to more effectively meet PD targets. Unfortunately, β-lactam assays are not routinely available to most hospital laboratories or clinicians, and TDM for β-lactam antibiotics is not currently feasible. Plasma concentrations of certain antifungal agents such as voriconazole and posaconazole are also occasionally

measured, and a routine role for TDM has been advocated,124-127 but routine TDM practices for antifungal agents have not yet been established. For most antimicrobials, reliance on population PK studies and close clinical monitoring for evidence of clinical response to therapy and drug toxicities remain the only available option. In light of the many challenges in determining appropriate dosing of antimicrobials, newer dosing strategies (e.g., extended infusions for βlactams) may play an important role in optimizing drug therapy in order to more reliably meet desired PK/PD goals. Such strategies have been purposely developed and studied in order to provide more reliable and effective dosing options for treatment of difficult pathogens in severely ill patients. Critically ill patients certainly have many risk factors for poor outcomes of antimicrobial therapy, and newer dosing options as discussed in later sections of this chapter should be considered for patients in the ICU.

PD CONSIDERATIONS FOR DRUG DOSING IN THE ICU The rate and extent of the activity of an antimicrobial drug is dependent on many factors including the interaction between drug concentrations at the infection site and the MIC of the pathogen. A change in the PK properties of an antimicrobial agent may therefore affect the activity of the drug against a particular pathogen and may also affect the outcome of therapy. Conversely, developing dosing regimens that optimize the PK characteristics of the drug in relation to the MIC potentially improve clinical responses, accelerate the rate of clinical response with the potential for reducing durations of drug therapy, and minimize the risk of developing antibacterial resistance. An understanding of the PD properties of drugs, which describe the nature of such PK-MIC interactions, is necessary in order to make informed decisions regarding selection of an appropriate regimen for a given patient. Given the potential for extreme variability of antimicrobial PK properties in critically ill patients, maximizing the PD “performance” of a drug is often very challenging. However, a working knowledge of the PD relationships of various drugs as well as an understanding of critical

illness maximizes the potential for optimizing dosing regimens for individual critically ill patients. Clinicians also need to be familiar with MICs relevant to the chosen antibacterial agent for suspected or known pathogens in the ICU setting. The remainder of this chapter will review currently recommended PK/PD targets for common antimicrobials, discuss examples of clinical applications of PD principles, and describe potential limitations to the application of PK/PD in the clinical setting.

PD Goals Pharmacodynamic parameters correlating with antimicrobial efficacy have been widely published and are summarized in Table 12.4.5,7,8,117,128-135 These parameters have been determined from in vitro and in vivo studies and, for many drugs, also validated in humans through clinical data obtained either retrospectively or prospectively. It is important to recognize that these targets have sometimes been modified over time as additional studies are performed and our understanding of PK/PD relationships is increased. However, PD parameters summarized in Table 12.4 reflect our current understanding of the complex relationships governing antimicrobial actions and efficacy. Because plasma or tissue concentrations are not routinely measured for most of these agents, computer modeling techniques such as Monte Carlo simulation (MCS) form the basis for dosing recommendations that seek to maximize the attainment of PD goals in patients requiring antimicrobial therapy. Antibacterials Time-Dependent Drugs In general, the goal of a dosage regimen for a time-dependent antibiotic is to optimize the duration of drug exposure above the MIC. Although meeting a minimum effective concentration of drug is also necessary, increasing the concentration beyond 4–6 times the MIC does not appear to result in enhanced killing but may instead require

unnecessarily high doses of drug.5,7,11 Once effective concentrations have been reached, extending the time those concentrations remain above the MIC should enhance antibacterial activity and presumably efficacy as well. The f T>MIC is the PK/PD parameter considered most predictive of bactericidal activity of many time-dependent antimicrobials such as the β-lactams, although the AUC0-24/MIC is a good predictor of efficacy for some time-dependent drugs such as vancomycin and linezolid.5,7,8,11,131

Table 12.4 PD Parameters and Goal Values Correlating with Efficacy of Antimicrobial Drugs PD Characteristics

Antimicrobials

Specific PK/PD Goal

Time-dependent

Penicillins

50% fT>MIC

Cephalosporins

60%–70% fT>MIC

Monobactams

60%–70% fT>MIC

Carbapenems

40% fT>MIC

Vancomycin

AUC0-24/MIC ≥ 350–400 (TDM: trough 15–20 mg/L for severe infections)

Linezolid

> 85% fT>MIC AUC0-24/MIC > 85

Flucytosine

> 40% fT>MIC (TDM: peak < 100 mcg/mL, trough < 10–50 mcg/mL)

Concentrationdependent

Aminoglycosides

Cmax/MIC > 8–10 AUC0-24/MIC 80–125

Fluoroquinolones

Cmax/MIC > 10–12

AUC

/MIC > 125–250a 0-24

AUC Daptomycin

/MIC > 30–50b 0-24

AUC

/MICc 0-24

Tigecycline

fAUC0-24/MIC > 0.9

Colistin

AUC0-24/MIC > 60

Metronidazole

AUC0-24/MIC > 70

Fluconazole

fAUC0-24/MIC > 25 (Dose in mg/MIC >50 has also been recommended as a surrogate PK/PD indicator)

Itraconazole

fAUC0-24/MIC > 25 (TDM: trough > 1.0 mcg/mL for treatment)

Voriconazole

fAUC0-24/MIC > 25 (TDM: trough > 2 for treatment efficacy, < 5.5 mcg/mL for ↓ toxicities)

Posaconazole

fAUC0-24/MIC > 25 (TDM: trough > 0.7 mcg/mL for prophylaxis, > 1.5 mcg/mL for treatment)

Echinocandins

fAUC0-24/MIC > 10d fAUC0-24/MIC > 10e

Amphotericin B deoxycholate

aFor

gram-negative bacteria.

bFor

Streptococcus pneumoniae.

cSpecific

fCmax/MIC > 40

goal value not determined.

dFor

treatment of Candida infections.

eFor

treatment of Aspergillus infections.

AUC0-24/MIC = ratio of the 24-hour area under the serum concentration versus time curve divided by the MIC; Cmax/MIC = ratio of maximum serum concentration divided by

the MIC; fAUC0-24/MIC = ratio of the 24-hour area under the serum concentration versus time curve for unbound/free drug divided by the MIC; fCmax/MIC = ratio of maximum serum concentration of unbound/free drug divided by the MIC; fT>MIC = time during which unbound/free drug remains above the pathogen MIC; MIC = minimum inhibitory concentration; PD = pharmacodynamic; PK = pharmacokinetic; TDM = therapeutic drug monitoring.

For β-lactam antibiotics, in vitro and in vivo studies have shown that f T>MIC is the best predictor of bacterial killing and microbiological response against gram-negative bacteria.5,7,8,11 However, these studies have also shown that the specific f T>MIC target is different for the various types of β-lactam antibiotics.5,7,8,11 For penicillins, an f T>MIC of 30% produces bacteriostatic effects on bacteria, whereas a 50% f T>MIC is required for maximal bactericidal effects. Cephalosporins require somewhat greater f T>MIC than do penicillins: 35%–40% for bacteriostatic activity and 60%–70% for bactericidal effects. For bacteriostatic and bactericidal effects, the carbapenems require f T>MIC values of about 20%–30% and 40%, respectively. The AUC0-24/MIC ratio is the best PK/PD predictor of response to vancomycin therapy according to data from animal models and in vitro studies. Those studies suggest that an AUC0-24/MIC ratio of at least 350–400 is essential for a good clinical outcome.132,136-141 The current recommendations to target trough vancomycin concentrations of 15–20 mg/L for treatment of severe infections are based on the fact that these trough concentrations correlate with AUC0-24/MIC values of 350– 400 or greater in the treatment of Staphylococcus aureus infections caused by strains with MICs less than 1 mg/L.136-140 Linezolid is also a time-dependent antibiotic that has been associated with both f T>MIC and AUC0-24/MIC as the parameters that best describe its antibacterial activity.131,142 Clinical efficacy of linezolid has been correlated with an f T>MIC of 85% and greater and an AUC0131 Similar numbers have also been associated 24/MIC greater than 85. with high microbiological cure rates, which may in turn relate to reduced risk of selecting gram-positive resistance to linezolid.131

Concentration-Dependent Drugs The PD parameters associated with bactericidal effects of concentration-dependent drugs include both Cmax/MIC and AUC024/MIC ratios. Aminoglycosides and fluoroquinolones are among the antibiotics that have these PK-PD relationships. In vitro time-kill studies have shown that the rate and extent of bactericidal activity increases as antibiotic concentrations increase in relation to the bacterial MIC for these drugs.5 Bactericidal activity and clinical efficacy of the aminoglycosides have been associated with a Cmax/MIC ratio of greater than 8–10.143-146 The AUC0-24/MIC has also been studied as a determinant of clinical efficacy, and it has been suggested that this parameter is a better indicator of total aminoglycoside exposure.144,146148 Several studies have evaluated the AUC 0-24/MIC and determined that a target of 80–125 is a good predictor of bactericidal killing and antibacterial efficacy in animal models. Although the exact AUC0-24/MIC target is unknown and may in fact vary somewhat depending on bacterial organism and type of infection being treated, the range of 80– 125 seems to provide the best combination of maximizing the probability of clinical efficacy while minimizing nephrotoxicity risk.144,146148

Studies have clearly shown that the fluoroquinolones have concentration-dependent bacterial killing.148-153 Many studies, including a prospectively developed model of the PD response to levofloxacin during treatment of respiratory tract, skin, and urinary tract infections, have provided evidence that achieving a Cmax/MIC ratio of greater than 10–12 appears to be predictive of clinical drug efficacy and successful bacterial eradication.148-153 The AUC0-24/MIC has also been shown in vitro and retrospectively in vivo to be predictive of favorable clinical response and reduced development of resistance.148-153 Although the optimal AUC0-24/MIC ratio breakpoints are still unclear, favorable AUC0-24/MIC ratios appear to be 125–250 for gram-negative organisms and 30–50 for S. pneumoniae.148-153 These PD targets are generally applied to all currently used fluoroquinolones including ciprofloxacin, levofloxacin, and moxifloxacin. Whether either the

Cmax/MIC ratio or the AUC0-24/MIC ratio is superior to the other parameter and which specific ratios are most predictive of drug efficacy remain somewhat controversial; however, the strong relationships between these PD parameters and the clinical and microbiological outcomes during fluoroquinolone therapy have been well established. Daptomycin is important to note among other the other concentration-dependent drugs.154-156 Although PK/PD parameters best associated with clinical and microbiological efficacy of daptomycin have not been well established, its concentration-dependent properties serve as the basis for use of doses larger than the 4- to 6-mg/kg (depending on indication) doses currently recommended in the manufacturer’s approved labeling.157 Clinical data definitively showing improved outcomes of these higher doses (e.g., 8–12 mg/kg) are not yet available, although daptomycin has been shown to be safe and well tolerated at these doses.158,159 Antifungals Similar to antibacterial agents, antifungal drugs have different PK/PD properties in vivo. These patterns of activity may be correlated with drug dose and pathogen MIC to identify dosing strategies that maximize antifungal efficacy while reducing the risk of toxicity. Similar to antibacterial drugs, inadequate dosing of antifungals may contribute to both treatment failure and the emergence of resistance.160,161 With the increasing prevalence of non-albicans Candida spp. and their reduced susceptibility to certain antifungal agents,162 appropriate choice and dosing of antifungals is essential for optimizing clinical outcomes and minimizing resistance. Pharmacodynamic data may also be useful for predicting infection sites where antifungal drugs have a higher risk of treatment failure because of poor tissue penetration and resultant low drug concentrations. Although for many years there was a paucity of data related to antifungal PK/PD properties, these characteristics have more recently been reasonably well characterized and are increasingly recognized as

potentially important factors for drug selection in the treatment of invasive fungal infections. Although PD principles are best established for Candida bloodstream infections, PK/PD principles have more recently also been successfully applied to the treatment of molds including Aspergillus spp. Of interest, PD characteristics of antifungal agents can be described using the same PK/PD parameters as those used for antibacterial drugs: Cmax/MIC ratio, AUC0-24/MIC ratio, and T>MIC. For the antifungal agents, these parameters all seem to be best correlated with free unbound concentrations of drug;134 thus, the following terms will be used to describe the PK/PD properties of the antifungals as they relate to free drug concentrations: fCmax/MIC ratio, fAUC0-24/MIC ratio, and f T>MIC. These descriptions of antifungal PK/PD goals will of necessity be very brief, but several excellent review articles are available that provide comprehensive overviews of how antifungal PK/PD goals were derived and how they should be applied clinically.124,126,133-135,163,164 Time-Dependent Drugs Flucytosine appears to be the only antifungal agent that has timedependent antimicrobial activity in a manner similar to time-dependent antibacterials such as the β-lactams. Flucytosine has fungistatic activity against Candida spp. with 40% f T>MIC being the apparently optimal measure of drug exposure. This f T>MIC of 40% has been associated with favorable clinical outcomes in several studies.124,126,133-135,163,164 Concentration-Dependent Drugs Fluconazole and the other azole-type antifungals have concentrationdependent PD properties and are best characterized against Candida spp. by fAUC0–24/MIC. AnfAUC0–24/MIC of 25 or greater (using the Clinical and Laboratory Standards Institute [CLSI] MIC method) has been reported to maximize the efficacy of fluconazole with improved clinical outcomes shown in in vitro, in vivo, and clinical studies.124,126,133135,163,164 This same PD target of fAUC 0–24/MIC of 25 or greater

appears to also describe other azoles reasonably well; clinical trial data analyses from mucosal and systemic candidiasis have identified a similar PD target for voriconazole and itraconazole.124,126,133135,163-168 Clinical data analyses regarding PD targets in the treatment of Aspergillus spp or other invasive molds remain limited. However, in patients receiving voriconazole for invasive aspergillosis for whom drug monitoring and clinical outcome data were available, rates of clinical success and survival were significantly higher in patients who achieved serum trough concentrations of 1–2 mg/mL.169,170 Factoring in protein binding characteristics and the MIC for Aspergillus isolates, the resulting value for fAUC0–24/MIC was again around 25.169,170 In contrast to the azoles, amphotericin B deoxycholate has concentration-dependent fungicidal activity against Candida spp., and its efficacy is best correlated with an fCmax/MIC ratio of 2–4.124,126,133135,163,164 Unfortunately, few data exist for the lipid formulations of amphotericin B (LAMB). According to a study of children that included a small cohort with invasive aspergillosis, maximal antifungal efficacy of LAMB was observed with an fCmax/MIC greater than 40.171 Echinocandins also have concentration-dependent fungicidal activity against Candida spp., and both fCmax/MIC and fAUC0–24/MIC have been associated with clinical efficacy.124,126,133-135,163,164,172 Studies of both animal models and patients with invasive candidiasis have identified similar PD targets with maximal antifungal efficacy achieved at an fAUC0–24/MIC near 10. Data analyses defining PK/PD targets for treatment of invasive aspergillosis with echinocandins are few. However, one study found an fCmax/MIC ratio of 10–20 to be associated with maximal efficacy.173 Antivirals and Antiprotozoals Although antiviral agents such as acyclovir and ganciclovir are used with regularity in the ICU, the PD properties of antiviral agents are not well characterized, and no formal PK/PD-based dosing recommendations can be made. Aggressive dosing in seriously ill patients, thoughtful assessment of organ function with recommended

dosage adjustments made as appropriate, and close monitoring of patients for evidence of clinical response and drug-related toxicities continue to be the mainstays of antiviral use in the ICU. Similarly, the PDs of antiprotozoal drugs have not been well described, and no formal recommendations for use in ICU patients can be made.

CLINICAL APPLICATIONS OF PD PRINCIPLES IN THE CRITICALLY ILL Prolonged and Continuous Infusions of β-Lacam Antibiotics Optimization of drug exposure for time-dependent antibiotics such as the β-lactams requires maintaining antibiotic concentrations above the MIC for prolonged periods. With an increased understanding of PK/PD characteristics of the β-lactams, there has also come a concern that the traditional method of administering antibiotics by intermittent shortinfusion methods may not actually optimize drug use in many patients. As has been previously reviewed, significant alterations in β-lactam PK parameters may lead to significantly reduced total drug exposure in critically ill patients. Increases in Vss may reduce peak concentrations after intermittent dosing, whereas increases in clearance (as with ARC) may further significantly reduce the period during which antibiotic concentrations remain above the pathogen MIC. Intermittent dosing of β-lactams may therefore result in a concentration versus time profile that actually minimizes the chance of achieving an optimal PD profile and favorable clinical outcome, particularly in patients with potentially significant PK alterations. Intermittent dosing of β-lactams has historically produced excellent clinical efficacy in the treatment of infections caused by susceptible pathogens with very low MICs. However, as multidrug-resistant pathogens such as P. aeruginosa have become more common and even susceptible strains often have relatively high MICs (often at or near the susceptibility breakpoint), potentially suboptimal intermittent dosing of β-lactams has become of more concern.

There are several potential methods of increasing the timedependent PD exposure of β-lactams antibiotics, including increasing the daily dose using higher doses or dosing more often, administering the drug by continuous infusion, and administering the drug by prolonged infusion (or extended infusions) (i.e., increasing administration time from 0.5–1.0 hour to 3–4 hours). Administering higher daily doses by increasing dose or frequency is usually less desirable because it is more expensive, may place patients at higher risk of drug-related adverse effects and toxicities, and increases workload of hospital personnel. Moreover, from a PK/PD standpoint, using higher daily doses is inefficient because doubling the dose of βlactams leads to an increased f T>MIC of only one additional half-life (only about 1 hour for most agents).174 There has been a renewed interest in administering β-lactam antibiotics by a 24-hour continuous infusion because this represents an efficient way of optimizing the PD to achieving a 100% f T>MIC for even high-MIC pathogens while minimizing the risk of drug toxicities and using the least amount of total daily drug, drug supplies, and labor costs. Continuous infusion is also attractive for many β-lactam antibiotics because of their relatively short half-lives.174 Continuous infusions of β-lactams consistently provide better PD parameters than does intermittent dosing in less susceptible bacteria, although the method of dosing is not as critical in highly sensitive strains.106,175-180 Continuous infusions may also achieve higher tissue concentrations than intermittent dosing.105 Although administration of continuous infusions has many potential advantages, this administration strategy may not be practical in all patients. The use of continuous infusion medications generally requires a dedicated intravenous line to prevent potential incompatibilities and allow for concomitant administration of other intravenous medications. However, it is often not practical to dedicate a catheter line for an entire 24-hour period in critically ill patients who often require many other medications as well as fluids, blood products, and other reasons for intravenous access.128 In addition, given that antibiotics administered by continuous infusion are ideally best prepared once

daily and infused at room temperature over the full 24 hours, antibiotic stability may be insufficient under those conditions.128 The carbapenems in particular are relatively unstable at room temperature and may require preparation of fresh doses several times daily in order to be infused throughout the 24-hour day.181-183 Patients most likely to benefit from administration as continuous infusions are those infected with less susceptible bacteria with high MICs at or near their susceptibility breakpoints. As MICs potentially continue to increase, continuous infusion may become more beneficial because of the enhanced PD target attainment at higher MICs.128,129,174,178 However, for antibiotics with short room-temperature stability (e.g., carbapenems) or for use in critically ill patients for whom dedicated line access is not feasible, continuous infusions may not be the most viable option for antibiotic administration.128 Clinicians must also recognize that achieving the potential benefits of a continuous infusion assumes that the proper dose is being administered and that the pathogen MIC is in fact being exceeded by concentrations achieved at a given infusion rate. Use of inadequate total daily doses, particularly in the management of infections caused by pathogens with high MICs at or near the susceptibility breakpoint, has the potential for producing subtherapeutic concentrations that inconsistently (or even never) exceed the MIC and therefore could increase the risk of treatment failure. Extending β-lactam administration times over periods that are longer than intermittent infusions (0.5–1.0 hour) but shorter than 24-hour continuous infusions is another strategy that is becoming increasing popular in clinical practice, Administering β-lactams as a typically 3- to 4-hour prolonged infusion allows drug concentrations to remain in excess of the MIC for a longer period than would be possible after intermittent short infusions. This potential advantage also holds true against organisms with high MIC values where differences between prolonged infusion and intermittent infusion became more pronounced.184-186 With respect to achieving desired f T>MIC PD targets, continuous and prolonged infusion strategies often produce very similar profiles; modeling studies have generally shown little

difference between continuous infusions and prolonged infusions in achieving desired f T>MIC PD targets.184-187 Finally, use of prolonged rather than continuous infusions may help resolve issues related to drug stability and intravenous line access. Maximizing carbapenem exposure through use of prolonged infusions may allow for more aggressive dosing in patients with severe infections and/or those infected with pathogens with high MICs while still providing cost-effective therapy.128 Be-cause there appear to be few clinically relevant differences in achieving f T>MIC targets or proven clinical efficacy with prolonged infusions of carbapenems compared with continuous infusions, and because prolonged infusions avoid potential drug stability issues, it is recommended that carbapenems be administered over 3- or 4-hour infusion times.128 Likewise, prolonged and continuous infusion regimens of piperacillin/tazobactam provide similar probabilities of meeting f T>MIC targets when the same total daily doses are administered. Similar to carbapenems, administration of piperacillin/tazobactam by prolonged 4-hour infusions is recommended over continuous infusions.128,185 Of note, antibiotic therapy with continuous infusions should always be initiated with a loading dose. The ability to significantly improve the achievement of f T>MIC targets also depends on rapidly attaining steady state–like concentrations of antibiotics that are at or near desired target concentrations. Although the β-lactam antibiotics that are most likely to be administered by continuous infusion have short half-lives (about 1 hour) in patients with normal renal function, it will still require 5 hours or more to reach steady state at desired concentrations; it will take even longer in patients with reduced drug clearance and longer half-life. For this reason, as a rule, antibiotic loading doses should always be administered at the initiation of continuous infusion regimens. The β-lactam antibiotics that have been most extensively studied using alternative continuous and prolonged dosing regimens include piperacillin/tazobactam, cephalosporins (ceftazidime, cefepime), and the carbapenems (imipenem, meropenem, doripenem).11,12,187 Perhaps the most significant of the early studies of the potential benefits of

prolonged-infusion regimens was a retrospective pre-post trial evaluating implementation of prolonged-infusion piperacillin/tazobactam regimens in an academic medical center.187 Clinical outcomes achieved with piperacillin/tazobactam 3.375 g administered as standard infusions every 4 or 6 hours were compared with those obtained after switching to 3.375 g every 8 hours administered as a 4-hour prolonged infusion. All patients included in the study were being treated for P. aeruginosa infections. Overall, no significant differences in either 14-day all-cause mortality or hospital length of stay were observed across the entire population of 194 patients. However, when patients were stratified according to severity of illness as determined by Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, significant differences in both mortality (12.2% in the prolonged infusion group vs. 31.6% in the short infusion group; pMIC) requires that patientspecific PK and MIC data are able to be used. However, a large proportion of infections in critically ill patients are empirically treated for the duration of therapy; no specific pathogen is ever isolated and therefore the MIC of the pathogen causing the infection in an individual patient is never known. In addition, TDM is not available for most antimicrobials being used in clinical practice, and drug concentrations are rarely actually known. In actual practice, therefore, both PK parameters and MIC values must be estimated from other sources. This automatically imposes an inherent handicap on any attempts at individualization of antimicrobial therapy. Using mathematical modeling, it is possible to apply PKPD concepts

to clinical practice in an effort to overcome some of these practical limitations. Monte Carlo simulation is used to integrate PK, PD, and MIC data to design rational antimicrobial drug regimens with a high probability of achieving favorable PD targets against organisms that are likely to be encountered in practice.249 Monte Carlo simulation accounts for the variability in PK values within patient populations as well as the MIC distribution among the pathogens of interest in order to predict antibiotic exposure in entire populations of patients (i.e., MCS modeling simulates the variability in PK parameters that would be seen in a large population of individuals after administration of a specific drug dose or regimen). According to this PK variability, the probability of subsequently achieving specific PK/PD targets can then be determined. In summary, using this program, the probability of obtaining a target exposure that drives a microbiological effect for a given range of MIC values can be calculated.249 Monte Carlo simulation has become an extremely common method of evaluating the adequacy of existing regimens and designing new regimens that optimize PK/PD exposure in various patient populations. Although MCS is a very valuable tool when applied correctly, many limitations exist. A major consideration for MCS is the PK model used to estimate variability in PK parameters (Vss, clearance, etc.) likely to be encountered in practice. Pharmacokinetic studies of healthy volunteers may be used in MCS, especially when PK data from specific populations such as the critically ill are lacking. However, there is a concern that PK parameters from healthy volunteer studies may not accurately reflect the magnitude or variability in PK alterations within severely ill populations and may overestimate the probabilities of achieving desired PD targets. Another major consideration of PK/PD modeling and MCS is ensuring that appropriate MIC data are used. As much as possible, microbiological data used for MCS must accurately reflect the range and frequency of MICs actually encountered in critically ill patients or, even more ideally, within a specific institution. The role of tissue penetration of antimicrobial and the most appropriate way to include tissue concentrations into MCS modeling are also somewhat controversial and not truly known.250 Although useful as a quantitative measure of drug activity or

potency, the MIC itself is also not without several limitations.174 The MIC does not mirror true physiological conditions; instead, it is a static measure that does not reflect fluctuating drug concentrations typically observed during the administering of many doses of a drug regimen. Because the MIC measures only inhibition of growth, it does not reflect the rate at which bacteria are actually killed by bactericidal agents. Furthermore, the MIC only quantifies net growth over an 18- to 24-hour observation period. Killing and regrowth may well occur during this period as long as the net growth is zero. Finally, the MIC does not account for the post-antibiotic effects of antibiotics.174 As previously discussed in this chapter, estimates of organ function are imprecise and pose another limitation to applying PK/PD principles in the clinical setting. Assessments of renal and hepatic function and their effects on drug clearance within individual patients are potentially quite inaccurate. Related alterations in other PK parameters such as Vss, protein binding, and half-life are also difficult to estimate, and it can be quite difficult to individualize drug dosing with any precision. Although the science and practice of PD has made significant progress during the past 30 years and clinical outcomes have undoubtedly been improved through rational application of PK/PD principles, the current state of the art is still actually quite crude. It is currently not possible to fully account for factors such as age, comorbidities, immune function, severity of illness, changes in pathophysiology, and affected PK parameters over time during therapy, yet these and other factors are known to influence patient outcomes in the treatment of infections. Characterization and application of PD parameters that primarily consider only PK and MIC variables obviously lacks a degree of sophistication and highlights how much there is yet to learn regarding how to “optimize” antimicrobial therapy in order to achieve the best possible patient outcomes. Indeed, it has been shown that predicting patient outcomes on the basis of population-based PK/PD parameters is difficult at best and does not accurately predict clinical outcomes in individual patients.251 Finally, it is important to recognize that most of what is known and recommended regarding antimicrobial PD targets has been derived

from in vitro models, in vivo animal models, simulation modeling using techniques such as MCS, and retrospective data from humans. There are still relatively few prospective studies that were specifically conducted to validate PK/PD targets and to test whether the application of PD principles actually results in the desired outcomes, and until recently, well-designed prospective, randomized, controlled trials of the validity of PD principles were (and still are) almost nonexistent. There is clearly a need for additional prospective studies designed to specifically validate the PK/PD principles that are currently being applied to individual patients.

SUMMARY Antimicrobial treatment of critically ill patients remains a significant challenge to clinicians. Many factors, over which clinicians may have little control, may influence the response of an individual patient to antimicrobial therapy; however, optimization of antimicrobial therapy through appropriate drug selection and dosing is one area in which clinicians can make an important difference. Optimization of antimicrobial therapy remains a high priority in the treatment of critically ill patients and requires that drugs be dosed in a manner that maximizes their pharmacologic activity while minimizing the risk of adverse effects and toxicities. A wide variety of physiological alterations may occur in critically ill patients, many of which have the ability to significantly affect the PK/PD properties of drugs used in this patient population. Clinicians working with patients in the ICU must have a good working knowledge of many issues related to antimicrobial therapy: spectrum of activity of antimicrobials, potential PK alterations present in critically ill patients, how these alterations are likely to affect various types of antimicrobials, the PD properties of the drugs and how these are also likely to be affected in these patients, and how to appropriately apply knowledge of specific PK/PD targets to choose appropriate drugs and regimens that will provide favorable clinical outcomes. Understanding the rationale and limitations related to current clinical applications of

antimicrobial PK/PD properties is also important with respect to the ability of clinicians to optimize antimicrobial use in ICU patients. Although appropriate application of these concepts will likely always remain a significant challenge, PK/PD principles also provide valuable tools by which clinicians can make significant improvements in the care and therapeutic outcomes of the patients they serve.

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1999;2:133-9. 194. Kuti JL, Maglio D, Nightingale CH, et al. Economic benefit of a meropenem dosage strategy based on pharmacodynamic concepts. Am J Health Syst Pharm 2003;60:565-8. 195. Florea NR, Kotapati S, Kuti JL, et al. Cost analysis of continuous versus intermittent infusion of piperacillin-tazobactam: a timemotion study. Am J Health Syst Pharm 2003;60:2321-7. 196. DeRyke CA, Kuti JL, Mansfield D, et al. Pharmacoeconomics of continuous versus intermittent infusion of piperacillintazobactam for the treatment of complicated intraabdominal infection. Am J Health Syst Pharm 2006;63:750-5. 197. Nicasio AM, Eagye KJ, Kuti EL, et al. Length of stay and hospital costs associated with a pharmacodynamic-based clinical pathway for empiric antibiotic choice for ventilator-associated pneumonia. Pharmacotherapy 2010;30:453-62. 198. Xamplas RC, Itokazu GS, Glowacki RC, et al. Implementation of an extended-infusion piperacillin-tazobactam program at an urban teaching hospital. Am J Health Syst Pharm 2010;67:622-8. 199. Sader HS, Fey PD, Fish DN, et al. Evaluation of vancomycin and daptomycin potency trends (“MIC creep”) against methicillinresistant Staphylococcus aureus collected in nine United States medical centers over five years (2002-2006). Antimicrob Agents Chemother 2009;53:4127-32. 200. Patel N, Pai MP, Rodvold KA, et al. Vancomycin: we can’t get there from here. Clin Infect Dis 2011;52:969-74. 201. Blot S, Koulenti D, Akova M, et al. Does contemporary vancomycin dosing achieve therapeutic targets in a heterogeneous clinical cohort of critically ill patients? Data from the multinational DALI study. Crit Care 2014;18:R99. 202. Lodise TP, Lomaestro B, Graves J, et al. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents

Chemother 2008;52:1330-6. 203. Brinquin L, Rousseau JM, Boulesteix G, et al. Continuous infusion of vancomycin in post-neurosurgical staphylococcal meningitis in adults. Presse Med 1993;22:1815-7. 204. Conil JM, Favarel H, Laguerre J, et al. Continuous administration of vancomycin in patients with severe burns. Presse Med 1994;23:1554-8. 205. Cruciani M, Gatti G, Lazzarini L, et al. Penetration of vancomycin into human lung tissue. J Antimicrob Chemother 1996;38:865-9. 206. Byl B, Jacobs F, Wallemacq P, et al. Vancomycin penetration of uninfected pleural fluid exudate after continuous or intermittent infusion. Antimicrob Agents Chemother 2003;47:2015-7. 207. Di Filippo A, De Gaudio AR, Novelli A, et al. Continuous infusion of vancomycin in methicillin-resistant staphylococcus infection. Chemotherapy 1998;44:63-8. 208. Albanese J, Leone M, Bruguerolle B, et al. Cerebrospinal fluid penetration and pharmacokinetics of vancomycin administered by continuous infusion to mechanically ventilated patients in an intensive care unit. Antimicrob Agents Chemother 2000;44:13568. 209. Wysocki M, Delatour F, Faurisson F, et al. Continuous versus intermittent infusion of vancomycin in severe staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents Chemother 2001;45:2460-7. 210. Ingram PR, Lye DC, Fisher DA, et al. Nephrotoxicity of continuous versus intermittent infusion of vancomycin in outpatient parenteral antimicrobial therapy. Int J Antimicrob Agents 2009;34:570-4. 211. Vuagnat A, Stern R, Lotthe A, et al. High dose vancomycin for osteomyelitis: continuous vs intermittent infusion. J Clin Pharm Ther 2004;29:351-7.

212. Cataldo MA, Tacconelli E, Grilli E, et al. Continuous versus intermittent infusion of vancomycin for the treatment of grampositive infections: systematic review and meta-analysis. J Antimicrob Chemother 2011;67:17-24. 213. Hutschala D, Kinster C, Skhirdladze MD, et al. Influence of vancomycin on renal function in critically ill patients after cardiac surgery. Anesthesiology 2009;111:356-65. 214. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:1-38. 215. Jacqueline C, Batard E, Perez L, et al. In vivo efficacy of continuous infusion versus intermittent dosing of linezolid compared to vancomycin in a methicillin-resistant Staphylococcus aureus rabbit endocarditis model. Antimicrob Agents Chemother 2002;46:3706-11. 216. Bennett WM, Plamp CE, Gilbert DN, et al. The influence of dosage regimen on experimental nephrotoxicity: dissociation of peak serum levels from renal failure. J Infect Dis 1979;140:57680. 217. Galloe AM, Graudal N, Christensen HR, et al. Aminoglycosides: single or multiple daily dosing? Eur J Clin Pharmacol 1995;48:3943. 218. Chuck SK, Raber SR, Rodvold KA, et al. National survey of extended-interval aminoglycoside dosing. Clin Infect Dis 2000;30:433-9. 219. Barza M, Ioannidis JP, Cappelleri JC, et al. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996;312:338-45. 220. Munckhof WJ, Grayson ML, Turnidge JD. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses. J Antimicrob Chemother

1996;37:645-63. 221. Ferriol-Lisart R, Alós-Almiñana M. Effectiveness and safety of once-daily cimonglycosides: a meta-analysis. Am J Health Syst Pharm 1996;53:1141-50. 222. Freeman CD, Strayer AH. Mega-analysis of meta-analysis: an examination of meta-analysis with an emphasis on once-daily aminoglycoside comparative trials. Pharmacotherapy 1996;16:1093-102. 223. Hatala R, Dinh TT, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. Ann Intern Med 1996;124:717-25. 224. Ali MZ, Goetz MB. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997;24:796-809. 225. Bailey TC, Little JR, Littenberg B, et al. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997;24:786-95. 226. Hatala R, Dinh TT, Cook DJ. Single daily dosing of aminoglycosides in immunocompromised adults: a systemic review. Clin Infect Dis 1997;24:810-5. 227. Rybak MJ, Abate BJ, Kang SL, et al. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother 1999;43:1549-55. 228. Hitt CM, Klepser ME, Nightingale CH, et al. Pharmacoeconomic impact of once-daily aminoglycoside administration. Pharmacotherapy 1997;17:810-4. 229. Nicolau DP, Freeman CD, Belliveau PP, et al. Experience with a once-daily aminoglycoside program administered to 2:184 adult patients. Antimicrob Agents Chemother 1995;39:650-5. 230. Wallace AW, Jones M, Bertino JS Jr. Evaluation of four once-

daily aminoglycoside dosing nomograms. Pharmacotherapy 2002;22:1077-83. 231. Stankowicz MS, Ibrahim J, Brown DL. Once-daily aminoglycoside dosing: an update on current literature. Am J Health Syst Pharm 2015;72:1357-64. 232. Rea RS, Capitano B. Optimizing use of aminoglycosides in the critically ill. Semin Respir Crit Care Med 2007;28:596-603. 233. Conil JM, Georges B, Ruiz S, et al. Tobramycin disposition in ICU patients receiving a once daily regimen: population approach and dosage simulations. Br J Clin Pharmacol 2010;71:61-71. 234. Zazo H, Martin-Suarez A, Lanao JM. Evaluating amikacin dosage regimens in intensive care unit patients: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation. Int J Antimicrob Agents 2013;42:155-60. 235. Matsuo H, Hayashi J, Ono K, et al. Administration of aminoglycosides to hemodialysis patients immediately before dialysis: a new dosing modality. Antimicrob Agents Chemother 1997;41:2597-601. 236. Teigen MM, Duffull S, Dang L, et al. Dosing of gentamicin in patients with end-stage renal disease receiving hemodialysis. J Clin Pharmacol 2006;46:1259-67. 237. Sowinski KM, Magner SJ, Lucksiri A, et al. Influence of hemodialysis on gentamicin pharmacokinetics, removal during hemodialysis, and recommended dosing. Clin J Am Soc Nephrol 2008;3:355-61. 238. O’Shea S, Duffull S, Johnson DW. Aminoglycosides in hemodialysis patients: is the current practice of post dialysis dosing appropriate? Semin Dial 2009;22:225-30. 239. Veinstein A, Venisse N, Badin J, et al. Gentamicin in hemodialyzed critical care patients: early dialysis after administration of a high dose should be considered. Antimicrob Agents Chemother 2013;57:977-82.

240. Fish DN. Fluoroquinolone adverse effects and drug interactions. Pharmacotherapy 2001;21(suppl):253S-72S. 241. Rosemurgy AS, Markowsky S, Goode SE, et al. Bioavailability of fluconazole in surgical intensive care unit patients: a study comparing routes of administration. J Trauma 1995;39:445-7. 242. Buijk SLCE, Gyssens IC, Mouton JW, et al. Pharmacokinetics of sequential intravenous and enteral fluconazole in critically ill surgical patients with invasive mycoses and compromised gastrointestinal function. Intensive Care Med 2001;27:115-21. 243. Zhou W, Nightingale CH, Davis GA, et al. Absolute bioavailability of fluconazole suspension in intensive care unit patients. J Infect Dis Pharmacother 2001;5:27-35. 244. Mohammedi I, Piens MA, Padoin C, et al. Plasma levels of voriconazole administered via a nasogastric tube to critically ill patients. Eur J Clin Microbiol Infect Dis 2005;24:358-60. 245. Myrianthefs P, Markantonis SL, Evaggelopoulou P, et al. Monitoring plasma voriconazole levels following intravenous administration in critically ill patients: an observational study. Int J Antimicrob Agents 2010;35:468-72. 246. Hagihara M, Kasai H, Umemura T, et al. Pharmacokineticpharmacodynamic study of itraconazole in patients with fungal infections in intensive care units. J Infect Chemother 2011;17:224-30. 247. Andes D, Pascua A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother 2009;53:24-34. 248. Goodwin ML, Drew RH. Antifungal serum concentration monitoring: an update. J Antimicrob Chemother 2008;61:17-25. 249. Roberts JA, Kirkpatrick CMJ, Lipman J. Monte Carlo simulations: maximizing antibiotic pharmacokinetic data to optimize clinical practice for critically ill patients. J Antimicrob Chemother 2011;66:227-31.

250. Theuretzbacher U. Tissue penetration of antibacterial agents: how should this be incorporated into pharmacodynamic analyses? Curr Opin Pharmacol 2007;7:498-504. 251. Fish DN, Kiser TH. Correlation of pharmacokinetic/pharmacodynamic-derived predictions of antibiotic efficacy with clinical outcomes in severely ill patients with Pseudomonas aeruginosa pneumonia. Pharmacotherapy 2013;33:1022-34.

Chapter 13 Laboratory Testing

Considerations Kali Martin, Pharm.D.; Shanna Cole, Pharm.D.; and Michael Klepser, Pharm.D.

LEARNING OBJECTIVES 1. Compare and contrast various platforms used to provide data regarding the identity and susceptibility of infecting pathogens. 2. Evaluate the benefits and limitations of rapid diagnostic tests used for infectious diseases. 3. Outline how rapids diagnostic tests should be used to optimize patient outcomes and return on investment.

ABBREVIATIONS IN THIS CHAPTER MALDITOF MS

Matrix-assisted laser desorption ionization time-offlight mass spectrometry

PCR

Polymerase chain reaction

PNA FISH

Peptide nucleic acid fluorescence in situ hybridization

INTRODUCTION

An ever-important area of infectious diseases in the critical care setting remains identifying infecting microorganisms and determining antimicrobial susceptibility profiles in order to swiftly initiate appropriate antimicrobial therapy. However, the timely selection of an appropriate antibiotic continues to be a challenge for clinicians, especially for patients in the intensive care setting, where a delay of minutes can profoundly affect outcomes. Various studies have shown the significance of promptly administering appropriate antibiotics on survival in patients with high acuity.1-3 Methods for culture and susceptibility testing remain suboptimal with respect to the timeliness of data availability. This delay leaves the clinician without critical information and places the patient at risk of suboptimal antimicrobial therapy. Conversely, de-escalation of antibiotics may be needlessly postponed without timely knowledge of the pathogen’s identity and susceptibility, leading to overuse of broad-spectrum agents. Fortunately, advances in technology have presented substantial advances in rapid microbiological diagnostic testing. Various tests have been approved that can now provide vital data within hours rather than days and hold the promise of the decreasing mortality, length of hospital stay, and hospital costs that are associated with managing infectious processes.4

DIAGNOSTIC TESTS AVAILABLE FOR USE IN INFECTIOUS DISEASES Cultures/Gram Stain Culture and in vitro susceptibility testing remain the gold standard for identifying the causative pathogen and characterizing antimicrobial activity. Theoretically, these techniques allow for the detection of as few as 1 CFU of bacteria or fungi per unit of blood. Although culturebased methods for biochemical species identification and susceptibility determination have been used for decades, these techniques are far from ideal. Growing cultures is time- and resource-consuming. It can take more than 18 hours to get adequate bacterial growth from a

specimen to use in subsequent biochemical tests. The time to detection of a microbe is considerably longer for some slow-growing bacteria and fungi.5 Furthermore, the time required to detect the presence of a pathogen in a specimen can be prolonged when the amount of microbe in the collected specimen is low or if the patient has previously been exposed to antimicrobials. Another limitation of culture-based detection methods is that they can only detect viable organisms. Unfortunately, culture-based methods cannot identify cellular components such as antigens or genetic fragments that are released after cell lysis. In addition, even though blood is the most common specimen used for culture, circulation of viable organisms in the blood often does not consistently occur, which limits the sensitivity of these tests. In total, all of these limitations can result in delays in detecting and identifying a pathogen and adversely affect decisions regarding antimicrobial use.5 Despite their drawbacks, culture and susceptibility testing continue to serve as first line for identifying and characterizing infectious etiologies owing to the familiarity with the techniques and the relatively low cost associated with these tests.6-9 As such, culture-based methods continue to be the standard against which new rapid detection tests are compared. A primary value of cultures is that they provide the microbial growth that is used in determining in vitro susceptibilities and nucleic acid testing. Although in vitro susceptibility testing has its own problems, these data continue to be used to direct patient care, construct antibiograms, and guide antibiotic selection and dosing decisions on the basis of optimizing pharmacodynamic parameters.

Nucleic Acid Testing Decreasing the time in identifying an organism significantly decreases mortality and improves patient outcomes. As mentioned, culture and susceptibility, although widely used, are less than optimal, especially in critically ill patients because of the delayed time to obtaining results. For the past several years, the availability of rapid tests for organism detection has increased.9 Examples of tests include those that are based on pathogen lysis, nucleic acid extraction and purification,

nucleic acid amplification, and identification. Various methods to accomplish these tasks have been evaluated, including pathogenspecific assays for targeting species-specific genes, broad-range assays that target genomic sequences, and multiplex polymerase chain reaction (PCR) that focuses on species-specific targets of different organisms. Some of these tests are even intended to detect genes associated with antimicrobial resistance such as mecA in staphylococci or vanA and vanB in enterococci. Currently, many of these tests are used only as a complement to cultures, especially in serious clinical situations. The drawback of this approach is that the tests fail to overcome the technical and sensitivity issues of cultures.10 Some nucleic acid tests, however, are considered first line for the diagnosis of pathogens such as hepatitis C virus, enteroviruses, Bordetella pertussis, herpes simplex virus (in the setting of herpes encephalitis), and Chlamydia trachomatis. Historically, use of nucleic acid testing has been limited owing to cost, technical complexity, limited applicability, and the need to determine antimicrobial susceptibility after pathogen identification.11 However, as test robustness continues to improve and isothermal methods are developed, these technologies may eventually supplant culture as the gold standard for pathogen identification.12 The primary limitations associated with the current generation of nucleic acid tests predominantly include the inability to assess antimicrobial susceptibility, complexity, and ability to differentiate between viable and non-viable organisms. Although tests capable of detecting broad arrays of pathogens may be of clinical value, their use may be limited because of the higher risk of contamination owing to the many steps involved in processing specimens. Furthermore, although many of these tests have quick turnaround times, actual timing may be longer because of issues such as transportation of specimens and availability of staff.4 One improvement already developed and implemented in nucleic acid testing is the use of nanoparticle probe technology. This technology improves specificity for both nucleic acid and protein detection. Nanosphere has developed the Verigene system. This

system is a novel, multiplex platform that allows for the screening of a sample directly from positive culture medium. Following automated nucleic acid extraction and PCR amplification, the test uses nanoparticle probe technology resulting in target hybridization. The total run time post-inoculation is about 2.5 hours.13-15 The gram-positive blood culture (BC-GP) nucleic acid test targets 12 genus- or speciesspecific targets and mecA and vanA/B genes (Table 13.1). The sensitivity and specificity for the various targets are 92.6%–100% and 95.4%–100%, respectively.16 The gram-negative blood culture (BCGN) test is approved for eight genus- or species-specific targets and six resistance genes, including the extended-spectrum β-lactamase CTX-M and the carbapenemases IMP, KPC, NDM, OXA, and VIM (www.nanosphere.us/products/gram-negative-blood-culture-test). The percent agreement with this assay and routine methods for identifying and detecting resistance markers was 97.4% and 92.3%, respectively.13 Although the tests perform well in monomicrobial cultures, test performance declines in the presence of polymicrobial cultures. Another limitation of the assay is its inability to associate a resistance determinate with a particular organism in a polymicrobial culture.

Table 13.1 Targets Identified by the Verigene GramPositive Blood Culture Test (BC-GP) Species Staphylococcus aureus Staphylococcus epidermidis Staphylococcus lugdunensis Streptococcus anginosus group Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Enterococcus faecalis Enterococcus faecium Genus Staphylococcus spp. Streptococcus spp.

Listeria spp. Resistance mecA (methicillin) vanA (vancomycin) vanB (vancomycin)

Several studies have assessed the impact of receipt of data from the Verigene test system compared with routine methods. On average, identification results are available 30–40 hours earlier with the Verigene system and susceptibility information 40–50 hours earlier.15 When acted on in a timely manner, these data can significantly and positively affect treatment decisions. In one study, when results from the Verigene system were acted on by a critical care/infectious diseases pharmacist, the time to receipt of appropriate antibiotic therapy was decreased by 23.4 hours, length of hospitalization was 21.7 days shorter, and hospital costs were $60,729 lower.17

Polymerase Chain Reaction Polymerase chain reaction allows for the amplification of a single copy of DNA or DNA fragment. The process involves repeated cycles of heating and cooling in the presence of primers and DNA polymerase, resulting in the amplification of the targeted sequence. Traditionally, results are determined when the presence or absence of the genetic fragment is noted on gel electrophoresis. Polymerase chain reaction can be a highly sensitive method for microbial detection; however, sensitivity is affected by primer and amplicon selection and contamination.10 Some examples of U.S. Food and Drug Administration (FDA)-cleared PCR-based test systems include the Roche Molecular Systems LightCycler SeptiFast MecA, the BD GeneOhm Cdiff assay, the Cepheid Xpert C. difficile assay, and the Gen-Probe Prodesse ProGastro Cd. Real-time PCR allows for monitoring of DNA amplification while the assay is in progress rather than at the end of the run. Real-time PCR assays can be used for analysis of genetic polymorphisms, gene

expression, and species identification. The GeneXpert system uses real-time PCR with preparation and detection in a closed compartment to detect methicillin resistance or susceptibility. Depending on the cartridges selected, this system can be used to detect an array of pathogens/resistance determinants, including methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile, vanA in enterococci, influenza virus, Norovirus, and resistance in Mycobacterium tuberculosis. For staphylococci, the system can detect mecA and SCCmec genes with a sensitivity of 100% and specificity of 98.6% for methicillin-susceptible S. aureus and a 98.3% sensitivity and 99.4% specificity for MRSA.4,18 Results are available within 1 hour. Broad-range or multiplex PCR provides the ability to rapidly and efficiently amplify different DNA sequences simultaneously using several sets of primers and DNA polymerases. Tests initially use PCR amplification, followed by downstream approaches for identification such as hybridization and sequencing. Examples of multiplex PCR tests currently available include the BD GeneOhm StaphSR assay, the Cepheid Xpert MRSA/SA BC and C. difficile/Epi assays, the Mobidiag Prove-it Sepsis, and the BioFire Diagnostics FilmArray blood culture identification (BCID). The value of these platforms is the rapid, simultaneous screenings of clinical samples for several pathogens. For example, the Prove-it Sepsis can screen for more than 60 bacteria and 13 fungi that produce more than 90% of sepsis-causing pathogens. In addition, resistance markers for genes such as mecA and vanA and vanB can be identified. Results are available in as few as 3 hours with a sensitivity of 95% and specificity of 99%.19 Real-time PCR tests are available to detect the genes encoding for C. difficile toxin B (tcdB) or the toxin regulatory gene (tcdC). Although these tests have sensitivities of 90% and specificities of 96%, their clinical value has been questioned. The positive predictive value (PPV) of these tests varies with the prevalence of disease.20 When the prevalence of disease is low (less than 10%), the PPV for an accurate diagnosis is low. Conversely, when the prevalence of disease is high (greater than 20%), the PPV is higher, and the value of the test for making a diagnosis increases. The negative predictive value of the

tests does not change with disease prevalence. Therefore, these tests may be of limited diagnostic value under endemic rates of disease but may be useful in ruling out infection. That the PCR tests detect genes rather than the gene product is another drawback. As a result, individuals colonized with non–toxin-producing strains of C. difficile may be inappropriately identified as being infected. Because it is possible to obtain false-positive results with PCR, clinicians must either use PCR in combination with initial screening using enzyme immunoassays for C. difficile glutamate dehydrogenase or toxins A and B or use PCR in select patients with a high probability of having C. difficile infection. Failure to use the tests judiciously can result in overtreatment of patients and excess cost and can foster antimicrobial resistance in collateral bacterial flora. Real-time PCR systems greatly reduce the time that meaningful information regarding the causative pathogen and/or expression of resistance is available to clinicians. When appropriately disseminated and interpreted, these data and the ability to rapidly access them can affect antimicrobial use and patient outcome. A study by Carver and colleagues showed that when specimens from patients thought to have S. aureus infections underwent rapid screening with PCR for the mecA gene and data were acted on by an infectious diseases clinical pharmacist, the time to initiating appropriate antibiotic therapy was reduced by 25.4 hours.21 Shortening the time to administering appropriate antibiotics may be associated with decreased mortality among patients with sepsis. Additional studies have shown that use of these tests is associated with decreased costs and length of stay owing to a reduction in the use of inappropriate antibiotics and decreased time to appropriate therapy.22-24 However, if use of these tests is not coupled with an effective implementation strategy, their value for affecting antibiotic use may be limited.25

Peptide Nucleic Acid with Fluorescence In Situ Hybridization Peptide nucleic acid fluorescence in situ hybridization (PNA FISH), a

platform developed by AdvanDx (Wo-burn, MA), uses fluorescently labeled probes with neutral charges that penetrate the cell membrane and cell wall of intact organisms. Peptide nucleic acid probes are DNA mimics that rapidly hybridize to species-specific ribosomal RNA (rRNA) sequences. Bacteria and fungi produce an abundance of highly conserved, species-specific rRNA sequences; therefore, these represent good targets for molecular probes. In addition, because rRNA is naturally amplified in viable cells, targeting rRNA may be accomplished without additional amplification procedures, thus allowing for organism identification without cell rupture and with minimal risk of sample contamination. A probe is a synthetic oligomer mimicking a DNA or an RNA sequence, and the target is the nucleic acid being detected. Probe detection is accomplished using a fluorescent microscope after hybridization. Results for first-generation tests took about 3 hours to obtain after a positive Gram stain. Newer QuickFISH tests have reduced this time to less than 30 minutes with high sensitivity and specificity. The PNA FISH and QuickFISH systems are available for detecting and differentiating S. aureus and coagulase-negative staphylococci, Enterococcus faecalis and Enterococcus faecium, gramnegative pathogens (i.e., Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa), and Candida spp. (i.e., Candida albicans, Candida glabrata, and Candida parapsilosis). In addition, newer XpressFISH assays can identify phenotypic resistance markers such as mecA. The diagnostic accuracy of this platform has been excellent. Rates of agreement between PNA FISH and other diagnostic methods have generally exceeded 95%.26,27 Several studies have determined that PNA FISH testing can help lead to decreased hospital costs, length of stay, and mortality for infections caused by a variety of pathogens, including various grampositive, gram-negative, and Candida pathogens.11,28-31 In one study, use of PNA FISH aided in detecting coagulase-negative Staphylococcus spp., resulting in decreased hospital length of stay from 6 to 4 days (p

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lsPaco2 < 35 mm Hg?

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8 Surgery indicated ?

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9 Transport to OR

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Insert ICP monitor or ventriculostomy

'’ 11 Transport to ICU and continue supportive care: Mechanical ventilation: goal arterial oxygen saturation > 90% Maintain CPP > 50 mm Hg with fluids ± vasopressors Initiate phenytoin therapy Maintain fluid, electrolyte homeostasis Stress uleer and VTE prophylaxis Maintain normothermia Monitor vital signs and neurologie status

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Go to 10 during or after surgery

Figure 20.1 Algorithm for the acute management of traumatic brain injury. ABG = arterial blood gas; CBC = complete blood cell count; Cp = plasma concentration; CPP = cerebral perfusion pressure; GCS = Glasgow Coma Scale; ICP = intracranial pressure; NS = normal saline; OR = operating room; PRBC = packed red blood cell; SBP = systolic blood pressure; VTE = venous thromboembolism. Adapted from: Boucher BA. Neurotrauma. Pharmacotherapy Self-Assessment Program, 3rd ed. Module 2: Critical Care, Lenexa, KS: American College of Clinical Pharmacy, 1995:215-38.

Patientwith ICP > 20 mm Hg *

1 Administer1mannitol (0.5 g /kg IV q4h) or hypertonic saline (3% 2 mL /kg IV q4h ) Open ventriculostomy (if present) for ICP > 20 mm Hg Consider sedation with propofol (alternative: midazolam) ± short-acting opiate

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5 Administer sedation as in box 1 ( especiallyifagitated)

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Continuous ICP and vital signs monitoring Monitor neurologic status If Temp > 37.5’C, administer acetaminophen, use cooling blanket

7 Is ICP > 20 mm Hg*

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Gotol

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16 Remove ICP monitor Supportive care

8 SecondTine tberapies: Pentobarbital 25 mg /kg IV; then 1mg /kg /h. Obtain EEG. Considershort-term hyperventilation to Paco2 30-35 mm Hg Consider short acting neuromuscular blocker if sedation is maximized Consider furosemide if not hypovolemic

Yes

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10 Has the patient achieved burst suppression or Cp < 30 mg/ L?

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Wean pentobarbital over 24 h No

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Partial pentobarbital loading dose based on Cp' Increase pentobarbital 1mg/kg/ h (max dose 3 mg/kg / h )

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12 Reevaluateall medical andsurgical options. Consider hypothermia induction totarget 33"C

1

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I Go to 9

Figure 20.2 Algorithm for the management of ICP. aTreatment

thresholds: ICP 20–29 mm Hg for > 15 min, ICP 30–39 mm Hg for > 2 min, ICP > 40 mm Hg for > 1 min. Note: Transient increases may occur after respiratory procedures (e.g., suctioning, chest physiotherapy, bronchoscopy, intubation). bHold

if serum osmolality > 320 mOsm/kg or mOsm gap > 20.

cPartial

pentobarbital loading dose (mg) = (30 mg/L – measured Cp) (1 L/kg × wt(kg))

EEG = electroencephalogram; IV = intravenously; q = every. Adapted from: Boucher BA. Neurotrauma. Pharmacotherapy Self-Assessment Program, 3rd ed. Module 2: Critical Care, Lenexa, KS: American College of Clinical Pharmacy, 1995:215-38.

Hyperosmolar Therapy The two primary agents used for hyperosmotic therapy to control ICP are mannitol and hypertonic saline. Mannitol is a sugar alcohol that is usually prepared for intravenous administration as a 20%–25% solution. Mannitol can be administered by a central venous catheter or a peripheral venous catheter. Mannitol affects the cerebral blood flow and ICP though two primary mechanisms of action. Immediately after infusion of mannitol, blood viscosity is decreased, thus increasing cerebral blood flow throughout the brain. When autoregulation is intact, this increase in cerebral blood flow causes a compensatory vasoconstriction and rapid reduction in ICP. The osmotic effect of mannitol occurs about 15 minutes after infusion. Mannitol causes a dehydration of brain tissue and hyperosmolarity through diuresis. This in turn decreases ICP.16-18 Because mannitol is a strong osmotic diuretic, significant hypotension and significant fluid shifts can occur after administration. These rapid fluid shifts may be detrimental to patients with significant comorbidities (e.g., heart failure). Although the mechanism is not fully elucidated, mannitol can cause renal insufficiency in the setting of extreme hyperosmolarity. The dogmatic approach has been to discontinue or limit mannitol once the serum osmolarity reaches 320 mOsm; however, in clinical practice, this value is routinely exceeded. Acute renal insufficiency associated with mannitol may be related to accumulating mannitol plasma concentrations and cumulative mannitol dose.19 The serum osmole gap, calculated as (measured osmolarity – calculated osmolarity), correlates with accumulating plasma concentrations better than serum osmolarity.20 Compared with serum osmolarity, the serum osmole gap may be a better monitor for mannitol toxicity. Literature suggests that

maintaining a serum osmole gap of less than 55 reduces the risk of renal insufficiency21,22; however, many practitioners conservatively target an osmolar gap of less than 18–20. In addition, mannitol is renally eliminated. Thus, in patients with significant renal insufficiency, mannitol may accumulate, necessitating a change in treatment agent. Hypertonic saline, usually prepared in concentrations of 1.5%–23.4%, must be administered by a central venous catheter when concentrations are greater than 3%. It decreases ICP by directly causing hyperosmolarity. This effectively dehydrates brain tissue, thus decreasing ICP. Hypertonic saline has been administered as a bolus or continuous infusion. The bolus dose varies depending on the concentration of sodium chloride; however, the osmolarity of the dose administered should be comparable with that of a therapeutic mannitol dose.23 Table 20.2 contains equimolar doses of mannitol and hypertonic saline. Unlike mannitol, hypertonic saline does not cause diuresis and will expand the intravascular volume. Consequently, care should be taken when using hypertonic saline in patients when expanded intravascular volume would be deleterious (e.g., patients with heart failure). In addition, there is concern for osmotic demyelinating syndrome when using hypertonic saline in patients with chronic hyponatremia. Therefore, in patients with chronic hyponatremia, hypertonic saline therapy for increased ICP should be avoided.24 The BTF guidelines only give recommendations for the use of mannitol to control intracranial hypertension. They state that “mannitol is effective for control of raised ICP at doses of 0.25 gm/kg to 1 g/kg body weight. Arterial hypo-tension (systolic blood pressure less than 90 mm Hg) should be avoided (level II evidence).”24 Since those guidelines were published in 2007, a significant amount of data comparing hypertonic saline and mannitol for the control of ICP have been published. A 2011 meta-analysis by Kamel et al. evaluated five trials that compared equimolar doses of mannitol and hypertonic saline. The authors found that patients treated with hypertonic saline had a better risk of achieving ICP control (relative risk [RR] 1.16; 95% confidence interval [CI], 1.00–1.13).25 A second meta-analysis from 2012 found 12 studies that compared hypertonic saline with mannitol.

Of those, nine found hypertonic saline superior to mannitol for reduction of ICP. Eight studies compared hypertonic saline and mannitol with respect to treatment failure or insufficient ICP reduction. Compared with patients treated with mannitol, significantly fewer patients had treatment failure or insufficiency when treated with hypertonic saline (odds ratio 0.36; 95% CI, 0.19–0.68).23 This meta-analysis compared non-equimolar doses of agents; thus, it may overestimate the treatment effect of hypertonic saline. However, because the results are similar to those of previous meta-analyses, the trend of less treatment failure with hypertonic saline remains. Choice of the most appropriate hyperosmolar therapy to decrease ICP must be linked not only to efficacy but also to speed of agent availability, access for administration (i.e., central vs. peripheral catheter), and patient-specific considerations (e.g., volume status, presence of hyponatremia, renal dysfunction). Therefore, a single approach cannot be taken with these agents. Although data suggest that hypertonic saline is more effective at reducing ICP, mannitol remains a useful agent.

Table 20.2 Equivalent Doses of Hyperosmolar Agents Based on Osmolality

Barbiturate Therapy

Compared with hyperosmotic therapy, barbiturates are not as effective at reducing ICP.26-30 However, barbiturates may have a role in control of refractory ICP. The BTF guidelines give level II evidence for the use of barbiturates “to control elevated ICP refractory to maximum standard medical and surgical treatment.”31 Many barbiturate regimens have been used, but most commonly, medications are titrated to induce and maintain electroencephalographic burst suppression.27,28,32-35 There is little correlation between barbiturate plasma concentrations and achievement of electroencephalographic burst suppression; thus, barbiturate plasma concentrations should not be used to monitor the efficacy of a treatment regimen. Table 20.3 lists the most commonly used barbiturate regimens. A 2012 meta-analysis evaluated the effect of barbiturate coma and found no effect on outcome. In addition, the investigators found a significant risk of hypotension associated with the use of barbiturate coma, which may decrease this treatment’s clinical significance.30 A prospective cohort of five European countries was used to evaluate the use of barbiturates in patients with TBI. Compared with the time before barbiturate administration, patients who received high-dose barbiturates had a significant reduction in time with ICP greater than 25 mm Hg (6.4 hours ± 7.05 hours vs. 4.2 hours ± 5.9 hours; p 1/3 cerebral hemisphere) 3. History of intracranial hemorrhage 4. Blood pressure remaining > 185/110 mm Hg at time of intravenous TPA administration despite treatment 5. Arteriovenous malformation, neoplasm, or aneurysm 6. Witnessed seizure at stroke onset 7. Active internal bleeding or acute trauma (fracture) 8. Platelet count < 100,000/mm3 9. Heparin administration within 48 hours resulting in aPTT > upper limit of normal 10. Anticoagulant use with INR > 1.7 or PT > 15 seconds 11. Intracranial or intraspinal surgery, serious head trauma, or previous stroke within 3 months 12. Arterial puncture at noncompressible site within 7 days Relative contraindications 1. Minor or rapidly improving stroke symptoms

2. Major surgery/trauma within 14 days 3. GI or urinary tract hemorrhage within 21 days 4. Myocardial infarction within 3 months 5. Post-myocardial infarction pericarditis 6. Blood glucose concentration < 50 or > 400 mg/dL 7. Additional criteria 3–4.5 hours from symptom onset Exclusion criteria 1. Age > 80 years 2. Severe stroke defined as NIHSS > 25 3. Taking oral anticoagulant regardless of INR 4. History of both diabetes and previous AIS AIS = acute ischemic stroke; TPA = tissue plasminogen activator.

Other Fibrinolytic Agents Although intravenous TPA is the only U.S. Food and Drug Administration (FDA)-approved fibrinolytic for AIS in the United States, tenecteplase, bioengineered from 3 amino acid substitutions on human tissue plasminogen activator (alteplase), has increased fibrin specificity, has a longer half-life (22 minutes vs. 3.5 minutes), and is less susceptible to PAI-1 (plasminogen activator inhibitor-1) compared to alteplase.14 In a randomized controlled phase IIb trial of patients with AIS presenting within 6 hours of symptoms, patients who received tenecteplase had significantly improved reperfusion, NIHSS scores, and excellent or good recovery at 90 days compared with alteplase, with a nonsignificant decrease in intracerebral bleeding.15 Tenecteplase also has a practical advantage over alteplase because it may be administered as a rapid intravenous bolus compared with a 1-hour

infusion for alteplase. A large Norwegian phase III randomized trial is ongoing (NOR-TEST) to compare 3-month clinical outcomes in alteplase- versus tenecteplase-treated patients presenting within 4.5 hours of AIS symptom onset.16 Derived from bat saliva, desmoteplase has a very high fibrin selectivity compared with intravenous TPA, but a recent study (DIAS-3) reported no improvement in functional outcome in patients who received desmoteplase compared with placebo when administered between 3 and 9 hours of symptom onset in AIS.17 As such, this drug is no longer in development for the indication of AIS.

Endovascular Interventions Treatment of AIS has evolved beyond intravenous administration of TPA to include endovascular interventions such as intraarterial TPA, mechanical clot aspiration (e.g., Penumbra device) or retrieval (e.g., Merci catheter, Trevo retriever, Solitaire stent retriever), and angioplasty and stenting. These interventions are often used in combination, and in addition to intravenous TPA. For instance, patients eligible for intravenous TPA may receive this intervention followed by endovascular treatment with intra-arterial TPA and clot retrieval. Although intravenous TPA is considered the “gold standard” for AIS, it may be less effective for certain types of strokes such as large middle cerebral artery (MCA) occlusions. Of note, the same “time is brain” principle also applies to any endovascular intervention.

Table 21.2 Management of Hypertension in Patients with Acute Ischemic Stroke

Patient Characteristic

Eligible for IV TPA

GoalBlood Pressure, mm Hg < 185 /110 before

administration

During and after IV TPA administration

< 180 /105 for

24 hr after administration

Pharmacotherapy

Labetalol 10-20 mg IV over 1-2 min; may repeat * 1or

Nicardipine 5 mg / hr; titrate by 2.5 mg/ hr every 5 min up to 15 mg / hr

Systolic 180-230 or diastolic 105-120: Labetalol 10-20 mg IV over 1-2 min; may repeat every 10-20 min or

Labetalol 10 mg IV » 1; then 2-8 mg /min infusion

Monitoring

lf blood pressure does not decline and remains > 185/110 mm Hg, do not administerIVTPA

Monitor blood pressure every 15 min during IV TPA treatment and then every 15 min for the next 2 hr; then every 30 min for 6 hr; then every 1hr for 16 hr (first 24 hr after IV TPA )

Systolic > 230 or diastolic 121-140: Labetalol 10-20 mg IV over 1-2 min; may repeat every 10-20 min or

Labetalol 10 mg IV x 1; then 2-8 mg /min infusion or Nicardipine 5 mg / hr; titrate by 2.5 mg/ hr every 5 min up to 15 mg / hr

Uncontrolled by above measures: Nitroprusside 0.5 mcg /kg /min Not eligible for IV TPA

< 220/120

Systolic > 220 or diastolic 121-140: Labetalol 10-20 mg IV over 1-2 min; may repeat every 10-20 min or

Nicardipine 5 mg/ hr; titrate by 2.5 mg/ hr every 5 min up to 15 mg / hr

Frequent monitoring of blood pressure with goal reduction of 10%—15% diastolic in first 24 hr

Diastolic > 140: Nitroprusside 0.5 mcg/ kg /min

IV = intravenous(ly).

Intra-arterial TPA Patients with AIS may have a contraindication to intravenous TPA therapy, commonly presentation outside the time window for intravenous TPA window. Although intra-arterial TPA is not FDA approved for this indication, two clinical trials that used other fibrinolytic agents provide most of the (extrapolated) evidence for intra-arterial TPA. In the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) study, patients who received recombinant pro-urokinase within 6 hours of symptom onset for MCA occlusions had improved modified Rankin scores at 90 days and better recanalization than control. Symptomatic ICH was numerically higher in the treatment group (10%) than in control (2%), but this was not statistically significant.18 In the MELT (middle cerebral artery embolism local fibrinolytic intervention trial) study, patients who received urokinase within 6 hours of AIS were more likely to have modified Rankin scores of 0–1 (no significant disability) than was control. Symptomatic ICH occurred in 9% of

patients, similar to that seen in PROACT II.19 Current guidelines recommend intra-arterial fibrinolysis within 6 hours of symptom onset in patients with large MCA strokes who are ineligible for intravenous TPA (class I recommendation) and those with other types of stroke who have a contraindication to intravenous TPA (class IIa recommendation).7 Combination Intravenous Fibrinolysis and Endovascular Interventions Patients with proximal cerebral artery occlusions (e.g., MCA) often have large clot burdens, greater neurologic deficits, and subsequently increased likelihood of intravenous TPA failure. In this setting, eligible patients receive intravenous TPA and then endovascular administration of intra-arterial TPA if necessary (“salvage” or “rescue” therapy). In the Interventional Management of Stroke (IMS)-1 and IMS-2 trials, patients presenting within 3 hours of symptom onset received a reduced dose of intravenous TPA 0.6 mg/kg (max of 60 mg), followed by intra-arterial TPA up to 22 mg administered by a standard microcatheter or the EKOS microinfusion catheter. Good clinical outcome was reported in both studies (modified Rankin score 0–2) as well as better outcomes than the placebo group from NINDS.20,21 Rescue intra-arterial fibrinolysis is currently considered a reasonable approach in patients with large artery occlusion.7 As discussed previously, endovascular interventions are often used in combination. A recent multicenter randomized open-label Dutch study (MR CLEAN) compared endovascular therapy (intra-arterial fibrinolysis, mechanical treatment, or both) plus usual care (mostly intravenous TPA) with usual care alone.22 Patients were required to receive intraarterial treatment within 6 hours of symptom onset and have an occlusion of the distal intracranial carotid artery, MCA, or anterior cerebral artery. Intra-arterial fibrinolysis consisted of either alteplase or urokinase with maximum doses of 30 mg and 400,000 international units if intravenous TPA was given (87% of the intervention group). Most patients in the intervention group received mechanical intraarterial therapy, although the proportion of patients who received intra-

arterial fibrinolysis is unclear. At 90 days, 32.6% of patients were functionally independent (as defined by a modified Rankin score of 0– 2) compared with only 19.1% in the usual care group. Symptomatic ICH was reported in 7.7% of patients in the intervention group compared with 6.4% of patients in the usual care group, which was not statistically significant and was similar to bleeding rates from studies of patients who received intravenous TPA only. Of note, 82% of patients in the intervention group from this study received treatment with “modern” retrievable stents, which are more effective than first-generation devices. Success of combination therapy has been confirmed in the ESCAPE (Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times) and EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-arterial) studies because endovascular treatment (with primarily the Solitaire stent retrieval device) was superior to intravenous TPA alone.23,24

Early Antiplatelet Administration The CAST (Chinese Acute Stroke Trial) and IST (International Stroke Trial) trials both reported a small benefit from aspirin 160–300 mg/day administered early during hospitalization for AIS.25,26 Current recommendations are to administer aspirin 325 mg/day orally beginning within 48 hours of stroke onset.7 In patients who receive fibrinolysis, an antithrombotic should not be initiated until 24 hours afterward, but may be initiated on hospital day 1 in patients who do not receive fibrinolysis. Patients who fail swallowing studies and have no enteral access may receive aspirin rectally. In patients with aspirin allergy, there is little evidence regarding alternative antiplatelet medications, but it is reasonable to administer clopidogrel with the understanding that a loading dose is necessary to rapidly achieve inhibition of platelet aggregation. Administration of antithrombotic medications by the end of hospital day 2 is a performance measure of the Joint Commission Stroke National Hospital Inpatient Quality Measures for certified stroke centers.

SUPPORTIVE CARE Temperature Control Fever is common in patients with AIS and has been associated with poor neurological outcomes. However, hypothermia may be neuroprotective by decreasing metabolic demand, acidosis, calcium influx, free radical production, and production of inflammatory cytokines and excitatory amino acids. Current recommendations are to lower body temperature in patients with a temperature greater than 38°C using antipyretic medications.7 Sur-face cooling devices (e.g., Arctic Sun) may also be used in patients with fever who do not respond appropriately to medications. Induced hypothermia for the purpose of neuroprotection is not recommended because of a lack of robust clinical evidence.

Glucose Control Hyperglycemia on admission and while in hospital has been associated with poor outcomes in AIS and may increase the risk of hemorrhagic conversion. Hypoglycemia may mimic stroke but, when prolonged, can also lead to ischemia and should be urgently treated in patients with AIS. The target blood glucose concentration is unclear, but current recommendations suggest a goal of 140–180 mg/dL.7

Intravenous Fluids Most patients with AIS are either euvolemic or hypovolemic, the latter often requiring administration of intravenous fluids in the acute setting because of impaired swallowing or altered mental status. Hypovolemia may decrease cerebral perfusion and worsen ischemic injury, whereas hypervolemia may exacerbate ischemic brain edema and increase stress on the heart; therefore, euvolemia is recommended in patients with AIS. Intravenous solutions containing substantial amounts of free water (e.g., dextrose 5%, 0.45% sodium chloride) should be avoided

because of the potential to increase brain swelling.7

Prophylaxis Venous Thromboembolism Deep venous thrombosis and pulmonary embolism are potential complications in patients with AIS, likely because of the combination of immobility and the presence of other risk factors for venous thromboembolism (VTE). Mechanical prophylaxis should be used in all patients with immobility and combined with pharmacologic prophylaxis, with the caveat that all anticoagulant medications should be held for 24 hours after fibrinolytic administration. One clinical trial found enoxaparin 40 mg daily to be superior to unfractionated heparin 5,000 units twice daily for the prevention of VTE in patients with AIS, but this trial has been criticized because of the small dose of heparin used.27 In the absence of conclusive studies, either low-molecular-weight heparin or unfractionated heparin (5,000 units three times daily for most patients) is a reasonable option for VTE prophylaxis in patients with AIS. Seizure Seizures after AIS are less common than in patients with ICH, but the incidence may be increased in patients who have hemorrhagic transformation. It is currently not recommended to administer medications for seizure prophylaxis in patients with AIS.7 Clinical seizures should be treated, and the risk of non-convulsive seizures should be appreciated in patients with neurological injuries.

INTRODUCTION: HEMORRHAGIC STROKE Stroke consistently ranks as the second leading cause of death around the world, claiming 6.7 million lives in 2012.28 Al-though hemorrhagic stroke accounts for 10%–20% of strokes, it appears to carry with it a higher mortality rate. One study in Denmark showed a 49.2% mortality

in the hemorrhagic sub-category, whereas ischemic stroke had a mortality of 25.9%.29 The National Stroke Association estimates that although hemorrhagic strokes account for only about 15% of strokes, more than 30% of stroke deaths can be attributed to hemorrhages.30 A hemorrhagic stroke is defined by a cerebral blood vessel leaking blood into the brain and can be divided further into two categories: ICH and aneurysmal subarachnoid hemorrhage (aSAH). Intracerebral hemorrhage describes a vessel rupture in the brain parenchyma resulting in the formation of a hematoma.31 In contrast, aSAH represents the subcategory of stroke that occurs when blood enters the subarachnoid space.32 The focus of this chapter will be ICH.

Epidemiology, Incidence, and Risk The incidence of ICH is about 24.6 per 100,000 person-years, making it the most common subtype of hemorrhagic stroke.31 The yearly incidence in the United States is about 795,000 people per year, with most being new strokes.33 Intracranial hemorrhage appears to be less common in women and has a strong association with age. Those 85 years and older appear to have an almost 10-fold higher yearly risk compared with those 45–54 years. Modifiable risk factors include hypertension (most important), smoking, alcohol use, diabetes mellitus, and anticoagulant/anti-platelet use. Of interest, lower cholesterol and triglyceride concentrations are associated with a higher risk. Other, non-modifiable risk factors include genetic predisposition, cerebral amyloid angiopathy, and Asian ethnicity.31 The incidence of ICH secondary to hypertension has decreased over time because of better treatment, yet the overall incidence of ICH has remained steady throughout the years. This has been explained by the increasing incidence of ICH caused by anticoagulant use.34

Pathophysiology Although the pathophysiology of hemorrhagic stroke is not quite as well defined as that of ischemic stroke, it is known that the damage is both

mechanical and chemical. The mechanical damage is secondary to mass effect. A hemorrhage with a volume greater than 30 mL is associated with a significant increase in morbidity and mortality. Mass effect can lead to increased intracranial pressure (ICP), herniation, and death,32,33 although the chemical changes occur secondary to the blood components and products of degradation. Intracerebral hemorrhage occurs after a rupture of a cerebral artery leading to blood entering the parenchymal space. This can be secondary to a complication from a preexisting lesion (e.g., vascular malformation or tumor) and is called secondary ICH. A primary ICH is the result of a hemorrhage in the absence of a clear underlying lesion. Primary is the most common ICH subcategory.31 As the hematoma starts to expand, there is an increase in ICP, causing a disruption in local tissue integrity and the blood-brain barrier. The hematoma also leads to an obstruction in venous outflow, thereby causing the release of tissue thromboplastin, leading to local coagulopathy. Cerebral edema then begins to form around the hematoma and can continue to develop over days after the initial insult. In up to 40% of cases, the hemorrhage extends into the cerebral ventricles, leading to another condition known as intraventricular hemorrhage, which is associated with a significantly worse prognosis. The onset of edema can cause mass effect in addition to the hematoma formation, leading to compression of local tissue and neurological dysfunction.33

Clinical Presentation, Diagnosis, and Severity The patient with classic ICH presents with focal neurological deficits progressing over minutes to hours, rather than the typically more abrupt progression seen in AIS. The patient with ICH often has accompanying headache, nausea, vomiting, increased blood pressure, and decreased level of consciousness. The symptoms are typically because of an increase in ICP and evidenced from the Cushing triad (hypertension, bradycardia, irregular respiration). Often, dysautonomia accounting for hyperventilation, tachypnea, bradycardia, fever, hypertension (systolic blood pressure greater than 220 mm Hg), and

hyperglycemia is also present.33 Because the symptoms are relatively indistinct, neuroimaging is imperative to diagnosis. Computed tomography is considered the gold standard for identification and is very sensitive for acute hemorrhage identification. Although magnetic resonance imaging (MRI) can be as sensitive for acute identification, it is more sensitive for prior hemorrhage than is CT. However, time, cost, and patient tolerance are some of the considerations that can inhibit emergency MRI. Intracerebral hemorrhage is a medical emergency, and rapid deterioration is not uncommon within the hours after onset. It has been shown that more than 15% of patients have a GCS (Glasgow Coma Scale) score decrease of 2 points or more within the first hour of hospital presentation.35,36 Although there is no widely used standard of grading for the severity of ICH, the most widely validated scoring tool is the ICH score (Table 21.3). It represents a 6-point scale that stratifies the severity according to the five risk factors that were deemed independent 30-day mortality indicators. Table 21.4 represents the 30-day mortality associated with the scoring in the original trial.37 Of note, no scoring system for ICH should be used as a solitary prognostic indicator. Treatment

Anticoagulant Reversal As mentioned before, although the incidence of stroke secondary to hypertension is decreasing because of better medical management, those presenting with hemorrhagic stroke secondary to oral anticoagulant use are now estimated to represent 12%–14% of patients with ICH. Therefore, identifying an underlying coagulopathy as a cause and risk of expansion should be at the forefront of the clinician’s mind. Vitamin K Antagonists If the ICH is related to a vitamin K antagonist (VKA), vitamin K 5-10 mg

intravenously should still be given for international normalized ratio (INR) reversal; however, the onset of even intravenous vitamin K typically begins at around 2 hours and therefore should not be used as the sole reversal agent, but should be part of the reversal algorithm for all VKA-related bleeds. Fresh frozen plasma (FFP), dosed at 10–15 mL/kg, was historically the adjunctive agent used with vitamin K in reversal of VKA, but its use is limited secondary to processing and thawing time, volume to be delivered, and immunologic reactions. The goal of INR reversal varies within the literature but ranges from less than 1.3 to less than 1.5.35,38 In more recent years, especially with the addition of the non- vitamin K antagonist oral anticoagulants (NOACs), direct thrombin inhibitors and factor Xa inhibitors to the market, factor products have gained much attention in the treatment of these bleeds. Prothrombin complex concentrates (PCCs) are plasma-derived concentrates that were developed to treat hemophilia. Three-factor PCCs contain factors II, IX, and X, whereas four-factor PCCs also contain factor VII. These products can rapidly be prepared for administration, do not require prolonged administration times, and do not have to be cross-matched, making them operationally advantageous to FFP. A study published in 2013 compared four-factor PCCs with FFP for emergency warfarin reversal with acute bleed (24 were patients with ICH) and found that the rate of achieving an INR less than 1.3 within 30 minutes was 62.2% and 9.6% for four-factor PCC and FFP, respectively.39 The study also showed similar betweengroup thromboembolic event rates (7.8% PCC and 6.4% FFP) but described fluid overload more commonly in the FFP group (12.8% vs. 4.9%). However, the literature comparing three- and four-factor PCC is not abundant. A study published in 2015 comparing the effectiveness of three- and four-factor PCC showed that patients who received fourfactor PCC and patients who had an INR reversal to 1.5 or less regardless of product were more likely to survive.40 In the United States, four-factor PCC is labeled for use in emergency reversal of warfarin, and dosing can be found in Table 21.5.41 However, of note, the four-factor product used in the United States does contain heparin and would be contraindicated in a patient with a history of heparin-

induced thrombocytopenia; therefore, a three-factor PCC product (Profilnine) could be considered as an alternative because the threefactor product Bebulin also contains heparin. Recombinant activated factor VII (rFVIIa) would not be expected to restore the thrombin generation inhibited by a VKA as well as PCC because it does not contain all the inhibited factors and is therefore not recommended for routine use in warfarin reversal.42,43 In addition, rFVIIa has been shown to have an increased risk of thromboembolic event,44 and adding rFVIIa to a three-factor PCC product would not be recommended. A higher risk of thromboembolic events would also be expected when using activated PCCs (factor eight inhibitor bypassing activity [FEIBA]) because of their activated prothrombotic components.

Table 21.3 ICH Score Component

Value Associated

GCS 3–4

2

5–12

1

13–15

0

Volume, cm 3 ≥ 30

1

< 30

0

IVH Yes

1

No

0

Infratentorial origin Yes

1

No

0

Age, years

≥ 80

1

< 80

0

GCS = Glasgow Coma Scale (score); IVH = intraventricular hemorrhage.

Table 21.4 30-Day Mortality Association with the ICH Score Score

30-Day Mortality (%)

N

0

0

26

1

13

32

2

26

27

3

72

32

4

97

29

5

100

6

6

Unknown

0

Non-vitamin K Antagonist/NOACs Although the literature describing the reversal of VKA provides needed guidance, the data describing the reversal of the NOACs is much less dense. Although PCC has been evaluated for use, the data are inconsistent. Increasing the levels of circulating factors is the rationale for using PCCs for VKA; however, in NOACs, the purpose of these products and of factor replacement, in general, is more an attempt to overcome the inhibition by creating a supranormal factor level.45 One study that evaluated the use of four-factor PCC (50 units of factor IX per kilogram) did show a correction of the prolonged PT and abnormal

endogenous thrombin potential in healthy subjects taking rivaroxaban.46 However, the data regarding reversal of direct thrombin inhibitors (e.g., dabigatran) are not as convincing.47 Activated PCCs (FEIBA) have also been studied for use in NOAC reversal and showed the ability to normalize abnormal thrombin generation times as well as reducing clot initiation time in patients receiving dabigatran. Therefore, it has been suggested that PCC has more of a role in reversal of factor Xa inhibitors, whereas patients with bleeds secondary to direct thrombin inhibitors may benefit from FEIBA (80 international units/kg).47 These suggested antidotes for NOACs do not actually affect the ongoing inhibition of the drugs on factors IIa and Xa, and although they may limit the extent of bleeding, the actual outcome in relation to morbidity or mortality is likely minimal.48 It is also prudent to note that if doses were recently ingested, charcoal may be an option, and dabigatran is not highly protein bound; therefore, circulating levels can be successfully removed by dialysis. In general, PCC and FEIBA are both reasonable options for the reversal of NOACs in the setting of lifethreatening ICH. The results are preliminary, but FEIBA may be a better option in the setting of bleeding secondary to a direct thrombin inhibitor, whereas four-factor PCC may be a more appropriate first-line option for factor Xa inhibitors. Of note, use of these products for this indication is off-label, and consultation with a hematology service is recommended, if available, and reasonable in the setting of the emergency. Although the current options and data for NOAC reversal are not well researched, new targeted antidotes are on the horizon, with idarucizumab for dabigatran reversal gaining significant attention, having just gained accelerated approval by the FDA on October 16, 2015.49

Table 21.5 Four-Factor PCC Dosing for Emergency VKA Reversal

INRbefore treatmcnt

2 to < 4

4 6

>6

Dosefunits of

25

35

50

-

factor IX )/ kg, maximumweight 100 kg

PCC = prothrombin complex concentrate; VKA = vitamin K antagonist.

Antiplatelet Reversal Although anticoagulants have been reliably linked to ICH, the data are more conflicting on the effects of prior antiplatelet treatment. It has been shown that platelet transfusion within 12 hours of symptom onset is associated with smaller final hemorrhage and even level of independence at 3 months.50 There are currently ongoing studies evaluating platelet transfusion in patients with ICH on prior antiplatelet therapy, which will hopefully elucidate the topic.

Blood Pressure Management It is unsurprising that elevated blood pressure is a common presentation in patients with ICH. This presentation can be related to persistent and pre-ICH elevations, as well as stress, pain, and increased ICP. Nonetheless, it is well documented that elevated systolic blood pressure is associated with hematoma expansion, neurological deterioration, and death or dependency after an event.5153 Although the safety and efficacy of systolic blood pressure lowering to 140 mm Hg or less has been well established in the literature,54-57 there is only a paucity of data relating to the safety and efficacy of this goal for those presenting with a systolic blood pressure greater than 220 mm Hg. Nonetheless, it may still be reasonable to explore

aggressive blood pressure lowering in those patients.35 Reasonable options for initial blood pressure lowering include bolus doses of labetalol or hydralazine or more aggressive management by a nicardipine or esmolol infusion.36

Surgical Intervention In addition to the medical interventions that can be made, surgical intervention is an option. Surgical interventions typically include clot removal or craniotomy. These procedures are typically reserved for rapidly deteriorating patients and are generally not recommended in early aggressive treatment of the non-rapidly deteriorating patient.35 Supportive Care

Location of Initial Care It is recommended that the initial care of the patient with ICH occur in a dedicated stroke unit or an ICU. In fact, care in a dedicated unit has been shown to improve mortality.58 Patients require close monitoring, and it is ideal to have staff trained specifically in the care of neurological injury.

Temperature Control One parameter that should be monitored is temperature. A temperature fluctuation in the patient with ICH is a predictor of outcome, and fever is a common occurrence in these patients and may be an indicator of hematoma expansion or increased ICP.59 Therefore, treatment of fever in patients with ICH is a reasonable clinical decision.55 Although there is a paucity of data to suggest that cooling reduces edema, the treatment is still considered experimental at this time.35

VTE Prophylaxis Patients presenting with an ICH are also at an increased risk of thromboembolic events, with women and African Americans being at the highest risk; therefore, consideration must be given to prevention of such complications during the patient’s admission. It is generally accepted that these patients should use an intermittent pneumatic compression device in addition to compression stockings for prevention.60-62 Although it may seem counterintuitive, these patients may also benefit from prophylaxis with low-molecular-weight or unfractionated heparin. A meta-analysis published in 2011 showed that early use of chemical thromboprophylaxis was associated with a reduction in pulmonary embolism. There was no difference in hematoma enlargement between groups.35,63 The ideal timing of initiation of pharmacologic prophylaxis is unclear.

Glucose Management Glucose monitoring is an important component of post-ICH management. Although clearly defined goals have not so far been established, both hyperglycemia and hypoglycemia are associated with worse outcomes. Therefore, therapy should be initiated to prevent hyperglycemia and hypoglycemia.64,65

Seizure Prophylaxis Secondary to the neurologic nature of ICH injury, patients are at risk of seizures, and ICH has an early seizure (within 1 week) frequency of about 16%. Although anti-epileptic drugs reduce the number of clinical seizures, this has yet to be associated with improved neurologic outcome or mortality. However, data suggest that prophylaxis with these medications (especially phenytoin) is associated with increased mortality and disability. Therefore, routine use of seizure prophylaxis is not currently recommended and should be used when patient examination indicates a suspicion of seizure.35

REFERENCES 1. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:227-76. 2. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 2014;129:e28-e292. 3. Varon J, Marik PE. The diagnosis and management of hypertensive crises. Chest 2000;118:214-27. 4. Hall MJ, Levant S, DeFrances CJ. Hospitalization for stroke in U.S. hospitals, 1989-2009. NCHS Data Brief 2012;95:1-8. 5. Maaijwee NA, Rutten-Jacobs LC, Schaapsmeerders P, et al. Ischaemic stroke in young adults: risk factors and long-term consequences. Nat Rev Neurol 2014;10:315-25. 6. Jauch EC, Cucchiara B, Adeoye O, et al. Part 11: adult stroke: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2010;122(18 suppl 3):S818-28. 7. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870947. 8. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-29. 9. Francart SJ, Hawes EM, Deal AM, et al. Performance of coagulation tests in patients on therapeutic doses of rivaroxaban. A cross-sectional pharmacodynamic study based on peak and trough plasma levels. Thromb Haemost 2014;111:1133-40.

10. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-7. 11. Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA 2000;283:1151-8. 12. Fugate JE, Kalimullah EA, Wijdicks EF. Angioedema after tPA: what neurointensivists should know. Neurocrit Care 2012;16:4403. 13. Maertins M, Wold R, Swider M. Angioedema after administration of tPA for ischemic stroke: case report. Air Med J 2011;30:276-8. 14. Tanswell P, Modi N, Combs D, et al. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet 2002;41:1229-45. 15. Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med 2012;366:1099-107. 16. Logallo N, Kvistad CE, Nacu A, et al. The Norwegian tenecteplase stroke trial (NOR-TEST): randomised controlled trial of tenecteplase vs. alteplase in acute ischaemic stroke. BMC Neurol 2014;14:106-2377-14-106. 17. Albers GW, von Kummer R, Truelsen T, et al. Safety and efficacy of desmoteplase given 3-9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet Neurol 2015;14:575-84. 18. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. the PROACT II study: a randomized controlled trial. prolyse in acute cerebral thromboembolism. JAMA 1999;282:2003-11. 19. Ogawa A, Mori E, Minematsu K, et al. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral

artery stroke: the middle cerebral artery embolism local fibrinolytic intervention trial (MELT) Japan. Stroke 2007;38:2633-9. 20. IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the interventional management of stroke study. Stroke 2004;35:904-11. 21. IMS II Trial Investigators. The interventional management of stroke (IMS) II study. Stroke 2007;38:2127-35. 22. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med 2015;372:11-20. 23. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015;372:1009-18. 24. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015;372:1019-30. 25. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) collaborative group. Lancet 1997;349:1641-9. 26. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997;349:1569-81. 27. Sherman DG, Albers GW, Bladin C, et al. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL study): an open-label randomised comparison. Lancet 2007;369:1347-55. 28. World Health Organization. The Top 10 Causes of Death 2014. Available at www.who.int/mediacentre/​factsheets/fs310/en/​ index4.html. Accessed October 14, 2015.

29. Andersen KK, Olsen TS, Dehlendorff C, et al. Hemorrhagic and ischemic strokes compared: stroke severity, mortality, and risk factors. Stroke 2009;40:2068-72. 30. National Stroke Association. Hemorrhagic Stroke Fact Sheet. 2009. Available at www.stroke.org/strokeresources/library/hemorrhagic-stroke. Accessed October 14, 2015. 31. Ikram MA, Wieberdink RG, Koudstaal PJ. International epidemiology of intracerebral hemorrhage. Curr Atheroscler Rep 2012;14:300-6. 32. Fagan SC, Hess DC. Stroke. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill, 2008:373-81. 33. Magistris F, Bazak S, Martin J. Intracerebral hemorrhage: pathophysiology, diagnosis and management. MUMJ 2013;10:1522. 34. Lovelock CE, Molyneux AJ, Rothwell PM. Change in incidence and aetiology of intracerebral haemorrhage in Oxfordshire, UK, between 1981 and 2006: a population-based study. Lancet Neurol 2007;6:487-93. 35. Hemphill JC III, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015;46:203260. 36. Morgenstern LB, Hemphill JC III, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2010;41:210829. 37. Hemphill JC III, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage.

Stroke 2001;32:891-7. 38. Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012;43:171137. 39. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013;128:123443. 40. Voils SA, Holder MC, Premraj S, et al. Comparative effectiveness of 3- versus 4-factor prothrombin complex concentrate for emergent warfarin reversal. Thromb Res 2015;136:595-8. 41. Behring C. Frequently Asked Questions 2014. Available at www.kcentra.com/professional/resources/frequently-askedquestions.aspx?role=pharmacist. 42. Rosovsky RP, Crowther MA. What is the evidence for the offlabel use of recombinant factor VIIa (rFVIIa) in the acute reversal of warfarin? ASH evidence-based review 2008. Hematology Am Soc Hematol Educ Program 2008:36-8. 43. Tanaka KA, Szlam F, Dickneite G, Levy JH. Effects of prothrombin complex concentrate and recombinant activated factor VII on vitamin K antagonist induced anticoagulation. Thromb Res 2008;122:117-23. 44. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352:777-85. 45. Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost 2014;111:189-98. 46. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of

rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-9. 47. Siegal DM, Cuker A. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis 2013;35:391-8. 48. Lazo-Langner A, Lang ES, Douketis J. Clinical review: clinical management of new oral anticoagulants: a structured review with emphasis on the reversal of bleeding complications. Crit Care 2013;17:230. 49. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-20. 50. Naidech AM, Liebling SM, Rosenberg NF, et al. Early platelet transfusion improves platelet activity and may improve outcomes after intracerebral hemorrhage. Neurocrit Care 2012;16:82-7. 51. Rodriguez-Luna D, Pineiro S, Rubiera M, et al. Impact of blood pressure changes and course on hematoma growth in acute intracerebral hemorrhage. Eur J Neurol 2013;20:1277-83. 52. Sakamoto Y, Koga M, Yamagami H, et al. Systolic blood pressure after intravenous antihypertensive treatment and clinical outcomes in hyperacute intracerebral hemorrhage: the stroke acute management with urgent risk-factor assessment and improvement-intracerebral hemorrhage study. Stroke 2013;44:1846-51. 53. Zhang Y, Reilly KH, Tong W, et al. Blood pressure and clinical outcome among patients with acute stroke in Inner Mongolia, China. J Hypertens 2008;26:1446-52. 54. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368:2355-65. 55. Anderson CS, Huang Y, Wang JG, et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a

randomised pilot trial. Lancet Neurol 2008;7:391-9. 56. Arima H, Huang Y, Wang JG, et al. Earlier blood pressurelowering and greater attenuation of hematoma growth in acute intracerebral hemorrhage: INTERACT pilot phase. Stroke 2012;43:2236-8. 57. Qureshi AI, Palesch YY, Martin R, et al. Effect of systolic blood pressure reduction on hematoma expansion, perihematomal edema, and 3-month outcome among patients with intracerebral hemorrhage: results from the antihypertensive treatment of acute cerebral hemorrhage study. Arch Neurol 2010;67:570-6. 58. Diringer MN, Edwards DF. Admission to a neurologic/neurosurgical intensive care unit is associated with reduced mortality rate after intracerebral hemorrhage. Crit Care Med 2001;29:635-40. 59. Schwarz S, Hafner K, Aschoff A, et al. Incidence and prognostic significance of fever following intracerebral hemorrhage. Neurology 2000;54:354-61. 60. Dennis M, Sandercock P, Reid J, et al. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. Lancet 2013;382:516-24. 61. Dennis M, Sandercock P, Reid J, et al. The effect of graduated compression stockings on long-term outcomes after stroke: the CLOTS trials 1 and 2. Stroke 2013;44:1075-9. 62. Dennis M, Sandercock PA, Reid J, et al. Effectiveness of thighlength graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial. Lancet 2009;373:1958-65. 63. Paciaroni M, Agnelli G, Venti M, et al. Efficacy and safety of anticoagulants in the prevention of venous thromboembolism in patients with acute cerebral hemorrhage: a meta-analysis of controlled studies. J Thromb Haemost 2011;9:893-8.

64. Oddo M, Schmidt JM, Carrera E, et al. Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: a microdialysis study. Crit Care Med 2008;36:3233-8. 65. Fogelholm R, Murros K, Rissanen A, et al. Admission blood glucose and short term survival in primary intracerebral haemorrhage: a population-based study. J Neurol Neurosurg Psychiatry 2005;76:349-53.

Chapter 22 Critical Care

Management of Aneurysmal Subarachnoid Hemorrhage Denise H. Rhoney, Pharm.D., FCCP, FCCM, FNCS; Kathryn Morbitzer, Pharm.D.; and J. Dedrick Jordan, M.D., Ph.D.

LEARNING OBJECTIVES 1. Describe the epidemiology and risk factors of aneurysmal subarachnoid hemorrhage (aSAH). 2. Explain the complex pathophysiological mechanisms of early brain injury and delayed cerebral ischemia. 3. Discuss the clinical presentation of patients with aSAH and clinical severity scores. 4. Outline the predictors of outcome after aSAH. 5. Recognize the common neurological and medical complications associated with aSAH. 6. Develop an evidence-based treatment plan for preventing and treating each neurological and medical complication.

ABBREVIATIONS IN THIS CHAPTER aSAH

Aneurysmal subarachnoid hemorrhage

CPP

Cerebral perfusion pressure

CSF

Cerebrospinal fluid

DCI

Delayed cerebral ischemia

DVT

Deep venous thrombosis

GCS

Glasgow Coma Scale

ICP

Intracranial pressure

ICU

Intensive care unit

TCD

Transcranial Doppler

INTRODUCTION Subarachnoid hemorrhage refers to bleeding that occurs in the subarachnoid space, between the pia and the arachnoid membranes, and can be spontaneous or secondary to trauma. The focus of this chapter will be spontaneous subarachnoid hemorrhage, which is caused by the rupture of a saccular aneurysm in 80% of cases. Aneurysmal subarachnoid hemorrhage (aSAH) accounts for about 7% of all strokes and is associated with high morbidity and mortality.1 The disease course can be prolonged and can be associated with serious neurological and medical complications that compromise patient outcomes. The clinical effects of aSAH are biphasic, consisting of early brain injury as a result of the initial impact of the hemorrhage, followed by several secondary pathophysiological events. As a result, patients are routinely admitted to an intensive care unit (ICU) and are ideally cared for by a multidisciplinary care team.

Epidemiology The annual incidence of aSAH varies widely in different regions of the world, from 2 to 20 cases per 100,000.2 Studies from the World Health Organization report an age-adjusted annual incidence of 2 cases per 100,000 population in China to 22.5 cases per 100,000 in Finland.1 Overall, the incidence is higher in Finland and Japan and lower in South and Central America. In the United States, the incidence is estimated at 14.5 cases per 100,000 annually.3 This may be an underestimate, however, because up to 15% of patients die before receiving medical care.2 The incidence of aSAH is reported to be 1.24 times (95% confidence interval [CI], 1.09–1.42) higher in women than in men and increases with age, with the typical age of onset at 50 years or older.1,3,4 Race and ethnicity also affect aSAH incidence, with African Americans and Hispanics having a higher incidence than white Americans.5

Risk Factors Independent modifiable risk factors include hypertension, smoking, alcohol use, and use of sympathomimetic drugs, whereas nonmodifiable risk factors include sex, age, size of aneurysm, and family history.6,7 When assessing risk factors, it is important to consider the risk factors for aneurysm formation and growth together with aSAH. Cigarette smoking has been identified as an important risk factor for aneurysm formation, growth, and rupture.6,8-10 Hypertension can be considered a significant risk factor for aSAH but may be less of a risk than in other types of stroke. Data on the role of hypertension on aneurysm formation and growth are inconsistent; however, hypertension should be treated for many other reasons, and in doing so, the risk of aSAH may be reduced. If the systolic blood pressure exceeds 130 mm Hg, the risk is twice as high, and if the systolic blood pressure is above 170 mm Hg, the risk is 3 times as high.6,10,11 The role of alcohol use is a less-established risk factor than cigarette

smoking, with several studies showing that excessive alcohol consumption (greater than 150 g/week) increases the risk of aSAH.9,10 More traditional cardiovascular risk factors like diabetes and hypercholesterolemia have a less-defined relationship for aSAH or aneurysm formation and growth. A family history of intracranial aneurysms suggests a genetic component to this disease. Siblings of patients with aSAH have a 6-fold increased risk of developing aSAH, and there is a 3–7 times higher risk in first- degree relatives of patients with aSAH than in the general population.12 Familial aneurysms are usually larger at the time of rupture and are more likely located in the middle cerebral artery; also, the age at presentation is typically younger.12 Other risk factors for forming intracranial aneurysms include sickle cell disease, α2antitrypsin deficiency, polycystic kidney disease, and inheritable connective tissue disorders (e.g., fibromuscular dysplasia).

Outcomes Although mortality rates have declined throughout the past 3 decades, aSAH remains a devastating neurological disease. Estimations of current mortality rates show that 10%–15% of patients die before reaching the hospital, whereas 40% die within the first week and 50% die within the first 6 months. Rebleeding also carries a high mortality rate of 51%–80%.13 Of those who survive, up to 50% have some degree of cognitive dysfunction long term.14 Survivors commonly have deficits in memory, executive function, and language that significantly affect their day-to-day function. These deficits in cognition are further compounded by anxiety, depression, fatigue, and sleep disturbances.15 The most important predictive factors for an acute prognosis after aSAH include the following16-19: Level of consciousness and neurological grade on admission Patient age (younger patients do better) Amount of blood on the initial head computed tomography (CT) scan and location of blood (presence of intraventricular

hemorrhage carries a worse prognosis) Presence of comorbid conditions and the hospital course (e.g., infections, myocardial ischemia, anemia) Location of aneurysm (anterior circulation aneurysms carry a more favorable prognosis) Aneurysm rebleeding Global cerebral edema Hyperglycemia The rebleeding rate is 2%–4% within the first 24 hours and 15%– 20% within the first 2 weeks if the aneurysm is not secured and is a significant cause of poor outcomes early on. Factors associated with poor outcomes that develop later include cerebral infarction, delayed cerebral ischemia (DCI), fever, and use of anticonvulsant agents, particularly phenytoin.16

PATHOPHYSIOLOGY Aneurysm Formation The pathogenesis of intracranial aneurysms is complex. Historically, congenital causes were thought to play a major role in aneurysm development; however, only 10% of cases appear to be attributable to genetic/familial causes. The current theory is that aneurysms develop gradually throughout an individual’s lifetime because of acquired changes in the intracranial arterial wall. In patients without the previously discussed risk factors, the prevalence of aneurysms is only 2.3%.20 Inflammation may also play a role in aneurysm formation, with several inflammatory cytokines being implicated in endothelial injury and remodeling.21 Inflammation is becoming an attractive therapeutic target because aspirin may reduce the rate of aneurysm rupture, given its anti-inflammatory properties; however, more definitive studies are required.22 Saccular or berry aneurysms account for 80% of aSAH cases and

are specific to intracranial arteries because their walls lack an external elastic lamina and contain a very thin adventitia. Rupture of arteriovenous malformations is the second most identifiable cause of aSAH, accounting for 10% of cases. The remaining cases can result from rupture of these pathologic entities: mycotic aneurysm, angioma, neoplasm, or cortical thrombosis. The circle of Willis is the most common area in the cerebral circulation for the development of cerebral aneurysms (see Figure 22.1). The bifurcations of these major vessels are particularly vulnerable to aneurysm formation because of hemodynamic factors such as wall sheer stress and mechanical stretch.23 Most ruptured aneurysms (89%) arise from the anterior circulation.24 In 25% of cases, aneurysms are present. Most aneurysms do not rupture according to radiographic and autopsy studies, which report a higher incidence of intracranial saccular aneurysms than of aSAH.25 The probability of rupture is related to the tension on the artery wall and is directly related to the aneurysm size. Aneurysms with a diameter of 5 mm or less have a 2.5% risk of rupture, whereas 41% of those with a diameter of 6–10 mm have already ruptured on diagnosis. Aneurysms larger than 10 mm in diameter are 5 times more likely to rupture than small aneurysms. The annual risk of rupture for aneurysms less than 10 mm is 0.7%. The exact mechanism for aneurysm rupture is not fully understood, but it may be precipitated in activities that result in a sudden increase in arterial blood pressure (e.g., sneezing, exercise, sexual intercourse) in less than one-third of cases.26

Early Brain Injury Early brain injury has been used to describe the mechanisms of acute (first 72 hours) neurological deterioration after aSAH and is the result of physiological derangements such as increased intracranial pressure (ICP), decreased cerebral blood flow, and global cerebral ischemia. These physiologic derangements result in blood-brain barrier dysfunction, inflammation, and oxidative cascades that lead to neuronal

cell death. The consequences can result in death or severe neurological deficits. Although vasospasm is thought to be the main cause of clinical deterioration after aSAH, more recent thinking has focused on the fact that vasospasm is not the only pathophysiological factor contributing to poor patient outcomes.27 Recently, a study showed an increase in the neuroinflammatory response after aSAH at days 2–3 with no evidence angiographically of vasospasm, and this response was associated with a poor outcome at 3 months.28 Evidence also suggests that the cascade of events set in motion in early brain injury contributes to the delayed neurological deterioration traditionally attributed to vasospasm.27 Figure 22.2 describes the complex pathophysiological events after aSAH that lead to early brain injury and DCI.

Anterior Communicating Artery Anterior Cerebral Artery

Anterior Cerebral Artery

i

r 35%

Middle Cerebral Artery

\

40% 20%|

X

\

Middle Cerebral Artery

Internal Carotid Artery

Posterior Communicating Artery

>





60 mm Hg

• CPP > 60 mm Hg

CPP > 60 mm Hg

GEDI: Avoid < 680 mL/m

• GEDI: Avoid < 680 mL/m

ELWI < 10 mL / kg

•

Hgb > 8 mg /dL

• Hgb > 8 mg/dL

Sa02 > 93%

•

2

2

GEDI: Avoid < 680 mL/m2

ELWI < 10 mL / kg

ELWI < 10 mL/kg Hgb > 8 mg/ dL

Blood glucose < 200 mg /dL ( avoidhypoglycemia )

Blood glucose < 200 mg / dL ( avoid hypoglycemia ) Serum magnesium > 2 mg /dL

• Serum magnesium > 2 mg /dL •

Serum sodium > 135 mEq / L

Serum sodium > 135 mEq / L

Mean cerebral blood flow velocity < 120 cm /s Intervention( s)

• Early aneurysm repair

• Oral /enteral nimodipine 60 mg PO

PO q 4hr x 21 days •

•

Controlagitation/maintain adequate analgesia /sedation (ifintubated )

• Controlagitation/maintain adequate analgesia/sedation (ifintubated )

as indicated •

Consideranticonvulsant agent for 3-7 days

agent ( nicardipine/clevidipine )

•

0.9 % NaCI1-1.5 mL / kg/ hr

0.9 % NaCI1-1.5 mL/ kg/ hr

•

VTE prophylaxis ( heparin 5000 units SC q8-12hr or LMWH 40 mg q24hr) + graduated compression devices

• Continuous infusion BP -lowering

•

• Consideranticonvulsant agent for 3-7 days • Maintain head of bead elevation 20 -30"

•

Maintain head of bed elevation 20 -30°

• Graduated compression devices

•

Considerhypertonicsaline if hyponatremic

• Swallowassessmentbeforeoral

intake

• Control agitation /maintain adequate analgesia /sedation ( if intubated) •

• Treat ICP using stepwise approach

Nausea / vomitingtreatment

• Bowel regimen

Oral /enteral nimodipine 60 mg PO q 4hr x 21 days

q4hr x 21days

• Oral /enteral nimodipine 60 mg

•

Treat ICP using stepwise approach as indicated Induced hypertension witb vasopressors ( phenylephrine or norepinephrine) and /or

hemodynamic augmentation with inotropes ( dobutamine or milrinone ) for symptomatic vasospasm •

0.9% NaCI 1-1.5 mL/ kg / hr

• DVT prophylaxis ( heparin 5000 units SC

q8-12 hror LMWH 40 mgq24hr) •

Maintain head of bed elevation 20 -30°

• Consider hypertonic saline if hyponatremic •

Consider anticonvulsant agent for 3-7 days

•

Bowel regimen

BP = blood pressure; CPP = cerebral perfusion pressure; ELWI = extravascular lung water index; GEDI = global end-diastolic volume index; ICP = intracranial pressure; LMWH = low-molecular-weight heparin; NaCl = sodium chloride; PO = orally; q = every; Sao2= arterial oxygen saturation; SBP = systolic blood pressure; SC = subcutaneously; TCD =

transcranial Doppler; VTE = venous thromboembolism.

Table 22.3 Pharmacotherapy Recommendations from Clinical Guidelines

AHA / ASA Guideline44

Class of Evidence

Level of Evidence

Between the time of aSAH symptom onset and aneurysm obliteration, BP should be controlled with titratable agent

I

B

Magnitude of BP control has not been established, but a decease to < 160 mm Hg isreasonable

Ila

C

For patients with an unavoidable delay in obliteration of aneurysm, a significant risk of rebleeding, and no compelling medication contraindications, short -term (< 72 hr ) therapy with tranexamic acid or aminocaproic acid is reasonable to reduce the risk of early aneurysm rebleeding

Ila

B

NCS Consensus Statements45

Qualityof Evidence

Recommendation

Low

Weak

Antifibrinolytic therapy is relatively contraindicated in patients with risk factors for thromboembolic complications

Moderate

Strong

Antifibrinolytic therapy should be discontinued 2 hr before planned endovascular aneurysm ablation

Very low

Weak

High

Strong

lf nimodipine administration results in hypotension, dosing intervals should be changed to more frequent lower doses. If hypotension continues to occur, nimodipine may be discontinued

Low

Strong

Patients clinically suspected of h åving DCI should undergo a trial of induced hypertension; choice of vasopressor should be based on the other pharmacologic properties of the agents ( e.g., inotropy, tachycardia )

Moderate

Strong

BP augmentation should progress in a stepwise fashion with assessment of neurologic function at each MAP level to determine whether a higher BP farget is appropriate

Poor

Strong

Recommendation Prevention of Rebleeding:

Treatment / Prevention of DCI:

Oral nimodipine ( 60 mg q 4hr x 21 days ) is indicated to reduce poor outcome relatedtoaSAH

I

A

Induction of hypertension is recommended for patients with DCI unless BP is elevated at baseline or cardiac status precludes it

I

B

Maintenance of euvolemia and normal circulating blood volume is recommended to prevent DCI

I

B

Moderate

Strong

B

High

Strong

In patients with a persistent negative fluid balance, use of fludrocortisone or hydrocortisone may be considered

Moderate

Weak

Consider a saline bolus to increase CSF in areas of ischemia as a prelude to other interventions

Moderate

Weak

Isotonic crystalloid is the preferred agent for volume replacement

Moderate

Weak

If patients with DCI do not improve with BP augmentation, a trial of inotropic therapy may be considered

Low

Strong

Inotropes with prominent p2-agonist properties ( e.g., dobutamine) may lower MAP and require increase in vasopressor dosage

High

Strong

Hemodilution in an attempt to improve rheology should not be undertaken except in cases of erythrocythemia

Moderate

Strong

Patients should receive packed RBC transfusions to maintain hemoglobin concentration above 8-10 g / dL

Moderate

Strong

Prophylactic hypervolemia or balloon angioplasty before the development of angiographic spasm is not recommended

Higher hemoglobin concentrations may be appropriate for patients at risk of DCI, but whether transfusion is useful cannot be determined from the available data

No

Strong

Moderate

Strong

Moderate

Strong

Low

Strong

Very low

Weak

lf anticonvulsant prophylaxis is used, a short course (3-7 days) is recommended

Low

Weak

In patients who have a seizure after presentation, anticonvulsants should be continued for a duration defined by local practice

Low

Weak

High

Strong

Moderate

Strong

Unfractionated heparin for prophylaxis could be initiated 24 hr after undergoing surgery

Moderate

Strong

Unfractionated heparin and LMWH should be withheld 24 hr before and after intracranial procedures

Moderate

Strong

LMWH or unfractionated heparin for prophylaxis should be withheld in patients with unprotected aneurysms who are expected to undergo surgery

Low

Strong

The duration of DVT prophylaxis is presently uncertain, but may be based on patient mobility

Low

Weak

High

Strong

Endovascular treatment using intra- arterial vasodilators and/ or angioplasty may be considered for vasospasm-related DCI

Ila

B

The timing and triggers of endovascular treatment of vasospasm remain unclear, but generally, rescue therapy should be considered for ischemic symptoms that remain refractory to medical treatment

SeizureProphylaxis: Routine use of anticonvulsant prophylaxis with phenytoin is not recommended after aSAH

Routine use of other anticonvulsants for prophylaxis may be considered

The use of prophylactic anticonvulsants may be considered in the immediate posthemorrhagic period

Ila

The routine long -term use of anticonvulsants is not recommended May consider use of long -term anticonvulsants in patients considered at risk of delayed seizures such as prior seizure, intracerebral hematoma , intractable hypertension, infarction, or aneurysm at the middle cerebral artery

B

B I Ib

B

General Critical Care Management:

Hypoglycemia ( serum glucose < 80 mg /dL) should be avoided

Serum glucose should be maintained at < 200 mg / dL Careful glucose management with strict avoidance of hypoglycemia may be considered as part of the general critical care management of patients with aSAH

llb

B

Sequential compression devices should be routinely used in all patients Heparin -induced thrombocytopenia and DVT are relatively common complications after aSAH. Early identification and targeted treatment are recommended, but further research is needed to identify the idea screening paradigms

I

B

Aggressive control of fever to target normothermia using standard or advanced temperature -modulating systems is reasonable in the acute phase of aSAH

Ila

B

Antipyretic agents ( acetaminophen, ibuprofen) should be used as first line therapy, even though efficacy is low

Moderate

Strong

Surface cooling or intravascular devices should be used when antipyretics fail it fever control is highly desirable

High

Strong

During the period of risk for DCI, control of fever is desirable; intensity should reflect the individual patients relative risk of ischemia

Low

Strong

Moderate

Strong

Moderate

Weak

Hypomagnesemia should be avoided The use of fludrocortisone acetate and hypertonic saline solution is reasonable for preventing and correcting hyponatremia Do not treat hyponatremia with fluid restriction

Ila

B

Weak

Strong

Early treatment with hydrocortisone or fludrocortisone may be used to limit natriuresis and hyponatremia

Moderate

Weak

Mild hypertonic saline Solutions can be used to correct hyponatremia

Very low

Strong

Weak

Strong

Extreme caution to avoid hypovolemia is needed if vasopressinreceptor antagonists are used for treatment of hyponatremia

Very low

Strong

Hormonal replacement with stress- dose corticosteroids for patients with vasospasm and unresponsiveness to induced hypertension may beconsidered

Free water intake by intravenous and enteral routes should be limited

Weak

Weak

High- dose corticosteroids are not recommended

High

Weak

Moderate

Weak

Low

Strong

Consider hypothalamic dysfunction in patients unresponsive to vasopressors Patients taking statins before presenting with aSAH should have their medication continued in the acute phase

SAH = aneurysmal subarachnoid hemorrhage; DCI = delayed cerebral ischemia.

Strict blood pressure control in the acute phase until the aneurysm is secured is reasonable to reduce the risk of rebleeding. Although no prospective studies show a reduction in rebleeding with aggressive blood pressure control, the consensus guidelines recommend a treatment systolic blood pressure threshold of 160 mm Hg.44,45 If antihypertensive therapy is indicated, an intravenous agent that is easily titratable to goal blood pressure and that has minimal negative effects on cerebral hemodynamics should be used.58 The use of intermittent bolus doses of antihypertensives such as labetalol may be effective; however, intermittent bolus dosing may lead to significant blood pressure variability. A continuous intravenous infusion such as nicardipine or clevidipine can be titrated more effectively to maintain the blood pressure goal.59 Please see Table 22.4 for a comparison of the acute blood pressure–lowering agents that can be used to manage

blood pressure before securing the aneurysm. The use of antifibrinolytics (tranexamic acid or amino-caproic acid) in the immediate period after hemorrhage and before treatment of the aneurysm is reasonable; antifibrinolytics should be considered primarily in patients who cannot have the aneurysm secured in a timely manner. Data have been conflicting regarding the effectiveness and safety of these agents; however, much of the debate surrounds the timing and duration of treatment. Patients treated with antifibrinolytic therapy for a prolonged period appear to have an increased risk of DCI.60 A recent Cochrane analysis does not support the use of antifibrinolytics to reduce the risk of rebleeding; however, this analysis included only one study that limited the use to 72 hours.61 More recent studies limiting the use of therapy to 72 hours have shown a benefit in reducing the risk of rebleeding from about 10% to 3%.62-64 Short-term treatment with antifibrinolytics can be considered, especially for patients who cannot be treated immediately.44,45 The definitive prevention for rebleeding is aneurysmal coiling or clipping, and any benefit from antifibrinolytics in SAH is likely to be a temporary measure until the offending aneurysm is secured. Delayed (greater than 48 hours from ictus) or prolonged (greater than 3 days) use of antifibrinolytic agents exposes patients to adverse effects such as cerebral infarction during the time for which the risk of rebleeding is reduced and vasospasm is increased and thus should be avoided.45 The key treatment in aSAH is stabilizing the aneurysm to prevent rebleeding. Two approaches can be taken: surgical clipping and endovascular coiling. In endovascular coiling, a catheter is placed in the artery to gain access to the aneurysm, after which platinum coils are placed inside the aneurysm to embolize the aneurysm. Clipping is an invasive surgical intervention whereby a surgical clip is placed over the aneurysm, obliterating it and blocking blood flow into the aneurysm. Long-term controversy exists on which intervention is preferred because both interventions are effective. To date, the International Subarachnoid Aneurysm Trial (ISAT) has been the largest study (more than 2,100 patients) to compare coiling and clipping.65,66 The results showed that endovascular coiling was associated with a lower 1-year

mortality rate compared with surgical clipping (absolute risk reduction 7.4%; relative risk reduction 23.9%). However, long-term follow-up showed that rebleeding rates and the need for additional coiling were more frequent in patients treated with intravascular coiling. The risk of death at 5 years was significantly lower in the coiling group.67 Attempts have been made to identify subgroups of patients for which one approach may be preferred to the other. Most clinicians agree that clipping may be preferred in patients presenting with large (greater than 50 mL) intraparenchymal hematomas and middle cerebral artery aneurysms, whereas endovascular coiling may be considered in older adults (older than 70 years), those presenting with poor-grade aSAH (World Federation of Neurological Surgeons classification IV/V), and those with aneurysms of the basilar tip.44 Overall, the current guidelines recommend that surgical clipping or coiling be done as early as feasible in most patients to reduce the rate of rebleeding (class I; level of evidence B), and the determination of treatment should be a multidisciplinary decision based on characteristics of the patient and the aneurysm (class I; level of evidence C).44

Seizures Seizures after aSAH are of concern because of their association with early complications, such as rebleeding and poor outcomes.68,69 The reported incidence of seizures remains highest at the time of aneurysm rupture, with a rate varying from 4% to 26%. This discrepancy in reported events is partly because of the occurrence of both seizures and seizure-like phenomena, which may be difficult to distinguish, at the time of aneurysm rupture.69-73 After aneurysm treatment, the incidence of seizures appears low and may be related to the method in which the aneurysm was secured, thickness of the subarachnoid clot, aneurysm location, presence of subdural hematoma, and secondary cerebral infarction.72 The ISAT study reported that the frequency of seizures was 0.65% after hospitalization but before treatment and 2.3% between treatment and discharge. The frequency of seizures after treatment and before

discharge was doubled in patients treated with surgical clipping (3.1%) compared with patients undergoing endovascular treatment (1.5%).66 In a 14-year follow-up, 10.9% of patients enrolled in ISAT had a seizure. During this period, there was a higher incidence of posttreatment seizures in patients who underwent surgical clipping compared with endovascular coiling (13.6% vs. 8.3%, p=0.014).74 Appropriate management of seizures related to aSAH remains an area of debate. Although the use of prophylactic antiepileptic drugs in the setting of aSAH is common, there is a paucity of evidence showing the safety and efficacy of this practice. This has led to highly variable practice between institutions and physicians.69 Most literature evaluating the use of prophylactic antiepileptic drugs in the setting of aSAH is observational and focuses mainly on phenytoin. One of the first studies published evaluating this area described the early use of a short perioperative course of phenytoin for seizure prophylaxis in lowrisk patients. Patients without a history of seizure disorder, cerebral ischemia, parenchymal clot, postoperative hematoma, or concomitant arteriovenous malformation received a phenytoin 900- to 1100-mg load, followed by 300 mg/day for an average of 5.3 days. The overall seizure rate was 5.4% with an average follow-up of 2.4 years, leading the authors to advocate for no more than 7 days of phenytoin for seizure prophylaxis in most patients with aSAH.75 A retrospective review of 453 patients built on these data by comparing phenytoin prophylaxis (1000-mg loading dose, followed by 300 mg/day) through hospital discharge (average 14 days) to 3 days. This review found a similar incidence of seizures between the two groups during hospitalization (discharge 1.3% vs. 3 days 1.9%, p=0.6) and at followup (5.7% vs. 4.6%, p=0.6; follow-up ranged from 3 to 12 months).76 Of note, few of these studies included a high percentage of patients who were treated with coiling of the aneurysm, so most of the data are from aneurysm clipping. The use of phenytoin is not without risk because several studies have shown phenytoin to have a negative impact on neurological outcomes.77,78 In addition, phenytoin is a significant inhibitor and inducer of many hepatic enzymes, leading to potential drug-drug

interactions.72 Literature regarding the use of alternative antiepileptic drugs for seizure prophylaxis in the setting of aSAH is scarce, with the most support currently for levetiracetam. One retrospective study (n=442) compared short-course levetiracetam (500 mg twice daily; median therapy duration 3.6 days) with extended-duration phenytoin (15- to 20mg/kg loading dose, followed by maintenance dose; median therapy duration 13.7 days) for seizure prophylaxis after aSAH. The levetiracetam group had a higher incidence of in-hospital seizures (8.3% vs. 3.4%, p=0.03); however, this was driven by the increased incidence of late seizures in the levetiracetam group, which suggests a longer duration of prophylaxis is needed.79 Levetiracetam was also compared with phenytoin for seizure prophylaxis in a prospective, single-center, randomized trial of patients with severe traumatic brain injury or subarachnoid hemorrhage (n=52; 89% of patients included in the trial had a primary diagnosis of severe traumatic brain injury). Patients received either phenytoin (20 mg/kg load, followed by 5 mg/kg/day) or levetiracetam (20 mg/kg load, followed by 1000 mg twice daily) for 7 days. No difference was observed in seizure occurrence (phenytoin group: 16.7% vs. levetiracetam group 14.7%, p=1.0), and patients in the levetiracetam group had better outcomes in Disability Rating Scale scores and higher Glasgow Outcomes ScaleExtended scores at 3 and 6 months.80 The lack of high-quality literature available regarding seizure prophylaxis in this population is reflected in the current guidelines (see Table 22.3). The NCS guidelines recommend against the use of phenytoin for seizure prophylaxis, although they state that the role of other antiepileptic drugs is unclear. Both guidelines state that the use of prophylactic antiepileptic drugs may be considered in the immediate posthemorrhagic period for a short duration (NCS guidelines 3–7 days). A longer duration may be considered for patients with risk factors for a delayed seizure disorder such as a prior seizure or in those who have a seizure after presentation.44,45

Hydrocephalus

Hydrocephalus is a common acute complication of aSAH occurring in about 15%–20% of patients.81,82 This complication occurs because of either the obstructed circulation of CSF or the impairment in absorption of CSF that occurs by the arachnoid granulations.83 When symptomatic hydrocephalus occurs, the standard treatment is CSF diversion through an external ventricular drain. Placement of this type of drain allows for both the drainage of CSF and the measurement of ICP. When significant intraventricular blood is present, aggressive treatment with CSF diversion and drainage of the ventricular clot may reduce the risk of cerebral vasospasm.84 The alteration in CSF flow dynamics or reabsorption can be transient, during which the drain can be removed; however, it can also be permanent, necessitating the placement of a permanent shunt. In patients with an altered level of consciousness, the evaluation for hydrocephalus can be more difficult. An alteration in the level of consciousness is the most common symptom of hydrocephalus; therefore, a combination of clinical judgment and imaging are required to determine whether CSF diversion and ICP monitoring is indicated. Commonly, a GCS score of 8 or lower is used to determine when a patient requires ICP monitoring, which can be done through an external ventricular drain or an intraparenchymal ICP monitor. In those with hydrocephalus on head CT and a clinical picture consistent with symptomatic hydrocephalus, CSF diversion is warranted regardless of the GCS score. When ICP monitoring is used, the goal is to maintain the ICP within a normal range and to ensure adequate cerebral perfusion. The CPP is calculated by subtracting the ICP from the mean arterial pressure (MAP). The pressure differential, which is what drives perfusion of the brain, is termed the CPP. The goals are to maintain the ICP less than 20 mm Hg and the CPP greater than 60 mm Hg. Often, vasopressors (phenylephrine or norepinephrine) are required to increase the MAP or hyperosmolar therapy (mannitol or hypertonic saline) is used to decrease the ICP, both of which lead to an increase in the CPP. Intracranial hypertension is defined as a sustained (more than 5 minutes) elevation of ICP greater than 20 mm Hg. Please see the

article titled “Emergency Neurological Life Support: Intracranial Hypertension and Herniation” for a tiered treatment protocol.85

DELAYED CEREBRAL ISCHEMIA Cerebral vasospasm has traditionally been regarded as the cause of DCI, which occurs after aSAH and leads to cerebral infarction and poor neurological outcomes. However, data from more recent studies argue against a pure focus on vasospasm as the sole cause of DCI. Research is now intensifying on methods for intervention in the early brain injury pathophysiological process, which also contributes to DCI. Narrowing of the cerebral arteries through vasospasm resulting in a reduction in cerebral blood flow may lead to ischemia and infarction.86 About two-thirds of patients may develop angiographic evidence of vaso-spasm, although only 20%–30% have clinical symptoms.35 In up to 25% of patients, the delayed infarcts revealed on CT scans are not located in the vascular territory of the spastic artery, or they occur in patients who develop vaso-spasm.87,88 The predictive value of radiographic vasospasm for DCI is only about 67%.89 More recent studies using perfusion imaging methods now suggest that only severe vasospasm with at least a 50% luminal narrowing produces sufficient reductions in cerebral blood flow to cause symptomatic ischemia.90 Studies have tried to predict the patients more likely to develop vasospasm after aSAH.91 The strongest risk factor appears to be the volume of subarachnoid clot present, with patients having larger clot volumes being at highest risk.92 Several other risk factors have also been shown to be predictive of vasospasm, including clinical grade on admission, history of cigarette smoking, history of hypertension, and cocaine use.93,94 Nomenclature Many terms are used somewhat interchangeably in the literature when describing delayed neurological deficits. As previously discussed, many investigators use the terms vasospasm and DCI interchangeably,

making it difficult to evaluate treatments and associated outcomes from research studies. Cerebral vasospasm can be defined as the delayed narrowing of the large arteries within the basal cisterns, which may be associated with clinical or radio-graphic signs of ischemia in the areas of the brain supplied by the spastic artery. Delayed cerebral ischemia is an umbrella term in the literature that encompasses several clinical entities, including symptomatic vasospasm, delayed ischemic neurological deficit, and asymptomatic delayed cerebral infarction. Not all patients who develop vasospasm develop DCI. Delayed ischemic neurological deficit is a much broader term that includes delayed neurological deficits that occur with or without angiographic vasospasm. Ultimately, DCI is a clinical diagnosis of exclusion that may be difficult to recognize in patients with poor clinical grade aSAH. In 2010, a consensus statement by a multidisciplinary panel proposed new definitions for clinical deterioration caused by DCI and cerebral infarction after aSAH that were further supported by the 2011 NCS consensus guidelines.45,95 Overall both consensus groups advocated for a separation of DCI from vasospasm after aSAH. DCI = the occurrence of focal neurological impairment (e.g., hemiparesis, aphasia, apraxia, neglect) or a decrease of at least two points on the GCS (either the total scale or one component of the scale). This should last for at least 1 hour, not be apparent immediately after the aneurysm occlusion, and not be attributed to other causes. Cerebral infarction = the presence of cerebral infarction by CT or MRI within 6 weeks after aSAH, not present between 24 and 48 hours after early occlusions, and not attributable to other causes such as surgical clipping or endovascular treatment. Measuring and Monitoring Cerebral Vasospasm The easiest form of vasospasm monitoring involves a vigilant clinical examination. Frequent neurological examinations should be done to establish each patient’s baseline neurologic status and to detect any

changes. Newly identified deficits should be worked up immediately to rule out other causes such as hydrocephalus, seizures, and metabolic abnormalities. Although clinical examination can detect subtle changes in patients with low-grade aSAH, these same changes may not be apparent in a patient who is comatose; therefore, clinical examination alone cannot be used to screen for vasospasm. Transcranial Doppler (TCD) monitoring was introduced in the 1980s as a less-invasive approach for monitoring cerebral vasospasm and has become a mainstay of vasospasm monitoring in the ICU at many centers. This provides an indirect measure of the vessel diameter by measuring cerebral blood flow velocity. When the proximal cerebral arteries narrow, the velocity of blood flow in those arteries increases and can be detectable by TCD. Absolute velocity of blood flow in the middle cerebral artery shows a strong correlation with the lack or presence of vasospasm when it is low (less than 120 cm/second is low risk for vasospasm) or very high (greater than 200 cm/second is high risk for vasospasm) but does not correlate well in the intermediate range.44 The Lindegaard ratio is also predictive of vasospasm and is the middle cerebral artery velocity compared with the velocity in the proximal extra-cranial internal carotid artery (VMCA/VICA). A value greater than 3 is consistent with vasospasm.96 The disadvantage of this approach is the high interrater variability that is dependent on the operator. In addition, many patients may have dense temporal bone windows that prohibit an accurate measurement, and it is inadequate to identify spasm of more distal arteries. Even with these limitations, however, this tool can be used in the ICU to evaluate trends and complement the clinical examination. Imaging with perfusion methods such as CT, MRI, and/or positron emission tomography is being used to screen and confirm vasospasm and DCI. These perfusion studies can be combined with noninvasive arteriography to acquire more complete information. Computed tomography angiography is correlated with conventional angiography for large artery narrowing and can be used as a screening tool.45 Computed tomography perfusion imaging provides a measure of tissue perfusion. Severe vasospasm is associated with absolute cerebral

blood flows of less than 25 mL/100 g/minute and mean transit times greater than 6.4 seconds or 20% higher than average.97 The current consensus recommendations suggest that a mean transient time greater than 6.4 seconds on perfusion imaging is additive to CT angiography for predicting DCI. Serial use of these techniques can be limited by cumulative radiation exposure, higher cost, lower availability, and the need for patients to be admitted or transported to centers with this imaging capability. The gold standard diagnostic method for identifying vasospasm is digital subtraction angiography, which is invasive and expensive and carries the risk of other complications.45 The serious complication rate is 1%–2% and includes risk of the anesthetic regimen, puncture site complications, contrast nephropathy, allergic reactions, embolic or thrombotic strokes, perforation of the cerebral artery, and intracranial hemorrhage.98 The advantage of angiography is that is provides the opportunity to treat vasospasm by endovascular approaches; however, using this invasive approach is not appropriate for surveillance monitoring of vasospasm. Other tools can be used in the ICU to evaluate the physiologic impact of vasospasm, including electroencephalogram, brain tissue oxygen monitoring, and cerebral microdialysis.45 Electroencephalography has been used to detect reversible cerebral ischemia since the 1970s, and specific patterns have now been correlated with vasospasm.99,100 Continuous quantitative electroencephalogram monitoring that focuses on the ratio of fast alpha activity and slow delta activity, alpha variability, and the alpha/delta ratio may precede clinical signs of cerebral ischemia. Relative decreased alpha variability precedes clinical diagnosis of vasospasm by 3 days.101 Microdialysis may provide a modality for assessing bedside comparisons of neurochemical changes with the patient’s neurological examination. Lactate and glutamate are sensitive markers of impending cerebral ischemia.102 Brain tissue oxygenation, thermal diffusion cerebral blood flow, and near-infrared spectroscopy have also been used to monitor patients with aSAH with some success, although the value of these approaches is currently unknown. The NCS

published consensus statements on multimodality monitoring that provide a more comprehensive review of these monitoring approaches.103

Prevention Strategies Calcium Channel Blockers The only pharmacologic intervention that improves outcome after aSAH is the calcium channel antagonist, nimodipine.104 Nimodipine is a dihydropyridine calcium channel blocker that shows cerebral vascular selectivity by preferentially dilating cerebral blood vessels to a greater degree than the peripheral and coronary vasculature.105 Nimodipine has become the standard of care in the United States, according to a clinical trial published in 1983 in which 13% of patients who were randomized to the placebo group had severe neurologic deficits compared with 1.7% of patients randomized to nimodipine.106 A larger trial showed reductions of 34% in ischemic stroke and 40% in poor outcome at 3 months in patients treated with nimodipine compared with placebo.107 A subsequent meta-analysis that evaluated nine prospective randomized trials including 1,514 patients showed a significantly reduced incidence of delayed neurological deficits by 38% (odds ratio [OR] 0.62; 95% CI, 0.5–0.78) and cerebral infarcts by 48% (OR 0.52; 95% CI, 0.41–0.66).108 Originally, it was hypothesized that the benefit from nimodipine was related to a reduction in vasospasm; however, clinical trials did not show a reduction in vasospasm, even while showing an overall improvement in outcome. Clinical trials that have shown the benefit of enteral nimodipine in patients with aSAH used a dose of 60 mg every 4 hours for 21 days. The most common adverse effect is hypotension, which is reported to occur in about 7.7% of patients. This can be a serious concern because hemodynamic lability is independently associated with death or severe disability after aSAH.100 Avoiding blood pressure fluctuations is key in the management of these patients, so alterations in the dosing strategy of nimodipine (30 mg every 2

hours) have been suggested in patients who have hypotension, but this has not been evaluated in clinical trials. Nimodipine has also been shown to be cost-effective, given that it increased patient life-years at a very low incremental cost.109 The two guidelines recommend that oral nimodipine (60 mg every 4 hours) be given for 21 days after aSAH.44,45 Common practice in patients with a good Hunt and Hess grade aSAH is to discontinue nimodipine as patients are discharged from the hospital, provided there have been no complications from the aSAH or intervention. This practice is not based on evidence, but only on the clinical knowledge that patients with good Hunt and Hess grades are less likely to develop DCI beyond post-aSAH day 10. Similarly, if hypotension is too pervasive, nimodipine may have to be held in an effort to support cerebral perfusion, but this is not based on evidence. Some serious drug errors have been reported when oral nimodipine is administered intravenously instead of through a nasogastric tube when patients are unable to swallow the capsule. The drug comes with instructions for making a hole in both ends of the capsule with a standard 18-gauge needle for removing the contents with a syringe and then administering through the nasogastric tube. Because these needles do not fit on an oral syringe, an intravenous syringe is used, which has resulted in intravenous administration. Intravenous administration can result in cardiac arrest, dramatic drops in blood pressure, or other cardiovascular adverse events. The FDA issued a drug safety communication in 2010, for which it reported 25 intravenous nimodipine-prescribing or administration errors, where four of the patients died and five had near-death events.110 In 2013, the FDA approved a new oral nimodipine solution in an effort to reduce drug errors because this dosage form eliminated the need for needle extraction of nimodipine from the capsules.111 There are also potentials for drug interactions between nimodipine and strong inhibitors and inducers of cytochrome P450 (CYP) 3A4. The clinical significance of these drug interactions is the possibility of significant hypotension when administered with CYP3A4 inhibitors and lack of effectiveness when coadministered with CYP3A4 inducers. The future direction for non-enteral delivery of nimodipine compared

with enteral nimodipine is currently being investigated in clinical trials. EG-1962 is a novel polymeric nimodipine microparticle that is administered directly into the cerebral ventricles and provides sustained drug exposure throughout 21 days. EG-1962 uses a programmable, bio-degradable polymer-based development platform known as Precisa. This delivery system allows for targeted drug delivery to the site of injury to provide sustained drug exposure while avoiding systemic toxicities. This site-specific delivery of nimodipine microparticles reduces angiographic vasospasm after aSAH in dogs.112 EG-1962 is currently being evaluated in a phase I/II study, NEWTON (Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage), for safety, tolerability and pharmacokinetic properties.113,114 Nicardipine is another calcium channel blocker that has been evaluated for prophylactic use after aSAH. Intravenous nicardipine (0.15 mg/kg/hour for up to 14 days) was compared with placebo. In contrast to the results reported for nimodipine, nicardipine was associated with lower symptomatic vasospasm but was not associated with improvement in neurological outcome at 3 months. Hypotension, the main concern with the use of intravenous nicardipine, occurred in 34.5% of nicardipine-treated patients compared with 17.5% of placebo-treated patients. The potential positive effect on outcome may have been negated by the 3% incidence of life-threatening hypotension that developed.115,116

Statins Statins have generated much interest for the prevention of vasospasm after aSAH because of their pleiotropic effects, which include antiinflammatory properties, up-regulation of endothelial nitric oxide synthase, anti-adhesive effects on endothelium, amelioration of glutamate-mediated excitotoxicity, and inhibition of platelet aggregation.117,118 Because of strong experimental evidence, several studies examined the clinical effect of simvastatin and pravastatin for prevention of vasospasm and DCI. The primary difference between

these statins is that simvastatin has a higher affinity for hydroxymethylglutaryl coenzyme A reductase and is more lipophilic than pravastatin, so it has higher blood-brain barrier penetration.119 The results of these studies were critically appraised in two meta-analyses that included four published randomized trials with a total of 190 patients.95,120 Simvastatin 80 mg was used in three of the four studies, and pravastatin 40 mg was used in the other study. There was no statistical difference in TCD-detected vasospasm, incidence of DCI, or neurologic outcomes between statin treatment and placebo. The other meta-analysis included these four trials together with two unpublished randomized trials and five observational studies.120 Similar to the previous meta-analysis, there was no significant difference in the incidence of DCI. The results of these meta-analyses should be viewed cautiously because the definitions of DCI were inconsistent. Atorvastatin 40 mg/day for 21 days was studied in 142 patients to evaluate whether this statin could reduce vasospasm-induced ischemia by measuring serum S100B (biomarker for cerebral ischemia) and ischemic lesion volume by CT. Atorvastatin reduced the incidence of cerebral vasospasm, severity of vasospasm, volume of ischemia, and serum S100B concentrations, but there were no differences in clinical outcomes at 1 year.121 The STASH study (Simvastatin in Aneurysmal Subarachnoid Hemorrhage), a phase III randomized trial of 803 patients that compared simvastatin 40 mg with placebo for up to 21 days, was recently published.122 Despite showing no safety concerns, this trial failed to show any short- or long-term benefit in outcome, and the investigators concluded that simvastatin should not be routinely used during the acute stages. Several experimental and clinical studies suggest that sudden withdrawal of statins can suppress endothelial nitric oxide production, leading to a higher risk of hemorrhage and vaso-spasm.123,124 The current guidelines state that statins may be initiated in statin-naive patients for reducing DCI after aSAH, but these were published before the STASH results; therefore, statins should not be used in statin-naive patients. However, the guidelines do mention continuing patients on statins if they were receiving statins before

presenting with aSAH.44,45

Magnesium Magnesium is a noncompetitive calcium antagonist and is thought to result in smooth muscle relaxation and vessel dilation. Magnesium may also have neuroprotective properties because it decreases glutamate release and reduces calcium entry into cells.125,126 Hypomagnesemia occurs in more than 50% of patients with aSAH and is associated with poor outcome and a predictor of DCI.127 Several clinical trials have investigated the effects of magnesium after aSAH.128-136 The first phase III randomized controlled trial enrolled 327 patients within 48 hours of aSAH to either magnesium 20 mmol (5 g) over 30 minutes, followed by an infusion of 80 mmol (20 g)/day for up to 14 days posthemorrhage, or placebo (0.9% sodium chloride). The magnesium infusion was adjusted to achieve a magnesium concentration twice the patient’s baseline up to a maximum of 2.5 mmol/L. There were no significant differences in 6-month outcomes or in the percentage of patients with clinical vasospasm.135 The MASH-2 (Magnesium for Aneurysmal Subarachnoid Hemorrhage) study is another phase III randomized placebo-controlled trial of 1,204 patients that did not find significant benefit of intravenous magnesium infusion on favorable outcome.136 The investigators of this trial also completed a metaanalysis and confirmed the lack of benefit of magnesium after aSAH.136 Magnesium was administered intravenously in these clinical trials; however, this route of administration does not result in a significant increase in CSF magnesium values, even if the serum magnesium level is increased by 50% or more.137 Direct administration of magnesium into the basal cisterns may be a more effective approach, although there are currently no ongoing clinical trials investigating magnesium after aSAH.138,139 Intravenous administration of magnesium is not currently recommended. However, hypomagnesemia should be avoided.44,45

Clearance of Subarachnoid Spaces

Because the breakdown by-product of the subarachnoid clot is believed to play a key role in the development of vasospasm and DCI, removal of the hemorrhage would appear to be a rational preventive strategy. Some evidence suggests that subarachnoid clot removal achieved by way of intracisternal injections of recombinant tissue plasminogen activator reduces the risk of vasospasm.140 The recombinant tissue plasminogen activator is usually administered at the time of aneurysm clipping, and because endovascular approaches to aneurysm stabilization are increasingly being used, this approach is not practical for all patients. In addition, the results appear to be inconclusive, and this approach can increase the risk of intracerebral hemorrhage. Currently, the use of intracisternal thrombolytics cannot be recommended. Intraventricular administration of thrombolytic agents has been investigated as a method for preventing the development of vasospasm. A meta-analysis of five trials that included 465 patients showed significant reductions in the development of vasospasm and DCI.141 The results of this meta-analysis should be viewed cautiously, given that there were considerable differences in the study methodology of the trials included in the meta-analysis; as such, routine use cannot be currently recommended. The use of lumbar drains is another approach for clearing subarachnoid blood. A current clinical trial is investigating the benefit of this approach (EARLYDRAIN).142

Endothelin-1 Antagonist Endothelin-1 is a 21-amino acid peptide and one of the most potent vasoconstrictors produced in endothelial cells on stimulation by ischemia. It has been suggested that endothelin-1 contributes to an imbalance in vasoconstriction and vasodilation during aSAH. Endothelin1 can be found in high concentrations in the CSF on day 5 post-ictus, and it corresponds with increased cerebral blood flow velocity.143 Clazosentan is a selective endothelin-A receptor antagonist that decreases and reverses cerebral vasospasm in experimental aSAH.

The CONSCIOUS-1 (Clazosentan to Overcome Neurological Ischemia and Infarct Occurring After Subarachnoid Hemorrhage) trial showed significant dose-dependent effects on the angiographic incidence of vasospasm with a 65% reduction at the highest dose.144 The phase III trial, CONSCIOUS-2, was designed to target patients at highest risk of vasospasm and DCI, such as those with substantial blood clot thickness who had undergone surgical clipping. The results of the CONSCIOUS-2 trial showed that clazosentan at 5 mg/hour had no significant effect on mortality, vasospasm-related morbidity, or functional outcome. Pulmonary complications, anemia, and hypotension were more common in the patients who received clazosentan.145 A similar study of patients who were treated with coiling (CONSCIOUS3) was stopped early after 577 of the 1,500 patients were enrolled.146 The results of CONSCIOUS-3 showed findings similar to CONSCIOUS2 for the 5-mg/hour dose; however, the 15-mg/hour doses significantly reduced vasospasm-related morbidity and all-cause mortality but did not lead to improved outcomes at week 12. The CONSCIOUS-2 and CONSCIOUS-3 trials have raised questions regarding the efficacy of endothelin-1 antagonists in preventing vasospasm; however, the possibility remains that these agents have clinical utility as part of a complex treatment regimen for aSAH.

Treatment Strategies Hemodynamic and Fluid Goals Hemodynamic therapy known as triple-H therapy has been a popular approach to managing symptomatic vasospasm in patients who have secured aneurysms, despite the moderate quality of evidence supporting this intervention. Triple-H refers to hypervolemia (central venous pressures 10–12 mm Hg), hypertension (systolic blood pressure 180–220 mm Hg), and hemodilution (hematocrit 30%– 35%).147 The rationale for this therapy is for maintaining high circulating blood volume, increased CPPs, and decreased blood viscosity that will enhance cerebral blood flow in the face of vasoconstriction. There is

currently no supportive evidence from randomized controlled trials that triple-H therapy or its separate components improve cerebral blood flow or clinical outcome in patients with aSAH.148,149 The role of triple-H therapy has also been investigated as a prophylactic approach to prevent DCI, with the data showing no benefit and a higher risk of serious adverse effects and death; thus, this approach should be reserved for managing patients with symptomatic vasospasm.150,151 Hemodilution is the most controversial component of triple-H therapy. Although cerebral blood flow increases with a decreasing hematocrit, this approach is also associated with decreased oxygencarrying capacity and increased volume of ischemic areas of the brain.152 Higher hemoglobin values are associated with decreased rates of cerebral infarction, poor outcome, and death after aSAH.152 However, blood transfusions are associated with increased rates of angiographic vasospasm, cerebral ischemia, and worse functional outcomes.153 There are no convincing data to support an ideal hematocrit; thus, induced hemodilution to achieve a lower hemoglobin or hematocrit to improve blood rheology should be avoided. The current guidelines recommend maintaining hemoglobin concentrations of greater than 8–10 g/dL with packed red cells, although higher thresholds may be appropriate in patients at high risk of DCI.44,45 Transfusion with packed red blood cells, however, is not without risk, and a recent retrospective cohort study reported that transfusion with red cells was independently associated with increased mortality in patients with aSAH.154 Hypovolemia, which can commonly occur after aSAH, should be avoided because it is associated with worse clinical outcomes. Hypovolemia appears to be a cumulative process and is more prevalent 6–72 hours after aSAH for patients who undergo surgical intervention.155 Prophylactic hypervolemia does not improve cerebral blood flow or prevent symptomatic vasospasm or DCI and is associated with increased risk of cardiopulmonary complications because of the fluid overload.151 A recent survey showed that medical centers without a dedicated neuro-ICU are more likely to use prophylactic hypervolemia.156 The approach to intravascular volume

management should target euvolemia with isotonic crystalloids rather than prophylactic hypervolemia.44,45 The choice of fluid for use in aSAH is typically isotonic crystalloids, which is specifically mentioned in the guidelines. However, other fluid choices have been assessed in patients with aSAH. Hypertonic saline has not been part of the traditional regimen for triple-H therapy, although this fluid can be commonly used for the reduction of ICP and may have clinical benefits in patients with poor-grade aSAH. A prospective study administered a 2-mL/kg infusion of 23.4% sodium chloride over 10–30 minutes to 44 patients with poor-grade aSAH and showed that hypertonic saline increased systemic blood pressure, reduced ICP, and improved cerebral blood flow, cerebral oxygenation, and brain tissue pH. The effects lasted 2–4 hours after administration. Although these data evaluations are limited, hypertonic saline may be an alternative fluid for use in patients with poor-grade aSAH.157 Albumin is another fluid currently being investigated because it is believed to possess neuroprotective properties through several mechanisms, including increasing serum oncotic pressure, improving microcirculatory blood flow, decreasing the inflammatory response, and free radical scavenging properties.158 Many of the triple-H regimens evaluated in the literature included albumin as part of their regimen, but there is no good study comparing albumin with crystalloids. A retrospective evaluation of high doses of 25% human albumin used to increase the central venous pressure above 8 mm Hg reported an association with improved outcomes and reduced costs in patients with aSAH.159 A phase I dose-escalation study evaluated the safety and efficacy of 25% albumin in doses of 0.625, 1.25, 1.875, and 2.5 g/kg/day for up to 7 days.160 Doses up to 1.25 g/kg/day were well tolerated, but the study was terminated early once the dose reached 1.875 g/kg/day because of the development of pulmonary edema. Albumin in Subarachnoid Hemorrhage (ALISAH) II, a phase III randomized placebo-controlled trial powered to test the efficacy of albumin, is planned. Until the results of this study are complete, it is not recommended to routinely use albumin in the management of these patients because patients with traumatic brain injury have shown

increased mortality with the administration of albumin.161 However, a recent survey reported that almost one-half (45.9%) of the respondents commonly administer albumin to their patients with aSAH, but they also acknowledged the need for a randomized clinical trial.162 Although prophylactic hypervolemia is no longer recommended, this approach is still commonly used for the treatment of cerebral vasospasm, though even in this setting, the safety and efficacy of hypervolemia are being reconsidered. In a study of 16 patients with severe vasospasm documented with angiography, the impact of hypervolemia (1,000 mL/day colloid plus 3,740 mL/day crystalloid; mean central venous pressure increase from 5.4 cm H2O to 7.4 cm H2O), induced hypertension with phenylephrine (MAP increase from 102 mm Hg to 132 mm Hg), or enhanced cardiac output with dobutamine (mean cardiac index increased from 4.1 L/minute/m2 to 5 L/minute/m2) was compared using cerebral blood flow as the outcome measurement. Improvements in cerebral blood flow were only observed in patients who received phenylephrine or dobutamine.163 Similar results were reported in an observational study of 45 patients wherein induced hypertension increased brain tissue oxygenation in 90% of patients with an 8% complication rate, whereas hypervolemia was only effective in 12% of patients but had a 53% complication rate.164 The role of hypervolemia as a single component of triple-H therapy does not appear to be supported by these small studies. The NCS consensus recommendations suggest considering a saline bolus to increase cerebral blood flow in areas of ischemia as a prelude to other interventions, like induced hypertension.45 Case series have linked induced hypertension with improved neurological improvement and increased cerebral blood flow, especially in patients with angiographic vasospasm or in brain regions that are hypoperfused.165-168 Administering vasoactive agents produces a sustained increase in systemic blood pressure that results in improved CPP, cerebral blood flow, and cerebral tissue oxygenation. In clinical studies, induced hypertension was more effective at improving cerebral oxygenation than aggressive hypervolemia.164,169 Induced hypertension improves regional cerebral blood flow and brain tissue oxygenation, but

these benefits disappear after induction of hypervolemia.169 A computational model approach evaluated the effect of hypertension and hemodilution in managing vasospasm.170 This study found that in cases of severe vasospasm, the systemic blood pressure should be increased in order to reverse vasospasm. Any decreases in hematocrit had minimal impact on cerebral blood flow in a constricted vessel. Two systematic reviews have been published assessing the different components of triple-H therapy.148,149 The large heterogeneity in interventions and populations studied prohibited conducting a metaanalysis. Hypervolemia did not appear to be superior to normovolemia, but hypervolemia was associated with more adverse effects.149 Hemodilution was not associated with a change in cerebral blood flow, and hypertension was associated with higher cerebral blood flow, regardless of the volume status.148,149 Several vasopressors can be used to induce hypertension, including phenylephrine, norepinephrine, and dopamine. In a prospective case series, the use of high-dose phenylephrine had an acceptable safety profile.171 There are no studies comparing the effect of different agents on cerebral blood flow. Both phenylephrine and norepinephrine are equally used to induce hypertension.156 Vasopressin is an effective vasopressor agent but is not routinely used in patients with aSAH because of its potential to exacerbate the hyponatremia that can occur in these patients. When vasopressin (0.01–0.04 unit/minute) was added to maximal phenylephrine therapy (4–5 mcg/kg/minute) in patients with clinically symptomatic vasospasm, vasopressin was effective in reducing the phenylephrine dosage without reducing serum sodium concentrations or causing detrimental effects on cerebral perfusion or worsening vasospasm.172 Different approaches with respect to defining the blood pressure targets are used in clinical practice. Some clinicians target a percent increase from baseline blood pressure, whereas others target an arbitrary number. Pressure should be increased in a stepwise fashion, as guided by an assessment of the neurological examination, neuromonitoring, or radiological evidence of improved perfusion.45 Cardiac output augmentation is an alternative method for increasing

cerebral blood flow.163 In addition to treatment of vasospasm, patients with aSAH may have reduced cardiac output because of “stunned myocardium.” An alternative to induced hypertension is the use of inotropic agents like milrinone or dobutamine to induce a hyperdynamic state. One concern with routine use of these agents is the potential to lower blood pressure. Milrinone may be more potent than dobutamine in increasing cardiac output and is more effective in patients with normal vascular resistance and normal blood pressure yet reduced systolic function.173 Dobutamine may be a preferred option when vascular resistance or blood pressure is reduced.173 Inotropic agents may be useful in patients who lack response to induced hyper-tension or have poor cardiac function, but these agents cannot be recommended for prophylactic administration. Volume status should be routinely monitored in these patients. Although a target central venous pressure of 8 mm Hg or greater has been recommended, it is important to understand the lack of reliability of central venous pressure in estimating intravascular volume; therefore, the approach must be individualized. Goal-directed hemodynamic management using PiCCO has been successfully used in patients with aSAH.174,175 The specific targets that have been suggested include the following: Cardiac index greater than 3.0 L/minute/m2 Global end-diastolic volume index equal to 700–900 mL/m2 Extravascular lung water index less than 14 mL/kg Larger randomized controlled trials are needed to validate the usefulness of goal-directed hemodynamic monitoring in patients with aSAH. The current clinical guidelines recommend maintaining euvolemia and inducing hypertension in patients with DCI, except in those who have elevated blood pressure at baseline or have comorbid cardiac disease, which precludes its use.44 In patients with preexisting cardiac disease and older adults, the risk of complications with hypervolemic/hypertensive therapy is increased; risks include cardiac

failure, pulmonary edema, cerebral edema, and elevated ICP.171 Locally Administered Pharmacologic Agents Targeted delivery of pharmacologic agents through intra-arterial, intraventricular, or intrathecal administration is a method for treating cerebral vasospasm. It is important to evaluate the products directly administered into the central nervous system (CNS) and assess the potential risk of the diluent and other excipients that are contained in the product.176 Papaverine is a vasodilator agent that preferentially vasodilates cerebral and coronary vascular smooth muscle. Intraarterial administration of papaverine (150–600 mg) has shown success in treating cerebral vasospasm in published reports of clinical experience.177-183 The limitation with the use of papaverine is the potential for the development of neurotoxicity because of altered mitochondrial cellular respiration with high exposure.184 Other adverse events include increased ICP, hemiplegia, seizures, agitation, altered mental status, and hypotension.185 Because of these significant safety concerns, papaverine is no longer recommended. Nicardipine has shown promise when administered by intra-arterial, intrathecal, or intraventricular routes of administration for treating cerebral vasospasm.186-190 Intra-arterial administration involves diluting intravenous nicardipine with 0.9% sodium chloride to a concentration of 0.1 mg/mL and administering in 1-mL aliquots through the microcatheter to a maximum of 5 mg per vessel. Nicardipine is effective at inducing vasodilation and reducing mean peak systolic velocities on TCD from pretreatment for 4 days after the infusion. Overall, neurologic improvement was reported in 42% of patients.186 Intraventricular administration of nicardipine is an attractive treatment option because it can be administered in the ICU and avoids transport of the patient to the angiography suite. The evidence for this treatment approach is limited to a small case series of eight patients in which nicardipine 4 mg every 12 hours for 5–17 days was administered through the intraventricular catheter. The drug was well tolerated, and seven of the eight patients had good functional outcomes.188 There are

several other more recent studies, two of which report a significant and sustained reduction in mean cerebral blood flow velocity after intraventricular nicardipine; however, neither study was powered for clinical outcomes.191,192 Verapamil is another calcium channel antagonist that has been used by way of intra-arterial administration for treating cerebral vasospasm. The published data are from retrospective evaluations in which verapamil was administered at dosages of 25–369 mg per vessel by continuous infusion.193-196 Verapamil was effective in reversing vasospasm, but close hemodynamic monitoring is advised because the most common complications include hypotension and bradycardia. Sodium nitroprusside is another vasodilating agent that has been administered by the intraventricular route. In a prospective study of 25 patients with aSAH, nitroprusside 4 mg/mL was given in escalating doses (8–30 mg) and frequency according to mean blood flow velocity on TCD. An improvement in blood flow velocity was reported, together with hypotension and vomiting.197 Intra-arterial milrinone has also been used to treat cerebral vasospasm.198-200 Milrinone is a bipyridine inotropic vasodilator that inhibits peak III cyclic adenosine monophosphate phosphodiesterase isozyme. Combining intra-arterial milrinone (8 mg over 30 minutes repeated up to a maximum of 24 mg) with intravenous milrinone 0.5– 1.5 mcg/kg/minute until day 14 after the initial bleed was safe and effective for reversing cerebral vasospasm and was usually well tolerated.199 Local administration of all the agents discussed provides a more targeted approach for treating cerebral vasospasm. To date, most of the data for this approach are limited to small case series or case reports, making it difficult to provide definitive recommendations, which in turn leads to significant practice variation across centers treating these patients. Transluminal Balloon Angioplasty For significant symptomatic vasospasm in the proximal cerebral arteries, transluminal balloon angioplasty is an effective approach to

immediately produce dilation of the involved artery and increase distal cerebral blood flow.201 Transluminal balloon angioplasty has two limitations: suitability limited to vessels with a diameter of 2 mm or greater and the variability in effectiveness that is based on the operator’s expertise. This intervention also has the potential for serious complication rates of about 5%, including vessel rupture, thromboembolic complications, and delayed stenosis.202 The results of this intervention tend to be more durable compared with those of pharmacologic intervention. No current randomized trials confirm the clinical efficacy, although the current clinical guidelines state that angioplasty is reasonable in symptomatic patients who do not respond to medical therapies, including induced hypertension.44

MANAGEMENT AND PREVENTION OF MEDICAL COMPLICATIONS Renal Complications Intravascular Volume As discussed previously, hypovolemia is a common complication after aSAH, and it should be avoided because it is associated with worse clinical outcomes.155,203 Intravascular volume management should target euvolemia, with isotonic crystalloid the preferred agent for volume replacement. Assessment of intravascular volume in patients after aSAH is essential to daily management. In many institutions, fluid management is guided by calculations of the daily fluid balance of the patient. However, several studies have determined that fluid balance may not accurately reflect intravascular volume status after aSAH.203205

Accurate monitoring of volume status may be accomplished using minimally invasive techniques. One such method is using transpulmonary hemodynamic monitoring (PiCCO). Transpulmonary thermodilution measurements that are obtained using the PiCCO system correlate well with pulmonary artery catheter measurements

and provide an effective tool for the fluid management of patients.175,206 The PiCCO system for monitoring has fewer cardiac complications as well as fewer episodes of symptomatic vaso-spasm (p 21 hr

Renal (70 %)

No

Lowconc of AT may affect anticoagulant activity

Warfarin

Inhibitors II, VII, IX, X

25 min

3.5 hr

Hepatic

No

Dabigatran

Direct Ila inhibitor

39-51min

0.5-1hr

Renal ( 80%)

Yes

Rivaroxaban

Direct Xa inhibitor

lwk

lwk

Renal (36%)

No ( minimal)

Apixaban

Direct Xa inhibitor

12-17 hr

28 hr

Renal ( 25 %)

No ( minimal )

Direct Xa inhibitor

5-9 hr

10 hr

Renal ( 50 %)

No ( minimal )

Edoxaban

Donotopencapsule

aHalf-life

listed was determined in normal healthy individuals, and not in the critically ill for which it can be considerably longer. AT = antithrombin; UFH = unfractionated heparin; Hr = hours; Conc = plasma concentration; wk = week; min = minutes.

Initial therapy for an acute VTE may depend on the location of the thrombosis, its size, and any additional symptoms. Pulmonary embolisms may be classified as massive when congestion in the pulmonary circulation leads to expanded volume in the right ventricle upstream where the cardiac wall presses against the left ventricle, reducing stroke volume and leading to hemodynamic insufficiency. In this situation, initial therapy may include thrombolytic agents followed by a heparin infusion and eventually a long-term oral anticoagulant. For a sub-massive PE, the decision to use thrombolytic therapy may be weighed against the risks involved and the potential benefits. Most of the symptomatic PEs in the ICU are initially treated with a parenteral anticoagulant, followed by a long-term anticoagulant for at least 3 months, if possible (Table 23.3).

Table 23.2 Considerations with Anticoagulants for VTE

Prophylaxis8,9

aOrthopedic

hip/knee prophylaxis.

CrCl = creatinine clearance; CRRT = continuous renal replacement; IHD = intermittent hemodialysis; INR = international normalized ratio; IV = intravenous(ly); kg = kilogram; PO = oral(ly); q = every; SC = subcutaneous(ly); SLEDD = slow duration dialysis; VTE = venous thromboembolism.

Often, patients admitted to the ICU with pulmonary symptoms may have PE included in the potential problem list. The diagnosis of the PE may be assessed by a chest computed tomography (CT) or a ventilation/perfusion scan. Because the consequences of a VTE, and especially a PE, can include sudden death or long-term pulmonary insufficiency (pulmonary hypertension), therapy should not be delayed

for the results of diagnostic test results, but instead, instituted promptly and continued until a VTE or PE is ruled in or out. Additional approaches to therapy can include surgical removal or catheterdirected thrombolysis (Table 23.4). In the ICU, parenteral anticoagulation for at least 5 days is desired, and include transitioning (bridging) to long-term anticoagulation; typically, warfarin is used if there is no need to discontinue anticoagulation. This in part may be attributed to its ability to be rapidly reverse heparin and warfarin if necessary. Anticoagulation plans using longer-acting agents should address any planned procedures with risks of bleeding and be held until resolved. When transitioning to warfarin, the parenteral agent should be continued until the international normalized ratio (INR) is above 2. Guidelines suggest that INR greater than 2 plus 1 additional day; however, specific benefits of this particular timing has not been tested in clinical trials.10 Newer options include the direct-acting oral anticoagulants; however, most of these have been explored outside the critical care setting. Several limitations may exist, including the potential need to adjust dosing in organ failure, ability to measure the degree of effect or loss of effect for invasive procedures, and ability to reverse their effects. It is unclear whether they may be beneficial for other indications such as mechanical devices or in concurrent acute coronary syndromes (ACS) when other, more established agents have been used. Other options include 3 weeks of rivaroxaban 15 mg orally twice daily, followed by a dose deescalation to 20 mg daily, or apixaban 10 mg orally twice weekly for 7 days, followed by 5 mg twice daily. Dabigatran and edoxaban have been explored in VTE treatment but initiated after an initial period of parenteral anticoagulant therapy. With the use of the newer agents, there is no need to overlap with another anticoagulant. If the ICU stay is short and the patient can be discharged home, transitioning to longterm oral anticoagulation can be completed on an outpatient basis if the therapy can safely be implemented and the follow-up management arranged. Other modalities for VTE management may include invasive procedures such as thrombolysis by intravenous infusion, which is

considered for a massive PE and hemodynamic instability as the result of congestion in the right ventricle compressing against the left ventricle and reducing cardiac output. This strategy may also be considered in selected submassive PEs as well on a case-by-case basis. Catheterdirected thrombolysis incorporating thrombolytic therapy (e.g., EKOS catheters) or surgical thrombectomy can be used to remove the clot. For very high bleeding concerns outweighing those of the thrombosis when anticoagulation therapy is held, or if a lower intensity of anticoagulation is necessary, monitoring of a DVT can include repeat ultrasonography to determine whether the thrombosis is extending.

ANTICOAGULATION AGENTS Unfractionated Heparin Unfractionated heparin (UFH) is administered parenterally either by bolus or continuous intravenous infusion or subcutaneously for many indications in the critically ill patient. Heparin administered intravenously is completely bioavailable, but it is reduced to about 30% when administered subcutaneously, depending on the site of injection or the presence of vasopressors, which can decrease absorption.17 Heparin can be used to coat catheters to prevent thrombosis on their surface as well as prophylactically to prevent VTE, or it can be used in the acute management of VTE as well as several other situations. The advantage of heparin is its rapid onset of effect, its rapid removal out of the system, and the ability to reverse its effects rapidly with protamine. Heparin is available in many concentrations, and it is important to use standard concentrations for the various uses to minimize potential errors. For the treatment of VTE, premixed solutions of heparin are available, and it is best to choose one standard concentration and incorporate that into VTE management guidelines, order sets, and products that are dispensed from the pharmacy. Because heparin is removed by the liver, the dose need not be adjusted for renal insufficiency. It can be reconstituted in either dextrose or saline, providing options in selected situations when

another option may be preferred. For VTE prophylaxis, UFH may be administered subcutaneously or by continuous intravenous infusion. In the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE), a multicenter registry involving 15,156 acutely ill hospitalized medical patients of whom 5% were in the ICU, a marked variation in practices was seen in dosing frequency of low-dose UFH used to prevent VTE.18 Combined with other comparisons and the low quality of evidence, including the lack of head-to-head comparative trials exploring twiceversus three-times-daily dosing, no compelling evidence exists to support a benefit of three-times-daily low-dose UFH compared with twice-daily dosing for reduction in VTE or increase in bleeding.19 What is unclear is identifying the optimal approach in special populations that were not the focus of clinical trials such as surgical versus medical critically ill populations, populations with obesity, or populations with the presence of a hypercoagulable or bleeding state. This is evidenced by the fact that 7.7% of 3,746 medical-surgical ICU patients developed a DVT despite adequate thromboprophylaxis with either low-dose UFH or low-molecular-weight heparin (LMWH). A multivariate regression analysis suggests that patients with a personal or family history of TE, those with an elevated body mass index (BMI), and those receiving vasopressors appear more likely to have had failed standard thromboprophylaxis strategies.20 Although patients may prefer fewer daily injections, the lower dose can be presumed to lower the level of anticoagulation and increase the risk of thrombosis, but as mentioned previously, this has not been shown in clinical trials. Empirically, patients at an advanced age (e.g., older than 80 years) with a low body weight (e.g., less than 50 kg) may have a more pronounced effect from heparin. In such cases, 5,000 units twice daily may be considered, or a trough activated partial thromboplastin time (aPTT) can be measured to assess whether a higher-than-desired anticoagulation effect is present. Although there is no supporting evidence on using continuous infusions for prophylaxis, it is another consideration when target goals are a small 10-second rise in aPTT over baseline or when measuring an anti-factor Xa (anti-Xa) activity concentration of 0.2– 0.3 unit/mL.

When using heparin for prophylaxis in the absence of an acute clot, a bolus dose may be unnecessary.

Table 23.3 Considerations with Anticoagulants for Treatment of VTEa,b,9,11-13,21

Common Treatment Dose

Agent

UFH

IV

Dose Adjustment in Renallnsufficiency

Dialysis Dose Adjustment

No adjustment

No adjustment

CrCI 30-60 mL/min/1.73 m2: Can lower 25% or to the next lower syringe size

IHD: 0.6-0.7 mg / kg SC g24hr

3

aPTT 6

Anti -Xa 0.3-0.7 units /mL ( or aPTT calibrated to anti - Xa target range )

SC

1.2 x total 24-hrdose divided BID / TID Enoxaparin

1mg / kg SC ql2hr ( acute)

1.5 mg / kg SC g 24hr ( history of )

CrCI 15-30 mL / min /1.73 m2:1 mg / kg SC q 24hr

Dalteparin

200 units/ kg SC g24hr ( acute ) 150 units / kg SC q 24hr ( > 30 days since acute event )

Fondaparinux

Weight < 50 kg: 5 mg SC daily Weight 50-100 kg: 7.5 mg SC daily

CrCI > 20 mL/ min /1.73 m2 - no adjustment; no recommendations < 20 mL / min/1.73 m2

Not explored in VTE treatment

CrCI < 30 mL / min /1.73 m2: 2.5 mg SC q48 hr

0.03-0.05 mg / kg SC q48 hr -TIW or 2.5 mg SC q48 hr has been explored in IHD

CrCI 30- 60 mL / min /1.73 m2: 0.08-0.1mg / kg / hr

IHD: 0.5 mg /kg/ min

Weight > 100 kg: 10 mg SC daily

Bivalirudin

Argatroban

Warfarin

0.12-0.15 mg / kg / hr

CRRT: 0.7 mg / kg / min

CrCI 15-30 mL / min /1.73 m2: 0.03-0.5 mg / kg / hr

SLEDD: 0.7 mg / kg /min

0.2 mcg / kg /min

Decrease 0.1-0.6 mcg / kg / min foreach 30-mL /mindropin CrCI has been suggested

No dose adjustment specifically during dialysis. Reduce dose 75 % in severe hepatic impairment

Varies

No adjustment doses are generally 20%-25 % lower as renal function declines

Smaller -than-average doses may be

( INR 2-3 )

-

warranted

Dabigatran

150 mg PO BID after initial parenteral therapy

No recommendations in VTE

Contraindicated

Rivaroxaban

20 mg PO q24hr

CrCI > 30 mL/ min: no adjustment

No recommendation available for CrCI < 30 mL / min /1.73 m2

Apixaban

5 mg PO ql2 hr. After 6 months, the dose can be reduced to 2.5 mg twice daily ifcontinued

CrCI > 25 mL /min /1.73 mz or SCr > 2.5 mg / dL: no adjustment

No recommendation available because these patients were excluded. Dialysis dosing exists for atrial fibrillation according to a small pharmacokinetic study, but not in VTE treatment

Edoxaban

60 mg PO daily after initial parenteral

CrCI 15-50 mL / min /1.73 m2 ( or weight < 60 kg ) : 30 mg daily

No recommendation available witb CrCI < 15 mL / min /1.73 m2 or in dialysis

therapy

aDosing

in hemodialysis describes the approach the dose that was explored and may not apply to other forms of dialysis. bValues

for the aPTT depend on the reagent lot and range that fits within the 0.3–0.7 antiXa unit samples (typically, 30 heparin patient samples are used for the calibration). In the treatment of acute VTE, values in the upper range (e.g., 0.5–0.7 anti-Xa units) may be

considered unless bleeding risks are high. BID = twice daily; TID = three times daily; TIW = three times weekly.

In the treatment of acute VTE, heparin is commonly used in the ICU and initiated as an intravenous bolus followed by a continuous infusion, with a desire to achieve and sustain target goals as soon as possible. The approach to dosing may depend on additional factors such as the concurrent use of a thrombolytic agent or concurrent bleeding issues. For example, a patient with an acute major bleeding episode who subsequently develops a VTE may be dosed on the basis of a risk assessment of the VTE (including location and severity) versus the risk of additional bleeding. The initial bolus may vary, if done at all, and may empirically be based on a set number of units (e.g., 2,500–5,000 units) or loading doses individualized using the patient’s weight (e.g., 80 units/kg initially and potentially a lower amount when subsequent aPTT or anti-Xa activity concentrations are below target). If the bleeding concerns are very high, a lower bolus, if any at all, and a lower infusion rate may be considered. Currently, no standard proven approach to the optimal infusion rate of target therapy goals has been established. A variety of approaches to continuous dosing exist, with dosing at 18 units/kg/hour being the most commonly used starting rate for an acute VTE.21 The aPTT or anti-Xa activity can be measured 4–8 hours after initiating the infusion and the dose subsequently adjusted. The duration of effect by the bolus on the measured activity may be longer with higher doses. If no bolus is used, activity assessment can be done at 4 hours. A delay of 6–8 hours may be required, however, if a bolus is given to avoid elevated values driven in part by the bolus and resulting in infusion rates that may be below target.22 Monitoring patients on anticoagulation with a VTE includes assessing the VTE and, if it is continuing to expand, the bleeding or potential complications such as HIT. Typically, a complete blood cell count and aPTT or anti-Xa activity is checked before initiating the infusion and then periodically as needed to assess the impact of the therapy.

Table 23.4 Thrombolytic Therapy for Acute VTE14-16

Hct = hematocrit; Hgb = hemoglobin; hr = hours; IV = intravenous; kg = kilogram; LMWH = low-molecular-weight heparin; mg = milligram; PE = pulmonary embolism.

In rare cases, such as in the loss of intravenous access or if longterm heparin is needed, a subcutaneous route may be considered. To determine a subcutaneous dose from a currently administered intravenous infusion, the following equation may be used:

where IV is intravenous, SC is subcutaneously, and “1.2” reflects the 20% or so loss of bioavailability with the sub-cutaneous route. The common 250 unit/kg every 12 doses for VTE treatment is based on the concept of 20% over the common 18-unit/kg/hr intravenous infusion rate used in VTE. There are several approaches to measuring the intensity of heparin

therapy. Target ranges have in general been determined from experiences using the aPTT; however, discordance between the aPTT and the other assay approaches exist.23-28 Previously, a target aPTT prolonged to 1.5–2.5 times the patient’s normal baseline value was used.29-31 However, it was recently observed that different assay reagent sensitivities exist, leading to subtherapeutic or excessive doses of heparin. Several factors can drive the variability in reported laboratory results with either the aPTT or the anti-Xa activity value. These include the re-agent used and its sensitivity to heparin, presence of other factors influencing the result such as prolongation of the aPTT that is seen with lupus anticoagulant antibodies, certain congenital factor deficiencies, excessive factor VIII, fibrinogen or warfarin in the case of the aPTT, and AT deficiency for the anti-Xa activity assay. The current recommendations of the American College of Chest Physicians and the College of American Pathologists indicate that patients should be treated with intravenous UFH to prolong the aPTT to a range that corresponds with a whole-blood heparin concentration of 0.3–0.7 unit/mL by the anti-Xa heparin assay or 0.2–0.4 unit/mL by protamine titration.32,33 In recent years, some institutions have shifted from measuring the aPTT to using anti-Xa activity. Institutions that have made the change have noted fewer dosing titrations and earlier achievement of target goals.34 However, hard outcomes such as any differences in the resulting heparin dose, incidence of thrombosis, or incidence of bleeding have not been determined. Given the high variability in reagents and the reported results between laboratories for both the aPTT and the anti-Xa assays, it is important to know the specifics of the assay used to adjust heparin (or LMWH) therapy.35,36 Several challenges can occur with the management of heparin infusions. A diurnal pharmacokinetic elimination pattern has been shown with heparin infusions where higher aPTT or anti-Xa values can occur during sleeping times and then lower values during awake cycles.37 Because sleep cycles are often inconsistent in the ICU, it is difficult to coordinate them with measuring the level of anticoagulation. Another challenge is the observation of “heparin resistance,” in which the aPTT or anti-Xa concentration does not increase despite titration to higher

heparin infusion rates (e.g., above 25 units/kg/hour and values are still at baseline). Causes include elevated fibrinogen or factor VIII concentrations, which may limit the aPTT response, and depression in AT, which may blunt the action of heparin and potentially be missed if an anti-Xa assay is used that incorporates supplemented AT within the assay. To determine whether resistance is present, an AT, aPTT, antiXa assay, fibrinogen, and factor VIII concentration, if available, may be considered. Another means of determining potential resistance to heparin is to measure either the aPTT or the anti-Xa assay shortly after a bolus dose. If there is no response with either test, consider other approaches to anticoagulation management. Alternative tests such as activated clotting time (ACT) may be another consideration to assess whether an anticoagulation response is present. For VTE management, the low-range ACT is suggested because it may be better at detecting heparin concentrations in the target range.35

Low-Molecular-Weight Heparin Another option in patients at lower concern for bleeding and with no perceived need to immediately reverse anticoagulation includes use of an LMWH or one of the newer oral anticoagulants. This may also be a consideration when intravenous access is limited or there is inability to measure laboratory values to adjust therapy. The LMWHs are now commonly used for the prevention and treatment of VTE and may be seen in the ICU if emergency reversal is not a concern. The lowmolecular-weight tinzaparin (no longer available in the United States), dalteparin, and enoxaparin have been determined to be safe and effective in the prevention and treatment of VTE; however, most of the studies with them involved patients outside the ICU. Low-molecular-weight heparins administered subcutaneously are about 87%–92% bioavailable (F = 0.87– 0.92), which is considerably greater than that with sub-cutaneous doses of UFH (30%; F = 0.3).38 The degree of bioavailability may be lower in the critically ill surgical or medical patient.39-41 An impaired response to standard dosing as measured by anti-Xa, possibly leading to a greater incidence of VTE,

has been seen.42,43 Site of administration may be a factor. In one analysis of enoxaparin, the measured anti-Xa activity was significantly lower in patients with obesity when administered in the thigh than when administered in the abdomen.44 Compared with UFH, the LMWHs have a longer half-life and a more predictable anticoagulant response to weight-adjusted doses, allowing for either once- or twice-daily administration. The actual body weight should be considered for dosing, and it is suggested to avoid capping the dose at a certain weight (Table 23.2 and Table 23.3).45 When switching from UFH to an LMWH, the LMWH can generally be given when discontinuing the UFH infusion to simplify the process. Acute thrombus or bleeding is unlikely to occur when a slight difference in the time between discontinuing the UFH and initiating the LMWH occurs. For transitioning from an LMWH to a UFH infusion, consider initiating the UFH infusion when the next LMWH dose would be administered. A bolus dose of UFH is probably unnecessary. The management end point for anticoagulation therapy should focus on potential bleeding and thrombosis or other related undesirable events. Studies comparing various agents in general have shown no significant differences in lowering either thrombosis or bleeding.46,47 Clinicians should be cautious with measuring anti-Xa activity and applying the results to a dosing modification, especially when doses are outside those studied in clinical trials as supporting literature with hard outcomes is very limited. This would also hold true with special populations, including those with obesity and renal failure. It can be problematic to have a level drive a dosing modification in a direction that is very uncomfortable given the current clinical situation.

Fondaparinux Fondaparinux is a synthetic pentasaccharide that mimics the 5-sugar moiety binding sequence that gives heparin the ability to activate AT. Fondaparinux is highly selective for factor Xa inhibition with no appreciable inhibition of factor IIa (thrombin). Fondaparinux rapidly binds to AT, causing an irreversible conformational change. It is

subsequently released, allowing binding to other AT molecules. The ability of fondaparinux to trigger an immune-mediated HIT response is potentially less likely given its small molecular size and the absence of the additional side chains. Although HIT cases attributed to fondaparinux have been reported, fondaparinux is now an optional alternative anticoagulant in the management of HIT, or for VTE prophylaxis when there is a history of HIT.48 Fondaparinux is available in several different strengths (2.5, 5, 7.5, and 10 mg) for once-daily subcutaneous injection. Evaluated in several phase II trials, fondaparinux is approved for VTE prophylaxis in hip and knee replacement, treatment of acute DVT and PE, and treatment of ACS. Fondaparinux dosing in the treatment of a VTE is based on weight: 5 mg (weight less than 50 kg), 7.5 mg (weight 50–99 kg), and 10 mg (100 kg or greater). How- ever, the dose for ACS or VTE prophylaxis post-hip or knee is a fixed 2.5 mg regardless of patient weight. In one phase II dose-response trial, there were no observed differences in recurrent VTE rates or bleeding events between patients weighing 50–100 kg receiving fondaparinux 5, 7.5, or 10 mg subcutaneously daily.49 In a larger randomized phase III trial, weightadjusted fondaparinux was as effective as continuous infusion UFH and weight-adjusted enoxaparin in the treatment of VTE, with a slight decrease in thrombotic events countered by a small increase in bleeding events.50,51 Another phase II trial of ACS evaluating doses of 2.5, 4, 8, and 12 mg showed no difference in the primary end point of myocardial infarction, recurrent ischemia, death, or bleeding. Overall, fondaparinux is effective in the prophylaxis against and treatment of VTE and may be more potent than originally perceived. Fondaparinux is almost entirely renally eliminated and has a long half-life; thus, its use in patients with moderate to severe renal impairment is discouraged. To date, fondaparinux doses of 1.5 mg daily and 2.5 mg every other day in severe renal impairment have been described only in case reports and case series and a single cohort analysis.52,53 Fondaparinux use in hemodialysis seems to provide an adequate level of anticoagulation when properly dose adjusted. Dosing in dialysis appears to require a further dose reduction to either 0.05

mg/kg or 2.5 mg before the dialytic session.54 Providers should consider residual renal function because anuric patients are potentially more likely to accumulate fondaparinux at a faster rate, thus increasing the risk of a potential bleeding event compared with oliguric patients. Much of the data regarding the use of fondaparinux for VTE prophylaxis and treatment in obesity are confined to observational studies and subgroup analyses of larger randomized controlled trials. Fondaparinux is given as a single 10-mg subcutaneous, once-daily injection for patients weighing more than 100 kg. In one subgroup analysis, fondaparinux 10 mg subcutaneously daily was evaluated in patients weighing as much as 166 kg with a BMI of 46 kg/m2. Fondaparinux appeared to be as effective as therapeutic twice-daily enoxaparin and intravenous UFH in the initial treatment of VTE. Fondaparinux had numerically fewer recurrent VTE and major bleeding events than did enoxaparin and UFH.55 Use of fondaparinux in the obese population provides the opportunity for improved compliance compared with a twice-daily therapy, using multiple syringes, together with the convenience of a single once-daily injection. Dosing fondaparinux for VTE prophylaxis is even less clear. The current U.S. Food and Drug Administration (FDA)-approved dose of 2.5 mg subcutaneously daily has been debated regarding whether the dose should be increased for those with morbid obesity or at a certain weight cutoff. Some authors have suggested a dose increase to 5 mg subcutaneously daily in weights greater than 120 kg because of a lack of data for the approved prophylactic dose in this population.56 Anti-Xa activity within range greater than half of the time in the patient with morbid obesity (BMI less than 50 kg/m2; weight less than 150 kg) with fondaparinux 2.5 mg subcutaneously daily has also been seen.57

Reversing Heparin and LMWH Effect The effects of UFH and, to a lesser degree, LMWH can be neutralized using protamine sulfate. In general, each milligram of protamine sulfate neutralizes around 100 units of heparin calcium, with a maximum of 50 mg as a single dose suggested.21 Excessive dosing of protamine

should be avoided because it can independently promote bleeding. Protamine should be administered slowly over at least 10 minutes to reduce the possibility of hypotension and anaphylaxis. When dosing protamine, the clinician should consider how long heparin has been held. Because UFH administered intravenously has an elimination half-life of 60–90 minutes, only heparin given during the preceding several hours needs to be considered when calculating the dose of protamine sulfate. For example, a heparin infusion at 1,250 units/hour requires about 30 mg of protamine sulfate for neutralization. Neutralization of UFH administered by subcutaneous injection may require a prolonged infusion or repeat doses of protamine sulfate because of continued absorption from the site of administration. The effectiveness of the neutralization can be assessed by measuring either the aPTT or the anti-Xa activity.33 For the LMWHs, protamine only partly neutralizes their effects, with a potentially greater response to higher sulfated compounds (tinzaparin > dalteparin > enoxaparin); however, the clinical significance of this is unclear.58 A 1-mg dose of protamine for every 100 anti-Xa international units of dalteparin or 1 mg of enoxaparin has been recommended for reversal if less than 8 hours has elapsed since the dose of LMWH. Fondaparinux is currently without a specific antidote. Protamine is ineffective in neutralizing the anticoagulant effect of fondaparinux because of the lack of sulfations in the synthetic pentasaccharide. Doses of recombinant activated factor II (rFVIIa) up to 90 mcg/kg have shown only partial correction in the thrombin-generating capacity of an ex vivo analysis, whereas a low dose (20 units/kg) of the activated prothrombin complex concentrate (aPCC) factor eight inhibitor bypassing activity (FEIBA) showed a complete correction in the assay.59

Direct Thrombin Inhibitors The parenteral direct thrombin inhibitors (DTIs), typically administered by continuous infusion, provide an alternative option when commonly used therapies such as UFH or LMWH cannot be used (Table 23.5).

This may occur in patients who have heparin allergies, concerns for HIT, or AT deficiency. The two currently available parenteral DTIs are argatroban and bivalirudin. Most of the experiences with these agents in the management of VTE arise in the setting of acute HIT-with or without associated thrombosis, HIT post-initial therapy for VTE, or history of HIT requiring VTE prophylaxis. Fondaparinux may be an option in some cases where use of a DTI infusion is not desired and a long acting agent is permissible. The elimination half-lives for argatroban and bivalirudin are relatively short, according to an analysis of healthy individuals. In the critically ill patient, especially in the presence of heart, kidney, or liver dysfunction, elimination rates can be considerably longer, thus taking longer to reach steady state and longer for the effects to leave after discontinuing the infusion. In addition, the amount of drug needed to achieve treatment targets may be lower. The infusion rate is typically adjusted on the basis of observed aPTT or dilute thrombin time values.22,60 The aPTT target concentrations are based on achieving ratios of 1.5–2.5 for bivalirudin and 1.5–3.0 for argatroban from the patient’s baseline value. The upper end of the range is commonly targeted in patients at higher thrombosis concerns such as for acute thrombosis, and the lower end for thromboprophylaxis. Although the aPTT is also used for heparin, the target value during DTI therapy may be different.

Table 23.5 DTIs in the Management of VTE22 Argatroban

Bivalirudin

FDA-approved indication

HIT, PCI

PCI

Route of elimination

Hepatic

Renal (20%); proteolytic cleavage

Elimination half-life

39–51 min

25 min

Common

1.6 mcg/kg/min

0.12–0.15 mg/kg/hr

dose aPTT target

1.5–3 × baseline; not to exceed 100 seconds

1.5–2.5 baseline

Assay approach

aPTT,a TT, dTT,a ECTa

Dose in critically ill

0.5–1.2 mcg/kg/min

0.08–0.17 mg/kg/hr

Dose in renal failure

Decrease 0.1–0.6 mcg/mL/min for each 30-mL/min decrease in CrCl

CrCl 30–60 mL/min: 0.08–0.1 mg/kg/hr CrCl < 30 mL/min: 0.03–0.05 mg/kg/hr

Dose in hepatic failure

≤ 0.5 mcg/kg/min

No adjustment

aNo

nationally standardized test; thus, test results and sensitivity may vary between institutions. aPTT = activated partial thromboplastin time; dTT = diluted thrombin time; ECT = ecarin clotting time; HIT = heparin-induced thrombocytopenia; min = minute; TT = thrombin time; PCI = percutaneous coronary intervention.

Argatroban is primarily eliminated in the liver, but it also requires dosing reductions in renal insufficiency.61,62 The aPTT target is 1.5–3 times control according to the range set in the ARG 911 trial. Although the prescribing information notes starting at 2 mcg/kg/minute, the mean dose in the ARG 911 and the subsequent postmarketing ARG 915 trial was lower at 1.5–1.6 mcg/kg/minute. Experiences with the use of argatroban in the critically ill patient suggest even lower doses less than 1 mcg/kg/minute.63 For liver failure with a Child-Pugh score greater than 6 or a total bilirubin greater than 1.5 mg/dL, the dose should be reduced to 25% of normal, or 0.5 mcg/kg/minute; however, lower doses may occur.22 For renal insufficiency, the observations have suggested a dose reduction of 0.1–0.6 mcg/kg/minute for every 30-

mL/minute decrease in CrCl.11 There is no known reversal agent for argatroban, and it is not removed by hemodialysis. Bivalirudin is another DTI primarily developed for use in ACS; however, there are several postmarket, single-center experiences describing its use in the management of HIT at much lower doses. The commonly targeted aPTT value is 1.5–2.5 times control, and it is eliminated primarily by enzymatic degradation by thrombin; however, the dose may need to be reduced as renal function declines. The common dose is 1.5 mg/kg/hour; however, lower doses are commonly seen in the critically ill patient as well. Unlike argatroban, bivalirudin may be removed by hemo-dialysis, and enzymatic elimination may be impaired in hypothermia.9,64 The aPTT should not be measured during, or for several hours after, intermittent hemodialysis. In the setting of continuous renal replacement therapy, a higher dose may be necessary to account for removal by hemofiltration.9 Although package labeling suggests that steady state may occur within hours, it may take considerably longer in the critically ill patient. One strategy is to assess an aPTT within a few hours of initiating the infusion, and if the value is in the upper part of the target range or above (and before reaching steady state), an excessive level of anticoagulation could shortly occur. As such, the infusion rate may tapered down earlier as a precaution.65 In a bleeding patient with acute thrombosis concerns, the infusion can be initiated at a lower rate and titrated to effect using more frequent aPTT assessments.65 Management of bleeding during parenteral DTI therapy includes targeting lower aPTT values, giving blood transfusions as needed, and providing hemofiltration, if necessary, for bivalirudin. Concentrated clotting factors, fresh frozen plasma, and vitamin K do not expedite removal; however, in theory and according to very limited case experiences, it is possible that the thrombin burst with rFVIIa can accelerate the enzymatic removal of bivalirudin.64 Of additional note, heparin and the parenteral DTIs can independently cause an increase in measured INR values. These are not thought to reflect independent pharmacologic activity, but they are the result of influencing the INR assay.35,66 The higher the drug

concentration, the greater the impact on the observed INR value, which may vary between laboratories and the assay used. Some laboratories perform an additional step and neutralize the heparin before measuring the INR, eliminating the influence. It is important to know whether your laboratory does this neutralization step because many clinicians may otherwise target an INR of 2.5 or higher with warfarin before discontinuing heparin to account for the assay differences. In the absence of warfarin, an INR value at or above target ranges does not indicate a need to discontinue the infusion, but it could be an indication of excessive anticoagulation effect from the DTI, again depending on the sensitivity of the INR assay to the DTI. For the DTIs, the INR assay is more sensitive to argatroban followed by bivalirudin.66 This can be an advantage in patients for whom the aPTT response is not very robust. In some patients, the aPTT response curve may flatten and may not increase despite significant increases in the infusion rate. In such situations, a thrombin time can be measured, and if a very high result is noted, excessive anticoagulation can be present despite a low aPTT. In such situations, the dose can empirically be capped and the patient monitored for thrombosis and bleeding. The effect on the aPTT could be transient, so it should continue to be measured, and if excessive values subsequently occur, the infusion rate might need to be reassessed.

ORAL AGENTS Vitamin K Antagonists For longer-term anticoagulation, the vitamin K antagonists have been the preferred agent for treatment of a VTE after initial management with a parenteral anticoagulant, or prevention of VTE. This class of agents, for which warfarin is the most common agent used in North America, decreases the production of the vitamin K–dependent clotting factors (II, VII, IX, and X) in the liver to lower concentrations, blunting the drive for thrombosis. The INR is the common means for measuring the intensity of anticoagulation with vitamin K antagonists, where target

values of 2–3 are typically used in the management of VTE. Many factors can influence the dose response to warfarin; these are described in detail elsewhere.67 Many can be present in the critically ill patient, typically leading to lower doses. Examples include renal, liver, and heart failure; concurrent drug interactions; inflammatory responses; infections, and low vitamin K stores. Some such as rifampin or continuous tube feeds, or improvement in organ function and resolution of an infection, may lead to a dosing increase. For an acute VTE, warfarin can be initiated once anticoagulation with a parenteral agent has been established. This would be 4 hours after an LMWH dose or when a therapeutic aPTT value on UFH occurs. When initiating therapy, the clotting factor with the shortest life span, factor VII, is eliminated faster than is factor II. Because factor II remains longer and is the primary driver for thrombosis, rapidly rising INR values may underpredict the level of anticoagulation.68 Before initiating warfarin, a baseline INR should be determined and then measured daily, if possible, at least 8–10 hours post-dose (longer may be preferred, if feasible) to assess any early potential dose response. Because warfarin is eliminated through the liver, lower doses may be common in liver disease. However, renal failure may also block the elimination of selected cytochrome enzymes (in the case of warfarin 2C19), resulting in lower warfarin dosing.69 If the INR is not a feasible test because of other influencing factors (e.g., lupus anticoagulant), clotting factors such as factor II or X can be directly measured. For acute VTE, the parenteral bridge therapy may be discontinued once the INR is greater than 2 and determined to be believable. Unexpected INR values may be repeated to determine if the result is believable or not before a dosing decision. Warfarin can be crushed, and the effects of a particular dose may not reach maximal influence for several days; however, in some patients, a marked response may be seen after 8–12 hours. Thus, an INR may be measured at some point after the first dose to determine whether the patient is very sensitive to it.

Directing Acting Oral Anticoagulants

Until recently, warfarin was the mainstay of prolonged VTE therapy; however, dosing can be difficult because of the many influencing factors. Several new agents recently became available and have been approved for VTE management. Dabigatran is a DTI, and rivaroxaban, apixaban, and edoxaban are factor Xa antagonists. Patients enrolled in the clinical trials exploring the use of these agents for VTE were probably not critically ill, limiting any clear insights of any advantages over warfarin. The designs of the VTE trials were also very different. Although most patients received heparin or an LMWH initially while being randomized, initial therapy for edoxaban and dabigatran included a parenteral agent for 1 week or so, which was then switched to oral therapy. For rivaroxaban, a higher dose of 15 mg twice daily was administered for 3 weeks, followed by a lower 20-mg once-daily dose. For apixaban, the initial dose was 10 mg orally twice daily for 7 days, followed by 5 mg twice daily in VTE treatment. Rivaroxaban and apixaban can be crushed and mixed for nasogastric administration; however, the dabigatran capsule should not be opened; rather, it should be given as manufactured because any alterations can substantially increase the bioavailability 8- to 10-fold.70-72 Critically ill patients such as those with severe liver failure or high risk of bleeding were pre-determined exclusions in the clinical trials. Unlike warfarin, which requires invasive INR tests for adjusting dosing, the newer agents do not require or have commonly available measures of anticoagulation intensity and subsequent dosing adjustments. However, drug interactions do exist with the newer agents, and the presence of organ failure can result in higher levels of anticoagulation that may be difficult to recognize. Assays to directly measure the intensity of anticoagulation with the newer agents have been developed or are under development; however, they are not commonly available. The thrombin time is very sensitive to the presence of dabigatran and can be used to detect its presence; however, it can exceed maximum values when normal serum concentrations are present.73 For the INR, prothrombin time, and aPTT, the various assay regents available can respond differently to the presence of the newer agents, depending on their sensitivity. Elevated values beyond what may be

expected for a selected assay may be a signal for excessive anticoagulation, especially if a clinical condition (e.g., overdose, organ failure, or a drug interaction) is present. Anti-Xa activity can be increased depending on the assay and the calibrator used, creating notable variability in results and limiting its usefulness.74,75 Several agents that can directly reverse the DOACs (direct oral anticoagulants) are currently under development. Idarucizumab is a monoclonal antibody fragment (Fab) currently in phase III trials but recently approved by the FDA specifically binds to dabigatran and rapidly neutralizes its anticoagulant effect in minutes.76,77 It has no activity against other anticoagulants. In the REVERSE-AD phase III trial, the median time for hemostasis took 11 hours.77 As such, it is unclear in situations with massive hemorrhage whether concurrent use of a concentrated clotting factor or tranexamic acid is necessary if rapid hemostasis is critical. Andexanet alfa is a modified recombinant version of factor Xa that works as a decoy to block any anticoagulant with antiXa activity.78 Both agents are initiated with a bolus dose; however, andexanet may require continued therapy with a continuous infusion. During anticoagulation therapy, situations may arise in which the concerns for bleeding outweigh those for thrombosis, either for high bleeding risk situations, including necessary invasive procedures, or active bleeding. Approaches can include reducing the level of anticoagulation, holding anticoagulation, expediting removal, or independently promoting hemostasis. Agent-specific reversal strategies are listed in Table 23.6. For a bleeding event, if a patient has a history of VTE, the reversal approach may consider the brevity of the situation. If severe morbidity or mortality is perceived and no emergency reversal occurs, more aggressive management may be considered. If time permits or a desire not to fully reverse effects is present, more conservative reversal regimens can be considered and titrated to the desired effect. In the critical bleeding situation, administration of reversal approaches should be accomplished without delay. For heparin or LMWH, protamine can be administered. For warfarin, a prothrombin complex concentrate (PCC) together with parenteral vitamin K can be

given. Three-factor PCCs (which have a lower amount of factor VII compared with factors II, IX, and X); four-factor PCCs, which have all four factors; and, to a limited extent, aPCCs, which have all four factors with factor VII in a activated form, have been explored.79 In addition, recombinant activated factor VIIa (rVIIa) has been explored for reversing anticoagulants. The dosing of PCCs to reverse warfarin may depend on the observed INR; however, waiting for a value to return before dosing may delay therapy. If the INR is not yet available, therapy can be initiated with the initial three or four factor PCC dose of 25 units/kg using a weight up to 100 kg, and if the INR suggests a higher dose, an additional agent can be given. To avoid delays in the admixture of several vials, therapy with a single 1,000-IU vial can be reconstituted and given while the remaining dose is determined and prepared. One of the challenges with using PCCs is their association with increased risk of thrombosis. Combined with a history of VTE, the concern for an additional VTE can be even greater. In the setting of warfarin, vitamin K can be given orally or parenterally. Parenteral vitamin K has a more rapid onset in INR reduction; however, little difference is seen between the two routes after 24 hours. Recent experiences have suggested that doses greater than 2 mg intravenously provide no additional reduction in the INR after 24 hours, but more prolonged reversal.80 If the goal is a partial reversal of the INR, low doses of vitamin K (e.g., 0.25–0.5 mg intravenously) can be considered. If anticoagulation is reinitiated shortly, higher doses of vitamin K may lead to prolonged bridge therapy before a response to warfarin occurs. If there is no plan to reinitiate therapy, a vitamin K dose of 10 mg is feasible. For the newer oral anticoagulants, approaches to reverse their effects have not been established. Dabigatran can be removed by hemodialysis, and given the potential for tissue rebound, prolonged dialysis may be necessary.81 However, recent availability of an antibody to dabigatran, idarucizumab, may limit the need for hemodialysis. Case reports have suggested that an aPCC can establish hemostasis; however, the optimal dose has not been established.81-84 The effectiveness of non-activated PCC is less clear.

For rivaroxaban, edoxaban, and apixaban, any difference between aPCC and non-activated PCC is unclear. Ideally, the lowest effective dose necessary to establish hemostasis may be preferred. If time permits, a lower dose can be used and titrated to effect depending on hemoglobin values and symptoms of bleeding. Once the bleeding issue resolves, reinitiating anticoagulation may be a consideration. For a previous VTE, obtaining the history of the previous VTE event, including whether it was provoked or nonprovoked, the previous number of events, and the duration elapsed, can assist in determining the subsequent management plan. If it has been more than 3 months after a provoked VTE, continued anticoagulation may be unnecessary. In contrast, if there is a history of several non-provoked VTE events, continued therapy may be strongly encouraged.

CONSIDERATIONS IN SPECIAL POPULATIONS Because the critically ill patient is at high risk of VTE, prevention and management decisions continually require assessment each day instead of just during times of admission or transferring between services. Mechanical methods, unless there is a specific reason not to use them, should be used and will be effective as long as they are in use. If anticoagulation therapy is not an option in the presence of a VTE, clinicians may consider temporary placement of an inferior vena cava (IVC) filter. These filters may prevent subsequent PEs, but they have also been associated with a higher rate of VTE; thus, it is preferred that they be removed once it is safe to do so.85 Decisions to initiate systemic anticoagulation in the presence of an IVC filter should include the plan for filter removal. The dynamics of a critically ill patient can also continuously be changing between degrees of instability and more stable conditions. The dynamics of other patients, although requiring ICU-level care, can be for the most part very stable, and response to therapy may be consistent with the post-ICU setting. In the unstable patient, decisions on pharmacologic therapy should include the current risk of bleeding

and thrombosis as well as any trends or future events that may alter them. In addition, decisions should include timely assessment of the patient’s clinical presentation such as improving or declining trends, together with trends in organ function. Assessing such trends in today’s management decisions will help clinicians achieve goals in subsequent days.

Table 23.6 Reversal Approaches to Anticoagulation

Anticoagulant

Examples of Laboratory AssaystoConsider

Pharmacologic Reversal Agents

Comment

UFH

aPTT or anti -Xa

Protamine

For urgent situations. Effects of heparin dissipate several hours after holding. Post- cardiopulmonary bypass, an aPTT rebound may be detected after up to 6 hours requiring an additional dose of protamine ( -25 mg)

LMWH

Anti-Xa drawn 4 hr post- dose in selected situations

Protamine

Partial reversal of effects with protamine . Degree of reversal and ability to reduce bleeding is unclear

Fondaparinux

Anti-Xa has been proposed, butnoknowneffect on outcomes. Not recommendedatthistime

Unclear

One assessment showed a greater impact with an aPCC of 25 units / kg than with rFVIIa

Argatroban

aPTT

Effective means to reverse argatroban has not been established

ACT in selected cardiac procedures Bivalirudin

aPTT

Hemofiltration

Limited evidence suggests that rFVIIa ( e.g., 1-2 mg) reverses effects

Vitamin K, PCC ( three or fourfactor), FFP

Vitamin K doses ( 0.25-10 mg IV ) take 12-48 hours for full e f feet

ACT in selected cardiac procedures Warfarin

INR

PCC 4 ( Kcentra ) dosing:

Max dosing weight 100 kg

INR 2-4: 25 units / kg ( aetual body weight ) INR 4.1-6: 35 units / kg ( aetual body weight ) INR > 6: 50 units/ kg ( aetual body weight ) lf INR > 1.5 and severe bleeding, can consider a PCC

Some experience with low- dose aPCC ( 500-1,000 units «1) Option: Administer 1,000 units PCC4 up front, and balance when INR is back . Some produets have heparin and are not recommended in Fl IT. Repeat INR 10-15 min post-dose

Dabigatran

TT, aPTT, INR, and if available - ECT- or dTT- derived dabigatran conc

Idarucizumab aPCC or PCC

Hemodialysis

INR may be elevated at high concentrations

Idarucizumab 5 gm can be rapidly administered as a bolus orinfusion to neutralize the anticoagulation effects of Dabigatran. Another option is hemodialysis to remove dabigatran, depending on the amount present in the plasma. Drug concentrations have been shown to rebound on cessation of hemodialysis from tissue rebound; therefore, prolonged dialysis may be warranted in selected situations ( can consider lowering the blood flow rate). For minor bleeding, monitor and recheck laboratory values

Major bleeding: Consider tranexamic acid or PCC for more rapid hemostasis. Some limited data analyses have shown positive effects with an aPCC ( FEIBA ) 8-50 units / kg have been explored. PCC dose is 25-50 units / kg may be another consideration.

Can consider starting at low doses and titrating to effect. Can administer just before catheter placement for hemodialysis

Rivaroxaban, apixaban, edoxaban

aPTT, chromogenic anti-Xa ( consider calibrating to agent involved ). UHF and LMWFH calibrators can be used, but resuitsmayvary

PCCoraPCC

Data on the agent and dose to reverse the effects of rivaroxaban has not been established. Not dialyzable

Minorbleeding, monitorand recheck laboratory values Major bleeding: PCC or aPCC Some limited data analyses have observed positive effects with an aPCC ( FEIBA ) of 8-50 units/ kg. PCC dose is 25-50 units / kg

Can consider initiating at low doses and titrating to effect

ACT = activated clotting time; aPCC = activated prothrombin complex concentrate (FEIBA or factor eight inhibitor bypassing activity is a aPCC); aPTT = activated partial thromboplastin time; dTT = diluted thrombin time; ECT = ecarin clotting time; FPP = fresh frozen plasma; HIT = heparin-induced thrombocytopenia; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; PCC = prothrombin complex concentrate (PCC4 = four factor PCC); rFVIIa = recombinant activated factor VII; TT = thrombin time.

For acute decompensated heart failure or notable hypotension, poor perfusion to the kidney or liver may lead to reduced drug clearance and increased levels of anticoagulation and lower dosing requirements. Reductions in the liver’s capacity to produce clotting factors may also occur. Acute and transient changes in response to warfarin may be seen with an infection or new interacting drug added. As the transient influencing factors such as heart function recover or the infection diminishes, drug elimination will recover, and dosing may need to be increased. For such situations with warfarin, for example, and with a desire to sustain its effects, the INR may be notably elevated and dosing held or reduced. As the INR begins to drop, the dosing should be reinstituted or increased before the INR drops to the target range. Holding warfarin until reaching target range after several days of low or no doses may result in a continued drop below target range and require bridge therapy, especially if there was a recent VTE event. Bedside observations and timely assessment of the patient’s clinical presentation, including shifts in factors influencing decisions for management trends in advance, may allow earlier adjustments and minimize time outside the treatment goals. Acute changes in renal function can alter the dynamics of anticoagulation therapy as well as the balance between bleeding and thrombosis for many factors. Unfortunately, patients with severe forms of renal failure or the requirements for renal replacement therapy have

been poorly studied and excluded from large clinical trials. Dosing of renally influenced agents as noted earlier can also be difficult to manage when kidney function is unstable. Having the ability to measure the level of anticoagulation, if available, may assist in assessing the regimen. In this setting, heparin therapy may be considered because the kidney does not alter its elimination. However, at times, it may not be feasible to use heparin if there is no intravenous access or ability to measure. One option recently explored and included for acutely ill patients requiring hemodialysis was enoxaparin dosed at about 0.6–0.7 mg/kg daily.12 Anti-Xa activity was not measured in this analysis because it may not accurately describe the balance between thrombosis and hemostasis effects of enoxaparin in this setting as other drivers notable in renal failure may influence outcomes.53 Anticoagulation in acute liver injury and/or failure, including chronic conditions, can be difficult to manage, not only because of altered effects of the drugs and some assays but also between the balance of thrombosis and the bleeding potential. Although indicators such as the INR may suggest poor clotting factor production and a hypocoagulable state, other factors such as the natural anticoagulants may also be impaired.86,87 Management decisions must carefully weigh this. In some cases, acute reductions in liver function could also be caused by portal thrombosis, which would require a separate management approach. When initiating warfarin in the setting of an elevated INR, it has not been established what the subsequent target range should be, and this is typically determined on a case-by-case basis. Use of newer anticoagulants in severe liver impairment is unclear because this population was excluded. When initiating warfarin in an unstable setting such as liver disease or other factors that may suggest an increased response to a dose, consider allowing as much time as possible between the dose and the subsequent INR to unmask the sensitivity. Remember that when the INR is abruptly rising, it is mainly being driven by a fall in factor VII instead of factor II. As such, the INR may suggest a higher level of anticoagulation than truly exists. Anticoagulation management decisions relative to invasive

procedures should consider the risk of thrombosis and bleeding before, during, and after surgery. In the pre-operative setting, a bridge to a shorter-acting agent may be considered if the VTE risk is high. Heparin can typically be turned off several hours before the procedure. For LMWH, the last dose may be 24–48 hours prior, and for warfarin, the INR may be allowed to drop to a predetermined level on the basis of bleeding assessments. For other anticoagulants, holds may depend on the perceived time for effects to diminish. If neuroaxial anesthesia is being considered, a longer hold of the anticoagulant to allow the complete absence of anticoagulation may be preferred. This may be used for up 5 days for some agents if their effects cannot immediately be reversed.88 Postprocedure management decisions should consider outcomes of the procedure and potential complications or requirements for additional procedures. Anticoagulation may be initiated slowly after procedures with higher risks for bleeding, especially if the CNS or other critical areas are involved when there is no drain in place or ability to transfuse. In some situations, such as in the eye, heart, or spine, a small amount of blood can be devastating. Once bleeding risks subside, either prophylaxis or full anticoagulation therapy can be initiated. With the exception of reinitiating warfarin, bridging between agents is unnecessary. In some situations, other indications for anticoagulation may be present. In these settings, target ranges or doses may be considered, typically using the higher of the two variables unless there is a bleeding-related issue suggesting the lower intensity. For some of the agents approved for use in VTE, the anticoagulant may need to be switched to an agent that has been determined to be effective in both settings.

HEPARIN-INDUCED THROMBOCYTOPENIA Immune-mediated HIT is a rare complication associated with exposure to heparin or LMWH that can lead to venous and arterial thrombosis or death. Heparin-induced thrombocytopenia can occur in three time

settings: immediate exposure (within minutes with recent previous exposure to heparin), typical exposure (5–10 days after exposure to heparin), and delayed exposure (up to 40 days after heparin exposure). Because of delayed-onset HIT, patients presenting with acute thrombosis and recent heparin exposure should have their platelet count checked before initiating heparin or LMWH. The presence of antibodies related to immune HIT can be determined using selected assays as a means of separating this from other causes of thrombocytopenia. Common assays include the enzyme-linked immunosorbent assay and the serotonin release assay, which is more specific but may take longer for results to be reported. The process of ordering a test for HIT and for knowing when alternative therapy should be initiated creates notable decisions on how to proceed with anticoagulation management. When making decisions to test for HIT, consider the impact of results because there is the potential for falsepositive observations. Because thrombocytopenia for many reasons can occur in the critically ill patient, clinicians should carefully think about adding in HIT testing as part of a global approach to determining the cause for the low platelet count unless clinical suspicion is sufficient. Commonly used HIT predictive tools such as the 4T score include the magnitude of the platelet count drop, timing in relation to heparin exposure, presence of new thrombosis after initiating heparin, and absence of other causes of thrombocytopenia.48 Platelet counts can commonly drop post-cardiopulmonary bypass surgery, and here, the pattern for HIT is the presence of platelet count recovery, followed by a second drop in platelet count. Other common devices in the ICU such as aortic balloon pumps can commonly cause thrombocytopenia and are not suggestive of HIT. For HIT, alternative anticoagulation with a DTI or fondaparinux is suggested. Holding heparin or LMWH alone is not recommended. Once platelet counts are sufficiently recovering or have recovered, warfarin can be considered for prolonged anticoagulation. The parenteral anticoagulant should be continued until the INR adjusted for any assay influenced by the DTI is greater than 2.0. At times in the ICU, other causes of thrombocytopenia may be present, and platelet counts may

not recover, resulting in a prolonged course of parenteral anticoagulation. Alternative anticoagulation in the setting of isolated HIT should be continued until the platelet count has recovered and the risk of thrombosis is resolved. For thrombosis, either as the reason for initial anticoagulation or for thrombosis attributed to HIT (heparin-induced thrombocytopenia thrombosis or HITTS), anticoagulation should be continued for at least 3 months. Given that the antibody response driving HIT is transient, lasting for around 3 months, alternative anticoagulants such as fondaparinux or a DTI may be considered.48 Such decisions should weigh the risks involved. If transitioning the patient to warfarin, current observations encourage continuing the initial parenteral therapy until the INR is in a target range adapted to the false elevation caused by the DTI. This can be determined by looking at the INR on the DTI before initiating warfarin and adding the elevation to the INR target. For example, if the INR on argatroban is 2.0 before initiating warfarin, an INR above 3.0 should be observed before discontinuing the DTI. Minimal change in the DTI dose between the two INR determinations would be preferred to limit changes in the DTI effect in the INR. Caution should be exercised against dosing that leads to having excessive effects from warfarin during initiation of therapy because it may pose a risk of venous limb gangrene. In addition, guidelines suggest waiting for the platelet count to recover to more than 150,000/mm3.48 However, in the critically ill patient especially, platelet counts may not recover, resulting in prolonged DTI therapy. One recent observation noted no difference between the strategies of waiting for platelet count recovery compared with initiating warfarin in conservative dosing once two consecutive rising platelet counts had occurred.89

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Chapter 24 Hemostatic Agents for

the Prevention and Management of Hemorrhage in the ICU Robert MacLaren, Pharm.D., MPH, FCCP, FCCM; Bradley A. Boucher, Pharm.D., FCCP, FCCM; and Laura Baumgartner, Pharm.D.

LEARNING OBJECTIVES 1. Describe the physiologic integration of coagulation, fibrinolysis, platelets, and the vessel wall to achieve optimal hemostasis. 2. Delineate the extrinsic and intrinsic coagulation pathways, and compare the common laboratory values used to measure their activities. 3. Define coagulopathy and thrombocytopenia, and outline common etiologies of both in critically ill patients. 4. Explain the pathophysiologic mechanisms contributing to coagulopathy for hypothermia, acidosis, dilutional, inflammation (disseminated intravascular coagulopathy), hepatic dysfunction, renal dysfunction, inherited abnormalities, and medications. 5. Formulate a treatment plan and goals of therapy for fluid resuscitation during hemorrhage. 6. Compare and contrast the blood products (red blood cells, platelets, fresh frozen plasma, prothrombin complex concentrates, and cryoprecipitate) with respect to indications,

goals of therapy, and adverse events. 7. Compare and contrast the pharmacologic agents (local hemostatics, vitamin K, recombinant activated factor VII, desmopressin, conjugated estrogen, and fibrinogen concentrate) with respect to indications, goals of therapy, and adverse events. 8. Develop a plan for the prevention and management of hemorrhage associated with surgery, trauma, hepatic dysfunction, obstetric, and anticoagulants.

ABBREVIATIONS IN THIS CHAPTER ADP

Adenosine diphosphate

aPTT

Activated partial thromboplastin time

ATP

Adenosine triphosphate

DIC

Disseminated intravascular coagulation

DTI

Direct thrombin inhibitor

FFP

Fresh frozen plasma

GP

Glycoprotein

ICU

Intensive care unit

INR

International normalized ratio

MTP

Massive transfusion protocol

PCC

Prothrombin complex concentrate

PPH

Postpartum hemorrhage

PRBC

Packed red blood cell

RBC

Red blood cell

rFVIIa

Recombinant activated factor VII

ROTEG

Rotational thromboelastography

TACO

Transfusion-associated cardiac overload

TEG

Thromboelastography

TRALI

Transfusion-related acute lung injury

TRIM

Transfusion-related immunomodulation

vWF

von Willebrand factor

INTRODUCTION Hemostatic pathways act to promote and maintain blood flow. Coagulation is an orchestration of interactions between blood vessels, procoagulant mediators, anticoagulant mediators, and platelets. Several etiologies may disrupt these homeostatic processes, leading to hemorrhage. The clinician must understand these pathologic causes in order to facilitate appropriate management and monitoring. Therapies may include blood products, pharmacologic agents, and nonpharmacologic interventions, each with their own considerations that must be understood to optimize treatment and prevent further hemorrhage. This chapter will review the common causes of disruption to the hemostatic pathways; delineate the properties of blood products, pharmacologic agents, and nonpharmacologic interventions that clinicians need to consider when applying them in a clinical scenario; and discuss appropriate management for common types of hemorrhage.

AN OVERVIEW OF HEMOSTASIS Hemostasis is a complex homeostatic system that integrates coagulation, fibrinolysis, platelets, and the vessel wall to limit hemorrhage and prevent thrombus propagation. Under normal

conditions, the endothelial cells have antithrombotic properties such as heparin-like glycosaminoglycans, platelet inhibitors, coagulation inhibitors, and activators of fibrinolysis. In contrast, the subendothelium is highly thrombotic with mediators that include collagen, von Willebrand factor (vWF), and platelet adhesion molecules. This hemostatic balance, however, may be disrupted by pathological conditions such as trauma/surgery, blood abnormalities, or inflammation.1,2 Any vascular insult results in arteriolar vasospasm, mediated by reflex neurogenic mechanisms and the release of local mediators like endothelin and platelet-derived thromboxane A2. Platelets are disc shaped and normally do not adhere to intact vascular endothelium. Vessel injury releases vWF, a glycoprotein (GP) always present to some degree in plasma, to cause platelets to undergo a morphological change that increases their surface area. von Willebrand factor also promotes platelet adhesion by acting as a bridge between endothelial collagen and platelet surface receptors GPIb. After adhesion, platelets are activated and undergo degranulation that causes the release of Pselectin; factors I (also called fibrinogen), V, and VIII; platelet factor IV; platelet-derived growth factor; tumor growth factor α; adenosine triphosphate (ATP); adenosine diphosphate (ADP); calcium; serotonin; histamine; and epinephrine. Hypoxia from blood loss or other causes up-regulates P selectin and can initiate coagulation through the recruitment of factor III (also called tissue factor) containing monocytes. Calcium binds to phospholipids to provide a surface for the assembly of various coagulation factors. Thromboxane A2 and ADP stimulate further platelet aggregation leading to the formation of a platelet plug, which temporarily seals the vascular injury. Adenosine diphosphate binding also causes a conformational change in GPIIb/IIIa receptors on the platelet surface leading to the deposition of fibrinogen and platelet clumping. Thrombin generation catalyzes the conversion of fibrinogen to fibrin, which stabilizes the platelet plug by forming a matrix for additional adhesion.1,2 Comprehending the tissue factor pathway (extrinsic pathway) and the contact activation pathway (intrinsic pathway) is necessary to understand the coagulation cascade, the possible disorders associated

with major hemorrhage, and the laboratory values that describe coagulation and define coagulopathy (Figure 24.1).1,2 Most clotting factors are precursors of proteolytic enzymes and circulate in an inactive form. With the exception of tissue factor and factors IV and VIII, clotting factors are produced in the liver. Factors II (also called prothrombin), VII, IX, and X undergo post-translational modification by vitamin K–dependent carboxylation of the glutamic acid residues. Naturally occurring anticoagulants include antithrombin (which inactivates thrombin and factors IXa, Xa, XIa, and XIIa), tissue factor plasminogen inhibitor, proteins C and S, thrombomodulin, and protein Z. The extrinsic pathway is plasma-mediated hemostasis. It is activated by tissue factor that is expressed in the subendothelial tissue and exposed during direct vascular injury, functional injury (activation of circulating tissue factor), hypoxia, malignancy, or inflammation. Tissue factor binds to calcium to activate factor VII (now called factor VIIa), which further activates factors X, V, and II. The intrinsic pathway is a parallel pathway to the extrinsic system. It is initiated by collagen exposure, which activates factor XII, which in turn activates factors XI, IX, and VIII to form tenase complex on a phospholipid surface. The propagation requires calcium, high-molecular-weight kininogen, and prekallikrein. The extrinsic and intrinsic pathways merge at the common pathway where activated factor X, cofactor V, tissue and platelet phospholipids, and calcium form a prothrombinase complex. This complex converts prothrombin to thrombin to cleave fibrinogen to fibrin and activates factor XIII. This leads to the formation of covalent crosslinks of fibrin (polymers) that are incorporated in the platelet plug.1,2 The intrinsic pathway also augments thrombin generation primarily initiated by the extrinsic pathway. Coagulation can be described as four steps: initiation, amplification, propagation, and stabilization. During the initiation phase, the expression of tissue factor from the inured vessel complexes with factor VIIa, which activates factor IX. The tissue factor-VIIa complex represents a bridge between the two pathways as factor Xa activates thrombin. The generation of thrombin is not robust and can be terminated by tissue factor pathway inhibitor. This thrombin is often

called “priming thrombin” because it binds to platelets to activate them and factors V and VIII, the latter of which serves as a cofactor in the prothrombinase complex and accelerates the formation factor Xa. This process represents amplification. Propagation occurs when the accumulated enzyme complexes (tenase and prothrombinase) on the platelet surface produce robust thrombin, often called a thrombin burst, which further activates platelets creating a positive loop. This ensures continuous thrombin generation and fibrin production in sufficient amounts to form a stable clot. Stabilization is the factor XIIIa process of forming covalently linked fibrin polymers that provide strength to the platelet plug. Thrombin also activates thrombin activatable fibrinolysis inhibitor, which protects the clot from degradation.1,2

Figure 24.1 Coagulation cascade delineating the intrinsic, extrinsic, and common pathways.1,2

Measuring Hemostasis To fully comprehend the limitations of treatments used to promote

hemostasis, it is necessary to understand the assays used to measure coagulation (Figure 24.1).2 The prothrombin time (PT) and the international normalized ratio (INR) monitor the extrinsic pathway (tissue factor pathway) and common portions of the clotting cascade.3,4 Platelets are removed from citrate anticoagulated plasma by centrifugation to isolate the role of the soluble clotting factors to which tissue factor and calcium are added to initiate clotting. This process preferentially activates factor VII, which in turn activates factors X, V, and II to ultimately convert fibrinogen to fibrin; this last step is captured optically or electrically and measured in seconds.3,4 Because factor VII circulates in the highest abundance of any factor, the PT is relatively resistant to change and requires single factor levels to decline to less than 10% of normal before becoming prolonged.3,4 The only factor unique to this pathway is factor VII, so the only manner in which PT can be prolonged without affecting PTT is a selective factor VII deficiency.3,4 The PT is commonly referenced to an international standard (INR) because the sensitivities of the reagents measuring PT vary. The INR is calibrated to assess anticoagulation in patients receiving stable warfarin therapies. Its applicability to other causes of an elevated PT is uncertain, although commonly done. In hepatic dysfunction, the extent of coagulopathy as measured by the PT or INR is not predictive of bleeding complications.3,4 Normal values for PT and INR are 12–13 seconds and 0.8–1.2, respectively. The activated partial thromboplastin time (aPTT) measures the intrinsic pathway and is more complex than the PT. A particulate contact activator (hence the name “activated”) like ellagic acid, kaolin, celite, or silica is added to platelet-poor citrate anticoagulated plasma to which a “partial thromboplastin” (lacking tissue factor) is added and the citrate reversed with calcium.3,4 The particulate activates factor XII, which in turn activates factors XI, IX, and VIII and the common sequence of factor X through fibrin formation. Like PT, aPTT is measured in seconds with normal reference values of 25–35 seconds, but unlike PT, single factors unique to the aPTT must decline to only 15%–30% of normal values for the aPTT to be prolonged.3,4 This may reflect the lengthier clotting sequence contributing to the aPTT and/or

the fact that these clotting factors are already lower in concentration than factor VII. Milder deficiencies of many factors can prolong the aPTT, so it may be more sensitive than PT for assessing factor changes, especially factors VIII and IX.3,4 Prekallikrein, high-molecularweight kininogen, antiphospholipid antibodies, and factor XII deficiencies prolong aPTT, but none increases the risk of hemorrhage. Other tests used to measure coagulation include anti-Xa activity, activated clotting time, and assessments of fibrinolysis. Anti-Xa activity is often used to assess anticoagulation in patients receiving lowmolecular-weight heparins, especially in patients at the extremes of weight or those with reduced or increased kidney function.3,4 Activated clotting time nonspecifically measures the time for an activating agent to produce clot in whole blood and is often used to monitor unfractionated heparin or direct thrombin inhibitors (DTIs) during surgery. Fibrinolysis is the process of dispersing and dissolving clot. This process may be described by the term fibrin degradation product or D-dimer. The fibrin degradation product assay refers to the breakdown products of fibrin and fibrinogen produced by plasmin.3,4 The nonspecific fibrin degradation product or fibrin split product assay may be present in the absence of clot. In contrast, the D-dimer is only formed from the degradation of fibrin from an intact clot. Both assays lack specificity and are commonly positive in critically ill patients regardless of the presence of thromboembolic disease or coagulopathy.3,4 In addition, fibrin degradation product and D-dimer are hepatically eliminated, so liver function may influence their specificities. Moreover, various commercially available assay methods differ significantly (e.g., latex or red blood cell [RBC] agglutination, enzymelinked immunoassays) resulting in varying sensitivities. Normal values for D-dimer are below 500 ng/mL.

Measuring Platelet Function Platelet function may be assessed for a variety of reasons including identifying bleeding disorders, monitoring response to antiplatelet therapies, evaluating perioperative hemostasis, and guiding platelet

transfusion therapy.5,6 Several tests are available to assess platelet function and include light transmission platelet aggregation, impedance aggregometry on whole blood, lumi-aggregometry, platelet activation by flow cytometry, and shear stress platelet activation.5,6 Light transmission platelet aggregation is considered the gold standard test and incorporates in vitro platelet-to-platelet clump formation in a GPIIb/IIIa-dependent manner. The assay measures the light transmission after platelet-rich plasma is activated with various platelet agonists (e.g., collagen, ADP, thrombin, epinephrine, arachidonic acid). Light transmission increases as platelets aggregate. Although this method can assess different platelet aggregation pathways and is sensitive to antiplatelet therapy, it is time-consuming and not reflective of whole blood activity because it uses platelet-rich plasma. It also requires relatively large volumes of blood to generate platelet-rich plasma. Impedance aggregometry, which uses smaller volumes of citrated whole blood, is based on the principle that activated platelets stick by their surface receptors to artificial surfaces of electrodes within the sample. Electrical impedance is generated by aggregated platelets, which is measured by diminishing current between electrodes. This method is available as point-of-care testing and is sensitive to antiplatelet therapy. Lumi-aggregometry measures the ATP released from platelets that are activated in vitro by various agonists. The ATP reacts with a luciferinluciferase reagent, and the intensity of light emitted is proportional to the ATP concentration. This method may be used to assess several platelet aggregation pathways and is particularly useful for assessing platelet function when thrombocytopenia is present. Flow cytometry, which uses citrate anticoagulated whole blood, is based on the optical and fluorescence evaluation of the physical and antigenic properties of platelets. Therefore, it assesses the internal complexity and conformational changes of platelets in response to in vitro platelet activation. Antibodies that bind to specific proteins on the platelet surface or inside the platelet are conjugated to fluorescence dyes so that light is emitted on platelet activation. The results are expressed as a histogram with fluorescence intensity plotted against platelet number. This method is

sensitive to antiplatelet therapy and may be used when thrombocytopenia is present. Shear stress platelet activation applies physical stress to citrate anticoagulated whole blood and measures either the time taken for platelets to occlude a collagen-coated orifice or the percentage of a polystyrene plate covered by platelet aggregates. This method is available as point-of-care testing and is sensitive to antiplatelet therapy.

COAGULOPATHY AND THROMBOCYTOPENIA IN CRITICALLY ILL PATIENTS Hemostatic abnormalities are common in critically ill patients, ranging from an isolated laboratory abnormality to complex derangements. By far the most common causes of abnormal clotting assays and low platelet counts are errors incurred during sample collection or laboratory analyses, so laboratory aberrations should always be confirmed, especially in the absence of clinical manifestations. As discussed in the previous section, coagulation and hemostasis require complex interactions between the vessel wall, platelets, and soluble coagulation factors. Hemostatic abnormalities can result when any one of these three systems is defective. However, several causes may contribute to the mechanisms of abnormal hemostasis, making it difficult to diagnose and manage hemostatic derangements in critically ill patients.7-10

Coagulopathy Alterations in coagulation factors, including decreased levels of coagulation factors, reduced levels of endogenous anticoagulants, and enhanced fibrinolysis, all contribute to hemostatic abnormalities in critically ill patients.7-10 De-spite their poor reflection of in vivo hemostasis, laboratory values such as aPTT, PT or INR and platelet counts are often used to assess the degree of coagulopathy (Table 24.1).3,4,7-11 Up to one-third of patients in the intensive care unit (ICU) have coagulopathy, as defined by an INR of 1.5 or greater or an aPTT

of 1.5-fold or greater than the upper limit of normal.10 The presence of coagulopathy increases the likelihood of hemorrhage by 4- to 5-fold and is an independent risk factor for mortality (odds ratio [OR] 1.5– 4.3).12 Causes of coagulopathy are generally categorized by the extent that either or both the PT/INR and the aPTT are prolonged (Table 24.1).3,4,7-11 Mechanisms contributing to coagulopathy include hypothermia, acidosis, dilution from administration of fluids and blood products, disseminated intravascular coagulation (DIC), liver dysfunction, renal dysfunction, inherited disorders, and medications.4,711

Hypothermia Hypothermia may be the result of several causes, including iatrogenic etiologies such as therapeutic hypothermia, surgery, or invasive interventions (e.g., dialysis, extracorporeal membrane oxygenation, plasmapheresis) or non-iatrogenic etiologies such as prolonged exposure to cold ambient temperatures, impaired thermoregulation (e.g., injuries to the central nervous system, hypothyroidism), or excessive heat loss (e.g., thermal injuries, drug intoxication).12 The mechanisms of hypothermia-induced coagulopathy vary with the magnitude of hypothermia, and the extent of coagulopathy grows exponentially as the core body temperature decreases.13 Although temperatures of 35°C and greater have very little effect on coagulation, temperatures of 32°C–34°C alter platelet number and function by reducing platelet adhesion and aggregation.14,15 Temperatures of 33°C or less decrease the synthesis and kinetics of coagulation factors. Therapeutic hypothermia to temperatures of 32°C–34°C for up to 24 hours may improve neurologic recovery in comatose patients with the return of spontaneous circulation after cardiac arrest.16 The occurrence of bleeding requiring transfusions in the setting of therapeuticallyinduced hypothermia is 6%.17 The risk of hemorrhage should not be viewed as a reason to withhold therapeutic hypothermia treatment in patients who are not actively bleeding. In patients who are at high bleeding risk or are actively bleeding, the hemorrhage risk should be considered in the context of possible neurologic benefit.17 Hypothermia

should be reversed and core body temperatures maintained at 35°C or greater when hypothermia is the result of other iatrogenic or noniatrogenic etiologies.

Table 24.1 Causes of Coagulopathies as Defined by Laboratory Values3,4,7-11

DIC = disseminated intravascular coagulopathy; DTI = direct thrombin inhibitor.

Acidosis Acidosis is a common clinical problem in critically ill patients and is a known predictor of coagulopathy in the ICU. Acidosis can present as a result of both respiratory and metabolic disturbances; however, coagulopathy is often caused by a hypoperfused state resulting in increased lactate generation. Coagulopathy is heightened when hypothermia is also present as acidosis and hypothermia synergistically impair coagulation.18,19 The clinical effects include both prolonged clotting times and increased bleeding times, with a direct correlation

between the extent of acidosis and coagulation impairment.19 The mechanisms of acidosis-induced coagulopathy primarily involve severe inhibition of the propagation phase of thrombin generation and increased fibrinogen degradation.20 However, clotting factor function is also significantly impaired because acidotic environments hinder protease activity and limit anion exposure of phospholipids. When pH drops below 7.2, the functional activities of factor VIIa, tissue factorfactor VIIa complex, and the factor Xa/Va complex are diminished. As a result, clotting time is prolonged, and overall clot strength is weakened.18-20 Although few studies have reported on outcome assessments looking strictly at acidosis-induced coagulopathy, it is usually regarded as a poor prognostic sign.18 It is common practice before giving procoagulants to ensure that pH values are 7.2 or greater by temporarily inducing hyper- ventilation or administering intravenous bicarbonate. Dilutional Critically ill patients often require rapid resuscitation with large volumes of crystalloids, colloids, or RBCs if critical bleeding is present. As a result, these patients often have dilutional coagulopathy, a combination of decreased plasma concentrations of coagulation factors and platelets.10-12,21 The degree of coagulopathy is directly related to the total volume transfused, in addition to preexisting hemostatic abnormalities, and the effects are synergistic with coagulopathy from hypothermia and acidosis.22 Dilutional coagulopathy is the result of an uncompensated loss of platelets and coagulation factors. This occurs most commonly during situations involving major blood loss or large-volume resuscitation, but it can also occur in critically ill patients with increased consumption or sequestration of platelets.10,21,22 Red blood cell concentrates contain negligible amounts of platelets and coagulation factors, so they can further exacerbate a patient’s risk of developing dilutional coagulopathy when transfused in large quantities. A platelet count of less than 50 × 109/L is expected when two blood volumes have been replaced by fluid

and RBC concentrates.22 Similarly, coagulation factor deficiencies occur after blood volume losses exceed 150% because fibrinogen concentrations fall first, followed by other labile coagulation factors such as prothrombin and factors V and VII.22 Hospital-specific “massive transfusion protocols” (MTPs) help reduce the incidence of dilutional coagulopathy by augmenting RBC supplementation with platelets, fresh frozen plasma (FFP), cryoprecipitate, and pharmacologic agents.10,11,21,22 Disseminated Intravascular Coagulopathy Disseminated intravascular coagulopathy is an acquired syndrome characterized by systemic intravascular activation of coagulation that can occur in up to 25% of critically ill patients.7,23 It originates secondary to fibrin deposition and intravascular microthrombi and may lead to significant complications including major bleeding and multiorgan dysfunction.10,24 Critically ill patients with DIC often have rapidly decreasing platelet counts, low plasma concentrations of coagulation factors, prolonged coagulation tests, increased markers of fibrinogen formation, and hyperfibrinolysis. These abnormalities often lead to bleeding as the first sign of DIC, with only 5%–10% of cases presenting with microthrombi alone.7 A DIC scoring tool developed by the International Society on Thrombosis and Haemostasis assigns points according to the extent of thrombocytopenia (platelet counts of 50–100 × 109/L = 1 point, platelet counts less than 50 × 109/L = 2 points), fibrin concentrations (moderate rise = 2 points, strong rise = 3 points), PT prolongation (3–6 seconds = 1 point, greater than 6 seconds = 2 points), and fibrinogen concentrations (less than 100 mg/dL = 1 point).5 A score of at least 5 points in the presence of an underlying disorder associated with DIC is indicative of DIC.5,23,24 There are several etiologies of DIC among critically ill patients, with the most common cause being sepsis, followed by systemic infection, trauma, surgery, malignancy, thermal injury, and pancreatitis.9,24 Less common etiologies include immunologic reactions (e.g., transplant rejection, host vs. graft disease, transfusion reactions, venomous bites

or stings), vascular abnormalities, and cardiopulmo-nary bypass.9,11,24,25 The mechanism of DIC is multifactorial but is commonly mediated by pathogen-associated molecular patterns and the generation of an overwhelming inflammatory response. Proinflammatory cytokines activate mononuclear cells and endothelial cells, which in turn express tissue factor, the main initiator of the extrinsic pathway of coagulation.9,11,24,25 The physiological anticoagulation mechanism and endogenous fibrinolysis are stimulated but are inadequate to counterbalance the thrombin generation and intravascular fibrin formation. This, in combination with continuous consumption of platelets and clotting factors, leads to multiorgan failure and severe bleeding complications. Treatment with anticoagulants (e.g., heparin, DTIs) may be attempted, but this often hastens the development of hemorrhage. Instead, therapies usually focus on preventing hemorrhage and reversing the underlying disorder causing the proinflammatory state.7,9,11 Hepatic Dysfunction Hepatic insufficiency is the most common cause of acquired coagulation abnormalities.1,7 Thrombopoietin and most hemostatic proteins are synthesized in the liver; thus, reduced hepatic function often results in prolonged coagulation tests.7 Splenic sequestration of platelets can also occur, further contributing to thrombocytopenia. Recent data suggest that patients with hepatic insufficiency are not naturally “auto-anticoagulated,” as once believed.26-28 Therefore, these patients may be at increased risk of both hemorrhage and thrombosis.26-28 The coagulopathy abnormalities seen in patients with hepatic insufficiency are complex. Anticoagulation occurs because hepatic synthesis of coagulation factors II, V, VII, IX, and X is reduced, the metabolism of tissue plasminogen activator is impaired, and fibrinogen production is lessened.7,9,11 In addition, moderate to severe vitamin K deficiencies can occur in hepatic insufficiency. In contrast, levels of factor VIII and vWF, potent drivers of thrombin generation, are

increased to enhance coagulation. In addition, there is a concomitant reduction in endogenous anticoagulants (proteins C, S, and Z; antithrombin; and Z-dependent pro-tease inhibitor) and fibrinolytic mediators (thrombin activatable fibrinolysis inhibitor) that enhance coagulation and clot stability.7,9,11 Thus, patients with hepatic insufficiency and prolonged coagulation tests may not be at increased bleeding risk.3,12,26,27 Because discerning the likelihood of hemorrhage is clinically impossible, most clinicians try to minimize the extent of the coagulopathy before invasive procedures or during a bleeding event. It is plausible that bleeding in patients with hepatic insufficiency is the result of other etiologies of coagulopathy acquired from the acute situation (e.g., a systemic infection causing DIC). Renal Dysfunction Kidney failure produces uremia-induced qualitative defects in platelets that arise from insufficient vWF, decreased production of thromboxane A2, increased cyclic adenosine monophosphate and cyclic guanosine monophosphate, and anemia.7,27 In addition, the quantity of GPIIb receptors on platelet surfaces is diminished. Platelet function is improved with dialysis.27,29 The anemia that commonly accompanies renal disease reduces ADP production and diminishes laminar flow in the vasculature, which hampers platelet and clotting factor migration, ultimately leading to prolonged clotting times and coagulopathy. Treatment of the anemia with erythropoiesis-stimulating agents or the administration of RBC transfusions helps reverse the coagulopathy.27,29 Renal dysfunction also leads to impaired fibrinolysis and reduced generation of factor VIII–related antigen, impairing both clot breakdown and formation, respectively.27,29 Inherited Abnormalities Consideration should be given to an inherited bleeding disorder if unexplained coagulation abnormalities are present in a critically ill patient.1,7 Although uncommon, hemophilia and von Willebrand disease can pose significant bleeding complications among critically ill

patients.11 Hemophilia A is characterized by deficiencies in factor VIII, whereas hemophilia B is characterized by deficiencies in factor IX. Both disorders are inherited X-chromosome– linked conditions that range in severity from mild surgery or trauma-related bleeding to severe spontaneous bleeding into muscles and joints.1,7 Acquired hemophilia is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation factors, most commonly factor VIII. In general, spontaneous bleeding occurs only in cases with less than 2% of coagulation factors.27 However, patients with greater than 10% of coagulation factors may be at risk of excessive hemorrhage after trauma, surgery, or other invasive procedures.27 von Willebrand disease is characterized by a deficiency in vWF, which plays an essential role in both platelet adhesion and binding to factor VIII to prevent rapid degradation of factor VIII.1,11 Other rare congenital disorders that lead to coagulation abnormalities include factor V Leiden deficiency, factor XI deficiency (also known as Rosenthal syndrome or hemophilia C), factor VII deficiency, prothrombin deficiency, fibrinogen disorders, and plasminogen activator inhibitor deficiency.1,9 Medications Coagulation abnormalities can also occur in critically ill patients taking or receiving medications that alter the coagulation cascade or interfere with platelet function. Therapeutic anticoagulation with agents such as unfractionated heparin, low-molecular-weight heparins, warfarin, antiXa inhibitors, and/or DTIs inhibits coagulation and increases a patient’s risk of bleeding.7,30,31 In addition, fibrinolytic medications or medications that interfere with platelet aggregation can alter a patient’s ability to maintain hemostasis (Table 24.2).7,11,12,30-33 Anticoagulants, platelet inhibitors, and fibrinolytic agents are commonly administered to patients for therapeutic reasons or to prevent clot formation during surgical procedures (e.g., cardiopulmo-nary procedures) or when invasive devices (e.g., dialysis, extracorporeal membrane oxygenation) are used.30-33

Thrombocytopenia Thrombocytopenia in the ICU ranges from 15% to 60%, depending on the definition used and the population evaluated, with trauma/surgery patients having a higher prevalence than medical patients.7,34 Thrombocytopenia is typically defined as a platelet count less than 150 × 109/L or a decrement of 50% or greater from a recent previous measurement.35-37 The presence of platelet counts less than 50 × 109/L increases the likelihood of hemorrhage by 4-to 5-fold and is an independent risk factor for mortality (OR 1.9–4.2).34-37 The incidence of spontaneous hemorrhage, however, is low for patients with a platelet count exceeding 10 × 109/L.35 Although fewer than 5% of ICU patients develop platelet counts of 20 × 109/L or less, this value is often used as a threshold to maintain in an effort to prevent hemorrhage.34,35 Values of 30–50 × 109/L are targeted when hemorrhage is present.34-37

Table 24.2 Drug-Induced Therapeutic Coagulopathies and Reversal Options7,11,12,30-33

Half -Life and Duration of Action

Mechanism of Action

Agent ( s )

ReversalOptions

Aspirin

Antiplatelet by irreversible inhibition of cyclooxygenase-1and cyclooxygenase-2

tU2 = 20 min but effect can last 5-7 days

Platelet transfusjon ± desmopressin

Dipyridamole

Antiplatelet by increasing adenosine and cyclic adenosine monophosphate and inhibiting thromboxane A2

tw = 6-15 hr but effect can last 5-7 days Hold 5-7 days before procedure

Platelet transfusjon ± desmopressin

Clopidogrel, prasugrel, ticagrelor

Antiplatelet by antagonizing P2Y12 ADP

tw = 6-15 hr but effect can last 5-7 days

Abciximab, eptifibatide, tirofiban

Antiplatelet byantag

Abciximab tU2 = 0.5-4 hr

nizing binding of fibrinogen to GPIIb/ llla receptors (eptifibatide and tirofiban are reversible inhibitors; abciximab is an irreversible inhibitor )

Eptifibatide = 2.5 hr

Unfractionated heparin

.

receptor

Potentiates the action ofantithrombinto inactivate thrombin

Platelet transfusjon

Hold 5-7 days before procedure Nospecificantidote

Tirofiban = 2 hr

tU2 = 30-90 min

Protamine

Hold 2-12 hr before procedure

tw = 4-7 hr; prolonged in renal impairment

Enoxaparin dalteparin

Similar to unfractionated heparin butwith greater inhibition of factor Xa

Hold 12-24 hr before procedure

Protamine (partial reversal) + FFP or PCCs

Fondaparinux

An tithrombin -mediated inhibition offactorXa

tiy 2 = 17-20 hr; prolonged in renal

aPCC ± rFVIIa

impairment

Hold 48 hr before procedure

Bivalirudin

Reversible DTI

Argatroban

Direct inhibition of free and fibrin-bound thrombin

tjj2 = 25 min; prolonged in renal impairment Hold 1-2 hr before procedure

aPCC ± rFVIIa + hemodialysis or plasmapheresis

ty2 = 39-51min; prolonged in hepatic

PCCs oraPCC ± rFVIIa

impairment

Hold 1-2 hr before procedure

-

20-60 hr; highly variable among patients (effects can last up to 5 days )

Warfarin

Inhibition of vitamin K-dependentclotting factors (II, VII, IX, and X ) and proteins C andS

trø

Dabigatran

Direct inhibition of both free and fibrin-bound thrombin

trø= 11-17 hr; prolonged in renal

aPCC ± rFVIIa + hemodialysis

Hold 2-5 days before procedure

(idarucizumabwhen available)

Apixaban tU2 = 9-14 hr

Four -factor PCCs ± rFVIIa

Rivaroxaban, apixaban

Direct inhibition of factor Xa

Alteplase, tenecteplase

Fibrinolytic; converts plasminogen to plasmin

impairment

Vitamin K (IV 5-10 mg) + FFP or PCCs ± rFVIIa

Rivaroxaban tr ø = 5-13 hr

Hold 18-48 hr before procedure

Alteplase tr ø = 5-10 min ( effects may last for up to 1hr )

Antifibrinolytic + cryoprecipitate

Tenecteplase tU2 = 20—120 min

aPCC = activated prothrombin complex concentrate; FFP = fresh frozen plasma; IV = intravenous; PCC = prothrombin complex concentrate; rFVIIa = recombinant activated factor VII.

Platelets participate in hemostasis through several mechanisms, including the release of vasoactive substances (e.g., thromboxane A2

and serotonin), activation of the coagulation cascade by releasing attractants for additional platelets (e.g., thromboxane A2 and ADP), provision of a phospholipid scaffold formed when activated platelets bind to circulating fibrinogen, and adherence and aggregation at the site of injury to form a platelet plug.1,35 Causes of thrombocytopenia are generally categorized according to decreased platelet production in the bone marrow, sequestration of platelets in the spleen, or enhanced platelet destruction (immunological or non-immunological, mechanical) (Table 24.3).7,8,34-37 Rare inherited platelet disorders include Glanzmann disease and Bernard-Soulier disease. Screening tests to investigate the source of thrombocytopenia should include a confirmatory platelet count, full blood count with peripheral blood film, coagulation tests, platelet function tests, fibrinogen, B12, folate, renal function tests, liver function tests, HIV, hepatitis C, and imaging to examine for the presence of portal hypertension or splenomegaly.5,6,8,34-37 Up to 25% of critically ill patients develop drug-induced thrombocytopenia (Table 24.4).7,34,35 With the exception of heparin-induced thrombocytopenia, drug-induced causes are etiologies of exclusion that often necessitate careful examination of the daily platelet count profile and the medication administration record.7,34,35

HEMORRHAGE PREVENTION, RESUSCITATION, AND MANAGEMENT The prevention of hemorrhage is targeted at avoiding excessive coagulopathy and thrombocytopenia. Although few data exist, the goals of therapy are to lower the INR less than 1.5 and the aPTT less than 1.5-fold the upper limit of normal and maintain platelet counts of 20 × 109/L or greater.1,2,7,8,35-38 Several etiologies exist for coagulopathy and thrombocytopenia, and providing procoagulant therapies may be relatively or absolutely contraindicated in some circumstances (e.g., DIC, cases of immune-mediated thrombocytopenia like heparin-induced thrombocytopenia). In practice, the reversal of coagulopathy and thrombocytopenia to prevent bleeding is similar to the correction of

these during hemorrhage, except that time is of less concern during prevention so that the causative etiology may be investigated and possibly therapeutically targeted, whereas early support of coagulation is required during hemorrhagic resuscitation. Agents used to reverse coagulopathy include vitamin K, FFP, prothrombin complex concentrates (PCCs), and recombinant activated factor VII (rFVIIa).1-4 Platelet administration is used to correct thrombocytopenia.35-38 The basic goals of therapy in the management of hemorrhage are achieving fluid resuscitation and bleeding cessation by correcting anemia, reversing coagulopathy, optimizing platelet activity, and inhibiting fibrinolysis, all while minimizing adverse events and bleeding sequel-ae.13,39-41 Early resuscitation is often characterized by uncertainty regarding the exact source of the bleeding, quantity of blood loss, and anticipated duration of hemorrhage. The manifestations of hemorrhage, however, may be used as a crude estimate of blood loss. Tachycardia and light-headedness are often evident after 15%– 30% blood volume depletion, hypotension develops after 30% or greater depletion, and severely altered sensorium usually requires 40% or greater depletion. Initial resuscitation is targeted at rapidly repleting intravascular volume and is commonly performed with the administration of a warmed isotonic crystalloid solution.39,40 The initial response to 1–2 L of normal saline indicates the extent of hemorrhage and may help predict the need for additional therapies.39,40 The return of normal vital signs suggests the hemorrhage was mild-moderate (estimated blood loss less than 2 L) and likely ceased, so the need for additional resuscitation is unlikely. A transient improvement in vital signs suggests the hemorrhage was moderate (estimated blood loss of 2–3 L) and likely ongoing, so the need for additional resuscitation and blood product administration is probable. Little to no change in vital signs suggests the hemorrhage was severe (estimated blood loss of greater than 3 L) with ongoing active bleeding, so the need for additional resuscitation and blood product administration is immediate. The patients with little to no change in vital signs require emergency medical therapy to treat the etiology of the hemorrhage, necessitating the planning process for many possible interventions by several services

(e.g., interventional radiology, general or specialized surgery services, trauma, gastroenterology, critical care, nursing, pharmacy). In all cases, rapidly controlling the source of hemorrhage must be a priority, and delaying an intervention while obtaining a laboratory or radiological study, placing an invasive monitor, or awaiting other therapies increases the likelihood of exsanguination.

Fluid Resuscitation Initial resuscitation should be administered through a large-bore intravenous catheter using either normal saline or lactated Ringer solutions.13,42,43 Specialty infusion systems provide real-time warming and have high-flow capacities with built-in filters so that resuscitation fluids and blood products can be administered rapidly in emergency situations. Saline solutions may induce hyperchloremic acidosis, whereas lactated Ringer solutions may worsen lactic acidosis or induce hyperkalemia if hepatic impairment or renal dysfunction is present, respectively.13,42,43 Racemic lactated Ringer solutions may be proinflammatory and induce apoptosis. Other resuscitation fluids include hyper-tonic saline solutions and colloid fluids. Hypertonic saline solutions increase transmembrane sodium gradients, may produce more rapid hemodynamic improvement with less cumulative fluid volume than isotonic solutions, and have been shown in rodent models to ameliorate immunodepression.13,42,43 Colloid fluids are usually reserved for patients with moderate hypovolemia without adequate response to crystalloid or showing manifestations of pulmonary or cerebral edema or cardiac overload.13,42,43 Although the Committee on Trauma of the American College of Surgeons recommends lactated Ringer solutions, the choice of fluid will ultimately be guided by local practice patterns, prescriber preferences, and perhaps cost.12,42 The goals of resuscitation should focus on restoring tissue perfusion and hemodynamic status.13 Although adequate resuscitation should optimize oxygen delivery and stabilize hemodynamic deviations, systolic blood pressures of 80–90 mm Hg should be the goal of resuscitation because the bleeding rate and cumulative blood loss are lessened with

permissive or deliberate hypotension.1,41 Overly aggressive fluid resuscitation shifts the Frank-Starling curve to increase cardiac output, which causes a reflex vasodilation, both of which increase blood flow to the injured vasculature to possibly enhance the rate of blood loss. Increased blood pressure may also wash away early clot formation, and the resuscitation fluid will decrease the blood viscosity and dilute clotting factors, RBCs, and platelets at the site of injury.11 These reasons may explain the results of a recent systematic review that found liberal fluid resuscitation strategies were associated with higher mortality than restrictive strategies (risk ratio [RR] 1.25; 95% confidence interval [CI], 1.01–1.55) across three randomized trials of trauma patients.44 As a result, clinical goals have shifted from the traditional approach of rapid bolus fluid administration to a systematic approach that includes supporting coagulation while providing the least amount of fluid to reverse hemodynamic compromise without overly increasing cardiac output.13 Therefore, early resuscitation requires substantial clinical judgment and experience, so management recommendations are guidelines and not standards of care. Global tissue perfusion may be assessed by blood lactate concentrations with restored perfusion indicated by declining lactate values over minutes to hours because lactate production is a function of anaerobic metabolism in the presence of tissue hypoxia.13,42,43 The adequacy of regional perfusion can be assessed by indices of specific organ perfusion. These measurements may include the following13,39-41: normalization of coagulation abnormalities, improvement in renal dysfunction as indicated by adequate urine production (greater than 0.5 mL/kg/hour) and/or decreasing serum concentrations of blood urea nitrogen and creatinine, improvement in hepatic parenchymal dysfunction as indicated by normalizing serum concentrations of transaminases and bilirubin, change in extremities from cool and mottled to warm with rapid capillary refill and normalizing temperature gradient

between the toe and core body, normalization of elevated troponin concentrations from cardiac ischemia, reversal of altered sensorium.

Table 24.3 Causes of Thrombocytopenia7,8,34-37 Differential Diagnosis

Cancers

Mechanism of Thrombocytopenia • Decreased production

• Acute leukemia • Metastatic bone marrow infiltration • Myelodysplasia Congestive cardiac failure

• Sequestration

Disseminated intravascular coagulation

• Increased destruction/consumption

Drug induced (see Table 24.4 for further information)

• Decreased production

HELLP syndrome

• Increased destruction/consumption

Hepatic insufficiency/cirrhosis

• Sequestration

Irradiation

• Decreased production

Immune mediated

• Increased destruction/consumption

• Antiphospholipid syndrome

• Increased destruction/consumption

• ITP • Post-infusion purpura • Systemic lupus erythematosus Infections

• Decreased production

• Chronic (hepatitis B, HIV, malaria)

• Increased destruction

• Transient (mumps, rubella, varicella, EBV, CMV) Intravascular devices • Extracorporeal membrane

• Increased destruction/consumption

• oxygenation • Intraaortic balloon pump • Post-cardiopulmonary bypass • Renal dialysis Massive blood loss

• Hemodilutional

Malnutrition

• Decreased production

• B12 or folate deficiency Sepsis

• Decreased production • Increased destruction/consumption • Sequestration

Thrombotic microangiographies • Clot formation

• Increased destruction/consumption

• Hemolytic-uremic syndrome • TTP

CMV = cytomegalovirus; EBV = Epstein-Barr virus; HELLP = hemolysis, elevated liver enzymes, and low platelet count associated with pregnancy; ITP = immune thrombocytopenic purpura; TTP = thrombotic thrombocytopenic purpura.

Table 24.4 Examples of Drugs Commonly Associated with Thrombocytopenia in the Intensive Care

Medication

Mechanism

Antiarrhythmics ( amiodarone, procainamide)

Bone marrowsuppression and immune mediated

(5-Lactamantibiotics

Immune mediated - haptendependentantibody

Fluoroquinolones GPIIb/llla inhibitors

Heparin

Resulting Effect

Time to Platelet Recovery

9-71 days after initiation

5-11 days after discontinuation

Increased destruction / consumption

Dose/drug-dependent

Dose/drug- dependent

Immune mediated

Increased destruction / consumption

10 days after initiation

8 days after discontinuation

Immune mediated; binds to platelet - GPIIb/ llla complexandinduces neoepitope formation

Increased destruction / consumption

Abrupt reduction ( within 2 hr after initiation); may be prolonged with abciximab therapy

Eptifibatide, tirofiban = immediately after discontinuation

Nonimmune mediated ( type I) or immune mediated ( type II) - formation

Increased destruction / consumption

Type I =1-4 days after initiation

Type I = 2-4 days after discontinuation

Type II = 5-14 days after

Type II = 2-14 days after

Decreased production and

increased destruction/ consumption

ofimmunoglobulinG antibodies that cause platelet activation by binding to platelet-heparinfactor -4 complexes

Histamine -2 receptor antagonists

Time toMean Platelet Nadir

Bone marrow suppression and immune mediated

initiation

Decreased production and

Abciximab = 2-5 days after discontinuation

discontinuation

14 days after initiation

7 days after discontinuation

14-40 days after initiation

4-13 days after

increased destruction/ consumption

Linezolid

Bone marrow suppression and immune mediated

Decreased production and

discontinuation

increased destruction/ consumption Phenytoin

Immune mediated

Increased destruction / consumption

Variable

Variable

Rifampin

Immune mediated

Increased destruction / consumption

Unknown

Unknown

Trimethoprim/ sulfamethoxazole

Immune mediated

Increased destruction / consumption

9 days after initiation

7 days after discontinuation

Vancomycin

Immune mediated

Increased destruction / consumption

days after -8 days after initiation -8discontinuation

aRecent exposure to chemotherapeutic agents or transplant (immunosuppressive) medications can cause thrombocytopenia.

anti-rejection

Correction of Anemia Red blood cell administration is used clinically to increase hemoglobin with the intent of enhancing oxygen-carrying capacity and tissue

perfusion. About 2 units of packed RBCs (PRBCs) are procured from each whole blood donation.2,38 Packed RBCs are stored at 1°C–6°C in a solution containing citrate, phosphate, dextrose, adenine, and nutrients. Each unit has a shelf-life of 42 days.2,38 Major or massive blood loss is defined as a loss of 100% of the circulating blood volume within 24 hours, at least 50% within 3 hours, the transfusion of 6 units of PRBCs in a 12-hour period, or a bleeding rate of 1.5 mL/kg/hour or greater.13 Clinical practice guidelines recommend maintaining hemoglobin values of 7 g/dL, primarily on the basis of studies of non-bleeding critically ill patients and patients with upper gastrointestinal (GI) hemorrhage. The combined results of these studies found lower mortality rates, fewer cardiopulmonary adverse events, and reduced ongoing hemorrhage in patients allocated to restrictive transfusion strategies aimed at a hemoglobin value of 7 g/dL.39,40,45-47 Retrospective data from hemorrhaging Jehovah’s Witness patients support limited detrimental outcomes of permissive anemia.46-49 The transfusion threshold may be increased to 8 g/dL in patients with preexisting cardiovascular disease or active cardiac ischemia. The decision to transfuse PRBCs must consider intravascular volume status, the presence of shock, the duration and extent of anemia and coagulopathy, cardiopulmonary parameters, and the extent of lactic acidosis. Packed RBCs are usually required only when the estimated blood loss exceeds 1.5–2 L.40,42,47 In general, hemorrhaging patients should receive a single unit of PRBC at a time with response assessed thereafter; however, the patient with massive hemorrhage or in hypovolemic shock may need several units rapidly transfused simultaneously.3,13,27,47 In the stable patient of average size, 1 unit of PRBC will elevate hemoglobin by about 1 g/dL or the hematocrit by 3%.47 Increases less than these thresholds may be the result of dilution from the concomitant administration of crystalloid solutions, or it may indicate ongoing hemorrhage, which warrants further investigation. The process of compatibility testing takes 45 minutes to complete and includes ABO and Rhesus blood typing and antibody screening.27,38 In emergency situations, O/Rh-negative blood is used without antibody

screening. Several concerns surround PRBC administration. First, many evaluations have failed to show meaningful increases in end-organ oxygen delivery and use despite increases in hemoglobin.38 This is contradictory to the common goal of using allogenic administration of PRBCs to enhance tissue perfusion. This contradiction may be explained by the timing of the intervention relative to the onset of hemorrhage. Alternatively, storage of the RBCs may induce biochemical changes in rheology to enhance microcirculatory occlusion and increase hemoglobin’s affinity for oxygen (rapid decline in Snitrosohemoglobin, 2,3-diphosphoglycerate, and ATP) to reduce oxygen dis-association and promote tissue ischemia.38,48 Allogenic RBC administration may contribute to coagulopathy because RBCs contain citrate, which binds calcium, a cofactor for many clotting factors, and are stored at pH values of 6.5–7 (lactate concentrations increase 15-fold, and pH declines to 6.7 after 3 weeks of storage).38 Many transfusion protocols recommend monitoring systemic ionized calcium values and preemptively administering intravenous calcium when 4 units of PRBCs have been given.38 Each PRBC unit also provides about 7–10 mEq of potassium because potassium leaks from RBCs during storage.38 Allogeneic PRBCs may also promote coagulation by activating host platelets through thromboxane generated by the stored RBC and by producing thrombin in the host in response to phospholipid exposure caused by membrane vesiculation of the stored RBC. A recent study of “fresh” (average storage time of 6.1 ± 4.9 days) versus “old” (average storage time of 22 ± 8.4 days) PRBC transfusions in critically ill patients without hemorrhage showed similar outcomes of mortality, length of stay, transfusion reactions, and duration of organ-specific support.49 Another concern of allogenic RBC transfusions, and other allogeneic blood products, is the profound effects they have on the recipient’s immune function, which contributes to transfusion-related acute lung injury (TRALI) and transfusion-related immunomodulation (TRIM).38,5052 Transfusion-related acute lung injury is defined as new-onset acute lung injury occurring within 6 hours after completing the transfusion of a

plasma-containing blood product. The pathogenesis of TRALI relates to blood products that contain antibodies to the recipient’s human leukocyte antigen or human neutrophil antigen.50 Allorecognition leads to the activation of neutrophils that are marginated in the lung to cause inflammation and disruption of the lung-alveolar-capillary permeability barrier. Monocytes and activated platelets also contribute. Experimental models have also implicated cell membrane phospholipids, specifically lysophosphatidylcholine, which are generated during storage of cellular blood products and can prime neutrophils. The incidence of TRALI is 1 in 12,000 PRBC transfusions, and the mortality rate is 6%, substantially lower than the estimate for other forms of acute lung injury.38,50,51 Excluding females with a pregnancy history as blood donors lowers the TRALI rate by 10- to 20fold because these females are more likely to have anti– human leukocyte antigen or anti–human neutrophil antigen antibodies given their exposure to fetal blood.38,50,51 The process of leukoreduction by specialized filtration or irradiation of donated blood also reduces the likelihood of TRALI. Irradiated blood products are indicated in severely immunocompromised patients or transplant populations where leukocytes are speculated to contribute to graft-vs.-host disease; however, the process reduces RBC viability and increases the release of intracellular potassium. Leukocyte-reduced blood components contain less than 5 × 106/L of leukocytes. Around 70% of transfused PRBCs are leukoreduced in the United States.50,51 Transfusion-related immunomodulation refers to a state of proinflammation and immunosuppression associated with transfusions of allogeneic blood products. The pathogenic mechanism is still speculative, but the process is likely mediated by allogeneic mononuclear cells, white blood cell–derived soluble mediators, and soluble human leukocyte antigen peptides circulating in allogeneic plasma.38,50-52 During RBC storage, cytokines and inflammatory mediators such as interleukin (IL)-1, IL-6, and tumor necrosis factor also accumulate and may contribute to the pathogenesis of TRIM. Transfusion-related immunomodulation likely contributes to the association of the administration of blood products with acquired

infections and organ failures.52 Leukoreduction of donated blood decreases the likelihood of TRIM. Transfusion-associated cardiac overload (TACO) is acute pulmonary edema secondary to congestive heart failure precipitated by the volume of fluid in transfusions that overwhelm the recipient’s circulatory system.38,50,51 Risk factors for TACO include both the total volume and the transfusion administration rate, number of blood products administered, preexisting fluid balance, renal dysfunction, preexisting cardiac dysfunction, and extremes of age.38,50,51 Transfusionassociated cardiac overload is not as prevalent as TRALI but is associated with higher morbidity and mortality. Other concerns of PRBCs include hemolytic reactions from the transfusion of mismatched blood products caused by the recipient’s complement antibodies attaching to donor RBC antigens, fevers and rigors associated with nonhemolytic immunological responses, other allergic reactions like urticaria and anaphylaxis, and the transmission of infectious diseases (HIV risk is 1 in 2 million units; hepatitis B, C, and A risks are each 1 in 250–500,000 units).38,50-53 Costs of PRBCs vary depending on what expenses are included, but estimates per unit range from $250 as a rudimentary approximation to $750 when all costs associated with donation and procurement, processing, storage, matching, preparation, and administration are included.54,55

Reversal or Prevention of Coagulopathy The presence of coagulopathy is an independent risk factor for mortality during hemorrhage, and many factors may contribute to its development.10 The general goals for reversing coagulopathy are an INR less than 1.5, an aPTT less than 1.5-fold the upper limit of normal, platelet count of 30–50 × 109/L or greater (or 20 × 109/L or greater to prevent hemorrhage), optimizing platelet function, fibrinogen of 100 mg/dL or greater, arterial pH of 7.20 or greater, core body temperature of 35°C or greater, and normal blood values of ionized calcium.1,2,7,8,3538 Several agents are available that may be tried to reverse prolonged clotting times (Table 24.5 and Table 24.6).2,3,7,35-38,56-66 These include

vitamin K, FFP, PCC products, and rFVIIa. Vitamin K Vitamin K1, also known as phytonadione or phylloqui-none, is a fatsoluble compound that aids in the carboxylation of glutamate residues of certain proteins to form γ-carboxyglutamate residues, which can then bind calcium to activate these proteins. Within the realm of coagulation, vitamin K1 activates factors II, VII, IX, and X and proteins C, S, and Z by oxidative carboxylation in the liver.2,57,67 Activation of these coagulation factors is essential for hemostasis and normal functioning of the coagulation cascade. Variables contributing to the development of vitamin K1 deficiency include inadequate diet; malabsorption; hepatic dysfunction, antibiotic ;therapy, which alters the GI flora; lack of vitamin K1 supplementation; major surgery; and the use of warfarin.67 Critically ill patients, who may have many of these variables,67 are at high risk of developing coagulopathy associated with vitamin K1 deficiency.2 Re-ports indicate that as many as 51% of hospitalized patients have vitamin K1 deficiency,10,11 with 34% resulting in hemorrhage and 24% associated with mortality.67 Vitamin K1 is commonly administered to patients with coagulopathies thought to be from vitamin K1 deficiency and/or hepatic dysfunction.2,57 It may be administered enterally, subcutaneously, or intravenously. Although either the enteral or the intravenous route of administration is recommended for urgent coagulopathy reversal, a recent study found that intravenous administration lowers INR quicker.2 If given intravenously, the rate of administration should not exceed 1 mg/minute to avoid immunoglobulin E–mediated anaphylactoid reactions that are associated with the solubilizing vehicle. For patients with an elevated INR because of warfarin, the American College of Chest Physicians recommends oral vitamin K for an INR greater than 10 and no signs of bleeding and intravenous vitamin K 5–10 mg for all major hemorrhage regardless of the INR.68 Cumulative intravenous doses of 20–30 mg are required to lower the INR from other causes of vitamin K

deficiency; however, the efficacy of vitamin K is unpredictable, especially in the more severely ill and those with hepatic dysfunction.67 The half-life of vitamin K is 1.5–3 hours, and its full effect is achieved only after 6–12 hours.2 Therefore, vitamin K’s activity is slow, but the duration of action may last several days, irrespective of the route of administration. It is inexpensive and readily available.

Table 24.5 Procoagulant Blood Products2,3,7,35-38,56-66

Product

Platelets

Contents

Thrombocytes in plasma

Indications and Usual Dosage Regimen

Considerations

-

-Platelet < 30—50 « 109/L (bleeding )

-Stored at 24’C

-Platelet < 20 x 109/ L ( prevention)

- Bacterial contamination 1/20001/3000 units

—

- Requires ABO/Rh typing and antibody screening -Contributes to TRAU, TRIM, and TACO -Worsens immune reactions

-Likely contributes to thrombosis -Variable costs

FFP

Coagulation factors and fibrinogen in variable amounts

-Use early in massive bleeding -Prevention of bleeding if INR > 1.5 -15 mL/ kg -30% factor replacement

-Stored at -18"C and requires thawing -Requires ABO/ Rh typing and antibody screening

-Limited effectiveness at reducing INR < 1.5

-Hypervolemia -TRAU (1/ 5-10,000)

-Contributes to TRIM -TACO (6%)

-Likely contributes to thrombosis -Variable costs

Prothrombin complex concentrates

Factors II, VII, IX, X and prothrombin, proteinsC, S, Z in variable amounts

-Use early in massive bleeding

-Fasteronsetthan FFP

-25-50 IU/ kg (based on factor IX)

-Variable amounts of factors and

Prevention of bleeding if INR > 1.5

limited factor VII in some products -May contain heparin -Severaldonors -Thrombosis (0.9%—2.3%) -NoTRALIorTRIM -Substantially less fluid than FFP

-Costly Cryoprecipitate

Factors VIII, XIII, vWF, fibrinogen, fibronectin

-Fibrinogen < 100 mg/dL

-Stored at -18'C and requires thawing

-lunitwill t fibrinogen 5-10 mg /dL

- Requires ABO typing

-vWF deficiency

-Contributes to thrombosis

-

-Contributes to TRALI and TRIM -Costly

TACO = transfusion-associated cardiac overload; TRALI = transfusion-related acute lung injury; TRIM = transfusion-related immunomodulation; vWF = von Willebrand factor.

Fresh Frozen Plasma Fresh frozen plasma is derived from donated blood that has been centrifuged and separated from the cellular components.2,56,57 Each

250- to 300-mL unit contains soluble clotting factors and inhibitors, 1– 2.5 mg/mL of fibrinogen, complement, albumin, and proteins C and S. Once frozen, plasma is kept at -18°C and can be stored for 12 months.2,56,57 After thawing, it must be kept at 1°C–6°C, labeled as “thawed plasma,” and transfused within 4 days. The process of freezing and thawing may affect the temperature labile clotting factors. The low and varying amounts of fibrinogen in FFP means that large volumes are often required to reverse coagulopathy; a dose of 15 mL/kg restores clotting factor levels to 30% of normal, and doses exceeding 30 mL/kg are required to increase fibrinogen concentrations.10,57 A target INR of less than 1.5 may never be reached by solely administering FFP because the fibrinogen concentration of FFP is below the target fibrinogen concentration required to fully reverse the coagulopathy.10,57 Normalization of the INR occurs in only 0.8% of patients, and a dose-response effect is inconsistent. The need for large doses, however, heightens the risk of fluid overload that may contribute to ongoing hemorrhage, cerebral edema, portal hypertension in the presence of liver dysfunction, and TACO, which occurs in 6% of patients receiving FFP.10,51,57 Hypervolemia leading to edema is of particular concern in patients with preexisting renal, cardiac, and pulmonary disorders.51 Plasma is also associated with TRALI at estimated rates of 1 in 5–10,000 units, a risk exceeding that of PRBC transfusions.10,51,57 Transfusion-related immunomodulation is also associated with FFP at occurrence rates exceeding RBC transfusions. Another concern is that extensive preparation time is required before FFP is ready to administer. After determining appropriate compatibility with the recipient, FFP must be thawed, which can take 30–60 minutes to process. Clinically, it is often difficult to estimate the number of FFP units that should be thawed for a given situation. Some centers ensure they have a constant supply of thawed or never-frozen plasma that is universally compatible; however, this can lead to units being wasted and may not be cytomegalovirus safe.57 Like other procoagulants, FFP is associated with thromboembolic adverse effects. The cost per unit of FFP is $70– $350.54,55

Table 24.6 Procoagulant Pharmacologic Products2,3,7,3538,56-66

EACA = ε-aminocaproic acid; INR = international normalized ratio; IV = intravenous(ly); SC = subcutaneous; TA = tranexamic acid; TACO = transfusion-associated cardiac overload.

Despite the aforementioned concerns, the use of FFP increased 23% between 2005 and 2012.2 Clinically applicable indications for FFP include replacement of an inherited single coagulation factor for which a virus-safe fractionated product does not exist, replacement of a specific protein deficiency such as C-1 esterase inhibitor, replacement of many coagulation factor deficiencies (DIC, hemorrhage), replacement of removed plasma during plasmapheresis in cases of thrombotic thrombocytic purpura, reversal of warfarin-associated hemorrhage, prevention of dilutional coagulopathy during hemorrhage, and prevention of bleeding in patients with advanced hepatic dysfunction and coagulopathy awaiting an invasive procedure or surgery.2,38,57 The most common reason to administer FFP in the United States is to prevent hemorrhage in patients with prolonged coagulation tests awaiting an invasive procedure. Limited data support this indication because a prophylactic dose of 12 mL/kg lowered the INR to less than 1.5 in only 54% of patients and did not lower the rate of bleeding after various invasive procedures compared with placebo.8 Moreover, clinically relevant bleeding problems in patients with hepatic dysfunction may be precipitated by increased venous pressures that may be associated with the large volume of fluid that accompanies FFP administration. Rather than trying to shorten clotting times, a conservative approach to plasma therapy in these patients using clinical judgment may prove beneficial. Fresh frozen plasma’s duration of action is typically 6–12 hours.2,57 Prothrombin Complex Concentrates Prothrombin complex concentrates are an inactive concentrate of variable, yet balanced, amounts of the vitamin K– dependent clotting factors. The concentration of vitamin K–dependent clotting factors in PCCs is about 25-fold higher than in plasma, and usual doses are equivalent to about 2 L of FFP.2 Prothrombin complex concentrates are

purified from pooled human plasma and lyophilized, which allows them to be reconstituted, as opposed to frozen and thawed.57,58 This provides significant advantages over FFP, including rapid administration, avoidance of compatibility testing, and the absence of risk of TRALI and TRIM.57,58 Like allogenic blood products, however, PCCs carry the potential risk of transmitting infectious microbes. Prothrombin complex concentrates contain factors II, IX, and X and are available with low amounts of factor VII (three-factor PCCs) and higher concentrations of factor VII (four-factor PCCs). Unlike three-factor PCCs, four-factor PCCs also contains albumin, proteins C and S, antithrombin, and heparin. Although the inclusion of anticoagulants theoretically reduces the occurrence of thromboembolic events that are associated with rapid induction of coagulation, they need to be considered in patients with known sensitivities to them (e.g., heparininduced thrombocytopenia).2,57,58 The weighted mean average of thrombotic events with PCCs through 2008 was 2.3%, with higher rates associated with larger and repeated doses.57 A lower rate of 0.9% was identified in a review of eight clinical trials, although all of these studies included patients requiring warfarin reversal.57 Because of their rapid effect at reversing coagulopathy, PCCs may slightly increase the risk of thromboembolic events compared with FFP.57,58 Prothrombin complex concentrates are derived from human plasma, so patients declining blood products should be consulted before PCCs are administered. Dosage regimens of PCCs typically involve the administration of 50–200 mL of total fluid, so TACO and other manifestations of fluid overload are unlikely to occur. The acquisition costs of PCCs vary but are about $1.30 per unit with typical doses exceeding 2,000 units, and it is common practice to round to the nearest vial size.57,58 Prothrombin complex concentrates are available as a kit that contains the lyophilized powder and a provided diluent that is commonly mixed at the bedside but must be administered within 4 hours of reconstitution. Institutional procurement, storage, and distribution may originate from the blood bank rather than the pharmacy department. In the United States, three-factor PCCs are only indicated for the

prevention and control of bleeding in patients with factor IX deficiency caused by hemophilia B.57,58 In contrast, four-factor PCCs are labeled for rapid reversal of acquired coagulation deficiency induced by warfarin in adult patients with acute major bleeding or the need for urgent surgery or an invasive procedure.57,58 The general consensus of several guidelines that have been published regarding the use of PCCs to reverse anticoagulation indicates that four-factor PCCs are the preferred therapy, FFP may be needed if three-factor PCCs are used, and FFP is likely not needed if four-factor PCCs are used.57 One guideline suggests that rFVIIa can be considered in addition to threefactor PCCs when emergency reversal is required.57 The results of studies comparing four-factor PCCs with FFP in patients receiving anticoagulation with vitamin K antagonists show that four-factor PCCs reverse INR more rapidly with less fluid administration and achieve greater rates of effective hemostasis.69,70 The dosage regimens are based on units of factor IX, but an adjustment for four-factor PCCs includes the INR (INR of 2–4 = 25 units/kg, INR of 4–6 = 35 units/kg, INR of greater than 6 = 50 units/kg). This latter adjustment for the INR is often applied to dosage regimens of all products when they are used in clinical scenarios of prolonged clotting in the absence of anticoagulation. In a retrospective assessment of patients with coagulopathy caused by trauma, adding PCCs to FFP accelerated INR reversal, reduced the number of units of PRBCs and FFP administered, lessened the total costs associated with procoagulant administration, and lowered mortality.71 Although not systematically studied for the prevention of bleeding in patients with coagulopathies owing to causes other than anticoagulation and awaiting surgery or an invasive procedure, PCCs likely reverse INR more rapidly than does FFP with substantially less fluid and may expedite the time to the intervention. The duration of action depends on the dose of PCC administered but is typically 12–24 hours.57,58 Activated PCC or factor VIII inhibitor bypassing complex (FEIBA; Baxter Healthcare, Westlake Village, CA) is an anti-inhibitor coagulation complex used in the management of hemorrhage in patients with hemophilia and acquired factor VIII inhibitors.61 It is composed of

factors II, IX, and X; small amounts of activated factor VII; and factor VIII antigen. It acts by facilitating thrombin generation on the surface of activated platelets and activating factor X. It is not commonly used to manage or prevent hemorrhage in patients without factor VIII inhibitors, but case reports show it may successfully reverse new oral anticoagulant agents.61 It is associated with thrombosis and the propagation of DIC, and it may pose a risk of transmitting infectious microbes because it is manufactured from human blood pools. Recombinant Activated Factor VII Recombinant activated factor VII is indicated for the treatment and prevention of bleeding in patients with hemophilia with inhibitors, cases of factor VII deficiency, and individuals with Glanzmann thrombasthenia with little to no response to platelets.57 Recombinant activated factor VII stimulates the extrinsic pathway by interacting with exposed endothelial tissue factor to activate factors IX and X. At pharmacologic doses, rFVIIa bypasses the need for tissue factor by generating thrombin on the surface of activated platelets that are localized to the site of injury.67 Both mechanisms ultimately produce activated factor X, which drives thrombin burst to cleave fibrinogen to fibrin. Factor VII levels are often extremely low in patients with major hemorrhage. To optimize the activity of rFVIIa, patients should be normothermic with an arterial pH greater than 7.20.67,72 Results from studies using dosage regimens of 10–90 mcg/kg are mixed with respect to reducing hemorrhage expansion and limiting the administration of other procoagulant products and/or PRBCs in bleeding cases associated with vitamin K antagonists, liver disease, liver transplant, trauma- and surgery-associated coagulopathy, cardiothoracic surgery, and spontaneous intracranial hemorrhage.57,72 None of these studies, however, has shown clinical benefits of morbidity or mortality.57 Recombinant activated factor VII reduces prolonged clotting times within 15–30 minutes of administration and typically lasts 2–6 hours. Reversal time is faster than that of PCCs and FFP, but duration may be shorter. Several studies comparing rFVIIa with FFP show that rFVIIa may expedite invasive procedures or surgery in patients with

coagulopathies from causes other than anticoagulants. These nonproprietary indications represent more than 95% of rFVIIa use in the United States.57,72 Some have recommended against the use of rFVIIa in favor of PCCs for INR reversal, regardless of the etiology of prolonged clotting, because rFVIIa may not adequately restore thrombin generation over time to the same extent as other products, resulting in a duration of action that is substantially shorter.2,57 The rate of thromboembolic events associated with rFVIIa administration is 11.1% across studies, but only the rate of arterial events exceeds that of placebo (5.5% vs. 3.2%, p 90%) LY30 (< 7.5%)

-The greatest vertical amplitude of the TEG tracing -Reflects strength of clot and platelet activation -The amplitude 60 min after MA as a percentage of MA

Fibrinogen (cryoprecipitate) ± rFVIIa Platelets ± desmopressin

Antifibrinolytics

-Reflects fibrinolysis -The rate of amplitude reduction 30 min after MA

Antifibrinolytics

-Reflects fibrinolysis

LY = lysed; MA = maximum amplitude; TEG = thromboelastogram.

Traumatic Injury Hemorrhagic shock is most commonly seen after acute injury. However, non-trauma cases of massive hemorrhage include patients with GI bleeding, obstetrical patients, and surgical procedures with the potential for massive bleeding complications. The overarching goal in hemorrhagic shock is improving patient outcomes through source control, restoration of adequate end-organ perfusion, increased oxygen-carrying capacity of the circulating blood, and reversal of the hypocoagulable state often accompanying massive blood loss. As with surgery, coagulopathy from trauma is the consequence of many factors including hypothermia, acidosis, DIC, and dilution.75,81 About 9% of patients with trauma present with hypothermia, and about 65% of hypothermia can be attributed to radiant heat loss from removal of clothing, muscle relaxation, frequent removal of blankets for examinations, or resuscitation with cold intravenous fluids.12,40 Unlike elective surgery where normovolemic hemodilution conserves blood,

excessive resuscitation during trauma with crystalloid fluids dilutes clotting factors, increases hydrostatic pressure, and reduces quality clot formation. Acute coagulopathy of trauma is recognized as a distinct entity as patients progress from an early hypocoagulable/profibrinolytic phase to a prothrombotic phase.12,81,82 The defining etiology is traumatic shock leading to systemic hypoperfusion, which slows the clearance of thrombin.81,82 Enhanced binding of thrombin to endothelial thrombomodulin activates protein C, inactivates factors Va and VIIIa, and abrogates plasminogen activator inhibitor and thrombin activatable plasminogen inhibitor to produce greater fibrinolysis. Tissue hypoperfusion generates new expression of thrombomodulin, furthering the hypocoagulable state. In contrast, massive tissue destruction also releases damage-associated molecular pattern molecules such as histones and mitochondrial DNA, which lead to micro-vascular thrombosis by inducing platelet activation, promoting thrombin generation, and impairing protein C activation. Tissue injury also releases the proinflammatory cytokines, IL-1β and tumor necrosis factor α, which elicit tissue factor expression on the surface of monocytes and endothelium to propagate thrombosis and possibly incite DIC. Traumatic brain injury also causes the release of tissue factor from injured neurons.81,82 The reversal of coagulopathy with blood products and pharmacologic agents is critical because coagulopathy is an independent risk factor for morbidity and mortality in trauma patients with hemorrhagic shock (Table 24.8).39,40 Massive transfusion protocols were developed in an effort to minimize RBC transfusions and crystalloids in trauma patients with hemorrhagic shock (Figure 24.3).12,38,40 Increasing the speed and efficiency of transfusions are other potential benefits of MTPs. Massive transfusion protocols are processes for administering RBCs, plasma, and platelets in a set ratio, as well as hemostatic agents in a standardized manner versus guiding blood product administration on the basis of laboratory data.83-87 These protocols are often initiated by an order set or telephone call to the blood bank, and the blood products are delivered to the bedside

ready to use. The first MTP used a ratio of 1:1:1 (PRBC/plasma/platelets) for civilian trauma patients and was based on military data.12,38 Massive trans-fusion protocols are physiologically rational because whole blood has an RBC/plasma ratio of 1:1.12,38 Although studies are almost uniformly positive, most were observational and usually based on before-after methodology at single centers.12,38 The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study was conducted across 10 U.S. level 1 trauma centers and evaluated 1,245 patients who received at least 1 PRBC unit within 6 hours of admission.88 Findings from the PROMMTT study indicate that ratios of RBC to FFP of 1:1 or less and ratios of RBC to platelets less than 1:2 within 6 hours of admission were independently associated with decreased 30-day mortality rates. A follow-up study examining the optimal PRBC/FFP/platelet ratios, known as the Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) study, randomized 680 hemorrhaging patients to PRBC/plasma/platelets in ratios of 1:1:1 to 2:1:1.89 The results showed similar mortality rates between groups at 24 hours and 30 days despite fewer deaths from exsanguination within 24 hours (9.2% vs. 14.6%, p=0.03) and greater achievement of hemostasis in the 1:1:1 group (86% vs. 78%, p=0.006). Most trauma centers have an MTP in place, but significant variability exists relative to the fixed ratio of blood products within the protocol. An average of 10 MTP studies of more than 4,000 trauma patients showed a mean RBC/plasma ratio of less than 3:2 and an RBC/platelet ratio less than 2:1.86,87

a angle

MA \ 2 mm

20 mm

GO min

r time

>

*

» K time

CM gul fit ion

Fibrinolysis

—

I Time

A . Normal TEG Trace

B, Fibrinolysis

C. Hypercoagulable D . Hypocoagulable

Dilutional

Figure 24.2 Schematic diagram of thromboelastogram showing reaction time (r), clot formation time (K), alpha (α) angle, maximum amplitude (MA), and maximum amplitude (A60). Compared with a normal trace (A), fibrinolysis (B) is associated with prolonged r and K times, reduced MA and A60, greater LY30, and possibly obtuse α angle; hypercoagulation (C) is associated with shorter r and K times, heightened MA and A60, relatively normal LY30, and acute α angle; hypocoagulation (D) is associated with lengthened r and K times, reduced MA and A60, relatively normal LY30, and obtuse α angle.67,77,78

A significant limitation of studies examining MTPs is survival bias. Plasma must be thawed before administration, so patients bleeding profusely may die after receiving PRBCs but before receiving FFP.12 In addition, administering platelet transfusions in trauma patients without thrombocytopenia is questionable, and the “shotgun” approach may result in over-replacement of products with limited supply and contribute to adverse events and/or the propagation of DIC.12 In many cases, systemic pharmacologic agents or factor-specific products are included in these MTPs.86,87 Consideration of other blood products for inclusion in MTPs such as PCCs, cryoprecipitate, and fibrinogen concentrates may also be directed by this strategy.86,87 Massive transfusion protocols are often applied to etiologies of hemorrhage other than trauma.87

^\ ^

Patient at risk of uncontrolled bleeding

^

Type and cross

Activehemorrhage AND immediateneed for transfusjon ?

J

No

Conventional resuscitation

Stat Labs: CBC, ABG, iCa, lactate, INR, aPTT, fibrinogen, D-dimer, FSP

I

Yes

Correct: acidosis, hypothermia, hypocalcemia

c

Anticipate total requirements > 10 units of total blood produets?

No

)

Conventional resuscitation + tranexamic acid 1g load followed by 1g over 10 hr if trauma

Yes

Activate MTP: 6 units O-neg PRBC + 4 units FFP + 6 -unit platelet pack + tranexamic acid 1g load followed by 1g over 10 hr if trauma

C

Lab results return ?

Consider rFVIIa 40-90 mcg/ kg

Consider TEG

No

Repeat initial MTP + cryoprecipitate Yes

If INR 1.5, give 4 units of FFP May consider PCC if volume overload is ofconcern

If Plt count < 30-50 x 109/L, give 6-unit platelet pack

If fibrinogen < 100 mg /dL, give cryoprecipitate

I Monitor labs every 30-60 min

>

fr

^

Yes

Ongoingbleed ?

No

Deactivate MTP

Figure 24.3 Example of a massive transfusion protocol showing the considerations and incorporation of blood product ratios, pharmacologic agents, laboratory parameters, and thromboelastogram.12,38,40 ABG = arterial blood gas; aPTT = activated partial thromboplastin time; CBC = complete blood count; FSP = fibrin split product; iCa = ionized calcium; INR = international normalized ratio; MTP = massive transfusion protocol; Plt = platelet; rFVIIa = recombinant activated factor VII; TEG = thromboelastogram.

There is a trend toward using a hybrid, more individualized approach to treating patients, which combines visco-elastic testing data and a structured MTP. Thromboelastography (TEG) or rotational TEG (ROTEG) is an integral element of this point-of-care management approach.77,78 The primary advantage of these tests over other conventional tests used during surgery and trauma is that they offer delineated assessments of coagulation, clot stability, and fibrinolysis (Table 24.9; Figure 24.2).67,77,78 Disadvantages of the TEG or ROTEG include cost, differences in results, and time to obtain results on the basis of technique and device.67 Several reports suggest that viscoelastic testing used during surgery or trauma to specifically direct the appropriate use of therapies improves coagulation, minimizes fibrinolysis, and limits patient exposure to unnecessary blood products.77,78 Used in this way, these tests can facilitate the efficient use of blood products and hemostatic agents while reducing blood loss and potentially improving clinical outcomes.77,78 Of note, these viscoelastic hemostatic assays are commonly used during non-trauma surgical procedures to monitor coagulation and guide therapies and are becoming more commonly applied across ICUs in nonsurgical types of hemorrhage.77,78 Tranexamic acid and rFVIIa are two pharmacologic products that have been systematically studied in trauma patients at high risk of hemorrhage. The Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH)-2 trial was a multicenter study of

274 hospitals in 40 countries that randomized 20,211 adult trauma patients actively hemorrhaging or at high risk of hemorrhage and within 8 hours of injury to tranexamic acid (loading dose 1 g over 10 minutes; then infusion of 1 g over 8 hours) or matching placebo.90 All-cause 28day hospital mortality, the primary outcome, was lower with tranexamic acid (14.5% vs. 16%; RR 0.91; 95% CI, 0.85– 0.97, p=0.0035). The risk of death caused by bleeding was also lower (4.9% vs. 5.7%; RR 0.85; 95% CI, 0.76–0.96, p=0.0077). The greatest survival benefit was most evident for the day of injury and when treatment was initiated within 3 hours of injury.91,92 Exploratory analyses of the CRASH-2 trial found that treatment given after 3 hours increased the risk of death caused by bleeding (4.4% vs. 3.1%; RR 1.44; 95% CI, 1.12–1.84, p=0.004).92-94 The contrasting survival benefit, given the timing of administration, may pertain to the pathophysiology of coagulopathy from acute trauma because early administration may help control the hypocoagulable/profibrinolytic phase seen shortly after trauma.92,93 Vascular occlusive events (1.7% vs. 2%; RR 0.84; 95% CI, 0.68–1.02, p=0.084) and the use of blood products were similar between groups.91-93 Cost-effectiveness analyses show that the incremental cost of using tranexamic acid per life-year gained is less than $100, especially when administered within 3 hours of injury.94,95 Because of these results, most trauma centers administer tranexamic acid when patients present within 3 hours of injury. Considerable controversy exists about the administration beyond 3 hours. Before tranexamic acid was studied, rFVIIa was evaluated in 301 bleeding patients with blunt or penetrating trauma across 32 hospitals.96 Patients requiring 6 units of PRBCs within 4 hours of injury were randomized to receive rFVIIa 200 mcg/kg, followed by two doses of 100 mcg/kg 1 and 3 hours after the first dose or placebo. In blunt trauma, rFVIIa reduced RBC transfusions within 48 hours (2.6 units, p=0.02), the primary outcome, and the need for massive transfusion, as defined by greater than 20 PRBC units (14% vs. 33%, p=0.03).96 The rate of acute respiratory distress syndrome was also decreased (29% vs. 42%, p=0.03). These results were not statistically different for the penetrating trauma group. Mortality and thromboembolic rates

were similar between groups. A subgroup analysis showed that the greatest benefit occurred when coagulopathy was present.97 A phase III study of patients who bled 4–8 RBC units within 12 hours of injury and were still bleeding despite resuscitation and operative management using a similar dosing scheme was terminated early after 573 patients (481 with blunt trauma) of 1,502 planned subjects because mortality rates (11% vs. 10.7%, respectively) were lower than anticipated, resulting in futility concerns.98,99 Similar to the previous study, blunt trauma patients randomized to rFVIIa received fewer PRBC units (7.8 ± 10.6 vs. 9.1 ± 11.3, p=0.04) and total units of allogenic blood products (19 ± 27.1 vs. 23.5 ± 28, p=0.04). Thromboembolic rates were similar between groups. Because of the cost of rFVIIa and the newer data with tranexamic acid, most trauma centers reserve rFVIIa use for patients with refractory hemorrhage and often use dosage regimens of 40–90 mcg/kg rather than the cumulative dose of 400 mcg/kg that was studied.

Management and Prevention of Bleeding in Patients with Cirrhosis The complex nature of the coagulation system in patients with hepatic insufficiency makes management difficult and often controversial. Traditionally, clinicians associated hepatic insufficiency with an anticoagulated state and increased bleeding tendency, so management was targeted at reversing coagulation tests such as PT/INR.26-28 However, recent literature suggests that patients with hepatic insufficiency have a balanced coagulation system and that prolonged coagulation tests do not correlate with bleeding risk.26-28 The focused use of blood products in clinical scenarios is currently the mainstay of therapy for these patients, in addition to the potential use of vitamin K, rFVIIa, and PCCs.7,27,28 Concomitant renal dysfunction is common in patients with hepatic insufficiency and hemorrhage, so desmopressin may be administered if uremia is present in an effort to improve platelet function.7,28 Despite the lack of literature proving their efficacy, blood products

(FFP, platelets, and cryoprecipitate) are commonly administered in patients with hepatic insufficiency to control active bleeding or reverse PT/INR before invasive procedures. Fresh frozen plasma may partly reverse prolonged values of PT/INR; however, achievement of an INR less than 1.5 occurs in fewer than 10% of cases.8 Similarly, correlation between a corrected PT/INR and clinically significant bleeding cessation or occurrence in the case of prophylactic administration has not been established in this patient population.4,26 The amount of plasma needed to consistently reduce the PT/INR is often 10–15 mL/kg, which exposes these patients to increased volume expansion and subsequent risks of TACO, TRALI, and cerebral edema and worsening portal pressure to promote ongoing hemorrhage.10,57 In addition, the effects of FFP are short lived, which is consistent with the short half-life of factor VII. The lack of clinical evidence and the risks associated with the administration of FFP in this patient population argue against its routine use; however, many clinicians are compelled to try to reverse the coagulopathy in cases of hemorrhage and to prevent bleeding. Administration of cryoprecipitate may aid in restoring “normal” concentrations of fibrinogen in patients with hepatic insufficiency who may have lower concentrations of fibrinogen and impaired aggregation of fibrin monomers.28,62 The exact target concentration of fibrinogen has not been established, and systemic fibrinogen concentrations may not give an accurate assessment of bleeding risk, given the uncertainty regarding the degree of dysfibrinogenemia found in patients with hepatic insufficiency. However, in clinical practice, doses of cryoprecipitate are typically titrated to achieve a fibrinogen concentration of 100–120 mg/dL in the setting of bleeding, and they typically range from 1 to 2 units/kg of body weight.28,62 Caution should be taken during administration because cryoprecipitate lacks certain clotting factors and can worsen the already imbalanced coagulation system seen in patients with hepatic insufficiency. The quantity and quality of platelets is also important to achieve primary hemostasis, and patients with hepatic insufficiency often have abnormalities in their platelet production and function.4,26 Transfusions

of platelets typically result in an immediate rise in platelet counts; however, the target platelet concentration in this patient population remains poorly defined. In-vitro studies have shown that platelet counts of 50 × 109/L or greater enable adequate thrombin generation, whereas concentrations of 100 × 109/L or greater may enable optimal thrombin generation. In clinical practice, it is reasonable to aim for platelet counts of 50 × 109/L or greater in the setting of active bleeding or of 20 × 109/L or greater to prevent hemorrhage in high-risk procedures.26,28,34,35 Vitamin K deficiency is a common complication of hepatic insufficiency and may occur because of malnutrition and malabsorption. In addition, vitamin K–dependent clotting factors (II, VII, IX, and X) are synthesized in the liver and are often deficient in patients with hepatic insufficiency.11,37 Prothrombin time and INR tests are nonspecific for vitamin K–dependent clotting factors and are often insensitive in patients with hepatic insufficiency because these patients may have an elevated PT/INR despite having normal concentrations of vitamin K.7,9,11,67 Despite the lack of literature proving its efficacy, vitamin K is commonly administered to patients with hepatic insufficiency to help correct their coagulopathy. Given the high safety profile and nominal cost of vitamin K, the risk-benefit profile of vitamin K will often favor its administration. There is no standardized dosing regimen; however, intravenous doses of 10 mg daily for 48–72 hours adequately replace vitamin K deficiency.2,28,67 Replacing factor VII in hepatic insufficiency with rFVIIa is physiologically reasonable because these patients often have low levels of factor VII, and the small volume needed to administer rFVIIa may improve safety compared with FFP.28 Although several studies show that rFVIIa effectively normalizes prolonged values of PT/INR in patients with cirrhosis, the efficacy of rFVIIa for reducing clinically significant bleeding remains unclear. Bosch et al. conducted a doubleblind study that randomized 245 patients with cirrhosis with upper GI bleeding to receive either eight doses of rFVIIa 100 mcg/kg or placebo, in addition to pharmacologic and endoscopic treatment.100 No significant differences were seen regarding the primary composite end

point (failure to control upper GI bleeding within 24 hours after the first dose, or failure to prevent rebleeding at 24 hours and day 5, or death within 5 days). However, subgroup analysis showed that administering rFVIIa in patients with Child-Pugh class B and C cirrhosis was more effective than placebo at improving the primary composite end point, whereas administration of rFVIIa in Child-Pugh A patients had no benefit. As a result of this subgroup analysis, the same investigators carried out a second randomized clinical trial that examined the same primary composite end point, but solely in patients with Child-Pugh class B and C cirrhosis.101 Results showed no significant differences between rFVIIa and placebo in these patients. As a result of these studies and the cost of rFVIIa, it is rarely administered to manage hemorrhage in patients with hepatic insufficiency. The role of rFVIIa in the management of bleeding secondary to major surgical operations such as liver transplantation, resections, and/or liver biopsies also remains unclear.74 A multicenter, randomized, double-blind study examining the efficacy and safety of repeated perioperative doses of rFVIIa in liver transplantation secondary to cirrhosis failed to show any significant differences between placebo and rFVIIa with respect to perioperative PRBC transfusion requirements.102 Furthermore, there were no differences in requirements of FFP, platelets, and fibrinogen, and overall blood loss and length of hospital stay were similar. Other trials examining the use of rFVIIa in this patient population provide inconclusive evidence, and use has not been widely accepted during major surgical procedures secondary to hepatic insufficiency.74 Finally, the prophylactic use of rFVIIa for invasive procedures in patients with acute liver failure is still highly debated. Limited data have shown that rFVIIa at a dose of 40 mcg/kg may be useful during invasive procedures, particularly the placement of intracranial pressure monitors.74,103 Compared with FFP alone, rFVIIa rapidly normalized PT/INR values, allowing for a higher number of successful intracranial pressure monitor placements. Despite the small amount of literature available, the role of rFVIIa as a prophylactic agent for invasive procedures remains uncertain, particularly because the normalization of

coagulation tests in these patients has not been associated with clinically significant cessation of bleeding.103 Similar to rFVIIa, the role of PCCs for the management or prevention of bleeding associated with hepatic insufficiency is currently undefined, with much less data to support its use.2,57,58 Like rFVIIa, PCCs provide much smaller volumes of administration than FFP. Although data from large, randomized trials are lacking, several smaller studies have examined the safety and efficacy of PCC use in bleeding patients with hepatic insufficiency. In general, four-factor PCCs reverse prolonged PT/INR values in these patients, whereas three-factor PCCs require the addition of rFVIIa to be effective. Thromboelastography- or ROTEG-guided use of PCCs in bleeding associated with liver transplantation further reduces the need for RBCs, FFP, and platelets with no change in thromboembolic or ischemic events. Most data analyses currently available for the use of PCCs for bleeding associated with hepatic insufficiency were done using PT/INR as a surrogate marker of efficacy, yet these parameters do not predict bleeding risk in these patients.2,57,58 Prothrombin complex concentrates are often substituted for FFP to reverse PT/INR in patients with cirrhosis about to undergo invasive procedures because PCCs act more predictably and rapidly and require less volume administration. Further studies are ongoing and will help guide the clinical use of PCCs for bleeding associated with hepatic insufficiency. Continued caution is warranted when using PCCs because it is unknown whether a disruption of the coagulation system in these patients could place them at an increased risk of thrombosis.

Major Obstetric Hemorrhage Pregnancy is associated with a hypercoagulable state because levels of factors V, VII, VIII, IX, X, and XII; vWF; and fibrinogen are increased with concomitant decreases in the anticoagulants protein C and S and heparin cofactor II and depressed antifibrinolytic activity.104,105 The transfusion rate in obstetrics in the United States is relatively low, from 0.9% to 2.3%. The incidence of postpartum

hemorrhage (PPH), however, is increasingly driven by the greater prevalence of uterine atony caused by higher rates of cesarian deliveries and the older average age of women at childbirth. Postpartum hemorrhage is defined as persistent bleeding of greater than 500–1,000 mL within 24 hours of birth that continues despite the use of initial measures.104,105 Fortunately, massive transfusion of 10 units or greater of blood products occurs in only 6 of every 10,000 deliveries. Although uterine atony represents about 80% of the causes of PPH, placental problems account for 27% of all cases of massive transfusion.104,105 Other etiologies of PPH include genital tract trauma and systemic medical disorders. Obstetrical DIC can occur secondary to placental abruption, amniotic fluid embolism, dead fetus syndrome, or massive hemorrhage. First-line treatment of PPH consists of identifying and correcting the cause (e.g., removal of a retained placenta), using uterotonic agents (e.g., oxytocin, carboprost, or misoprostol) that improve uterine tone and cause local vasoconstriction to reduce blood flow to the uterus, and using mechanical manipulations (e.g., massage, uterine tamponade, packing).104,105 Persistent hemorrhage should mandate the activation of the MTP (Figure 24.3)12,38,40 with therapies directed to achieve or maintain the aforementioned laboratory goals for INR, platelet count, and fibrinogen concentrations (Table 24.6 and Table 24.8)2,3,7,35-40,56-66 or normal viscoelastic hemostatic parameters (Table 24.9; Figure 24.2)67,77,78 (see Traumatic Injury section for more detail). In some cases, topical hemostats may be applied. The results of a randomized, double-blind study of 144 women with PPH (greater than 800 mL of estimated blood loss after vaginal delivery) found that tranexamic acid (4 g loading dose, followed by 1 g/hour for 6 hours) significantly reduced blood loss, RBC transfusion requirement, bleeding duration, and progression to severe PPH.106 Although guidelines suggest the use of tranexamic acid in persistent PPH, a large, multicenter study is ongoing that will investigate the impact of tranexamic acid on the rates of hysterectomy and mortality. Recombinant activated factor VII may also cease or slow PPH, but it has only been assessed in retrospective cohort studies, most

commonly at doses of 90 mcg/kg.104,105 Recombinant activated factor VII may be a plausible option before the definitive treatment of a hysterectomy is performed.

Managing Hemorrhage Associated with Anticoagulants About 1%–10% of patients receiving anticoagulation therapies will have a hemorrhagic complication.67 In all cases of hemorrhage, the benefit of reversing the anticoagulant in an effort to stop the bleed must be considered against the risk of thrombosis for which the anticoagulant is being used. In general, life-threatening bleeding events or those with long-term severe morbidities such as intracranial hemorrhage, retroperitoneal hemorrhage, GI hemorrhage, or intraocular hemorrhage mandate the temporary discontinuation and reversal of the anticoagulant. The extent of anticoagulation, if assessable, must be considered. In addition, the projected duration of effective anticoagulation after discontinuing the anticoagulant must be considered because reversal agents may have shorter half-lives than the anticoagulant, especially when organ dysfunction is present. For some bleeding sources, invasive or surgical procedures may be warranted. Until recently, vitamin K antagonists such as warfarin were the only oral anticoagulants available for the prevention of thrombosis. In intracranial hemorrhage, the mortality rate doubles when it is associated with warfarin.1,2 Early hematoma expansion is associated with neurological deterioration and poor clinical outcomes.7,8 In severe or life-threatening intracranial hemorrhage, rapid reversal of anticoagulation is associated with clinical improvements, likely because hematoma expansion is minimized.9,10 Conventional therapies used to reverse the anticoagulant effects of warfarin include vitamin K, FFP, and PCCs (Table 24.5 and Table 24.6).2,3,7,35-38,56-66 Early administration of these agents is associated with greater reversal of INR, so these and other therapies should not be delayed for the results of coagulation tests.9,10 Intravenous vitamin K 5–10 mg should be administered in cases of major hemorrhage. Four-factor PCCs reduce

INR more rapidly than FFP and have become the primary reversal option for warfarin-associated hemorrhage. Recombinant activated factor VII is the most effective agent at reversing INR, but its use is controversial because it is costly and short acting relative to the duration of action of warfarin, and few studies have evaluated it for warfarin reversal. Studies evaluating rFVIIa for warfarin reversal are poor quality, and the results of studies of patients with spontaneous intracranial hemorrhage are mixed with respect to neurological improvement, although rFVIIa consistently reduces hematoma expansion at the risk of increasing thromboembolic events. Target-specific oral anticoagulants include dabigatran (DTI) and the factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). These newer agents have rapid onset of action and predictable pharmacokinetics, allowing for fixed dosing and mitigation of laboratory monitoring. Unlike warfarin, however, they do not currently have a known antidote. Several reversal agents are in development or at various stages of testing. The furthest along is idarucizumab, a monoclonal antibody that binds to free and thrombin-bound dabigatran and was recently shown to normalize clotting times in patients (79% at 24 hours) requiring urgent or emergency reversal of dabigatran.107 However, most data to treat hemorrhage associated with these agents are derived from animal models, in vitro studies of plasma from patients, or healthy volunteer studies that used outcomes of coagulation parameters or surrogate markers of clot formation such as thrombin generation (Table 24.2).7,11,12,30-33 Although dabigatran may be removed through dialysis, the factor Xa inhibitors cannot. Fourfactor PCCs inconsistently reverse the effects of dabigatran, whereas they appear effective at promoting coagulation when anticoagulation is from factor Xa inhibitors. Both aPCCs and rFVIIa improve thrombin generation when anticoagulation is with dabigatran. Other anticoagulants include heparin (stimulate anti-thrombin), lowmolecular-weight heparins (stimulate antithrombin and anti-Xa activity), fondaparinux (indirect anti-Xa activity), other DTIs, and fibrinolytic agents (Table 24.2).7,11,12,30-33 The effects of heparin are reversed with protamine (1.0–1.5 mg protamine sulfate for every 100 U of heparin,

not to exceed 50 mg). Reversal of the anti-Xa activity of low-molecularweight heparins can be 60% achieved with protamine, so FFP or PCCs are commonly administered as adjunctive therapy to replace additional factors. Anticoagulation associated with fondaparinux or the DTIs may partly be reversed by PCCs, aPCCs, or rFVIIa. Bleeding associated with fibrinolytic agents may be treated with antifibrinolytics and fibrinogen replacement with cryoprecipitate. Platelets and desmopressin are often administered to reverse the effects of antiplatelet agents (Table 24.2).7,11,12,30-33

CONCLUSION This chapter reviewed the common causes of disruption to the hemostatic pathways; delineated the properties of blood products, pharmacologic agents, and nonpharmacologic interventions; and discussed the appropriate management for common types of hemorrhage. Many questions remain regarding the pathophysiology of coagulopathy and hemorrhage and the appropriate use of procoagulant strategies.

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progresses in clinical application. Biomed Res Int 2014;2014:456569. 7. Marks PW. Coagulation disorders in the ICU. Clin Chest Med 2009;30:123-9. 8. Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care 2006;10:222. 9. Zimmerman LH. Causes and consequences of critical bleeding and mechanisms of blood coagulation. Pharmacotherapy 2007;27(9 pt 2):S45-56. 10. Wheeler AP, Rice TW. Coagulopathy in critically ill patients. Part 2 – soluble clotting factors and hemostatic testing. Chest 2010;137:185-94. 11. Dutton RP. Haemostatic resuscitation. Br J Anaesth 2012;109(suppl 1):i39-i46. 12. Ruzicka J, Stengl M, Bolek L, et al. Hypothermic anticoagulation: testing individual responses to graded severe hypothermia with thromboelastography. Blood Coagul Fibrinolysis 2012;23:285-9. 13. Rohrer MJ, Natale AM. Effect of hypothermia on the coagulation cascade. Crit Care Med 1992;20:1402-5. 14. Wolberg AS, Meng ZH, Monroe DM, et al. A systemic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma 2004;56:1221-8. 15. Hazinski MF, Nolan JP, Billi JE, et al. Executive summary: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 2010;122:250-75. 16. Polderman KH. Mechanisms of action, physiological effects, and complications of hypothermia. Crit Care Med 2009;37:186-202. 17. Dirkmann D, Hanke AA, Gorlinger K, et al. Hypothermia and acidosis synergistically impair coagulation in human whole blood. Anesth Analg 2008;106:1627-32.

18. Thorsen K, Ringdal KG, Strand K, et al. Clinical and cellular effects of hypothermia, acidosis, and coagulopathy in major injury. Br J Surg 2011;98:894-907. 19. Martini WZ. Coagulopathy by hypothermia and acidosis: mechanisms of thrombin generation and fibrinogen availability. J Trauma 2009;67:202-8. 20. D’Angelo MR, Dutton RP. Management of trauma-induced coagulopathy: trends and practices. AANA J 2010;78:35-40. 21. Sihler KC, Napolitano LM. Complications of massive transfusion. Chest 2010;137:209-20. 22. Gando S, Saitoh D, Ogura H, et al. Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: results of a multi-center, prospective study. Crit Care Med 2008;36:145-50. 23. Levi M, Toh CH, Thachil J, et al. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009;145:24-33. 24. Levi M, van der Poll T. Coagulation in patients with severe sepsis. Semin Thromb Hemost 2015;41:9-15. 25. Schaden E, Saner FH, Goerlinger K. Coagulation pattern in critical liver dysfunction. Curr Opin Crit Care 2013;19:142-8. 26. Gopinath R, Sreekanth Y, Yadav M. Approach to bleeding patient. Indian J Anaesth 2014;58:596-602. 27. Dasher K, Trotter JF. Intensive care unit management of liverrelated coagulation disorders. Crit Care Clin 2012;28:389-98. 28. Levy JH, Szlam F, Wolberg AS, et al. Clinical use of the activated partial thromboplastin time and prothrombin time for screening: a review of the literature and current guidelines for testing. Clin Lab Med 2014;34:453-77.

29. Oudemans-van Straaten H. Hemostasis and thrombosis in continuous renal replacement treatment. Semin Thromb Hemost 2015;41:91-8. 30. Miller MP, Trujillo TC, Nordenholz KE. Practical considerations in emergency management of bleeding in the setting of targetspecific oral anticoagulants. Am J Emerg Med 2014;32:375-82. 31. Kalus JS. Pharmacologic interventions for reversing the effects of oral anticoagulants. Am J Health Syst Pharm 2013;70(suppl 1):S12-21. 32. Nutescu EA, Dager WE, Kalus JS, et al. Management of bleeding and reversal strategies for oral anticoagulants: clinical practice considerations. Am J Health Syst Pharm 2013;70:1914-29. 33. Yorkgitis BK, Ruggia-Check C, Dujon JE. Antiplatelet and anticoagulation medications and the surgical patient. 2014;207:95101. 34. Parker RI. Etiology and significance of thrombocytopenia in critically ill patients. Crit Care Clin 2012;28:399-411. 35. Wang HL, Aguilera C, Knopf KB, et al. Thrombocytopenia in the intensive care unit. 2013;28:268-80. 36. Rice TW, Wheeler AP. Coagulopathy in critically ill patients. Part 1: platelet disorders. Chest 2009;136:1622-30. 37. Thiele T, Selleng K, Selleng S, et al. Thrombocytopenia in the intensive care unit-diagnostic approach and management. Semin Hematol 2013;50:239-50. 38. Kor DJ, Gajic O. Blood product transfusion in the critical care setting. Curr Opin Crit Care 2010;16:309-16. 39. Ferraris VA, Brown JR, Despotis GJ, et al. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011;91:944-82. 40. Spahn DR, Bouillon B, Cerny V, et al. Management of bleeding

and coagulopathy following major trauma: an updated European guideline. Crit Care 2013;17:R76. 41. Kozek-Langenecker SA. Coagulation and transfusion in the postoperative bleeding patients. Curr Opin Crit Care 2014;20:4606. 42. Gill R. Practical management of major blood loss. Anaesthesia 2015;70(suppl 1):54-7. 43. Dutton RP. Management of traumatic haemorrhage – the US perspective. Anaesthesia 2015;70(suppl 1):108-27. 44. Wang CH, Hsieh WH, Chou HC, et al. Liberal versus restricted fluid resuscitation strategies in trauma patients: a systematic review and meta-analysis of randomized controlled trials and observational studies. Crit Care Med 2014;42:954-61. 45. Carson JL, Grossman BJ, Kleinman S, et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2012;157:49-58. 46. Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev 2012;4:CD002042. 47. Retter A, Wyncoll D, Pearse R, et al. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol 2013;160:445-64. 48. Hess JR. Measures of stored red blood cell quality. Vox Sang 2014;107:1-9. 49. Lacroix J, Hébert PC, Fergusson DA, et al. Age of transfused blood in critically ill adults. N Engl J Med 2015;372:1410-8. 50. Sayah DM, Looney MR, Toy P. Transfusion reactions: newer concepts on the pathophysiology, incidence, treatment, and prevention of transfusion-related acute lung injury. Crit Care Clin 2012;28:363-72. 51. Osterman JL, Arora S. Blood product transfusions and reactions.

Emerg Med Clin North Am 2014;32:727-38. 52. Hart S, Cserti-Gazdewich CN, McCluskey SA. Red cell transfusion and the immune system. Anaesthesia 2015;70(suppl 1):38-45. 53. Rohde JM, Dimcheff DE, Blumberg N, et al. Health careassociated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA 2014;311:1317-26. 54. Toner RW, Pizzi L, Leas B, et al. Costs to hospitals of acquiring and processing blood in the US: a survey of hospital-based blood banks and transfusion services. Appl Health Econ Health Policy 2011;9:29-37. 55. Shander A, Hofmann A, Ozawa S, et al. Activity-based costs of blood transfusions in surgical patients at four hospitals. Transfusion 2010;50:753-65. 56. Grotke O. Coagulation management. Curr Opin Crit Care 2012;18:641-6. 57. Goodnough LT. A reappraisal of plasma, prothrombin complex concentrates, and recombinant factor VIIa in patient blood management. Crit Care Clin 2012;28:413-26. 58. Ferreira J, DeLosSantos M. The clinical use of prothrombin complex concentrate. J Emerg Med 2013;44:1201-10. 59. Spahn DR, Goodnough LT. Blood transfusion 2. Alternatives to blood transfusion. Lancet 2013;381:1855-65. 60. McQuilten ZK, Crighton G, Engelbrecht S, et al. Transfusion interventions in critical bleeding requiring massive transfusion: a systematic review. Transfus Med Rev 2015;29:127-37. 61. Cromwell C, Aledort LM. FEIBA: a prohemostatic agent. Semin Thromb Hemost 2012;38:265-7. 62. Nascimento B, Goodnough LT, Levy JH. Cryoprecipitate therapy. Br J Anaesth 2014;113:922-34. 63. Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeutic

target for bleeding: a review of critical levels and replacement therapy. Transfusion 2014;54:1389-405. 64. Gabay M, Boucher BA. An essential primer for understanding the role fo topical hemostats, sugical sealants, and adhesives for maintaining hemostasis. Pharmacotherapy 2013;33:935-55. 65. Spotnitz WD, Burks S. Hemostats, sealants, and adhesives III: a new update as well as cost and regulatory considerations for components of the surgical toolbox. Transfusion 2012;52:2243-55. 66. Achneck HE, Sileshi B, Jamiolkowski RM, et al. A comprehensive review of topical hemostatic agents: efficacy and recommendations for use. Ann Surg 2010;251:217-28. 67. MacLaren R. Key concepts in the management of difficult hemorrhagic cases. Pharmacotherapy 2007;27(9 pt 2):S93S-102. 68. Guyatt GH, Akl EA, Crowther M, et al. Introduction to the ninth edition: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(suppl 2):S48-52. 69. Goldstein JN, Refaai MA, Milling TJ Jr, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 2015;385:2077-87. 70. Khorsand N, Kooistra HA, van Hest RM, et al. A systematic review of prothrombin complex concentrate dosing strategies to reverse vitamin K antagonist therapy. Thromb Res 2015;135:9-19. 71. Joseph B, Aziz H, Pandit V, et al. Prothrombin complex concentrate versus fresh-frozen plasma for reversal of coagulopathy of trauma: is there a difference? World J Surg 2014;38:1875-81. 72. Levi M, Peters M, Buller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systemic review. Crit Care Med 2005;33:883-90.

73. Yank V, Tuohy CV, Logan AC, et al. Systematic review: benefit and harms of in-hospital use of recombinant factor VIIa for offlabel indications. Ann Intern Med 2011;154:529-40. 74. Levi M, Levy JH, Andersen HF, et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2011;363:1791-800. 75. Manjuladevi M, Vasudeva Upadhyaya KS. Perioperative blood management. Indian J Anaesth 2014;58:573-80. 76. Ranucci M. Hemostatic and thrombotic issues in cardiac surgery. Semin Thromb Hemost 2015;41:84-90. 77. da Luz TL, Nascimento B, Rizoli S. Thromboelastography (TEG®): practical consideration on its clinical use in trauma resuscitation. Scand J Trauma Resusc Emerg Med 2013;21:29. 78. Hunt H, Stanworth S, Curry N, et al. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma induced coagulopathy in adult trauma patients with bleeding. Cochrane Database Syst Rev 2015;2:CD010438. 79. Ker K, Prieto-Merino D, Roberts I. Systemic review, metaanalysis and meta-regression of the effect of tranexamic acid on surgical blood loss. Br J Surg 2013;100:1271-9. 80. Ker K, Edwards P, Perel P, et al. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative metaanalysis. BMJ 2012;344:e3054. 81. Gando S. Hemostasis and thrombosis in trauma patients. Semin Thromb Hemost 2015;41:26-34. 82. Ward KR. The microcirculation: linking trauma and coagulopathy. Transfusion 2013;53:S38-47. 83. Godier A, Samama CM, Susen S. Plasma/platelets/red blood cell ratio in the management of the bleeding traumatized patient: does it matter? Curr Opin Anaesthesiol 2012;25:242-7. 84. Kutcher ME, Kornblith LZ, Narayan R, et al. A paradigm shift in

trauma resuscitation: evaluation of evolving massive transfusion practices. JAMA Surg 2013;148:834-40. 85. Malone DL, Hess JR, Fingerhut A. Massive transfusion practices around the globe and a suggestion for a common massive transfusion protocol. J Trauma 2006;60:S91-96. 86. Lal, DS, Shaz BH. Massive transfusion: blood component ratios. Curr Opin Hematol 2013;20:521-5. 87. McDaniel LM, Etchill EW, Raval JS, et al. State of the art: massive transfusion. Transfusion Med 2014;24:138-44. 88. Holcomb JB, Del Junco DJ, Fox EE, et al. The prospective, observational multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time varying treatment with competing risks. JAMA Surg 2013;148:127-36. 89. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 2015;313:471-82. 90. Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010;376:23-32. 91. Roberts I, Prieto-Merino D, Manno D. Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial. Crit Care 2014;18:685. 92. Roberts I, Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011;377:1096-101. 93. Roberts I, Prieto-Merino D. Applying results from clinical trials: tranexamic acid in trauma patients. J Intensive Care 2014;2:56. 94. Roberts I, Shakur H, Coats T, et al. Effect of tranexamic acid on

mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ 2012;345:e5839. 95. Roberts I, Shakur H, Coats T, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess 2013;17:1-79. 96. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma 2005;59:8-15. 97. Rizoli SB, Boffard KD, Riou B, et al. Recombinant activated factor VII as an adjunctive therapy for bleeding control in severe trauma patients with coagulopathy: subgroup analysis from two randomized trials. Crit Care 2006;10:R178. 98. Hauser CJ, Boffard K, Dutton R, et al. Results of the CONTROL trial: efficacy and safety of recombinant activated factor VII in the management of refractory traumatic hemorrhage. J Trauma 2010;69:489-500. 99. Dutton RP, Parr M, Tortella BJ, et al. Recombinant activated factor VII safety in trauma patients: results from the CONTROL trial. J Trauma 2011;71:12-9. 100. Bosch J, Thabut D, Bendtsen F. Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: a randomized, double-blind trial. Gastroenterology 2004;127:112330. 101. Bosch J, Thabut D, Albillos A, et al. Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: a randomized controlled trial. Hepatology 2008;47:1604-14. 102. Planinsic RM, van der Meer J, Testa G, et al. Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease. Liver Transpl

2005;11:895-900. 103. Caldwell SH, Chang C, Macik BG. Recombinant factor VII (rVIIa) as a hemostatic agent in liver disease: a break from convention in need of controlled trials. Hepatology 2004;39:592-8. 104. Abdul-Kadir R, McLintock C, Ducloy AS, et al. Evaluation and management of postpartum hemorrhage: consensus from an international expert panel. Transfusion 2014;54:1756-68. 105. Butwick AJ, Goodnough LT. Transfusion and coagulation management in major obstetric hemorrhage. Curr Opin Anaesthesiol 2015;28:275-84. 106. Ducloy-Bouthors AS, Jude B, Duhamel A, et al. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care 2011;15:R117. 107. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-20.

Chapter 25 Laboratory Testing with

Anticoagulation Tyree H. Kiser, Pharm.D., FCCP, FCCM, BCPS

LEARNING OBJECTIVES 1. Describe the most common laboratory methods for evaluating anticoagulation in critically ill patients. 2. Discuss the potential limitations of laboratory tests used to evaluate anticoagulation in critically ill patients. 3. Identify patient characteristics common to critically ill patients that should be considered when interpreting laboratory tests used for monitoring anticoagulation. 4. Compare and contrast different laboratory methods used to evaluate commonly prescribed anticoagulants.

ABBREVIATIONS IN THIS CHAPTER ACT

Activated clotting time

aPTT

Activated partial thromboplastin time

DOAC

Direct-acting oral anticoagulant

DTI

Direct thrombin inhibitor

dTT

Dilute thrombin time or plasma diluted thrombin time

ICU

Intensive care unit

LMWH

Low-molecular-weight heparin

MA

Maximum amplitude

PT

Prothrombin time

ROTEM

Rotational thromboelastography

TEG

Thromboelastography

TT

Thrombin time

UFH

Unfractionated heparin

VTE

Venous thromboembolism

INTRODUCTION Coagulation tests are often used within critical care medicine. Accurate measurement of the coagulation status can be crucial for the correct treatment of an intensive care unit (ICU) patient. Coagulation tests may be used to evaluate patients for coagulation abnormalities or comorbidities, for diagnostic purposes, or to monitor antithrombotic medications.1 Many variables, including critical illness, must be considered when interpreting coagulation tests in the ICU because they may affect the accuracy of test results.2 This chapter will review most of the coagulation tests available for critical care clinicians. When interpreting information provided within this chapter, it is important to understand that different instruments and testing approaches are used depending on the health care institution. Therefore, tests may be used differently, and variability in reported values should be expected when comparing information provided within this chapter, data from available clinical studies, and laboratory results in your clinical setting. Of note, laboratory tests used for monitoring anticoagulants are by definition a surrogate marker for anticoagulation outcomes. In many situations, laboratory tests and therapeutic ranges have been developed according to in vitro mechanisms and have not been formally evaluated in clinical trials to determine their correlation with definitive outcomes

such as thromboembolism or bleeding. It is critical that interpretation of the results from the coagulation tests used be confirmed with the clinical scenario observed at the bedside.

METHODS OF COAGULATION TESTING Coagulation testing can be conducted by different methodologies, with most tests being either functional or antigenic (Box 25.1). Clot-based assays typically use citrated platelet-poor plasma. The testing is performed with the use of re-agents at normal body temperature (37°C). Some tests (e.g., activated partial thromboplastin time [aPTT]) require a short incubation period to allow activator and phospholipids to interact with plasma factors. The clotting end point is determined by changes in light scattering because of turbidity induced by fibrin formation.3 Chromogenic versions of assays use a color formed after the addition of reagent to determine the anticoagulant activity present (Figure 25.1). Antibody-related assays incorporate an antigen/antibody complex to measure a specific antigen or antibody present within the patient sample. Some assays must be performed by a laboratory, whereas others can be conducted at or near the bedside (commonly called point-of-care testing). Point-of-care testing, which has increased in availability and popularity, is often used in operating rooms and in some critical care specialty units. As a rule, point-of-care testing results should be evaluated in comparison with central laboratory results. Bias in results should be expected, especially at the low and high ends of the testing range for many tests.3

Box 25.1. Coagulation Test Methodology3 Functional tests: Clotting end point – Adding patient plasma to reagent(s) and then determining the amount of clot formation. Examples: PT (prothrombin time), aPTT (activated partial thromboplastin time), ACT (activated clotting time), TT (thrombin time), fibrinogen, factor

activity Chromogenic testing – Adding patient plasma to reagent(s) and then determining the amount of color formation. Examples: Factor activity, anti-Xa, antithrombin activity Aggregation – Adding patient plasma (platelet poor or containing platelets) to platelets and/or agonist(s) and measuring light scattering (agglutination) or platelet clumping (aggregation). Examples: Heparin-induced thrombocytopenia, platelet function Antigenic tests: Immunologic – Adding patient plasma or serum to beads or microwells containing target antigen or antibody and then assessing color changes, changes in agglutination, hemagglutination, etc. Examples: Fibrinogen, factor activity, Ddimer, heparin-induced thrombocytopenia, antithrombin

Most screening coagulation assays (e.g., prothrombin time [PT] or aPTT) are based on how rapidly fibrin clots form in patient samples. The type of activator used will trigger different coagulation pathways. For example, thromboplastin is used to trigger the extrinsic pathway, kaolin is used to trigger the intrinsic pathway, and viper venoms are used to trigger the common pathway. There are different methods of detecting the formation of fibrin in these assays, including visual, mechanical, photo-optical, and viscoelastographic techniques (Figure 25.2).

REGULATORY REQUIREMENTS FOR CLINICAL USE OF LABORATORY TESTS Clinical Laboratory Improvement Amendments (CLIA) regulations govern the use of laboratory tests in patients. The U.S. Food and Drug Administration (FDA)-approved commercially available tests must comply with these regulations. However, in many coagulation tests,

institutions must individually determine the accuracy, precision, and reportable ranges. Any modifications to an FDA-approved test, the use of a “for research purposes only test,” or the use of a homegrown test requires that the laboratory evaluate the performance of the assay according to the CLIA regulations, with additional testing for sensitivity and specificity.

OBTAINING A RELIABLE SAMPLE FOR TESTING Acquiring and appropriately delivering a patient sample to the laboratory for analysis is a critical step in evaluating anticoagulant intensity. The sample should be free of tissue and intravenous solutions delivered through indwelling lines. Obtaining a proper sample is most problematic in patients with a central venous catheter, particularly those being used for extracorporeal circuits or that have large volumes of medication infusions running through them. If syringes are used for collecting the sample, immediate (within 1 minute) transfer to the collection tube will minimize alterations in coagulation test results. Adequate techniques should be used to avoid dilution of the sample or contamination with infusing medications during the collection process. Samples should not be placed on ice because this can affect factor and platelet function. Withdrawal and waste of 5–10 mL of volume may be necessary before a proper blood draw can be obtained. Once the sample is obtained, it should be sent to the laboratory quickly and preferably tested within 2 hours. Prolonged incubation at room temperature for greater than 24 hours can result in significantly altered activity of clotting factors.4 The appropriateness of a blood draw should be considered any time a result is discordant with what is being observed clinically in a patient. If the test is believed to be misrepresenting the clinical scenario, repeating a test may be necessary before making clinical decisions.

X x Heparin + ATIII Heparin -f

x X

+ ATIII *ATIIIHeparm X

^

Heparin -t - ATIII

X

Figure 25.1 Chromogenic anti-Xa test. Figure 25.1 depicts how the chromogenic anti-Xa assay is performed. Blood activates the patient’s antithrombin III, and they both act to deactivate the factor X. As heparin level in the blood increases, more factor X is deactivated, and the less active Xa is left in the test tube. Factor II (marked with a yellow marker) is added into the test tube. The active Xa remaining interacts with the factor II, and the yellow marker is released. This is then measured. The amount of heparin is deduced from the amount of color change.

BASELINE LABORATORY STUDIES FOR PATIENTS INITIATED ON ANTICOAGULATION All critically ill patients should have certain laboratory tests measured before initiation of anticoagulation therapy. At a minimum, a baseline complete blood cell count to evaluate platelets, hemoglobin, and hematocrit and an assessment of renal function and hepatic function tests should be considered. Platelet monitoring should continue during therapy for patients taking heparin products (see Chapter 23, “Prevention and Treatment of Venous Thromboembolism”). Laboratory tests to evaluate for thrombophilias such as lupus anticoagulant (e.g.,

dilute Russell viper venom time and lupus-sensitive PTT) should be considered in patients with an unexplained thrombosis in a vein or artery, recurrent miscarriages, or an unexplained prolonged PTT test. For many anticoagulant tests, it is important to determine whether the patient’s baseline values are within normal limits so that clinicians can determine whether alterations in the target therapeutic range or additional testing is needed. These include the PT/international normalized ratio (INR) (if initiating Coumadin) and the aPTT (if initiating UFH or a direct thrombin inhibitor [DTI]). The patient’s weight and creatinine clearance should be measured for any weight-based medications that are renally eliminated. The decision to monitor these laboratory values and the frequency of monitoring throughout anticoagulation therapy should be considered depending on the anticoagulant chosen, laboratory test, and clinical situation. Physical examination findings, ultrasonography, Doppler, computed tomography, or other imaging studies may be useful for evaluating the presence or extension of thromboembolism and should be evaluated as appropriate in addition to coagulation tests to assist with anticoagulant choice, dosing, and monitoring strategies.

ALTERATIONS IN COAGULATION TESTING When interpreting the results of a coagulation test, it is critically important to determine whether the test is providing an accurate assessment of the patient’s coagulation status. To do this, everything from the time of the blood draw until the result is reported from the laboratory must be evaluated. Most blood samples collected for coagulation testing will be placed in a tube containing citrate, which inhibits coagulation by binding to calcium. As mentioned previously, it is preferred to use systems that allow for direct transfer from a vascular device to the collection tube. In addition to alterations in results because of improper acquisition or handling of the sample, patient factors or conditions can affect laboratory tests. Common conditions affecting PT and aPTT are listed in Table 25.1. In certain situations listed in Table 25.1, the CLSI (Clinical & Laboratory Standards

Institute) guidelines require special processing of specimens. For example, in specimens from patients with polycythemia or hematocrit values greater than 55%, a spurious prolongation of coagulation studies may occur because of a relative excess of citrate anticoagulant in relation to plasma volume. If the citrate concentration is not adjusted in this situation, citrate may bind to calcium added to initiate the clotting process and slow its initiation, leading to prolonged PT and aPTT.5

Figure 25.2 Methods of clot detection. Mechanical: There are different mechanical methods, but these are either based on the movement of a metal ball between two magnets or based on the movement of two probes inserted within the patient sample. Fibrin formation restricts movement of the magnetic

ball or movement of the probe in relation to each other, resulting in a finite end point, which is recorded as the clotting time. Photo-optical: With this technique, fibrin formation is detected by the change in optical density or turbidity of the sample. The results are usually recorded as the time to clot; however, some analyzers also provide a curve of clot formation. Viscoelastic: With this technique, a probe is inserted into a cup containing the patient sample. Then, either the probe is rotated within the cup or the cup is rotated around a fixed probe. Changes in the movement of the cup in relation to the probe result in a tracing that reflects the kinetics of fibrin formation and fibrinolysis, with numerical measurements pertaining to these kinetics and the strength of the resulting fibrin clot.

The complex interplay of patient, sample, and laboratory environment factors makes communication with the laboratory an important part of patient care. Alerting laboratory staff to the anticoagulant being monitored and the condition of the patient may provide them with enough information to allow for sample alteration (e.g., dilution of sample), additional testing, or correction of values. They can also provide clinicians with specific information regarding the reagents being used and their sensitivity to outside influences commonly occurring in critically ill patients.

PT AND INR The PT is a measure of the extrinsic and final common pathway of clotting. This consists of tissue factor, fibrinogen (I), and coagulation factors II, V, VII, and X (Figure 25.3). In hospitalized patients, the PT is done on a venipuncture-acquired sample and analyzed using a laboratory-based coagulation analyzer. In the test, clotting is initiated by recalcifying citrated patient plasma in the presence of thromboplastin. The PT measures the time it takes plasma to form a fibrin clot after the addition of calcium and thromboplastin. The clot can be detected by visual, optical, or electromechanical means. The PT result is expressed in seconds. Variations in PT occur because of the source of thromboplastin and the type of instrument used for clot detection. Therefore, thromboplastin reagent sensitivity is expressed using the term international sensitivity index (ISI). The INR was created as a mechanism to adjust for variation in PTs because of

thromboplastin reagent sensitivity. The equation for the INR is as follows:

The PT/INR is sensitive to the vitamin K– dependent clotting factors (e.g., factors II, VII, and X); therefore, it is commonly used to evaluate the anticoagulant effects of vitamin K antagonists. Of note, the INR describes only the activity of factors II, VII, and X, and not factor IX or protein C and S. Most PT reagents also contain heparin-binding chemicals to block the effect of unfractionated heparin (UFH), lowmolecular-weight heparin (LMWH), and fondaparinux. However, at high heparin levels, the heparin binders may become saturated, and the PT may be prolonged.

Table 25.1 Common Diseases or Conditions Affecting the Accuracy of PT or aPTT Results Increased PT and/or aPTT Low-volume sample (increased citrate/ plasma ratio) Elevated hematocrit (> 55%) Prolonged time between draw and analysis Hemodilution Contamination with infusing medication (e.g., heparin, citrate) Hypothermia Deficiency in factor II, V, VII, VIII, IX, X, XI, or XII Hereditary factor deficiencies Antiphospholipid antibodies Hepatic disease Consumptive coagulopathy

Decreased PT and/or aPTT Decreased hematocrit (< 25%) Elevated calcium concentrations Administration of plasma products (e.g., FFP, cryoprecipitate, prothrombin complex concentrates)

Disseminated intravascular coagulation Excess PRBC transfusion Citrate administration Volume expansion (e.g., starches) Medications: Daptomycin Activated protein C Direct thrombin inhibitors Heparin or LMWH Thrombolytics

aPTT = activated partial thromboplastin time; PRBC = packed red blood cell; PT = prothrombin time.

For most patients taking warfarin, the goal steady-state INR for most indications is 2–3. The full anticoagulant effect of warfarin is delayed until the normal clotting factors are eliminated from the circulation. The INR is less accurate during the initial few days of warfarin therapy because the INR is most reflective of reductions in factor VII, which has a much shorter half-life than factor II. This may lead a clinician to assume that a greater degree of anticoagulation is present in the patient than actually exists. In contrast, as warfarin is held or removed, an increase in factor VII activity may have a reduction in INR that underestimates the degree of anticoagulation present. Inaccuracies can also occur because of errors in ISI reporting or use and differences in laboratory instrumentation. Comorbidities such as hepatic disease and the presence of lupus anticoagulant can prolong the INR. The use of anticoagulants such as DTIs can prolong the PT/INR in a dose-dependent fashion. The DTIs interact with the coagulation test, and of note, a prolonged PT/INR is not indicative of their anticoagulant effect. The elevation in INR can be significant, particularly with the parenteral anticoagulants, with argatroban causing greater increases than bivalirudin, lepirudin, and desirudin. The effects

of dabigatran on the INR are less pronounced.

CHROMOGENIC FACTOR X ACTIVITY The chromogenic factor X assay is an alternative to the INR for monitoring patients taking warfarin. The chromogenic factor X assay is a phospholipid-independent test, which prevents it from being altered by coagulation abnormalities such as lupus anticoagulant. In this case, the chromogenic factor X activity can be measured at same interval as the INR would typically be completed. Chromogenic factor X results are reported as a percentage of normal activity and are inversely related to INR values. A chromogenic factor X level of 20%–25% approximates an INR of 3, and a level of 40%–45% approximates an INR of 2. The main drawbacks of the test include its expense and availability. Results may take 24–72 hours depending on the availability of the laboratory within the institution. In addition to using it in patients with altered INR values at baseline, the chromogenic factor X activity assay may be useful for monitoring warfarin in critically ill patients who are taking DTIs and transitioning to warfarin therapy. Interpretation of the INR can be difficult in these patients because DTIs inhibit thrombin and prevent fibrin clot formation. This results in a falsely elevated PT and INR in a concentrationdependent manner. Because DTIs do not affect factor X, a potential option to evaluate the effects of warfarin without having to hold DTI therapy is to use the chromogenic factor X assay. The chromogenic factor X assay is capable of evaluating the effects of warfarin while excluding the anticoagulant effects of DTIs. Similar to patients on warfarin monotherapy, a chromogenic factor X level of less than 45% predicts an INR of 2 or greater with around 80% specificity and 60%– 90% sensitivity.6,7 Once this level is achieved, a therapeutic INR for warfarin should be verified by discontinuing the DTI and measuring a PT/INR after the DTI has been appropriately cleared (typically 4 hours or more after discontinuing the DTI) from the systemic circulation. Although this approach is likely to be reasonable for most critically ill patients, the reliability of the chromogenic factor X assay is diminished

in patients with hepatic dysfunction or vitamin K deficiency.

ACTIVATED PARTIAL THROMBOPLASTIN TIME The aPTT is a global assay of coagulation. The aPTT can be used to screen for inhibitors and deficiencies of the intrinsic pathway (prekallikrein, high-molecular-weight kininogen, factors XII, XI, IX, and VIII) and the final common pathway (factors II, X, V, prothrombin) and fibrinogen (Figure 25.3). The aPTT is performed by recalcifying citrated plasma in the presence of a thromboplastic material that does not have tissue factor activity and a negatively charged substance (e.g., kaolin), which results in contact factor activation, thereby initiating coagulation by the intrinsic pathway. Several variables can affect the aPTT including sample timing, site of sample, citrate concentration, and sample handling and processing time (Table 25.1). The reagents used for the aPTT vary in type of contact activator, phospholipid composition, and concentration. Deficiency in all clotting factors except factor VII can cause prolongation of the aPTT. The relationship between the factor activity in the blood and the aPTT result is logarithmic. For elevated baseline aPTTs, a lower level of change is needed for additional prolongation.

Figure 25.3 The coagulation cascade delineating the intrinsic, extrinsic, and common pathways. Used with permission from Robert MacLaren, Chapter 24, page 470. The aPTT is the most common test used for monitoring UFH therapy, although the evidence for adjusting the UFH dose to maintain a therapeutic aPTT range is based on a post hoc analysis of a prospective descriptive study.8,9 Most patients evaluated (n = 162) were receiving heparin therapy for venous thromboembolism (VTE). Heparin was titrated to an aPTT between 1.5 and 2.5 times control values, and the analysis showed that an aPTT greater than 1.5 times control was associated with reduced recurrent VTE.9 Therefore, this goal aPTT range became widely accepted in clinical practice. Unfortunately, this therapeutic range has not been confirmed by a randomized clinical trial, and it does not account for significant variability in the aPTT test observed both within and between institutions. Because of this, the goal therapeutic aPTT range varies, depending on the aPTT reagent, the instrument, and the reagent’s responsiveness to each lot of UFH. Therefore, the traditional reported therapeutic range of 60–80 seconds (e.g., about 1.5–2.5 times control) cannot accurately be used within hospital settings without evaluation of a specific aPTT reagent’s sensitivity to heparin. The therapeutic range is calculated using a regression analysis evaluating values obtained from samples containing known levels of heparin and samples from patients on UFH therapy by aPTT versus the anti-factor Xa (anti-Xa) activity (e.g., heparin levels). In the original study described previously, the investigators established that an aPTT ratio of 1.5–2.5 corresponded to a heparin level of 0.2–0.4 international units/ mL by protamine titration and a heparin level of 0.3–0.7 international units/mL measured by anti-Xa assay.9 Therefore, most institutions set their aPTT goal range for VTE at 0.3–0.7 international units/mL of anti-Xa activity (Figure 25.4).8 The goal therapeutic aPTT range for other UFH

indications is less clear, which commonly results in a variety of goal ranges depending on the type of critically ill patient and the therapeutic end points. The sensitivity of a reagent will determine the aPTT response, with more sensitive reagents resulting in steeper regression slopes and higher aPTT goal ranges. It is important for institutions to use plasma samples from patients on heparin treatment rather than simply using spiked heparin samples because using spiked samples often results in therapeutic ranges higher than those calibrated from actual patient samples. The heparin therapeutic range needs to be reevaluated with each new lot number of reagent or change in reagent manufacturer. If there is a clinically significant change in the therapeutic range (e.g., greater than 5–10 seconds), adjustment of the therapeutic range reported by the laboratory is needed. In addition, protocols used throughout the health system should be adjusted as appropriate (Figure 25.5). Monitoring anticoagulants by the aPTT can be problematic for many reasons and may be reflective of factors independent of the anticoagulant being used. As mentioned previously, results vary depending on the aPTT reagent and lot number. The aPTT can be shortened or prolonged because of deficiency or excess of coagulation factors. In addition, the phospholipids within the assay make it vulnerable to interference from lupus inhibitors. Discordance between anti-Xa activity and aPTT results can occur in a significant number of hospitalized patients on UFH. As seen in Figure 25.6, patients with a goal aPTT measurement may actually have a sub- or supratherapeutic anti-Xa level. Conversely, patients with an aPTT outside the goal range may actually have a therapeutic anti-Xa level. For this reason, many institutions have changed to monitoring UFH according to anti-Xa results; however, consideration of the concordance or discordance with aPTT values in critically ill patients may provide a clearer picture of global coagulation and correlate better with clinical outcomes. In a recent study of 2,321 paired values from 539 patients, 42% of data pairs had a high aPTT value relative to the anti-Xa value. Patients with elevated baseline PT/INR or aPTT often had disproportionate relative prolongation of the aPTT. Patients with at least two consecutive high aPTT to anti-Xa values had increased 21-day major bleeding (9% vs.

3%; p = 0.0316) and 30-day mortality (14% dead vs. 5% dead at 30 days; p = 0.0202) compared with patients with consistently concordant values.10 The results of this study call for the potential need to evaluate both tests at least initially to identify patients with significantly discordant aPTT and anti-Xa findings to proactively determine whether they may be at risk of bleeding or thrombosis.

Figure 25.4 Calibrating the goal activated partial thromboplastin time range that corresponds to an anti-Xa activity of 0.3–0.7 for unfractionated heparin.

Standard - Dose Heparin Therapy ( DVT/ PE Treatment) Goal aPTT range is equivalent to heparin level of 0.3 -0.7 units/

Lower -Dose Heparin Therapy ( ACS/ MI, Stroke, AF, Other) Goal aPTT Range is equivalent to 1.5-2.5 times baseline aPTT

mL aPTT( s) < 40

aPTT( s)
200

>

(check q6hr), then decrease infusion

by 4 units/ kg / hr

decrease in-fusion by 2 units/kg/ hr

Hold infusion for 1hour, decrease infu-sion by 3 units/ kg / hr >

Send stat aPTT, contact physician, HOLD infusion until aPTT < 200 ( check q6hr ); then decrease infusion by

4 units /kg /hr

ACS = acute coronary syndromes; AF = atrial fibrillation; DVT = deep venous thrombosis; Ml = myocardial infarction; PE = pulmonary embolism; q = every.

Figure 25.5 Creation of goal aPTT targets and titration algorithms according to the correlation between anti-Xa and activated partial thromboplastin time results.

A

150.0

125.0

> |

r

Oral p-blocker Aspirin 81mg daily P2YU inhibitor MD ACL inhibitor ( or ARD) Statin Stoolsoftener

Figure 33.1 Treatment algorithm for management of non–ST-segment elevation acute coronary syndrome. a

If the last dose of enoxaparin is given within 8 hours of PCI, no additional anticoagulant is needed. If the last dose of enoxaparin is given 8–12 hours before PCI, an additional IV bolus dose of 0.3 mg/kg of enoxaparin should be given at the time of PCI. bBivalirudin

should not be used in this setting if a glycoprotein IIb/IIIa inhibitor is being used because the patient has high-risk features (e.g., positive troponin). cData dUse

for high-dose tirofiban in this setting are based on surrogate end point data.

of upstream or early glycoprotein IIb/IIIa inhibitor therapy may be preferred only in patients who have not, or will not, receive a loading dose of an oral P2Y12 inhibitor or

cangrelor before PCI. ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; D/C = discontinue; IV = intravenous; LD = loading dose; MD = maintenance dose; NTG = nitroglycerin; PCI = percutaneous coronary intervention; SC = subcutaneous; SL = sublingual; UFH = unfractionated heparin.

The role of GP IIb/IIIa inhibitors has become more complex in the past decade. Currently, use of these agents should be reserved for patients with high-risk features such as an elevated troponin.2,102 Once the decision to use a GP IIb/IIIa inhibitor is made, the timing of initiating the agent also needs to be considered. One approach is to provide an upstream GP IIb/IIIa inhibitor, which is initiating the agent early, several hours or even days before PCI. The other approach is waiting to administer the GP IIb/IIIa inhibitor at the time of PCI. These approaches have been compared in the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation Acute Coronary Syndrome) trial.120 In this trial, upstream GP IIb/IIIa inhibitor use did not improve clinical outcomes but did produce more major bleeding. Therefore, there seems to be limited justification for this approach. One instance when the upstream approach may be rational is when patients with high-risk features are not planned to receive P2Y 12 therapy until the time of PCI. The delayed use of P2Y 12 inhibitors is occasionally employed by clinicians or institutions that prefer to know when the coronary anatomy is amendable to PCI and when CABG surgery has been ruled out. The justification follows that this avoids the need to wait 5–7 days for platelet recovery from P2Y 12 inhibitor therapy. Anticoagulant therapy with UFH in patients with NSTE ACS using an invasive approach is a class I, LOE C recommendation.2 Enoxaparin was compared with UFH in patients with NSTE ACS with an invasive approach in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) trial.121 The overall results of the trial showed no difference between the agents in the incidence of death or MI and showed an increase in major bleeding in patients receiving enoxaparin. Of interest, 39% of

patients in the trial received both agents sometime during the study. It obviously becomes difficult to determine how two agents are different if patients receive both agents. When patients who received only UFH or enoxaparin throughout the study are analyzed, there is a significant reduction in death and MI with the use of enoxaparin compared with UFH, without an increase in major bleeding. Patients who have received their last subcutaneous dose 8–12 hours before PCI, or have received less than two subcutaneous doses of enoxaparin, should receive an additional 0.3-mg/kg intravenous bolus dose at the time of PCI to ensure adequate anticoagulant effect (class I, LOE B).2,121 Although fondaparinux is discussed in the ACC/AHA NSTE ACS guidelines, use in the United States with PCI is limited. In the Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-5 trial, patients undergoing PCI receiving fondaparinux have significantly higher rates of catheter thrombosis than do patients receiving enoxaparin.122,123 Therefore, using fondaparinux alone in patients undergoing PCI is a class III, LOE B recommendation.2 If patients are receiving fondaparinux and need to receive PCI, additional anticoagulant therapy with UFH is required. The dose of UFH at the time of PCI differs depending on whether the patient is taking a GP IIb/III inhibitor (85 units/kg) or not (60 units/kg). Additional doses of UFH may need to be given during the procedure passed on the ACT. Therefore, in patients for whom it is expected that PCI will be needed, fondaparinux is typically avoided. Bivalirudin is also an alternative for anticoagulant therapy in patients with NSTE ACS with an early invasive approach (class I, LOE B).2 Evidence for using bivalirudin in these patients comes from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial.124 Compared with many other ACS trials of AT, the ACUITY trial used a quadruple composite end point (death, MI, unplanned revascularization for ischemia, and major bleeding) and a fairly liberal definition for major bleeding. Consequently, a 5-cm bruise was counted as equal to a death or MI as an end point event. Regardless, patients receiving a heparin (UFH or LMWH) and a GP IIb/IIIa inhibitor had efficacy and safety similar to patients receiving bivalirudin and a GP

IIb/IIIa inhibitor. Therefore, the ACUITY trial showed that bivalirudin and a GP IIb/IIIa inhibitor therapy should not be used together because of a lack of any benefit, and this approach would significantly increase costs compared with a heparin and a GP IIb/IIIa inhibitor. The group receiving bivalirudin alone with only a “bailout” GP IIb/IIIa inhibitor had a reduction in the primary end point compared with a heparin and a GP IIb/IIIa inhibitor, which was driven by a reduction in major bleeding (3.0% vs. 5.7%; p 120 min

No

Yes

Yes

Fibrinolytic therapy contraindicated

Reperfusion with fibrinolysis

Reperfusion with primary PCI

Stress testing with reperfusion therapy with primary PCI for selected patients

P2Y12 inhibitor LD

r

'

IVUFH, or IV bivalirudin, or IV enoxaparin

"

ClopidogreILD1 r

'

GPIIb/llla inhibitor* unless bivalirudin Is selected 1

r

IV, then SC enoxaparin11, or IV UFH, or IV, then SC fondaparinuxe

D/C anticoagulant after PCI D / C abciximab 12 hr after PCI D /C eptifibatide or tirofiban 18-24 hours after PCI

r

D/C UFH after at least 48 hr Continue enoxaparin or fondaparinux until patient discharge or up to 8 days

'

Oral p -blocker Aspirin 81 mg daily P2Y2 inhibitor MD ACE inhibitor (or ARB) Statin

Oral p-blocker Aspirin 81mg daily ACE inhibitor ( or ARB) Statin

Figure 33.2 Treatment algorithm for management of STsegment elevation myocardial infarction. aA

clopidogrel loading dose has not been evaluated in patients > 75 years receiving fibrinolysis; therefore, the risk of bleeding in these patients is unknown. bThe

first subcutaneous dose of enoxaparin should follow within 15 min of the intravenous

dose in this setting. cThe

first subcutaneous dose of fondaparinux is given 24 hr after the intravenous dose in this setting. dEnoxaparin eAbciximab

is not mentioned in this setting in the current guidelines.

has the highest level of evidence for use in this setting.

There are decades of experience with the use of UFH as anticoagulant therapy in patients undergoing primary PCI for STEMI (class I, LOE C).1 Because of how rapid PCI needs to occur in the treatment of STEMI and because anticoagulant therapy is not typically needed post-procedure, bolus doses are all that may be required. If a GP IIb/IIIa inhibitor is also being given, a bolus dose of 50–70 units/kg intravenously is recommended to achieve a therapeutic ACT of 200– 250 seconds. If a GP IIb/IIIa inhibitor is not being used, a higher dose of 70–100 units/kg intravenously is recommended to achieve a therapeutic ACT of 250–300 seconds with the HemoTec device or 300– 350 seconds with the Hemochron device. Bivalirudin use in primary PCI is supported by the HORIZONS (Harmonizing Outcomes with Revascularization and Stents) trial.137 Using bivalirudin alone had similar efficacy with significantly less major bleeding than did using a heparin and a GP IIb/IIIa inhibitor (4.9% vs. 8.3%; p alteplase > reteplase.141 Agents that are more fibrin-specific may have an efficacy and safety advantage. A more fibrin-specific agent would be expected to have better efficacy because the occluding thrombus is mainly composed of fibrin, and activity on free fibrinogen would not provide benefit. This may be especially true in an “older” thrombus that is more than 2 hours old in which more fibrin would be incorporated in the thrombus. There may also be less bleeding with a fibrin-specific agent because fewer fibrin degradation products, which have antithrombotic activity, are formed by not breaking down both fibrin and fibrinogen. This may also allow more free fibrinogen available for use for potential bleeding episodes. It remains to be determined whether the fibrin specificity of a fibrinolytic agent affects clinical outcomes. The significantly less major bleeding (not ICH), need for transfusion, and reduced mortality in patients presenting within 4–6 hours after symptom onset with the use of tenecteplase compared with alteplase suggest the potential for fibrin specificity to affect outcomes, but this is not definitive.142 Although alteplase had been the fibrinolytic of choice for more than a decade, the newer bolus-only agents provide easier use and less potential for dosing errors. Despite the worldwide experience with fibrinolytic therapy, there are limitations that must be considered. Regardless of the fibrinolytic agent used, patency (TIMI grade 2 and 3 flow) is restored in 60%–85% of patients, but only 50%–60% of patients achieve full myocardial reperfusion (TIMI grade 3 flow).143,144 Even if optimal myocardial blood

flow is achieved, fibrinolytic therapy has a reocclusion rate of 10%– 15%. Fibrinolytic therapy is associated with a higher rate of ICH than is antithrombotic therapy or primary PCI (see Box 33.1). The incidence of ICH has been estimated to occur in 1 in 150–200 treated patients; however, the incidence was slightly higher in the GUSTO-III trial, occurring in about 1 in 100 treated patients.142,145,146 Patients with ICH on fibrinolytic therapy is typically a catastrophic event, resulting in death or disabling stroke. Adjunctive Antithrombotic Therapy As with all other management strategies for ACS, patients receiving fibrinolysis for STEMI should also receive a loading dose of chewable aspirin (class I, LOE A), followed by 81 mg daily (class IIa, LOE B).1 Using DAPT with fibrinolysis is more limited than with other areas of ACS management. Clopidogrel is the only P2Y 12 inhibitor to be studied with the use of fibrinolytics; therefore, prasugrel and ticagrelor should not be used.46,47 In the CLARITY-TIMI 28 trial, DAPT with clopidogrel and aspirin provided significant benefit over aspirin alone in patients with STEMI receiving fibrinolysis as primary reperfusion therapy (15% vs. 21.7%; p 180 mm Hg or diastolic blood pressure > 110 mm Hg) • Prior ischemic stroke more than 3 months ago • Dementia • Traumatic or prolonged cardiopulmonary resuscitation (more than 10 minutes) • Major surgery within 3 weeks • Internal bleeding within 2–4 weeks • Noncompressible vascular punctures • Pregnancy • Active peptic ulcer disease • Oral anticoagulant therapy • Known intracranial pathology not mentioned in absolute contraindications

Using half-dose fibrinolytic therapy with a GP IIb/IIIa inhibitor has been studied extensively.147 Although initial studies showed significant improvement in patency of the infarct-related artery and myocardial perfusion with this combination, no improvement in mortality was shown.148 Although the combination did produce a reduction in MI, this did not lead to a reduction in mortality at 1 year and came at the cost of significantly higher major bleeding. Therefore, this combination is no longer recommended. Many of the initial trials evaluating the efficacy and safety of fibrinolytic therapy used UFH as the anticoagulant. Because of this experience, UFH has a class I, LOE C recommendation from the ACC/AHA for use for 48 hours, or until revascularization, if needed.1 Enoxaparin is also recommended for use in patients with STEMI receiving fibrinolysis (class I, LOE A).1 In the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment, Thrombolysis in Myocardial Infarction-Study 25) trial, enoxaparin provided a significant reduction in death and MI compared with UFH (9.9% vs. 12.0%; p 150 mm Hg or MAP > 130 mm Hg with possibility of increasedICP

“Acute lowering of SBP to 140 is

SBP > 220 mm Hg or DBP > 120 mm Hg

Reduction in SBP recommended

Common first-line Cl:

Ischemic stroke

nicardipine/clevidipine, labetalol

probablysafe" -Current data do support a goal SBP < 140 mm Hg in ICH

In patients post-thrombolysis with tPA:

Initial lowering of SBP by 15% and follow neurologic status

Goal SBP < 180 mm Hg & DBP < 120 mm Hg

SBP lowering < 120 mm Hg may be associated with pooroutcome

Labetalol ( bolus & Cl) and nicardipine typical first-line agents for BP lowering

Subarachnoid hemorrhage

Unsecured aneurysm, SBP > 160 mm Hg (associated with higher rebleed rate)

SBP < 160 mm Hg

Optimal magnitude of BP decrease notestablished Postoperative hypertension

Lackof consensus

Lackof consensus

SBP 180-200 mm Hg ( > 140 mm Hg in neurosurgical patients )

Cardiacsurgery: BP > 140 /90 mm Hg or a

DBP > 110 mm Hg (> 95 mm Hg in neurosurgical patients )

MAP of at least 105 mm Hg

Cardiac surgery: BP > 140 /90 mm Hg ora

SBP al60 mm Hg

Labetalol, nicardipine, clevidipine, sodium nitroprusside, nitroglycerin are typical first-line agents

Addressing reversible causes: pain, anxiety, hypothermia

MAP of at least 105 mm Hg

Lackof consensus

Cl nicardipine may achieve BP goal faster than bolus labetalol dosing

Avoid hydralazine, enalaprilat if possible

MAP 20% from baseline

Acute pulmonary embolism

Labetalol, nicardipine, clevidipine typical first -line agents

SBP > 160 mm Hg

Nitroglycerin if evidence of acute severe pulmonary congestion

MAP 120 mm Hg

CI = continuous infusion; HR = heart rate; ICP = intracranial pressure; tPA = tissue plasminogen activator.

Commonly used agents include intravenous hydralazine and labetalol as first-line options with safety evidence established in pregnant patients, though limited comparative data exist. Nicardipine may also be used in pregnant patients, with a recent meta-analysis showing increased success of blood pressure control in patients receiving nicardipine compared with labetalol, with a more favorable fetal adverse event profile warranting further investigation.56 Sodium nitroprusside may be considered as a last-line agent, though accumulation of cyanide or thiocyanate limits its use. Enalaprilat should be avoided because ACEI agents and angiotensin receptor blocking agents are contraindicated in the second and third trimesters of pregnancy. Esmolol should be avoided unless necessary by another compelling indication (such as aortic dissection) because it crosses the placenta and is associated with fetal bradycardia and persistent βblockade (Figure 37.1).57

Neurologic Injury

Intracerebral Hemorrhage Elevated blood pressure is commonly seen in patients with hemorrhagic stroke. The newly published 2015 guidelines for the management of spontaneous intracerebral hemorrhage (ICH) from the American Heart Association/American Stroke Association (AHA/ASA) contain updated recommendations for blood pressure management. For patients with ICH having an SBP between 150 and 220 mm Hg, the guidelines now state that lowering the SBP to 140 mm Hg is safe and can be effective for improving functional outcome, provided there are no contraindications to acute blood pressure treatment. This is a stronger recommendation for an SBP goal of 140 mm Hg in ICU patients than the previous 2010 guideline. For patients with an SBP greater than 220 mm Hg, the guidelines state that it may be reasonable to consider aggressive reduction in blood pressure, but they do not provide a specific target or goal at this time (Table 37.3).58 Much of this is based on data from the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT1) and the Antihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) and the second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) investigations.59–61 The phase III ATACH II trial is currently enrolling patients to investigate early intensive compared with standard blood pressure control in patients with spontaneous ICH, which may help further guide care in these patients.62 One area where specific blood pressure recommendations remain unclear from a guideline perspective is in patients with oral anticoagulant–associated ICH. Patients with oral anticoagulant– associated ICH present with challenges similar to those in patients with spontaneous ICH, but they also carry consideration for urgent reversal of anticoagulation. Oral anticoagulant therapy not only increases the risk of ICH in general but is also associated with an increased rate of hematoma enlargement.63 A recent review of a large cohort of patients with oral anticoagulant– associated ICH shows decreased hematoma expansion in patients with an SBP less than 160 mm Hg within 4 hours after hospital admission.64 There is no evidence assessing intensive treatment with an SBP goal of less than 140 mm Hg in the setting of

oral anticoagulant–associated ICH, though this may be an appropriate goal for this population. Currently, no specific medication agents are recommended as firstline agents from guideline recommendations (Figure 37.2). It is stated, however, that for patients with an SBP greater than 220 mm Hg, aggressive management of blood pressure reduction with a continuous intravenous infusion should be considered.58 Despite no guidelineendorsed agents of choice, some data suggest certain optimal agents for blood pressure management in ICH. Typical first-line agents for intermittent administration include labetalol and hydralazine, with calcium channel antagonists, sodium nitroprusside, and labetalol as continuous infusion when required.65 Many direct comparisons between agents are small and retrospective and suggest overall similar lowering of MAP and clinical outcomes in patients with labetalol versus nicardipine, with differences dependent on route of administration (i.e., intravenous vs. intermittent bolus) meriting further investigation.66,67 The ongoing ATACH II trial will hopefully shed more light on characterizing nicardipine use in this population. Open-label, single-agent investigations using nicardipine and clevidipine show efficacy in maintaining blood pressure goals in patients with ICH and tolerable safety profiles.68,69 Sodium nitroprusside has fallen out of favor because of its unfavorable adverse effect profile and the availability of newer agents, and, according to one large database review, it may be associated with higher mortality than nicardipine in patients with ICH.69

Preg nan cy / Postpar tu m Hypertensi ve C risis

Hyperterisive Emergency: Persistent HTN: SBP slGO and/or DBP * 110 WITH Ecl a mps ia / Preecl a tnpsia

Immediate BPLowering Reduce BP by 15 25% and/ or Goal SBP 140-150/DBP 90-100

^

Hyperterisive Urgency: SBP 180 and/ or DBP sl20 WITH No End -OrganDamage

Lower BP over 24-48 hr wilh oral antlhypertenslve agents

I Medication Optioes

Cl MayBe Preferable Contmuous Infisitm:

Use with CaUtiOn:

Nicardipine

SodiLim Nitraprusside

Bolus : Labetalol /Hydralazirie

Agents to Avoid: Enalaprilat

Qsmolol

Figure 37.1 Management of hypertensive crisis in pregnancy. BP = blood pressure; HTN = hypertension.

Ir tra cerebral Hemorrhage 1

r

SBP 150-220: lo wer SBP to 140 SBP - 220: co nsid er aggressive BP reduction wilh continuous inhjsion agent

I Medication Oplions

'r Bolus -Dose Labetalol Hydralazine

Continuous Infusion Nicardipine Clevidipine Labetalol

Refractory HTN Sodium Nitroprusside

Figure 37.2 Management of intracerebral hemorrhage.

Ischemic Stroke As in hemorrhagic stroke, elevated blood pressure may be observed in patients with ischemic stroke, which is often higher in those with preexisting hypertension, and management of extreme hypertension must be balanced with maintaining cerebral perfusion to vulnerable tissue. Although an absolute blood pressure target in the acute phase is as yet undefined, elevated blood pressure in patients with ischemic stroke has been associated with poorer outcomes. Observational data show a U-shaped relationship between blood pressure parameters and outcome measures, such as early neurologic deterioration, poor neurologic outcome, and mortality, with poor outcomes associated with extremes of both hypotension (120/70 mm Hg or less) and hypertension (200/110 mm Hg or greater).70,71 The AHA/ASA Guidelines for the Early Management of Patients with Acute Ischemic Stroke

recommend limited blood pressure intervention in the initial 24-hour period after ischemic stroke unless blood pressure is 220/120 mm Hg or greater or there is a concomitant indication for intervention such as myocardial infarction or aortic dissection. Although an absolute numerical target for blood pressure management of hypertension in acute ischemic stroke has yet to be defined, guideline-based treatment calls for an SBP reduction by 15% in concert with clinician judgment in patients with hypertension in early acute ischemic stroke.72 The more recent China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) found that acute blood pressure lowering by 10%–25% in patients with non-recombinant tissue plasminogen activator with SBP 140–220 mm Hg during the first 24 hours of acute ischemic stroke may be safe; however, further investigation is needed before early intervention for patients with a blood pressure of 220/110 mm Hg or less becomes part of routine management in the early phase of ischemic stroke (Table 37.3).73 One subset of patients with ischemic stroke with clearly defined blood pressure goals consists of patients eligible for antifibrinolytic therapy with recombinant tissue plasminogen activator.72,74 Retrospective evaluations of recombinant tissue plasminogen activator in ischemic stroke use suggest that any protocol deviations with thrombolytic use, including blood pressure control, as well as hyperglycemia and baseline coagulation, are associated with an increased incidence of hemorrhage.75–77 Blood pressure control in patients receiving recombinant tissue plasminogen activator should be monitored closely to ensure mitigation not only of hemorrhagic events, but also as a component of overall progress toward optimal outcomes.78,79 For patients eligible for recombinant tissue plasminogen activator therapy, blood pressure should be maintained greater than 185/110 mm Hg before administration using medical therapy (labetalol, nicardipine) as needed. After administration of recombinant tissue plasminogen activator, blood pressure should be monitored frequently to maintain a goal of 180/105 mm Hg or greater for 24 hours.72 Although recommendations can be made for blood pressure thresholds for treatment of extreme hypertension in ischemic stroke

and management of post–recombinant tissue plasminogen activator administration, evidence-based data recommending the specific agents of choice for initial management of hypertension are limited and littered with conflicting findings.66,80,81 The BEST (Beta-Blocker Evaluation in Survival Trial) study found no benefit to administering atenolol or propranolol within 48 hours of ischemic stroke; however, labetalol is often used as a first-choice agent for treatment of hypertension in the ischemic stroke population.65,82 In INWEST (Intravenous Nimodipine West European Stroke Trial), subjects receiving intravenous nimodipine had poorer outcomes, though whether this was related to specific properties of nimodipine itself or the pronounced effect seen in DBP is unclear.80 Retrospective evaluations of the use of continuous infusion nicardipine, another calcium channel antagonist, support its use as an alternative to other antihypertensive agents such as labetalol without evidence of drug class–mediated deleterious effects, though prospective data in ischemic stroke are needed. The pharmacodynamic profile of the only intravenous ACEI, enalaprilat, limits the use of this class of agents in acute hypertension in ischemic stroke.73,83 Although no specific agents are specified in the AHA/ASA Guidelines for the Early Management of Patients with Acute Ischemic Stroke, a general approach to management of hypertension is described, based largely on clinical opinion and agents used in recombinant tissue plasminogen activator investigations. Labetalol is recommended as the first-line agent of choice for intermittent bolus administration together with nicardipine for continuous infusion. Although not specified in the 2013 guidelines, clevidipine may be considered according to institutional availability and preference. The guidelines do mention consideration of other agents such as hydralazine and enalaprilat when clinically appropriate and consideration of sodium nitroprusside in patients with uncontrolled hypertension with the agents previously mentioned or a DBP greater than 140 mm Hg (Figure 37.3).72

Figure 37.3 Management of ischemic stroke. tPA = tissue plasminogen activator.

Subarachnoid Hemorrhage Patients presenting with aneurysmal subarachnoid hemorrhage (aSAH) may have a variety of blood pressure management needs throughout their treatment process because altered autoregulation, concern for rebleeding events, and delayed neurologic defects are just a few processes in aSAH that may be affected by blood pressure alterations. Rebleeding in aneurysm rupture is associated with increased mortality

and morbidity, with peak rebleeding seen within the first 24 hours after aneurysm rupture, often within the first 6–12 hours.84,85 Early surgical or endovascular intervention has helped attenuate the incidence of inhospital rebleeding in aSAH; however, rebleeding may occur, and due consideration should be given to management of hypertension before aneurysm obliteration. Systolic blood pressures greater than 160 mm Hg and MAPs less than 70 mm Hg or greater than 130 mm Hg have been associated with rebleeding and poor outcome in aSAH (Table 37.3).86,87 The AHA/ASA Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage recommend that acute hypertension be controlled, particularly before definitive aneurysmal intervention, with a recommendation that “a decrease in systolic blood pressure to less than 160 mm Hg is reasonable.”88 There are no specified blood pressure parameter recommendations post-intervention within the guideline, but close attention should be paid to blood pressure monitoring after intervention. Although there is some evidence specific to the aSAH population regarding antihypertensive selection, the AHA/ASA guidelines make no specific endorsements for particular agents. One retrospective investigation shows efficiency in achieving blood pressure goals with improved time within goal MAP, decreased needs for additional antihypertensive agents, and number of treatment failures with continuous infusion nicardipine similar to that with bolus-dose labetalol.89 It has also been shown that continuous infusion labetalol versus continuous infusion nicardipine has similar maintenance of blood pressure goals in patients with aSAH and ICH, though with a faster time to goal MAP with nicardipine.67 A prospective evaluation of nicardipine and sodium nitroprusside infusions for acute blood pressure control has been done in patients with aSAH and ICH. Overall blood pressure control was similar between both treatment groups, with similar time spent within target blood pressure range but with overall fewer adjustments to infusion doses and requirements of additional asneeded medication in patients receiving nicardipine.90 An open-label pilot study of five patients also suggests that clevidipine can successfully be used for acute blood pressure management in aSAH,

though larger investigations are warranted.91 Although firm recommendations regarding antihypertensive agent selection cannot be made at this time, institutional blood pressure goals and medication availability should be considered. Given the risk of early rebleeding and the recommended SBP goals of 160 mm Hg or less, continuous infusion preparations may yield less blood pressure variability, which may correlate with improved overall patient outcomes, though there is scant evidence at best to support this at this time (Figure 37.4).

Postoperative Hypertension Hypertension is a common occurrence in postoperative patients, and though commonly seen, no specific criteria exist for diagnosis. Acute postoperative hypertension (APH) typically has an early onset, within 2 hours after surgery, and typically abates within 6 hours or less, though may persist beyond that period. Factors predisposing patients include preoperative conditions such as hypertension, diabetes mellitus, and renal disease; postoperative factors such as pain, anxiety, and emergence from anesthesia; and intraoperative factors such as type of surgery performed, duration of procedure, and anesthetic agents used. Although many factors play a role in APH, preoperative hypertension is highly associated with the development of postoperative hypertension and should be considered in the perioperative workup.92–94 Although several risk factors exist for APH, activation of the sympathetic nervous system with elevation of plasma catecholamines appears to be higher in patients with APH. It does not appear that the RAAS plays a significant role in the development of postoperative hypertension, at least in the cardiac surgery population, though data suggest that the RAAS does play a role in other patient populations.95–97 Although the full pathophysiology of APH has yet to be fully described, interventions should be made to prevent serious sequelae such as hemorrhagic stroke or cerebral ischemia, cardiovascular complications, pulmonary edema, or complications related to surgical site and bleeding.

SubaFaChnOid

Hemorrhage 1

F

Witti Presence of Unsecured Aneurysm: SBP < 160 isrea & onable Some may consider SBP < 140 1

F

Medication Options

1

F

TitratableContinuøus Infusion Preferred:

Nifardipine Clevidipine Comider Sodium Ni(ropruss id e / Labetalol

Figure 37.4 Management of aneurysmal subarachnoid hemorrhage. At this time, there is a lack of consensus regarding both the definition of APH and the optimal treatment goals for patients with noncardiac surgery. Definitions for APH in non-cardiac surgery as defined by clinical investigations range from blood pressure measurements of SBP of 180–200 mm Hg or greater (140 mm Hg or greater in neurosurgical postoperative investigations), DBP of 110 mm Hg or greater (95 mm Hg or greater in neurosurgical postoperative investigations), MAP of 20% or greater of baseline value, or some combination thereof (Table 37.3).98–100 Treatment interventions should include mitigation of causes of APH such as hypothermia and shivering, optimization of ventilatory parameters, adequate analgesia and sedation as needed, management of volume status, and other reversible causes. Once these are optimized, antihypertensive medication can be considered for treatment of APH with goal blood

pressure lowering at surgeon/anesthesiologist discretion in non-cardiac surgery. Because most APH is transient, short-acting agents, such as labetalol, as well as agents that are easily titratable, such as nicardipine, clevidipine, and sodium nitroprusside, can be considered. Agents with less uniform responses to therapy or with long durations of action, such as hydralazine and enalaprilat, are not routinely recommended for use in APH and should be used with caution, if at all. A few key studies have compared various intravenous agents for the management of APH. One multicenter, prospective, randomized study that sought to compare the safety and efficacy of nicardipine with that of sodium nitroprusside in both cardiac and non-cardiac surgical patients found that both agents were equally effective.101 Patients receiving nicardipine appeared to have more rapid control of APH. Furthermore, the total number of dose titrations to achieve target blood pressure was fewer in the group receiving nicardipine. No difference occurred in rates of adverse events. In a randomized, double-blind, placebo-controlled trial completed by investigators in the ESCAPE-2 (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke) trial, researchers sought to determine the safety and efficacy of clevidipine in treating APH after cardiac surgery. Clevidipine was associated with lower rates of treatment failure than placebo with no difference of adverse events. The ECLIPSE (Evaluation of Clevidipine in the Perioperative Treatment of Hypertension Assessing Safety Events) trial compared the efficacy of clevidipine with that of sodium nitroprusside, nitroglycerin, and nicardipine for the management of acute hypertension post–cardiac surgery. This study was a multicenter, prospective, openlabel, randomized, parallel comparison study. The primary end point of this trial was a composite end point of safety assessed by the incidence of all-cause mortality, stroke, myocardial infarction, and renal dysfunction. Mortality was significantly higher in the treatment group receiving sodium nitroprusside versus clevidipine. Clevidipine was also more effective than nitroglycerin or sodium nitroprusside in maintaining blood pressure within target ranges. There was no difference in efficacy between clevidipine and nicardipine unless the target blood

pressure range was narrowed (Figure 37.5).102

Pheochromocytoma Pheochromocytomas are catecholamine-producing tumors arising from the chromaffin cells of the adrenal gland, though 10%–15% of tumors may be extra-adrenal. Although the prevalence in patients with hypertension is only 0.2%–0.4%, pheochromocytoma is often on the differential diagnosis for patients with acute, otherwise unexplained hypertensive crisis. Of note, patients with pheochromocytoma may also be normotensive or only moderately hypertensive (Table 37.3). About one-fourth of pheochromocytomas are hereditary, and typical symptoms such as headache, sweating, and palpitation are caused by tumor-secreted catecholamines. In most cases, catecholamines are released intermittently, typically both epinephrine and norepinephrine with a predominance of norepinephrine. For patients with pheochromocytoma with hypertensive crisis, management with an αreceptor antagonist such as phentolamine is the recommended initial treatment. After initiation of α-receptor blockade, β-receptor antagonists, such as esmolol, may be required for additional mediation of epinephrine-mediated effects or tachycardia induced by α-receptor antagonism. Surgical resection is often used for definitive treatment of patients with pheochromocytoma, though around 10% of cases are malignant, requiring additional interventions with chemotherapy and radiation. Preoperative initiation of α-blockade with phenoxybenzamine is recommended with the addition of β-receptor antagonists as needed. There is some evidence using calcium channel antagonists in the preoperative period, but data regarding use in pheochromocytomainduced hypertensive crisis are scarce. Clinical judgment on a case-bycase basis is recommended in patients with pheochromocytoma with hypertensive crisis not responding adequately to α- and β-receptor antagonism.103,104

Aortic Dissection Aortic dissection, although present in only 2% of patients presenting

with hypertensive crisis, is rapidly fatal and can be considered a surgical emergency.4 Elevated blood pressures in conjunction with atherosclerosis within the aorta can result in tears within the intimal layer of the blood vessel. These tears permit the development of a false lumen within the wall of the aorta. As blood is ejected from the left ventricle and into the aorta, the resulting high pulsatile pressure separates the aortic wall into two layers. Therefore, clinically, patients with dissection present with symptoms of retrosternal or interscapular chest pain that radiates down the back. Dissection can result in impeded blood flow to branches of blood vessels from the aorta, leading to end-organ ischemia. Diagnosis is usually confirmed by transesophageal echocardiography, CT (computed tomography), or MRI (magnetic resonance imaging). There are three major classification systems for aortic dissection (Table 37.4). The Stanford system is the most classically used by surgeons because it is a simple guide to determine whether the patient is a surgical emergency. A type A dissection according to the Stanford system would likely be considered a surgical emergency. These patients may present with symptoms associated with malperfusion of the brain and coronary arteries. Conversely, type B dissections may present with symptoms of malperfusion of the spinal cord, liver, small intestines, kidneys, or lower extremities. Several different patientspecific features have been seen among patients presenting with dissection. Disease states such as hypertension, hyperlipidemia, diabetes, and Marfan syndrome have been associated with increasing risk. Furthermore, pregnancy, cocaine abuse, a history of cardiac surgery, or the presence of a bicuspid aortic valve may also be associated with dissection.105 To avoid propagation of intimal dissection, patients presenting with aortic dissection require immediate intravenous antihypertensive treatment as soon dissection is suspected.15 An exception to this would be a subset of patients who may present as hypotensive as a result of their dissection. Progression of the dissection depends on the degree of blood pressure elevation as well as the velocity of left ventricular ejection. For this reason, therapeutic interventions aimed at both heart

rate and blood pressure are used for these cases. Emergency intervention usually involves rapid intravenous administration of βblocking agents such as esmolol in an attempt to reduce heart rate to less than 60 beats/minute.43 Vasodilating agents such as nicardipine or sodium nitroprusside may be added to β-blocking agents to achieve an SBP less than 120 mm Hg. The DBP should be reduced by 10%–15%, or at least to less than 110 mm Hg. These interventions and targets are ideally obtained within 20 minutes (ideally within 5–10 minutes) of presentation to the health care setting.106 Although esmolol is not FDA approved for hypertensive crisis with aortic dissection, it has been used to treat hypertension associated with acute aortic dissection (Figure 37.6). In sequence of administration, β-blocking agent administration should precede the initiation of any antihypertensive agent that may cause reflexive tachycardia or position inotropy to avoid exacerbating the dissection. These hemodynamic end points should be maintained as long as the patient remains symptomatically stable or until the patient can be taken to the operating room for more definitive management of the dissection.107

2 ht fromSurgery

SBP 330-200 ( a 140 in neurosurgical procedures ) and/ or DBP 110 ( a 95 in neurosurgical procedures) and/or % 20 of baseline value MAP

Mitigate Potent i al Cau ses : Hypothermia Shivering * Optimize venlilalion Anal ges ia /s edation Vollme stat JS

øns Medication Optt

Labetalol

Nicardipine

Clevidipine

Sodium

Nitroprusside

Figure 37.5 Management of postoperative hypertension

Table 37.4 Classification Systems of Aortic Dissection Stanford • Type A: ascending aorta affected

• Type B: ascending aorta not affected De Bakey • Type 1: entire aorta affected • Type 2: ascending aorta affected • Type 3: descending aorta affected Svensson • Class 1: classic dissection with true and false lumen • Class 2: intramural hematoma or hemorrhage • Class 3: subtle dissection without hematoma • Class 4: atherosclerotic penetrating ulcer • Class 5: iatrogenic or traumatic dissection

Acute Coronary Syndromes Hypertensive crisis can negatively affect both the structure and the function of the left ventricle as well as coronary circulation. The RAAS is activated, resulting in systemic vasoconstriction and increased myocardial oxygen demand and subsequent left ventricular hypertrophy. Coronary blood flow is negatively affected by both this hypertrophy and the endothelial destruction within the capillaries as a result of acute rises in blood pressure. Therefore, patients with hypertensive crisis can present with acute coronary syndromes (Table 37.3). In patients with coronary artery disease presenting with an acute coronary syndrome, the theoretical “coronary steal” (i.e., redistribution of oxygenated blood away from non-vasodilating areas of ischemia toward nonischemic myocardium with dilated coronary arteries) results in reduced coronary perfusion pressure to further exacerbate and potentiate injury.108 A study by Mann and colleagues examined the effects of sodium nitroprusside on regional myocardial blood flow in patients with coronary artery disease. These investigators found that sodium nitroprusside significantly reduced regional myocardial specific blood flow and increased coronary artery vascular resistance. This effect was seen regardless of the presence of collateralization.109 Therefore, sodium nitroprusside should not routinely be administered to

patients with hypertensive emergency in the setting of acute coronary syndromes because it has been associated with increased mortality. This was especially prominent when it was administered within 9 hours of onset of chest pain in patients with acute coronary syndrome and elevated left ventricular filling pressure.

Figure 37.6 Management of aortic dissection. Nitroglycerin decreases preload and myocardial oxygen consumption by decreasing left ventricular end-diastolic volume and myocardial wall tension, making it the preferred agent in the setting of hypertensive crisis complicated by myocardial ischemia.2 However, before the administration of any nitrate medication, the medical team should determine whether the patient has been taking a phosphodiesterase type 5 (PDE-5) inhibitor because the combination can cause profound hypotension for up to 48 hours after the last dose of a PDE-5 inhibitor. In one study, standing SBP fell below 85 mm Hg in

more patients receiving tadalafil than in placebo (p 90 50mmHg

Or

Or Heart rata = 50 beals per minute

^

Heart rate

< 50 beats per minute

T DO NQT filart clontdine Giue 75pg of donldme . Measure blood pnessune after 30 minutea treatment SIH

Blood pre saure drope

*

Blood pnessure does not drop . Palient is nol dizzy

T DO MOT start clonidine S tart clomdi ne treatment trcatrn & nt Table 4: Clonidine dosing for moderate / severe opioid withdrdwal Morning

Day 1 Day 2

Pay 3

Day 4 Day 5

150 pg 150- 300 pg 150- 300 pg 75 Mg 75 pg

Early Attømoon

150 pg 150- 300 pg 150- 300 p9 75 pg Nil

Night

150 pg 150- 300 pg 150- 3Q0 pg 75 pg 75 pg

Figure 38.3 Procedure for administering clonidine for moderate/severe opioid withdrawal. Reprinted from: World Health Organization (WHO). Clinical Guidelines for Withdrawal Management of Drug Dependence in Closed Setting. Geneva: WHO, 2009.

Table 38.5 High-Dose Benzodiazepine Reduction Schedulea

Morning

Afternoon

Evening

Nighttime

Start of taper

10

10

10

10

First reduction

10

5

5

10

Second reduction

5

5

10

Third reduction

10

Fourth reduction

5

aDoses

reported in milligrams of diazepam.

α2-AGONIST WITHDRAWAL Background α2-Adrenergic agonists and imidazoline derivatives (e.g., clonidine, guanfacine, tizanidine, dexmedetomidine) are treatments for a variety of medical diagnoses, including essential hypertension, attentiondeficit/hyperactivity disorder, nasal congestion, Gilles de la Tourette syndrome, opioid withdrawal, spasticity, sedation, open-angle glaucoma, ocular hypertension, and tension-type headaches. This class of medications may be administered by oral (immediate- and extendedrelease formulations), intravenous, transdermal, and topical (nasal and ophthalmologic) routes.89 α2-Adrenergic receptors are found in the central and peripheral nervous systems; the central effects of presynaptic agonism inhibit sympathetic outflow, resulting in bradycardia and hypotension.90 Individual agents differ in their affinity for imidazoline and α2receptors, centrally and peripherally. The effects of each receptor subtype, together with the interplay between central α2 and imidazoline receptors’ contributions to hypo-tension, have not been fully elucidated. Dexmedetomidine has high affinity for the α2A-receptor, which is thought to provide the sedative effects of this and other α2-agonists.91 Although structurally dissimilar, α2-agonists (particularly clonidine) attenuate the untoward effects of opioid withdrawal.92 Along these

same lines, the opioid-receptor antagonist naloxone reverses some effects of clonidine overdose.93 This effective overlap is hypothesized to stem from the similar effects of opioids and α2-agonists on potassium efflux in the locus ceruleus.94

Diagnosis Abrupt tapering or cessation of centrally acting α2-adrenergic agonists can induce withdrawal symptoms, including rebound hypertension, insomnia, delirium, irritability, tremor, and palpitations.90,95-100 Neuroleptic malignant syndrome, malignant hyperthermia, and serotonin syndrome are examples of potentially medication-induced symptoms that can easily be confused with α2-agonist withdrawal.99 Expanding beyond medication-induced causes, withdrawal can easily be overlooked in critically ill patients, given the nonspecific symptoms associated with an increase in sympathomimetic activity. Withdrawal symptoms from oral clonidine are expected to present within 16–72 hours of cessation.99,100

Table 38.6 Oral Benzodiazepine Approximate Equipotent Doses70,79,87,88 Alprazolam

0.5–1 mg

Chlordiazepoxide

25–50 mg

Clonazepam

0.5 mg

Diazepam

10 mg

Lorazepam

1–2 mg

Midazolam

5 mg

Adapted from: World Health Organization (WHO). Clinical Guidelines for Withdrawal Management of Drug Dependence in Closed Setting. Geneva: WHO, 2009.

A case of clonidine prescribed to alleviate withdrawal symptoms that

resulted in a prolonged stay in the ICU secondary to iatrogenic clonidine withdrawal highlights the need to keep α2-agonist withdrawal in the differential diagnosis.99 A patient on an intrathecal clonidine pump failure had severe withdrawal, which resulted in stress-induced cardiomyopathy, highlighting the serious consequences of clonidine withdrawal.101 Reports of dexmedetomidine withdrawal exist in the literature with features similar to clonidine and other α2-agonist withdrawal.96,97 These cases are associated with prolonged use of dexmedetomidine and can be managed through modalities described in the next section.

Management α2-Agonists may be used for opioid withdrawal; conversely, morphine administration attenuates hypertension-associated α2-agonist withdrawal in rats.71,102 Because opioids are commonly administered in the ICU setting for analgesia,85 this theoretically may blunt some of the effects seen with α2-agonist withdrawal. More studies in humans are needed before opioids can be recommended solely for α2-agonist withdrawal. Given the safety concerns with opioids, regardless of a patient’s sex, we do not recommend using opioids solely to manage α2agonist withdrawal.103 Mild cases of α2-agonist withdrawal may be managed nonpharmacologically with monitoring and supportive care. Cases increasing in severity may be managed either indirectly (with supportive measures) or directly (administration of the recently withdrawn agent or another α2-agonist).96,97 We are unaware of any reports using dexmedetomidine to manage withdrawal of an α2-agonist agent and do not recommend this approach at present. Clonidine has the largest body of literature regarding its withdrawal, partly because of its widespread use but also because of the pharmacokinetic properties relative to other α2-agonists (e.g., shorter half-life than guanfacine). The longer half-life agents are thought to self-taper and are hypothesized to have less severe withdrawal symptoms as a

result.100

CONCLUSION The intent of this chapter was to provide a brief overview of the diagnosis, management, and potential treatments for patients with medication withdrawal; we recognize that this does not list all the potential medications that patients may withdraw from. Together with resource use, safety, cost, and other considerations, clinicians are encouraged to weigh the risks and benefits of withdrawal management in the ICU. An interdisciplinary approach to determining a patient’s actual medication use, with a well-trained clinical pharmacist readily available, is invaluable in identifying patients with potential medication withdrawal early in their ICU stay. Clinicians are encouraged to consider iatrogenic withdrawal syndromes in addition to prehospital medication withdrawal manifesting in the ICU. Medication withdrawal is rarely the cause for a patient’s ICU admission; however, if withdrawal is not identified, or is left untreated, it can further complicate the care of ICU patients. All members of the interdisciplinary ICU team should be aware of these potentially serious medical issues.

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surge. BMJ Case Rep 2015; Jun 2;2015. 100. Wilson MF, Haring O, Lewin A, et al. Comparison of guanfacine versus clonidine for efficacy, safety and occurrence of withdrawal syndrome in step-2 treatment of mild to moderate essential hypertension. Am J Cardiol 1986;9:43E-49E. 101. Lee HM, Ruggoo V, Graudins A. Intrathecal clonidine pump failure causing acute withdrawal syndrome with “stress-induced” cardiomyopathy. J Med Toxicol 2015 Sep 14. [Epub ahead of print] 102. Thoolen MJ, Timmermans PP, van Zwieten PA. The influence of continuous infusion and sudden withdrawal of azepexole (BHT 933) on blood pressure and heart rate in the spontaneously hypertensive and normotensive rat. Suppression of the withdrawal responses by morphine. J Pharmacol Exp Ther 1981;3:786-91. 103. Kaplovitch E, Gomes T, Camacho X, et al. Sex differences in dose escalation and overdose death during chronic opioid therapy: a population-based cohort study. PloS One 2015;8:e0134550.

Chapter 39

Endocrine Disorders Robert L. Talbert, Pharm.D.

LEARNING OBJECTIVES 1. Describe the epidemiology, pathophysiology, clinical presentation (signs and symptoms), and management of myxedema coma, thyroid storm, adrenal insufficiency, hypercortisolism, and pheochromocytoma. 2. Outline nonpharmacologic and pharmacologic management of the disease states described above.

ABBREVIATIONS IN THIS CHAPTER ACTH

Adrenocorticotropin hormone

CS

Cushing syndrome

FT4

Free thyroxine

TSH

Thyroid-stimulating hormone

T3

Triiodothyronine

T4

Thyroxine

THYROID DISORDERS Myxedema Coma

Definition and Epidemiology Myxedema coma is the term given to the most severe presentation of profound hypothyroidism, which is often fatal despite therapy. Decompensation of the patient with hypothyroidism into a coma may be precipitated by a few drugs (e.g., amiodarone, lithium, and sunitinib), systemic illnesses (e.g., pneumonia), and other causes. Myxedema coma typically presents in older women in the winter months and is associated with signs of hypothyroidism, hypothermia, hyponatremia, hypercarbia, and hypoxemia. Treatment must be initiated promptly in an intensive care unit setting. Although thyroid hormone therapy is critical to survival, it remains uncertain whether it should be administered as thyroxine (T4), triiodothyronine (T3), or both. Adjunctive measures, such as ventilation, warming, fluids, antibiotics, vasopressors, and corticosteroids, may be essential for survival. Mortality in myxedema coma is estimated to be as high as 25%–65%, and early recognition is key to survival.1 The most typical precipitating factor is discontinuation of thyroid hormone replacement therapy, but this entity may be confused with other disease states such as hepatotoxicity. Careful attention to nonspecific complaints, myxedematous changes (e.g., puffiness and slowed mentation), and signs of dysfunction of any organ system, especially in older female patients, may lead to the ultimate correct diagnosis. Any history of thyroid disease and evidence of a surgical scare indicating thyroid surgery would be important. Myxedema coma must be recognized and treated emergently, usually before laboratory confirmation. Ventilatory support and thyroid hormone replacement are the two most important therapeutic maneuvers in the treatment of myxedema coma.2 In critical illness, thyroid function tests can be difficult to interpret, and some of these situations are summarized in Figure 39.1. Pathophysiology The underlying cause is a profound lack of T3 and T4; however, reduced deiodinase activity limiting the conversion of T4 to T3 may be a contributing factor. Some authors prefer intravenous T3, but others

consider treatment with T3 or T4 equivalent. Controversy exists whether the combination of T3 and T4 is better than single-agent therapy. An important drug-induced presentation for myxedema coma is the concurrent use of amiodarone.3,4 It is thought that amiodarone interferes with the extrathyroidal production of T3 from T4. Clinical Presentation and Laboratory Diagnosis Typical signs and symptoms of hypothyroidism (dry skin, brittle nails, weight gain, and lethargy as well as hypothermia, hyponatremia, hypercarbia, hypoxemia, and altered mental status) must be present. The recent development of rating scales may aid in the rapid diagnosis of impending and frank myxedema coma. The scoring systems include a composite of alterations of thermoregulatory system, central nervous system (CNS), cardiovascular system, gastrointestinal (GI) system, and metabolic system and presence or absence of a precipitating event.5 In the scale developed by Chiong et al., six variables were created for the screening tool: heart rate, temperature, Glasgow Coma Scale, thyroid-stimulating hormone (TSH), free thyroxine (FT4), and precipitating factors. The screening tool has a sensitivity and specificity of about 80%; however, this study was based on a small number of patients, and validation with a larger population is needed. The screening tool for assessing myxedema coma is presented in Table 39.1. Typical laboratory abnormalities include low FT4 and high TSH in primary myxedema coma and low TSH in secondary myxedema coma. In a series of 10 patients, Chiong et al. found TSH to range from about 10 mU/mL to 140 mU/L. The FT4 concentrations ranged from undetectable to 1.7 ng/dL.5 Although this is a small study, it makes the point that interpretation of thyroid tests must be done in the context of the patient’s clinical findings and with the understanding that concurrent disease states can influence thyroid tests and interpretation (see Figure 39.1). Treatment

The mainstay of treatment is intravenous T3 or T4. Given that T3 is several times more potent than T4 and that T4 needs to be converted for the greater activity, T3 is the preferred drug. Although there are no randomized trials of intravenous T3, some authors recommend that T3 doses be normally administered at least 4 hours—and not more than 12 hours—apart. An initial intravenous dose of T3 is 25–50 mcg for emergency treatment and then a daily dose of 10–20 mcg. If the patient has underlying cardiovascular disease, this dose may be excessive. According to the author’s experience, oral dosing of T3 or T4 should be avoided because the bioavailability appears to be reduced, and normal absorption may not occur until several days after therapy is initiated. Once the clinical condition is stabilized, oral therapy may be resumed or initiated.

Figure 39.1 Patterns of thyroid function tests as

affected by nonthyroidal factors. ATD = antithyroid drug; FDH = familial dysalbuminemic hyperthyroxinemia; FT3 = free triiodothyronine; FT4 = free thyroxine; NTI = non-thyroidal illness; TKI = tyrosine kinase inhibitor; TSH = thyroid-stimulating hormone.

Glucocorticoid support is empirically administered if adrenal gland failure has occurred simultaneously and to help stabilize blood pressure. Hydrocortisone 100 mg intravenously every 8 hours is the standard approach. Some patients require intravenous vasopressor support, and norepinephrine is a logical choice. Ventilatory support as needed may be required in some patients. Addressing other precipitating factors such as underlying infection and sepsis is also an important aspect of care. Because many patients present with hypothermia, warming should be considered with very low body temperatures (less than 95°F). Assessment of Outcomes The two most important parameters to gauge the success of treatment are improving mental status as measured by the Glasgow Coma Scale and increasing levels of thyroid hormones and reduction in TSH.

Thyroid Storm (Thyroid Crisis) Definition and Epidemiology Thyroid storm, also known as thyroid crisis, is thyrotoxicosis in the extreme. It is considered a medical emergency and presents with many of the typical symptoms associated with hyperthyroidism, except that thyroid storm must have the component of altered mental status. The most common trigger for thyroid storm is discontinuation or irregular use of antithyroidal agents. Although the prevalence of thyroid storm is imprecise because of the rare nature of this disorder, recent retrospective cohort studies suggest a prevalence of about 0.2 per 100,000 population.6 Reports and

reviews from 2 decades ago suggested that mortality with thyroid storm ranged from 20% to 100%, but more recent reports have found mortality rates ranging from 9.5% to 11%. This disparity is most likely because of better and earlier recognition of patients at risk of thyroid storm and more aggressive and earlier treatment. The most common cause of death is heart failure or multiorgan failure (see Tables 39.2 and 39.3). Pathophysiology The underlying pathophysiology is similar to thyrotoxicosis and is mediated by thyroid-stimulating autoantibodies directed against the thyrotropin receptor on the surface of the thyroid cell. Binding of these immunoglobins to the receptor activates downstream G-protein signaling and adenylate cyclase in the same manner as TSH. Because the thyroid hormones T3 and T4 bind to receptors in many tissues in the body, the symptoms and clinical presentation can affect many organ systems.

Table 39.1 Myxedema Coma Screening Tool Criterion

Score

GCS 0–10

4

11–13

3

14

2

15

0

TSH > 30 mU/L

2

15–30 mU/L

1

Low FT4a

1

Hypothermia (< 95°F)

1

Bradycardia (< 60 beats/min)

1

Precipitating eventb

1

Total Score

Category

8–10

Recommendation Proceed with treatment

5–7

Likely

Treat if there are no other plausible causes

39.4°C or 103°F)

Anxiety

Tachycardia

Palpitations

Tachypnea

Emotional liability

Dehydration

Heat intolerance

Vomiting

Nausea

Diarrhea

Psychosis

Hypotension

Lethargy

PHEOCHROMOCYTOMA Definition and Epidemiology Pheochromocytomas are catecholamine-producing neuroendocrine tumors that can be adrenal or extra-adrenal in origin. In patients with an established mutation or hereditary syndrome, the condition may manifest at a younger age than in those with sporadic disease. Pheochromocytoma can be associated with certain genetic syndromes such as MEN 2 (multiple endocrine neoplasia type 2), NF (neurofibromatosis), and VHL (von HippelLindau) syndrome. Pheochromocytoma is diagnosed with biochemical confirmation of hormonal excess followed by anatomical localization (CT [computed tomography] or MRI [magnetic resonance imaging]). Pheochromocytoma occurs in 2–8 patients in 1,000,000, with about 1,000 cases diagnosed yearly in the United States. It mainly occurs in young or middle-aged adults, though it presents earlier in hereditary syndrome. About 15% are extra-adrenal (located in any orthosympathetic tissue); of these, 9% are in the abdomen, and 1%

are located elsewhere. Some extra-adrenal pheochromocytomas are probably actually paragangliomas, but the distinction is only possible after surgical resection. Pheochromocytoma has an estimated prevalence of 0.1%–0.6% in individuals with hypertension; it is therefore a rare disease.

Pathophysiology These tumors secrete high amounts of catecholamines, mainly epinephrine, plus norepinephrine to a lesser extent.

Clinical Presentation and Laboratory Diagnosis The classic symptoms of pheochromocytoma are headache, palpitation, anxiety, and diaphoresis, and the tumor can occur at any age with equal sex distribution. Signs and symptoms of pheochromocytomas often include the following: ■ High blood pressure ■ Rapid or forceful heartbeat ■ Profound sweating ■ Severe headache ■ Tremors ■ Paleness in the face ■ Shortness of breath

Table 39.5 Point Scale for the Diagnosis of Thyroid Storm Criteria

Points

Temperature (°F) 99.0–99.9

5

100.0–100.9

10

101.0–101.0

15

102.0–102.9

20

103.0–103.9

25

≥ 104.0

30

Cardiovascular, tachycardia (beats per minute) 100–109

5

110–119

10

120–129

15

130–139

20

≥ 140

25

Atrial fibrillation Absent

0

Present

10

Heart failure Absent

0

Mild

5

Moderate

10

Severe

20

GI-hepatic dysfunction Absent

0

Moderate (diarrhea, abdominal pain, nausea/vomiting

10

Severe (jaundice)

20

CNS disturbance Absent

0

Mild (agitation)

10

Moderate (delirium, psychosis, extreme lethargy)

20

Severe (seizure, coma)

30

Precipitant history Positive

0

Negative

10

Scores totaled > 45

Thyroid storm

25–44

Impending storm

< 25

Storm unlikely

Modified from: Bahn et al. Hyperthyroidism and other causes of thyrotoxicosis; management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011;21:593-646

Less common signs or symptoms may include the following: ■ Anxiety or sense of doom ■ Abdominal pain ■ Constipation ■ Weight loss These signs and symptoms often occur in brief spells of 15–20 minutes. Spells can occur several times a day or less often. Blood pressure may be within the normal range or remain elevated between episodes. Diagnosis depends on biochemical evidence of excessive production

of catecholamines. This is straightforward when test results are orders of magnitude above the concentrations expected in healthy individuals and those with essential hypertension. Equivocal results pose a management dilemma. Evidence now indicates that initial screening for pheochromocytoma should include measurements of plasma-free metanephrines or urinary fractionated metanephrines. Liquid chromatography/mass spectrometry offers several advantages over other analytic methods and is the method of choice when measurements include methoxytyramine, the O-methylated metabolite of dopamine. The plasma test offers advantages over the urine test, although it is rarely implemented correctly, rendering the urine test preferable for mainstream use. To ensure optimal diagnostic sensitivity for the plasma test, reference intervals must be established for blood samples collected after 30 minutes of supine rest and after an overnight fast when measurements include methoxytyramine. Similarly, collected blood samples during screening, together with use of age-adjusted reference intervals, further minimize false-positive results. Extents and patterns of increases in plasma normetanephrine, metanephrine, and methoxytyramine can additionally help predict size and adrenal versus extra-adrenal locations of tumors, as well as the presence of metastases and underlying germline mutations of tumor susceptibility genes.10 One diagnostic test used in the past for a pheochromocytoma was to administer clonidine, a centrally acting α2-agonist used to treat high blood pressure. Cloni-dine mimics catecholamines in the brain, causing it to reduce the activity of the sympathetic nerves controlling the adrenal medulla. A healthy adrenal medulla will respond to the clonidine suppression test by reducing catecholamine production; lack of a response is evidence of pheochromocytoma.

Treatment Surgical resection of the tumor is the treatment of first choice, by either open laparotomy or laparoscopy. Given the complexity of perioperative management, and the potential for catastrophic intra- and

postoperative complications, such surgery should be performed only at centers experienced in the management of this disorder. In addition to the surgical expertise that such centers can provide, they have the necessary endocrine and anesthesia resources. It may also be necessary to carry out adrenalectomy, a complete surgical removal of the affected adrenal gland(s). Either surgical option requires prior treatment with the non-specific and irreversible α-adrenoceptor blocker phenoxybenzamine or a short-acting α-antagonist (e.g., prazosin, terazosin, or doxazosin).11 Phenoxybenzamine is lipophilic and may have blood pressuring–lower effects for up to 7 days after dosing. Initial doses in adults are 10–20 mg/day and up to 20–40 mg/day for maintenance. Bioavailability is 20%–30%, and variation from patient to patient is to be expected. An alternative rapid-acting α1-antagonist is phentolamine. The initial dose is 5 mg intravenously/intramuscularly 1–2 hours before surgery, and repeated dosing if needed is 5 mg intravenously/intramuscularly every 2–4 hours. Unfortunately, the manufacturer has discontinued production of phentolamine, and currently, there is a shortage. Before surgery, the patient is conventionally prepared with α-adrenergic blockade (over 10–14 days), and subsequently, additional β-adrenergic blockade is required to treat any associated tachyarrhythmias. In preoperative assessment, it is obligatory to monitor arterial blood pressure. Doing so permits the surgery to proceed while minimizing the likelihood of severe intraoperative hypertension (as might occur when the tumor is manipulated). Some authorities would recommend that a combined α/ β-blocker such as labetalol also be given to slow the heart rate. Regardless, a β1-receptor selective β-blocker such as atenolol must never be used in the presence of a pheochromocytoma because of the risk of such a treatment leading to unopposed α-agonism and, thus, severe and potentially refractory hypertension. Studies have shown that labetalol is effective in the treatment of essential hypertension, renal hypertension, pheochromocytoma, pregnancy hypertension, and hypertensive emergencies.12 The patient with pheochromocytoma is invariably volume depleted. The chronically elevated adrenergic state

characteristic of an untreated pheochromocytoma leads to near-total inhibition of renin-angiotensin activity, resulting in excessive fluid loss in the urine and thus reduced blood volume. Hence, once the pheochromocytoma has been resected, thereby removing the major source of circulating catecholamines, a situation arises where there is both very low sympathetic activity and volume depletion. This can result in profound hypotension. Therefore, it is usually advised to “salt load” patients with pheochromocytoma before their surgery. This may consist of simple interventions such as consumption of high-salt food preoperatively, direct salt replacement, or administration of intravenous saline solution.

Assessment of Outcomes The signs and symptoms of catecholamine excess (elevated heart rate and blood pressure, anxiety, etc.) should abate soon after surgery. As mentioned previously, blood pressure should be monitored closely, and a significant decrease in blood pressure should be anticipated because of the volume-depleted state. Normal saline or lactated Ringer solution should be titrated to maintain mean arterial pressure in a near-normal range.

ADRENAL DISORDERS Adrenal Insufficiency (Addison Disease) Definition and Epidemiology Primary adrenal insufficiency or Addison disease most often involves destruction of all regions of the adrenal gland, leading to deficiencies in cortisol, aldosterone, and various androgens with elevation in corticotropin-releasing hormone and adrenocorticotropin hormone (ACTH). In developed countries, the most common cause is autoimmune destruction of the adrenal gland, whereas tuberculosis is more commonly the cause in developing countries. In chronic adrenal

insufficiency, adrenal crisis (AC) occurred in 8.3 crises per 100 patientyears. Precipitating causes were mainly GI infection, fever, and emotional stress (20% for each), but other stressful events (e.g., major pain, surgery, strenuous physical activity, heat, pregnancy) or unexplained sudden onset of AC (7%) were also documented. Given that corticosteroids are metabolized primarily through cytochrome P450 (CYP) 3A4, many drugs (e.g., carbamazepine, phenytoin) can increase the replacement doses needed. Patients with a previous AC were at a higher risk of crisis (odds ratio 2.85; 95% confidence interval [CI], 1.5–5.5; p 8.0 mg/dL

Hyperkalemia

Potassium > 6.0 mmol/L

Hyperphosphatemia

Phosphorus > 4.5 mg/dL

Hypocalcemia

Corrected calcium < 7.0 mg/dL Clinical Tumor Lysis Syndrome (CTLS)b

Seizures Cardiac arrhythmias Elevated serum creatinine (> 1.5 × ULN) Death aLTLS

requires two or more metabolic abnormalities occurring within the same 24-hr

window either 3 days before or up to 7 days after initiating chemotherapy. bCTLS

requires the presence of LTLS plus one of the clinical manifestations. ULN = upper limit of normal.

Incidence/Epidemiology Tumor lysis syndrome typically occurs in response to the treatment of hematologic malignancies, specifically high-grade lymphomas—most commonly, Burkitt lymphoma and acute lymphoblastic leukemia—but it has also been associated with low-grade lymphomas, including indolent non-Hodgkin lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma and solid tumors with high tumor burden including metastatic breast cancer, small cell lung cancer, melanoma, and non– small cell lung cancer.2,3,8,9 Tumor lysis syndrome can also occur spontaneously in the absence of treatment. Spontaneous TLS is usually observed in the setting of Burkitt lymphoma but has also been associated with other hematologic malignancies and solid tumors. Although the risk factors for developing spontaneous TLS are not clearly defined, spontaneous TLS is typically associated with a poor prognosis compared with classic TLS.2,3,5 Workup of TLS should be considered when there is a malignancy with unexplained reason of acute kidney failure. Risk factors for TLS include both tumor- and patient-specific factors. Tumor-specific risk factors include tumor burden, which is related to the bulkiness of the tumor mass, and the extent of tumor infiltration and/or metastasis and cell lysis potential, which is related to lactate dehydrogenase concentrations, the rate of cell proliferation, and the sensitivity of the tumor to chemotherapy including Burkitt lymphoma, lymphoblastic lymphoma, and B-cell acute lymphoblastic leukemia. The intensity of chemotherapy is also grouped with tumor-related factors when assessing the risk of TLS; the higher the intensity of the chemotherapy, the greater the potential for tumor cell lysis. Patientspecific factors can also determine the risk of TLS and include baseline nephropathy, dehydration, and hypotension, all of which can result in decreased urine flow and increase the propensity for uric acid and/or

calcium phosphate precipitation (Table 40.1).1,2,8 Assessment of risk factors allows for stratification of patients according to predicted risk of TLS and can direct the management strategy of TLS. Most risk assessment models center on the underlying malignancy and stratify patients as high, intermediate, or low risk depending on the presence and/or degree of tumor-related manifestations and baseline patient-specific characteristics.2,8 The risk stratification model proposed by Cairo et al. stratifies patients according to the underlying malignancy (Table 40.3) and extent of metastasis/bulkiness of the disease, type of chemotherapy, and preexisting renal dys-function, among other factors. This model, however, does not directly outline treatment recommendations for each stratification group, thereby creating challenges when applying it to clinical practice for the management of TLS.2,8

MANAGEMENT OF TLS The goal of managing TLS is to prevent the potentially serious renal, neurologic, and cardiac sequelae that can result from TLS. The initiation of preventive and treatment interventions is directed by the initial risk assessment of patients at risk of these serious complications.

Prophylaxis Hydration/Urine Output Goals All patients at risk of TLS and without contraindications to aggressive fluid therapy should be initiated on intravenous hydration therapy. Fluids should be initiated at least 24–48 hours before chemotherapy and continued through the completion of chemotherapy. The role of fluids in the setting of TLS is 2-fold: (1) dilute the extracellular space to reduce serum concentrations of potassium, phosphate, and uric acid; and (2) increase renal blood flow and filtration, promote high urine output, and prevent the accumulation of nephrotoxic calcium phosphate and uric

acid precipitates within the kidneys.2,5,7,10 Fluid therapy should be titrated as needed to achieve a target urine output of 80–100 mL/m2/hour or maintained at 1–2 times fluid maintenance requirements. Loop diuretics can be considered if target urine outputs are not achieved with continuous hydration therapy.2,7,10 Historically, urine alkalinization with sodium bicarbonate was recommended as part of the management of TLS. Although mechanistically, urine alkalinization increases the renal clearance of uric acid, the solubility of uric acid precursors, including hypoxanthine and xanthine, is decreased. The risk of xanthine nephropathy increases, particularly in the setting of the concomitant use of allopurinol, which acts as a competitive inhibitor of xanthine oxidase and prevents the conversion of hypoxanthine and xanthine to uric acid, ultimately increasing the concentration of these uric acid precursors. Furthermore, urine alkalinization decreases the solubility of calcium phosphate, thereby exacerbating the underlying risks associated with calcium phosphate precipitation. Therefore, given the risk of xanthine and calcium phosphate precipitation, sodium bicarbonate is no longer recommended for the prevention of TLS.1,3,5,7,10,11

Table 40.3 Incidence of Tumor Lysis Syndrome by Risk Category Malignancy High risk Acute lymphocytic leukemia (ALL) Acute myeloid leukemia (AML) with WBC>75,000 B-cell ALL

Incidence (%)

5.2-23 18 26.4 14.9

Burkitt’s lymphoma Intermediate risk AML with WBC=25,000-50,000 Diffuse large B-cell lymphoma Low risk

6 6

AML with WBC 50%

Cephalosporins

fT > MIC

> 50%–70%

Carbapenems

fT > MIC

> 40%

Aminoglycosides

fCmax/MIC

> 8–10:1

Fluoroquinolones

AUC/MIC

Gram-negative: >

125:1 Gram-positive: > 30:1 Vancomycin

AUC/MIC

> 400:1

Linezolid

fT > MIC AUC/MIC

> 40%–80% > 80–120:1

fT > MIC = percentage of time the free concentration (fT) is above the minimum inhibitory concentration (MIC); fCmax/MIC = ratio of maximum free concentration (fCmax) to MIC; AUC/MIC = ratio of area under the curve (AUC) to MIC. Data from: Adembri C, Fallani S, Cassetta MI, et al. Linezolid pharmacokinetic/pharmacodynamic profile in critically ill septic patients: intermittent versus continuous infusion. Int J Antimicrob Agents 2008;31:122-9; DeRyke CA, Kuti JL, Nicolau DP. Reevaluation of current susceptibility breakpoints for Gram-negative rods based on pharmacodynamic assessment. Diagn Microbiol Infect Dis 2007;58:337-44; Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med 2009;37:840-51; quiz 59.

Treatment Penicillins, Cephalosporins, and Carbapenems β-Lactams are one of the more commonly prescribed classes of antimicrobials in the critically ill, and data evaluations describing their pharmacokinetics in obesity are beginning to accumulate, although they are still limited. In general, both volume of distribution and clearance are increased in patients with obesity and thereby have the potential to decrease their time above the MIC. One study evaluated β-lactam pharmacokinetics (piperacillin/tazobactam, cefepime, ceftazidime, and meropenem) in a cohort of critically ill patients with and without obesity.63 Overall, marked variability was noted, and a substantial number of patients both with and without obesity did not attain adequate serum concentrations with standard dosing regimens. This highlights the influence that critical illness may have on drug pharmacokinetics and the limitations with extrapolating data from nonICU settings. A second report evaluated only piperacillin/tazobactam dosing in patients with morbid obesity admitted to a trauma/surgical ICU.64 In this study, pharmacodynamic goals were successfully reached (up to the susceptibility breakpoint of 16 mg/L) using a standard dose of 4.5 g every 6 hours infused over 30 minutes.

Cefepime dosing has been described in patients with morbid obesity who underwent bariatric surgery.65 Using patient-specific pharmacokinetic data, pharmacodynamic models were developed for two dosing scenarios: 2 g every 12 hours and 2 g every 8 hours. The time above the MIC fell below the goal of 60% when the MIC was greater than 4 mg/L for the every-12-hour regimen and greater than 8 mg/L for the every-8-hour regimen. Cefepime should therefore be administered using a dose of 2 g every 8 hours. Most studies evaluating carbapenem pharmacokinetics in obesity were conducted in the non-ICU population, but one study assessed meropenem dosing in nine critically ill patients with morbid obesity.66 Meropenem volume of distribution was slightly larger than the averages reported in nonobese patients (38 L vs. 22–29 L), but clearance was similar (10.5 L/hour vs. 9.3–11.5 L/hour). Pharmacodynamic modeling showed that standard dosing (1 g every 8 hours over 30 minutes) could attain target pharmacodynamic goals when MICs were 2 or lower. A second study reported doripenem pharmacokinetics in 10 non-ICU patients with morbid obesity.67 In this study, obesity was associated with both higher volumes of distribution and clearance compared with those previously reported in nonobese patients. However, these changes did not lead to the inability to reach pharmacodynamic targets because standard dosing (500 mg intravenously every 8 hours over 60 minutes) was sufficient for MICs of 2 or less. Finally, ertapenem pharmacokinetics were evaluated in 30 healthy volunteers whose weight ranged from normal (i.e., BMI less than 25 kg/m2) to morbidly obese (average BMI was 43 kg/m2).68 Area under the curve was significantly lower in individuals with obesity than in those with normal weight. Standard dosing (1 g daily) failed to reach pharmacodynamic targets in any of the patients (obese and nonobese). Of interest, one study compared clinical outcomes in colorectal surgery patients who received either ertapenem or cefotetan, and surgical site infections were greater in both treatment groups when the BMI exceeded 30 kg/m2 than in patients whose BMIs were below 30 kg/m2 (ertapenem 27% vs. 13%; cefotetan 42% vs. 26%).69 In summary, it appears that standard doses of both meropenem and doripenem can be used in

patients with morbid obesity, but use of ertapenem should be reconsidered, based on its inability to reach pharmacodynamic goals and the higher incidence of clinical failure in patients with obesity. Fluoroquinolones Even though fluoroquinolones are one of the more commonly used classes of antimicrobials in the critically ill, data describing their dosing in obesity are limited. One study reported increases of 23% for volume of distribution and 29% for renal clearance in a cohort of healthy volunteers with obesity (vs. nonobese controls) who received ciprofloxacin.70 A second report described a patient weighing 226 kg who received ciprofloxacin 800 mg intravenously every 12 hours and achieved a peak serum concentration within the desired therapeutic range.71 In contrast, one study of healthy volunteers reported no differences in either volume of distribution or clearance after a weightbased ciprofloxacin dose of 2.85 mg/kg.72 Levofloxacin pharmacokinetics were described in one study that included hospitalized patients with obesity and ambulatory volunteers.73 In this study, wide variability occurred, but both volume of distribution (liters) and clearance (milliliters per minute) were similar to that reported in the package labeling. Dosage adjustments therefore appear to be unnecessary. Nevertheless, pharmacodynamic goals can be difficult to reach with levofloxacin, even in normal-sized individuals.74 Caution is warranted when using levofloxacin in patients with morbid obesity, especially when treating gram-negative organisms with an MIC of 1 or greater. Aminoglycosides Several studies have evaluated aminoglycosides in obesity, and both volume of distribution and clearance values tend to increase. However, there is much variability regarding the extent of that change, and it is not proportional to weight gain. One review noted an increase of 9%– 58% for volume of distribution and 15%–91% for clearance in patients with obesity compared with nonobese controls.75 Aminoglycoside doses in patients with obesity should be determined using AdjBW with a correction factor of 0.4, recognizing that a range of correction factors

have been reported.75 Intervals are more often chosen according to the estimated half-life. An important factor when considering an aminoglyco-side as a potential option in the morbidly obese population is whether the required dose for attaining optimal peak concentrations is within the individual clinician’s range of comfort. With large-dose (e.g., 7 mg/kg AdjBW) and extended-interval (e.g., 24 hours for normal renal function) aminoglycoside dosing strategies, it is not uncommon for calculated initial doses to exceed 1 g (for gentamicin or tobramycin) in patients with morbid obesity, which could prompt the use of a dose-capping strategy. Dose capping has the potential to prolong the time to reach goal peak concentrations while waiting for concentrations to be measured/reported and could possibly affect the clinical outcome. For this reason, other appropriate antibiotics should be considered as firstline therapy for treating gram-negative infections in patients with morbid obesity. Vancomycin Vancomycin is one of the more challenging antibiotics to dose in obesity because of the many factors that influence its clearance beyond size and calculated creatinine clearance.76 Several studies have shown that vancomycin pharmacokinetics correlate best with TBW, which is the weight descriptor recommended in published guidelines.77,78 However, this does not imply dose proportionality, and clinicians must evaluate the specific differences identified in both volume of distribution and clearance in patients with morbid obesity. For example, Bauer et al. reported a volume of distribution of 52 L in a cohort of patients with morbid obesity (average weight 165 kg) compared with 46 L in those with normal weight (average weight 68 kg),79 with clearance values of 197 mL/minute and 77 mL/minute, respectively. In this example, the principles of dose proportionality would apply for clearance but not for volume of distribution. Blouin et al. found a volume of distribution of 43 L in patients with morbid obesity (average weight 165 kg) versus 29 L in normal-weight patients (average weight 75 kg),80 with clearance values of 188 mL/minute and 81 mL/minute, respectively. Similarly, the

concept of dose proportionality is valid for clearance but not for volume of distribution. Adane et al. evaluated vancomycin pharmacokinetic parameters in a cohort of patients with morbid obesity (median weight 148 kg) with confirmed Staphylococcus aureus infections.81 Population mean volumes of distribution were 0.51 L/kg based on TBW (0.76 L/kg based on AdjBW with a 0.4 correction factor), and clearance was 6.54 L/hour. Scatterplots had better correlation of volume of distribution and clearance with TBW than with AdjBW. Several papers have linked vancomycin-induced nephrotoxicity to exposure and AUC, but nephrotoxicity may also be influenced by weight.82 In one study, weight in excess of 101 kg was significantly associated with nephrotoxicity (hazard ratio 3.17 [1.18–8.53], p=0.022) together with trough value and ICU residence.83 This could be related to more extensive vancomycin exposure because the mean trough values were only slightly higher (12.5 vs. 9.8 mg/L, p=0.03). In summary, some disparity exists in the available pharmacokinetic data regarding the relationship between weight and volume of distribution. This would be most relevant for calculating a loading dose because volume of distribution is the primary determinant of concentration. Given the concern with dose-related adverse drug events, a conservative approach would be to use AdjBW for weightbased calculations, especially because loading doses are typically 25– 30 mg/kg. However, maintenance doses and the resultant AUCs are largely influenced by clearance; therefore, TBW may be the more appropriate weight descriptor. Regardless of the weight descriptor chosen to calculate the initial regimen, therapeutic drug monitoring should be used with adjustments as necessary. Measuring two serum concentration samples with an individualized pharmacokinetic assessment may be superior to a trough-only monitoring method in these patients.84 Linezolid Linezolid is more commonly used for methicillin-resistant S. aureus in critically ill patients, but data in patients with obesity are limited. Studies have shown lower serum concentrations in patients with morbid obesity, but substantial differences in clinical cure have not been

recognized.85–87 However, one case report described failure with linezolid in a patient weighing 265 kg (BMI 82 kg/m2). In this report, peak and trough concentrations were only 4.13 and 1.27 mcg/mL, respectively.88 Therefore, standard dosing regimens (600 mg intravenously every 12 hours) can be considered when the BMI is 50 kg/m2 or less, but caution should be used in patients with more extreme forms of obesity or with organisms having a high MIC. Daptomycin The daptomycin product label recommends TBW as the measure for weight-based dosing, even in patients who are obese.89 However, pharmacokinetic studies have not shown dose proportionality with parameters such as volume of distribution and clearance.90,91 Higher concentrations have been noted with daptomycin (after weight-based dosing) in patients with obesity compared with nonobese patients, which may in fact be advantageous because of concentrationdependent killing. Adverse effects, however, may be more prevalent because several studies have reported increased creatinine phosphokinase concentrations when daptomycin was dosed as milligrams per kilogram using TBW in obesity.92,93 This has prompted some to suggest consideration for LBW or some correction factor AdjBW in this population.94,95

CONSIDERATIONS FOR UNDERWEIGHT PATIENTS Few data exist to evaluate drug dosing in patients who are markedly underweight. In general, standard drug doses or doses on the lower end of the dosing range should be appropriate. One precaution, though, pertains to anticoagulant medications. Fixed doses of medications such as LMWH, when used for VTE prophylaxis, can yield concentrations more consistent with therapeutic anticoagulation than with prophylaxis. In fact, the product label for enoxaparin cites increased exposure when weight is less than 45 kg for women and 57 kg for men.96 Bleeding rates may be higher if standard doses are administered. Bleeding rates may also be higher with weight-based

dosing of anticoagulants. A large registry trial of patients with acute VTE who received either LMWH or unfractionated heparin reported bleeding rates of 8.3% and 3.9% when TBW was less than 50 kg and between 50 and 100 kg, respectively (odds ratio [95% confidence interval] 2.2 [1.2–4.0]).97 This difference occurred primarily because of minor bleeding. A second complication that can occur in underweight patients is the presence of cachexia. Cachexia is a weight-loss syndrome characterized as an involuntary weight loss of 5% or more (or a BMI less than 20 kg/m2) plus at least three of the following: decreased muscle strength, fatigue, anorexia, low fat-free mass, and/or abnormal biochemistry.98 It is not synonymous with age-related muscle loss, starvation, malabsorption, or other conditions where TBW may be low. Pharmacokinetic alterations encountered with cachexia include decreased volume of distribution, altered protein binding (because of hypoalbuminemia), and reduced metabolism.99 Although most of these data are in the cancer and HIV populations, there are implications for medications administered in the ICU. Critical care clinicians should be cognizant of these alterations and calculate their medication regimens accordingly.

PREGNANCY Critically ill obstetric patients present many challenges to the ICU team because of their unique physiology and specific medical disorders that occur during pregnancy and the postpartum period.100,101 The most common reasons for ICU admission are hemorrhage and hypertension, but about 20%–30% of obstetric ICU patients present with nonobstetric causes for ICU admission such as sepsis.102 One of the overarching considerations when caring for a pregnant woman is to consider the benefits and risks of medications for both mother and fetus. That said, the mother’s life and safety are the top priority, and medications should not be withheld because of fetal concerns.102 Fetal compromise is often the result of maternal decompensation.103 For many disease processes, the initial assessment during the acute phase

of illness is no different from that of a nonpregnant patient. For example, treatment of severe sepsis or septic shock should be consistent with the recommendations from the Surviving Sepsis Campaign guidelines.102,104 In fact, these guidelines have been endorsed by the Royal College of Obstetricians & Gynaecologists.105,106 Aggressive fluid resuscitation should be sought with early administration of broad-spectrum antimicrobial therapy. If fluids alone cannot maintain adequate tissue perfusion, vasopressor therapy with norepinephrine should be implemented. Although norepinephrine has been associated with uterine contractions and decreased uterine blood flow, its benefit on maternal resuscitation outweighs any risks.107,108

Pharmacokinetic Considerations Pregnancy induces physiologic changes in virtually every organ system, which can substantially affect drug pharmacokinetics.100,101 The most significant change is the increase in blood volume, which is about 50% greater than in a nonpregnant patient.109 This results in a larger volume of distribution, particularly for hydrophilic medications or medications with a small volume of distribution. In addition, the increase in blood volume leads to a dilutional hypoalbuminemia whereby albumin concentrations can decrease by 20%–30%.100 Activity of the cytochrome P450 (CYP) system is increased, specifically isoenzymes CYP3A4, CYP2D6, and CYP2C9. Glomerular filtration increases by about 50%; thus, medications that are predominantly renally eliminated require a dosage adjustment. Of interest, one report suggested that only 1.29% of published pharmacokinetic studies provide data for pregnant women.110 Careful assessment and monitoring is necessary.

Medication Classification in Pregnancy Most clinicians are familiar with the categories used by the U.S. Food and Drug Administration to characterize the relative safety of medications used during pregnancy. This system consists of five categories (A, B, C, D, and X), which represent the overall ratio of

benefit-risk for use. One misconception is that these categories solely represent risk and increase proportionally from category A to X. For example, isotretinoin is commonly prescribed for acne and is labeled pregnancy category X because of its well-known association with birth defects. Phenytoin is labeled pregnancy category D because of congenital fetal malformation. The difference between the two drugs is not that one has a higher risk of fetal harm, but the benefit to be gained with its use (i.e., treatment of a life-threatening seizure vs. treatment of acne). Examples of medications that should be avoided in pregnancy (because of safer alternatives) are listed in Table 41.4. Effective June 30, 2015, a new rule was implemented for labeling regarding pregnancy and lactation.111 The old categories (A, B, C, D, and X) were removed together with the subsections “pregnancy,” “labor and delivery,” and “nursing mothers.” These subsections were replaced by “pregnancy,” “lactation,” and “females and males of reproductive potential.” Under the new rule, the pregnancy subsection is more thorough and includes information regarding available registries of data (if existent), a summary of the risks, a statement regarding systemic absorption, and information to assist health care providers in making prescribing decisions about the medication (e.g., dose adjustments during pregnancy and the postpartum period, disease-associated maternal/fetal risk, maternal and fetal adverse reactions, and the effect of the drug on labor and delivery).

Medication-Specific Recommendations Vasopressors Most data surrounding vasopressor therapy are in the setting of blood pressure management during spinal anesthesia for cesarean delivery. Ephedrine and phenylephrine have been the two preferred medications for this indication. Historically, ephedrine had been preferred because of animal studies showing better preservation of utero-placental blood flow and concerns with the use of pure α-agonists.112,113 However, better fetal acid-base status with phenylephrine has been cited in several reports.114,115 In lieu of these data, several groups (including

the American Society of Anesthesiologists) have recommended phenylephrine as first-line therapy for spinal anesthesia-induced hypotension except in the setting of maternal bradycardia, where ephedrine may be preferred.116–119

Table 41.4 Commonly Used Medications in Critical Care That Should Be Avoided in Pregnancy Medication

Alternative

Comments

ACE inhibitors/​ angiotensin II receptor blockers

Labetalol, hydralazine, nicardipine, nifedipine

ACE inhibitors are associated with fetal renal failure and teratogenic effects and are contraindicated

Echinocandins

Amphotericin B

Teratogenic effects have been reported in animal studies. Human data are nonexistent

Esmolol

Labetalol

Esmolol has the potential to cause fetal bradycardia

Fluconazole

Amphotericin B

Doses > 300 mg are considered teratogenic

Fluoroquinolones

β-Lactams, cephalosporins, macrolides. Specific agent will be based on clinical situation

Concerns exist for abnormal fetal development (particularly from animal studies), but fluoroquinolones can be considered when multidrug-resistant organisms are encountered

Sodium nitroprusside

Nicardipine

Concerns for fetal cyanide toxicity limit the use of sodium nitroprusside

Tetracyclines

β-Lactams, cephalosporins, macrolides. Specific agent will be based on clinical situation

Tetracyclines bind calcium and cause permanent discoloration of teeth

Trimethoprim/​ sulfamet​ hoxazole

β-Lactams, cephalosporins. Specific agent will be based on clinical situation

Teratogenic effects noted with use in first trimester. Sulfonamides may be harmful in third trimester

Valproate

Levetiracetam

Valproate should be considered a last resort in status because of its association with links to spina bifida

Voriconazole

Amphotericin B

Voriconazole is teratogenic in animals. Data in humans are limited to one observation (with a good outcome)

Warfarin

Low-molecularweight heparin

Warfarin is associated with teratogenic effects and is contraindicated

For the treatment of severe sepsis or shock, the choice of a specific vasopressor should be no different from in a nonpregnant patient. Restoring maternal perfusion pressure is of greatest importance and should override concerns for uterine vasoconstriction. Norepinephrine is therefore the agent of choice. If hypotension persists despite norepinephrine, second-line agents include epinephrine and vasopressin. Data analyses describing these agents in pregnancy are sparse. Epinephrine crosses the placenta and can inhibit contractions. Case reports have described the use of epinephrine in the setting of anaphylaxis during pregnancy.120 In one report, an epinephrine infusion was administered for 3.5 hours, and no fetal adverse effects were reported.121 Antimicrobial Therapy Early, appropriate antimicrobial therapy is crucial in the care of the critically ill, infected patient. Similar to therapy for nonpregnant patients, broad-spectrum therapy should be implemented as soon as possible. Empiric antibiotic selection should address safety to the infant, especially during the first trimester when major organogenesis takes place. However, little safety information is available for many of the newer anti-infective agents—those commonly considered for

empiric therapy in the ICU. Antibiotics such as β-lactams and macrolides have substantial data, and their use in pregnancy is generally well accepted.122 One large population-based, multisite, case-control study of more than 18,000 participants confirmed the safety of penicillins, cephalosporins, and macrolides, but sulfonamides and nitrofurantoin were associated with birth defects.123 Tetracyclines readily cross the placenta and, when used beyond the second trimester, bind calcium and cause permanent discoloration of teeth.122 Fluoroquinolones are often avoided during pregnancy because of concerns with abnormal fetal cartilage development. An additional concern pertains to their mechanism of action (inhibition of DNA synthesis) and theoretical mutagenic and carcinogenic potential. These concerns originate from animal models with doses that are substantially higher than those used in the clinical arena.124 In humans, most studies have not shown an association with fluoroquinolones and fetal harm. Ciprofloxacin has been the most extensively studied. Therefore, although routine use of fluoroquinolones is not recommended, they can be considered when multidrug-resistant organisms are encountered.124 Vancomycin is often considered for resistant gram-positive infections, but there is little information regarding its transplacental passage to the fetus. One study measured maternal and cord blood vancomycin levels at delivery after three different dosing regimens: 1 g every 12 hours, 15 mg/kg every 12 hours, and 20 mg/kg every 8 hours.125 Maternal and cord blood vancomycin concentrations were therapeutic in 32% and 9% with a 1-g dose every 12 hours, 50% and 33% with a 15-mg/kg dose every 12 hours, and 83% and 83% with a 20-mg/kg dose every 8 hours. No adverse effects were noted. These data analyses show significant passage of vancomycin to the fetus, but higher doses are required to reach therapeutic levels. Although vancomycin use is generally considered safe, therapeutic drug monitoring should be used.126 The treatment of fungal infections in obstetric patients can be challenging because of the limited therapeutic options and the high morbidity and mortality associated with these infections. Fluconazole is widely considered for empiric therapy; however, several reports have

shown significant teratogenic risk, particularly with doses used to treat systemic infections (i.e., greater than 300 mg/day).127 Because voriconazole has been shown to be teratogenic in animal studies, it should not be considered. Similarly, the echinocandins have been studied in animal models, and teratogenic effects were recognized. There are no data in humans. Amphotericin B is the safest antifungal drug in pregnancy and considered the agent of choice. Although nephrotoxicity is an important limitation, its incidence is similar to that reported in nonpregnant patients.127 Liposomal amphotericin B can also be considered safe in pregnancy, but limited data exist with other lipidic derivatives. These products should only be considered when other polyenes are unavailable. Antihypertensive Medications Various antihypertensive agents can be considered to manage hypertension during pregnancy, but this discussion will focus on managing acute hypertensive crises in critically ill pregnant women. Intravenous hydralazine and labetalol have long been considered firstline agents because of their favorable adverse effect profile and extensive clinical experience in the critical care setting.128 Several groups, including the European Society of Cardiology, have recommended labetalol over hydralazine in pregnant patients.129,130 In fact, hydralazine is no longer listed as a first-line option because of concerns with more perinatal adverse effects. In one meta-analysis, hydralazine was associated with several adverse outcomes compared with alternative therapy (e.g., labetalol and nifedipine), including more maternal hypotension, placental abruption, adverse effects on fetal heart rate, cesarean section, maternal oliguria, and low Apgar scores.131 The calcium channel blockers nifedipine and nicardipine are potential options, and both are safe and effective during pregnancy.132,133 In fact, nifedipine is listed as either a first- or a second-line agent, according to many guideline groups.128,130 Nifedipine should be administered orally (vs. sublingually); thus, administration in the critically ill patient may not be possible. Of note, pregnant patients

often receive concomitant magnesium therapy, and isolated reports of profound hypotension or neuromuscular blockade with nifedipine exist.133 Several antihypertensive agents should be avoided. Agents that act on the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers) are contraindicated because of increased fetal mortality and morbidity, including oligohydramnios, renal dysgenesis calvarial hypoplasia, and fetal growth restriction.133 These agents should not be used. Esmolol has the potential to cause fetal bradycardia, and loop diuretics are controversial because of theoretical concerns for reduced plasma volume. Sodium nitroprusside should be reserved for severe, lifethreatening emergencies when other agents have failed because of its potential for cyanide and thiocyanate toxicity for both mother and fetus. Sedatives and Analgesics Data describing sedative and analgesic use specific to pregnancy are limited, but in general, recommendations from evidence-based guidelines should apply.134 For example, validated sedation scoring systems should be used, and light levels of sedation should be maintained. Non-benzodiazepine medications are preferred to benzodiazepines because of their association with shorter lengths of ICU stay. Propofol is the most commonly used regimen in the ICU, and its use has been described in the operating room during cesarean sections. Overall, propofol rapidly crosses the placenta but seems to have no major neonatal adverse effects.135–138 Reports characterizing the safety of propofol for longer-term sedation are limited. Case reports have described propofol use ranging from 10 to 48 hours.139–141 Although significant teratogenic events were not evident, neonatal respiratory depression (postdelivery) can occur. Dexmedetomidine is a second, non-benzodiazepine option commonly considered in the ICU, but no studies describe its use in critically ill, pregnant women. Limited experiences with dexmedetomidine near the time of cesarean section have resulted in the delivery of healthy infants.142,143 Fetal bradycardia has not been reported, but more

rigorous evaluation is necessary, particularly with higher doses of dexmedetomidine. Dexmedetomidine may increase the frequency of uterine contraction, which may preclude its use in some pregnant ICU patients. Studies conducted in the 1970s suggested that benzodiazepines contribute to malformations such as facial clefts when used during the first trimester, but later studies (that were better controlled) have refuted this association.144 However, benzodiazepines do readily cross the placenta; therefore, neonatal respiratory depression may occur if used before delivery. High doses of intravenous lorazepam may lead to propylene glycol toxicity, given that its clearance is reduced in neonates.145 Nevertheless, as with all medications used in the ICU during pregnancy, risk-benefit must be assessed, and therapy should not be withheld if necessary (e.g., treatment of status). Data with opioid analgesics during pregnancy in the ICU setting are limited, with most data in reference to maternal illicit substance abuse or opioid dependency.146 In general, several reports have shown that short-term use of morphine or fentanyl is considered safe. As with all opioids, though, respiratory depression can occur with higher doses or more prolonged use near the end of pregnancy. Overall, the general principles of pain management used in nonpregnant patients can be applied to pregnant ICU patients. These include using validated pain scales, not relying on vital signs alone to assess pain, and avoiding morphine in renal failure. Anticoagulants Pregnancy is associated with a hypercoagulable state that is caused by a combination of physical and hormonal factors, together with changes in the balance of procoagulant versus anticoagulant factors.147,148 Critically ill pregnant patients should receive VTE prophylaxis with either LMWH or unfractionated heparin. Neither crosses the placenta, and both are safe.148,149 Low-molecular-weight heparin may be preferred to unfractionated heparin because of its increased bioavailability and lower risk of maternal osteoporosis and heparin-induced thrombocytopenia.150 Dosing recommendations for

LMWH are similar to those recommended in nonpregnant patients (e.g., enoxaparin 40 mg subcutaneously daily).148,150 In some cases, though, twice-daily dosing may be necessary because of changes in renal excretion and protein binding. With unfractionated heparin, higher doses have been recommended by the American College of Obstetricians and Gynecologists: 5,000–7,500 units subcutaneously during the first trimester, 7,500–10,000 units subcutaneously during the second trimester, and 10,000 units subcutaneously during the third trimester, each every 12 hours.148 Of note, multidose vials of both LMWH and unfractionated heparin contain benzyl alcohol, which has been reported to cause gasping syndrome in neonates. Either preservative-free formulations or single-dose syringes are advised.151 For treatment of acute VTE, either LMWH or unfractionated heparin is acceptable.148,150,152 Unfractionated heparin may be preferable because of its rapid onset and the ability to make frequent dosing adjustments.108,147,152 Inadequate anti-Xa levels have occurred with standard weight-based dosing of LMWH, which is worrisome in the setting of pulmonary embolism. If LMWH is chosen for initial therapy, twice-daily dosing should be considered.147,152 Warfarin, which has well-known fetal teratogenic effects, should not be used. For patients with heparin-induced thrombocytopenia, either argatroban or fondaparinux can be considered. No fetal adverse effects have been reported with these agents in case reports.153–157 Medications for Postpartum Hemorrhage Postpartum hemorrhage is an obstetric emergency and one of the most common causes of maternal morbidity and mortality.158,159 Oxytocin is widely regarded as the drug of choice and works by inducing fast and long-acting contractions of the myometrium. After intravenous administration, uterine contractions have been reported within 1 minute.158 Administration methods (bolus vs. infusion) vary depending on the organization, but rapid administration may lead to peripheral vasodilation, hypotension, and an increase in cardiac output.158,160 As such, the American College of Obstetricians and Gynecologists recommends 10–40 units in 1 L of normal saline or

lactated Ringer solution administered by continuous infusion.161 If oxytocin is ineffective, ergot alkaloids (e.g., methylergonovine) are second line. These agents, which produce strong α-adrenergic stimulation, are contraindicated in patients with hypertension, preeclampsia, or a history of myocardial infarction. An alternative to ergot alkaloids is carboprost, a prostaglandin analog. Because carboprost causes bronchospasm, it should not be used in patients with asthma or respiratory insufficiency. Other agents that have recently been considered include recombinant factor VII and tranexamic acid. Data analyses assessing the efficacy of recombinant factor VII are primarily through case reports, case series, and registry data; there are no randomized controlled trials.162–166 One systematic review reported that recombinant factor VII was effective in stopping or reducing bleeding in 85% of cases.164 Collectively, the most common dose was about 80– 90 mcg/kg. There is one randomized controlled trial evaluating the benefit of tranexamic acid in 144 women with post-partum hemorrhage.167 Women with blood loss exceeding 800 mL after vaginal delivery were randomized to receive tranexamic acid (4-g load over 1 hour, followed by 1 g/hour for 6 hours) or not. Blood loss at 6 hours post-enrollment was lower with tranexamic acid (median 173 vs. 221 mL, p=0.041), as was duration of bleeding and progression to severe hemorrhage. A second trial is ongoing that is anticipated to enroll 20,000 women.168 Of note, this trial will use a lower dose: 1 g followed by an additional 1 g if bleeding continues. In summary, both recombinant factor VII and tranexamic acid could be useful therapies for postpartum hemorrhage; however, the current data are not robust enough to recommend them as early options. These agents can be considered when bleeding fails to resolve after traditional therapies. Further studies are needed to establish the safest and most cost-effective dose for each therapy.

THERAPEUTIC PLASMA EXCHANGE

Therapeutic plasma exchange or plasmapheresis is an extra-corporeal procedure wherein plasma is separated from the cellular components of blood and all solutes in plasma are removed. To maintain normal plasma volume, replacement solutions, which are typically albumin or fresh frozen plasma, are infused. By removing and discarding plasma, any medication or solute present in plasma is thereby lost. In the ICU, therapeutic plasma exchange may be used to treat a vast array of disorders such as thrombocytopenic purpura, myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Goodpasture syndrome, rapidly progressive glomerulonephritis, and acute antibody-mediated renal allograft rejection.169,170 Elimination through plasma exchange is a passive process that follows linear kinetics.171 A single exchange of 1 plasma volume will remove around 63% of all solutes, whereas an exchange of 1.5 times the plasma volume will remove around 78%.172 In general, a drug is more likely to be removed if it has a small volume of distribution (i.e., less than 0.2 L/kg) or a high degree of protein binding (i.e., greater than 80%).169 This differs from renal replacement therapies, where drugs with high protein binding are not effectively removed. One of the most influential factors, even more important than drug pharmacokinetics, is the time between dose administration and therapeutic plasma exchange initiation. Several studies have shown a strong correlation of drug removal when therapeutic plasma exchange was initiated shortly after dose administration.169,173 In fact, for some drugs—even those with a small volume of distribution—removal can be minimized by allowing for an adequate distribution time before initiating therapeutic plasma exchange.174 Distribution half-life can therefore be an important parameter to assess in these instances. Exchanges at the end of a dosing interval will lead to a smaller loss of drug than exchanges occurring just after a dose.

Agent-Specific Recommendations Several pharmacokinetic studies have evaluated the effect of therapeutic plasma exchange on drug removal. Most of the available

data are not with medications commonly used in the ICU. For a review of these medications, the reader is referred elsewhere.169,171,175 Cephalosporins Several papers have described cephalosporin dosing in patients undergoing therapeutic plasma exchange.174,176-178 One report described cefepime removal after a single 2-g dose administered over 30 minutes and given 2 hours before the plasma exchange.174 Cefepime has a volume of distribution of around 0.2–0.3 L/kg, and its degree of protein binding is less than 20%.173 Despite a low volume of distribution, the amount of drug removed was only about 4%, indicating that supplemental doses are not required, provided the drug is administered at least 2 hours before plasma exchange. The pharmacokinetic profile of ceftazidime is similar to that of cefepime, with a volume of distribution of 0.23 L/kg and protein binding of less than 20%.173 In one report, a single dose of ceftazidime 2 g was administered 15–120 minutes before plasma exchange.177 The amount of drug removal ranged from 2% to 9%, with greater extraction occurring with shorter intervals between drug administration and the procedure. It is therefore recommended to administer ceftazidime at least 2 hours before therapeutic plasma exchange.173 Ceftriaxone has a small volume of distribution (0.1–0.2 L/kg), but unlike cefepime or ceftazidime, it is highly protein bound (90%– 95%).173 One study assessed ceftriaxone concentrations when administered immediately and 6 hours before plasma exchange.178 Drug removal was greater when ceftriaxone was given immediately before the exchange (23% mg vs. 17%). A second study compared ceftriaxone concentrations after a 2-g dose administered 3 hours versus 15 hours before a plasma exchange.176 The fraction of drug removed was significantly greater with early administration (12.7% vs. 5.7%, p 2 standard deviations (SD) above agespecific norms • Progressive tachypnea Adults > 25 beats/min not ventilated, or minute ventilation > 12 L/min ventilated Children > 2 SD above agespecific norms • Thrombocytopenia (only applicable at least 3 days after initial resuscitation) Adults < 100,000/microliters Children < 2 SD below agespecific norms Hyperglycemia in the absence of preexisting diagnosis of diabetes mellitus Plasma glucose > 200 mg/dL before treatment

Insulin resistance (e.g., 25% increase in insulin requirements over 24 hr) • Inability to continue enteral feeding for at least 24 hr Abdominal distension Enteral feeding intolerance Uncontrollable diarrhea (> 2.5 L/day for adults or > 400 mL/day for children) Severe Sepsis • This term is not recognized by the ABA Septic Shock • Sepsis PLUS traditional hemodynamic alterations

Because of the massive inflammatory response associated with severe burn injury, the traditional criteria for recognizing sepsis (e.g., leukocytosis, fever, tachypnea, and tachycardia) cannot be used. Traditional definitions for systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock are discussed in chapter 15, “Severe Sepsis and Septic Shock.” In patients with burn injury, the ABA defines sepsis as a trigger for concern for infection that must include at least three of six possible criteria, together with documented infection (Box 42.2).81 The ABA does not recognize the term severe sepsis, and the criteria for septic shock include those defining sepsis plus the traditional hemodynamic parameters defined by the Surviving Sepsis Campaign. Of note, these burn-specific criteria were initially developed as an initiative of a consensus conference, and they have not yet been fully validated. Subsequently, studies have confirmed that the traditional SIRS criteria have poor predictive value for sepsis within the burn population.82 Almost all patients with severe burn injury have traditional SIRS criteria, regardless of the suggestion of sepsis, and more than 95% of patients met SIRS criteria, even

during periods of clinical stability. Although the ABA criteria have improved clinical value, additional criteria to assist in more accurately identifying sepsis in this population have been proposed. Additional factors to consider include a more stringent heart rate threshold (heart rate greater than 130 beats/minute), serum glucose concentrations greater than 150/dL or increasing glycemic variability, hemodynamic instability (mean arterial pressure less than 60 mm Hg or use of vasoactive agents), and evidence of pulmonary and additional diagnostic laboratory values (procalcitonin and serum N-terminal pro– B-type natriuretic peptide).82-84

Pharmacokinetic and Pharmacodynamic Considerations for Antimicrobial Agents in Burn Injury The hypermetabolic alterations observed in severe burn injury are accompanied by significant pharmacokinetic alterations that can affect optimal drug dosing in this complex population.85,86 Although there is published literature to aid practitioners in determining dosing adjustments for this population, there are limitations to the data, including significant variability in methodology and patient characteristics and small sample sizes. These studies have also shown that burn severity alone cannot predict the dosing alterations required to overcome the pharmacokinetic alterations. Practitioners should consider standard key criteria when optimizing drug dosing in burn patients (Box 42.3). During the initial ebb phase, patients with severe burn injury have an initial decrease in creatinine clearance that returns to normal or above normal after fluid resuscitation is achieved.87,88 Significant alterations in hepatic metabolism occur as well during the flow phase because of increased hepatic perfusion. Phase 1 metabolism (i.e., oxidation) is significantly decreased, and phase 2 metabolism (i.e., conjugation, glucuronidation) is either unchanged or increased. Significant increases in volume of distribution also occur as a result of fluid resuscitation, hyperdynamic circulation, and capillary leak. These alterations have an impact on pharmacokinetics, primarily for drugs that distribute into the extracellular fluid (e.g., aminoglycosides). Decreased protein synthesis,

including both albumin and total protein concentrations, results in increased free concentrations of highly protein bound medications (e.g., phenytoin, valproic acid). In contrast, increases in acute phase proteins, including α1-acid glycoprotein, can significantly lower free concentrations of drugs that bind to α1-acid glycoprotein after burn injury (e.g., imipramine and lidocaine). Antimicrobial agents with specific dosing recommendations to overcome these pharmacokinetic changes are summarized in Table 42.6.

OTHER SUPPORTIVE THERAPY IN BURN INJURY Glycemic Control in Burn Injury Box 42.3. Key Considerations for Pharmacokinetics in Burn Injury 1. Burn size and depth • Burns of increasing severity are more likely associated with a profound hypermetabolic response 2. Age • Older patients are more likely to have preexisting renal and hepatic insufficiency 3. Time since burn injury • Depending on timing, pharmacokinetic alterations differ (i.e., ebb vs. flow phase) Although metabolic rate can remain increased for years, early in the flow phase, the alterations are more profound 4. Creatinine clearance • Although calculated creatinine clearance may not be accurate in this population, it can be used to trend changes in renal function across time

5. Serum protein concentrations • Decreased albumin concentrations and increased α1-acid glycoprotein may affect free drug concentrations 6. Volume status • Once adequately fluid resuscitated, volume of distribution will likely be increased because of added fluid volume and capillary leak 7. Presence of sepsis as defined by the ABA • Sepsis is known to increase hypermetabolism 8. Drug properties • Specifics regarding volume of distribution, protein binding, metabolism, and modes of elimination are needed to estimate response in patients with burn injury 9. Other information • Data from indirect calorimetry and interventions known to decrease metabolic rate (i.e. excision and grafting) can be used to augment assessment of hypermetabolism

Table 42.6 Suggested Antimicrobial Dose Adjustments in Patients with Burn Injury86,87,89-102

Agent

Reference

Suggested Dosing

Additional Considerations

Extended-interval dosing using at least 20 mg /kg

Studies have identified inverse relationship between Cmax/ MIC ratio and bumsize

Gram-negative Antimicrobials

Amikacin

Weinbren 1999 Conil 2007

Institutional data regarding MICs should be used to target Cmax/MIC ratio of > 8-10 Tobramycin

Arnould 2009 Vella 2014

Extended -interval dosing using at least 9 mg/ kg

Institutional data regarding MICs should be used to target Cmax/MIC ratio of > 8-10

Up to 45 days after injury: 10-13 mg /kg > 45 days after injury

8-10 mg /kg

(3 -Lactams:

Weinbren 1999

Ceftazidime

Bourget 1996

Meropenem

Conil 2007

Imipenem

Dailly 2003

Consider both extended and continuous infusions

Higher-than-traditional recommended doses maybeen necessary in additionto extended infusions toachieve target time above MIC

Piperacillin /tazobactam Doh 2010 Ciprofloxacin

Garrelts 1996

400-600 mg IV every 8 hr

Lesne-Hulin 1999 Levofloxacin

Kiser 2006

750 mgevery 24 hr

Consider alternative agents for organisms with MIC > 0.5 mcg/mL

48 hr to 14 days after injury :

Vancomycin has Vd twice normal and shorter half -life

Gram -positive Antimicrobials

Vancomycin

Ellingsen 2011

25 mg/ kg every 8 hr OR 20 mg/ kg every 6 hr

Dosing dependson institutional MICs forpertinentorganism. These recommendations are based on an MIC of 1mcg /mL

> 14 days after injury:

20-25 mg / kg every 8 hr 15-20 mg every 6 hr

Linezolid

Lovering 2009

Consider 600 mg every 8 hr

Daptomycin

Mohr 2008

10-12 mg /kg daily

Fluconazole

Boucherl998

No data

Half - life decreased byl3%, clearanceincreased by 30%

Caspofungin

Jullien 2012

No data

Report of two patients showed significant interpatient variability

Antifungals

Cmax = maximum drug concentration; MIC = minimum inhibitory concentration; Vd = volume of distribution.

During the flow phase of burn injury, hyperglycemia and insulin resistance are common. Both early and prolonged hyperglycemia after burn injury is associated with poor clinical outcomes in the burn

population. Hyperglycemia has been shown to delay wound healing, promote lean muscle losses, and suppress immune function.103,104 Although a significant body of research supports the benefits of glucose control within the critically ill population, limited data are available within the burn population. Van den Berghe’s pivotal study supporting intensive insulin control in the surgical intensive care unit included only 8 total burn and trauma patients from the total 1,548 randomized subjects.105 Most burn centers aim for euglycemia for patients with burn injury, based on extrapolation of the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation) study and the assumption that avoiding hyperglycemia may improve wound healing, reduce infections, and possibly reduce mortality.13,103,106,107 Insulin itself has been extensively studied in burn injury as an anabolic agent and has shown antiinflammatory properties. It reduces muscle catabolism and improves protein synthesis and wound healing.108-110 In 2005, Pham and colleagues reported their experience with tight glycemic control (glucose target 90–120 mg/dL) by insulin infusion in 33 pediatric burn patients with a TBSA greater than 30% injured compared with 31 historical control patients.107 Patients who received the intensive insulin protocol had a lower reported incidence of urinary tract infections and a higher rate of survival, despite similar baseline characteristics. In an adjusted logistic regression analysis, intensive insulin was associated with an adjusted odds ratio of 5.52 in favor of survival, although this failed to reach statistical significance (p=0.06). Although prevalence of hypoglycemia was not reported, administration of dextrose 50% for glucose less than 50 mg/dL was required on nine occasions in the tight glycemic control group, with no occurrences in the control group. Given these results, a prospective, randomized trial of pediatric patients with a TBSA greater than 30% burned compared tight glycemic control (n=49, glucose target 80–110 mg/dL) with conventional control (n=137, glucose target 140–180 mg/dL).108 Intensive insulin was associated with significant reductions in the rate of infection and sepsis compared with conventional control. Although there were no differences between the groups in REE, intensive insulin significantly modulated the acute

inflammatory response and resulted in improvement in lean muscle mass and bone density compared with control. The intensive insulin group also had a lower mortality rate than did controls, although this failed to reach statistical significance (4 vs. 11%, p=0.14). As observed in other critically ill populations, hypoglycemia is associated with increased morbidity and mortality with burn injury, and intensive insulin is associated with increased incidence of hypoglycemia.111 There are no randomized, prospective studies regarding glycemic control in adult patients with burn injury. A retrospective observational study showed significantly decreased rates of pneumonia and urinary tract infections with an insulin protocol targeting a blood glucose of 100–140 mg/dL in 152 adult burn injured patients with percent TBSA injured of 19% in the control group and 15% in the insulin protocol group.106 This protocol was also deemed safe because no differences in the rate of hypoglycemia were observed. In another retrospective observational study of 46 patients with severe burns, early glycemic control also improved outcomes.112 A standardized protocol was used for all patients, targeting a glucose of 110–150 mg/dL with sliding-scale insulin administration and insulin infusion initiation with repeated glucose concentrations greater than 200 mg/dL. Failure to achieve early glycemic control, defined as achievement of a daily average blood glucose of 150 mg/dL or less for a minimum of 2 consecutive days by post-burn day 3 was independently associated with an increase in mortality by 6.75-fold. Although data are limited in both pediatric and adult patients with burn injury, it is generally accepted that protocols to maintain euglycemia while avoiding both hyperglycemia and hypoglycemia (e.g., target glucose range 90–140 mg/dL) should be implemented as standard of care in this population.111

Venous Thromboembolism Prophylaxis Clinical diagnosis of deep venous thrombosis in patients with burn injury can be challenging. Clinical signs that are common to both burn injury and deep venous thromboembolism include erythema, edema, and tenderness. Current data suggest a much lower incidence of venous thromboembolism (VTE) in patients with burn injury than in the general

trauma population. Reported prevalence in burn patients is 1%–6%, whereas in trauma patients, reported prevalence is 5%–63%, depending on methods of diagnosis and means of mechanical or pharmacologic prophylaxis.113-117 The current CHEST guidelines recommend pharmacologic prophylaxis with either low-dose unfractionated heparin or low-molecular-weight heparin agents with or without mechanical prophylaxis for trauma patients.118 Literature is limited to establish the efficacy of varying VTE prophylaxis therapies in patients with burn injury, which forces extrapolation from data published in non-burn injury populations. Routine VTE prophylaxis with either unfractionated heparin or low-molecular-weight heparin is recommended by the ABA for patients with additional risk factors for VTE and no contraindications to treatment. Known VTE risk factors in burn injury include advanced age, male sex, alcoholism or tobacco use, morbid obesity, extensive or lower-extremity burns, concomitant lowerextremity trauma, use of a femoral or other central venous catheter, increased number of surgeries or blood transfusions, and prolonged immobility.113,119 If contraindications to pharmacologic prophylaxis exist because of bleeding risk, patients should receive mechanical prophylaxis at least until this risk resolves. However, mechanical prophylaxis can prove to be potentially difficult in patients with leg burns, depending on location of injury. The ABA guidelines do not recommend one agent over another for pharmacologic prophylaxis, but a retrospective review showed no difference in the efficacy of unfractionated heparin versus enoxaparin.120 This 10-year retrospective, cohort analysis compared patients who received prophylaxis with low-dose unfractionated heparin (n=600) or enoxaparin (n=511) with a primary end point of acute VTE according to ICD-9 coding. Among the enoxaparin-treated patients, 109 received 30 mg twice daily, and 402 received 40 mg once daily, whereas the patients given low-dose unfractionated heparin received 5,000 units twice daily. Five patients who received low-dose unfractionated heparin developed VTE (three with deep venous thromboembolism and two with pulmonary embolism), whereas no patients in the enoxaparin group developed VTE. Limitations of this study include twice-daily

heparin dosing, significant baseline differences between groups including a higher number of VTE risk factors in the low-dose unfractionated heparin group, and retrospective study design. This is the only comparative study for low-dose unfractionated heparin and low-molecular-weight heparin in burn injury, and the ideal prophylactic agents therefore remain uncertain at this time. Recent concerns regarding low-molecular-weight heparin dosing in the critically ill population have indicated a possible role for dose titration using anti-factor Xa (anti-Xa) concentration. Lin and colleagues evaluated 74 patients with burn injury who received enoxaparin 30 mg every 12 hours, which was then titrated by 20% increments to achieve a goal anti-Xa concentration of 0.2–0.4 units/mL.121 Initial dose of 30 mg every 12 hours resulted in concentrations less than the targeted goal in 76% of the patients. On titration, the median dose to achieve an anti-Xa concentration within the goal range was 33% of the normal dosing at 40 mg every 12 hours. However, anti-Xa concentrations have not been correlated with clinical outcomes, and two patients with appropriate anti-Xa concentrations developed VTE in this study.121 The calculation identified from this study for twice-daily enoxaparin dosing [dose (mg) = 22.8 + (3.3 × % TBSA/10) + (1.89 × (weight in kg)/10] was validated in a comparison of protocolized enoxaparin calculation and titration with historical controls by Faraklas and colleagues.122 This comparison study found that use of this prophylactic enoxaparin dose calculator was associated with a significantly higher proportion of patients with an anti-Xa concentration within goal range (0.2–0.4 unit/mL) with the initial measurement and fewer patients who failed to achieve goal range before discontinuing enoxaparin therapy. However, two patients—one in the calculation group and one in the control group —developed VTE despite adequate anti-Xa concentrations. Although anti-Xa concentrations are used in some institutions for enoxaparin monitoring, additional research is needed to determine the role of antiXa concentrations and enoxaparin titration in the burn population, and data correlating anti-Xa concentrations and clinical outcomes are lacking.

MANAGEMENT OF SPECIAL POPULATIONS Electrical Injury Electrical injury accounts for 3.7% of all patients presenting with burn injuries, with higher rates among adults up to age 60 years than among children and older adults.1 Electrical injuries are responsible for greater than 500 deaths annually in the United States.123 The primary cause of death is cardiac or respiratory arrest.124 Most electrical injuries occur in adults and are work related (61.1%). Although electrical injuries are rarer in children, they often occur within the home, and patients present with oropharyngeal injuries from biting on live wires.124 Injuries caused by electrical exposure are unique because they involve direct damage from the electricity as well as indirect injuries.123 Direct damage results from the effect of the electrical current directly on tissues involving electrical charge (e.g., cardiac complications), as well as conversion of the energy to heat and the subsequent tissue necrosis. Indirect injuries can be caused by muscular contractions triggered by the electrical impulses or other associated trauma, depending on the circumstances surrounding the electrical exposure (e.g., spinal cord injury or traumatic brain injury secondary to fall). The extent of the electrical injury is determined by the electrical voltage and resistance within the tissues exposed (i.e., lowest amount of resistance in nerves, blood, muscles; highest amount of resistance in bones, tendons, fat). Higher voltage (greater than 1000 V) is associated with more severe injury than is lower voltage. Electrical injury can cause multisystem dysfunction and is associated with higher complication rates than other burn injuries, including development of cardiovascular, neurovascular, cutaneous, and pulmonary complications.1,123 Electrical exposure can result in the direct necrosis of myocardium as well as arrhythmias. The severity of the damage is proportional to voltage and is more severe with AC (alternating current) than with DC (direct current). Cardiac dysrhythmias can occur even with low voltage, but high-voltage current exposure carries a higher risk of ventricular asystole. Patients with electrical injury should initially be assessed with an electrocardiogram

(ECG). Patients with a normal initial ECG are considered at low risk of late arrhythmias, whereas patients with transthoracic current, tetany, loss of consciousness, or a high-voltage source (greater than 1000 V) may need continuous telemetry.125 Echocardiogram and monitoring of cardiac enzymes may also be warranted. Severity of cutaneous electrical burn injury is related to voltage and duration of exposure. Because of alterations in resistance as the result of moisture, minimal cutaneous damage may be visible on examination, whereas the subcutaneous tissue may have extensive necrosis. Therefore, the use of percent TBSA injured to determine resuscitative needs may grossly underestimate fluid volume requirements for patients with electrical injury. Higher-than-expected volumes may be required to maintain a goal urine output of 0.5–1 mL/kg/hour. Patients presenting with electrical injury may have seizures, neurologic deficits, and tetanic muscle contractions. Common presenting symptoms include confusion, loss of consciousness, and difficulty with recall. In addition, tetany can result in rhabdomyolysis and subsequent renal failure. Monitoring of creatinine kinase and urine myoglobin and ensuring adequate fluid resuscitation are necessary to prevent renal insufficiency in this population.

Frostbite Frostbite is a clinical diagnosis, and it is typically defined as the acute freezing of tissues when exposed to temperatures below the freezing point of intact skin. Historically, military personnel were considered at the greatest risk of developing frostbite. More recently, risk factors that are commonly identified include homeless people, alcohol or illicit drug consumption, and psychiatric illness. Classification of frostbite injury is applied once the tissues have been rewarmed, and it is categorized into four degrees. First-degree frostbite injuries present with a numb central white plaque with surrounding edema. In second-degree injury, blisters form with surrounding edema and erythema. Third-degree injury is characterized by hemorrhagic blisters that result in a hard black eschar about 2 weeks later. Fourth-degree injury produces a complete necrosis and

tissue loss. Initially, patients may present with symptoms of numbness in the affected areas. Once the tissues are re-warmed, the numbness will fade, and a throbbing sensation may begin that can last for days or weeks. Pain is managed with opioids or nonsteroidal anti-inflammatory drugs (e.g., ibuprofen). Treatment of frostbite injury begins with rewarming of the affected tissues, typically with warm water at 40°C–42°C. The temperature of the water should be carefully monitored not to reach a threshold that could potentially inflict a scald burn injury given that the patient may be unable to sense the temperature. Once the tissues have been rewarmed, the second goal of treatment is to restore arterial flow. One way to achieve this is using tissue plasminogen activator (tPA). Studies have suggested that treatment with tPA can decrease the number of amputations in patients with frostbite affecting the extremities.126,127 Patients with frostbite injury are typically considered for tPA therapy if they present within 24 hours of injury, have evidence of vascular compromise on physical examination, and have significant injury consisting of second-degree frostbite. Patients are often excluded from tPA therapy if any of the following apply: recent surgery or major trauma, uncontrolled psychiatric illness or active withdrawal from an illicit substance or alcohol, pregnancy, recent cerebral vascular accident or brain metastasis, recent gastrointestinal bleed, severe hypertension, bleeding diathesis, or irreversible ischemia (presenting greater than 24 hours from injury). Treatment of frostbite in pediatric patients with tPA has not been evaluated. Both intra-arterial and intravenous administration of tPA has been investigated. Early surgical intervention is typically not indicated in frostbite injury. The adage “Frostbite in January, amputation in July” is often used to describe frostbite injury. Rarely, escharotomy or fasciotomy may be indicated if compartment syndrome develops. However, if any surgical intervention is warranted in severe injury, it is often delayed for weeks to months post-injury. As with any burn injury, prevention is the best way to avoid frostbite injury. Individuals should use protection from the environment with

multilayer clothing that is dry and non-compressing. Awareness of warning signs such as cold, pain, and numbness should prompt individuals to seek shelter and warmth.

Chemical Burns Chemical burns account for about 3% of admissions to burn centers every year, with almost 50% of these injuries occurring in a workrelated setting, although many injuries can occur with exposure to common household chemical products.1 Acidic agents can cause a caustic injury and typically account for less than half of chemical burn injuries.128 Alkali substances, by contrast, can cause liquefaction destruction and tend to penetrate deeper, creating a worse burn injury. Alkali injuries tend to make up more than half of injuries caused by chemicals.128 Initial treatment of any chemical burn is immediate removal of the substance to prevent further tissue damage, such as removal of affected clothing and continuous irrigation with water or saline until skin pH returns to normal using litmus paper. Injuries to the eyes should be irrigated copiously and should be evaluated by an ophthalmologist. Some chemicals have specific treatment to prevent further tissue damage, such as burns caused by hydrofluoric acid. Free fluoride ions immobilize intracellular calcium and magnesium, causing extreme pain to the affected areas. Treatment with topical calcium gluconate gel to the burned areas is the mainstay of therapy to reduce the pain. Intravenous calcium gluconate, magnesium sulfate, or both may be indicated.

CONCLUSION Patients with burn injury constitute a unique subset of the critically ill population. Pharmacists can play a key role with respect to optimizing care, from managing inhalation injury and metabolic modulation to recognizing sepsis and optimizing medication dosing on the basis of pharmacokinetic/pharmacodynamic alterations. The ABA recognizes the importance of the pharmacist in the care of this population and

requires the involvement of a pharmacist with an understanding of the pharmacokinetic implications for patients with acute burn injuries for a burn center to become ABA verified.

REFERENCES 1. American Burn Association (ABA). 2014 National Burn Repository: report of data from 2004–2013 Dataset Version 10.0. American Burn Association NBR Advisory Committee, 2014. 2. Peck ME. Epidemiology of burns throughout the world. Part I. Distribution and risk factors. Burns 2011;37:1087-100. 3. LaBorde P. Burn epidemiology: the patient, the nation, the statistics, and the data resources. Crit Care Nurs Clin North Am 2004;16:13-25. 4. Jeschke MG, Herndon DN. Burns in children: standard and new treatments. Lancet 2014;383:1168-78. 5. Herndon DN. Total Burn Care, 3rd ed. Philadelphia: Saunders Elsevier, 2007. 6. Atiyeh BS, Gunn SWA, Dibo SA. Metabolic implications of severe burn injuries and their management: a systematic review of the literature. World J Surg 2008;32:1857-69. 7. Gauglitz GG, Jeschke MG. Pathophysiology of burn injury. In: Jeschke MG, ed. Handbook of Burns. New York: SpringerVerlag/Wien, 2012:131-49. 8. Butler KL, Sheridan RL. Organ responses and organ support. In: Jeschke MG, ed. Handbook of Burns. New York: SpringerVerlag/Wien, 2012:193-201. 9. Baxter CR, Shires T. Physiological response to crystalloid resuscitation of severe burns. Ann N Y Acad Sci 1968;150:87494. 10. Hansbrough JF. Enteral nutritional support in burn patients. Gastroenterol Endosc Clin North Am 1998;3:645-67.

11. Miller JT, Btaiche IF. Oxandrolone treatment in adults with severe thermal injury. Pharmacotherapy 2009;29:213-26. 12. Ballian N, Rabiee A, Andersen DK, et al. Glucose metabolism in burn patients: the role of insulin and other endocrine hormones. Burns 2010;36:599-605. 13. Gauglitz GG, Herndon DN, Jeschke MG. Insulin resistance postburn: underlying mechanisms and current therapeutic strategies. J Burn Care Res 2008;29:683-94. 14. Vanhorebeek I, Langouche L, Van den Berghe G. Tight blood glucose control with insulin in the ICU: facts and controversies. Chest 2007;132:268-78. 15. Sjoberg F. Pre-hospital, fluid and early management, burn wound evaluation. In: Jeschke MG, ed. Handbook of Burns. New York: Springer-Verlag/Wien, 2012:105-16. 16. Haller HL, Giretzlehner M, Dirnberger J, et al. Medical documentation of burn injuries. In: Jeschke MG, ed. Handbook of Burns. New York: Springer-Verlag/Wien, 2012:117-29. 17. Colohan SM. Predicting prognosis in thermal burns with associated inhalational injury: a systematic review of prognostic factors in adult burn victims. J Burn Care Res 2010;31:529-39. 18. Sheppard NN, Hemington-Gorse S, Shelley OP, et al. Prognostic scoring systems in burns: a review. Burns 2011;37:1288-95. 19. Gomez M, Wong DT, Stewart TE, et al. The FLAMES score accurately predicts mortality in burn patients. J Trauma 2008;65:636-45. 20. Barrow RE, Spies M, Barrow LN, et al. Influence of demographics and inhalation injury on burn mortality in children. Burns 2004;30:72-7. 21. Barrow RE, Przkora R, Hawkins HK, et al. Mortality related to gender, age, sepsis, and ethnicity in severely burned children. Shock 2005;23:485-7.

22. Erickson EJ, Merrell SW, Saffle JR, et al. Differences in mortality from thermal injury between pediatric and adult patients. J Pediatr Surg 1991;26:821-5. 23. Thombs BD, Signh VA, Milner SM. Children under 4 years are at greater risk of mortality following acute burn injury: evidence from a national sample of 12,902 pediatric admissions. Shock 2006;26:348-52. 24. Barrow RE, Jeschke MG, Herndon DN. Early fluid resuscitation improves outcomes in severely burned children. Resuscitation 2000;45:91-6. 25. Pham TN, Cancio LC, Gibran NS. American Burn Association practice guidelines burn shock resuscitation. J Burn Care Res 2008;29:259-66. 26. Alvarado R, Chung KK, Cancio LC, et al. Burn resuscitation. Burns 2009;35:4-14. 27. Gille J, Klezcewski B, Malcharek M, et al. Safety of resuscitation with Ringer’s acetate solution in severe burn (VolTRAB) – an observational trial. Burns 2014;40:871-80. 28. Pruitt BA. Protection from excessive resuscitation: “pushing the pendulum back.” J Trauma 2000;49:567-8. 29. Endorf FW, Dries DJ. Burn resuscitation. Scand J Trauma Resusc Emerg Med 2011;19:69. 30. Saffle JR. The phenomenon of “fluid creep” in acute burn resuscitation. J Burn Care Res 2007;28:382-95. 31. Snell JA, Loh NH, Mahambrey T, et al. Clinical review: the critical care management of the burn patient. Crit Care 2013;17:241. 32. McBeth PB, Sass K, Nickerson D, et al. A necessary evil? Intraabdominal hypertension complicating burn patient resuscitation. J Trauma Manag Outcomes 2014;8:12. 33. Medina MA, Moore DA, Cairns BA. A case series: bilateral ischemic optic neuropathy secondary to large volume fluid

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on cell-mediated immunity following burn injury in an animal model. Burns 1999;25:113-8. 45. Kremer T, Harenber P, Hernekamp F, et al. High-dose vitamin C treatment reduces capillary leakage after burn plasma transfer in rats. J Burn Care Res 2010;31:470-9. 46. Matsuda T, Tanaka H, Yuasa H, et al. The effects of high-dose vitamin C therapy on postburn lipid peroxidation. J Burn Care Rehabil 1993;14:624-9. 47. Tanaka H, Lund T, Wiig H, et al. High dose vitamin C counteracts the negative interstitial fluid hydrostatic edema generation in thermally injured rats. Burns 1999;25:569-74. 48. Tanaka H, Matsuda T, Miyagantani Y, et al. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study. Arch Surg 2000;135:326-31. 49. Kahn SA, Beers RJ, Lentz CW. Resuscitation after severe burn injury using high-dose ascorbic acid: a retrospective review. J Burn Care Res 2011;32:110-7. 50. Buehner M, Pamplin J, Studer L, et al. Oxalate nephropathy after continuous infusion of high-dose vitamin C as an adjunct to burn resuscitation. J Burn Care Res 2015. [Epub ahead of print] 51. Kahn SA, Lentz CW. Fictitious hyperglycemia: point-of-care glucose measurement is inaccurate during high-dose vitamin C infusion for burn shock resuscitation. J Burn Care Res 2015;36:e67-e71. 52. Sartor Z, Kesey J, Dissanaike S. The effects of intravenous vitamin C on point-of-care glucose monitoring. J Burn Care Res 2015;36:50-6. 53. Barbosa E, Faintuch J, Moreira EAM, et al. Supplementation of vitamin E, vitamin C, and zinc attenuates oxidative stress in burned children: a randomized, double-blind, placebo-controlled pilot study. Burn Care Res 2009;30:859-66.

54. Palmieri TL, Gamelli RL. Diagnosis and management of inhalation injury. In: Jeschke MG, ed. Handbook of Burns. New York: Springer-Verlag/Wien, 2012:163-72. 55. Dries DJ, Endorj FW. Inhalation injury: epidemiology, pathology, treatment strategies. Scand J Trauma Resusc Emerg 2013;21:31. 56. Toon MH, Maybauer MO, Greenwood JE, et al. Management of acute smoke inhalation injury. Crit Care Resusc 2010;12:53-61. 57. Desai MH, Micak R, Richardson J, et al. Reduction in mortality in pediatric patients with inhalation injury with aerosolized heparin/Nacetylcysteine therapy. J Burn Care Rehabil 1998;19:210-2. 58. Holt J, Saffle JR, Morris SE, et al. Use of inhaled heparin/Nacetylcysteine in inhalation injury: does it help? J Burn Care Res 2008;29:192-5. 59. Miller AC, Abel R, Ziad S, et al. Influence of nebulized unfractionated heparin and N-acetylcysteine in acute lung injury after smoke inhalation injury. J Burn Care Res 2009;30:249-56. 60. Elsharnouby NM, Eid HEA, Elezz NFA, et al. Heparin/Nacetylcysteine: an adjuvant in the management of burn inhalation injury, a study of different doses. J Crit Care 2014;29:182.e1-182. e4. 61. Glas GJ, Muller J, Binnekade JM, et al. HEPBURN-investigating the efficacy and safety of nebulized heparin versus placebo in burn patients with inhalation trauma: study protocol for a multicenter randomized controlled trial. Trials 2014;15:91. 62. Weaver LK. Hyperbaric oxygen in the critically ill. Crit Care Med 2011;39:1784-91. 63. Buckley NA, Juurlink DN, Isbister G, et al. Hyperbaric oxygen for carbon monoxide poisoning. Cochrane Database Syst Rev 2011;4:CD002041. 64. Gracia R, Shepherd G. Cyanide poisoning and its treatment. Pharmacotherapy 2004;24:1358-65.

65. Shepherd G. The role of hydroxocobalamin in acute cyanide poisoning. Ann Pharmacother 2008;42:661-9. 66. Lawson-Smith P, Jansen EC, Hyldegaard O. Cyanide intoxication as part of smoke inhalation – a review on diagnosis and treatment from the emergency perspective. Scand J Trauma 2011;19:14. 67. Barillo DV. Diagnosis and treatment of cyanide toxicity. J Burn Care Res 2009;30:148-52. 68. Hart DW, Wolf SE, Zhang XJ, et al. Efficacy of a highcarbohydrate diet in catabolic illness. Crit Care Med 2001;29:1318-24. 69. Venter M, Rode H, Sive A, et al. Enteral resuscitation and early enteral feeding in children with major burns – effect on McFarlane response to stress. Burns 2007;33:464-71. 70. Pereira CT, Murphy KD, Herndon, DN. Altering metabolism. J Burn Care Rehabil 2005;26:194-9. 71. Demling RH, Desanti L. Oxandrolone induced lean mass gain during recovery from severe burns is maintained after discontinuation of the anabolic steroid. Burns 2003;29:793-7. 72. Wolf SE, Edelman LS, Kemalyan N, et al. Effects of oxandrolone on outcome measures in the severely burned: a multicenter prospective randomized double-blind trial. J Burn Care Res 2006;27:131-9. 73. Murphy KD, Thomas S, Mlcak RP, et al. Effects of long-term oxandrolone administration in severely burned children. Surgery 2004;136:219-24. 74. Porro LF, Herndon DN, Rodriguez NA, et al. Five-year outcomes after oxandrolone administration in severely burned children: a randomized clinical trial of safety and efficacy. J Am Coll Surg 2012;214:489-504. 75. Orr R, Singh MF. The anabolic androgenic steroid oxandrolone in the treatment of wasting and catabolic disorders: review of

efficacy and safety. Drugs 2004;64:725-50. 76. Demling RH. Comparison of the anabolic effects and complications of human growth hormone and the testosterone analog, oxandrolone, after severe burn injury. Burns 1999;25:21521. 77. Breederveld RS, Tuinebreijer WE. Recombinant human growth hormone for treating burns and donor sites. Cochrane Database Syst Rev 2012;12:CD008990. 78. Herndon DN, Hart DW, Wolf SE, et al. Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001;345:12239. 79. Herndon DN, Rodriguez NA, Diaz EC, et al. Long-term propranolol use in severely burned pediatric patients: a randomized controlled study. Ann Surg 2012;256:402-11. 80. Arabi S, Ahrns KS, Wahl WL, et al. Beta-blocker use is associated with improved outcomes in adult burn patients. J Trauma 2004;56:265-71. 81. Greenhalgh DG, Saffle JR, Holmes JH, et al. American Burn Association consensus conference to define sepsis and infection in burns. J Burn Care Res 2007;28:776-90. 82. Mann-Salinas EA, Baun MM, Meininger JC, et al. Novel predictors of sepsis outperform the American Burn Association sepsis criteria in the burn intensive care unit patient. J Burn Care Res 2013;34:31-43. 83. Paratz JD, Lipman J, Boots RJ, et al. A new marker of sepsis post burn injury? Crit Care Med 2014;42:2029-36. 84. Ren H, Li Y, Han C, et al. Serum procalcitonin as a diagnostic biomarker for sepsis in burned patients: a meta-analysis. Burns 2015;41:502-9. 85. Blanchet B, Jullien V, Vinsonneau C, et al. Influence of Burns on pharmacokinetics and pharmacodynamics of drugs used in the

care of burn patients. Clin Pharmacokinet 2008;47:635-54. 86. Ortwine JK, Pogue JM, Faris J. Pharmacokinetics and pharmacodynamics of antibacterial and antifungal agents in adult patients with thermal injury: a review of current literature. J Burn Care Res 2015;36:e72-84. 87. Weinbren MJ. Pharmacokinetics of antibiotics in burn patients. J Antimicrob Chemother 1999;44:319-27. 88. Zdolsek HF, Kagedal B, Lisander B, et al. Glomerular filtration rate is increased in burn patients. Burns 2010;36:1271-6. 89. Conil JM, Georges B, Breden A, et al. Increased amikacin dosage requirements in burn patients receiving a once-daily regimen. Int J Antimicrob Agents 2007;28:226-30. 90. Arnould JG, Le Floch R, Piloget A. Which tobramycin dose is needed in the burn patient [letter to the editor]. Burns 2009;35:901-6. 91. Vella D, Walker SA, Walker SE, et al. Determination of tobramycin pharmacokinetics in burn patients to evaluate the potential utility of once-daily dosing in this population. J Burn Care Res 2014;35:e240-e249. 92. Bourget P, Lesne-Hulin A, Le Reveille R, et al. Clinical pharmacokinetics of piperacillin-tazobactam combination in patients with major burns and signs of infection. Antimicrob Agents Chemother 1996;40:139-45. 93. Dailly E, Kergueris MF, Pannier M, et al. Population pharmacokinetics of imipenem in burn patients. Fund Clin Pharmacol 2003;17:645-50. 94. Doh K, Woo H, Hur J, et al. Population pharmacokinetics of meropenem in burn patients. J Antimicrob Chemother 2010;65:2428-35. 95. Garrelts JC, Jost G, Kowalsky ST, et al. Ciprofloxacin pharmacokinetics in burn patients. Antimicrob Agents Chemother

1996;40:1153-6. 96. Lesne-Hulin A, Bourget P, Ravat F, et al. Clinical pharmacokinetics of ciprofloxacin in patients with major burns. Eur J Clin Pharmacol 1999;55:515-9. 97. Kiser TH, Hoody DW, Obritsch MD, et al. Levofloxacin pharmacokinetics and pharmacodynamics in patients with severe burn injury. Antimicrob Agents Chemother 2006;50:1937-45. 98. Ellingsen M, Walker SAN, Walker SE, et al. Optimizing initial vancomycin dosing in burn patients. Burns 2011;37:406-14. 99. Lovering AM, Le Floch R, Hovsepian L, et al. Pharmacokinetic evaluation of linezolid in patients with major thermal injuries. J Antimicrob Chemother 2009;63:553-9. 100. Mohr JF, Ostrosky-Zeichner L, Wainright DJ, et al. Pharmacokinetic evaluation of single-dose intravenous daptomycin in patients with thermal injury. Antimicrob Agents Chemother 2008;52:1891-3. 101. Boucher BA, King SR, Wandschneider HL, et al. Fluconazole pharmacokinetics in burn patients. Antimicrob Agents Chemother 1998;42:930-3. 102. Jullien V. Pharmacokinetics of caspofungin in two patients with burn injuries [letter to the editor]. Antimicrob Agents Chemother 2012;56:4550-1. 103. Gore DC, Chinkes D, Heggers J, et al. Association of hyperglycemia with increased mortality after severe burn injury. J Trauma 2001;51:540-4. 104. Gore DC, Chinkes DL, Hart DW, et al. Hyperglycemia exacerbates muscle protein catabolism in burn-injured patients. Crit Care Med 2002;30:2438-42. 105. 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. 106. Hemmila MR, Taddonio MA, Arbabi S, et al. Intensive insulin

therapy is associated with reduced infectious complications in burn patients. Surgery 2008;144:629-35; discussion 35-7. 107. Pham TN, Warren AJ, Phan HH, et al. Impact of tight glycemic control in severely burned children. J Trauma 2005;59:1148-54. 108. Jeschke MG, Kulp GA, Kraft R, et al. Intensive insulin therapy in severely burned pediatric patients: a prospective randomized trial. Am J Respir Crit Care Med 2010;182:351-9. 109. Pierre EJ, Barrow RE, Hawkins HK, et al. Effects of insulin on wound healing. J Trauma 1998;44:342-345. 110. Thomas SJ, MorimotoK, Herndon DN, et al. The effect of prolonged euglycemic hyperinsulinemia on lean body mass after severe burn. Surgery 2002;132:341-7. 111. Jeschke MG. Clinical review: glucose control in severely burned patients – current best practice. Crit Care 2013;17:232. 112. Murphy CV, Coffey R, Cook CH, et al. Early glycemic control in critically ill patients with burn injury. J Burn Care Res 2011;32:58390. 113. Mullins F, Aian MAH, Jenkins D, et al. Thromboembolic complications in burn patients and associated risk factors. J Burn Care Res 2013;34:355-360. 114. Purdue GF, Hunt JL. Pulmonary emboli in burned patients. J Trauma 1988;28:218-20. 115. Rue LW, Cioffi WG, Rush R, et al. Thromboembolic complications in thermally injured patients. World J Surg 1992;16:1151-4; discussion 5. 116. Toker S, Hak D, Morgan SJ. Deep vein thrombosis in trauma patients. Thrombosis 2011;Article ID 505373. 117. Wahl WL, Brandt MM. Potential risk factors for deep venous thrombosis in burn patients. J Burn Care Rehabil 2001;22:128-31. 118. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and

Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 suppl):e227S-277S. 119. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:381S-453S. 120. Bushwitz J, LeClaire A, He J, et al. Clinically significant venous thromboembolic complications in burn patients receiving unfractionated heparin or enoxaparin as prophylaxis. J Burn Care Res 2011;32:578-82. 121. Lin H, Faraklas I, Saffle J, et al. Enoxaparin dose adjustment is associated with low incidence of venous thromboembolic events in acute burn patients. J Trauma 2011;71:1557-61. 122. Faraklas I, Ghanem M, Brown A, Cochran A. Evaluation of an enoxaparin dosing calculator using burn size and weight. J Burn Care Res 2013;34:621-7. 123. Koumbourlis AC. Electrical injuries. Crit Care Med 2002;30:S424S430. 124. Glatstein MM, Ayalon I, Miller E, et al. Pediatric electrical burn injuries: experience of a large tertiary care hospital and a review of electrical injury. Pediatr Emerg Care 2013;29:737-40. 125. Bailey B, Gaudreault P, Thivierge RL. Cardiac monitoring of highrisk patients after an electrical injury: a prospective multicentre study. Emerg Med J 2007;24:348-52. 126. Bruen KJ, Ballard JR, Morris SE, et al. Reduction in the incidence of amputation in frostbite injury with thrombolytic therapy. Arch Surg 2007;142:546-53. 127. Johnson AR, Jensen HL, Peltier G, et al. Efficacy of intravenous tissue plasminogen activator in frostbite patients and presentation of a treatment protocol for frostbite patients. Foot Ankle Spec 2011;4:344-8.

128. Hardwicke J, Hunter T, Staruch R, et al. Chemical burns –an historical comparison and review of the literature. Burns 2012;38:383-7.

Chapter 43 The Role of

Pharmacotherapy in the Treatment of the Multiple Trauma Patient Rita Gayed, Pharm.D.; Prasad Abraham, Pharm.D., FCCM, BCPS; and David V. Feliciano, M.D., FACS

LEARNING OBJECTIVES 1. List the components of the primary survey. 2. Explain the rationale for each component of the primary survey (ABCDE). 3. List the classes of hemorrhagic shock. 4. Describe the components and their roles in the massive transfusion protocol. 5. Evaluate the data for support of tranexamic acid in the management of traumatic hemorrhage. 6. Compare the data for anticoagulant versus antiplatelet therapy in the management of blunt cerebrovascular injury. 7. Evaluate the data for neuroprotection in traumatic brain injury (TBI) management. 8. Compare mannitol with hypertonic saline in the management of intracranial hypertension. 9. Review the data supporting the management of early seizures

associated with TBI. 10. State the complications of spinal cord injury (SCI). 11. Review the evidence for steroids in SCI. 12. Differentiate the benefits of endovascular repair versus open surgical repair of blunt thoracic aortic aneurysms. 13. Review the evidence for somatostatin/octreotide in the management of enterocutaneous fistulas. 14. Review the pharmacologic treatment options for the management of short bowel syndrome. 15. Recall the evidence for the prevention of contrast-induced nephropathy. 16. Compare the evidence for low-molecular-weight heparins versus unfractionated heparin for venous thromboembolism prophylaxis in trauma patients. 17. State the pharmacokinetic challenges with low-molecular-weight heparin dosing in trauma.

ABBREVIATIONS IN THIS CHAPTER AKI

Acute kidney injury

aPTT Activated partial thromboplastin time BCVI

Blunt cerebrovascular injury

CT

Computed tomography

DVT

Deep venous thrombosis

ECF

Enterocutaneous fistula

GH

Growth hormone

IH

Intracranial hypertension

ICP

Intracranial pressure

ICU

Intensive care unit

ISS

Injury severity score

MTP

Massive transfusion protocol

PBRC Packed red blood cell RIFLE Risk, Injury, Failure, Loss, and End-stage Renal Disease SBS

Short bowel syndrome

SCI

Spinal cord injury

TBI

Traumatic brain injury

TIC

Trauma-induced coagulopathy

TPN

Total parenteral nutrition

VTE

Venous thromboembolism

INTRODUCTION Traumatic injury is a significant health care concern, accounting for almost 200,000 deaths in the United States in 2010, and is the No. 1 cause of death among people 1–44 years of age and the No. 3 killer overall.1 This translates to an economic burden of around $406 billion annually related to health care costs and loss of productivity.2 Although treatment of patients with traumatic injury is primarily surgical in nature, the clinical pharmacist plays a critical role in optimizing drug therapy because drug therapy is an essential part of the support care in these patients. This chapter will review the initial evaluation of the trauma patient, the physiologic changes related to traumatic injury, and the various types of traumatic injuries and the subsequent complications that require pharmacologic intervention.

INITIAL EVALUATION OF THE PATIENT (ADVANCED TRAUMA LIFE SUPPORT) Initial evaluation of the trauma patient involves a systemic approach, divided into a primary and secondary survey, to stabilize the patient and identify any life-threatening conditions.

Primary Survey The primary survey encompasses a series of steps designed to identify life-threatening injuries and immediately initiate management. It involves Airway maintenance with cervical spine protection, Breathing and ventilation, Circulation with hemorrhage control, Disability with respect to neurological status, and Exposure/environment (ABCDE).3 Airway Maintenance Airway maintenance is of utmost importance for the trauma patient. Pulse oximetry is used as an adjunct to the primary survey to detect and monitor hypoxia. During airway maintenance, the patient’s ability to maintain and protect the airway is assessed while maintaining cervical spine precautions. Some indications for securing a definitive airway when patients are unable to protect their own airway include unconsciousness or an obtunded neurological state (defined as a Glasgow Coma Scale [GCS] score less than 8), severe maxillofacial fractures, risk of aspiration (e.g., vomiting or bleeding), and risk of obstruction (e.g., stridor, laryngeal or tracheal injuries, neck hematoma). Concern for ventilation or oxygenation and the need for a definitive airway may arise in patients presenting with apnea; inadequate respiratory efforts such as tachypnea, hypoxia, hypercarbia, and cyanosis; severe closed head injury (with need for brief hyperventilation if acute neurological decompensation occurs); or massive blood loss and need for large-volume resuscitation. A definitive airway is defined as a cuffed endotracheal tube in the trachea, which is often achieved by rapid sequence intubation (RSI).4 When RSI fails to secure the airway, a surgical airway becomes necessary.

Breathing and Ventilation After airway assessment, the trauma patient is evaluated for breathing and ventilation, which includes adequate oxygenation and carbon dioxide exchange. A patent airway does not automatically ensure adequate ventilation.5 Pulse oximetry allows noninvasive measurement of oxygenation; however, it can be inaccurate in different settings such as vasoconstriction, carbon monoxide poisoning, hypothermia, or severe anemia.5 Therefore, an arterial blood gas is often required to assess the partial pressure of oxygen. Evaluation of breathing by inspecting chest wall movement, auscultation of breath sounds, and percussion is essential to help detect any abnormalities that need immediate attention such as a pneumo- or hemothorax. A tension pneumothorax can develop from either blunt or penetrating trauma and involves continuous air flow from the trachea, bronchi, or chest wall into the pleural space, causing a shift of the mediastinum, deviation of the trachea away from the tension, respiratory distress, increased intrathoracic pressures, decreased venous return, hypotension, and, ultimately, shock if unrecognized and untreated. Managing a pneumothorax includes inserting a chest tube. A hemothorax is the collection of blood in the pleural space caused by blunt or penetrating trauma and can lead to mediastinal shift, respiratory distress, and hypovolemic shock, prompting emergency management with tube thoracostomy and transfusion and immediate surgery.3 Circulation with Hemorrhage Control One of the main concerns in the trauma patient is uncontrolled bleeding, which can lead to hemorrhagic shock and, if not detected and treated early, death secondary to organ hypoperfusion. Locations of hemorrhage include thoracic cavity, abdominal cavity, pelvic fracture (retroperitoneum), and long bones or obvious external bleeding.3 Clinical assessment of hypovolemic shock secondary to hemorrhage includes parameters such as heart rate, pulse pressure, urine output, skin color, temperature, and mental status. Hemorrhagic shock is broken into four classes, based on estimated blood loss (Table 43.1).

Managing hemorrhage in the trauma patient begins with securing two large-bore venous catheters for appropriate fluid resuscitation together with hemorrhage control. Trauma patients with hypovolemic shock can be classified as fluid rapid responders, transient responders, or nonresponders (Table 43.2). Bleeding control can be done through applying direct pressure on the bleeding vessel for obvious bleeding. For less obvious sources, proximal pressure over the femoral artery in the groin or the brachial artery in the upper extremity can be applied.6 A hemothorax is managed with insertion of a chest tube and operative control. Intraabdominal bleeding in the setting of shock requires emergency laparotomy, and a pelvic fracture leading to hemorrhage is treated by pelvic stabilization or extraperitoneal packing. Disability: Neurological Status Once the ABCs have been completed, a neurological assessment including GCS score and pupillary examination (including size, symmetry, and reaction to light) is performed. Possible blunt trauma to the brain warrants a computed tomography (CT) scan for further evaluation. Exposure and Environmental Control A patient’s clothing should be removed immediately to allow appropriate evaluation; however, it is important to ensure that the patient does not become hypothermic using warmed blankets, fluids, and air. Findings during this part of the assessment will drive further evaluation and intervention. Adjuncts Adjuncts to the primary survey include frequent monitoring of oxygenation and ventilation, vital signs, hemodynamics, and neurological status. In addition, a urinary catheter and a nasogastric/orogastric tube are inserted. Diagnostic imaging such as

radiographs and CT scans is ordered as appropriate. The focused assessment with sonography for trauma (FAST) examination helps identify fluid or blood in the pericardial and peritoneal cavity. Four windows are examined using sonography: the pericardium, the spaces between the liver and the kidney (Morison pouch), the spaces between the spleen and the kidney (splenorenal recess), and the space over the bladder.7-9 An unstable patient with a positive FAST is transferred emergently to the operating room for definitive control of the hemorrhage.

Table 44.1 Classes of Hemorrhagic Shock

American College of Surgeons Committee on Trauma. Advanced Trauma Life Support for Doctors, 8th ed. Chicago: American College of Surgeons Committee, 2008:61.

Table 44.2 Responses to Initial Fluid Resuscitationa

Minimal or No Response

Transient Response

Rapid Response

Vitalsigns

Return to normal

Transient improvement

Remains abnormal

Estimated blood loss

Minimal (10%-20%)

Moderate and ongoing ( 20%—40%)

Severe (> 40%)

Need for more crystalloid

Low

High

High

Need for blood

Low

Moderate to high

Immediate

Blood preparation

Type and crossmatch

Type-specific

Emergency blood release

Need for operative intervention

Possibly

Likely

Highly likely

Early presence of surgeon

Yes

Yes

Yes

a2

L of isotonic solution in adults.

American College of Surgeons Committee on Trauma. Advanced Trauma Life Support for Doctors, 8th ed. Chicago: American College of Surgeons Committee, 2008:61.

On completion of the primary survey, the decision for early transfer to a more specialized trauma center is made, depending on the patient’s injuries and the available resources.

Secondary Survey The secondary survey follows the primary survey once the patient’s ABCs have been stabilized and includes obtaining a medical history and completing a detailed physical examination. On the patient’s arrival to the hospital, prehospital personnel can furnish much of the patient’s history using the mnemonic AMPLE (A – allergies, M – medications currently used, P – past illness/pregnancy, L – last meal, E – events/environment related to injury).3 The patient should always be asked about tetanus status. The physical examination includes a complete assessment from head to toe, including the head and face, neck and spine, chest, abdomen, and musculoskeletal and peripheral vascular systems. The neurological examination includes a motor and sensory examination, and patients with altered consciousness should have a CT scan of the brain. Adjuncts to the secondary survey include routine radiography and angiography, among others. Laboratory results should be reviewed, including base deficit and lactate concentrations, which are markers of

hypoperfusion. After completing the secondary survey, continuous reassessment of the patient is essential. If there is any clinical worsening, steps of the primary survey are repeated.

INITIAL MANAGEMENT Physiology of Hypovolemic Shock Hypovolemic shock is a state of inappropriate delivery of oxygen and nutrients to organs secondary to volume loss. Hallmarks of hypovolemic shock include hypoperfusion secondary to an unbalanced oxygen demand and supply at the cellular level. This leads to cellular injury, which initially can be reversible but can progress to irreversible damage if not recognized and managed early enough. Hemorrhagic shock is a type of hypovolemic shock secondary to blood loss. During early hemorrhagic shock, compensatory mechanisms including neuroendocrine and cardiovascular responses are activated to maintain hemodynamics and perfusion.10 As the bleeding continues, however, compensatory mechanisms fail, and the patient goes into cardiovascular collapse. Decompensated hypovolemic shock leads to multiorgan dysfunction, inflammation, and microcirculatory shock. Once parenchymal and microvascular injury has ensued, volume resuscitation strategies cannot reverse the process. Reperfusion injury can further worsen the initial insult. If decompensated hemorrhagic shock is left untreated, the outcome can be fatal. Non-trauma causes of hemorrhagic shock include antithrombotic therapy, coagulopathies, gastrointestinal (GI) bleeding, and a ruptured aneurysm. Pulmonary etiologies include lung cancer and cavitary lung disease, whereas obstetric/gynecologic causes include ruptured ectopic pregnancy, ruptured ovarian cyst, and placenta previa, among others. In the trauma patient, hemorrhage can be external and visible or can be internal. Lacerations, penetrating trauma (e.g., gunshot wounds), blunt trauma, and ruptured major vessels can all lead to lifethreatening hemorrhage.11

A 70-kg patient is composed of 60% total body water (42 L), which can be further divided into 28 L of intra-cellular water (2 L of red cell volume and 26 L within muscles and organs) and 14 L of extracellular water (3 L of plasma volume and 11 L of interstitial space fluid, which mostly comprises the interstitial space matrix). The average adult blood volume is 7% of body weight, which is about 5 L in a 70-kg patient.12 There are four classes of hemorrhagic shock (classes I–IV), based on blood loss (Table 43.1). The physiology of hemorrhagic shock consists of three phases. Phase I describes the state of shock and active hemorrhage (from admission to the end of surgery/definitive bleeding control). Phase II is the obligatory extravascular fluid sequestration phase from the end of surgery to the time of maximal weight gain. Phase III describes the time during which fluid mobilization and diuresis occur (from maximal weight gain to positive fluid balance).12

Management of Hemorrhagic Shock: Fluid Resuscitation The goals of managing hemorrhagic shock are to stop the bleeding and to restore hemodynamics to minimize hypoperfusion and associated ischemic damage to all organs. Management of hemorrhagic shock starts with establishing vascular access for fluid and blood resuscitation, which is accomplished by inserting at least two short, large-bore intravenous catheters.10,13 Intravenous fluid resuscitation is an important strategy in restoring intravascular volume.

Resuscitation Goals The aim of trauma resuscitation is to restore normal hemostasis by addressing shock and the resulting oxygen debt.14 Oxygen debt is evaluated by monitoring either serum lactate or base deficit. The goal of trauma resuscitation is the normalization of either parameter.15 Available resuscitation fluids include crystalloids (0.9% sodium chloride solution [“normal saline”], lactated Ringer, Plasmalyte [“balanced

crystalloid”]) and colloids (albumin [4%–25%], hydroxyethyl starches, gelatin solutions).15 Classically, lactated Ringer has been the resuscitation fluid of choice for trauma resuscitation, but other fluids have been used as well, with varying efficacy and safety profiles.10 Plasmalyte Plasmalyte is a balanced crystalloid solution with different available formulations, designed to mimic human plasma.15 It can be used for fluid resuscitation (filling the intravascular space) or fluid replacement (extravascular deficit).15 Plasmalyte is different from lactated Ringer because it contains acetate as a buffer instead of lactate, which theoretically reduces carbon dioxide production. A theoretical concern with the use of Plasmalyte in trauma resuscitation is that it contains magnesium, which has undesirable hemodynamic effects (bradycardia, decreased peripheral vascular resistance).16 To date, only one study has evaluated its use in trauma resuscitation. Young et al. compared resuscitation with normal saline with resuscitation with Plasma-Lyte A, a calcium-free balanced crystalloid solution, in adult trauma patients (n=46) requiring blood transfusion and operative management within 60 minutes of hospital arrival and found that the mean base excess improvement from 0 to 24 hours, the primary outcome of the study, was significantly greater with PlasmaLyte A (7.5 ± 4.7 vs. 4,4 ± 3.9 mmol/L; difference 3.1 [95% confidence interval {CI}, 0.5–5.6]; p = not available), with a higher pH at 24 hours (7.41 ± 0.06 vs. 7.37 ± 0.07; difference 0.05 [95% CI, 0.01–0.09]) and a lower chloride concentration at 24 hours (104 ± 4 vs. 111 ± 8 mEq/L; difference -7 [95% CI, -10 to -3]). There were no differences in the volumes of fluids administered, 24-hour urine output, resource use measures, or mortality.17 Although the concept of balanced resuscitation fluids with a physiology similar to human plasma is appealing and the clinical evidence in trauma is promising, more studies are needed to validate use in this population.

Colloids Colloids are suspensions of molecules within a carrier solution, usually incapable of crossing a healthy semipermeable capillary membrane because of their molecular weight.15 The use of colloids is supported by the rationale that they can expand the intravascular volume and maintain colloid oncotic pressure without causing fluid overload. This volume-sparing effect is traditionally thought to be in a 1:3 ratio of colloids to crystalloids to replete intravascular depletion.15 Different colloids are available, including human albumin and semisynthetic colloids including hydroxyethyl starches, gelatin products, and dextrans. Albumin is considered the reference colloid. Hydroxyethyl starch is produced by hydroxyethyl substitution of glucose molecules from maize, potatoes, or sorghum. This substitution leads to protection against hydrolysis and, hence, a prolonged intravascular volume expansion; however, it also increases the risk of accumulation in different tissues such as the skin, liver, and kidneys.15 Theoretically, semisynthetic colloids are a good alternative to costly albumin because they are good volume expanders, can be manufactured cheaply, and do not bear the risk of bloodborne infections; however, they have been shown to accumulate in different organs, causing adverse effects. In addition, high-molecular-weight hydroxyethyl starch products can cause coagulopathies. The use of hydroxyethyl starch solutions with molecular weights greater than 200 kD and a molar substitution ratio of more than 0.5 has been linked to higher rates of mortality, acute kidney injury (AKI), and renal replacement therapy use in patients with sepsis. The recommended maximal daily dose of hydroxyethyl starch is 33–50 mL/kg.15 Albumin The SAFE trial, a multicenter, randomized, double-blind study, assessed the use of 4% albumin versus normal saline for intravascular fluid resuscitation in a mixed intensive care unit (ICU) patient population (43% surgical admissions vs. 57% medical admissions) and found no difference in 28-day mortality (relative risk [RR] of death 0.99; 95% CI,

0.91–1.09; p=0.87), new single-organ and multiorgan failure (p=0.85), ICU (p=0.44) or hospital length of stay (p=0.30), days of mechanical ventilation (0.74), or days of renal replacement therapy (p=0.41).18 In a subgroup analysis of patients admitted with trauma, the albuminreceiving group had a trend toward higher 28-day mortality than the saline-receiving group (13.6% vs. 10.0%; p=0.06). The SAFE trial investigators conducted a further post hoc analysis specifically targeting patients with a traumatic brain injury (TBI) because of concern for increased mortality in the albumin group.19 This group of patients had an increased 24-month mortality if they had received albumin (33.2% vs. 20.4%; RR 1.63; 95% CI, 1.17–2.26; p=0.003). The effect was attributed to increased intracranial pressure (ICP). The CRISTAL study, a multicenter, randomized, open-label trial (with investigators blinded to treatment assessment), included 2,857 patients from different ICUs receiving colloids (including gelatins, dextrans, hydroxyethyl starches, and 4% or 20% albumin) versus crystalloids (iso-tonic or hypertonic saline or lactated Ringer) for hypovolemic shock.20 Seventy percent of patients were admitted to the ICU because of medical diagnosis, followed by about 20% admitted secondary to an emergency surgery (6.2%–7.8% admitted because of a scheduled surgery and 1.6%–2.5% admitted secondary to trauma). The primary outcome, 28-day mortality, did not differ between groups (25.4% in colloids vs. 27.0% in crystalloids; RR 0.96 [95% CI, 0.88– 1.04]; p=0.26); however, 90-day mortality was higher in the crystalloid group (34.2% in crystalloids vs. 30.7% in colloids; RR 0.92 [95% CI, 0.86–0.99]; p=0.03). Other secondary outcomes, including the number of days alive without mechanical ventilation and without vasopressors at days 7 and 28, were all higher in the colloid group. In a recent study evaluating the effects of intraoperative use of colloids on postoperative fluid needs, non-colloids (balanced electrolyte solution) plus low fresh frozen plasma (FFP)/red blood cell (RBC) ratio resuscitation (0.35 or less) were compared with the administration of colloids (human albumin) plus high FFP/RBC ratio resuscitation (greater than 0.35). Administering albumin and high FFP/RBC resuscitation did

not prevent phase II fluid uptake (fluid sequestration phase). In contrast, it caused a decrease in urine output despite increased plasma volume.21 The authors theorized that colloids reduce glomerular filtration and increase tubular reabsorption, thus increasing extracellular fluid and prolonging phase II. Hydroxyethyl Starches The Crystalloid versus Hydroxyethyl Starch Trial (CHEST), with 42% of patients admitted after surgery and 8% trauma patients, randomized patients 1:1 to either 6% hydroxyethyl starch (molecular weight 130 kD and molar substitution ratio of 0.4) or normal saline for fluid resuscitation and found no 90-day mortality difference (18% in hydroxyethyl starch group vs. 17% in normal saline group; 95% CI, 0.96–1.18; p=0.26).22 More patients in the hydroxyethyl starch group required renal replacement therapy (7% vs. 5.8% in saline group; RR 1.21; 95% CI, 1.00–1.45; p=0.04), and more patients in the hydroxyethyl starch group developed renal injury (according to the RIFLE criteria) (7% vs. 5.8%; RR 1.21; 95% CI, 1.00–1.45; p=0.04). The use of hydroxyethyl starch was also associated with more adverse events such as pruritus and rash (5.3% vs. 2.8%, p 5 mEq/L • Increased arterial lactate > 2 times the upper limit of normal • Oliguria: Urine output < 0.5 mL/kg/hr • Prolonged capillary refill: > 5 s • Core to peripheral temperature gap > 3°C Respiratoryb • Pao2/Fio2 < 300 in absence of cyanotic heart disease or preexisting lung disease OR • Paco2 > 65 torr or 20 mm Hg over baseline Paco2 OR • Proven needc or > 50% Fio2 to maintain saturations > 92% OR Need for nonelective invasive or noninvasive mechanical ventilationd Neurologic • GCS < 11 OR • Acute change in mental status with a decrease in GCS ≥ 3 points from abnormal baseline Hematologic • Platelet count < 80,000/mm 3 or a decline of 50% in platelet count from highest value recorded during the past 3 days (for chronic hematology/oncology patients) OR • International normalized ratio > 2 Renal • Serum creatinine > 2 times the upper limit of normal for age or a 2-fold increase in baseline creatinine Hepatic • Total bilirubin ≥ 4 mg/dL (not applicable for newborn) OR • ALT 2 times the upper limit of normal for age

aSee

Table 44.5.

bAcute

respiratory distress syndrome must include a Pao2/Fio2 ratio < 200 mm Hg, bilateral infiltrates, acute onset, and no evidence of left heart failure. Acute lung injury is defined identically except that the Pao2/Fio2 ratio must be < 300 mm Hg. cProven

need assumes oxygen requirement was tested by decreasing flow if required.

dIn

postoperative patients, this requirement can be met if the patient has developed an acute inflammatory or infectious process in the lungs that prevents him or her from being extubated. ALT = alanine transaminase; GCS = Glasgow Coma Scale.

The relative ability of infants and children to augment CO through increased heart rate, as seen in adults, is limited by their preexisting elevated heart rate, which precludes proportionate increases in heart rate without compromising diastolic filling time. In addition, in adults, ventricular dilation is a compensatory response used to maintain CO. However, the increased connective tissue content of the infant’s heart and the diminished content of actin and myosin limit the potential for acute ventricular dilation.23 Neonatal septic shock can further be complicated by the physiologic transition from fetal to neonatal circulation. Sepsis-induced acidosis and hypoxia can increase pulmonary vascular resistance and thus arterial pressure, thereby maintaining the patency of the ductus arteriosus. This results in persistent pulmonary hypertension (PPHN) of the newborn and persistent fetal circulation. Neonatal septic shock with PPHN will increase the workload on the right ventricle, leading to right ventricular failure, tricuspid regurgitation, and hepatomegaly. Therefore, therapies directed at reversing right ventricular failure by reducing pulmonary artery pressures are commonly needed in neonates with fluid-refractory septic shock and PPHN. The treatment of PPHN will not be discussed in this chapter.

INITIAL MANAGEMENT Since the landmark study by Rivers in 20019 showed a 33% reduction

in mortality in adult patients with sepsis when patients were aggressively treated with early fluid resuscitation, early red cell transfusion, and early inotropic therapy within 6 hours of presentation, goal-directed therapy has been advocated for patients who present in septic shock. Although aggressive interventions to allow for optimization of oxygen delivery (e.g., placing central lines to measure central venous pressure [CVP] or mixed venous oxygen saturation [Svo2]) are no longer recommended, the components of early goaldirected therapy include prompt resuscitation of poor perfusion through the administration of intravenous fluids and appropriately targeted inotropic and/or vasopressor therapy, early empiric antimicrobial therapy, drainage of infection, and appropriate and continuous monitoring of hemodynamic status.5,9-12 In addition to goal-directed therapy, support of the airway and breathing is essential to optimize oxygen delivery. Supplemental oxygen should be administered to all patients presenting with signs of septic shock, and endotracheal intubation may be necessary. Because goaldirected therapy includes aggressive fluid resuscitation, early and immediate vascular access is essential to the treatment of septic shock. Ideally, two peripheral intravenous catheters should be placed promptly. Intraosseous access should be considered in any patient for whom peripheral vascular access is not rapidly established. Although ideal, a central venous line is not required for initial fluid resuscitation. All patients with septic shock have some degree of hypovolemia because of many factors, including increased insensible losses (i.e., excessive sweating, fever, and increased respiratory rate), excessive fluid losses from diarrhea or vomiting, third spacing of fluid caused by capillary leak, and diminished oral intake. Relative hypovolemia occurs because of systemic vasodilation. With the exception of the FEAST trial in Africa discussed earlier, no data suggest a difference in the survival rates of pediatric patients after resuscitation with colloids (blood products) compared with crystalloid fluids.24 The choice of fluid is less important than the volume administered. Adequate volume is necessary to sustain cardiac preload, increase stroke volume, and improve oxygen delivery.

Crystalloids and colloids, specifically packed red blood cells, have equal effects on improving stroke volume. In addition, both restore tissue perfusion to the same degree if they are titrated to the same level of filling pressure. The optimal hemoglobin for patients in septic shock has not been established. In the early management of sepsis in adults, maintaining hemoglobin concentrations of 7–9 g/dL to improve oxygen-carrying capacity has been documented to improve sepsis survival by improving tissue perfusion. Anemia in sepsis has been associated with increased mortality, but so has the administration of blood.25 Therefore, according to the limited data available, the Society of Critical Care Medicine has recommended that hemoglobin concentrations be maintained at 8–10 g/dL with the understanding that data for this practice are limited.5 Because pediatric data are limited, it is appropriate to extrapolate from the adult literature of maximizing tissue oxygen delivery if there is evidence of poor tissue perfusion. Once tissue hypoperfusion, acute hemorrhage, or lactic acidosis has resolved, red cell transfusion should be administered only when hemoglobin concentrations are less than 7 g/dL with a target goal of 8–10 g/dL.5,26 Fresh frozen plasma may be infused to correct abnormal prothrombin time (PT) and partial thromboplastin time (PTT) values, but fresh frozen plasma should not be pushed because it may produce acute hypotensive effects because of vasoactive kinins and high citrate concentrations. Finally, there is no literature to suggest that 5% albumin administration improves outcome with respect to sepsis mortality. Albumin administration may be considered in patients who are hypoalbuminemic, but routine use of albumin is not recommended.27 As described previously for the management of hypovolemic shock, patients with septic shock should be reassessed for signs of improved perfusion using clinical criteria such as reduction in heart rate, improvement in blood pressure, capillary refill, quality of pulses, and mental status with each fluid bolus. If the clinical signs of shock persist, another 20 mL/kg of isotonic fluid should be administered, reaching, if necessary, 60 mL/kg within the first 15–30 minutes of treatment.4,5 Some children with septic shock require as much as 200 mL/kg in the

first hour.11 The results of the FEAST trial have raised the question of whether certain patient populations with shock may be harmed by the administration of aggressive intravenous fluid.6 This question remains to be answered. Patients remaining in shock despite fluid resuscitation are given inotropic support to attain normal blood pressure for age and capillary refill time of less than 2 seconds. Every hour that goes by without implementing these therapies is associated with a 1.5-fold increased risk of mortality.26 Patients who do not respond rapidly to initial fluid boluses or those with insufficient physiologic reserve should be considered for invasive hemodynamic monitoring. Invasive monitoring of CVP is instituted to ensure that the satisfactory right ventricular preload is present, typically using a goal of 10–12 mm Hg, and that oxygencarrying capacity is optimized by packed red blood cell transfusion to correct anemia to a goal hemoglobin concentration greater than 7 g/dL.5,11 Fluid-refractory shock is defined as the persistence of signs of shock after sufficient fluids have been administered to achieve a CVP of 8–12 mm Hg and/or signs of fluid overload, as evidenced by newonset rales, increased work of breathing and hypoxemia from pulmonary edema, hepatomegaly, or a diminished mean arterial pressure (MAP). Diuretics and peritoneal dialysis/continuous renal replacement therapy are indicated for patients who develop signs and symptoms of fluid overload. Up to 40% of CO may be required to support the work of breathing; therefore, in the presence of respiratory distress, an elective tracheal intubation followed by mechanical ventilation will contribute to redistributing blood flow away from respiratory muscles toward other vital organs. Mechanical intubation, however, is not without adverse effects. It is imperative that the patient receive adequate fluid resuscitation before the intubation because the change from spontaneous breathing to positive pressure ventilation will decrease the effective preload to the heart. Ventilation may reduce the left ventricular afterload that may be beneficial in patients with low cardiac index and high SVR. In addition, ventilation may allow an alternative method to

alter acid-base balance. If sedatives and analgesics are used for intubation, it is critical to choose agents that do not cause further vasodilation. Although laboratory studies rarely affect the management of septic shock in the first hour of therapy, patients should have laboratory studies sent routinely, assessing for hematologic abnormalities, metabolic derangements, or electrolyte abnormalities that may contribute to morbidity. A peripheral white blood cell count may aid in the choice of broad-spectrum antibiotics, whereas hemoglobin and platelet count will help assess the need for early blood transfusion. A type and screen should be sent to the blood bank to prepare for any necessary transfusions. Electrolyte abnormalities are common in sepsis; recognition and treatment of metabolic abnormalities such as hypoglycemia and hypocalcemia will improve outcome. A disseminated intravascular coagulation panel, including PT, PTT, and fibrinogen, will aid in assessing the severity of illness. If abnormalities exist, they may need to be corrected before performing invasive procedures. Finally, an arterial or venous blood gas will determine the adequacy of ventilation and oxygenation and the severity of acidemia. Unfortunately, clinical response to fluid resuscitation is a relatively insensitive indicator of the completeness of restoration of microvascular blood flow. The success of adequate fluid resuscitation can be guided by additional parameters: invasive blood pressure monitoring, CVP, measurement of Svo2, measurement of blood lactate, and urine output. An elevated serum lactate concentration suggests that tissue is hypoperfused and undergoing anaerobic metabolism, even in patients who are not hypotensive. Because low CO is associated with increased O2 extraction, Svo2 can be used as an indirect indicator of whether CO is adequate to meet tissue metabolic demand. If tissue oxygen delivery is adequate, Svo2 should be greater than 70%.12 In the goal-directed study by Rivers,9 the patients in whom maintaining an Svo2 greater than 70% using blood transfusion to a hemoglobin concentration of 10 g/dL and inotropic support to increase CO had a 40% reduction in mortality compared with patients in whom only MAP and CVP were monitored. This finding in children with septic shock was

reproduced by de Oliveira, reducing mortality from 39% to 12% when directing therapy to a goal Svo2 greater than 70%.13

CARDIOVASCULAR DRUG THERAPY Pharmacologic support in children with septic shock must be individualized because different hemodynamic abnormalities exist in pediatric patients, and the primary hemodynamic abnormalities may change with time and progression of the patient’s disease. Twenty percent of children present with predominant vasodilatory shock, called “warm” shock. This form of shock is associated with vasodilation and capillary leak, but normal or elevated CO. The patients have strong pulses, warm extremities, good capillary refill, and tachycardia. In warm shock, using a vasopressor such as dopamine, norepinephrine, phenylephrine, or vasopressin to promote vasoconstriction would be of most benefit. Fifty-eight percent of children present with “cold shock,” or predominantly a poor CO state. Clinically, this manifests as weak pulses, cool extremities, slow capillary refill, and hepatic and pulmonary congestion. Using an inotrope (e.g., dobutamine, epinephrine, or milrinone) with or without a vasodilator would be most beneficial in cold shock. Careful assessment of clinical response is critical because a combination of vasodilatory and cold shock with a low SVR and poor CO can occur in 22% of children.

Dopamine In shock unresponsive to initial fluid resuscitation, the initial vasopressor of choice is dopamine, according to the pediatric advanced life support guidelines.4 Dopamine has direct and indirect effects on dopamine receptors, α-receptors, and β-receptors on both the heart and the peripheral vasculature. One of the mechanisms of dopamine action is improvement in endogenous catecholamine release. In severe septic states, presynaptic vacuoles may be depleted of norepinephrine, which may explain why dopamine may have diminished activity. In addition, infants younger than 6 month may not have developed their component

of sympathetic innervations; therefore, they have reduced releasable stores of epinephrine.11 Dopamine should be initiated at 5 mcg/kg/minute and titrated in increments of 2.5 mcg/kg/minute every 3–5 minutes until the goal of improved perfusion, blood pressure, or both is achieved.4 The maximum recommended dopamine dose is 20 mcg/kg/minute; doses higher than 20 mcg/kg/minute may contribute to increased myocardial oxygen demand without much improvement in vasopressor activity. Dopamine-resistant shock is diagnosed after titrating dopamine to 20 mcg/kg/minute with the persistence of signs and symptoms of shock. At this point, the patient should be reassessed. Measure the patient’s hemoglobin, and administer packed red blood cells to improve the hemoglobin to 8–10 g/dL. This may improve tissue oxygenation. Measure CVP to assess intravascular volume status with the goal of achieving a CVP of 8–12 mm Hg; Svo2 can be used as a marker of CO (if the hemoglobin concentration is within the normal range), together with the clinical examination. Dopamine-resistant shock commonly responds to epinephrine or norepinephrine. A recent double-blind, prospective, randomized controlled trial evaluated dopamine versus epinephrine as the initial vasoactive drug for pediatric septic shock in 120 pediatric patients (63 dopamine; 57 epinephrine). There were 17 deaths (14.2%): 13 (20.6%) in the dopamine group and 4 (7%) in the epinephrine group (p=0.033). Early administration of epinephrine appeared to be associated with increased survival in this population. However, dopamine was dosed at 5–10 mcg/kg/minute (the low end of the dosing range) and epinephrine at 0.1–0.3 mcg/kg/minute. The dosing of epinephrine could be considered more aggressive; thus, the two treatment arms are not comparable. More studies are needed before epinephrine is considered the drug of choice in children.28 Recent adult data analyses raise the concern of increased mortality with dopamine use. One possible explanation is dopamine’s ability to reduce the release of hormones such as prolactin from the anterior pituitary gland through stimulation of the dopamine DA2 receptor, thus reducing cell-mediated immunity and inhibiting thyrotropin-releasing

hormone release, worsening the impaired thyroid function known to occur in critical illness. For these reasons, some clinicians prefer lowdose epinephrine or norepinephrine as a first-line agent for fluidrefractory hypotensive hyperdynamic shock.10

Epinephrine Epinephrine is a direct agent that is naturally produced in the adrenal gland and is the principal stress hormone with widespread metabolic and hemodynamic effects. It has both inotropic and chronotropic effects. Epinephrine is a reasonable choice for the treatment of patients with low CO and poor peripheral perfusion because it increases heart rate and myocardial contractility.25 Depending on the dose administered, epinephrine may exert variable effects on SVR. At low doses (less than 0.3 mcg/kg/minute), epinephrine exerts greater β2-adrenergic receptor activation, resulting in vasodilation in skeletal muscle and cutaneous vascular beds, shunting blood flow away from the splanchnic circulation. At higher doses, α1-adrenergic receptor activation becomes more prominent and may increase SVR and heart rate. For patients with markedly elevated SVR, epinephrine may be administered simultaneously with a vasodilator. Epinephrine increases glucogenesis and glycogenolysis, resulting in elevated serum blood glucose concentrations. Therefore, patients receiving epinephrine infusions should have their serum glucose concentration monitored closely. Epinephrine should be initiated at 0.1 mcg/kg/minute and titrated in increments of 0.1 mcg/kg/minute every 3–5 minutes until the goal of improved perfusion and/or blood pressure is achieved.

Norepinephrine Norepinephrine is a direct agent and is naturally produced in the adrenal gland. It is a potent vasopressor that redirects blood low away from skeletal muscle to the splanchnic circulation, even in the presence of decreased CO. Norepinephrine has been used extensively to elevate SVR in adults and children with sepsis. If the patient’s clinical state is

characterized by low SVR (e.g., wide pulse pressure with diastolic blood pressure less than one-half the systolic blood pressure), norepinephrine is recommended. About 20% of children with volumerefractory septic shock have a low SVR.20 In addition, in children who are intubated and receiving sedatives or analgesics, the incidence of low SVR may be higher. In patients with impaired contractility, the additional afterload imposed by norepinephrine may substantially compromise CO. In some patients with both impaired or marginal CO and decreased SVR, myocardial contractility may need to be supported by adding an agent such as dobutamine.

Dobutamine Dobutamine is a nonselective β2-adrenergic agonist that produces improved myocardial contractility, chronotropy, and some lusitropy and improved myocardial relaxation. Its β2 activity can lead to peripheral vasodilation, which must be considered before using it in a patient who may already be hypotensive. If hypotension does exist, dobutamine should be used in combination with other vasopressor therapy. Thus, dobutamine should be considered in the patient who has signs and symptoms or laboratory values consistent with poor tissue perfusion, but with an adequate blood pressure to tolerate some degree of vasodilation. Dobutamine should be initiated at 2.5 mcg/kg/minute and titrated in increments of 2.5 mcg/kg/minute every 3–5 minutes, to a maximum infusion rate of 20 mcg/kg/minute. Careful attention to the patient’s blood pressure is critical. Improved perfusion, decreased lactate, and increased Svo2 will help determine appropriate dosing.

Vasopressin Although not a recommendation in the 2015 pediatric advanced life support guidelines, vasopressin has been suggested as an alternative therapy for refractory cardiac arrest or hypotension caused by a low SVR in children whose epinephrine infusion exceeds 1 mcg/kg/minute.4 Vasopressin exerts its hemodynamic effects by the V1α receptor,

promoting an increase in intracellular calcium in the peripheral vasculature, thus enhancing vasoconstriction and restoring systemic vascular tone. In a preliminary case series, vasopressin at a dose of 0.3–2 milliunits/kg/minute (18–120 milliunits/kg/hour) improved blood pressure and urine output in patients with catecholamine-refractory, vasodilatory shock and allowed weaning of catecholamines once treatment was initiated.29 In a more recent analysis by the American Heart Association, however, vasopressin use was associated with a lower rate of return to spontaneous circulation.30 The use of vasopressin in critically ill children remains controversial.4,5,11

Vasodilators Vasodilator medications are occasionally required in the treatment of pediatric patients with sepsis having markedly elevated SVR and normal or decreased CO. Vasodilators decrease SVR and improve CO by decreasing ventricular afterload. Nitroglycerin or nitroprusside may be used for this indication. Each has a short half-life; therefore, if hypotension occurs, the agent can rapidly be reversed by stopping the infusion. Both drugs can be infused at an initial rate of 0.5 mcg/kg/minute and titrated in increments of 0.5 mcg/kg/minute to a maximum infusion rate of 5–10 mcg/kg/minute. If nitroprusside is used, it is necessary to observe for sodium thiocyanate accumulation in the setting of renal failure and cyanide toxicity with hepatic failure or with prolonged infusions (greater than 72 hours) of more than 3 mcg/kg/minute. If the patient has tolerated infusions of nitroglycerin or nitroprusside, switching to the longer-acting agent milrinone should be considered. Milrinone is a phosphodiesterase type 3 inhibitor that produces its hemodynamic effects by inhibiting the degradation of cyclic AMP in smooth muscle cells and cardiac myocytes. Phosphodiesterase type 3 inhibitors work synergistically with catecholamines, which produce their hemodynamic effects by increasing the production of cyclic AMP. Milrinone is useful in the treatment of patients with diminished myocardial contractility and output and decreased systemic

resistance.5,31 The concern with milrinone is its long half-life (2–6 hours); milrinone takes several hours to reach steady state. To achieve rapid serum concentrations, a loading dose of 50 mcg/kg administered over 10–30 minutes is recommended. This must be done with caution in patients with sepsis and shock because it may precipitate hypotension, requiring volume infusion, vasopressor infusion, or both. Administering the loading dose over several hours may avoid this adverse effect.

Corticosteroids Although adjunctive corticosteroid therapy in patients in septic shock has not made a significant difference in outcome in any of the studies published to date, replacement may be of benefit in some patients.32-34 In a recent study, 77% of children with septic shock admitted to two PICUs for 6 months had adrenal insufficiency.34 Because of the limited evidence of their efficacy and safety in children, corticosteroids should be reserved for children with catecholamine-resistant shock, severe septic shock, and purpura; those who have previously received steroid therapies for chronic illness; those with pituitary or adrenal abnormalities; and those who previously received etomi-date.7-9,32-35 Assessment of serum cortisol should be used to guide treatment. There are no strict definitions, but adrenal insufficiency in adults with catecholamine-resistant shock has been defined as a random cortisol concentration of less than 18 mcg/dL or an increase in cortisol of 9 mcg/dL or less at 30 or 60 minutes after an adrenocorticotropic hormone stimulation test.32 Similar values have been recommended for assessing serum cortisol in children with septic shock.35 Published guidelines for hemodynamic support of pediatric and neonatal patients with septic shock recommend hydrocortisone 0.5–1 mg/kg intravenously every 6 hours (maximum 50 mg per dose).16 As an alternative, some clinicians use a hydrocortisone regimen of a 50mg/m2 loading dose, followed by the same dose (50 mg/m2) divided into four doses and given every 6 hours (maximum 50 mg per dose).35

SEPSIS SUMMARY The outcome of sepsis and septic shock depends on implementing time-sensitive goal-directed therapies. Early recognition of septic shock is critical to initiating rapid aggressive fluid resuscitation. Concurrent with the administration of oxygen, diagnosis of the source of the infection should be attempted and appropriate antibiotics administered within 1 hour of presentation. Vasopressor administration should be initiated if signs of shock persist despite adequate volume administration. If signs of shock persist, packed red blood cells should be administered to maintain hemoglobin at 8–10 g/dL. Frequent assessment, both clinical and laboratory, needs to be performed to allow adjustments in vasopressor and/or inotropic therapy, depending on the clinical presentation and ongoing physiologic derangements. Using a central venous catheter for measuring CVP and Svo2 can help guide therapy.

RESPIRATORY DISTRESS Respiratory distress, related to problems at all levels of the respiratory tract from the nose to the lungs, is a common occurrence in children.4 The nose provides almost half the total airway resistance in children. Infants younger than 2 months are obligate nasal breathers, and their nose is short, soft, and small with almost circular nares. The nares will double in size from birth to 6 months, but they can easily be occluded from edema, secretions, or external pressure. Simply clearing the nasal passageways with saline and bulb suctioning can significantly improve an infant’s respiratory condition. Other physiologic reasons for a high incidence of respiratory failure in infants and children are small and collapsible airways, an unstable chest wall, inadequate collateral ventilation for alveoli, poor control (tone) of the upper airway (particularly during sleep), tendency for the respiratory muscles to fatigue, reactivity of the pulmonary vascular bed (increased sensitivity of the vasculature, particularly in young infants), inefficient immune system, genetic disorders or syndromes, and residual problems related to premature birth such as bronchopulmonary dysplasia.

The most common reason for hospital admission in the first year of life is respiratory distress. This can be explained by the many physiologic differences seen in an infant. Although all the conducting airways are present at birth and the airway branching pattern is complete, the airways are small.36 The airways will increase in size and length throughout childhood. As the airways increase in size, the incidence of respiratory distress will decrease. Not only are the airways smaller in an infant, but also the supporting airway cartilage and elastic tissue are not developed until the child is of school age. For these reasons, the child’s airways are susceptible to collapse and may easily become obstructed as a result of laryngospasm, bronchospasm, and edema or mucus accumulation. Normal airway resistance is highest in infants because it is inversely proportional to 1/radius.32 Therefore, any airway narrowing from bronchospasm, edema, or mucus accumulation will significantly increase the airway resistance and the infant’s work of breathing. The cartilaginous ribs of the infant and young child are twice as compliant as the bony ribs of the older child or adult. During episodes of respiratory distress, the infant’s chest wall will retract further than will that of a patient with a bony rib cage. This will reduce the patient’s ability to maintain functional residual capacity or increase tidal volume, thus further increasing the patient’s work of breathing. The respiratory muscles consist of muscles of the upper airway, lower airway, and diaphragm. They contribute to the expansion of the lung and the maintenance of airway patency. Lack of development of the small airway muscles may render young infants less responsive than older children to bronchodilator therapy. Finally, the intercostal muscles are not fully developed until school age, so they act primarily to stabilize the chest wall during the first years of life. Because the intercostal muscles have neither the ability nor the strength to lift the rib cage in the young child, the diaphragm is responsible for generating tidal volume. Therefore, anything that impedes diaphragm movement, such as a large stomach bubble, abdominal distension, or peritonitis, can result in respiratory failure in the young child. To assess a patient for respiratory distress, four areas should be

evaluated: respiratory rate and effort, work of breathing, quality and magnitude of breath sounds, and mental status. Normal respiratory rates and definitions of respiratory distress vary with age (Table 44.7). A respiratory rate greater than 60 breaths/minute is abnormal in a child of any age but is of greatest concern in an older child. An abnormally slow or decreasing respiratory rate may herald respiratory failure. Inter-, sub-, and supracostal retractions increase with increasing respiratory distress. Although increased retractions are seen in infants, the efficiency of respiratory muscle function is decreased during the first years of life; therefore, the benefit in infants is reduced. Decreasing respiratory rate and diminished retractions in a child with a history of distress may signal severe fatigue. Nasal flaring is an effort to increase airway diameter and is often seen with hypoxemia. In addition, some infants will have an expiratory grunting noise. This noise is produced by children’s involuntary effort to counter the loss of functional residual capacity by closing their glottis on active exhalation. Grunting produces positive end-expiratory pressure in an effort to prevent airway collapse. An expiratory grunt is classically seen in the presence of extensive alveolar pathology and is considered a sign of serious disease.

Table 44.7 Age-Normal Respiratory Rates Age

Respiratory Rate (breaths/minute)

Respiratory Distress (breaths/minute)

Newborn

30–60

60

2–12 mo

25–40

50

1–5 yr

20–30

40

6–10 yr

18–25

30

> 10 yr

15–20

20

Among the many causes of respiratory distress in infants and children, the most common are infectious diseases, asthma,

malignancies, trauma (both accidental and non-accidental), poisonings, foreign body aspiration, anatomic upper airway obstruction, cardiogenic shock, and untreated left-to-right intracardiac shunts. Respiratory syncytial virus is among the most common causes of respiratory distress in infants and young children, leading to an estimated 90,000 hospitalizations each year.33 However, only 7%–10% of infants admitted to the hospital for RSV will be admitted to the PICU. Although RSV can occur at any age, it is severest in children younger than 2 years. Prematurity, as well as chronic respiratory disease and congenital heart disease, increases the risk of severe RSV bronchiolitis requiring hospitalization. Unfortunately, there is no pharmacologic treatment for RSV. Treatment in the intensive care unit (ICU) is supportive care and intubation and mechanical support when necessary. Oxygen should be administered immediately in any patient when respiratory difficulty is suspected. Infants and children consume 2–3 times more oxygen per kilogram of body weight than do adults under normal conditions and even more when they are ill or distressed. The specific indications for intubation in infants and children are as follows: Apnea Acute respiratory failure (Pao2 less than 50 mm Hg in patients with fraction of inspired oxygen [Fio2] greater than 0.5 and Paco2 greater than 55 mm Hg acutely) Need to control oxygen delivery, with institution of positive end-expiratory pressure or to provide accurate delivery of Fio2 greater than 0.5 Need to control ventilation to decrease work of breathing, control Paco2, or administer neuromuscular blocking agents Inadequate chest wall function, as in patients with neuromuscular disorders such as GuillainBarré syndrome, spinal muscular atrophy, or muscular dystrophy Upper airway obstruction

Protection of the airway for patients whose protective reflexes are absent, such as those with head trauma

MEDICATIONS FOR INTUBATION AND MECHANICAL VENTILATION After the decision is made to proceed with intubation, the next decision needs to be whether pharmacologic agents are appropriate. Most pediatric patients require sedation before laryngoscopy and intubation. The goal is to depress the infant’s or child’s level of consciousness sufficiently to produce appropriate conditions for intubation. Pharmacologic therapy is used to produce adequate sedation, analgesia, and amnesia plus a blunting of the physiologic response to airway manipulation. Intubation in the awake state can elicit protective reflexes that trigger tachycardia, bradycardia, and elevation in blood pressure; increased intracranial pressure (ICP), intraocular pressure; cough; and bronchospasm. Pharmacologic control promotes a smoother intubation with less physiologic stress for the patient who often is already in a compromised state. Ideally, this should be accomplished while producing minimal hemodynamic compromise.34 Many factors should be considered when choosing agents for intubation: the agent’s onset of action, the patient’s hemodynamic status, the need to prevent increased intraocular or intracranial pressure that may be caused by intubation, and whether the stomach is full or empty. A wide variety of medications may be used for pediatric sedation, each with its own risk and benefits (Table 44.8).34 In general, agents that act rapidly and are eliminated quickly are ideal. Often, drug choices are made according to the clinician’s experience with a particular drug and the immediate availability of the drug. More importantly, the drug regimen chosen must be according to the patient’s physiologic state. Agents with adverse effects that would exacerbate any underlying medical conditions must be avoided. Narcotics used in combination with anxiolytics are commonly used. Patients with inadequate relaxation despite adequate sedation may require neuromuscular blockade, although these agents are not without

risk. In a patient with a partial airway obstruction, neuromuscular blockade may worsen pharyngeal collapse, potentially resulting in complete airway obstruction. Therefore, neuromuscular blocking agents should only be used if the clinician is certain that adequate ventilation can be provided or that the patient can be intubated. If adequate chest rise and oxygen saturation cannot readily be maintained with bag-mask ventilation, neuro-muscular blockers should not be used. Infants and children younger than 5 years have a high vagal tone and are therefore more likely to have bradycardia when intubated. Instrumentation of the airway can directly stimulate vagal receptors and induce bradycardia. In these patients, it is prudent to administer atropine 0.02 mg/kg (minimum 0.1 mg) before intubation to blunt the autonomic response. Lidocaine (1–1.5 mg/kg per dose with a maximum dose of 100 mg) may be administered intravenously to blunt the airway protective reflexes elicited by instrumentation. This may be particularly useful in a patient with elevated ICP. In the patient with asthma, drugs that release hista-mine (e.g., morphine or atracurium) and have the potential to produce laryngospasm or bronchospasm should be avoided. The beneficial bronchodilatory adverse effects of ketamine, however, make it a useful choice in these patients. In a child with increased ICP, the choice of pharmacologic agent depends on the patient’s hemodynamic status. Pentobarbital is an excellent choice in the hemodynamically stable patient, whereas etomidate is preferred if the patient is unstable or hypovolemia is suspected. Etomidate should not be used routinely in pediatric patients because a single dose administered for intubation has the potential to produce adrenal inhibition.37 In children and adults with septic shock, etomidate administration is associated with a higher mortality rate.37-39 For all intubation, preoxygenation is carried out to increase the available oxygen in the lungs during the procedure, thus giving the practitioner some buffer time to intubate the patient. However, in patients with an elevated ICP or pulmonary vascular hypertension, hyperventilation is recommended to produce hypocarbia also. In an infant or child with a full stomach, the risk of aspirating gastric

contents is high. Rapid sequence intubation is used when there is an aspiration risk, such as in the child with a full stomach, and there is no concern of a difficult intubation.40 The goal of rapid sequence intubation is to gain airway control with an endotracheal tube (ETT) as quickly as possible to prevent aspiration. The patient is preoxygenated by facemask; bag-mask ventilation should not be used because it causes gastric distension. Once all necessary intubation equipment is ready, rapidly acting sedative, analgesic, and paralytic medications are administered simultaneously. An end-tidal CO2 detector should be attached to the ETT after intubation to confirm proper placement in the trachea. Colorimetric end-tidal CO2 devices change from purple to yellow to confirm the presence of exhaled CO2 and tracheal placement.

Table 44.8 Pharmacologic Agents Used for Intubation and Continuous Sedation

Drug

Route

Dose

Onset

Duration

Benefits

2-4 hr in neonates

Reversible ( naloxone)

Adverse Effects

Narcotics

Morphine

IV

0.1 mg / kg /dose ( max initial dose 2 mg); may repeat to a maximum total dose of 15 mg

Peak: 20

min

hypotension, peripheral vasodilatation, euphoria, dysphoria, itching, central nauseaandvomiting, decreased response to hypercarbia

Neonates: 0.05 mg /kg/dose Continuousinfusion Children: 20-50 mcg /kg / hr

Neonates:15 mcg /kg / hr Premature neonates: 10 mcg / kg / hr

Fentanyl

IV

Histaminerelease, respiratory depression,

1-3 mcg / kg /dose ( max initial dose 100 1-3 min meg; may repeat to a total dose of 5 meg /kg or 250 meg)

30-90 min

Rapid onset, short acting, reversible ( naloxone), relatively stable hemodynamic profile

Continuousinfusion 1-3 mcg /kg /hr (max initial dose 50-100 meg /hr )

Patient with coronary heart disease with an open chest: 5 mcg /kg/ hr

Bradycardia, respiratory depression, decreased response to hypercarbia, acute chest wall rigidity, itching

IN

1-2 meg / kg maximum dose 100 meg

3-5 min

-30 min

Rapid onset, short acting, reversible ( naloxone), relatively stable hemodynamic profile

Diazepam

IV

0.05 mg / kg /dose ( max 5 mg ); may repeat in 0.05 -mg /kg increments ( max 1mg ) to a total maximum dose of 10 mg

0.5-2 min

3 hr

Reversible ( flumazenll)

Respiratory depression, lacks analgesic properties, hypotension and bradycardia, local irritation, pain

Lorazepam

IV

0.05-0.15 mg / kg /dose ( max 4 mg )

15-30 min

0.5-3 hr

Reversible ( flumazenil)

Respiratory depression, lacks analgesic properties, hypotension and bradycardia

Midazolam

IV/ IM

0.05-0.15 mg / kg /dose ( max initial dose 2 mg; may repeat in 1-mg increments to a total dose of 5 mg)

1-5 min

20-30 min

Rapid onset, short acting, provides amnesia, reversible ( flumazenil)

Respiratory depression, lacks analgesic properties, hypotension and bradycardia

2-5 min

30-60 min

May burn

Respiratory depression, lacks analgesic properties, hypotension and bradycardia

Fentanyl

Benzodiazepines

Continuous infusion 0.05-0.1mg/ kg /hr ( max initial dose 2 mg /hr)

Midazolam

IN

0.1-0.3 mg /kg/dose ( max 10 mg) Use the 5-mg/ mL concentration

slightlyon administration

Midazolam

PO

0.5-0.75 mg / kg /dose ( max 10-20 mg)

30 min

2-6 hr

May use IV form ofmedication mixedina beverage with flavor; otherwise, bitter in taste

IV

2 mg/ kg /dose (max 100 mg). May repeat in 1- mg / kg /dose increments to a total dose of 7 mg /kg. Do not exceed 200 mg total dose

lmin

15 min

Decreases intracranial pressure

IM:10-15 min

1-4 hr

Respiratory depression, lacks analgesic properties, hypotensionand bradycardia

Barbiturates

Pentobarbital

Continuous infusion 0.5-1mg /kg/hr

Pentobarbital

Ml

2-6 mg / kg /dose

PO/ PR

PR /PO: 15-60

min Miscellaneous

Ketamine

IV

1mg / kg /dose q 5 min titrated to effect

1-2 min

10-30 min

Continuous infusion

0.5-1mg /kg/hr

Rapidonset, airway protective reflexes stay intact, no hypotension or bradycardia

Bronchodilation, useful to intubate

Increases airway secretions and laryngospasm ( bluntedwith atropine ). Elevated intracranial and intraocular pressure. Emergence reactions ( bluntedwith benzodiazepines)

patients with asthma

Ketamine

IM

4-5 mg / kg /dose

Ketamine

PO

6-10 mg / kg /dose

Ketamine

IN

6-8 mg /kg/dose

3-10 min

Etomidate

IV

0.3 mg/ kg /dose initially; then 0.1 mg / kg /dose q 5 min to titrate to effect

10 -20 s

3-5 min

10-15 min

Same as above

Same as above

Same as above

Same as above

20-60 min

Same as above

Same as above

4-10 min

Rapidonset

Poten tial for adrenal inhibition, nausea and vomiting on emergence

Shortacting Stable hemodynamic profile, decreased ICP

Propofol

IV

1-2 mg / kg /dose initially; then 0.5-2 mg / kg/ dose q 3-5 min to titrate to effect

Continuous infusion Infants and children: 50-150 meg / kg /min

Adolescents: 10-50 meg / kg/ min

30-60 s

5-10 min

IV general anesthetic, rapid onset and recovery

Cardiovascular and respiratory depression, contraindicated in patients with egg allergy, pain on injeetion

Dexmedetomidine IV

0.5-1mg /kg/dose

Hypotensionand bradycardia

Continuousinfusion

0.4-0.7 mcg / kg/hr

Doses as high as 2.5 mcg / kg / hr have been used Dexmedetomidine

IN

0.5-2 mcg/ kg / dose

Neuromuscular Blockers

Succinylcholine

IV

1mg /kg /dose

30-60 s

4-7 min

Rapid onset

Shortduration

Vecuronium

IV

0.1 mg / kg /dose

1-3 min

30-40 min

Continuous infusion:

Cardiovascular stable

0.1 mg / kg /hr; monitor with TOF q shift

Rocuronium

Potentiates hyperkalemia. Contraindicated in headtrauma ( f ICP), crush injury, burns, hyperkalemia. May induce neuroleptic malignantsyndrome Slower onset

Longer duration of action

IV/ IM

0.6-1mg /kg/dose

60-75 s

20-30 min

Cardiovascular stable

IV

Overdose: 0.1 mg / kg /dose ( max 2 mg)

2 min

20-60 min

Rapid onset

Shorter duration than mostopioids; therefore, repeated doses may be needed

1-3 min

6-10 min

Rapid onset

Shorter duration than most benzodiazepines; therefore, repeated doses may be needed

Reversal Agents

Naloxone

Slight respiratory depression: 0.01-0.02 mg / kg /dose (max 0.4 mg); may repeat q 2-3 min

Flumazenil

IV

0.01mg/kg / dose (max 0.2 mg); may repeat 0.005 mg/ kg /dose at 1-min intervals to a max total dose of 1mg

ICP = intracranial pressure; IM = intramuscular(ly); IN = intranasal(ly); PO = oral(ly); PR = rectal(ly); TOF = train-of-four.

Endotracheal intubation and mechanical ventilation can be painful, frightening, and anxiety provoking, especially in a young child. To improve patient comfort, relieve anxiety, and lessen the work of breathing, anxiolytics, sedatives, and analgesics are commonly administered once the patient is intubated and mechanically ventilated. Maintaining adequate sedation is essential. Selection of appropriate agents is based on the patient’s physiology. Guidelines for using continuous infusions are outlined in Table 44.9. In the paralyzed patient, neuromuscular blockade neither alters consciousness nor provides analgesia; therefore, adequate sedation and analgesia are essential. Providing effective analgesia and sedation to the pediatric patient depends on accurate ongoing efforts to assess the intensity of the

patient’s pain or anxiety. Assessing pain and anxiety in infants and critically ill children who are unable to communicate relies heavily on physiologic and behavioral responses. Several pain and sedation tools have been developed and validated specifically for use in children.41 No single standard measure gives a complete qualitative or quantitative measure. Selection of an appropriate tool is based on the child’s age, underlying medical condition, and cognition level. It is essential that these tools be used to evaluate the adequacy of the ICU sedation. Policies and procedures need to be in place for the appropriate selection and use of each tool, in addition to the training of all health care professionals to use each tool appropriately. The goal is to use the minimum amount of sedation needed to adequately sedate the intubated child while minimizing adverse effects.

Table 44.9 ICU Treatment of Status Asthmaticus First-line Therapies Continuous albuterol inhalation

10–40 mg/hra

Corticosteroids (prednisolone/prednisone or methylprednisolone)

2–4 mg/kg/24 hr divided q 6–12 hr To maintain O2 saturations > 92%

Supplemental oxygen Early supplemental therapies IV magnesium Second-line therapies Noninvasive positive pressure IV terbutaline IV aminophylline

25–75 mg/kg/dose (max 2 g/dose) infused over 20 min Titrated to comfort and tidal volume 10–20 mcg/kg loading dose, followed by a continuous infusion of 0.1–10 mcg/kg/min Load 6 mg/kg/dose, followed by a continuous infusion of 1–9 yr = 0.85–1 mg/kg/hr Goal serum concentration: 1–20 mcg/mL

Rescue therapies

Intubation

Pressure-limited ventilation or pressureregulated volume control modes

Helium-oxygen

60%–80% helium/20%–40% oxygen

IV ketamine

Load of 2 mg/kg/dose (max 100 mg/dose) followed by 0.5–5 mg/kg/hr

aHigher

doses have been used in some centers.

STATUS ASTHMATICUS Status asthmaticus or severe asthma exacerbation is defined as an acute episode that does not respond to standard treatment with shortacting β2-agonists and corticosteroids.42 Status asthmaticus is a primary cause of acute illness in children and one of the top indications for PICU admission.42,43 The indications for ICU admission vary between institutions and may be determined by respiratory care staffing on the pediatric floor. Bronchial smooth muscle spasm, airway inflammation, and increased mucus production are the key components of an acute asthma exacerbation.42,43 These factors produce increased pulmonary resistance and small airway collapse leading to increased work of breathing. As the degree of airway obstruction progresses, expiration becomes prolonged, and inspiration starts before the termination of the previous expiration. This results in air trapping and the classic hyperinflation seen on chest radiography. Airway obstruction and premature airway closure lead to ventilation/perfusion mismatching44 and hypoxemia.45 Lung hyperinflation, progressive increase in lung volumes, and an increase in pulmonary vascular resistance contribute to a decrease in right ventricular preload. Pulmonary vasoconstriction caused by hypoxia and acidosis leads to an increase in right ventricular afterload, and the high negative pulmonary pressure generated during inspiration in spontaneously breathing patients with asthma causes an increase in left ventricular afterload. These changes can be observed clinically in pulsus paradoxus, which is a decrease in systolic blood pressure by more than 10 mm Hg during

inspiration.42,43,46 In addition, tachycardia caused by bronchodilators further reduces ventricular filling time and may further reduce CO. This is evidenced clinically as a widened pulse pressure or low diastolic blood pressure and the need for additional intravascular volume. Patients rarely require inotropic support for the cardiovascular changes observed in SA.

EVALUATION Prompt and rapid evaluations of the clinical status of patients with SA are essential to determine the appropriate pharmacotherapy and levels of monitoring. A gold standard for assessing SA in children does not exist. An assessment of observed signs and symptoms can be helpful to classify the disease severity. Peak expiratory flow rates (PEFRs) or FEV1 (forced expiratory volume in 1 second) is difficult to reliably perform in children with acute asthma, especially in those younger than 5 years. In children 6–18 years of age, only 64% could perform PEFRs adequately.47 As a result, many clinical asthma scores have been developed to quantify the child’s degree of respiratory distress. None of these clinical asthma scores has been shown to be superior to any other. However, clinical scores correlate with the need for hospitalization, need for prolonged bronchodilator therapy, and severity of the exacerbation.48 Clinical asthma scores are not as helpful in predicting disease progression.49 Scores can be used not only to choose level of care, but also to wean pharmacotherapy as the patient improves. Measuring pulse oximetry (Sao2) is an important tool to determine asthma severity combined with the patient’s physical examination. An initial Sao2 less than 91% on room air or an Sao2 unresponsive to oxygen treatment has been associated with the need for hospital admission.48 For most patients, chest radiographs are unhelpful in the emergency assessment of asthma. Children with SA often have an abnormal chest radiograph with a variety of findings: hyper/hypoinflation, atelectasis, or increased extravascular fluid. These findings rarely affect patient treatment. In a small subset of children, a

chest radiograph may be helpful: children with a temperature greater than 39°C, focal abnormalities on examination, and no family history of asthma as well as those who respond less favorably than anticipated to bronchodilator therapy. In addition, chest radiography may be warranted when there is clinical suspicion for pneumothorax, pneumomediastinum, or foreign body aspiration or after intubation. Previously, evaluation of children with SA routinely included ABG measurement. Less invasive means of assessing respiratory status are widely available by pulse oximetry (to evaluate oxygenation) and endtidal CO2 (for evaluating ventilation).50,51 These are simple, noninvasive methods of evaluating oxygenation and ventilation. Routine ABG measurement has also fallen out of favor because no set values for pH, Pco2, or Po2 are diagnostic of respiratory failure.52 Children with acute asthma commonly have mild to moderate hypoxemia and hypocarbia or normocarbia on their initial blood gas caused by hyperventilation and ventilation/perfusion mismatch. Arterial blood gas measurement may be helpful in patients with the severest SA when a rising Pco2 is worrisome, and an ABG is often predictive of respiratory failure. Once a decision is made to intubate a patient with SA, frequent ABG assessment through an indwelling arterial line is useful to follow clinical progress.

SYMPTOMS The presentation of SA varies by severity, asthmatic trigger, and patient age. Most children with severe acute asthma present with cough, tachypnea, and increased work of breathing; use of accessory muscles; nasal flaring; and anxiety. Wheezing is a common clinical finding; however, the degree of wheezing correlates poorly with the severity of disease.42 A noisy chest is a reassuring sign because it represents sufficient airflow to cause turbulence and vibration leading to wheezing. The presence of a silent chest because of limited airflow is an ominous sign in a patient with SA and heralds respiratory failure. Agitation or dyspnea, especially in adolescents, should be recognized as severe respiratory compromise. Other findings of impending

respiratory failure and the need for a PICU admission include disturbance in the level of consciousness, inability to speak, markedly diminished breath sounds, diaphoresis, and the inability to lie down.

TREATMENT General First-line treatment of acute severe asthma consists of supplemental oxygen for hypoxemia, aerosolized albuterol plus ipratropium for bronchodilation, and corticosteroids for airway inflammation and edema. Typically, these therapies are administered in the ED. Failure to improve with first-line pharmacotherapy defines the patient as having SA.

Oxygen Oxygen (humidified) is the first drug of choice in all patients with acute severe asthma. Children with SA have a greater frequency of hypoxia from ventilation/perfusion mismatching than do adults because of agerelated differences, including lower functional residual capacity/total lung capacity ratio, increased chest wall compliance, and higher peripheral airway resistance.42 Oxygen therapy is monitored by pulse oximetry with a goal Sao2 greater than 92%.

Fluids The need for intravenous fluid boluses should not be overlooked in children presenting with SA. These patients are often dehydrated because of poor oral intake and increased insensible fluid losses from tachypnea. In addition, the increased intrathoracic pressure from air trapping can lead to decreased venous return, and the tachycardia from bronchodilator therapy can reduce filling time, leading to decreased CO. The key is to avoid overhydration because this may lead to transpulmonary edema.

β-Agonists β-Agonists remain the mainstay of therapy in SA. They produce smooth-muscle relaxation by binding to β2-adrenergic receptors in the smooth muscles of the airways. Albuterol is the most commonly used β-agonist in the United States. It is a 50:50 racemic mixture of Ralbuterol and S-albuterol. The R-enantiomer is pharmacologically active, whereas the S-enantiomer is considered inactive. Levalbuterol is the pure R-enantiomer and is a preservative-free solution. One in vitro study indicated that the S-enantiomer may exaggerate airway hyperresponsiveness and also may have a proinflammatory effect.53 This has not been shown clinically. In a randomized controlled trial of albuterol versus levalbuterol in children with SA, Qureshi et al. found no difference in clinical asthma score or adverse effects in children presenting to the ED with moderate to severe asthma exacerbations.54 Considering the increased cost and lack of clinical benefit in clinical trials, levalbuterol should not be recommended routinely for patients with SA. Traditionally, albuterol is initially administered by intermittent nebulization at 2.5–5 mg per dose. However, administration by a metered dose inhaler (MDI) with spacer is as effective as nebulization (6 inhalations per 2.5 mg) in children who can use them correctly.53 The results of these studies should be evaluated carefully. Although the outcome with using an MDI was shown to be equivalent to administration by nebulization, the study personnel coached patients with the MDI and spacer to ensure adequate technique. This is not always practical in the clinical setting. For children who need more frequent doses of β-agonist, continuous nebulization (e.g., initial doses of 10 mg/hour) appears to be superior to intermittent doses and results in more rapid improvement.55 In addition, continuous albuterol nebulization is less labor-intensive than several intermittent doses and may be more cost-effective.55 A drawback of continuous therapy is that patients may be assessed less often, and adverse effects such as tachycardia, jitteriness, and hypokalemia may be more common. The maximum dose of nebulized albuterol in most studies is 40 mg/hour.

Corticosteroids Steroid administration is recommended for all patients who lack improvement clinically after standard asthma treatment of albuterol 2.5 mg/500 mcg of ipratropium aerosolized every 20 minutes for three doses. Steroids administered in the ED can reduce hospitalization rates,56 re-turn hospital visits, and relapses if continued on discharge. Steroids decrease the inflammatory response, up-regulate β2adrenergic receptors, and decrease microvascular permeability and mucus production. Short-term use is usually not associated with significant adverse effects. However, hypertension, hyperglycemia, and behavioral changes have been reported.42 The National Heart, Lung, and Blood Institute (NHLBI) guidelines currently recommend administering corticosteroids systemically rather than by the inhalation route.57 Oral administration can be used if the child can tolerate oral medication, but if not, intravenous medication is preferred. The NHLBI guidelines suggest that 1–2 mg/kg every 24 hours of systemic prednisone/prednisolone or methylprednisolone can be used for acute asthma (maximum 60 mg every 24 hours), but they offer no recommendations for impending respiratory failure.57 In a recent survey of pediatric intensivists, 66% of respondents reported using a starting dose of 4 mg/kg every 24 hours in SA in the PICU.58 Intensivists using 4 mg/kg every 24 hours cite clinical experience as their deciding factor. Future research is needed to determine the most appropriate corticosteroid dosage and therapy duration in this critically ill patient population.

SECOND-LINE TREATMENTS Magnesium For children who present with SA and lack response to initial therapies, intravenous magnesium sulfate may be considered. It works through smooth muscle relaxation secondary to the inhibition of calcium uptake leading to bronchodilation. Magnesium can also inhibit mast cell

degranulation, possibly decreasing inflammation. The NHLBI guidelines suggest a magnesium sulfate dose in children of 25–75 mg/kg per dose (maximum 2 g per dose) infused for 20 minutes.57 Some investigators have suggested continuous infusion to target a serum concentration of 4 mg/dL; however, well-designed clinical trials showing serum concentration–targeted therapy are lacking. Possible adverse effects are muscle weakness, hypotension, tachycardia, skin flushing, and fatigue; however, these are uncommon. If hypotension occurs, it responds to the administration of intravenous fluids.

Terbutaline Intravenous β-agonists should be considered in patients unresponsive to treatment with continuous nebulization. In severe exacerbations, inspiratory flow may be too poor to allow for adequate drug delivery of albuterol to the small airways, and intravenous therapy may be necessary to effectively provide β-agonist therapy. Terbutaline is considered the drug of choice in the United States. Intravenous terbutaline, administered according to a severity-related dosing algorithm, acutely improves lung function and gas exchange and shortens hospital and ICU length of stay.59 Carroll and colleagues60 have linked β2-adrenergic receptor genetic polymorphisms with either a quicker response to β2-agonist therapy and a shorter ICU and hospital length of stay or a poor response to β2-agonist therapy and a longer ICU and hospital length of stay. The children with the poor responder genotype were significantly more likely to be African American than the more rapid responder phenotypes. The genetic polymorphism of most patients admitted to the PICU is unknown. However, in African American children whose continuous albuterol nebulization fails, treatment with a bronchodilator having a different mechanism of action may be indicated.

Methylxanthines Theophylline and aminophylline act through the nonselective inhibition of

phosphodiesterase and antagonize adenosine receptors in smooth muscles and inflammatory cells. The end result is bronchodilation, improved mucociliary clearance, and down-regulation of inflammation. In critically ill children with SA admitted to the PICU with impending respiratory failure, theophylline was as effective as intravenous terbutaline.61 In addition, treatment with theophylline was more costeffective than treatment with terbutaline.61 Therefore, theophylline should be considered for patients whose continuous albuterol therapy fails.

NONINVASIVE POSITIVE PRESSURE VENTILATION Noninvasive positive pressure ventilation is increasingly used in the care of children with SA. In these patients, a low level of continuous positive airway pressure can maintain small airway patency, reduce premature airway closure, and reduce the work of breathing. Early intervention improves outcomes and potentially avoids intubation in this population.62,63

HELIUM-OXYGEN Heliox is a mixture of 60%–80% helium with 20%–40% oxygen. Because of its lower density, heliox flows through small and obstructed airways with less turbulence and resistance, reducing the work of breathing and improving oxygen delivery to the lower airways. Heliox mixtures have a high helium faction and a relatively low oxygen fraction, making the therapy useless in patients with profound hypoxia.

RESCUE THERAPIES Intubation should be a last-resort therapy for children with SA. Intubation may aggravate bronchospasm and precipitate circulatory collapse. Next to severe hypoxia, rapid deterioration in the child’s mental status, progressive exhaustion, and cardiac and respiratory arrests are indications to intubate. Once the decision to intubate has

been made, a fluid bolus should be given to prevent the hypotension associated with positive pressure ventilation. Ketamine, because of its bronchodilatory action, is the preferred induction agent. Children may require significant amounts of sedation to avoid tachypnea and ventilator dyssynchrony. Neuromuscular blockade should be reserved for patients in whom adequate ventilation cannot be achieved at acceptable inspiratory pressures. Despite many recent advances in the understanding of the pathophysiology of asthma, β-agonists and steroids remain the mainstay of treatment for SA. Current literature supports the use of adjuvant therapies such as magnesium as well as a resurgence in the use of methylxanthines. Noninvasive positive pressure ventilation may prevent the need for intubation. The goal in asthma is to avoid intubation, if possible. A summary of drug dosing in asthma may be found in Table 44.9.

PEDIATRIC TRAUMATIC BRAIN INJURY Among children, traumatic brain injury (TBI) is the leading cause of mortality and leads to significant morbidity among survivors. Each year, more than 400,000 U.S. children have a TBI requiring an ED visit, resulting in 30,000 hospitalizations and 3,000 deaths.64 The most common mechanisms of injury differ by patient age. Children younger than 4 years usually have injuries because of child abuse, falls, and motor vehicle collisions (MVCs). Child abuse, or nonaccidental trauma (NAT), represents up to two-thirds of severe TBI cases in some series. Although it is difficult to obtain accurate data, the incidence of TBI caused by NAT in the first 2 years of life was 17 per 100,000 personyears in a population-based study from North Carolina.65 According to the National Center on Shaken Baby Syndrome, this translates to around 1,300 children per year in the United States who have severe head trauma from child abuse. In school-aged children 5–12 years of age, pedestrian-MVC and bicycle-related injuries are among the more common causes of severe injuries. For adolescents, MVCs replace falls as the leading cause of all injuries, followed by assault and sports-

related injuries. The anatomic differences in the infant’s brain render it more susceptible to certain types of injuries after head trauma.66 Infants and young children have large, heavy heads. The head is unstable because of its relative size to the rest of the body. If an infant or young child falls a significant distance, is ejected during an MVC, or is thrown from a bicycle after colliding with an automobile, the head will tend to lead (i.e., the infant or child will fly head first), and severe head injuries will occur when the head ultimately strikes the ground or another object. The infant’s weak neck muscles also allow for greater movement when the head is acted on by acceleration/deceleration forces. The skull is thinner during infancy and early childhood, providing less protection for the brain and allowing forces to transfer more effectively across the shallow subarachnoid space. The base of the infant’s skull is relatively flat, which also contributes to greater brain movement in response to acceleration/deceleration forces. In addition, the infant’s brain has a higher water content (about 88% vs. 77% in an adult), which makes the brain softer and more prone to acceleration/deceleration injury. The water content is also inversely related to the myelination process, and the higher percentage of unmyelinated brain makes it more susceptible to sheer injuries. The infant brain is typically fully myelinated by 1 year of age. As the result of these physiologic differences, there are differences in the pathology after pediatric TBI by age group. In infants and young children, diffuse injury (e.g., diffuse cerebral swelling) and subdural hematomas are more common than the focal injury (e.g., contusions) that is typically seen in older children and adults. The typical pattern of hypoxic-ischemic injury in infants and young children after NAT is rarely seen in older children and adult survivors of abuse. Goldstein et al. have published risk factors for NAT according to data gathered from several earlier reports.67 They found that individuals with inflicted head injury tended to be younger, were more often from families of poorer socioeconomic backgrounds, and were more likely to have parents who were younger than 18 years and who had never been married. In addition, a history inconsistent with physical findings was strongly associated with the presence of inflicted head

injury. Additional risk factors reported as associated with NAT are alcohol or drug abuse, previous social service intervention, or a history of child abuse, in combination with either retinal hemorrhages or an inconsistent history or physical examination. These investigators found that a combination of these factors was 100% predictive of child abuse in children admitted to a PICU. Nonaccidental trauma should be suspected when the injury does not meet the story (e.g., a fall of about 3 ft is required to cause significant head injury to an infant or child; a standard couch is 18 inches from the floor).68 The ability to evaluate the severity of TBI is essential to appropriately direct care, predict outcomes, and compare results to evaluate and improve patient care. Initial symptoms on presentation have little or no correlation with injury severity after TBI. The Glasgow Coma Scale (GCS) is a widely accepted method for initially evaluating and characterizing trauma patients with head injuries (Table 44.10). The scale is composed of visual, motor, and verbal components, with lower scores representing more serious injuries. The severity of TBI may be characterized as mild (GCS 13–15), moderate (GCS 9–12), or severe (GCS 3–8) on presentation; however, continued evaluation of GCS scores is the best way to track the patient’s clinical progress.69

Table 44.10 Modified Glasgow Coma Scale

Eye Opening Score

0-1yr

lyr

4

Opens eyes spontaneously

Opens eyes spontaneously

3

Opens eyes to verbal command

Opens eyes toshout

2

Opens eyes in response to pain

Opens eyes in response to pain

1

No response

Noresponse

Best Motor Response Score

6

0-1yr

ilyr

N /A

Obeys command

5

Localizes pain

Localizes pain

4

Flexion withdrawal

Flexion withdrawal

3

Flexion abnormal ( decorticate)

Flexion abnormal ( decorticate)

2

Extension ( decerebrate)

Extension ( decerebrate)

1

No response

Noresponse

Best Verbal Response Score

> 5 yr

2-5 yr

0-2 yr

5

Oriented and able to converse

Uses appropriatewords

Cries appropriately

4

Disoriented and able to converse

Uses inappropriate words

Cries

3

Uses inappropriate words

Criesand/orscreams

Cries and/orscreams inappropriately

2

Makes incomprehensible sounds

Grunts

Grunts

Noresponse

No response

Noresponse

1

The radiologic examination of choice for the immediate assessment of a child with severe TBI is a noncontrast cerebral computed tomography (CT) scan. Most children with severe TBI undergo immediate CT imaging to delineate their injuries as soon as they have been fully assessed and sufficiently stabilized to permit safe transport to the radiology suite. If the brain injury does not need immediate surgical intervention, the patient’s care is continued in the PICU with the implementation of therapies designed to minimize secondary brain injury. In a retrospective review of 309 children presenting with TBI, Chung et al. found that GCS scores were more useful in predicting survival among pediatric patients with TBI than were CT findings and the presence of injuries to other organ systems.69 In addition, they identified a GCS score of less than 5, rather than a score of less than 8 as used in adults, as the threshold at which the patient was more likely to have a poor outcome. The authors also found that head CT findings of swelling or edema and subdural and intracerebral

hemorrhage were associated with worse outcomes than subarachnoid or epidural hemorrhage. Retinal hemorrhages are often, although not always, observed in inflicted head injury in infants and young children. These hemorrhages are the result of sheer forces disrupting vulnerable tissue interfaces. The vitreous body is adherent to the retina in early childhood; shaking can cause retinal hemorrhaging throughout several tissue layers, extending to the periphery of the retina. This pattern is unique to “shaken baby syndrome.” Although useful for diagnosis, the ocular examination is often deferred initially when evaluating an infant or child for TBI because the medications used to facilitate funduscopy will preclude the use of pupillary reactivity as a tool to monitor evolving intracranial events. According to the American Academy of Pediatrics guidelines on imaging for NAT, a skeletal survey is strongly recommended in all cases of suspected physical abuse in children younger than 24 months.70 A skeletal survey consists of films of the extremities, skull, and axial skeletal images. Follow-up radiographs of the ribs to assess for healing fractures not seen in the acute phase may be helpful 2–3 weeks after the skeletal survey. As with the eye examination, the skeletal survey is often delayed until the child is more stable. The initial treatment of a child with a head injury should focus on the basics of resuscitation: assessing and securing the airway, ensuring adequate ventilation, and supporting circulation.71 In addition, the treatment goals of TBI are directed toward protecting against secondary brain insults, which can exacerbate neuronal damage and brain injury. Secondary brain insults are often the result of systemic hypotension, hypoxia, hypercarbia, anemia, and hyperglycemia. Aggressive treatment strategies are needed to prevent or treat these conditions to decrease morbidity and improve neurologic outcome after TBI in children. The criteria for tracheal intubation include hypoxemia not resolved with supplemental oxygen, apnea, hypercarbia (Paco2 greater than 45 mm Hg), a GCS score of 8 or less, a decrease in GCS greater than 3 compared with the initial score, cervical spine injury, loss of pharyngeal reflex, or any clinical evidence of herniation. All patients

should be assumed to have a full stomach and cervical spine injury, so the intubation should be carried out with a rapid sequence intubation using appropriate short-acting sedatives and muscle relaxants. After intubation, mechanical ventilation goals include 100% oxygen saturation, normocarbia (35–39 mm Hg), and no hyperventilation, as confirmed by ABGs, end-tidal CO2 monitoring, and chest radiographs showing the tracheal tube in good position. Unless the patient has signs or symptoms of herniation, prophylactic hyperventilation (Paco2 less than 35 mm Hg) should be avoided.71 Hyperventilation causes cerebral vasoconstriction, which decreases cerebral blood flow and subsequent blood volume. Although it will lower ICP, hyperventilation may result in ischemia. Furthermore, respiratory alkalosis caused by hyperventilation makes it more difficult to release oxygen to the brain, shifting the oxygen-hemoglobin curve to the left. Short-term use of hyperventilation, however, may be useful in preventing herniation while other medical therapies are implemented. In addition to mechanical ventilation, the head of the bed should be kept in the neutral position, and jugular venous obstruction should be avoided to prevent ICP elevation. Elevating the head of the bed to 30 degrees usually decreases ICP. Assessment and reassessment of the patient’s circulatory status, including central and peripheral pulse quality, capillary refill, heart rate, and blood pressure, is critical. Hypotension after pediatric TBI is associated with increased morbidity and mortality.71 Initial treatment of hypotension in the child with a head injury is similar to that described earlier for pediatric shock; however, the goal systolic blood pressure in the patient with TBI is typically higher: the 50th–75th percentile for age, sex, and height or greater. Systolic blood pressure less than the 75th percentile has been associated with a 4-fold increase in the risk of poor outcome after severe TBI, even when values were 90 mm Hg or greater.72 This suggests the possible benefit of a higher blood pressure target until ICP or cerebral perfusion pressure (CPP) monitoring is in place to guide therapy. Because of the need for higher systolic blood pressure, norepinephrine and phenylephrine, agents with greater vasopressor effects, are more commonly used in this patient population.73

The solution of choice for intravenous maintenance fluids in children with TBI is normal saline for children older than 1 year and 5% dextrose with normal saline for infants. Because hyperglycemia is known to worsen secondary brain insults, initial intravenous fluids for children should not contain dextrose. Infants are an exception because their low glycogen stores make them prone to hypoglycemia, especially with poor oral intake. Hypoglycemia can also worsen neurologic outcome and should be avoided. Frequent assessment of blood glucose either by point-of-care testing or on an ABG is recommended. Fever increases metabolic demands and is associated with worse outcomes after TBI. Treatment should include 15 mg/kg per dose of acetaminophen orally or rectally every 6 hours as needed and a cooling blanket, when necessary. Ibuprofen should be avoided because it may increase the risk of bleeding. Patients who are hypothermic on arrival should only be actively rewarmed if there is hemodynamic instability or bleeding thought to be exacerbated by hypothermia. Serum electrolytes and osmolarity should be monitored regularly, together with an accurate assessment of urine output. This is important to identify the development of either syndrome of inappropriate antidiuretic hormone or diabetes insipidus. Both have been reported to occur after pediatric TBI.71 One of the most significant consequences of TBI is the development of intracranial hypertension. The presence of an open fontanel or sutures in an infant with severe TBI does not preclude the development of intracranial hypertension or negate the usefulness of ICP monitoring. Intracranial pressure monitoring is recommended for any child presenting with a GCS of 8 or less.73 When possible, placement of a ventriculostomy catheter provides accurate pressure monitoring and allows for acute drainage of cerebrospinal fluid (CSF) for treatment of elevated ICP and assessment of CPP. The CPP value is calculated by subtracting the ICP from the MAP: CPP = MAP – ICP. This value is important as an indication of blood flow and oxygen that reaches the brain. Maintaining CPP requires the optimization of MAP with fluid therapy, and if necessary, vasoactive drugs. In ICP elevation, inotropic or vasopressor agents may be used to optimize

CPP by increasing MAP, even to the point of relative systemic hypertension. In adults, a CPP of 60–70 mm Hg is usually targeted. No data correlate CPP in infants with outcome. However, pediatric TBI studies show that CPP values of 40–70 mm Hg are associated with a favorable outcome and that a CPP less than 40 mm Hg is associated with poor outcomes.74 Because infants and children normally have a lower MAP and ICP, the Society of Critical Care Medicine Pediatric Fundamental Critical Care Support course recommends the following CPP ranges: 40–50 mm Hg in infants, 50– 60 mm Hg in children, and 60–70 mm Hg in adolescents.75 This is more specific than the 2003 pediatric recommendations, which recommend maintaining a CPP greater than 40 mm Hg and an “age-related continuum” of CPP of 40–65 mm Hg in infants and adolescents.71 Uncontrolled increased ICP is deleterious and must be treated aggressively as soon as possible to reduce cerebral ischemia. In this setting, the goal of any therapy is to lower ICP enough to increase CPP and improve cerebral oxygenation. All initial treatments should be reassessed for efficacy, including treatment of fever, avoidance of jugular venous outflow tract obstruction, maintenance of normovolemia and normocarbia, and provision of sedation and analgesia. Providing sedation and analgesia is of considerable importance because anxiety and pain increase ICP. If a patient has a ventriculoscopy and an elevated ICP, CSF should be drained until an ICP value of 15 mm Hg is reached; it should never be drained to 0 mm Hg because edema and diffuse brain swelling could cause an obstruction in the lateral ventricles. When a ventriculostomy is in place and CSF is frequently drained, it is important to replace the CSF drained with an equal amount of normal saline. Draining of large amounts of CSF without intravenous normal saline replacement is associated with the development of hypochloremic metabolic alkalosis. In patients whose ICP drainage fails, the intervention recommended is either the addition of a vasopressor to increase systolic blood pressure or the institution of hyperosmolar therapy. Hyperosmolar therapy may be useful in preventing the ICP from exceeding 20 mm Hg and in maintaining normal CPP. Mannitol has long

been the standard of care for managing elevated ICP.71 However, although extensively used since 1961 to control elevated ICP, mannitol has never been compared with placebo. Mannitol reduces ICP by reducing blood viscosity, which promotes reflex vasoconstriction of the arterioles by autoregulation, thus decreasing cerebral blood volume and ICP. This mechanism is rapid but transient, lasting about 75 minutes and requiring an intact autoregulation. It also produces an osmotic effect by increasing serum osmolarity, causing the shift of water from the brain cell to the intravascular space. Although this effect is slower in onset (15–30 minutes), the osmotic effect lasts up to 6 hours. Mannitol is a potent osmotic diuretic; osmotic diuresis should be anticipated and fluid resuscitation available to avoid hemodynamic compromise. A Foley catheter is recommended in these patients for accurate measurement of urine output. Mannitol is excreted unchanged in the urine; serum osmolarity should be maintained lower than 320 mOsm/L to avoid the development of mannitol-induced acute tubular necrosis. Mannitol is recommended at 0.25–1 g/kg per dose. Although mannitol has traditionally been the drug of choice for reducing elevated ICP, hypertonic saline (3% sodium chloride) is gaining favor. The main mechanism of action of hypertonic saline is an osmotic effect similar to that of mannitol. Hypertonic saline has several other theoretical benefits such as restoration of normal cellular resting membrane potential and cell volume, inhibition of inflammation, stimulation of atrial natriuretic peptide release, and improvement in CO.71 The theoretical advantage over mannitol is that hypertonic saline can be administered in a hemodynamically unstable patient without the risk of a subsequent osmotic diuresis. Continuous infusions of 0.1–1 mL/kg/hour of hypertonic saline titrated to maintain an ICP less than 20 mm Hg have been used successfully in children.71 Bolus doses of 3–5 mL/kg of 3% sodium chloride have been administered over 20–30 minutes. Serum osmolarity and serum sodium increase when this regimen is used, but sustained hypernatremia and hyperosmolarity appear to be generally well tolerated. Hypertonic saline has been administered with a serum osmolarity reaching 360 mOsm/L without adverse effects in pediatric patients. Another potential concern with the

use of hypertonic saline is central pontine myelinolysis, which has been reported with rapid changes in serum sodium. Clinical trials have shown no evidence of demyelinating disorders. Two nonsurgical options are included in the TBI guideline: barbiturate coma and therapeutic hypothermia.71 Barbiturates exert neuroprotective effects by reducing cerebral metabolism, lowering oxygen extraction and demand, and alternating vascular tone. Barbiturate serum concentrations correlate poorly with clinical efficacy; therefore, monitoring of electroencephalographic (EEG) patterns for burst suppression is recommended. Burst suppression also represents near-maximum reduction in cerebral metabolism and cerebral blood flow. A pentobarbital loading dose of 10 mg/kg per dose may be administered over 30 minutes, followed by a continuous infusion of 1 mg/kg/hour. Additional loading doses, in 5-mg/kg per dose increments, may be necessary to achieve burst suppression. The primary disadvantage of barbiturate coma is the risk of myocardial depression and hypotension. In addition, the long-term effect on neurologic outcome is unknown. The TBI guideline states that high-dose barbiturate therapy may be considered in hemodynamically stable patients with salvageable severe head injury and refractory intracranial hypertension.71 Posttraumatic hyperthermia is defined as a core body temperature greater than 38.5°C, and hypothermia is defined as a temperature of less than 35°C. Although most clinicians agree that hyperthermia should be avoided in children with TBI, the role of hypothermia is unclear. Potential complications associated with hypothermia are increased bleeding risk, arrhythmias, and increased susceptibility to infection. A multicenter, international study of children with severe TBI randomly assigned to hypothermia therapy initiated within 8 hours after injury (32.5°C for 24 hours) or to normothermia (37°C) was published in 2008.76 The study reported a worsening trend with hypothermia therapy: 31% of the patients in the hypothermia group had an unfavorable outcome, compared with 22% in the normothermia group. However, this study had several methodological problems. Although the investigators screened patients within 8 hours, the mean time to

initiation of cooling was 6.3 hours, with a range of 1.6–19.7 hours. In addition, the protocol included a rapid rewarming of 0.5°C every 2 hours so that the patients were normothermic by a mean of 19 hours or 48 hours postinjury. The investigators found that the ICP was significantly lower in the hypothermia group during the cooling period but significantly higher than in the normothermic group during rewarming. Another trial conducted in Australia and New Zealand evaluated strict normothermia (temperature 36°C–37°C) versus therapeutic hypothermia (temperature 32°C–33°C).75 Patients were enrolled within 6 hours of injury, and therapeutic hypothermia or strict normothermia was maintained for 72 hours. The re-warming rate was at a maximum of 0.5°C every 3 hours or slower if needed to maintain normal CPP or ICP less than 20 mm Hg. Rewarming took a median of 21.5 hours (16–35 hours) and was without complications. However, there was no difference in pediatric cerebral performance category scores between the two groups at 12 months.77 It is unclear whether therapeutic hypothermia lacks efficacy because patients are not cooled soon enough (median time to target temperature 9.3 hours) or because of the heterogeneous nature of TBI. The pediatric TBI guideline states that despite the lack of clinical data, hypothermia may be considered in the setting of refractory hypertension.71 Decompressive craniectomy, removal of a section of skull to allow room for brain swelling without herniation, is another option for treating pediatric patients with TBI who lack response to standard therapies. A randomized trial of early decompressive craniectomy in children with TBI and sustained intracranial hypertension showed that 54% of the surgically treated patients had a favorable outcome compared with only 14% of the medically treated group.78 Additional case series have confirmed that patients who receive a decompressive craniectomy have improved survival and neurologic outcomes compared with patients undergoing medical management alone.55 However, as with barbiturate coma and therapeutic hypothermia, decompressive craniectomy is not without risk. A recent study reported an increased risk of posttraumatic hydrocephalus, wound complications, and epilepsy in children with severe TBI.79 Further studies are needed to

establish the timing, efficacy, and safety of this management strategy. The pediatric TBI guideline states that decompressive craniectomy should be considered in pediatric patients with severe TBI, diffuse cerebral swelling, and intracranial hypertension refractory to intensive medical management.

POSTTRAUMATIC SEIZURES Posttraumatic seizures are classified as early (occurring within 7 days after injury) or late (occurring after 7 days). In the immediate period after severe TBI, seizures increase the brain metabolic demands, increase ICP, and are associated with secondary brain insults. Therefore, it is prudent to prevent posttraumatic seizures when the patient is at the highest risk of secondary brain insults. Infants and children are reported to have a greater risk of early PTS than are adults. Children younger than 2 years have almost a 3-fold greater risk of early posttraumatic seizures after TBI than do children 2–12 years of age. In addition to age, a low GCS (8–11) has been linked with an increased risk of early posttraumatic seizures. The pediatric TBI guideline states that prophylactic antiseizure therapy may be considered as a treatment to prevent early posttraumatic seizures. No prophylactic anticonvulsant therapy is recommended to prevent late posttraumatic seizures.71 Most of the published studies of children have used phenytoin for posttraumatic seizure prophylaxis. Both phenytoin and carbamazepine have been reported to reduce the incidence of posttraumatic seizure in adults. A large (n=813) prospective multicenter trial evaluated the effectiveness of levetiracetam for seizure prophylaxis in adults with severe TBI.80 Although the trial showed that levetiracetam was as effective as phenytoin in preventing posttraumatic seizures after TBI, the authors concluded that the significant cost difference between the two treatments makes phenytoin the preferred therapy. There are currently no studies of levetiracetam for posttraumatic seizure prophylaxis in children.

STRESS-RELATED MUCOSAL BLEEDING The use of prophylaxis to prevent stress-related mucosal bleeding, although common in adult ICU patients, is not widely used in PICUs. Studies conducted to date have provided a wide range of gastrointestinal (GI) tract bleeding rates in children, 10%–50%, with rates of clinically significant bleeding of around 1%–4%.81,82 Several investigators have identified thrombocytopenia, coagulopathy, organ failure, and mechanical ventilation as important risk factors for GI bleeding, similar to studies conducted in adults. A recent systematic review suggested that critically ill pediatric patients benefit from prophylaxis; however, the results were limited by the small number of controlled studies available.79 There are no clear recommendations in pediatric patients for the use of histamine-2 blockers (H2-blockers) versus proton pump inhibitors (PPIs) for stress ulcer prophylaxis in the PICU. However, in 2015, a retrospective cohort analysis reviewed 336,010 PICU admissions in 42 freestanding children’s hospitals. Results showed that administering gastric acid suppressant medications, prescribed on the first day of PICU hospitalization, was common, occurring in 60% of hospitalizations. Among those receiving treatment, H2-blockers were used more often (70.4%) than PPIs (17.8%), and both types of agents were used in 11.8% of cases.83

THROMBOSIS PROPHYLAXIS Patients admitted to the PICU can range from newborns to young adults. Unlike in adults, there are no data on the use of subcutaneous heparin or low-molecular-weight heparins as prophylaxis to prevent deep venous thrombosis (DVT) in children. However, when children reach puberty, the hormone changes that take place appear to increase children’s risk of thrombosis compared with adults. Although no published guidelines or consensus papers currently exist to guide therapy, all pubescent adolescents should be considered for DVT prophylaxis. Most thrombosis cases in infants and young children are

associated with the long-term use of central venous catheters. Additional risk factors that have been reported in children include active inflammatory bowel disease, obesity, and infection.84,85 Unfortunately, a study evaluating low-dose heparin infused at 10 units/kg/hour did not prevent catheter-related thrombosis in infants after cardiac surgery.86 Of note, the heparin dose used in this study was less than the anticoagulant dose recommended for infants and children (15–25 units/kg/hour). The routine use of DVT prophylaxis in children remains controversial; however, it should be considered in pubescent children.

HYPOGLYCEMIA Hypoglycemia often develops in infants during episodes of stress, including shock, seizures, and sepsis. Infants have high glucose needs and low glycogen stores, which makes hypoglycemia a risk in a critically ill infant, especially one with poor enteral intake. Point-of-care glucose testing should be performed in any critically ill infant with a history of poor oral intake. The clinician should not wait to obtain serum chemistries. The aggressive fluid resuscitation recommended for hypovolemia and shock will only exacerbate hypoglycemia. More importantly, hypoglycemia needs to be prevented during cardiopulmonary and trauma resuscitation because it may cause seizures and has been linked with poor neurologic outcome.4,5 Hypoglycemia in pediatric patients must always be promptly identified and treated. After diagnosis, the patient should be treated with a bolus of 0.5–1 g/kg of glucose or 5–10 mL/kg of a 10% dextrose solution as required to achieve a serum glucose greater than 100 mg/dL. Neonates, especially premature neonates, are more prone to intraventricular hemorrhage with rapid changes in serum osmolarity than are older infants and children; therefore, 0.2 g/kg or 2 mL/kg of 10% dextrose is recommended in this population until the target serum glucose is achieved.

CONCLUSION

Common causes for admission to the PICU differ from causes for admission to adult ICUs. In addition, changes in physiology with normal growth and development can make the definitions of a disease differ between infants and children, as with supraventricular tachycardia, or predispose a specific age group to more severe disease. The clinician must recognize the many physiologic changes that take place during normal growth and development and understand how they affect the patient’s assessment and treatment. Pediatric health care providers practicing in critical care settings such as the ED or PICU must be adept at incorporating these physiologic differences into medication selection, dosing, and monitoring to optimize patient care.

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6. Maitlans M, Kaguli S, Opoko RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med 2011;364:2483-95. 7. Dupont HL, Spink WW. Infections due to gram-negative organisms: an analysis of 860 patients with bacteremia in the University of Minnesota Medical Center, 1958-1966. Medicine 1969;48:307-32. 8. Hartman ME, Linde-Zwirble WT, Angis DC, et al. Trends in the epidemiology of severe sepsis. Pediatr Crit Care Med 2013;14:686-93. 9. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77. 10. Carcillo JA, Fields AI; American College of Critical Care Medicine Task Force Committee Members. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med 2002;30:1365-78. 11. Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine [published correction appears in Crit Care Med 2009;37:1536]. Crit Care Med 2009;37:666-88. 12. de Oliveira CF, de Oliveira DS, Gottschald AF, et al. ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcome comparison with and without monitoring central venous oxygen saturation. Intensive Care Med 2008;34:1065-75. 13. de Oliveira CF. Early goal-directed therapy in treatment of pediatric septic shock. Shock 2010;34(suppl 1):44-7. 14. Wynn JL, Wong HR. Pathophysiology and treatment of septic shock in neonates. Clin Perinatol 2010;37:439-79. 15. Carcillo JA. Pediatric septic shock and multiple organ failure. Crit Care Clin 2003;19:413-40.

16. Goldstein B, Giroir B, Randolph A, et al. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2-8. 17. Boone RC, Sprung CL, Sibbald WJ. Definitions for sepsis and organ function. Crit Care Med 1992;20:724-6. 18. Boone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644-55. 19. Kline MW, Lorin MI. Bacteremia in children afebrile at presentation to an emergency department. Pediatr Infect Dis J 1989;6:197-8. 20. Bonadilo WA. Incidence of serious infections in afebrile neonates with a history of fever. Pediatr Infect Dis J 1987;6:911-4. 21. Ceneviva G, Paschall JA, Maffel F, et al. Hemodynamic support in fluid refractory pediatric septic shock. Pediatrics 1998;102:e19. 22. Pollack MM, Fields AI, Ruttimann UE. Distributions of cardiopulmonary variables in pediatric survivors and nonsurvivors of septic shock. Crit Care Med 1985;13:454-9. 23. Feltes T, Pignatelli R, Kleinert S, et al. Quantitated left ventricular systolic mechanisms in children with septic shock utilizing noninvasive wall stress analysis. Crit Care Med 1994;22:1647-58. 24. Akech S, Ledermann H, Maitland K. Choice of fluids for resuscitation in children with severe infection and shock: systematic review. BMJ 2010;341:c4416. 25. Zimmerman JL. Use of blood products in sepsis: an evidence based review. Crit Care Med 2004;32(11 suppl):S542. 26. Carcillo JA, Davis AI, Zaritsky A. Role of early fluid resuscitation in pediatric septic shock. JAMA 1991;266:1242-5. 27. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and

saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56. 28. Ventura AM, Sheih HH, Bousso A, et al. Double-blind prospective randomized controlled trial of dopamine versus epinephrine as first-line vasoactive drugs in pediatric septic shock. CCM 2015;43:2292-302. 29. Mann K, Berg RA, Nadkarni V. Beneficial effects of vasopressin in prolonged pediatric cardiac arrest: a case series. Resuscitation 2002;52:149-56. 30. Duncan JM, Meaney K, Simpson P, et al. Vasopressin for inhospital pediatric cardiac arrest: results from the American Heart Association National Registry of Cardiopulmonary Resuscitation. Pediatr Crit Care Med 2009;10:191-5. 31. Hoffman TM, Wernovsky G, Atz AM, et al. Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation 2003;107:996-1002. 32. Shott SR. The nose and paranasal sinuses. In: Rudolph CD, Rudolph AM, eds. Rudolph’s Pediatrics, 21st ed. New York: McGraw-Hill, 2003:1258. 33. Dawson-Caswell M, Muncie HL Jr. Respiratory syncytial virus infection in children. Am Fam Physician 2011;83:141-6. 34. Kumar P, Denson SE, Mancuso TJ, et al. Premedication for nonemergency endotracheal intubation in the neonate. Pediatrics 2010;125:608-15. 35. Watson RS, Carcillo JA, Linde-Zwirble WT, et al. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med 2003;63:695-701. 36. Perkett EA. Lung growth in infancy and childhood. In: Rudolph CD, Rudolph AM, eds. Rudolph’s Pediatrics, 21st ed. New York: McGraw-Hill, 2003:1905.

37. den Brinker M, Hokken-Koelega AC, Hazelzet JA, et al. One single dose of etomidate negatively influences adrenocortical performance for at least 24h in children with meningococcal sepsis. Intensive Care Med 2008;34:163-8. 38. Cuthbertson BH, Sprung CL, Annane D, et al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med 2009;35:1868-76. 39. Jackson WL Jr. Should we use etomidate as an induction agent for endotracheal intubation in patients with septic shock? A critical appraisal. Chest 2005;127:1031-8. 40. Zelicof-Paul A, Smith-Lockridge A, Schnadower D, et al. Controversies in rapid sequence intubation in children. Curr Opin Pediatr 2005;17:355-62. 41. Johansson M, Kokinsky E. The COMFORT behavioural scale and the modified FLACC scale in paediatric intensive care. Nurs Crit Care 2009;14:122-30. 42. Werner HA. Status asthmaticus in children. Chest 2001;119:191329. 43. Mannix R, Bachur. Status asthmaticus in children. Curr Opin Pediatr 2007;19:281-7. 44. Roca J, Ramis L, Rodriguez-Roison R, et al. Serial relationship between ventilation-perfusion inequality and spirometry in acute severe asthma requiring hospitalization. Am Rev Respir Dis 1988;137:1055-61. 45. Rodriguez-Roison R, Ballister E, Roca J, et al. Mechanisms of hypoxemia in patients with status asthmaticus requiring mechanical ventilation. Am Rev Respir Dis 1989;139:732-9. 46. Jardin F, Farcot JC, Boisante LD. Development of paradoxic pulse in bronchial asthma. Circulation 1982;66:887-94. 47. 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. 48. Keogh KA, Macarthur C, Parkin PC, et al. Predictors of hospitalization in children with acute asthma. J Pediatr 2001;139:273-7. 49. Baker MD. Pitfalls in the use of clinical asthma scoring. Am J Dis Child 1988;142:183-5. 50. Langhan ML, Zonfrillo MR, Spiro DM. Quantitative end-tidal carbon dioxide in acute exacerbations of asthma. J Pediatr 2008;152:829-32. 51. Moses JM, Alexander JL, Aqus MS. The correlation and level of agreement between end-tidal and blood gas PCO2 in children with respiratory distress: a retrospective analysis. BMC Pediatr 2009;9:20. 52. Carruthers DM, Harrison BD. Arterial blood gas analysis or oxygen saturation in the assessment of acute asthma? Thorax 1995;50:186-8. 53. Johnson F, Rydberg I, Aberg G, et al. Effects of albuterol enantiomers on in vitro bronchial reactivity. Clin Rev Allergy Immunol 1996;14:57-64. 54. Qureshi F, Zaritsky A, Welch C, et al. Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med 2005;46:29-36. 55. Papo MC, Frank J, Thompson AE. A prospective randomized study of continuous versus intermittent nebulized albuterol for severe status asthmaticus in children. Crit Care Med 1993;21:1479-86. 56. Bhogal SK, McGillivray D, Bourbeau J, et al. Early administration of systemic corticosteroids reduced hospital admission rates for children with moderate and severe asthma exacerbation. Ann Emerg Med 2012;60:84-91. 57. U.S. Department of Health and Human Services National Heart,

Lung and Blood Institute. National Asthma Education and Prevention Program Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Publication 08-4051. Bethesda, MD: U.S. Department of Health and Human Services, 2007. 58. Giuliano JS Jr, Faustino EV, Li S, et al. Corticosteroid therapy in critically ill pediatric asthmatic patients. Pediatr Crit Care Med 2013;14:467-70. 59. Carroll CL, Schramm CM. Protocol-based titration of intravenous terbutaline decreases length of stay in pediatric status asthmaticus. Pediatr Pulmonol 2006;41:350-6. 60. Carroll CL, Sala KA, Zucker AR, et al. Beta-adrenergic receptor polymorphisms associated with length of ICU stay in pediatric status asthmaticus. Pediatr Pulmonol 2012;47:233-9. 61. Wheeler DS, Jacobs BR, Kenreigh CA, et al. Theophylline versus terbutaline in treating critically ill children with status asthmaticus: a prospective, randomized controlled trial. Pediatr Crit Care Med 2005;6:142-7. 62. Thill PJ, McGuire JK, Baden HP, et al. Noninvasive positive pressure ventilation in children with lower airway obstruction. Pediatr Crit Care Med 2004;5:337-42. 63. Carroll CL, Schramm CM. Noninvasive positive pressure ventilation for the treatment of status asthmaticus in children. Ann Allergy Asthma 2006;96:454-9. 64. Bishop NB. Traumatic brain injury: a primer for primary care physicians. Curr Probl Pediatr Adolesc Health Care 2006;36:318. 65. Keenan HT, Runyan DK, Marshall SW, et al. A population-based study of inflicted traumatic brain injury in young children. JAMA 2003;290:621-6. 66. DeMeyer W. Normal and abnormal development of the neuroaxis. In: Rudolph CD, Rudolph AM, eds. Rudolph’s Pediatrics, 21st ed. New York: McGraw-Hill, 2003:2174.

67. Goldstein B, Kelly MM, Bruton D, et al. Inflicted versus accidental head injury in critically injured children. Crit Care Med 1993;21:1328-32. 68. Rorke-Adams L, Duhaime CA, Jenny C, et al. Head trauma. In: Reece RM, Christians CW, eds. Child Abuse: Medical Diagnosis and Management, 3rd ed. Elk Grove Village, IL: American Academy of Pediatrics, 2009:54. 69. Chung CY, Chen CL, Cheng PT, et al. Critical score of Glasgow Coma Scale for pediatric traumatic brain injury. Pediatr Neurol 2006;34:379-87. 70. American Academy of Pediatrics. Section on radiology: diagnostic imaging of child abuse. Pediatrics 2009;123:1430-5. 71. Adelson PD, Bratton SL, Carney NA, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents. Pediatr Crit Care Med 2003;4(3 suppl):S72-5. 72. Vavilala MS, Bowen A, Lam AM, et al. Blood pressure and outcome after severe traumatic brain injury. J Trauma 2003;55:1039-44. 73. Di Gennaro JL, Mack CD, Malakouti A, et al. Use and effect of vasopressors after pediatric traumatic brain injury. Dev Neurosci 2010;32:420-30. 74. Catala-Temprano A, Claret Teruel G, Cambra Lasaosa FJ, et al. Intracranial pressure and cerebral perfusion pressure as risk factors in children with traumatic brain injuries. J Neurosurg 2007;106(6 suppl):463-6. 75. Mejia R, ed. Traumatic Brain Injury in Pediatric Fundamental Critical Care Support. Mount Prospect, IL: Society of Critical Care Medicine, 2008. 76. Hutchison JS, Ward RE, Lacroix J, et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008;358:2447-56.

77. Beca J, McSharry B, Erickson S, et al. Hypothermia for traumatic brain injury in children – a phase II randomized controlled trial. Crit Care Med 2015;43:1458-66. 78. Taylor A, Butt W, Rosenfeld J, et al. A randomized trial of very early decompressive craniectomy in children with traumatic brain injury. Childs Nerv Syst 2001;17:154-62. 79. Jagannathan J, Okonkwo DO, Dumont AS, et al. Outcome following decompression craniectomy in children with severe traumatic brain injury: a 10-year single-center experience with long-term follow-up. J Neurosurg 2007;106(4 suppl):268-75. 80. Inaba K, Menaker J, Branco BC, et al. A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg 2013;74:766-71. 81. Deerojanawong J, Peongsujarit D, Vivatvakin B, et al. Incidence and risk factors of upper gastrointestinal bleeding in mechanically ventilated children. Pediatr Crit Care Med 2009;10:91-5. 82. Reveiz L, Guerrero-Lazano R, Camacho A, et al. Stress ulcer, gastritis, and gastrointestinal bleeding prophylaxis in critically ill pediatric patients: a systematic review. Pediatr Crit Care Med 2010;11:124-32. 83. Costarino AT, Dai D, Feng R, et al. Gastric acid suppressant prophylaxis in pediatric intensive care: current practice as reflected in a large administrative database. Pediatr Crit Care Med 2015;16:605-12. 84. Higgerson RA, Lawson KA, Christie LM, et al. Incidence and risk factors associated with venous thrombotic events in pediatric intensive care unit patients. Pediatr Crit Care Med 2011;12:62834. 85. Zitomersky NL, Levine AE, Atkinson BJ, et al. Risk factors, morbidity, and treatment of thrombosis in children and young adults with active inflammatory bowel disease. JPGN

2013;57:343-7. 86. Schroeder AR, Axelrod DM, Silverman NH, et al. A continuous heparin infusion does not prevent catheter-related thrombosis in infants after cardiac surgery. Pediatr Crit Care Med 2010;11:48995.

Chapter 45 Drug Shortages: An

Overview of Causes, Impact, and Management Strategies Samuel E. Culli, Pharm.D., MPH; and John J. Lewin III, Pharm.D., MBA, FASHP, FCCM, FNCS

LEARNING OBJECTIVES 1. List several of the multifactorial causes of drug shortages. 2. Describe the impact of drug shortages on patients, health care providers, and health care systems. 3. Gather information on current drug shortages from the ASHP and FDA websites. 4. Explain the various options for management and communication of a drug shortage that health care systems use to help mitigate the associated potential negative impact.

ABBREVIATIONS IN THIS CHAPTER ASHP

American Society of Health-System Pharmacists

FDA

Food and Drug Administration

FDASIA Food and Drug Administration Safety and Innovation Act

ISPE

International Society of Pharmaceutical Engineering

INTRODUCTION: PREVALENCE AND CURRENT TRENDS Drug shortages are a significant threat to the quality and safety of the medical care provided to critically ill patients. Despite new regulations signed into law in 2012 giving the U.S. Food and Drug Administration (FDA) more authority to help prevent shortages and enhancing collaboration between the FDA and manufacturers, shortages of commonly used medications persist. New drug shortages have decreased from their peak in 2011 (a 47%–80% decrease from 2011 to 2014, depending on the source) (Figure 45.1).1 However, at this time, there were more than 215 current drug shortages being tracked (Figure 45.2).2 About 44% of the shortages reported in 2011–2013 are of generic injectable medications, which are vital in the treatment of critically ill patients.3 In addition, four of the top five drug classes accounting for most shortages currently represent medications vital in the care of critically ill patients, including anesthetics/central nervous system agents, anti-infective agents, electrolytes/nutrition, and cardiovascular drugs (Figure 45.3).3 Some examples of generic injectable medications that have recently been on shortage include calcium gluconate, cefazolin, epinephrine, norepinephrine, piperacillin/tazobactam, and vecuronium.

Causes of Drug Shortages The causes of drug shortages are complicated and multi-factorial. Each shortage often has its own unique causes. According to the FDA, the main cause of drug shortages is quality problems with a product or manufacturing plant such as sterility issues or the presence of particulate matter. Both of these can lead to drug recalls.4 The FDA cites other causative issues, including plant shutdowns to address quality issues, concentration of the drug market to a few firms, and a

lack of redundancy in manufacturing.4 However, the cause of an individual shortage is reported as unknown almost 50% of the time (Table 45.1). The International Society for Pharmaceutical Engineering (ISPE) surveyed drug manufacturers in its 2013 Drug Shortages survey. Almost half of the respondents identified quality issues as a primary cause of shortages, echoing the FDA’s reports. Many of these quality issues related to equipment systems and facilities dealing with aseptic processing equipment. The issues were often the result of a mix of aging equipment and improper use of that equipment. However, ISPE noted that the most significant issue preventing maintenance or modernization of facilities is the length of time it may take to obtain proper regulatory approvals (up to 3–7 years).4

Figure 45.1 New drug shortages by year, January 2001 – June 30, 2015. Reprinted with permission from: University of Utah Drug Information Service.

National Drug Shortages Active Shortages by Quarter Active Shortages 350 300

2

^

239

250 200 152

167176

2Z

3260

22

92952 > 2M2a8 30 S 306

*

320

301 265

219

211

138

150 100

50 0 5 for up to 19 hr

Lansoprazole decreased the AUC by 94%

PPIs should be avoided, when possible

Omeprazole 40 mg /day decreased the AUC by 65%—75%

Consider H2RAs as alternatives, but need to spacel2 hrapart

In treatment-naive patients, if a PPI is warranted, the PPI dose should not exceed a dose comparable to omeprazole 20 mg and must be taken about 12 hr before atazanavir Mycophenolate mofetil111*

Omeprazole 20 mg BID decreased the AUC by 20 %

If coadministration is necessary, the dose of mycophenolate may need to be increased; can consider enteric-coated mycophenolate sodium to avoid interaction

Posaconazole**

Decreased bioavailability with increase in gastric pH

Use DR tablets, if possible Avoid suspcnsion formulation. If unavoidable, administer with a fatty meal or cola beverage

Omeprazole 20 mg /day decreased the AUC by 40%

Rilpivirine11

PPIs are contraindicated in all patients taking rilpivirine Only H2RAS that can be dosed once daily should be used. Administer at least 12 hr before or 4 hr after rilpivirine

Increased Gl motility Metoclopramide

’

Cyclosporine1

Metoclopramide increased the peak and AUC of cyclosporine by 50% and 30%, respectively

Monitor and adjust cyclosporine concentrations as necessary.

Monitor for signs and symptoms of cyclosporine toxicity, which may inelude acute kidney injury, cholestasis, or pares thesias Presence of a binder or chelator Complexmetals (calcium, aluminum iron, magnesium)

.

Fluoroquinolones (ciprofloxacinand

levofloxacin )

and

tetraeyelines

One randomized crossoverstudy of 12 healthy volunteers reported that when either calcium carbonate or aluminum hydroxide tablets were taken 5 min before ciprofloxacin, the bioavailability was reduced by 40%-85% of the

controlvalue

(doxycycline and minocycline)11'*2

Administer aluminum-, calcium-, or magnesium-containing produets at least 2-4 hr before or 6 hr after the fluoroquinolone Administer iron at least 2 hr after the fluoroquinolone; avoid sustained-release iron Consider switehing the fluoroquinolone to IV forsevere infections in critically ill hospitalized patients

Bile acid sequestrates

Digoxin

(cholestyramine)

Levothyroxine

Oralvancomycin Lipid-soluble vitamins

Warfarina*

Bind to various drugs and decrease their oral bioavailability

Much more likely to bind to acidic compounds than to basic compounds, but this is not an absolute because they can bind to basic medications as wellfe.g., propranolol )

Separate the administration times of all oral medications by at least 2 hr before or 4 hr after the administration of bile acid sequestrants

Carbapenems

”*

Valproic acid2

Carbapenems lowervalproicadd concentrations through several mechanisms: -Inhibits intestinal absorption ofvalproicacid -Inhibits p- glucuronidase, which increases the systemic clearance of the parent drug by reducing the amount of drug available for recirculation

Recommend an alternative antibiotic or antiepileptic agent. If valproic acid must be coadministered with a carbapenem: -Increasing the valproic acid doses may not be sufficient to achieve therapeutic levels; monitor valproic acid plasma

concentrations

-Improves glucuronidation of valproic acid Carbapenems reduce valproic acid plasma concentrations by 50%-80%; have led to breakthrough seizures in some patients Disruption of intestinal flora Ampicillin

DigoxinBK

Macrolides Tetracyclines

In about 10% of patients, digoxin is metabolized by Eubacterium lentum ( a gram-positive anaerobic Bacillus ).

Monitor digoxin concentrations, and monitor for signs and symptoms of toxicity. Less clinical relevance for patients taking Lanoxicaps ® or digoxin elixir because of more complete absorption, with less unabsorbed drug available for metabolism in the colon

Coadministration of digoxin with these particular antibiotics may increase digoxin’s bioavailability. Although not well delineated, P-gp inhibition may alsoplaya role Antimicrobials

Warfarin®35

Antimicrobials may reduce the synthesis of endogenously produced vitamin K by intestinal microflora. In addition, this phenomenon may be amplified by a cytokine-induced proinflammatory state that may inhibit CYP 2C 9, resulting in an increased risk of hå ving INR elevations and bleeding events with warfarin

Cefotetan and cefoperazone have an N-methylthiotetrazole (NMTT) side Chain, and cefazolin has an N-methylthiadiazole (NMTD) side Chain. Cleavage of the NMTT and NMTD side chains from the parent compounds mainly in the Gl tract can inhibit vitamin K epoxide reductase and amplify the pharmacology of coadministered warfarin

Monitor INR, and titrate to goal therapeutic INR; monitor for signs and symptoms of bleeding Greatest INR elevations observed with the following medications because of concurrent CYP2C9 inhibition:

Sulfamethoxazole

Metronidazole Fluconazole Voriconazole Efavirenz

BID = twice daily; DR = delayed release; IV = intravenous(ly).

DDIS AND DISTRIBUTION: DISPLACEMENT FROM A CARRIER PROTEIN Albumin and α1-acid glycoprotein are the two most common plasma proteins that bind to acidic drugs (e.g., antiepileptics, benzodiazepines) and basic drugs (e.g., lido-caine, synthetic opioids, tricyclic antidepressants [TCAs]), respectively.7,8,46 The extent of plasma protein binding depends on the concentration of plasma proteins, which may fluctuate in critical illness, and the affinity of the drug to the plasma protein. Albumin acts as a negative acute phase reactant, and the concentration decreases in the setting of sepsis, renal or liver failure,

burns, surgery, and malnutrition. However, α1-acid glycoprotein is a positive acute phase reactant in which increased concentrations are observed in inflammatory diseases, trauma, and acute myocardial infarctions.7,8,46

Table 46.2 Major Substrates, Inhibitors, and Inducers of P-glycoproteins39,40 Substrate

Inhibitor

Inducer

Apixaban

Amiodarone

Carbamazepine

Colchicine

Atorvastatin

Dexamethasone

Cyclosporine

Cyclosporine

Phenobarbital

Dabigatran

Diltiazem

Phenytoin

Digoxin

Dronedarone

Rifampin

Linezolid

Erythromycin

Tenofovir

Methotrexate

Lopinavir

Rivaroxaban

Ritonavir

Ticagrelor

Tacrolimus Verapamil

Table 46.3 Clinically Relevant Drug Interactions Affected by P-glycoprotein

Drug 2

Mechanism

Digoxin®

Results in increased serum digoxin concentrations. Affects enterally administered digoxin more than IV administered digoxin

Monitor digoxin concentrations and signs and symptoms of toxicity

Has not been studied, but potentially increases concentrations

Reduce apixaban dose to 2.5 mg orally BID

Rivaroxaban® *

Has marginal increases in rivaroxaban concentrations

Dabigatran -

Can increase dabigatran concentrations by up to 60%

Consider dose modifications only with concomitant renal impairment; avoid combination if the CrCI is < 30 mL/min

Drugl

Management

P- glycoprotein inhibitors Amiodarone

Cyclosporine Erythromycin Itraconazole

Verapamil Apixaban 2®

’

Amiodarone

42 ®

Apixaban 2-®

Apixaban, dabigatran, and rivaroxaban ( TOACs) concentrations were increased by 100%-160%

Combination should be avoided, if possible. Consider dose reductions for each agent, but must evaluate the net risk vs. the net benefit. May need to consider warfarin as an alternative oral anticoagulant

Linezolid*®

In a pharmacokinetic study, linezolid 600 mg gl2hr was given together with rifampin 600 mg q24hr. Concomitant administration led to a 21% decrease in linezolid Cmax and a 32% decrease in linezolid AUC. CYP3A has a small contribution ( 0.7%—10.5 %) to linezolid dearance, which may be enhanced by rifampin

Evaluate the need for rifampin, and consider an alternative agent

Apixaban 2®

Reduced concentration of all TOACs by greater than 50%. In addition, apixaban and rivaroxaban are CYP3A4 substrates, and enzyme induction may be a contributing factor

Combination should be avoided, if possible. May need to consider an alternative anticoagulant ( e.g., lowmolecular- weight heparin [ because of concomitant enzyme induction, may need to avoid warfarin ])

’

Any antifungal azole

DabigatranOJB

Rivaroxaban®-®

P- glycoprotein inducers Rifampin

’ ’

Dabigatran 2-® Rivaroxaban® -®

CrCl = creatinine clearance; q = every; TOAC = target-specific anticoagulant.

Displacement of one drug by another from plasma proteins can lead to an increase in the unbound free fraction of the displaced drug; the unbound free fraction is the pharmacologically active entity. For most drugs, displacement from plasma proteins results in only minor changes in free plasma drug concentrations and resultant enhanced distribution and elimination pharmacokinetics. Thus, the altered plasma binding would not be expected to clinically influence the pharmacologic response, and dose adjustments are not usually required.7,8,46 Plasma binding displacement interactions become clinically important when the displaced medication has a narrow therapeutic index. In addition, the route of drug administration may be important for the clinical realization

of displacement interactions. In theory, clinically important displacement interactions are most likely to occur shortly after an intravenous push administration of a highly protein bound drug. This interplay may be less clinically relevant with oral administration of the same medications given that the slow rate of enteral absorption may result in slow displacement and quick equilibration of plasma concentrations. Phenytoin and warfarin are two drug examples for which protein binding displacement interactions may be realized with the coadministration of higher-affinity albumin binders. Valproic acid, sulfamethoxazole, salicylates, and ceftriaxone are examples of medications that can potentially increase the free fraction of both phenytoin and warfarin.46 However, the clinical significance of this interaction may be temporary and self-correcting. When the unbound concentration increases, the total clearance of either phenytoin or warfarin also increases as the liver metabolizes excess free drug, and steady state will return to the pre-displacement value.7,8,46 One consideration with phenytoin specifically is that a marked increase in free drug could result in a reduction clearance because phenytoin follows nonlinear pharmacokinetics. Management of albumin displacement interactions includes therapeutic drug monitoring and monitoring for signs and symptoms of phenytoin or warfarin toxicity until a new steady state is achieved.

TARGETED TREATMENT STRATEGIES FOR DDI INVOLVING DISPLACEMENT FROM A CARRIER PROTEIN Displacement interactions tend to be transient and are usually not clinically significant. If a carrier protein displacement interaction is identified, vigilance in therapeutic drug monitoring, monitoring for the indices of clinical end points, and monitoring the signs and symptoms of toxicity needs to be used to determine the best clinical treatment course.

CYP AND ITS ROLE IN METABOLISM

The liver is the primary organ responsible for drug metabolism, followed by the GI tract, kidney, lung, integument, and blood.47-49 The liver has several sequential steps of drug elimination by metabolism and membrane transport. Phase 0 delivers drugs from the blood into the liver through a carrier-mediated uptake process.48 Once inside the metabolizing hepatocyte, drug metabolism is divided into phase I (oxidation, hydrolysis, reduction) and phase II (glucuronide, sulfate, and glycine conjugation) enzymatic reactions. Phase I reactions are mediated by the CYP enzyme system and convert a parent drug to a more hydrophilic metabolite. Phase II metabolism, not mediated by CYP, produces an inactive water-soluble product that can be readily excreted by the kidneys. Finally, phase III metabolism involves the excretion of these newly formed metabolites by transporter pumps such as MRP2, MDR1/P-gp, and BCRP at the canalicular hepatocyte membrane.48 The most common and significant DDIs involve the CYP enzyme system. Cytochrome P450 is a family of heme-containing proteins located in the smooth endoplasmic reticulum of the hepatocytes. The CYP enzymes are also located, to a lesser extent, in the small intestine, kidneys, and lungs. The predominant CYP enzymes responsible for more than 90% of human drug metabolism are as follows: CYP3A4 (36%), CYP2D6 (19%), CYP2C9 (16%), CYP1A2 (11%), CYP2C19 (8%), and CYP2E1 (4%).47-51 Other isoforms are minor contributors to total CYP activity and include CYP2B6 and CYP2J2. Individual CYP enzymes are specific to a substrate on the basis of a particular region of the drug molecule or enantiomer. Some substrates can be metabolized by more than one CYP enzyme, and these substrates can act as either an inducer or an inhibitor for these CYP enzymes.47-51 Enzyme inhibition is divided into reversible and irreversible inhibition.8,47-51 Reversible inhibition (most common) is characterized as a dose-dependent interaction in which the substrate and inhibitor compete for the same site on the enzyme; the metabolism of the substrate is decreased. Irreversible inhibition is distinguished by the formation of reactive metabolites, which alter the conformation of the

enzyme so that the active biotransformation site is no longer functional. This type of inhibition is both dose- and duration-dependent. The onset of inhibition typically occurs as soon as the inhibitor is in contact with the enzyme, and the maximal effect can be observed after steady state of the inhibitor and affected substrate has been reached.8,47-51 Restoration of the CYP system after cessation of an enzyme inhibitor depends on several drug characteristics such as dose, half-life, presence of Michaelis-Menten pharmacokinetics, presence of genetic polymorphisms, and presence of organ dysfunction. Conversely, enzyme induction occurs when an inducer enhances the synthesis or reduces the breakdown of a CYP enzyme. The net effect observed is a decreased concentration or an increased biotransformation or prodrug activation of the affected substrate. The onset of induction will become apparent over several days to weeks as the amount of enzyme increases enough to change the drug clearance of the substrate; the offset occurs within a similar time interval. The maximum time of onset for enzyme induction depends on the half-life of the inducing agent and the time to steady state of the inducer. For example, when comparing rifampin and phenytoin, rifampin will reach steady-state serum concentrations quicker than phenytoin because of rifampin’s shorter half-life. It will take longer for phenytoin to induce CYP enzymes compared with rifampin, and the induction will remain detectable for a greater length of time after discontinuation as a result of phenytoin’s long half-life.8,40,47-50 Table 46.4 provides a list of CYP isoenzymes and some common ICU medication substrates, inhibitors, and inducers. Table 46.5, Table 46.6, Table 46.7, and Table 46.8 review the effects of specific disease states and DDIs with the most common CYP metabolizing enzymes.

Table 46.4 Major Substrates, Inhibitors, and Inducers of the CYP Enzyme System40,47-51

Substrate

Inhibitor

Inducer

Acetaminophen

Cimetidine

Cartoamazepine

Lidocaine

Ciprofloxacin

Rifampin

CYP1A 2

Erythromycin Fluvoxamine

CYP2B 6 Bupropion Prasugrei

Propofol

CYP2C 9 Ketamine

Amiodarone

Carbamazepine

Phenytoir

Fluconazole, voriconazole

Dexamelhasone

Rosuvastatin

Isoniazid

Phenobarbital

S- warfarin

Metroridazole

Phenytoin

Valproicacid

Sulfamethoxazole

Rifampin

Voriconazole

Valproicacid

Citalopram

Esomeprazole

Clopidogrel

Fluconazole

Carbamazepine

CYP2C19

Diazepam

Fluoxetine

Dexamethasone

Lacosamide

Omeprazole

Phenobarbital

Phenytoin

Oxcarbazepine

Phenytoin

Proton pump inhibitors

Voriconazole

Rifampin

R - warfarin Voriconazole

CYP2D 6 Codeine

Amiodarone

Carvedilol metoprolol propranolol

Bupropion

Haloperidol

Fluoxetine, paroxetine, sertraline

Ondansetron

Haloperidol

Paroxetine

Quinidine

Tramadol

CYP2E1 Acetaminophen

Isoniazid

CYP3 A 4 Amlodipine, nifedipine, felodipine

Amiodarone

Carbamazepine

Apixaban, rivaroxaban

Amlodipine, nifedipine

Dexamethasone

Atorvastatin, simvastatin

Clarithromycin, erythromycin

Efavirenz

Boceprevir, telaprevir

Diltiazem, verapamil

Nevirapine

Carbamazepine

Fluconazole, itraconazole, posaconazole, voriconazole

Phenobarbital

Clarithromycin, erythromycin

Ritonavir

Phenytoin

Colchicine

Valproicacid

Rifabutin

Cyclophosphamide

Rifampin

Cyclosporine, tacrolimus Dexamethasone, hydrocortisone, methylprednisolone

.

Diazepam midazolam Diltiazem, verapamil Fentanyl

Haloperidol Ketamine

Nelfinavir, ritonavir, saquinavir Prasugrel, ticagrelor R- warfarin

Sirolimus

TARGETED TREATMENT STRATEGIES FOR DDI INVOLVING METABOLISM Many medications that are used in the care of critically ill patients are cleared by CYP hepatic biotransformation. The bedside clinician must have a thorough understanding of the principles of enzyme induction and inhibition, including the onsets and offsets of such interactions. The astute clinician needs to evaluate the circumstances of an identified DDI and the relevance and potential downstream effects. The decision to adjust any medication dosages, implement alternative pharmacotherapy, and implement any monitoring strategy must be made on a case-by-case basis. Team communication is a vital component of these decisions, with a plan to modify a treatment plan if the desired end point is not met or if an adverse event is identified.

RENAL ELIMINATION The kidneys, through a combination of passive glomerular filtration rate, active tubular secretion, and tubular reabsorption, are vital in the elimination of medications. Glomerular filtration is a passive process by which water and small-molecular-weight (less than 60 Da) ions and molecules diffuse across the glomerular-capillary membrane into the

Bowman capsule and then enter the proximal tubule.7,8 Tubular secretion is an active process that predominantly takes place in the proximal tubule and facilitates the removal of medications from plasma into the tubular lumen. Four distinct transporters mediate this secretory process: organic anion transporters (OATs), organic cation transporters (OCTs), nucleoside transporters, and P-gp transporters.69,70 The OAT, OCT, and nucleoside transporters are uptake transporters that are located on the basolateral membrane of the proximal tubule and facilitate the entry of drugs into cells. Efflux transporters at the apical membrane of the proximal tubule enhance the removal of drugs from cells and into urine. Renal uptake transporters are known to be associated with clinically relevant DDIs. Renal OAT1 and OAT3 are mainly involved in the secretion of acidic drugs.69,70 In general, these substrates transport endogenous compounds such as prostaglandins, folate, and urate as well as several drugs that are listed in Table 46.9. This active process is mediated by the exchange of extracellular drug for intracellular αketoglutarate. The only well-established inhibitor of the OAT transport system is probenecid, which may result in a 30%–90% reduction in total renal clearance and a significant increase in plasma exposure of drugs subject to this transporter. The OCT2 transporter is mainly involved in the secretion of basic drugs as shown in Table 46.9.69,70 This uptake process is facilitated by the proton gradient maintained at the apical membrane of proximal tubule cells, and efflux of drugs into the urine is mediated by the multidrug and toxin extrusion transporter 1 (MATE1).69,70 Many drugs can inhibit the cationic tubular secretion pathways (mainly MATE1), and several are highlighted in Table 46.9. Renal transport inhibition DDIs usually result in a less than 50% increase in the AUC of the substrate drug. Of note, inhibition of renal transport would limit the effect on drug clearance to the fraction that is usually cleared by this route.

Table 46.5 Disease States and Effects of CYP Metabolism40,47-52

Disease/Predisposition

Sepsis 53-58

Mechanism

Effect on Drug Metabolism

Lipopolysaccharide can cause the release of interleukin (IL)-1, IL-2, IL-6, and tumor necrosis factor (TNF)

Increased concentrations of circulating epinephrine and corticosteroids

IL-2 inhibits CYP 1A2, 2C, 2E1, and 3A4 isoenzymes by around 63%, 55%, 40%, and 61%, respectively

Decreased clearance of drugs metabolized through these particular pathways

TNFα inhibits 2C19 IL-6 inhibits 2C19, 1A2, and 3A4

Traumatic brain injury59

Hypothermia60

Polymorphism 61

Increased nitric oxide release during host-defense response inhibits drug metabolism by binding to the prosthetic heme of CYP

Decreased clearance of drugs metabolized through the CYP pathway

Decrease in cardiac output during late sepsis • Results in a decrease in hepatic blood flow

Mainly affects drugs with high hepatic extraction ratios (e.g., opioids, lidocaine, TCAs)

Induction of CYP3A4 enzymes increased by 27% and 91% at 24 hr and 2 wk, respectively

Increased metabolism of drug metabolized by CYP3A4

Decreased rate of redox reactions performed by CYP enzymes

Decreased clearance of drugs metabolized through the CYP pathway

Genetic polymorphism of the CYP2C9 enzyme: poor metabolizers contain a combination of *2 or *3 variant

Dose reductions of warfarin, rosuvastatin, and phenytoin may be

alleles (observed in 40% of the white population)

warranted

Genetic polymorphism of the CYP2C19 enzyme: poor metabolizers contain a combination of *2 or *3 variant alleles (observed in 30% of the Asian population)

Poor metabolizers of 2C19 will have decreased conversion of clopidogrel (prodrug) to its active metabolite

Genetic polymorphism of the CYP2D6 enzyme: poor metabolizers contain a combination of *3 or *4 variant alleles (observed in 20% of the African American population)

Higher risk of adverse effects from opioids and neuroleptics that are CYP2D6 substrates

Tubular reabsorption of most medications occurs predominantly along the distal tubule and collecting duct. The extent of drug reabsorption is determined by urine flow rate, lipid solubility, and degree of ionization of the drug. For organic acids and bases, diffusion is inversely related to the extent of ionization because the non-ionized molecule is more lipid soluble and more likely to be reabsorbed.7,8 For instance, the acidification of urine favors the excretion of weak organic bases, whereas the alkalinization of urine favors the elimination of weak organic acids. Medications that can alkalinize the urine such as sodium bicarbonate and acetazolamide can enhance the elimination of weak acids such as salicylates, phenobarbital, chlorpropamide, diflunisal, and methotrexate. These principles of drug trapping may be useful in the toxicologic management of certain drug intoxications (i.e., salicylate overdose with sodium bicarbonate infusions).69,70

TARGETED TREATMENT STRATEGIES FOR DDI INVOLVING RENAL ELIMINATION The clinical relevance of DDIs may be minimal. Possible explanations for this observation may be that few drugs mainly rely on tubular secretion for total body clearance, and the renal transport pathways

are generally low-affinity transporters.69,70 Nonetheless, DDIs involving renal elimination pathways may have implications in patients who have renal impairment or who are receiving drugs with narrow therapeutic indices (i.e., methotrexate). Therapeutic drug monitoring and vigilance for detecting adverse drug events are warranted when a known renal transport inhibitor is used concomitantly with a renal transport substrate.

Table 46.6 Drug Interactions Involving CYP3A440,47-51

RASS = Richmond Agitation-Sedation Scale.

PHARMACODYNAMIC DDIS Pharmacodynamic DDIs may occur in the ICU setting when two or more concomitant medications elicit a similar pharmacologic response. This additive or synergistic interplay may result in an exaggerated pharmacologic effect and possibly an adverse drug event. Several common examples are reviewed that may be observed by clinicians across a variety of ICU settings.

Serotonin Syndrome Serotonin syndrome is a potentially serious adverse event that can result from excess serotonergic activity at central and peripheral serotonin-2A receptors. Symptoms develop rapidly within hours of medication administration and may include altered mental status, clonus (typically greater in the lower extremities), tremor, hyperthermia, diaphoresis, tachycardia, and mydriasis.71-74 The available literature on serotonin syndrome in the ICU is scarce and mostly limited to small case series and reviews.71-74 Factors associated with a greater risk of serotonin syndrome include increased patient age, serotoninergic medication dosage, concomitant use of CYP inhibitors that can affect clearance of serotonergic medications, and renal or liver dysfunction.71-74 Severe toxicity resulting in death has occurred with combinations of monoamine oxidase (MAO) inhibitors or amphetamines and SSRIs.71-74 Table 46.10 highlights medications with clinically relevant serotonin-mediated effects. A clinically relevant serotonergic DDI that can be seen in the ICU setting may occur with linezolid because it has weak reversible MAO-A and MAO-B inhibitory effects. The incidence of serotonin syndrome with concomitant linezolid and serotonergic agents is 0.24%–4% (e.g., SSRIs and serotonin-norepinephrine reuptake inhibitors [SNRIs]).76 Linezolid should be avoided in patients taking concurrent SSRIs or SNRIs, if possible. If the serotonergic drug is to be discontinued, the physician must allow at least 5 half-lives of the parent drug and any active metabolites to clear before initiating linezolid, which may not be practical in the ICU setting.76

Targeted Treatment Strategies for Serotonergic Pharmacodynamic DDIs Although serotonin syndrome is uncommon, it has the potential to complicate the administration of drugs commonly used in the ICU setting. When prescribing a serotonergic agent, it is important to obtain a clear history of the other drugs or herbal agents the patient has recently taken or recently discontinued. Life-threatening cases of serotonin syndrome may occur with the use of an irreversible MAO inhibitor or with combinations of high dosages of serotonergic medications. In the example discussed, if linezolid and a serotonergic agent require concomitant administration and the benefits seem to outweigh any risks, clinicians should consider avoiding initiation of any additional serotonergic agents to the patient’s medication regimen. It is then important to monitor for signs and symptoms of serotonin syndrome and to discontinue linezolid and other serotonergic agents if signs or symptoms develop.

Table 46.7 Drug Interactions Involving CYP2C9 and CYP2C1940,47-51

Table 46.8 Drug Interactions Involving CYP1A2

Prolonged QT Interval Syndromes Prolongation of the QT interval can predispose patients to a lifethreatening polymorphic ventricular tachycardia called torsades de pointes (TdP).77 A threshold of QTc interval prolongation at which TdP is certain to occur is not well defined. To highlight this point, a prospective, observational study of patients admitted to a cardiac

critical care unit showed that 28% (n=251 of 900) of patients had a prolonged QT interval on admission, and 35% of these patients were administered a QT interval–prolonging medication during their ICU stay. Torsades de pointes did not occur throughout this study; the most common QT interval–prolonging medications administered were amiodarone, macrolides, and fluoroquinolones.78 Risk factors associated with a greater risk of QTc interval prolongation include age older than 65 years, female sex, hypokalemia, hypomagnesaemia, left ventricular systolic dysfunction, bradycardia, elevated plasma concentrations of QT interval–prolonging medications because of either a DDI or the absence of dose adjustment in the presence of organ dysfunction, and a history of QT interval prolongation.77,79

Table 46.9 Drugs That Undergo Active Tubular Secretion69,70 Transporter OAT1

Substrate

Inhibitors

Acyclovir

Furosemide

Adefovir, cidofovir

Probenecid

Methotrexate Oseltamivir Pravastatin OAT3

Cidofovir

Bumetanide

Famotidine, ranitidine

Furosemide

Oseltamivir

Probenecid

Pravastatin Valacyclovir OCT2

Amiodarone, dofetilide, procainamide

Cobicistat

Cisplatin

Dolutegravir

Digoxin

Quinolones

Diltiazem, verapamil

Rilpivirine

Levofloxacin

Ritonavir

Metformin

Trimethoprim

Drugs with the potential to precipitate TdP inhibit the rapid component of the delayed rectifier potassium current (IKr), which results in a reduction in the net repolarizing current and causes a prolongation of the ventricular action potential duration and a prolongation of the QT interval on the electrocardiogram (ECG).77,79 Medications known to prolong the QT interval include class IA and III antiarrhythmic agents, tyrosine kinase inhibitors, macrolides, fluoroquinolones, azole antifungals, prokinetic agents, antipsychotics, TCAs, antidepressants, methadone, serotonin-3 antagonists, and certain nonsedating antihistamines.79-81 However, not all QT interval– prolonging drugs (i.e., amiodarone) are associated with a risk of TdP. The low risk of TdP with amiodarone may be a result of minimized QTc dispersion, decreased early-after depolarization, and homogeneous prolongation of the action potential duration in all layers of the myocardial wall.82,83 Ranolazine is another example of a medication that may prolong the QTc interval but not precipitate TdP, probably through inhibition of late sodium currents.81

Targeted Treatment Strategies to Minimize Adverse Events from QT Interval–Prolonging Medication A thorough understanding of the risk factors for TdP and common medications that can prolong the QT interval is of paramount importance for all ICU clinicians. Care in understanding the influences of organ dysfunction and DDIs on prescribed medications is critical when these drugs are used in the ICU setting. If an identified DDI cannot be avoided, clinicians should obtain a baseline ECG and continue to monitor the effects of the drug combination with follow-up ECGs as necessary. The risk-benefit must be weighed and the patient evaluated for the potential of developing an arrhythmia when a decision is made to use QT interval–prolonging medications. Table 46.11

describes the most commonly encountered medication classes associated with QT interval prolongation and some possible management strategies.

Table 46.10 Medications with Clinically Relevant Serotonin-Mediated Effects71-75

MAOI = monoamine oxidase inhibitor.

Increased Risk of Bleeding All anticoagulant and antiplatelet agents must be used cautiously in the ICU setting. Risk factors associated with an increased risk of bleeding include age older than 65 years, systolic blood pressure readings greater than 160 mm Hg, abnormal renal or liver function, previous stroke, a bleeding history, labile international normalized ratio (INR), use of antiplatelet agents or nonsteroidal anti-inflammatory drugs

(NSAIDs), and recent alcohol use. Medications that can increase a patient’s bleeding risk include any anticoagulant, P2Y 12 inhibitors, glycoprotein IIb-IIIa inhibitors, aspirin, NSAIDs, cilostazol, dipyridamole, tissue plasminogen activator, corticosteroids, and SSRIs.84-86 The SSRIs, and to a lesser extent the SNRIs, have been associated with an increased risk of GI bleeding, especially when used in combination with NSAIDs.87-89 The proposed mechanism is by the blockade of platelet serotonin reuptake, leading to platelet serotonin depletion and impaired platelet aggregation. In addition, animal studies have shown a dose-dependent increase in gastric acid secretion with the administration of paroxetine, sertraline, and fluoxetine, which may increase aggressive factors that can lead to GI tract damage and hemorrhage.86-89 Furthermore, fluoxetine, fluvoxamine, and paroxetine inhibit several hepatic CYP enzymes (i.e., 1A2, 2D6, 3A4, and 2C9) and can significantly increase the serum concentrations of concomitant medications that may be associated with a bleeding risk (e.g., warfarin).87-89 Because of the potential compounded platelet dysfunction associated with SSRIs or SNRIs, it is recommended to discontinue these agents in patients admitted to the ICU with GI bleeds; monitoring for SSRI or SNRI withdrawal is prudent during this time.8 Use of the target-specific oral anticoagulants (TOACs) with antiplatelet agents is another area for potential concern.84 Published data are insufficient to guide clinical practice, and there is an element of uncertainty on how to safely use TOACs in combination with antiplatelet agents. It is highly recommended to formally assess the event and bleeding risk using the CHA2DS2-VASc and HAS-BLED scores, respectively.85,86 Table 46.12 delineates the risk associated with the combination of TOACs and anti-platelet agents according to the available literature. Targeted Treatment Strategies to Minimize Bleeding Risk in the ICU Setting

Bleeding diathesis can have a significant impact in the care of critically ill patients. Clinicians need to be cognizant of the role of each anticoagulant and antiplatelet agent used and how coadministration may positively or negatively affect clinical outcomes. Concomitant administration of these agents may be warranted, especially in the context of patients who have several disease states that may include the arterial and venous vascular systems. Prescribers need to be vigilant in monitoring for evidence of clinical efficacy as well as toxicity when these agents are used clinically. Continuously evaluating the need for coadministration, assessing for DDIs with the addition of any new medications, and providing good patient communication and follow-up are key elements for the safe use of these medication classes.

Table 46.11 Management Strategies to Reduce the Risk of Torsades de Pointes77,79-81 General management strategies to prevent drug-induced TdP 1. Obtain a baseline ECG before initiation 2. Manually measure and calculate the QTc interval 3. Maintain serum potassium and magnesium concentrations within the normal range 4. Adjust doses of QT interval–prolonging drugs that rely on renal elimination or hepatic metabolism 5. Reduce dose or discontinue QT interval–prolonging drug if the QT interval increases > 60 msec from pretreatment value 6. Avoid concomitant administration of QT interval–prolonging drugs or CYP-mediated inhibition of these drugs 7. Discontinue QT interval–prolonging drugs if the QTc is > 500 msec Specific drug classes that can prolong the QT interval Fluoroquinolones

Inhibition of potassium channels varies in potency among the listed agents (moxifloxacin > levofloxacin > ciprofloxacin) Overall, the risk of TdP is lowest with ciprofloxacin

Macrolides

Inhibition of potassium channels and strong inhibition of CYP3A4 metabolism with erythromycin or clarithromycin

Lower risk of TdP with azithromycin than with erythromycin or clarithromycin Antipsychotics

Anti-nausea

Ziprasidone, thioridazine, and haloperidol have the greatest potential for prolonging the QT interval, followed by risperidone, paliperidone, clozapine, olanzapine, quetiapine, and aripiprazole QT interval prolongation of ondansetron is dose-dependent Single IV doses should not exceed 16 mg. Subsequent IV doses must not exceed 8 mg and must be given 4–8 hr after the initial dose. All IV doses must be infused over at least 15 min

Antifungals

QT interval prolongation may occur because of either a pharmacodynamic drug-drug interaction with other QT interval–prolonging drugs or a strong inhibition of CYP3A4 metabolism of the azole antifungal agents Compared with posaconazole and voriconazole, fluconazole has less risk of inducing TdP

TdP = torsades de pointes.

DRUG-NUTRIENT INTERACTIONS Drug-nutrient interactions can negatively affect the care of a critically ill patient. Critical care clinicians can prevent possible complications, improve patient outcomes, and decrease cost simply by recognizing the severity and relevance of potential drug-nutrient interactions or interactions of medications with alimentary tract access devices. Several factors must be considered when analyzing for drug-nutrient interactions. First, various nutritional elements may interact with the drug and render the agent inactive or with altered efficacy. Second, the location of the enteral feeding tube may affect the absorption of a given medication. Finally, the different medication formulations and release mechanisms available add to the complexity of drug administration through the available feeding tube.8,95 Table 46.13 describes several

common interactions between select medications and enteral nutrition and possible actions that may minimize this effect. Targeted Treatment Strategies to Minimize Drug-Nutrient Interactions The management of drug-nutrient interactions must be individualized according to the drug, the patient’s underlying medical conditions, the availability of alternative treatment options, and the feasibility of the intervention according to the clinical setting. The plan must be communicated with all health care providers involved in the care of the patient and may be subject to change, depending on the patient’s clinical response. If enteral nutrition is held for the administration of a medication, the rate of enteral feeds must be adjusted to maintain the same 24-hour volume and administered calories. In addition, the total volume of flushes needs to be monitored and considered when assessing fluid intake and volume status.

EVALUATING THE PRESENCE OF DRUG INTERACTIONS AND DETERMINING THE CLINICAL SIGNIFICANCE There are few controlled DDI clinical studies, and significant variability is reported among individual cases.100-103 Databases such as Micromedex, LexiComp, Clinical Pharmacology, Facts and Comparisons eAnswers, and Drug Interactions: Analysis and Management can assist in identifying DDIs. However, each of these drug databases uses different approaches to identify and evaluate the same body of literature. For instance, Micromedex uses a 5-item rating scale (i.e., major, moderate, minor, none, and not specified) to classify the severity of DDIs.103 Drug Interactions: Analysis and Management uses a 5-item summary known as the ORCA (Operational Classification) system. The ORCA system is based on the severity of the interaction and the net benefit of administering the drug pair; ratings include avoid the combination, usually avoid the combination, minimize risk, no action needed, and no interaction.104 Sometimes little

agreement is found among these drug databases for what may be considered a serious and clinically relevant DDI. The overshadowing issue with these databases is that they are simply reporting DDIs that can occur.101-103 This is a reflection of DDIs that are included in the U.S. Food and Drug Administration–approved product labeling; classification of DDIs by therapeutic class rather than by individual agent and blanket inclusion of all drug formulations.102,103 From the prescriber’s perspective, if these drug databases are linked to a computer prescriber order entry system, too many alerts to fire may be caused that prescribers may consider clinically irrelevant and may result in alert fatigue and oversight of clinically significant alerts.

Table 46.12 Bleeding Risk Associated with TOACs in Combination with Antiplatelet Agents90-94

Anticoagulant Dabigatran

TOAC « Antiplatelet Agent

Trial

99% received dual antiplatelet therapy

”

RE-DEEM

Dabigatran 50-150 mg BID + ASA + clopidogrel

Rivaroxaban

ATLAS ACS-TIMI 46«

ATLAS ACS2-TIMI 5192

APPRAISE55

Increased the rates of TIMI major bleeding not related to CABG ( 2.2% vs. 0.6%, p 75 mg were Gl bleeding and epistaxis compared with placebo

22% received ASA monotherapy

Rivaroxaban total daily dose of 5-20 mg either daily or BID + ASA or ASA + clopidogrel

Safety End Point

The combination increased the rates of the primary composite outcome of major bleeding or clinically relevant minor bleeding with a total daily dose of apixaban 10 mg ( 5.6% vs. 0.8%, p 0.005)

Apixaban 2.5-10 mg BID + ASA or ASA + clopidogrel

-

The most common types of bleeding were subcutaneous bruising and hematomas, epistaxis and gingival bleeding, hematuria, and Gl bleeding. When major bleeding and reduction in ischemic events were considered, apixaban 10 mg daily resulted in an absolute net reduction of 1.6% in clinical events in the overall population. Therefore, apixaban 10 mg was reevaluated in the APPRAISE-2 trial APPRAISE-294

81% received dual

antiplatelet therapy Apixaban 5 mg BID + ASA + clopidogrel or ASA

Trial was terminated early because of excessive bleeding Combination therapy significantly increased TIMI major bleeding ( 2.4% vs. 0.9%, p 1 g/kg/day

Levothyroxine

Coadministration with enteral nutrition may decrease absorption May adhere to polyvinyl chloride walls of feeding tubes

Phenytoin

administration Monitor patients for Neuroleptic Malignant Syndrome (NMS)-like signs or symptoms or changes in Parkinson disease signs or symptoms Enteral nutrition should be held for 1–2 hr before and after levothyroxine administration Flush enteral feeding tube with 20 mL of water before and after medication administration Monitor thyroid function tests as needed

Binds to protein calcium caseinates

Enteral nutrition should be held for 1–2 hr before and after phenytoin administration

May adhere to polyvinyl chloride or polyurethane walls of feeding tubes

Flush enteral feeding tube with 20 mL of water before and after medication administration. Monitor plasma concentrations as needed If the nasogastric tube is the only available option and therapeutic plasma concentrations are not attained with holding enteral nutrition around medication dosing, can administer phenytoin sodium IV (diluted in normal saline) by the enteral feeding tube; phenytoin sodium IV has a pH of 11 and may avoid pH-dependent loss of drug to the polyurethane feeding tubing

Tetracyclines (e.g., minocycline)

Warfarin

Absorption is decreased by chelation with calcium in enteral nutrition formulas

Enteral nutrition should be held for 1–2 hr before and after minocycline administration

Current enteral

Enteral nutrition should be held for 1 hr

Flush enteral feeding tube with 20 mL of water before and after medication administration

nutrition formulations have minimal amounts of vitamin K; interaction with warfarin is minimal Hydrolyzed proteins in enteral nutrition formulas may bind to warfarin and decrease its bioavailability

before and after warfarin administration Flush enteral feeding tube with 20 mL of water before and after medication administration Monitor INR, and adjust the warfarin dose accordingly

Because this has become a growing and recognized problem, an expert workgroup funded by the Agency for Healthcare Research and Quality has developed guidelines for the systemic appraisal of DDIs and recommended principles for including and presenting DDIs into clinical decision support systems.100 These guidelines define a clinically relevant DDI as one that is associated with either toxicity or loss of efficacy and that warrants the attention of health care professionals. The primary goal of the evidence workgroup in this consensus guideline is to identify the best approach for evaluating whether a DDI truly exists.100 It is acknowledged that the evidence supporting a DDI may be derived from case reports or retrospective reviews or extrapolated from in vitro studies and a few controlled clinical studies. A standard approach is recommended in these guidelines in order to evaluate case reports; thus, the Drug Interaction Probability Scale (DIPS) and the Drug Interaction Evidence Evaluation (DRIVE) instrument were created to be used for a given body of literature.100,105 The DIPS is a 10-item scale that was designed to assess the probability of a causal relationship between an event observed in a patient and a potential DDI.105 The total score is used to estimate the probability that the observed event is causally related to the medications. Probability is assigned as doubtful, possible, probable, or highly probable. The DRIVE instrument establishes the existence of a DDI through the following methods: uses simple evidence categories, includes causality assessment with DDI case reports (by DIPS), applies reasonable

extrapolation from the existing data, addresses evidence or statements provided in product labeling, and describes study quality criteria and interpretation in the context of DDIs.100 If the evidence of a DDI has been appropriately analyzed using the DIPS and DRIVE instruments, clinicians must then determine the clinical relevance. The factors to consider include the clinical consequences to the patient, the incidence at which the DDI occurs, any risk factors or mitigating factors that determine the susceptibility to the DDI, and an assessment of the seriousness of the DDI.100,102 This process seems methodologically sound; however, the DRIVE instrument must be formally evaluated and validated before used in the large drug databases previously discussed. In addition, drugs that belong to the same pharmacologic class should be treated individually unless proven otherwise. Most classbased DDIs are pharmacodynamic in nature, whereas pharmacokinetic interactions can rarely be generalized and applied to all agents within a drug class.100,102 Even if the DDI was classified as a class effect, the magnitude of the effect may vary among each agent. A primary example of this point is that azoles have different potencies for the inhibition of the CYP3A4 enzyme. For instance, itraconazole causes a 27-fold increase in the AUC of triazolam, and fluconazole causes a 4.4fold increase in the AUC of triazolam; both are clinically relevant, but the magnitudes are very different. Therefore, the evidence workgroup recommends that, in the absence of drug-specific data, a class-based interaction be reasonably assumed if the mechanism of interaction is consistent with the known pharmacology of one or both drug classes involved.100,102 Additional work is needed to recognize, determine the significance of, and monitor clinically relevant DDIs. It is the responsibility of every clinician to be vigilant in identifying DDIs. Each member of the multidisciplinary team has a role in the prevention, identification, and resolution of DDIs in order to optimize patient care and ensure safe medication administration. Physicians should justify and review each drug regularly, screen for DDIs with each drug addition or deletion, and integrate the information that is discussed on multidisciplinary rounds.8

Pharmacists should review each medication order for DDIs, assist in drug selection or substitution, and monitor for any adverse drug events.8 Nurses should assess and monitor drug administration and document any adverse drug events or change in patient status.8 The health system multidisciplinary team should work together to regularly reevaluate and update the list of DDIs identified within its clinical decision support system to remain current with the evolving scientific literature.

CONCLUSION There are several factors to consider when identifying and determining the clinical significance of DDIs. Micromedex, LexiComp, Clinical Pharmacology, Facts and Comparisons eAnswers, and Drug Interactions: Analysis and Management can assist clinicians in identifying DDIs. The severity ratings may vary among these databases, and the clinical significance of the ratings used has not been fully established. The DDI alerting systems in every institution vary according to what is commonly observed as significant to that specific institution. Internal expert opinion and one of the mentioned drug information databases are commonly used to build an institution’s electronic DDI alerting system. Once an internal identification system has been determined, a clinician’s evaluation of an identified DDI should include understanding the mechanism and onset of the DDI, possible patient outcomes, and clinically appropriate alternative therapeutic options. This rationale and thought process may aid in the decision to either avoid or monitor a drug combination that is tailored to the pharmacotherapeutic need of an individual patient.

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Chapter 47 Acute Illness Scoring

Systems Thomas J. Johnson, Pharm.D., MBA, FASHP, FCCM, BCPS

LEARNING OBJECTIVES 1. Describe the utility of acute illness scoring systems in the critically ill. 2. List the common acute illness scoring systems. 3. Describe the application and benefits of each system.

ABBREVIATIONS IN THIS CHAPTER AKIN

Acute Kidney Injury Network

APACHE Acute Physiology and Chronic Health Evaluation APS

Acute Physiology Score

CURB-65 Confusion, urea, respiratory, blood pressure, 65 (age) GCS

Glasgow Coma Scale

ICU

Intensive care unit

ISS

Injury Severity Score

MELD

Model for end-stage liver disease

MODS

Multiple Organ Dysfunction Score

MPM

Mortality probability model

PSI

Pneumonia Severity Index

RIFLE

Risk, injury, failure, loss, and end-stage renal disease

SAPS

Simplified Acute Physiology Score

SOFA

Sequential Organ Failure Assessment

TISS

Therapeutic Intervention Scoring System

INTRODUCTION Many scoring systems are used in acute hospital settings and particularly in the critical care areas. Patients are admitted to intensive care units (ICUs) with a variety of primary diagnoses, and each patient presents with his or her own set of underlying conditions. Furthermore, the type and acuity of patients in a particular ICU is affected by the organization of the hospital, the patient population of that hospital or area, and the types of physicians and subspecialists that are available. Patient populations need to be defined by objective and clear criteria and not simply by the unit to which they are admitted. A “critically ill patient” could be defined in several ways according to these and more variables. Acute illness scoring systems try to provide specific, objective measurements that are reproducible in many ICU environments. Objective and reproducible measures are particularly necessary if research and quality improvement projects are to be successfully completed and the results applied to similar populations. Selecting an appropriate scoring system can be one of the key elements of developing a successful project. Scoring systems are often used to develop or identify risk stratification for a given patient population. By dividing patient populations into various risk groups, a researcher can better compare like patients and apply appropriate statistical tests and comparisons. Quality improvement projects effectively use scoring

systems by selecting validated scoring systems that are commonly used by facilities with like patient populations. For example, if a particular ICU selects a scoring system that is not used by similar units or institutions with similar patient populations, that system will not allow for appropriate comparisons and may give data that are unreliable or may lead to projects that are not focused on the correct outcome. In addition to research applications, clinicians are often faced with providing guidance to families or evaluating their own practices to help predict which patients will need continuing intensive care and which patients may benefit from lower acuity of care, or even withdrawal of care. Although most scoring systems are not intended for individual patient decision-making, they can help establish baseline statistics that can be used to better inform clinicians and families about the overall outcomes that may be expected given the available evidence.1-5 For all of these reasons, many types of acute illness scoring systems have been developed to provide consistency in the reporting and evaluation of patients with critical illness for a variety of disease states and predicted outcomes.

OVERVIEW OF ACUTE SCORING SYSTEMS Most scoring systems are developed by collecting data on many patients and comparing the available data with the patients’ ultimate outcome.1,2,5 Two key elements in the evaluation and use of scoring systems are calibration and discrimination.1,5 Calibration evaluates the performance of a scoring system across patient populations, comparing the actual outcome with the predictive outcome. One of the more common statistical tests for assessing calibration is the HosmerLemeshow test. Although this test provides better data as the size of the database increases, it should not be the sole test used to determine optimal test calibration for a particular patient population.6 Discrimination describes the ability of a model to accurately discriminate between patients who die and those who do not. Statistical tests such as the area under the receiver operating characteristic (ROC) curve describe discrimination of a particular

model.5 An ROC of 0.5 represents a purely chance association, and discrimination of a particular score improves as the ROC nears 1.0.1,6 Therefore, before using a given predictive scoring system in a quality improvement or research project, or before considering use in aiding a prognostic model for care decisions, the statistical reliability of the scoring system should be thoroughly investigated. Scoring systems can be applicable to acutely ill patient populations in general or applicable only to specific disease states. Selecting the best scoring system for a research project or identifying the most appropriate criteria for optimizing patient care can be challenging for any critical care practitioner. The key elements are understanding the validated populations for a scoring system, selecting the appropriate data points for a particular disease state, and then correctly and consistently calculating scores.7 In the past several years, the proliferation of online and application-based calculators has made the data entry and calculation components relatively easy. However, selecting the correct data for entry often depends on having a clear understanding of the score, the applicable populations, and how to accurately select the appropriate data points for entry into the system.3 This chapter reviews many of the common scoring systems used in clinical practice, identifies the basic calculation approaches, and lists the primary patient populations and uses for each score.

APACHE Score The Acute Physiology and Chronic Health Evaluation (APACHE; Cerner Corp., North Kansas City, MO) scoring system is one of the most wellknown and commonly used scoring systems to assess severity of illness in critically ill patients.1 The APACHE system was first developed in the late 1970s/early 1980s and is currently in the fourth revision of the system, although the APACHE II and III versions of the score remain in common use within practice.8-12 Clinicians should be trained on how to accurately calculate and use the score specific to the version in order to optimize inter- and intrarater reliability.1,13-15 Preferably, the required data points are

automatically fed to the APACHE scoring system from the medical record to minimize variability, but manual data collection is also an option although usually much more time-consuming.3 The APACHE II score consists of three domains that include the Acute Physiology Score (APS), the Age score, and the Chronic Health Score.8 The APS component is determined by identifying the worst values recorded (high or low) within the previous 24 hours or within 24 hours of admission.16 Because values may change, it is important to note the application of the scoring system and the ways in which data were reported in a quality project or research design. Those values are then converted to a score that is summed. Values not available result in a score of zero for that element. A similar methodology is used for the III and IV versions. Many versions of the APACHE scoring systems are available on the web. However, the APACHE III and IV systems have additional data points compared with APACHE II, and calculating the score without specific training and significant practice can lead to incorrect results and significant variability.13-15 By comparison, the APACHE II score is relatively easy to calculate by investigators or clinicians who lack full access to the APACHE IV data system. As with any scoring system, there is some intra- and interrater variation in calculating the scores with any of the APACHE versions, which can limit the usefulness of the score if strict attention to methodology is lacking.17 Two elements of the APACHE score can be especially prone to introducing variability into the scoring system. One of the most difficult data elements to determine is the Glasgow Coma Scale (GCS) score in patients who are mechanically ventilated and sedated. The GCS measures basic neurological function on the basis of response to pain (1–6 points), verbal response (1–5 points), and eye-opening response (1–4 points), with total scores ranging from 3 to 15. To avoid false elevation of the APS score within the APACHE system, the presedation GCS level should be recorded whenever possible. Medications and other therapies will likely affect the level of response of the patient and therefore the GCS.18 The Chronic Health Score component of the score is the second area that significantly affects

reliability of the system. Although this component is clearly defined when using most online calculators, it may not be easily described when homemade calculators or shortened versions of the scoring tool are used. Of note, multiple chronic conditions are not additive for this score because the patient can only receive a maximum of 5 points within the Chronic Health Score. The current version of the APACHE (APACHE IV) scoring system provides the most accurate information regarding the predicted mortality of a patient population as well as the predicted length of stay.10,19 However, the APACHE II version still provides reasonable calibration and discrimination for some patient populations.20 As an investigator or quality project leader chooses a tool, the resources available will often drive which version of APACHE is selected. Several websites offer online calculation of the score with good explanations of how to proceed. The version (II, III, or IV) being used should be noted because the appropriate collection and recording of data differ, depending on the version. Furthermore, online calculators often offer a calculated mortality rate or probability, but the rates determined by these systems may not be as accurate as the data that would be obtained with the APACHE IV system in full use and, in general, should not be used to predict mortality or outcome for specific individual patients. The APACHE scoring system remains one of the most common tools for comparing the outcomes of a particular unit with those of peers as well as a common risk stratification tool for research studies that need to quantify severity of illness for their study population(s). Critical care clinicians should have a functional knowledge of this system and understand how the reported results may affect quality outcomes or identify appropriate patient populations for applying research results.

SAPS Score The Simplified Acute Physiology Score (SAPS) was initially described in 1984 and was then revised in 1993 as the SAPS II.21,22 The SAPS II

score identifies 17 variables to provide a predicted mortality rate. The original study evaluated data within the first 24 hours of ICU admission; however, some calculators and investigators have used worst values in the past 24 hours to calculate the score.23 The mortality accuracy of the SAPS II score is somewhat questionable at this point because the data used to determine the mortality rates are now more than 20 years old.24 The SAPS 3 score was developed to address some of the inconsistencies with the SAPS II score, used patients from several regions of the world, and improves on the predictability of the score and simplifying data collection.1,24-26 The SAPS 3 score is an “admission score” because the data were collected within an hour before or after ICU admission.25,26 Furthermore, SAPS II and SAPS 3 were developed with data from patients in several countries as opposed to the APACHE system, which primarily used patients from the United States.1

Mortality Probability Model The mortality probability model (MPM) was originally developed in the 1980s, and the current revision (MPM0-III) has been in use since 2007.27,28 The MPM uses variables present on admission to the ICU such as comorbidi-ties, acute diagnoses, and only three physiologic variables to provide mortality prediction. The current revision has a slightly lower level of discrimination than other models (e.g., APACHE).27 A further limitation of this model is that it does not work as well for patients with rapid changes within the first 24–48 hours of ICU admission because it only uses admission variables. However, the level of data collection is less with the MPM0-III model, and it does not require a diagnosis for use, so it may have advantages, depending on how data are collected within an EMR (electronic medical record).27,28

SOFA Score The Sequential Organ Failure Assessment (SOFA) score is calculated on the basis of the function of six organ systems (pulmonary,

cardiovascular, central nervous system, renal, coagulation, and hepatic).29-32 Each organ system is scored on a 0–4 scale, and the SOFA has a maximum score of 24. In contrast to some of the other scoring tools, the SOFA score is intended to be tracked on a daily basis within the ICU, and the day-to-day change can be used as an objective measure to track the progress of an individual patient. Mortality rates have been correlated with both the peak SOFA score and the change in score from ICU admission.29,31,33 The SOFA score was also combined with the APACHE score to try to improve the prediction of mortality rates in at least one study.34 This score is particularly useful in research trials and quality projects where tracking and evaluating day-to-day progress of the patient is important to study outcome.

MODS Score The Multiple Organ Dysfunction Score (MODS) is very similar to the SOFA score. Six organ systems are scored on a 0–4 scale with a maximum total score of 24.35 The main difference between the MODS and SOFA scores is the scoring of the cardiovascular system. The MODS approach uses a computation with the heart rate and blood pressures, whereas the SOFA score uses an approach of recording both blood pressure readings and whether vasopressor support is necessary. The MODS score was specifically described as an outcomes measurement in the original publication.35 However, a predictive component is available with associated mortality rates based on the calculated score and the number of ICU days for the patient. The MODS and SOFA scores have been compared in clinical practice and found to be similar in predicting and measuring outcomes.30

TISS Score Not all scoring systems are focused on patient mortality. For example, the Therapeutic Intervention Scoring System (TISS) can be used to measure and help determine staffing needs (particularly nursing) by

measuring specific nursing activities.36-38 The score was initially developed in the 1970s, revised in the 1980s, and shortened to the TISS-28 score in the 1990s.36 The areas measured in the score include basic measures, cardiovascular support, ventilator support, renal support, neurological support, metabolic support, and specific interventions. The TISS and TISS-28 scores have also been used to measure certain outcomes and costs.39

SCORING SYSTEMS IN SPECIFIC DISEASE STATES Trauma Several scores are used in measuring the severity of injury in trauma patients.40-49 Many of the common scores described previously in this chapter can be applied to trauma patients, but many scores have also been developed to be used specifically in trauma patients.50 Some scores do not require full knowledge of all injuries.48,51 In addition, several scores are based on the anatomic location and type of injury to calculate the full score.41,45,46 Trauma scores are used to provide triage assistance, to quantify injury patterns for registry database submission, or both. Three of the most common scores are described in the sections that follow. ISS Score The Injury Severity Score (ISS) has been used for more than 40 years to describe the initial injury in trauma patients.46 The score is calculated on the basis of the sum of squares of the three most injured body areas, with a score range of 1–75. The ISS can help predict mortality, allow for data comparison for quality improvement for a trauma program, and be part of data submission to trauma registries. As with other scores, online calculators are readily available, but calculated scores should not be used as a sole method to predict mortality for individual patients. A revision to the ISS has also been published.52 The new ISS

provides improved mortality accuracy over the original score using the worst injuries regardless of body region.49,53 This better represents multiple injuries that may be more severe in one anatomic area. Revised Trauma Score The Revised Trauma Score is a calculation based on respiratory rate, systolic blood pressure, and the GCS.44,45 Each value is then coded to a score of 0–4. The coded score is then entered into a calculation to obtain to a final score that provides a mortality estimate that can be readily found with online calculators. Of note, this calculation more heavily weights the GCS to better represent the impact of head injury on overall survival. TRISS Score The Trauma Score and Injury Severity Score (TRISS) is a combination of the Revised Trauma Score and the ISS and incorporates the patient’s age.41 This score is used in several areas including many registry databases, trauma outcomes research, and internal quality improvement programs. The TRISS calculation provides a probability of survival, but as with any scoring system, this should be used cautiously for any individual patient decisions.

Acute Kidney Injury RIFLE Score The RIFLE acronym stands for risk, injury, failure, loss, and end-stage renal disease and is a system used to stratify acute kidney injury.54 The acute elements (risk, injury, and failure) are defined by a specific set of criteria listed in Table 47.1. Serum creatinine changes, glomerular filtration rate changes, and urine output concentrations are used to categorize the acute elements of the score. The use of urine output concentrations provides a more timely identification of kidney dysfunction than does the use of kidney injury definitions that rely solely

on laboratory values. Before the RIFLE system was developed, acute kidney injury was not consistently defined, and many studies have been completed in the past decade that evaluate the ability to predict outcome and stratify patients with acute kidney injury.55-61

Table 47.1 RIFLE Criteria for Acute Kidney Injury54 SCr Changes

Urine Output

Risk

1.5 × increase in SCr from baseline or decrease in GFR by ≥ 25%

< 0.5 mL/kg/hr for at least 6 hr

Injury

2 × increase in SCr from baseline or decrease in GFR by ≥ 50%

< 0.5 mL/kg/hr for at least 12 hr

Failure

3 × increase in SCr from baseline or a SCr of ≥ 4 mg/dL or decrease in GFR by ≥ 75%

< 0.3 mL/kg/hr for at least 24 hr or anuria for 12 hr

Loss

Complete loss of kidney function for at least 4 weeks

End-stage renal disease

Complete loss of kidney function for > 3 mo

GFR = glomerular filtration rate; SCr = serum creatinine.

The RIFLE system is one example of a scoring tool that can be used to describe either a patient population or individual patients. In describing a patient population for a research study, an investigator may use the RIFLE system to describe the number of patients who met each of the various criteria. However, the bedside clinician may use the RIFLE system to determine the degree of organ dysfunction for an individual patient.61 It is important to understand how a specific scoring tool is used in a particular context to understand the implications of the data that are presented.

AKIN Staging The Acute Kidney Injury Network (AKIN) has suggested alterations to the RIFLE criteria by adjusting the changes in serum creatinine and urine output; this is described in Table 47.2.55,62 However, the AKIN score has not shown demonstrable advantage over the RIFLE criteria with respect to discrimination or calibration.55,57-59,63 The RIFLE and AKIN criteria can be very important tools for the critical care pharmacist to remember and understand. Many medications used in the critically ill patient have the potential to induce damage to the kidney or are cleared by the kidneys and require dose adjustments with alteration in kidney function. Appropriate monitoring of both urine output and serum creatinine concentrations, using the RIFLE or AKIN criteria as a guide, is an important part of the overall patient care plan. Although the RIFLE and AKIN criteria can be helpful in determining the degree of kidney injury or failure, they do not directly assist with medication dose adjustments. Typically, the Cockcroft-Gault equation is used for most medication dose adjustment. However, this equation was not developed with critically ill patients that have many changing variables in mind.64

Table 47.2 Acute Kidney Injury Network Score62 Stage

Serum Creatinine

Urine Output

1

Increase of ≥ 1.5–2 × baseline or increase of ≥ 0.3 mg/dL

< 0.5 mL/kg/hr for > 6 hr

2

Increase of > 2–3 × baseline

< 0.5 mL/kg/hr for > 12 hr

3

Increase of > 3 × baseline or SCr > 4.0 mg/dL with acute increase of at least 0.5 mg/dL

< 0.3 mL/kg/hr for > 24 hr or anuria for > 12 hr

Pancreatitis

Pancreatitis can be a difficult disease state to accurately describe expected or predicted outcome because patients can become extremely ill very quickly. Therefore, several scoring systems have been developed through the years to describe objective measures and to accurately describe the likely outcomes of the disease process and assist in identifying patients in whom rapid aggressive care is most beneficial. The Ranson criteria are the oldest and most widely known set of criteria.65,66 However, in the 40+ years since these criteria were developed, other systems have been developed with increasing prognostic capabilities.67-70 The Ranson criteria use 11 variables scored as either 0 or 1.65,66 Five of the variables (age, white blood cell count, glucose, aspartate aminotransferase, and lactate dehydrogenase) are scored at admission, and the remaining six are scored within 48 hours (serum calcium, change in hematocrit, hypoxemia, blood urea nitrogen [BUN] increase, base deficit, and fluid overload). The scoring breakpoints are different depending on whether the pancreatitis episode was caused by gallstones. Severe pancreatitis is defined by a score of 3 or greater. Although the Ranson criteria provide a reasonable predictive outcome, it takes a full 48 hours to complete the score and requires that specific laboratory variables be drawn within the specified period. In contrast, the BISAP (Bedside Index of Severity in Acute Pancreatitis) is a simpler scoring system completed as soon as the variables are available after admission.67,69 These variables include a BUN concentration greater than 25 mg/dL, impaired mental status, SIRS (systemic inflammatory response syndrome), age older than 60, and pleural effusions. Each variable receives a score of 0 or 1, and the total score of greater than 3 describes severe acute pancreatitis. Each point scored is correlated with an increase in mortality. Compared with the Ranson criteria, the BISAP score performs at a similar specificity but somewhat lower sensitivity.67 Scoring systems for pancreatitis severity have also been evaluated according to computed tomography (CT) results. Scores like the CT severity index (CTSI) and Balthazar grading system have been compared with clinical (non-radiographic) scoring systems, but with

similar predictive results.69,71 The Atlanta classification (2012) is the standard consensus-driven tool for describing acute pancreatitis.68 This classification describes acute pancreatitis and mild, moderate, or severe acute pancreatitis on the basis of both CT findings and organ dysfunction described by the modified Marshall score. The modified Marshall score evaluates renal, respiratory, cardiovascular, hematologic, and neurological systems. Ultimately, several clinical- and radiologic-based scoring systems for acute pancreatitis perform at similar levels of sensitivity and specificity. Beyond the specific scores for pancreatitis, APACHE and other general critical illness scores have utility in pancreatitis scoring.71,72 Some scores provide for mortality prognostication and resource use, whereas others serve to better describe patient populations for research purposes.

Pneumonia Pneumonia scoring systems are not necessarily limited to ICU patients, but they are commonly used to describe the severity of illness of these patients in studies involving critically ill patients. Some of the most common pneumonia scores are the CURB-65 score and the Pneumonia Severity Index (PSI).73,74 The CURB-65 score is calculated by giving a point for each of the variables listed in Box 47.1.74 A score of 0 can likely be treated at home, whereas a score of 3 or more indicates a higher risk of death, and ICU admission should be considered particularly for a score of 4 or 5. The PSI uses a two-step process with a relatively simple yes/no algorithm to classify a patient into a lowrisk score (category I) or into the higher-risk II–V scoring range.73 The higher-risk calculation then assigns points from a variety of symptoms and comorbidities from five categories: age, place of residence, physical examination findings, comorbid conditions, and radiologic and laboratory findings. Clinical application of the CURB-65 score and the PSI may include use in some decision support tools or be used for predicting or directing location of care.75,76 The PSI has less discrimination for ICU

care, and the many data points make it difficult to use in a prospective manner unless data are automatically taken from the medical record.76 Although the CURB-65 score is fairly easy to calculate, it may underestimate the severity of illness in some patients, particularly older adult patients who are frail.76,77

Acute Liver Failure Acute liver failure is another common condition in critically ill patients and there are several scoring systems associated with the disease process.11,78-81 Patients appear very ill, and it is difficult to determine their prognosis and level of care. Furthermore, acute liver failure often occurs on top of underlying chronic liver failure. Therefore, scores such as the model for end-stage liver disease (MELD) score and the ChildPugh score are commonly used, but they often show no greater predictive ability than the APACHE system or scores like the SOFA score.11,78,80

Box 47.1. CURB-65 Score74 New-onset Confusion Urea > 7 mmol/L Respiratory rate > 30 breaths/minute Blood pressure < 90 mm Hg systolic or < 60 mm Hg diastolic Age older than 65 years

The Child-Pugh score ranges from 5 to 15 and is calculated with a score of 1–3 in each of these five categories: ascites, encephalopathy, international normalized ratio (INR), albumin, and bilirubin. The score then indicates class A (5–6), B (7–9), or C (10–15) depending on the score range. The MELD score uses the INR, serum creatinine

concentration, and bilirubin concentrations as well as the cause of liver disease within an equation to provide a score and a predicted mortality rate.82 Mortality increases with every 10 points in the MELD score. Prognostic scores for hepatic disease are sometimes used to prioritize patients for certain procedures or transplant selection on the basis of overall probability of survival.

SUMMARY Many scoring systems are available to evaluate critically ill patients. Some are disease-specific, whereas others are predictive simply on the basis of the presenting condition of the patient or the patient’s dayto-day progress. Some are a mix of disease-specific and physiologic values. Although scoring systems may at times be useful in predicting mortality and providing information to caregivers and families, most systems are primarily used to stratify patients for research purposes or to evaluate populations of patients to assist in quality improvement initiatives. With the advent of many mobile apps and decision support tools, many of these scores can be easily or even automatically calculated. An understanding of the use and application of such scoring systems is important for any clinician practicing in the ICU so that the most effective and accurate scoring system can be used appropriately and not misinterpreted or applied to patients or disease states for which that particular score was not intended. Pharmacists should be particularly aware of scoring systems that may affect the use of medications by accurately predicting patients or populations that are comparable with published literature. Furthermore, the interpretation of many studies of critically ill patients requires a knowledge of scoring systems so that patient populations can be matched appropriately.

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70. Bollen TL. Imaging of acute pancreatitis: update of the revised Atlanta classification. Radiol Clin North Am 2012;50:429-45. 71. Chatzicostas C, Roussomoustakaki M, Vardas E, et al. Balthazar computed tomography severity index is superior to Ranson criteria and APACHE II and III scoring systems in predicting acute pancreatitis outcome. J Clin Gastroenterol 2003;36:253-60. 72. Chatzicostas C, Roussomoustakaki M, Vlachonikolis IG, et al. Comparison of Ranson, APACHE II and APACHE III scoring systems in acute pancreatitis. Pancreas. 2002;25:331-5. 73. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336:243-50. 74. Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003;58:37782. 75. Jones BE, Jones J, Bewick T, et al. CURB-65 pneumonia severity assessment adapted for electronic decision support. Chest 2011;140:156-63. 76. Sligl WI, Marrie TJ. Severe community-acquired pneumonia. Crit Care Clin 2013;29:563-601. 77. Richards G, Levy H, Laterre PF, et al. CURB-65, PSI, and APACHE II to assess mortality risk in patients with severe sepsis and community acquired pneumonia in PROWESS. J Intensive Care Med 2011;26:34-40. 78. Boone MD, Celi LA, Ho BG, et al. Model for End-Stage Liver Disease score predicts mortality in critically ill cirrhotic patients. J Crit Care 2014;29:881.e887-813. 79. Chatzicostas C, Roussomoustakaki M, Notas G, et al. A comparison of Child-Pugh, APACHE II and APACHE III scoring systems in predicting hospital mortality of patients with liver cirrhosis. BMC Gastroenterol 2003;3:7.

80. Karvellas CJ, Bagshaw SM. Advances in management and prognostication in critically ill cirrhotic patients. Curr Opin Crit Care 2014;20:210-7. 81. Seak CJ, Ng CJ, Yen DH, et al. Performance assessment of the Simplified Acute Physiology Score II, the Acute Physiology and Chronic Health Evaluation II score, and the Sequential Organ Failure Assessment score in predicting the outcomes of adult patients with hepatic portal venous gas in the ED. Am J Emerg Med 2014;32:1481-4. 82. Cholongitas E, Papatheodoridis GV, Vangeli M, et al. Systematic review: the model for end-stage liver disease—should it replace Child-Pugh’s classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther 2005;22:1079-89.

Chapter 48 Leading and Managing

Intensive Care Unit Pharmacy Services Robert J. Weber, Pharm.D., M.S., FASHP, BCPS

LEARNING OBJECTIVES 1. Describe at least three ways that hospitals benefit from intensive care unit (ICU) pharmacy services. 2. Describe how a hospital’s strategic goals affect designing and implementing ICU pharmacy services. 3. List at least three factors that justify ICU pharmacy services. 4. Describe at least two ways that pharmacist clinical credentialing and privileging enhances ICU pharmacy services.

ABBREVIATIONS IN THIS CHAPTER ACCP

American College of Clinical Pharmacy

ASHP

American Society of Health-System Pharmacists

ICU

Intensive care unit

ME

Medication error

PGY2

Postgraduate year two

SCCM Society of Critical Care Medicine

INTRODUCTION Critical care medicine has grown from a small group of physicians participating in patient care rounds in surgical and medical intensive care units (ICUs) in the early 1980s to their integrated role on a hightechnology multidisciplinary ICU team in 2015. The first published textbook chapter on critical care pharmacy services in 1981 notes only 12 physician training programs in critical care medicine, with about 500 physicians practicing the specialty with no board-certifying examination. In addition, the Society of Critical Care Medicine (SCCM) was only 10 years old at the chapter’s publication.1 The year 2015 marks the 45th year of SCCM, with almost 16,000 trained professionals engaged in the multidisciplinary critical care model.2 Pharmacy’s growth in the area of critical care is as exponential. The first residency training programs for ICU pharmacists were designed by a few pioneers and at several institutions. Of note, in 1981, the Ohio State University recruited and trained one of the nation’s first critical care residents; that same institution was selected in 1982 to conduct the first critical care fellowship program, sponsored by the American Society of Health-System Pharmacists (ASHP).3 Similar to critical care physicians, pharmacists will be offered a board-certifying examination for the first time in October 2015.4 The role of the pharmacist in the ICU is to provide a broad-based approach to medication use through a comprehensive pharmacy service. For example, a pharmacist attending ICU patient care rounds may be able to recommend an appropriate drug for a specific critical condition—but may be unable to provide timely drug delivery because of the lack of a pharmacy distribution area (e.g., a pharmacy satellite) in the immediate vicinity of the ICU. The service provided by the pharmacist is not comprehensive because the pharmacist is unable to provide the medication in a timely manner. Or furthermore, the ICU nurse caring directly for a patient may be burdened with the responsibility of compounding an intravenous medication because of a lack of pharmacy intravenous admixture preparation services.

Pharmacy-based services for preparing intravenous products have been shown to prevent errors and improve efficiencies; lacking this service in the ICU does not provide a comprehensive approach to care. The lack of comprehensive pharmacy services shown in these two scenarios may lead to inefficiencies, errors, or delays in treatment. Today’s ICU requires a comprehensive pharmaceutical service that includes both operational and clinical services to meet its medication needs. A position statement published some 15 years ago by thought leaders in critical care pharmacy is still applicable today—that optimal critical care pharmacy services involve clinical cognitive pharmacists’ skills together with operational services such as a pharmacy satellite, preparation of intravenous admixtures, and an integrated electronic medical record supporting an automated medication administration record.5 Table 48.1 lists the components of comprehensive ICU pharmaceutical services. Critical care pharmacy specialists are uniquely positioned to provide comprehensive pharmacy services because of their cognitive skills and relationship with other members of the ICU team. However, establishing and maintaining operational services requires administrative skills not necessarily taught during postgraduate year two (PGY2) training. The administrative skills necessary to develop a comprehensive ICU pharmacy service such as pharmacy operations management, pharmacy practice model design, human resources management, and financial reporting are often not the focus of the training in residency or fellowship programs. Although ASHP’s educational outcomes, goals, and objectives for PGY2 training in critical care require the review and evaluation of leadership and practice management skills, the degree to which they are covered is often variable and dependent on the pharmacy’s organizational structure and residency resources. The following case exemplifies how an ICU pharmacist uses leadership and management skills to be an effective ICU practitioner. Recently, an academic medical center reviewed the drug costs associated with patients on mechanical ventilation greater than 96 hours. The costs were so much outside the range compared with those

of peers that the only suggested way to reduce expense was to significantly reduce the medication inventory or people. That review showed cost opportunities in the areas of extracorporeal membrane oxygenation (ECMO) therapy. The pharmacist reviewed the patient cases and combined his clinical knowledge of ECMO and appropriate medication use to the institution’s data. The ICU pharmacist then sorted the costs by various patient characteristics and developed a Pareto analysis for the senior management on the distribution of medication expenses in ECMO. The ICU pharmacist developed a presentation and executive summary for the chief of thoracic surgery, together with a plan for implementing a Plan-Do-Check-Act approach to decreasing costs. After 12 months, the medication costs for patients on ECMO were normalized to the 50th percentile for the compare group, preventing any other drastic reductions in staff or services for these patients. Without knowledge of some basic leadership and management skills, the ICU pharmacist would have been unable to effectively address a clinical problem that increased an organization’s use of resources. This chapter provides a primer to the critical care pharmacy specialist on leading and managing ICU pharmacy services. Specifically, this chapter describes the elements of a comprehensive ICU pharmacy service and its impact on a hospital organization, together with the skills necessary to lead and manage an ICU pharmacy service. This chapter also discusses the future role of pharmacists in the ICU and the impact of new technology on ICU pharmacy services. A large retrospective study showed that increased pharmacist staffing positively affects hospital mortality rates; however, the pharmacy services coverage is not consistent across hospitals.6 As a result, every critical care specialist must now possess skills that focus not only on the clinical care of ICU patients, but also on the business and leadership acumen to develop an effective role for the critical care pharmacist in the interdisciplinary ICU model. With a focus on skills in practice leadership and management, together with clinical skills, critical care pharmacy services will continue to grow in this country.

Table 48.1 Components of a Comprehensive ICU Pharmacy Service Component

Description

Facility

ICU pharmacy medication dispensing area separate from the traditional “med room.” Contains all appropriate inventory, equipment, and space for pharmacy order review, preparation, and clinical consultation

Staffing and competency

Pharmacist “on site” in the ICU for hours meeting the needs of patients, staff. Pharmacy technician support for medication dispensing. Pharmacists and technicians are appropriately credentialed to ensure that basic competency is met in pharmaceutical dispensing, preparation, and monitoring. A clinical privileging process or peer-review system must be implemented to ensure ongoing professional practice competence

Quality and safety

Resources to identify and track MEs; implementing a system for staff to report MEs and adverse drug reactions. Training of ICU staff on new medications and equipment to prevent MEs should be done by a pharmacist or pharmacy technicians. Databases should be used that compare a specific ICU performance in quality and safety with others across a region or by a similar patient demographic

Financial management

Resources to track the use of medications and associated costs. Financial performance should also be compared with that of other institutions of a similar demographic or financial profile

ME = medication error; ICU = intensive care unit.

ICU PHARMACY SERVICES AND THE HOSPITAL Comprehensive pharmaceutical services for ICU patients are based on the significant medication needs of these patients. In most ICUs, patients are admitted because of their need for intensive, one-on-one nursing care and the focused attention of the medical staff. Intensive care unit patients have multisystem and multiorgan failure, requiring

very specific pharmacotherapy to manage these issues. The ICU pharmacy service also promotes quality and safety in health care by reducing the risk of adverse drug events and medication errors (MEs).

Medication Needs of ICU Patients Intensive care unit patients require more medications than do non-ICU patients. An informal observational study in a university hospital showed that the ICU patient had on average 26 different medication orders, compared with 11 for the non-ICU patient. A large percentage (greater than 65%) of these medications are for intravenous formulations; ICU patients’ ability to take oral medication may be compromised by their inability to swallow or because edema of the gastrointestinal (GI) tract limits drug absorption. In addition, ICU patients may require the use of tubes or catheters to access the GI tract, requiring that medications be available in the oral formulation or compounded as an oral liquid. Intravenous medications are the primary dosage formulation administered to ICU patients—and many require extemporaneous compounding by hospital staff. Compounding of intravenous medications is most appropriately done under the proper conditions as required by the United States Pharmacopeia (USP). The USP sets the standards for drug product formulation and testing; USP chapter details the requirements for the safe compounding of intravenous medications for both immediate use and batch preparation.7 Most regulatory agencies, including the Joint Commission, state boards of pharmacy, and health departments, require hospitals to comply with USP guidelines for preparing intravenous admixtures. A significant medication need of patients is the timely delivery of medications in urgent and emergent situations. Some hospitals use satellite pharmacy spaces in the ICU to place the pharmacy staff and the medication dispensing equipment closer to the patients, reducing the logistics of medication delivery from a central pharmacy area. Many pharmacy departments are located in the basement of a hospital, and often, pneumatic tube carrier systems are unavailable. As

a result, delivering medication may require a technician to hand deliver the medication, using elevators, steps, and walkways to reach the ICU. Locating a pharmacy satellite area in or around the ICU eliminates these delivery issues and makes the medication available in a timely manner. The joint statement from SCCM and the American College of Clinical Pharmacy (ACCP) on critical care pharmacy services lists a satellite pharmacy with 24-hour, 7-day/week services as an optimal provision of pharmaceutical care services.8

Medication Costs and Quality in the ICU The costs of medications for ICU patients exceed those for non-ICU patients. In a study of almost 23,000 ICU patients, researchers showed that ICU drug costs accounted for almost 38% of total drug costs and increased at a rate much greater than for non-ICU drug expenses.9 Furthermore, pharmacy charges ranked as the fourth highest charge in an organization. These data emphasized the differences in the costs of ICU pharmacotherapy and the importance of developing evidence-based practices for drug use and disease state management in the ICU together with multidisciplinary collaborations. Patients treated in an ICU have multiorgan failure, leading to a significant risk of adverse drug reactions and MEs because of the organ toxicity of antibiotics, intravenous medications, and anticoagulant and antiarrhythmic drugs. In addition to complex drug therapy and the rapidly changing condition of ICU patients, the environment may be chaotic and confusing, leading to errors caused by communication issues. Other factors include complex drug administration requirements and altered pharmacokinetics. The incidence of ICU MEs in general has been documented at a median value of 106 per 1,000 patientdays, or around 10%.10 The severity of MEs in the ICU exceeds that in the non-ICU. The harm caused by an ME is usually an injury related to events such as hypotension from mistaken overdoses of medication, organ damage from overdosages of medication, and cardiac arrhythmias from rapid administration of cardiac medications. Because MEs have a greater incidence of harm, vigilance in monitoring patients

and preventing MEs is essential.

LEADERSHIP SKILLS REQUIRED IN LEADING AND MANAGING ICU PHARMACY SERVICES This chapter has reviewed important aspects of the impact of the comprehensive pharmaceutical service on the medication needs of ICU patients. Implementing ICU pharmaceutical services requires a broad knowledge of operational and clinical pharmacy services, specifically focused on the needs of ICU patients. This next section of the chapter discusses in some detail the important skills necessary to lead and manage ICU pharmacy services. These skills focus on basic leadership skills such as developing strategic planning, justifying pharmacy services, providing operational and clinical services management, managing personnel, and using alternative pharmacy practice models. In addition, resources for gaining these skills will be presented so that pharmacists can gain the necessary knowledge in a non-traditional manner (e.g., web resources, conference, home study programs). These leadership skills are also important for managing the relationships that the ICU pharmacist may have with the network of individuals who coordinate the care of ICU patients (Figure 48.1). For example, interactions with several members of this network require variable leadership and management skills. Moreover, the pharmacy administrator requires the ICU pharmacist to be a clinical expert but also to have the ability to effectively plan for service growth and deal effectively with physician relationships. The nursing leadership of the ICU requires the ICU pharmacist to understand how nursing workflow and priorities intersect with pharmacy operations, resolving any issues that may interfere with those priorities.

Strategic Planning Strategic planning is the skill of developing a work plan for a clinical service that is consistent with the strategic needs of an organization.11 The ICU pharmacy service consistently meets the strategic plan of any

hospital organization by addressing the specific impact of the pharmacy service previously discussed. Many organizations fail in their strategic plan because of a very simple shortfall—the plans are too detailed and complex. Simple plans are much more effective because it is easier for staff to remember and understand their applicability to the organization. A simple strategic planning framework focuses on three key elements: analysis, planning groups, and execution. These three areas, if given the proper attention, will result in an effective strategic plan for the ICU pharmacy service. Intensive care unit pharmacists must be involved in establishing the pharmacy’s plan for this area because their understanding of patient needs and how pharmacy meets patient needs is central to any strategic plan for an ICU. Because strategic planning is not often taught in training, excellent resources are available. In particular, the National Council of Nonprofits offers an excellent guide for strategic planning.12 An analysis of the ICU pharmacy service is usually conducted through interviews with key stakeholders, as well as examining essential ICU data on medication cost, quality, and safety metrics and staff and patient satisfaction. The stakeholders should include physicians, nurses, administrators, and patients. The interviews assess the stakeholders’ thoughts on the strengths and weaknesses of the ICU pharmacy program and thoughts on the department’s future directions. Additional analyses involve conducting a SWOT (strength, weakness, opportunity, and threat) analysis of the pharmacy services and surveying the pharmacy staff on their thoughts for future directions of the pharmacy service. The result of the analysis establishes strategic priorities and tactics for the ICU pharmacy services, examples of which are listed in Table 48.2 and Table 48.3. These priorities must match directly and contribute to the organization’s goals. The planning groups on the ICU pharmacy services address the priorities developed from the strategic planning process. For example, enhancing the ICU pharmacy practice model requires establishing a planning group that will develop guiding principles, conduct an assessment of the strengths and weaknesses of the model, and recommend a plan for practice model changes. Other planning groups

may include an employee satisfaction group and a research focus group. Through these planning groups, tactics can be developed to increase the ICU pharmacy service’s growth. A tactic is a careful action or plan to achieve a specific end.

Figure 48.1 Clinical care network of the ICU pharmacy. ICU = intensive care unit. P&T = pharmacy and therapeutics.

Table 48.2 Activities Necessary to Leading and Managing ICU Pharmacy Services Activity Strategic planning

Examples of Activities Conduct a SWOT analysis and gather stakeholder feedback; develop a summary document of a strategic plan; develop a database to track outcomes of a strategic plan (e.g., scorecard); communicate the results of the plan to other disciplines

Cost justification of ICU services

Develop a business plan for ICU pharmacy services; conduct costbenefit, cost-effectiveness, or cost-minimization analyses

Clinical service management

Develop standards for clinical practice related to patient assessment, management, and documentation; review and manage peer-review processes; identify and conduct interdisciplinary reviews of adverse events; design innovative and effective practice models; serve as a residency program director or preceptor in a PGY2 critical care specialty residency

Operations management

Prepare a staffing schedule to meet patient needs; provide a justification for new ICU pharmacy personnel or to maintain current ICU staffing; develop and implement a productivity and workload report; use Lean and other continuous quality improvement techniques to improve efficiency

Personnel management

Develop a recruitment and retention plan for ICU pharmacy staff; write an effective job description; conduct progressive discipline in accordance with fair labor standards

SWOT = strength, weakness, opportunity, and threat.

The most important aspect of a successful strategic plan for a comprehensive ICU pharmacy service is executing the tactics design to meet the strategic plan. Successful execution requires skill in communication and project management. Most strategic plans are designed as a sophisticated “to-do” list that outlines the tactics together with a time-line and the responsible individual for implementing those tactics. Meaningful metrics for the success of an ICU pharmacy service strategic plan include, but are not limited to, patient satisfaction scores, clinical productivity, harmful MEs, order processing times, readmission rates, staff satisfaction, and financial performance (cost of drugs adjusted for patient acuity). A strategic plan is a fundamental and required tool for pharmacy departments that want to improve their overall performance. A good plan involves having an effective analysis, establishing venues for employee input, and executing and tracking its progress. Patient-centered services for the ICU pharmacy can only be successful through a well-done and well-executed strategic plan.

The role of the ICU pharmacist in strategic planning is shown by the following example. A pharmacy director of a 300-bed hospital is moving the central pharmacy to another area of the hospital—far away from the ICU, which was previously serviced by the central pharmacy. As a result, the pharmacy director places developing an ICU pharmacy satellite as a key strategy in the department’s goals, tasking the ICU pharmacy to develop the strategic plan for the pharmacy design and operation. The ICU pharmacist surveys stakeholders to determine the needs of the pharmacy satellite, establishes an inventory to meet the clinical needs of the patients, and designs the appropriate staffing. Finally, the ICU pharmacist supervises the execution of the construction and opening plans for the pharmacy.

Justifying ICU Pharmacy Services The strategic plan sets the framework for establishing a comprehensive pharmaceutical service; often, the plan requires a justification through the administrative structure in a hospital organization. Justifying a new service or an expansion of an existing service requires a combination of information based on published literature and institutional data. Institutional-Specific Data There are very specific institutional data that are important to justifying pharmacy services. These data include staffing ratios for nurses and physicians, medication costs for ICU patients, reported harmful MEs, length of stay, readmission information, mortality, and patient and family satisfaction. Most institutions require that the pharmacy department submit a return on investment (ROI) for new programs; this requirement would be no different if the pharmacy department were justifying a comprehensive pharmacy service. An ROI is the benefit to the investor resulting from an investment of some resource. A high ROI means that the investment gains compare favorably with investment cost. As a performance measure, the ROI is used to evaluate the efficiency of an

investment or to compare the efficiency of many different investments.13 The ROI for a pharmacy service is calculated by determining the costs of the ICU pharmacy service (facilities/space, people, inventory) compared with the benefits of the service. The benefits of the service may be measured by cost savings or avoidable hospital deaths. Pharmacy-specific services that contribute to avoided hospital deaths that can be used in the ICU by pharmacists include managing policies and protocols, providing informal educational services, conducting medication use evaluations, attending medical rounds, conducting medication histories, managing adverse drug events, and responding to resuscitation events.13 Published Data Table 48.4 includes the fundamental, desirable, and optimal critical care pharmacy services. A 2013 report describes the role of the pharmacist as a member of the multidisciplinary team, including very specific clinical activities.14 The cost implications and potential adverse events prevented by the interventions of a critical care pharmacist were studied in an academic medical center. Interventions for an almost 5month period were analyzed in a retrospective manner, with almost 85% of the interventions determined to have prevented a potentially serious adverse event. The total cost impact of the pharmacist interventions annualized to around $600,000–$850,000 in cost avoidance.15 Another study shows the role of the critical care pharmacist in identifying significant drug-drug interactions. A prospective study showed that pharmacist involvement in a profile (medication regimen) review significantly reduced the incidence of drug-drug interactions compared with the control period (no pharmacist review of the medication regimen).16 Finally, pharmacists and physicians were surveyed on the perception of their impact on the clinical and financial impact of pharmacy services in the ICU. Critical care pharmacy services were perceived to have beneficial clinical and financial outcomes—specifically, the services considered fundamental by SCCM and ACCP. The study also showed strong support for the funding of

critical care pharmacy services and reimbursement for pharmacists practicing in the ICU.17

Operational and Clinical Services Management Managing operational and clinical services requires knowledge of several areas. The clinical services coverage requires planning to ensure that pharmacists are available to participate in patient care activities. For example, understanding the clinical rounding scheduled of the team is critical—and pharmacists should be scheduled appropriately to participate in those rounds. Documenting and measuring clinical workload is a critical skill that establishes the appropriate time standards for various clinical activities. These standards should be used to develop the required number of hours for providing clinical services. Managing operations also requires knowledge of Lean Six Sigma (Lean), a methodology that relies on a collaborative team effort to improve performance in the ICU pharmacy area (usually a satellite pharmacy, central pharmacy service, or infusion service) by systematically removing waste to include expired medications, errors, overproduction, and inventory.18 The elements of Lean include designing a process such that the defect-free rate is 99.99966%, or six sigma.

Table 48.3 Tactics for Leading and Managing ICU Pharmacy Services Strategic Priority

Examples of Tactics

Become a national leader in the ASHP Pharmacy Practice Model Initiative (PPMI) for the ICU

1. Finalize the framework of the ICU practice model that establishes all levels of staff working at the top of their license and in a coordinated way 2. Expand clinical privileges to 100% of ICU pharmacists 3. Complete implementing a computerized patient scoring system to prioritize ICU workflow

4. Define the framework and functions of pharmacy APPE students in the ICU 5. Develop a framework for collaboration with the college of pharmacy and obtain buy-in from all levels of the organization Optimize operational and clinical efficiency

1. Maintain ICU staffing levels at greater than or less than the 50th percentile of Reuters Action OI comparator institutions 2. Achieve 100% of the cost-reduction goal for nonlabor spending (medications) in the ICU

Exceed standards of medication safety in the ICU by maximizing technology and the roles of our staff

1. Reduce the number of harmful MEs by 5%–10% of FY 2015 baseline 2. Improve “smart pump” compliance in the ICU to national standards 3. Improve the effectiveness of the ICU Safety Solutions Committee

Retain qualified ICU pharmacists and technicians

1. Implement at least one to three initiatives that respond to issues addressed by the ICU pharmacy employees 2. Develop a committee to recommend ICU staff for local, state, and national pharmacy awards— and recommend at least one to three people for awards 3. Conduct at least one or two formal employee recognition ceremonies and one or two informal recognition ceremonies in the ICU pharmacy area

To contribute to the overall body of ICU pharmacy knowledge

1. Increase submitted peer-review publications and book chapters by 2%–5% from FY 2014 levels 2. Successfully complete our review with the ICU specialty residency program earning full accreditation 3. Publish a review of the success of the residency research program, with a focus on the ICU residency research projects

APPE = advanced pharmacy practice experience; FY = fiscal year. Adapted from: The Ohio State University Wexner Medical Center Strategic Plan, executive summary 2014-2015.

Table 48.4 Fundamental, Desirable, and Optimal Critical Care Pharmacy Services13

IV = intravenous. Reprinted with permission from the American College of Chest Physicians. Preslaski CR, Lat I, MacLaren R, et al. Pharmacist contributions as members of the Multidiscplin-nary ICU team. Chest 2013 Nov; 144(5).

An important aspect of operational and clinical services management is the ability to understand and use institutional data. Specifically, these data include staffing ratios for nurses and physicians, medication costs for ICU patients, reported harmful MEs, length of stay, readmission information, mortality, and patient and family satisfaction. For example, the ICU pharmacy service would use statistics on patient volume to appropriately provide staffing to the ICU pharmacy; drug expense data can be used to focus interventions to include appropriateness or cost-savings projects.

Pharmacoeconomic Analytical Skills The role of pharmacoeconomics in the ICU is important because ICU medications may be costly, but using these costly medications may be cost-effective in the treatment of a given ICU patient. The ICU pharmacist should understand the basic pharmacoeconomic terms and how to apply various analyses to drug use in the ICU. This is also important because many therapies in the ICU often lack the appropriate level of graded medical evidence. Table 48.5 lists the type of economic analyses and some examples in ICU patients.19

Personnel Management People are the most valued asset in health care; organizations are successful if they have engaged satisfied and passionate employees. In addition, employees expect to be supervised and managed in a way that provides them with job satisfaction and upward career mobility. It is important that the critical care specialist have the skills to manage both professional and technical personnel to include developing clear job descriptions, tracking performance management, and providing effective feedback on performance. Intensive care unit pharmacists are being selected for jobs that are located in a pharmacy satellite—with responsibilities to help in managing pharmacists and technicians. This management requires providing feedback to staff on issues around

clinical practice. In particular, the ICU pharmacist may also provide feedback to nursing staff on practice issues such as methods for administering and monitoring medications. There are several reasons to create clear job descriptions for the ICU pharmacy service; in general, job descriptions provide clear performance expectations, help with recruiting and hiring, and differentiate between various jobs within the pharmacy department. Job descriptions include the following: (1) the job or position title (and job code number, if applicable); (2) the reporting structure for the position; (3) a brief summary (one to three sentences) of the position and its overarching responsibility, function, or role within the organization and how it interrelates to other functions within the organization; (4) a list of the position’s essential or key job duties; (5) the qualifications for the position (the specific knowledge, skills, employment, or other experiences, training, language, or aptitudes required for the job); (6) the educational requirements for the job, if any, such as degrees and licensing; and (7) the qualities or attributes that contribute to superior performance in the position. A well-written job description is a necessary component of effective personnel management because this document provides clarity on role function and performance expectations. Clinical Privileging of ICU Pharmacists In May 2012, the Centers for Medicare & Medicaid Services (CMS) modified its definition of medical staff to include non-physician practitioners.20 Pharmacists practicing in the ICU are an example of non-physicians who can now be classified as part of the medical staff, which creates an opportunity to privilege pharmacists if state and federal regulations are observed. Institutional clinical pharmacists are still unable to bill for their patient care services, but this change in CMS policy provides additional strategies for pharmacists to generate revenue for clinical services.

Table 48.5 Economic Analyses with Examples for ICU

Patients Type of Study

Definition

ICU Examples

Cost minimization

Analyses that compares the cost per course of treatment when alternative therapies have demonstrably equivalent clinical effectiveness

• Formulary review of intravenous acetaminophen in managing febrile episodes in the ICU • Antibiotic therapy for ICU patients at low risk of nosocomial pneumonia

Cost benefit

Analysis in which benefits and costs are calculated in monetary terms

• Aminoglycoside dosing programs in burn patients • Control of endemic methicillin-resistant Staphylococcus aureus

Costeffectiveness

Analysis that compares the relative costs and outcomes (effects) of two or more courses of action

• Thrombolysis in acute myocardial infarction • Length-of-stay analysis of ICU patients

Cost utility

Analysis that estimates the ratio between the cost of a health-related intervention and the benefit it produces with respect to the number of years lived in full health by the beneficiaries

• Prophylaxis against recurrence of peptic esophageal strictures • Mechanical ventilation in chronic obstructive pulmonary disease

Adapted from: McKenzie C, Borthwick M, Thakeer M, et al. Developing a process for credentialing advanced level practice in the pharmacy profession using a multi-source evaluation tool. Pharm J 2011;286:1-4.

Privileging Basics Privileging is the process by which a health care organization authorizes an individual to perform a particular clinical service within a defined scope of practice.21 Privileging is integral to the ability of physicians and mid-level practitioners (e.g., nurse practitioners, physician assistants) to provide independent clinical activities in a hospital or clinic. Privileging should not be confused with credentialing. Credentialing is the process by which an organization reviews and verifies an individual’s credentials to ensure that they meet established standards. A brief case shows the differences between credentialing and privileging. A hospital’s cardiac surgery department may require that physicians have the credentials of a medical degree, a state license, and specific residency training in interventional cardiology. That same hospital may only privilege specific physicians’ valve replacements depending on the credentialed physician’s specific case experience and outcomes. For pharmacists, credentialing has been limited to verification by the health-system human resources department that pharmacists are graduates of an accredited school or college of pharmacy and that their license is in good standing. As an example, for a pharmacy department to credential and privilege pharmacists for administering immunizations, a pharmacist license as a credential and completion of a certificate program may be required. In addition, the department may require some competency assessment/review of knowledge on immunization indications, dosage, injection technique, and patient monitoring techniques. Privileging pharmacists for ICU pharmacy activities can be a complicated process, and the pharmacy director must understand the basic steps of privileging and be able to apply them to privileging of the pharmacy staff. Because privileging is conducted by a hospital’s medical staff, gaining the support of ICU physicians to privilege pharmacists is a key initial step in the process. The director of pharmacy must develop a strategy that shows the benefits and values of privileging pharmacists for medication-related clinical activities. Once the pharmacy gains support for pharmacist privileging in the

ICU, the necessary credentials for practicing pharmacists, specific scope of patient care service in the ICU, and initial and ongoing monitoring of quality performance in the patient care service must be determined. Although no official standards specify the credentials necessary for ICU pharmacists to become privileged, minimum requirements may include a pharmacy degree and a license to practice pharmacy. Expanded requirements can include residency training, board certification, number of years in practice, and level of specialization and competency examinations. As part of the privileging process, individuals will also need to undergo initial and ongoing quality monitoring. The institution must establish policies regarding which specific elements related to competency will need to be reviewed for ongoing evaluation and the frequency with which these reviews will need to occur. The scope of practice delineates the boundaries within which the pharmacist can provide clinical services and may differ depending on state pharmacy and medical laws and the bylaws of an organization’s medical staff. Independent activities where pharmacists can be privileged in the ICU may include the following: anticoagulation management; medication reconciliation (adjusting medication on discharge or transfer from the ICU); modification of drug regimens according to a patient’s renal, hepatic, and hematologic parameters; management of total parenteral nutrition therapy; conversion of intravenous medication to equivalent oral dosages; initiation of culturedirected antimicrobial therapy; Clostridium difficile management; and ventilator-associated prophylaxis management. Table 48.6 describes the specific activities involved with some privileges for ICU pharmacists. Privileging Activities Within each of these various clinical activities, specific procedures or tasks that fall within the scope of practice must be specified. For example, for pharmacists who are privileged to manage anticoagulation, specific procedures include selecting the medication and the proper dosage and frequency, ordering appropriate laboratories, and selecting the appropriate consultative help (e.g.,

dietitian consult to prevent food and drug interactions). The pharmacy department must also develop an internal process to approve pharmacists to be privileged for a specific ICU patient care service. This involves defining appropriate performance measures for specific clinical privileges. The United Kingdom Clinical Pharmacy Association established a critical care group that designed a process for credentialing advancedlevel practice in critical care; this framework may serve as a guide for the growth of critical care privileging in U.S. hospitals.22 The group proposed a multipronged glossary of assessment tools for critical care proficiency: practice portfolio, case-based discussion, mini-clinical evaluations, and a 360-degree peer assessment. The practice portfolio contained documents to validate the experience of a practitioner in a specific area. Of importance, the portfolio should contain data to support the ACLF (advanced to consultant level framework), which is a UK-recognized framework describing the level of competency in pharmacy practice. Case-based discussions are designed to assess clinical decision-making and a candidate’s ability to apply knowledge to resolving the issues presented in the patient case. The mini-clinical evaluation exercise is based on the American Board of Internal Medicine approach, and it involves a group discussion with candidates on a specific case, with a series of predetermined questions about the case. Finally, the 360-degree assessment seeks input from all practitioners who work with the pharmacist in the clinical arena; usually, the evaluators are members of the team in which the pharmacist is a member. This framework may serve as a guide to a comprehensive evaluation of the skills needed to determine the competency of a pharmacist independently practicing in an ICU as a member of a multidisciplinary team.23 Privileging Benefits Privileging of pharmacists in the ICU has a variety of benefits. It improves the efficiency of pharmacists and physicians by avoiding the need for direct physician oversight of pharmacist activities. For example, pharmacists may modify a drug dosage for a patient and

enter a verbal order change in the electronic medical record with a physician co-signature. Given the time to identify and sign verbal orders in an electronic system, eliminating this activity by privileging pharmacists to independently perform the activity allows physicians to increase their ability to care for more patients, increasing the organization’s clinical revenue. Pharmacists also can more effectively use their time optimizing drug therapy and addressing medicationrelated problems without being limited by the availability of a physician.

CONCLUSION Pharmacy services in the ICU are of great benefit to patients; in particular, comprehensive pharmacy services that use clinical and operational services to patients are the optimal pharmacy practice model. To establish comprehensive services, pharmacists must use both clinical and leadership skills. This chapter reviewed the leadership and management skills necessary for pharmacists to implement comprehensive ICU pharmacy services. Most pharmacists participating in PGY2 critical care pharmacy specialty training programs or pharmacists who have obtained their ICU pharmacy skills “on the job” have very little training in leadership and management. Lack of these skills may be a barrier to developing a comprehensive ICU pharmacy service.

Table 48.6 Examples of Clinical Privileges for ICU Pharmacists Clinical Privilege Core privileges – basic privileges that can be applied to all patient care units, including the ICU

Description • Evaluate subjective and objective patient information • Coordinate appropriate referrals • Provide consultation in decision-making/planning for clinical services • Following prescriber medication initiation, order and adjust laboratory tests related to monitoring medication therapy as necessary

• Following prescriber-determined enteral route (e.g., PO, NG, PEG), adjust medication route or dosage form of existing medication orders accordingly while maintaining the originally intended dose • Modify preoperative antimicrobial regimen on the basis of preoperative antimicrobial protocol • Delete duplicative medication therapy within the same therapeutic class when necessary IV to PO transition

• Transition patients from intravenous to oral therapy according to the pharmacy and therapeutics committee’s IV to PO policy

Pharmacokinetic and anticoagulant monitoring

• After prescriber initiation, monitor and adjust medications on the basis of renal, hepatic, antithrombotic indications and hematologic parameters

Total parenteral nutrition management

• Following prescriber initiation, modify and adjust TPN therapy and associated fluids and electrolytes in conjunction with a licensed dietitian

Clostridium difficile management

• After prescriber diagnosis of C. difficile and physician initiation, modify and adjust therapeutic management

ICU antimicrobial stewardship

• Following prescriber initiation, monitor and adjust culture-directed antimicrobial therapy with de-escalation of antimicrobials

Ventilator-associated pneumonia prophylaxis

• Following mechanical ventilation, assess need for chlorhexidine mouthwash

Stress ulcer prophylaxis

• After prescriber initiation of stress ulcer prophylaxis, assess, modify, or discontinue therapy as appropriate

Medication reconciliation on transition of patient care

• Assess and modify medication orders on the basis of the patient’s level of care

NG = nasogastric; PEG = percutaneous endoscopic gastrostomy; PO = oral; TPN = total parenteral nutrition. Adapted from: The Ohio State University Wexner Medical Center Credentialing and Privileging Program for Pharmacists.

Resources are available for pharmacists to develop their leadership and management skills. The ASHP Foundation’s Center for HealthSystem Pharmacy Leadership, through the Leadership Resource Center (LRC), provides tools and opportunities for a variety of ICU practitioners who are experienced, emerging, or aspiring leaders. The LRC can provide teachings for those learning new skills or those honing existing leadership skills with the ultimate goal of enhancing their leadership knowledge and personal development. The LRC offers a Leadership Primer that provides foundational concepts for leading in a complex health care environment. A Leadership Self-Assessment also offers personal insights into individual strengths and development opportunities. In addition, a Leader’s Tool Kit offers awareness, user tips, and access to worksheets for useful leadership tools that can be used in the ICU. Finally, the LRC’s Focused Learning Modules offer indepth self-study opportunities on key leadership topics, including (1) leading for influence and advocacy, (2) clinical microsystems: transformational framework for lean thinking, and (3) transformational change. Now, more than ever, the critical care specialist must possess skills that focus not only on the clinical care of ICU patients, but also on the business and leadership acumen needed to develop an effective role for the critical care pharmacist in the interdisciplinary ICU model. With a focus on the skills needed in practice leadership and management, together with clinical skills, critical care pharmacy services will continue to grow in this country.

REFERENCES 1. Angaran DM. Critical care pharmacy services. In: McLeod DC, Miller WA, eds. The Practice of Pharmacy. Cincinnati: Harvey Whitney, 1981:171-82. 2. Society of Critical Care Medicine. Critical Care Statistics. Available at www.sccm.org/Communications/Pages/CriticalCareStats.aspx. Accessed August 10, 2015. 3. The Ohio State University College of Pharmacy. Script News.

Available at www.pharmacy.ohiostate.edu/sites/default/files/forms/alumni/publications/ScriptNews_WI2008.pdf Accessed August 9, 2015. 4. Board of Pharmacy Specialties (BPS). Critical Care Pharmacy (First examination scheduled for Fall 2015). Available at https://www.bpsweb.org/specialties/criticalcarepharmacy.cfm. Accessed August 10, 2015. 5. Rudis MI, Brandl KM. Position paper on critical care pharmacy services. Crit Care Med 2000;11:3746-50. 6. Bond CA, Raehl CL, Francke T. Clinical pharmacy services, hospital pharmacy staffing, and medication errors in the United States hospitals. Pharmacotherapy 2002:22:134-47. 7. Pharmaceutical Compounding—Sterile Preparations. Available at www.doh.wa.gov/Portals/1/Documents/2300/USP797GC.pdf. Accessed October 6, 2015. 8. Erstad BL, Haas CE, O’Keefe T, et al. Interdisciplinary patient care in the intensive care unit: focus on the pharmacist. Pharmacotherapy 2011;31:128-37. 9. Weber RJ, Kane S, Oriolo VA, et al. The impact of ICU drug use on hospital costs: a descriptive analysis with recommendations for optimizing ICU pharmacotherapy. Crit Care Med 2003;31:S17S24. 10. Kane-Gill S, Weber RJ. Principles and practices of medication safety in the intensive care unit. Crit Care Clin 2006;22:273-290. 11. Sanborn M. Developing a meaningful strategic plan. Hosp Pharm 2009;44:625-9. 12. National Council of Nonprofits. Strategic Planning for Nonprofits. Available at https://www.councilofnonprofits. org/toolsresources/strategic-planning-nonprofits. Accessed September 23, 2015. 13. Pokhrel S. Return on investment (ROI) in public health: strengths

and limitations. Eur J Public Health 2015 Jul 29. [Epub ahead of print] 14. Preslaski C, Lat I, MacLaren R, et al. Pharmacist contributions as members of the multidisciplinary team. Chest 2013;144:1687-95. 15. Kopp BJ, Mrsan M, Erstad BL, et al. Cost implications of and potential adverse events by interventions of a critical care pharmacist. Am J Health Syst Pharm 2007;64:2483-7. 16. Rivkin A, Yin H. Evaluation of the role of the critical care pharmacist in identifying and avoiding or minimizing significant drug-drug interactions in medication intensive care patients. J Crit Care. 2011;26:104.1-104.e6. 17. MacLaren R, McQueen RB, Campbell J. Clinical and financial impact of pharmacy services in the intensive care unit: pharmacist and prescriber perceptions. Pharmacotherapy 2013;33:401-10. 18. Lamm MH, Eckel S, Daniels R, et al. Using lean principles to improve outpatient adult infusion clinic chemotherapy preparation turnaround times. Am J Health Syst Pharm 2015;72:1138-46. 19. Angus DC, Rubenfeld GD, Roberts MS, et al. Understanding costs and cost-effectiveness in critical care. Am J Respir Crit Care Med 2002;165:540-50. 20. Available at https://www.cms.gov/Regulations-andGuidance/Legislation/CFCsAndCoPs/Downloads/CMS-3244-F.pdf. Accessed July 12, 2015. 21. Council on Credentialing in Pharmacy. Credentialing and privileging of pharmacists: a resource paper from the Council on credentialing in Pharmacy. Am J Health Syst Pharm 1014;71:1891-900. 22. Young K, Farrell J, McKenzie C, et al. New Ways of Working— Adult Critical Care Specialist Pharmacy Practice. London: Department of Health and Clinical Pharmacy Association, 2005. 23. McKenzie C, Borthwick M, Thakeer M, et al. Developing a

process for credentialing advanced level practice in the pharmacy profession using a multi-source evaluation tool. Pharm J 2011;286:1-4.

Chapter 49 Medication Safety and

Active Surveillance Sandra L. Kane-Gill, Pharm.D., M.Sc., FCCP, FCCM; and Mitchell S. Buckley, Pharm.D., FCCP, FASHP, FCCM, BCPS

LEARNING OBJECTIVES 1. State the incidence of medication errors (MEs) and adverse drug events (ADEs). 2. Discuss the relationship between MEs and ADEs. 3. Explain why the critically ill population is at greater risk of MEs and ADEs. 4. Describe the retrospective and prospective methods of ADE detection in a medication safety surveillance system. 5. Consider surveillance strategies that can be used to prevent ADEs. 6. State how to measure an effective surveillance system.

ABBREVIATIONS IN THIS CHAPTER ADE

Adverse drug event

ADR

Adverse drug reaction

AKI

Acute kidney injury

CDS

Clinical decision support

DRHC

Drug-related hazardous condition

ICU

Intensive care unit

ME

Medication error

PPV

Positive predictive value

INTRODUCTION Medication errors (MEs) and adverse drug events (ADEs) remain a significant concern in the critically ill population. Several factors have been identified in the intensive care unit (ICU) population as increasing the risk of experiencing a ME or ADE. Medication errors are concerning because they can result in ADEs. Unfortunately, ADEs have been associated with deleterious outcomes including an increased risk of hospitalization, costs, and mortality. Medication errors and ADEs can occur at any stage within the medication use process (prescribing, transcription, dispensing, and administration) with preventative strategies targeting each of these phases. A multifaceted approach involving both, prospective and retrospective, medication surveillance systems can detect events for systematic improvements, mitigate ADE progression and reduce preventable ADEs.

MEDICATION SAFETY Terminology Medication errors and ADEs are terms often used in medication safety (Table 49.1).1,2 The National Coordinating Council for Medication Error Reporting and Prevention defines an ME as a preventable incident resulting in inappropriate drug use while the medication is in the control of the health care professional, patient, or consumer.3 Medication errors may occur at any step in the medication use process regardless

of whether patient harm occurred.4,5 An ADE is an injury experienced by the patient as a direct result of medication use, but it is not necessarily the result of an ME.4 Confusion in the literature arises for ADEs because clinicians and researchers are not decisive with their definition of injury. Injury should be explained by the occurrence of end-organ damage, so an episode of asymptomatic drug-induced hyperkalemia (no end-organ damage) is not classified as an ADE, and an episode of drug-induced hyperkalemia that results in an arrhythmia (end-organ damage) is considered an ADE.2 The elevated potassium concentration caused by a drug is considered a drug-related hazardous condition (DRHC) because high potassium concentrations from drugs are an antecedent to injury and the opportunity for a pharmacist to intervene, thus preventing injury—in this case, an arrhythmia.2,5,6 The idea of an intermediate step or a DRHC, before an ADE occurs, can be applied to physiologic parameters as well as to laboratory values. This is shown in druginduced hypotension that has not yet resulted in end-organ damage (i.e., acute kidney injury [AKI] or a myocardial infarction).6 Adverse events can be classified as “preventable” or “nonpreventable” as well as “potential.”1,5 An ME occurring with no patient injury is simply an ME. An ME that results in injury is a preventable ADE. The occurrence of an ADE without an ME is a non-preventable ADE. Non-preventable ADEs are more common than preventable ADEs.1,5,7 An ME that has the opportunity for injury is defined as a “potential ADE.” The classic example is a patient with a penicillin allergy who receives a penicillin antibiotic but has no reaction; thus, there is the potential for injury, but none has occurred. Potential ADEs may be intercepted. The inconsistency surrounding the definition of an ADE versus that of an adverse drug reaction (ADR) is challenging to interpret, making comparisons between studies difficult. For some clinicians, a nonpreventable ADE is considered synonymous with an ADR.1,5 For others, an ADR is thought to be any unexpected, unintended, undesired, or excessive response that requires medical attention.6,8,9 The relationship among these various terms is shown in Figure 49.1.2

Table 49.1 Definitions of Common Medication Safety Terms Term

Definition

ME

A preventable incident leading to the misuse of a drug at any stage within the medication use process, regardless of whether harm occurred

ADE

Any patient injury attributed to medications

Drug-related hazardous condition

Antecedent to drug-induced injury and the opportunity for a pharmacist to intervene, thus preventing injury

Preventable ADE

Injury caused by an ME that could have been avoided

Non-preventable ADE (i.e., adverse drug reaction)

Injury caused by a drug without an ME occurring

ADE = adverse drug event; ME = medication error.

No Response (Considor Change in Drug)

Intended Response ( Therapeutic Goal Achieved)

No Medication Error

+>

Potential for Injury (DRHC Positive)

Unintended Response ( Adverse Drug Reaction)

No Potential for Injury ( DRHC Negative)

Potential for Injury

Yes

^

No Injury Outcome ( APE Negative )

Injury Outcome ( APE Positive)

(DRHC Positive)

Unintended Response

Drug Administration Event

Injury Outcome ( APE Positive)

( Adverse Drug Reaction)

*

>

No

Medication

Error

No Response

-*

No Potential for Injury ( DRHC Negative)

No Injury Outcome ( ADE Negative )

(Consider Change in Drug)

Intended Response (Therapeutic Goal Achieved Despite Error)

Figure 49.1 Relationship between medication errors and adverse drug events. ADE = adverse drug event; DRHC = drug-related hazardous condition. Reprinted by permission from Wolters Kluwer Health, Inc. Kane-Gill SL, Dasta JF, Schneider PJ, Cook CH. Monitoring abnormal laboratory values as antecedents to druginduced injury. J Trauma 2005 Dec;59(6):1457-62.

Epidemiology of MEs and ADEs in the ICU Medical errors and adverse events remain unacceptably high in the ICU, with drug therapy as one of the main causes.7,10-12 Medication errors occur more commonly than ADEs. The reported rate of MEs in the critically ill population is highly variable, ranging from 1.2 to 947 events for every 1,000 patient-days, with a median rate of 105.9 errors for every 1,000 patient-days.13 Differences in definitions, detection techniques, and specific ICU populations observed explain the wide variance in reported ME rates.13 Medication errors are of concern because of the possibility of resultant injury, known as a preventable

ADE.1,2,13 The incidence of ADEs is about 2-fold higher in the ICU population than in the general ward population (19 vs. 10 events, respectively, for every 1,000 patient-days).14 However, the rate of ADEs is no different after adjusting for the number of medications. Adverse drug event rates in the ICU have been reported to occur in about one-third of patients at a rate as high 87.5 events for every 1,000 patient-days.15-17 The severity of ADEs is greater in the ICU than in the general ward. Cullen et al. found a higher rate of “life-threatening” consequences of ADEs in ICU patients than in non-ICU patients (26% vs. 11%, p 8 mg/dL or 25% increase from baseline

Hyperphosphatemia

Phosphorus > 4.5 mg/dL or 25% increase from baseline

Hyperkalemia

Potassium > 6.0 mmol/L or 25% increase from baseline

Cardiac arrhythmia or sudden death likely related to hyperkalemia

Hypocalcemia

Corrected calcium < 7.0 mg/dL or ionized calcium < 1.12 mg/dL or 25% increase from baseline

Cardia arrhythmia, sudden death likely related to hypocalcemia, seizure, or neuromuscular toxicity

Acute kidney injury

Not applicable

Increase in serum creatinine of 0.3 mg/dL or oliguria for ≥ 6 hr

aValues

diagnostic for adult patients only.

bDiagnosis

requires two or more metabolic abnormalities to be present within same 24hour period 3 days before or 7 days after initiation of cytotoxic therapy. cRequires

diagnosis of laboratory tumor lysis syndrome in addition to clinical symptoms.

The nucleic acids from the DNA released into the circulation from lysing cells are broken down into hypoxanthine. This is further metabolized to xanthine and then to UA by xanthine oxidase. Rapid accumulation of these products can contribute to acute kidney injury through formation of urate crystals in the distal renal tubules and collecting ducts, obstructing the tubular lumen.55 The process is potentiated by both an acid environment, due to a decrease in UA solubility, and the presence of calcium phosphate crystals, which causes UA to precipitate more readily. Even in the absence of precipitation, UA activates the renin-angiotensin system, reducing available nitric oxide and resulting in renal vasoconstriction.55 Rising xanthine concentrations may also cause nephropathy or urolithiasis, regardless of pH.49 Crystal-independent mechanisms play a role in acute kidney injury as well. Lysed malignant cells spill cytokines and chemokines into circulation, and these inflammatory mediators induce local vasoconstriction at the level of the kidney. Reduced renal perfusion and hypoxia add to the tubular injury caused by crystal precipitates.55 Prevention and Treatment Risk assessment and proactive implementation of preventive measures in high-risk patients remain the keys to detecting TLS and mitigating the severity of sequel-ae. Aggressive hydration and brisk urine output enhance excretion of UA and phosphate through expansion of intravascular volume and improvement in renal blood flow. Maintaining renal perfusion is also important in protecting the kidneys from ischemic injury. If tolerated, consider administering crystalloid fluids at a rate of 2.5–3 L/m2/day. The choice of fluids should be individualized according to the patient’s clinical status. For example, chloride-poor products such as Ringer lactate may more desirable than normal saline, given the latter’s potential to perpetuate an acidic environment. However, in patients with preexisting severe hyperkalemia, Ringer lactate should be avoided in large volumes; goal urine output remains 3–5 mL/kg/hour.49,56 After ruling out obstructive renal injury, loop diuretics may be used to maintain this goal urine output in the setting of

adequate intravascular volume.51 Of note, urinary alkalinization is no longer recommended for TLS prevention, given a lack of evidence supporting its efficacy. Although UA is more soluble in a basic environment, this increases the risk of precipitation of calcium phosphate crystals. Furthermore, xanthine, the precursor to UA, has low solubility, regardless of pH.55 By preventing the metabolism of nucleic acids via xanthine oxidase, allopurinol can help circumvent accumulation of UA and hypoxanthine and the resultant renal injury. Of note, doses for TLS prevention are typically higher than those used in the treatment of gout. Guidelines suggest initiating allopurinol at 50–100 mg/m2 orally three times daily or at 10 mg/kg/day given in divided doses. The maximum recommended oral daily dose is 800 mg.51 Although general dosing guidelines advocate for a 50% dose reduction in patients with significant renal impairment, the benefits of aggressive dosing in maintaining or recovering renal function must be considered. In the absence of clear allopurinol-related toxicity, data analyses do not support dose reduction in this population. Therapy should start 12–24 hours before cytoreductive treatment and continue until normalizations of UA concentrations, leukocyte count, and laboratory values occur and the tumor burden is significantly decreased. Routine electrolyte monitoring and prompt management of derangements when identified reduce the risk of deleterious clinical effects.54 Serum chemistries including UA, potassium, phosphate, and calcium should be monitored every 6 or 8 hours in patients at a high or moderate risk of TLS.51 Electrolyte, UA, and creatinine abnormalities are most likely to be appreciated within 48 hours of cytoreductive treatment. It is also important to evaluate patients’ medication profiles for external sources of these substrates, such as dietary in-take, maintenance fluids, or multivitamins. Phosphate binders may be used in patients with hyperphosphatemia, though calcium-containing products should be avoided in the setting of hypercalcemia. In cases of severe electrolyte abnormalities or clinical manifestation thereof, emergent dialysis may be considered.51,56 Rasburicase is an intravenous medication that catalyzes the

oxidation of UA to the inactive and soluble product, allantoin. It may be used for the prevention of hyperuricemia or, in the event of early detection, before the manifestation of renal injury. For patients already experiencing a decline in renal function, rapid metabolism of UA may mitigate further damage, with the ultimate goal being to avoid the need for dialysis.51,57,58 Uric acid concentrations are noted to decrease as soon as 4 hours after a single administration of rasburicase and may continue declining for up to 72 hours.57,59,60 Initial investigations studied treatment success with doses of 0.15–0.2 mg/kg given daily for up to 5 days.57,58 However, studies that are more recent show equivalent efficacy with fixed doses of 3 or 6 mg, with an infrequent need for repeat dosing. This represents a significantly more cost-effective strategy, optimizing health care resources.58-61 The drug properties of rasburicase are such that it is removed by dialysis; therefore, it may be prudent to avoid administration in patients for whom dialysis is imminent. When considering the use of rasburicase, note its contraindication in patients with G6PD (glucose-6-phosphate dehydrogenase) deficiency, given the potential for severe hemolysis in some patients.57 Proactive identification of patients at highest risk of TLS who may benefit from rasburicase allows for appropriate testing before initiating cytoreductive therapy. In addition, proper technique is required for accurate laboratory monitoring of UA after an administered dose. To avoid enzymatic degradation of UA by rasburicase, blood samples must be stored in pre-chilled, heparin-containing tubes; kept refrigerated; and analyzed immediately by laboratory personnel.

Acute Calcineurin Inhibitor–Associated Neurotoxicity Epidemiology and Pathophysiology Although a valuable component of modern immunosuppression, calcineurin inhibitors (CNIs) carry a risk of several troublesome adverse effects. This class of immunosuppressants is commonly used for rejection prevention after solid organ transplantation, graft-vs.-host disease suppression after blood and marrow transplantation, and

management of various other disease states that require immune modulation. In addition to nephrotoxicity, neurotoxicity is one of the most commonly encountered adverse effects of CNIs, with serious events reported in up to 43% of patients.62-64 Arguably, the most severe of these is posterior reversible leukoencephalopathy syndrome (PRES). There are two proposed mechanisms for the pathology behind PRES. The first describes T-cell activation, which initiates a cytokine response.65,66 Resultant inflammation damages vascular brain endothelium, leading to vasogenic edema and ultimately tissue hypoperfusion. This process may be precipitated by several concomitant comorbidities such as infection, hypertension, preeclampsia, or organ rejection.65 Second, severe systemic hypertension may lead to transient disruption of autoregulation, a consequence of which is cerebral vasodilation. This allows fluid and blood into brain parenchyma, causing cerebral edema.64 Evidence of these events can be seen with CT or magnetic resonance imaging, which is considered the gold standard for syndrome diagnosis.64,65 Symptoms commonly associated with PRES include encephalopathy, elevated blood pressure, and seizure activity. Encephalopathy ranges from mild disruption of consciousness or lethargy to severe agitation or coma.65,67 Reports describe seizures commonly preceded by vision changes or headache.68 Hypertension is often considered a hallmark of the clinical presentation of PRES associated with any cause; however, reports clearly indicate it is not present in all cases. Mean arterial pressure can exceed 115–130 mm Hg in some cases, but epidemiologic data suggest that around 50% of cases present with normal or only slightly elevated blood pressure.65,67 It is thought that the risk of PRES is highest within the first 30 days of CNI therapy,62 although reports detail cases occurring as many as 10 months after drug initiation.63,69,70 In some instances diagnosis is made when CNI blood levels are considered elevated beyond normal limits (greater than 12–15 ng/mL in most cases) or as a result of rapidly increasing concentrations. This is not universally the case, however, because literature reveals frequent occurrence with normal CNI blood

concentrations. This can indicate that blood concentrations may not accurately reflect those present in the brain.65 Treatment Practitioners must thoroughly evaluate patients for potential causes of PRES aside from CNI therapy. If a CNI is determined to be the cause or a contributor, syndromal reversal ultimately depends on adjustment of CNI therapy in the form of dose reduction or discontinuation. When PRES is first recognized, providers commonly withdraw these medications. Pharmacists should assist in evaluating the appropriateness of an alternative treatment approach, if one is available for the underlying disorder. For patients in whom CNI therapy is overwhelmingly favorable, several case reports detail successful resolution of symptoms with a reduction in the target blood concentration or switching to a different medication within the same class.66,68,70 If these strategies are chosen, the patient should be closely monitored for signs of PRES during the initial reintroduction of CNI therapy. Symptomatic management should include cessation of seizures, hemo-dynamic stabilization, and electrolyte optimization. Seizures should be managed initially with benzodiazepines or alternatively phenytoin, which may induce metabolism of CNIs. Other antiepileptics can be considered for refractory status epilepticus.71 Blood pressure should ideally be maintained at the patient’s premorbid baseline. Given the suspected role of cerebral hypoperfusion in the patho-physiology of PRES, rapid overcorrection and persistent hypotension should be avoided. Overall symptomatic improvement may lag behind normalization of CNI blood concentrations, given the slow transit of CNIs across the blood-brain barrier, but is typically seen within several days of treatment.72 Resolution of radiographic evidence of PRES may be further delayed or occasionally persist, showing permanent cerebral volume loss.

CONCLUSION Immune system suppression, whether as a result of disease or

medication, is seen in a variety of patients, and pharmacists play a pivotal role in the optimization of their care. This may include prompt recognition of opportunistic and other infections, initiation and monitoring of antimicrobial therapy, assessment of indications for infection prophylaxis, maintenance of the balance between immunosuppressive medications and host defenses, and identification of possible adverse drug reactions associated with therapy. By familiarizing themselves with the unique complications seen in critically ill immunocompromised patients, pharmacists can continue to contribute to multidisciplinary health care in distinct and significant ways.

REFERENCES 1. Klastersky J. Management of fever in neutropenic patients with different risks of complications. Clin Infect Dis 2004;39(suppl 1):S32-37. 2. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:e56-93. 3. Zuckermann J, Moreira LB, Stoll P, et al. Compliance with a critical pathway for the management of febrile neutropenia and impact on clinical outcomes. Ann Hematol 2008;87:139-45. 4. Baden LR, Bensinger W, Angarone M, et al. NCCN Guidelines, Version 2.2015. Prevention and Treatment of Cancer-Related Infections. 2015. Available at www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed July 9, 2015. 5. Paul M, Dickstein Y, Schlesinger A, et al. Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane Database Syst Rev 2013;6:CD003038.

6. Kumar A, Zarychanski R, Light B, et al. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care Med 2010;38:1773-85. 7. Paul M, Dickstein Y, Borok S, et al. Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database Syst Rev 2014;1:CD003914. 8. Ariano RE, Nyhlen A, Donnelly JP, et al. Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia. Ann Pharmacother 2005;39:32-8. 9. Bow EJ, Rotstein C, Noskin GA, et al. A randomized, open-label, multicenter comparative study of the efficacy and safety of piperacillin-tazobactam and cefepime for the empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies. Clin Infect Dis 2006;43:447-59. 10. Wade JC, Glasmacher A. Vancomycin does not benefit persistently febrile neutropenic people with cancer. Cancer Treat Rev 2004;30:119-26. 11. Clark OA, Lyman GH, Castro AA, et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. J Clin Oncol 2005;23:4198-214. 12. Garcia-Carbonero R, Mayordomo JI, Tornamira MV, et al. Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: a multicenter randomized trial. J Natl Cancer Inst 2001;93:31-8. 13. Mhaskar R, Clark OA, Lyman G, et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia. Cochrane Database Syst Rev 2014;10:CD003039. 14. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol

2006;24:3187-205. 15. Bennett CL, Weeks JA, Somerfield MR, et al. Use of hematopoietic colony-stimulating factors: comparison of the 1994 and 1997 American Society of Clinical Oncology surveys regarding ASCO clinical practice guidelines. Health Services Research Committee of the American Society of Clinical Oncology. J Clin Oncol 1999;17:3676-81. 16. Green M, Covington S, Taranto S, et al. Donor-derived transmission events in 2013: a report of the Organ Procurement Transplant Network Ad Hoc Disease Transmission Advisory Committee. Transplantation 2015;15:15. 17. Doucette KE, Al-Saif M, Kneteman N, et al. Donor-derived bacteremia in liver transplant recipients despite antibiotic prophylaxis. Am J Transplant 2013;13:1080-3. 18. Kaul DR, Covington S, Taranto S, et al. Solid organ transplant donors with central nervous system infection. Transplantation 2014;98:666-70. 19. Miceli MH, Gonulalan M, Perri MB, et al. Transmission of infection to liver transplant recipients from donors with infective endocarditis: lessons learned. Transpl Infect Dis 2015;17:140-6. 20. Wendt JM, Kaul D, Limbago BM, et al. Transmission of methicillin-resistant Staphylococcus aureus infection through solid organ transplantation: confirmation via whole genome sequencing. Am J Transplant 2014;14:2633-9. 21. Garzoni C, Ison MG. Uniform definitions for donor-derived infectious disease transmissions in solid organ transplantation. Transplantation 2011;92:1297-300. 22. Ison MG, Grossi P. Donor-derived infections in solid organ transplantation. Am J Transplant 2013;13(suppl 4):22-30. 23. Watkins AC, Vedula GV, Horan J, et al. The deceased organ donor with an “open abdomen”: proceed with caution. Transpl Infect Dis 2012;14:311-5.

24. Rosen MJ, Clayton K, Schneider RF, et al. Intensive care of patients with HIV infection: utilization, critical illnesses, and outcomes. Pulmonary Complications of HIV Infection Study Group. Am J Respir Crit Care Med 1997;155:67-71. 25. Kaplan JE, Hanson D, Dworkin MS, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 2000;30(suppl 1):S5-14. 26. HIV surveillance—United States, 1981-2008. MMWR Morb Mortal Wkly Rep 2011;60:689-93. 27. French MA. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal. Clin Infect Dis 2009;48:101-7. 28. Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS ONE 2009;4:e5575. 29. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed July 9, 2015. 1-282. 30. Lonergan JT, Behling C, Pfander H, et al. Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens. Clin Infect Dis 2000;31:162-6. 31. Escaut L, Liotier JY, Albengres E, et al. Abacavir rechallenge has to be avoided in case of hypersensitivity reaction. AIDS 1999;13:1419-20. 32. Rosen MJ, Narasimhan M. Critical care of immunocompromised patients: human immunodeficiency virus. Crit Care Med 2006;34(9 suppl):S245-250.

33. Fan LC, Lu HW, Cheng KB, et al. Evaluation of PCR in bronchoalveolar lavage fluid for diagnosis of Pneumocystis jirovecii pneumonia: a bivariate meta-analysis and systematic review. PLoS ONE 2013;8:e73099. 34. Onishi A, Sugiyama D, Kogata Y, et al. Diagnostic accuracy of serum 1,3-beta-D-glucan for Pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and meta-analysis. J Clin Microbiol 2012;50:7-15. 35. Consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome. The National Institutes of HealthUniversity of California Expert Panel for Corticosteroids as Adjunctive Therapy for Pneumocystis Pneumonia. N Engl J Med 1990;323:1500-4. 36. Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS. Clin Infect Dis 1992;15:211-22. 37. Torre D, Casari S, Speranza F, et al. Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethaminesulfadiazine for therapy of toxoplasmic encephalitis in patients with AIDS. Italian Collaborative Study Group. Antimicrob Agents Chemother 1998;42:1346-9. 38. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed March 12, 2015. 1-407. 39. Satishchandra P, Sinha S. Seizures in HIV-seropositive individuals: NIMHANS experience and review. Epilepsia 2008;49(suppl 6):3341.

40. Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group. N Engl J Med 1996;335:392-8. 41. Lee CK, Gingrich RD, Hohl RJ, et al. Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation. Bone Marrow Transplant 1995;16:175-82. 42. Capizzi SA, Kumar S, Huneke NE, et al. Peri-engraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;27:1299303. 43. Mossad S, Kalaycio M, Sobecks R, et al. Steroids prevent engraftment syndrome after autologous hematopoietic stem cell transplantation without increasing the risk of infection. Bone Marrow Transplant 2005;35:375-81. 44. Afessa B, Abdulai RM, Kremers WK, et al. Risk factors and outcome of pulmonary complications after autologous hematopoietic stem cell transplant. Chest 2012;141:442-50. 45. Majhail NS, Parks K, Defor TE, et al. Diffuse alveolar hemorrhage and infection-associated alveolar hemorrhage following hematopoietic stem cell transplantation: related and high-risk clinical syndromes. Biol Blood Marrow Transplant 2006;12:103846. 46. Agusti C, Ramirez J, Picado C, et al. Diffuse alveolar hemorrhage in allogeneic bone marrow transplantation. A postmortem study. Am J Respir Crit Care Med 1995;151:1006-10. 47. Metcalf JP, Rennard SI, Reed EC, et al. Corticosteroids as adjunctive therapy for diffuse alveolar hemorrhage associated with bone marrow transplantation. University of Nebraska Medical Center Bone Marrow Transplant Group. Am J Med 1994;96:32734. 48. Raptis A, Mavroudis D, Suffredini A, et al. High-dose

corticosteroid therapy for diffuse alveolar hemorrhage in allogeneic bone marrow stem cell transplant recipients. Bone Marrow Transplant 1999;24:879-83. 49. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med 2011;364:1844-54. 50. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004;127:3-11. 51. Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008;26:2767-78. 52. Krishnan G, D’Silva K, Al-Janadi A. Cetuximab-related tumor lysis syndrome in metastatic colon carcinoma. J Clin Oncol 2008;26:2406-8. 53. Noh GY, Choe DH, Kim CH, et al. Fatal tumor lysis syndrome during radiotherapy for non-small-cell lung cancer. J Clin Oncol 2008;26:6005-6. 54. Kraft MD, Btaiche IF, Sacks GS, et al. Treatment of electrolyte disorders in adult patients in the intensive care unit. Am J Health Syst Pharm 2005;62:1663-82. 55. Shimada M, Johnson RJ, May WS Jr, et al. A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome. Nephrol Dial Transplant 2009;24:2960-4. 56. Abu-Alfa AK, Younes A. Tumor lysis syndrome and acute kidney injury: evaluation, prevention, and management. Am J Kidney Dis 2010;55(5 suppl 3):56. 57. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 2001;97:2998-3003. 58. Pui CH, Mahmoud HH, Wiley JM, et al. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in

patients with leukemia or lymphoma. J Clin Oncol 2001;19:697704. 59. Knoebel RW, Lo M, Crank CW. Evaluation of a low, weight-based dose of rasburicase in adult patients for the treatment or prophylaxis of tumor lysis syndrome. J Oncol Pharm Pract 2011;17:147-54. 60. Vines AN, Shanholtz CB, Thompson JL. Fixed-dose rasburicase 6 mg for hyperuricemia and tumor lysis syndrome in high-risk cancer patients. Ann Pharmacother 2010;44:1529-537. 61. Darmon M, Guichard I, Vincent F. Rasburicase and tumor lysis syndrome: lower dosage, consideration of indications, and hyperhydration. J Clin Oncol 2011;29:e67-68. 62. Zivkovic SA, Eidelman BH, Bond G, et al. The clinical spectrum of neurologic disorders after intestinal and multivisceral transplantation. Clin Transplant 2010;24:164-8. 63. Bartynski WS, Tan HP, Boardman JF, et al. Posterior reversible encephalopathy syndrome after solid organ transplantation. Am J Neuroradiol 2008;29:924-30. 64. Wu Q, Marescaux C, Wolff V, et al. Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation. Eur Neurol 2010;64:169-77. 65. Bartynski WS. Posterior reversible encephalopathy syndrome, part 2: controversies surrounding pathophysiology of vasogenic edema. Am J Neuroradiol 2008;29:1043-9. 66. Horbinski C, Bartynski WS, Carson-Walter E, et al. Reversible encephalopathy after cardiac transplantation: histologic evidence of endothelial activation, T-cell specific trafficking, and vascular endothelial growth factor expression. Am J Neuroradiol 2009;30:588-90. 67. Lee VH, Wijdicks EF, Manno EM, et al. Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol 2008;65:205-10.

68. Kilinc M, Benli S, Can U, et al. FK 506-induced fulminant leukoencephalopathy after kidney transplantation: case report. Transplant Proc 2002;34:1182-4. 69. Heidenhain C, Puhl G, Neuhaus P. Late fulminant posterior reversible encephalopathy syndrome after liver transplant. Exp Clin Transplant 2009;7:180-3. 70. Thyagarajan GK, Cobanoglu A, Johnston W. FK506-induced fulminant leukoencephalopathy after single-lung transplantation. Ann Thorac Surg 1997;64:1461-4. 71. Staykov D, Schwab S. Posterior reversible encephalopathy syndrome. J Intensive Care Med 2012;27:11-24. 72. Eidelman BH, Abu-Elmagd K, Wilson J, et al. Neurologic complications of FK 506. Transplant Proc 1991;23:3175-8.

Chapter 51 Clinically Applied

Pharmacogenomics in Critical Care Settings Samuel G. Johnson, Pharm.D., FCCP; and Christina L. Aquilante, Pharm.D., FCCP

LEARNING OBJECTIVES 1. Recognize pharmacogenomic testing applications relevant to the intensive care unit. 2. Interpret a patient’s genotype in the context of drug therapy selection and monitoring. 3. Construct an efficient pathway to provide clinical pharmacogenomic testing in the intensive care unit.

ABBREVIATIONS IN THIS CHAPTER ADR

Adverse drug reaction

CPIC

Clinical Pharmacogenetics Implementation Consortium

EM

Extensive metabolizer

GWAS Genome-wide association study ICU

Intensive care unit

IM

Intermediate metabolizer

PD

Pharmacodynamic

PK

Pharmacokinetic

PM

Poor metabolizer

SNP

Single nucleotide polymorphism

TNFα

Tumor necrosis factor alpha

UM

Ultrarapid metabolizer

VKOR Vitamin K epoxide reductase

INTRODUCTION Patients in critical care settings are highly susceptible to adverse drug reactions (ADRs), mainly because of pharmacokinetic (PK) and pharmacodynamic (PD) changes. Adverse drug reactions are a significant public health concern leading to increased mortality, hospital admissions, length of stay, and health care costs. Inadequate therapeutic response to many commonly used drugs is also a common occurrence because medications are often prescribed using a “trialand-error” approach in the intensive care unit (ICU). The same is true for drug dosing in the critically ill, which largely remains a “one-size-fitsall” approach that is based on studies of healthy volunteers and lesscomplicated patient populations. Genetic variation contributes to interindividual differences in drug disposition, response, and toxicity, and as such, pharmacogenetic testing may reduce ADRs and increase therapeutic effectiveness. This chapter will review the available evidence for pertinent genetic variants that influence the PK, PD, and ADRs of drugs used in ICU patients. Current recommendations for pharmacogenetic testing in clinical practice and an exploration of drug, patient, regulatory, and practical issues that presently limit more widespread implementation of pharmacogenetic testing will also be discussed.

EMERGENCE OF CLINICAL PHARMACOGENOMICS Pharmacogenetics is the study of the relationship between single gene variants (i.e., polymorphisms) and variability in drug disposition, response, and toxicity.1 Pharmacogenomics represents an expansion of the field and includes the study of variants in a large collection of genes, up to the whole genome.1 A summary of common genetic terms is provided in Box 51.1. Pharmacogenetics and pharmacogenomics are both subsets of personalized (precision) medicine, with the goal of identifying patients who should not receive certain drugs or who should receive modified drug dosing because of inherited genetic variants. Interest in pharmacogenomics, as evidenced by the many publications in the field, has increased in the past 20 years. This growing body of literature provides many examples of significant alterations in drug metabolism, drug transport, and drug-gene interactions caused by variants in the respective genes.3 Despite a common belief that the field represents a future innovation, pharmacogenetics has been detailed in the medical literature since the early 1950s. Historically, pharmacogenetic studies examined the association between single gene variants, PK parameters (e.g., excessive exposure), and ADRs. From a research perspective, most pharmacogenetic investigations have used a candidate gene approach whereby prespecified genetic variants and their association with a phenotypic trait of interest were evaluated. One notable feature of this approach is the need for prior knowledge of the most likely mechanisms underlying drug disposition, response, or toxicity. However, completion of the Human Genome Project in 2003 set the stage for a more exploratory or agnostic approach to uncover the genetic underpinnings of drug response. In this respect, genomewide association studies (GWAS) are now used to interrogate variants that represent a large portion of variation across the human genome and to evaluate the association between these variants and variability in drug disposition, response, and toxicity. In contrast to the candidate gene approach, GWAS require no prior knowledge of drug action in the body. Landmark human genome sequencing and haplotype mapping efforts (e.g., the HapMap and 1000 Genomes projects) have further

informed pharmacogenomic research endeavors. Along these lines, genomic technologies have evolved at a rapid pace. For example, nextgeneration sequencing technologies, whereby millions of DNA strands are sequenced in parallel, have resulted in substantially higher throughput than older sequencing methods. This has led to an interrogation of all nucleotide bases in the genome (i.e., whole-genome sequencing) and all nucleotide bases in the protein-coding regions of the genome (i.e., whole-exome sequencing). It is anticipated that whole-genome and whole-exome sequencing will foster the expansion of pharmacogenomic research and application by aiding in the discovery of rare and novel variants that are not captured by GWAS. From a clinical perspective, the increasing affordability and availability of DNA microarrays provides a cost-effective mechanism for assessing thousands of variants simultaneously. This has ushered in the era of preemptive (“just in case”) genetic testing whereby DNA microarrays are used to test many variants in relevant pharmacogenes, and this information is stored electronically for future use. However, although many pharmacogenomic associations have been discovered during the past decade, only a few examples are actively being implemented in the clinical setting. Several factors influence the application of pharmacogenetic testing in clinical practice, including analytic validity (the ability of a genetic test to accurately and reliably measure the genotype of interest), clinical validity (the accuracy with which a genetic test can predict the presence or absence of the phenotype of interest), and clinical utility (the likelihood that the genetic test will lead to an improved outcome) (www.cdc.gov/genomics/gtesting/ACCE/). With respect to clinical utility, the Clinical Pharmacogenetics Implementation Consortium (CPIC) was formed as a shared project between the NIH (National Institutes of Health)-sponsored Pharmacogenomics Research Network and the Pharmacogenomics Knowledgebase, with a goal of developing peer-reviewed guidelines for certain drug-gene pairs to help clinicians understand how available genetic test results should be used to optimize drug therapy.4 The CPIC guideline development process uses systematic evidence review to rate the strength of recommendations

and primarily assumes that clinical genotyping results are already available.5 In addition to CPIC, the Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association has developed clinical practice guidelines that are based on systematic evidence reviews.6 Ultimately, critical care clinicians should include pharmacogenetic information in the therapeutic decision-making process with specific attention given to the strength of the available evidence, using available guidelines as a supportive framework. In the next sections, we will discuss key examples of genetic variants that influence the PK and/or PD of agents used in the ICU, together with factors that influence their clinical application (e.g., availability of evidence-based guidelines).

IMPACT ON PK CYP2D6 Polymorphisms Cytochrome P450 2D6 (CYP2D6) plays an important role in the metabolism and bioactivation of about one of every four drugs in clinical use, including many antidepressants (e.g., paroxetine, fluvoxamine, amitriptyline), antipsychotics (e.g., haloperidol, risperidone, clozapine), and opioids (e.g., codeine, tramadol).7-9 The CYP2D6 gene is highly polymorphic, with 120 allelic variants currently indexed by the CYP Allele Nomenclature Committee (The Human Cytochrome P450 [CYP] Allele Nomenclature Database; www.cypalleles.ki.se/). Variant CYP2D6 alleles include gene deletions, single nucleotide polymorphisms (SNPs), and copy number variations (e.g., gene duplications), among others. These polymorphic alleles translate into differences in CYP2D6 metabolizing enzyme activity and are broadly characterized as functional (normal or increased enzyme activity), reduced-function (decreased enzyme activity), or nonfunctional (inactive or no enzyme) alleles.10 According to the type and number of CYP2D6 alleles, individuals are assigned a CYP2D6 phenotype classification (i.e., extensive metabolizer [EM], intermediate metabolizer [IM], poor metabolizer [PM], or ultrarapid metabolizer [UM]). Individuals with the

CYP2D6 EM (i.e., “normal”) phenotype carry two functional alleles, two reduced-function alleles, one functional allele and one nonfunctional allele, or one functional allele and one reduced-function allele.10 Intermediate metabolizers carry one reduced-function allele and one nonfunctional allele.10 Poor metabolizers carry two nonfunctional alleles.9 Ultrarapid metabolizers carry several copies of a functional allele (e.g., as many as 13).10 CYP2D6 phenotypes vary by race and ethnicity. For example, the CYP2D6 PM phenotype is found in 5%– 10% of whites, 0%–19% of blacks, and less than 1% of Asians.11 Although genotype analysis has become the method of choice to predict a person’s CYP2D6 metabolic activity status, substantial differences exist in the number of genetic variants assayed as well as in the manner in which genetic tests are interpreted. The current process for translating CYP2D6 genotype results to phenotype assignments is not universal; however, in this section, the traditional phenotype terminology (i.e., EM, IM, PM, and UM) is used.12 For many CYP2D6 substrates, variation in CYP2D6 metabolizing enzyme activity is the primary factor contributing to interindividual variability in drug response. Determining an individual’s CYP2D6 metabolic activity status can help in the selection of individuals who require an alternative drug or dosage regimen. Patients with reducedfunction or nonfunctional CYP2D6 enzyme (e.g., IMs or PMs) attain high parent drug concentrations with standard medication dosing and have less metabolite formation. Depending on which pharmacologic moiety is active, the outcome may be exaggerated efficacy/increased toxicity associated with the parent drug, or therapeutic failure (if it is a prodrug that must be converted to an active metabolite). In UMs, the converse can be expected (i.e., therapeutic failure if an active parent drug or exaggerated efficacy/increased toxicity if a prodrug).13 Even though CYP2D6 potentially influences response or toxicity to many drugs, clinical acceptance of CYP2D6 genotyping in routine practice is currently rare outside of academic or specialty medical centers.14 Furthermore, evidence to support specific clinical applications for ICU patients is even less developed. However, the Pharmacogenomics Knowledgebase (www.pharmgkb.org) currently

lists 34 different CPIC guidelines to help manage drug-gene interactions for CYP2D6 (Table 51.1). In addition, a summary of commonly used drugs in the critical care setting with pharmacogentic associations is provided in Table 51.2.

Box 51.1. Glossary of Genomics Terms1,2 Allele: One of two or more alternative forms of a gene that arise by inheritance and that are found at the same location on a chromosome. For most autosomal genes, an individual will have two alleles, one inherited from the mother and one inherited from the father. Autosomal trait: A trait caused by a chromosome that is not a sex chromosome. Candidate gene study: An evaluation of prespecified genetic variants and their association(s) with a phenotypic trait or disease. This approach requires prior knowledge of the likely mechanisms underlying drug disposition, response, or toxicity. Diplotype: A pair of haplotypes, with one haplotype inherited from the mother and one haplotype inherited from the father. DNA microarray: Solid support on which thousands of DNA sequences from different genes are attached. This technology is used to genotype many (e.g., thousands) variants at one time. DNA microarrays that are specifically designed to interrogate single nucleotide polymorphisms (SNPs) are known as SNP arrays. Genetic variant: A difference in DNA sequence compared with a reference sequence. Genome: Complete set of genetic material for an organism. Genome-wide association study: An evaluation of variants that

represent a large portion of variation across the human genome and their associations with a phenotypic trait or disease. This approach does not require prior knowledge of the mechanisms underlying drug disposition, response, or toxicity. Genotype: Broadly defined, the genetic makeup of an organism with reference to a single trait or set of traits. This term is also used to describe the combination of alleles an individual inherits at a specific region of DNA. Genotyping: Laboratory testing that reveals the specific alleles inherited by an individual at a particular region of DNA. Haplotype: Set of closely linked alleles that are located on one chromosome and inherited together as a unit or “block.” Homozygous: The same alleles at a specific region of DNA. Heterozygous: Different alleles at a specific region of DNA. Linkage disequilibrium: Nonrandom association of alleles at different loci on the same chromosome. Mutation: A genetic variant that is rare, often defined as occurring in less than 1% of the population. Mutations are often associated with genetic diseases, such as cystic fibrosis or sickle cell anemia. Pharmacogenetics: Study of the relationship between single gene variants and variability in drug disposition, response, and toxicity. Pharmacogenomics: Study of the relationship between variants in a large collection of genes, up to the whole genome, and variability in drug disposition, response, and toxicity. Phenotype: The set of measurable characteristics of an individual caused by genotype, environment, or a combination of both. Polymorphism: A genetic variant that is common, often defined as occurring in 1% or more of the population.

Single nucleotide polymorphism (SNP): Difference in one nucleotide (base pair) in a DNA sequence. SNPs are the most common type of polymorphism in the genome. Wild type: A characteristic that refers to the typical form of a trait as it occurs in nature. Also called the most common allele in a population.

Although no CPIC guideline currently exists, a gene-drug interaction of particular interest to critical care clinicians is CYP2D6 and haloperidol, given the common use of this drug to treat delirium. Haloperidol clearance has been directly correlated with the number of functional CYP2D6 genes in psychiatric patients. In general, studies have found that CYP2D6 PMs receiving haloperidol have a greater incidence of ADRs, including pseudoparkinsonism (increased sum of extrapyramidal symptom scores; p=0.02), a prolonged elimination halflife (19.1 ± 3.6 vs. 12.9 ± 4.0 hours, p=0.04), and a lower apparent oral clearance (12.8 ± 4.1 vs. 27.0 ± 11.3 mL/minute/kg, p=0.02), than do EMs.15,16 However, additional factors (i.e., smoking status and body weight) also contribute to the observed ADRs.16 Although haloperidol is a useful example, the prescribing of risperidone for psychosis and other behavioral disorders is increasingly common. In studies involving risperidone, the CYP2D6 PM phenotype was associated with a moderate-to-marked increase in drug discontinuation attributable to ADRs (namely pseudoparkinsonism).28,29 Pharmacokinetic analyses support these observations, with evidence that PMs have a 63% decrease in the metabolism and fraction of the active metabolite.30 Studies exploring the impact of CYP2D6 polymorphisms on variability in toxicity or response to cardiovascular drugs (i.e., βblockers) also suggest a need for individualized therapy. One large population-based study reported that CYP2D6 PMs receiving βblockers metabolized by CYP2D6 (e.g., metoprolol, carvedilol, nebivolol, propranolol, and alprenolol) had a significantly lower heart

rate and diastolic blood pressure than EMs,31 which was not reproduced in patients receiving β-blockers not metabolized by CYP2D6 (e.g., atenolol). Understanding opioid metabolism and disposition is essential for assessing the risk of toxicity and, in some cases, for providing additional information regarding the risk of therapeutic failure. Opioids significantly metabolized by the CYP enzyme system may be subject to drug-gene interactions. Codeine provides a good example of the potential clinical utility of CYP2D6 genotyping.14 Codeine, a prodrug, is metabolized by CYP2D6 to form morphine. CYP2D6 PMs do not effectively convert codeine to morphine, resulting in decreased analgesic effects compared with EMs.9 Conversely, CYP2D6 UMs have increased conversion of codeine to morphine compared with EMs, as well as an increased risk of morphine toxicity and a clinically significant risk of severe morbidity and mortality.32

Table 51.1 Available Evidence-Based Dosing Guidelines for Drugs According to CYP2D6 and CYP2C19 Genotypes Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines

Dutch Pharmacogenetics Working Group (DPWG) Guidelines

Amitriptyline and CYP2C19, CYP2D6

Amitriptyline and CYP2D6

Clomipramine and CYP2C19, CYP2D6

Aripiprazole and CYP2D6

Codeine and CYP2D6

Atomoxetine and CYP2D6

Desipramine and CYP2D6

Carvedilol and CYP2D6

Doxepin and CYP2C19, CYP2D6

Clomipramine and CYP2D6

Imipramine and CYP2C19, CYP2D6

Clozapine and CYP2D6

Nortriptyline and CYP2D6

Codeine and CYP2D6

Trimipramine and CYP2C19, CYP2D6

Doxepin and CYP2D6 Duloxetine and CYP2D6 Flecainide and CYP2D6 Flupenthixol and CYP2D6

Haloperidol and CYP2D6 Imipramine and CYP2D6 Metoprolol and CYP2D6 Mirtazapine and CYP2D6 Nortriptyline and CYP2D6 Olanzapine and CYP2D6 Oxycodone and CYP2D6 Paroxetine and CYP2D6 Propafenone and CYP2D6 Risperidone and CYP2D6 Tamoxifen and CYP2D6 Tramadol and CYP2D6 Venlafaxine and CYP2D6 Zuclopenthixol and CYP2D6

From: the Pharmacogenomics Knowledge Base. https://www.pharmgkb.org/gene/PA128. Accessed March 2, 2015.

Available

Table 51.2 Commonly Used Drugs in Critical Care Settings with Pharmacogenetic Associations Drug or Drug Class

Gene

Therapeutic Recommendations

Haloperidol

CYP2D6

PMs: Reduce dose by 50% or select alternative drug (e.g., pimozide, flupenthixol, fluphenazine, quetiapine, olanzapine, clozapine)16

Proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, rabeprazole)

CYP2C19

UMs: Helicobacter pylori eradication: Increase dose by 100%–200%. Be alert to insufficient response.

Antifungals (voriconazole)

CYP2C19

PMs and IMs: Monitor serum concentrations to minimize toxicity (i.e., QTc prolongation)20

at

UMs: Monitor serum concentrations to ensure effectiveness (especially for invasive fungal infections in immunocompromised patients)21,22 Opioids (codeine, tramadol, oxycodone)

CYP2D6

PMs and IMs: Analgesia: Select alternative drug (e.g., acetaminophen, NSAID, morphine—not tramadol or oxycodone), or be alert to symptoms of insufficient pain relief9,14,23 UMs: Analgesia: Select alternative drug (e.g., acetaminophen, NSAID, morphine—not tramadol or oxycodone), or be alert to ADRs. Cough: Be extra alert to ADRs caused by increased morphine plasma concentrations 9,14,23-27

IM = intermediate metabolizer; PM = poor metabolizer; QTc = corrected QT interval; UM = ultrarapid metabolizer. From: the Pharmacogenomics Knowledge Base. https://www.pharmgkb.org/gene/PA128. Accessed 2015 March 2, 2015.

Available

at

Patient response to tramadol, an alternative opioid agent commonly used for pain management, is also affected by CYP2D6 genotype, with CYP2D6 PMs at risk of insufficient analgesia and UMs at risk of serious ADRs (e.g., respiratory depression).6,33 The extent to which other opioids (e.g., hydrocodone, oxycodone) are affected by CYP2D6 variation is under investigation. Preliminary evidence suggests that CYP2D6 PMs have lower peak concentrations of hydromorphone after a dose of hydrocodone; however, CYP2D6 metabolizer status does not appear to affect response to hydrocodone therapy. Similarly, CYP2D6 PMs have lower peak concentrations of oxymorphone after a dose of oxycodone than do EMs.34 However, discordant findings from prospective clinical studies currently suggest limited clinical utility of CYP2D6 genotyping for oxycodone therapy. In general, the CPIC guidelines recommend that opioids not metabolized by CYP2D6, including morphine, oxymorphone, buprenorphine, fentanyl, methadone,

and hydromorphone, together with nonopioid analgesics, be considered as alternatives for use in CYP2D6 PMs and UMs according to the type, severity, and chronicity of the pain being treated.9 Antiemetic therapy—particularly with ondansetron—is the last example for clinical utility of the CYP2D6 genotype in critically ill patients. Patients having CYP2D6 EM, IM, or PM phenotypes are more likely to have an increased response to ondansetron than are patients having CYP2D6 UM phenotypes. This increased response leads to a reduced risk of vomiting after chemotherapy or anesthesia. However, no significant associations have been found for nausea.35,36

CYP2C9 Polymorphisms Cytochrome P450 2C9 is another drug-metabolizing enzyme involved in the phase I metabolism of about 10% of drugs, including oral anticoagulants (e.g., warfarin), antiepileptics (e.g., phenytoin), oral antidiabetics (e.g., glyburide), NSAIDs (nonsteroidal anti-inflammatory drugs) (e.g., celecoxib), and anti-infectives (e.g., sulfamethoxazole).3739

Several variants have been identified in the CYP2C9 gene that influence CYP2C9 metabolizing enzyme function. CYP2C9*1 is the normal-activity allele, and CYP2C9*2 and CYP2C9*3 are the most commonly studied decreased-function alleles. CYP2C9*2 is present in about 13%, 0%, and 3% of whites, Asians, and blacks, respectively. CYP2C9*3 is present in about 7%, 4%, and 2% of whites, Asians, and blacks, respectively.39 An individual carrying two normal-activity alleles (i.e., *1/*1) is assigned the EM phenotype. An individual carrying one normal-activity allele and one decreased-function allele (i.e., *1/*2 or *1/*3) is assigned the IM phenotype. An individual carrying two decreased-function alleles (i.e., *2/*2, *2/*3, or *3/*3) is assigned the PM phenotype.39 To date, warfarin has been heavily studied with respect to CYP2C9 genetics because of its frequent use and narrow therapeutic index. The FDA’s Adverse Event Reporting System affirms that ADRs attributable to warfarin are common; in fact, warfarin is among the top 10 most

commonly reported drugs during the past 20 years.40 CYP2C9 genotype accounts for 9%–12% of the observed variance in warfarin maintenance dose requirements.41 In general, individuals carrying CYP2C9*2 or *3 alleles have lower warfarin dose requirements and a longer time to achieve a therapeutic international normalized ratio (INR) than do EMs.42 A recent retrospective study found that patients carrying variant CYP2C9 alleles (e.g., *2, *3) had a significantly increased risk of serious or life-threatening bleeding events after warfarin therapy.43 However, a prospective study revealed conflicting data showing no association between variant CYP2C9 alleles and the risk of warfarin-associated bleeding.44 Depending on the approach to initiating anticoagulation in clinical practice, CYP2C9 genotype is a factor to consider for warfarin, in addition to VKORC1 (drug target) genotype, drug-drug interactions, drug-disease interactions, and drugdiet interactions. The practicalities and controversies of warfarin genotyping in clinical practice are discussed in more detail in the VKORC1 section. A CYP2C9 drug-gene interaction also exists for phenytoin, one of the most commonly used antiepileptics in the ICU. Phenytoin clearance through CYP2C9-mediated hydroxylation is a primary mechanism, although at high concentrations, CYP2C19 is also involved. Many studies have reported higher phenytoin plasma concentrations and lower phenytoin dose requirements in CYP2C9 variant allele carriers (i.e., IMs or PMs) than in EMs. In this respect, CYP2C9 genotype– guided dose adjustments have been recommended for phenytoin therapy (e.g., 25% dose reduction for IMs and 50% dose reduction for PMs).39 Despite this information, data supporting the link between altered phenytoin plasma concentrations and ADRs are lacking, presumably because of the nonlinear, saturable PK, and auto-inductive effects of this drug.

CYP2C19 Polymorphisms Cytochrome P450 2C19 is responsible for the metabolism of antiplatelet agents (e.g., clopidogrel), proton pump inhibitors (e.g.,

lansoprazole, omeprazole), antidepressants (e.g., amitriptyline, citalopram, sertraline), and antifungal agents (e.g., voriconazole).45 The CYP2C19 gene is highly polymorphic, with SNPs that result in decreased or increased CYP2C19 metabolizing enzyme activity. CYP2C19*1 is the normal-activity allele, CYP2C19*2 and CYP2C19*3 are loss-of-function (i.e., decreased or no function) alleles, and CYP2C19*17 is an increased-function allele. An individual with two normal-function alleles (i.e., *1/*1) is assigned the EM phenotype. An individual with one normal-function allele and one loss-of-function allele (e.g., *1/*2 or *1/*3) is assigned the IM phenotype. An individual with two loss-of-function alleles (e.g., *2/*2 or *3/*3) is assigned the PM phenotype. An individual carrying two increased-function alleles (e.g., *17/*17) or one normal-function allele and one increased-function allele (e.g., *1/*17) is assigned the UM phenotype.8,46 The frequency of the CYP2C19 PM phenotype is 2%–5% in whites, 2%–5% in African Americans, and 15% in Asians.47 The frequency of the CYP2C19*17 allele is about 22% in whites, 19% in African Americans, and 17% in Asians (South/Central).8 The impact of the CYP2C19 genotype on clinical outcomes associated with clopidogrel anti-platelet therapy has received much attention in patients with acute coronary syndromes. Clopidogrel undergoes a two-step bioactivation process to form an active thiol metabolite. The CYP2C19 enzyme is important in each step of this process. Clopidogrel response varies widely in the general population, and many studies have shown that CYP2C19*2 carriers (e.g., *1/*2 or *2/*2 genotypes) have lower concentrations of the clopidogrel active metabolite and higher on-treatment platelet aggregation than non-carriers.46,48 In addition, several studies link CYP2C19 PM and IM status to an increased risk of major adverse cardiovascular events in clopidogrel-treated patients with acute coronary syndromes, likely because of reduced formation of the active clopidogrel metabolite.46,49-52 Although the primary concern in this respect is loss of efficacy, CYP2C19 UMs may be at higher risk of ADRs (e.g., hemorrhage), likely because of increased formation of the active clopidogrel metabolite.53,54 The primary takeaway is that variability in response to clopidogrel treatment associated with an

increased risk of death or thrombotic recurrences is present in 5%– 40% of patients treated with conventional doses of clopidogrel, with a multifactorial etiology that includes genetic polymorphisms and nongenetic factors (e.g., comorbidities, drug-drug interactions, age).55 Another relevant example of the application of CYP2C19 pharmacogenetics to critical care is in the use of proton pump inhibitors. The CYP2C19 genotype is responsible for 80% of the metabolism of omeprazole, lansoprazole, and pantoprazole.17,56,57 Clinical data show that CYP2C19 PMs have 4- to 15-fold higher plasma concentrations of omeprazole and lansoprazole, and superior acid suppression, relative to EMs.17 Having CYP2C19 IM or PM status may lead to enhanced proton pump inhibitor–mediated Helicobacter pylori eradication and ulcer healing; however, a consistent demonstration of improved outcomes relative to the CYP2C19 phenotype remains elusive. Future research endeavors are needed to firmly establish the clinical utility of CYP2C19 genotyping for the proton pump inhibitors; however, when preemptive testing is available, clinicians may consider relevant drug-gene interactions for individual patient management. Voriconazole is a narrow therapeutic index antifungal agent with nonlinear PK whose plasma exposure is influenced, in part, by CYP2C19 metabolizer status.21 For example, in healthy volunteers, CYP2C19 PMs had 4-fold higher voriconazole exposure than EMs.58 Although CPIC has not yet developed guidelines for this drug, the Dutch Pharmacogenetics Working Group guidelines recommend the monitoring of voriconazole serum concentrations in CYP2C19 IMs and PMs. This will help minimize the risk of concentration-dependent ADRs. In addition, knowledge of CYP2C19 UM status may help prevent therapeutic failure caused by inadequate drug concentrations.21 Given the high costs associated with hospitalization for treatment-resistant invasive fungal infections, health systems are increasingly considering CYP2C19 genotyping and therapeutic drug monitoring for voriconazole therapy to prevent avoidable health care use.20,22

CYP3A Polymorphisms

Tacrolimus is a calcineurin inhibitor immunosuppressant commonly used in solid organ and hematopoietic stem cell transplantation. Tacrolimus has a narrow therapeutic range and large interpatient variability in the dose required to achieve therapeutic trough concentrations.59 Low tacrolimus exposure may increase the risk of graft rejection, whereas high tacrolimus exposure may increase the risk of ADRs (e.g., nephrotoxicity, neurotoxicity, hyperglycemia).60 Tacrolimus is predominantly metabolized by CYP3A5 and, to a lesser extent, by CYP3A4. The CYP3A5 gene contains several variants, *3, *6, and *7, which result in loss of protein expression or nonfunctional protein.61 Individuals carrying two copies of the CYP3A5*1 allele (CYP3A5 *1/*1) are assigned the expresser (EM) phenotype. An individual carrying one functional allele and one nonfunctional allele (i.e., *1/*3, *1/*6, or *1/*7) is assigned the expresser (IM) pheno-type. An individual carrying two nonfunctional alleles (e.g., *3/*3, *6/*6) is assigned the non-expresser (PM) pheno-type.59 Substantial differences in CYP3A5 variant allele frequencies exist on the basis of race. For example, CYP3A5*3 is present in 92% of whites, 32% of African Americans, and 74% of Asians.59 Therapeutic drug monitoring is routinely used to manage tacrolimus blood concentrations in clinical practice, but therapeutic drug monitoring does not identify the optimal starting dose of tacrolimus for an individual patient. Several studies, in various transplant populations, have shown that CYP3A5 expressers have lower dose-adjusted tacrolimus trough concentrations than do CYP3A5 nonexpressers.59 In this respect, a prospective study of kidney transplant recipients showed that CYP3A5 genotype–guided tacrolimus dosing resulted in a significantly higher percentage of patients with tacrolimus in the target range 3 days after initiating therapy compared with the control arm (43.2% vs. 29.1%, respectively).62 This study did not show a significant difference in clinical outcomes (e.g., acute rejection) between genotype-guided and standard tacrolimus dosing. However, a recent meta-analysis of kidney transplant recipients showed a modestly increased risk of acute rejection in CYP3A5 expressers (odds ratio 1.32, p=0.04).63 According to the CPIC guidelines, no definitive

evidence exists to indicate that CYP3A5 genotype–guided tacrolimus dosing improves long-term clinical outcomes. However, the clinical utility of CYP3A5 genotyping appears to be in the ability to more effectively achieve target trough tacrolimus concentrations, particularly at the initiation of therapy.59 In this respect, CPIC guidelines recommend that CYP3A5 expressers (EMs or IMs) receive 1.5–2 times the recommended tacrolimus starting dose, not to exceed 0.3 mg/kg/day. In contrast, it is recommended that CYP3A5 nonexpressers (PMs) start therapy with standard recommended doses. In both cases, therapeutic drug monitoring should be used to guide dose adjustments. These recommendations apply to the use of tacrolimus in patients with kidney, heart, lung, and hematopoietic stem cell transplants and in patients with liver transplants when the donor and recipient genotypes are identical. In sum, CYP3A5 genotyping may be most helpful to guide initial tacrolimus dosing in the hopes of more rapidly achieving target trough concentrations.59 Genetic testing does not preclude the need for therapeutic drug monitoring or the need to consider other patient-specific factors that may influence tacrolimus therapy (e.g., age, drug-drug interactions).

N-Acetyltransferase 2 N-acetyltransferase 2 is a phase II drug-metabolizing enzyme that acetylates several agents, including isoniazid, hydralazine, procainamide, phenelzine, dapsone, and sulfonamides. Observations that some patients receiving isoniazid were more prone to peripheral neuropathy led to identification of the slow acetylator phenotype. Across the general population, phenotype frequencies vary among different ethnic populations (e.g., about 50% of whites are slow acetylators, whereas the frequency is much lower in Asians). For critically ill patients, slow acetylators have an increased risk of immunemediated toxicity (systemic lupus erythematosus) with specific agents used in the ICU (i.e., hydralazine, procainamide, and sulfamethoxazole). In addition, fast acetylators may carry a higher risk of preventable ADRs. For example, procainamide, which is bio-

activated in vivo to a pharmacologically active class III antiarrhythmic metabolite, N-acetylprocainamide, increases the risk of torsades de pointes—especially in renally compromised patients. Because procainamide is still used in specific clinical scenarios (e.g., rate control for patients with Wolff-Parkinson-White syndrome and atrial fibrillation), N-acetyltransferase 2 phenotype remains important to evaluate as a clinical consideration.64,65

SLCO1B1 Genotype Statins are widely used lipid-lowering agents with a proven record for reducing cardiovascular morbidity and mortality. Statins are associated with myalgias, myopathy, and, rarely, rhabdomyolysis. Mechanisms leading to increased risk of statin-induced myopathy have been incompletely characterized and are likely multifactorial—including comorbidities, presence of significant drug-drug interactions, and genetic variation. Several clinical factors are associated with statininduced myopathy, including advanced age, slight body mass index, female sex, metabolic comorbidities, drug-drug interactions, hypothyroidism, and Asian ancestry.66 Statin dose remains perhaps the strongest predictor of statininduced myopathy, with a reported incidence that is almost 10-fold higher in patients on high-dose statin therapy. Although this dosedependent relationship appears to be a class effect for statins, evidence suggests that this effect is most clinically significant with respect to simvastatin.67 Of importance, statins are substrates of the organic anion transporting polypeptide 1B1 (OATP1B1), an up-take transporter located on the basolateral surface of hepatocytes. Variation in SLCO1B1, the gene that encodes OATP1B1, produces a defective transport protein, which increases systemic exposure and toxicity.68-70 A GWAS identified a significant association between the functional SLCO1B1 c.521T>C SNP and simvastatin-induced myopathy, showing a 4.5-fold increased risk in heterozygotes and a 16.9-fold increased risk in variant homozygotes.71 The c.521 T>C SNP is contained in the

SLCO1B1*5 haplotype, which is carried in about 1%–3% of whites, up to 2% of Africans, and up to 1% of Asians, and also in the SLCO1B1*15 haplotype, which is carried in about 14% of whites, 3% of Africans, and up to 13% of Asians.67,72 CPIC guidelines exist for simvastatin dosing in relation to SLCO1B1 c.521 T>C genotype.72 Specifically, individuals with SLCO1B1 c.521 T/T (normal function) genotype have a normal simvastatin-induced myopathy risk and may be prescribed the desired starting dose, with doses adjusted on the basis of disease-specific guidelines. Individuals with the SLCO1B1 c.521 T/C (intermediate function) genotype have an intermediate simvastatininduced myopathy risk. CPIC guidelines recommend a lower simvastatin dose or consideration of an alternative statin (e.g., pravastatin or rosuvastatin). Finally, individuals with the SLCO1B1 c.521 C/C (low function) genotype have a high simvastatin-induced myopathy risk. It is recommended that these patients be prescribed a lower dose or that an alternative statin be considered (e.g., pravastatin or rosuvastatin). In each case presented, the FDA recommends against simvastatin 80 mg/day unless the dose has already been tolerated for 12 months.72

IMPACT ON PD VKORC1 Polymorphisms The vitamin K epoxide reductase (VKOR) enzyme catalyzes the recycling of reduced vitamin K, which is essential for the formation of clotting factors II (prothrombin), VII, IX, and X. Warfarin inhibits this enzyme, thereby producing anticoagulant effects. Many common SNPs exist in VKORC1, the gene encoding VKOR. The g.-1639G>A SNP is contained in a haplotype associated with reduced VKOR expression. Individuals with this SNP are more sensitive to warfarin, as evidenced by decreased therapeutic dose requirements (28% smaller per allele carried). In addition to CYP2C9 polymorphisms, VKORC1 genotype is an important consideration for predicting warfarin dose requirements and accounts for 25%–30% of observed dose variance in white

populations. In addition, combining VKORC1 and CYP2C9 genotypes explains up to 59% of the variability in warfarin dose requirements. Two GWAS analyzing hundreds of thousands of SNPs across the human genome further confirmed that VKORC1 and CYP2C9 provide the greatest contributions to warfarin dose variability in whites. Although variation in both genes has been associated with excessive anticoagulation, VKORC1 variants, unlike CYP2C9, have not been associated with an increased risk of hemorrhage.73-76 Two recent randomized trials evaluating the clinical impact of genotype-guided warfarin dosing are the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial and the Clarification of Optimal Anticoagulation Through Genetics (COAG) trial. Both trials examined the effects of genotype-guided warfarin dosing compared with empiric dosing strategies; however, only the EU-PACT study showed an overall improvement in time to achieve therapeutic INR, which was shorter in the genotyping arm (21 vs. 29 days; pA has been among the most thoroughly studied in this context. Mira et al. reported that the g.-308A allele (also known as TNF2) was more common in patients with sepsis and was associated with a significantly increased risk of mortality compared with case-matched controls.93 Similarly, O’Keefe et al. reported that the presence of TNF2 was associated with an increased risk of the development of sepsis, but not mortality, after severe injury in a cohort of patients.94 In contrast, Tang et al. reported that TNF2 occurred with no greater frequency in patients with sepsis than in patients without sepsis. However, for the subset of patients who developed shock, this genetic variant was associated with an increased rate of mortality.95 Inconsistent findings in studies examining the clinical significance of the TNFA g.-308G>A SNP in patients with sepsis or those at risk of this disease are representative of problems with geneassociation studies in general. Systematic analyses of studies trying to link genetic variants to complex traits have shown that the significant results reported in the initial studies are often not replicated in subsequent experiments. Linkage-disequilibrium studies can be confounded because the effects of variants in a locus of interest (for example, the TNFA g.-308 SNP) may be influenced by the effects of adjacent variants (e.g., those present elsewhere in the TNFA gene), genetic variants present in independently segregating loci (e.g., those encoding other inflammatory mediators), and nongenetic factors. For the critically ill individual, these nongenetic factors include the nature and location of the inciting infection, the manner in which supportive

care is provided, and the age and premorbid health status of the patient. In addition, populations studied in many trials are heterogeneous. In the reports cited, populations differed substantially with respect to geography as well as in their underlying clinical condition. The challenge for critical care investigators will be to design gene-association studies that are both appropriately controlled and of sufficient power so that the genetic determinants of disease susceptibility and drug effect can be measured accurately.96-98

INCORPORATING PHARMACOGENOMICS INTO PATIENT CARE Despite the many established associations between genetic variants and drug response, pharmacogenomic testing and genotype- or phenotype-based prescribing have not been widely implemented in clinical practice. Drug, patient, research design, regulatory, and practical issues currently limit the integration of pharmacogenomics into the clinical setting, including the ICU. Regarding drug factors, knowledge that an enzyme is involved in the metabolism of a drug and that a genetic variant exists is not sufficient to recommend genetic testing. The functional consequences of the variant, the quantitative role of the gene product to the drug’s overall PK and PD, and the agent’s therapeutic index must be considered. Clopidogrel, for example, is metabolized by several CYP enzymes, yet only CYP2C19 variants are important for the increased risk of major adverse cardiovascular events. Few examples currently exist in which a drugADR relationship can be predicted by variation at a single gene locus (e.g., abacavir and HLA-B*57:01). In contrast, most drug response and toxicity examples (e.g., torsades de pointes or warfarin doseresponse) are polygenic. Drugs may also have a wide therapeutic index or a toxicity that is mild or easy to detect, suggesting that genotyping is not necessary, such as with CYP2D6 polymorphisms and β-blockers. Drugs that are pharmacologically active themselves and that have active metabolites, such as some tricyclic antidepressants, also complicate efforts to associate genetic variants with ADRs. Many

patient issues facing the critically ill are known to produce wide variability in drug response and ADR risk. In addition to considering genetic variation, multidisciplinary critical care teams must evaluate the impact of impaired organ function, comorbidities, polypharmacy, drug interactions, and many other factors when providing pharmacotherapy. The paucity of pharmacogenomic research involving critically ill patients undermines an appreciation of the potential role that genetics play in this population. Of the 107 pharmacogenomic studies currently listed as seeking volunteers in an online repository of human clinical studies being conducted globally, most involve oncology drugs.99 Only one study specifically mentions recruiting in the ICU, and 14 studies involve drugs with relevance to critically ill patients.100 Future investigations must determine the relative contribution of genetics to overall drug response and ADR risk in the critically ill in order to advance pharmacogenomics in the ICU setting. Practical issues also hamper the widespread clinical adoption of genotyping. Medical education has not kept up with the rapid pace of pharmacogenomics. Citing this, recommendations for bolstering training in medical, pharmacy, and nursing schools globally have been advanced.101 An urgent need also exists for reliable bedside genetic testing because the turnaround time for tests that must be sent to accredited laboratories is not ideal. For example, according to the manufacturer, AmpliChip102 results can be generated in 8 hours, with the printed report received within several days. This time interval is problematic when appropriate drug dosing is needed immediately, such as with clopidogrel after myocardial infarction. It is less of an issue for long half-life drugs used for chronic therapy, such as warfarin, because algorithms have been created for dose modification once genetic information becomes available. Furthermore, alternative therapies with more favorable safety profiles and less monitoring than warfarin exist. As these issues are resolved, it is likely that more data from studies evaluating genetic predisposition to ADRs will be implemented in ICU clinical practice. Critical care practitioners should continue to be aware of new data and advances in the field of pharmacogenomics to appreciate the contribution that genetic variation makes to

interindividual variation in drug disposition, response, and toxicity.

SUMMARY Critically ill patients have an increased risk of ADRs. Although many factors contribute to the variation in patient response to pharmacotherapy, the impact of genetic variation on drug PK and PD is increasingly being appreciated. Clinical pharmacogenomics provides critical care practitioners with additional tools to optimize medication effectiveness and improve safety profiles for the armamentarium of medications used in the critical care setting.

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pravastatin, valsartan, and temocapril. Clin Pharmacol Ther 2006;79:427-39. 70. Niemi M, Schaeffeler E, Lang T, et al. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1). Pharmacogenetics 2004;14:429-40. 71. Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statininduced myopathy—a genomewide study. N Engl J Med 2008;359:789-99. 72. Ramsey LB, Johnson SG, Caudle KE, et al. The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther 2014;96:423-8. 73. Li X, Liu R, Yan H, et al. Effect of CYP2C9-VKORC1 interaction on warfarin stable dosage and its predictive algorithm. J Clin Pharmacol 2014 Sep 4. [Epub ahead of print] 74. Nahar R, Saxena R, Deb R, et al. CYP2C9, VKORC1, CYP4F2, ABCB1 and F5 variants: influence on quality of long-term anticoagulation. Pharmacol Rep 2014;66:243-9. 75. Shaw K, Amstutz U, Hildebrand C, et al. VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children. Pediatr Blood Cancer 2014;61:1055-62. 76. Tatarunas V, Lesauskaite V, Veikutiene A, et al. The effect of CYP2C9, VKORC1 and CYP4F2 polymorphism and of clinical factors on warfarin dosage during initiation and long-term treatment after heart valve surgery. J Thromb Thrombolysis 2014;37:177-85. 77. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 2013;369:2294-303. 78. Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic

versus a clinical algorithm for warfarin dosing. N Engl J Med 2013;369:2283-93. 79. Karlin E, Phillips E. Genotyping for severe drug hypersensitivity. Curr Allergy Asthma Rep 2014;14:418. 80. Chen P, Lin JJ, Lu CS, et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med 2011;364:1126-33. 81. Chung WH, Hung SI, Chen YT. Genetic predisposition of lifethreatening antiepileptic-induced skin reactions. Expert Opin Drug Saf 2010;9:15-21. 82. Chung WH, Hung SI, Chen YT. Human leukocyte antigens and drug hypersensitivity. Curr Opin Allergy Clin Immunol 2007;7:31723. 83. Leckband SG, Kelsoe JR, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLAB genotype and carbamazepine dosing. Clin Pharmacol Ther 2013;94:324-8. 84. Martin MA, Hoffman JM, Freimuth RR, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLAB genotype and abacavir dosing: 2014 update. Clin Pharmacol Ther 2014;95:499-500. 85. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358:568-79. 86. Yang P, Kanki H, Drolet B,, et al. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 2002;105(16):1943-8. 87. Tabata T, Yamaguchi Y, Hata Y, et al. Modification of KCNH2encoded cardiac potassium channels by KCNE1 polymorphism. Circ J 2014;78:2331. 88. Liu L, Hayashi K, Kaneda T, et al. A novel mutation in the transmembrane nonpore region of the KCNH2 gene causes

severe clinical manifestations of long QT syndrome. Heart Rhythm 2013;10:61-7. 89. Warner B. Genetic variation in KCNH2 and a unique hERG isoform in patients with schizophrenia: efficacy-safety link. Am J Psychiatry 2012;169:1318-9. 90. Winkel BG, Larsen MK, Berge KE, et al. The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases. J Cardiovasc Electrophysiol 2012;23:1092-8. 91. Sato A, Chinushi M, Suzuki H, et al. Long QT syndrome with nocturnal cardiac events caused by a KCNH2 missense mutation (G604S). Intern Med 2012;51:1857-60. 92. Galen BT, Sankey C. Sepsis: an update in management. J Hosp Med 2015 July 28. [Epub ahead of print] 93. Mira JP, Charpentier J. [Can genetics guide or modify the management of severe sepsis?]. Ann Fr Anesth Reanim 2003;22 Spec No 1:48-52. 94. O’Keefe GE, Hybki DL, Munford RS. The G-->A single nucleotide polymorphism at the -308 position in the tumor necrosis factoralpha promoter increases the risk for severe sepsis after trauma. J Trauma 2002;52:817-25. 95. Tang BM, Huang SJ, McLean AS. Genome-wide transcription profiling of human sepsis: a systematic review. Crit Care 2010;14:R237. 96. Azevedo ZM, Moore DB, Lima FC, et al. Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) single nucleotide polymorphisms: importance in ARDS in septic pediatric critically ill patients. Hum Immunol 2012;73:661-7. 97. Paskulin DD, Fallavena PR, Paludo FJ, et al. TNF -308G > a promoter polymorphism (rs1800629) and outcome from critical illness. Braz J Infect Dis 2011;15:231-8.

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CONTRIBUTORS Erik Abel, Pharm.D., BCPS The Ohio State University Wexner Medical Center Department of Pharmacy Columbus, Ohio Prasad Abraham, Pharm.D., FCCM, BCPS Grady Health System Department of Pharmacy and Drug Information Atlanta, Georgia Ohoud A. Aljuhani, Pharm.D. University of Arizona Department of Pharmacy Practice Tucson, Arizona Christina L. Aquilante, Pharm.D., FCCP University of Colorado Department of Pharmaceutical Sciences Aurora, Colorado Jeffrey F. Barletta, Pharm.D., FCCM Midwestern University Department of Pharmacy Practice

Glendale, Arizona Seth R. Bauer, Pharm.D., FCCM, BCPS Cleveland Clinic Department of Pharmacy Cleveland, Ohio Laura Baumgartner, Pharm.D., BCPS, BCCCP Touro University Department of Clinical Sciences Vallejo, California Michael L. Bentley, Pharm.D., FCCP, FCCM, FNAP Virginia Tech Carilion School of Medicine, Roanoke, Virginia Director, Global Health Science, The Medical Affairs Company, Kennesaw, Georgia representing Global Health Science Center, The Medicines Company Karen Berger, Pharm.D., BCPS New York Presbyterian Hospital, Weill Cornell Medical Center Department of Pharmacy New York, New York Katherine Bidwell, Pharm.D., BCPS University of Virginia Health System Department of Pharmacy

Charlottesville, Virginia P. Brandon Bookstaver, Pharm.D., FCCP, BCPS (AQ-ID), AAHIVP University of South Carolina Department of Clinical Pharmacy and Outcomes Sciences Columbia, South Carolina Bradley A. Boucher, Pharm.D., FCCP, MCCM, BCPS University of Tennessee Department of Clinical Pharmacy Memphis, Tennessee Gretchen M. Brophy, Pharm.D., FCCP, FCCM, FNCS, BCPS Virginia Commonwealth University Pharmacotherapy and Outcomes Science and Neurosurgery Richmond, Virginia Jeffrey J. Bruno, Pharm.D., BCPS, BCNSP University of Texas MD Anderson Cancer Center Department of Pharmacy Houston, Texas Mitchell S. Buckley, Pharm.D., FCCP, FASHP, FCCM, BCPS Banner—University Medical Center Phoenix Department of Pharmacy Phoenix, Arizona

Todd W. Canada, Pharm.D., FASHP, FTSHP, BCNSP University of Texas MD Anderson Cancer Center Department of Pharmacy Houston, Texas Shanna Cole, Pharm.D. Western Michigan University Homer Stryker, MD School of Medicine Kalamazoo, Michigan Samuel E. Culli, Pharm.D., MPH The Johns Hopkins Hospital Department of Pharmacy Baltimore, Maryland William E. Dager, Pharm.D., FCCP, FCCM, FCSHP, FASHP, MCCM, BCPS-AQ Cardiology University of California Davis Department of Pharmacy Sacramento, California Joseph F. Dasta, M.S., FCCM, MCCM The Ohio State University Division of Pharmacy Practice and Science Columbus, Ohio Ashlee Dauenhauer, Pharm.D.

Banner University Medical Center Tucson, Arizona Caroline B. Derrick, Pharm.D., BCPS University of South Carolina Department of Internal Medicine Columbia, South Carolina John W. Devlin, Pharm.D., FCCP, FCCM Northeastern University Department of Pharmacy and Health System Sciences Boston, Massachusetts Paul P. Dobesh, Pharm.D., FCCP, BCPS-AQ Cardiology University of Nebraska Medical Center Department of Pharmacy Practice Omaha, Nebraska Thomas C. Dowling, Pharm.D., Ph.D., FCCP, FCP Ferris State University College of Pharmacy Grand Rapids, Michigan Amy L. Dzierba, Pharm.D., FCCM, BCPS New York-Presbyterian Hospital Columbia University Medical Center Department of Pharmacy

New York, New York Brian L. Erstad, Pharm.D., FCCP, MCCM, FASHP, BCPS University of Arizona Department of Pharmacy Practice and Science Tucson, Arizona Elizabeth Anne Farrington, Pharm.D., FCCP, FCCM, FPPAG, BCPS New Hanover Regional Medical Center Wilmington, North Carolina David V. Feliciano, M.D., FACS Indiana University Medical Center Department of Surgery Indianapolis, Indiana Douglas N. Fish, PharmD, FCCP, FCCM, BCPS-AQ ID University of Colorado Department of Clinical Pharmacy Aurora, Colorado Jeremy Flynn, Pharm.D., FCCP, FCCM University of Kentucky College of Pharmacy Lexington, Kentucky

David R. Foster, Pharm.D., FCCP Purdue University Department of Pharmacy Practice Indianapolis, Indiana Gilles L. Fraser, Pharm.D., MCCM Maine Medical Center Department of Pharmacy Portland, Maine Robert N. E. French, M.D., MPH University of Arizona College of Medicine/Arizona Poison and Drug Information Center Tucson, Arizona Andrew C. Fritschle Hilliard, Pharm.D., BCPS, BCCCP Eskenazi Health Indianapolis, Indiana David J. Gagnon, Pharm.D., BCCCP Maine Medical Center Department of Pharmacy Portland, Maine Rita Gayed, Pharm.D., BCCCP Grady Health System Department of Pharmacy and Clinical Nutrition Atlanta, Georgia

James F. Gilmore, Pharm.D., BCCCP, BCPS Brigham and Women’s Hospital Department of Pharmacy Services Boston, Massachusetts Katja M Gist, DO, MA, MSCS University of Colorado, Department of Pediatrics Children’s Hospital Colorado Aurora, Colorado Curtis E. Haas, Pharm.D. University of Rochester Medical Center Department of Pharmacy Rochester, New York Martina C. Holder PharmD, BCPS University of Florida Health Shands Department of Pharmacy Gainesville, Florida Nicholas B. Hurst, M.D., M.S. University of Arizona College of Medicine Tucson, Arizona Judith Jacobi, Pharm.D., MCCM, FCCP, DPNAP, BCPS, ACCP President 2014–2015

Indiana University Health Methodist Hospital Indianapolis, Indiana Samuel G. Johnson, Pharm.D., BCPS, FCCP University of Colorado Department of Clinical Pharmacy Aurora, Colorado Thomas J. Johnson, Pharm.D., MBA, FASHP, FCCM, BCPS, BCCCP Avera McKennan Hospital and University Health Center Sioux Falls, South Dakota J. Dedrick Jordan, M.D., Ph.D. University of North Carolina School of Medicine Department of Neurology Chapel Hill, North Carolina Melanie S. Joy, Pharm.D., Ph.D., FCCP, FASN University of Colorado Department of Pharmaceutical Sciences Aurora, Colorado Sandra L. Kane-Gill, Pharm.D., M.Sc., FCCP, FCCM University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania

Salmaan Kanji, Pharm.D. Ottawa Hospital Department of Pharmacy Ottawa, Ontario Stephen R. Karpen, Pharm.D. University of Arizona College of Pharmacy Tucson, Arizona David C. Kaufman, M.D. University of Rochester Medical Center Department of Surgery Rochester, New York Tyree H. Kiser, Pharm.D., FCCP, FCCM, BCPS University of Colorado Department of Clinical Pharmacy Aurora, Colorado Michael Klepser, Pharm.D. Ferris State University College of Pharmacy Kalamazoo, Michigan Marin H. Kollef, M.D. Washington University School of Medicine

Division of Pulmonary and Critical Care Medicine St. Louis, Missouri Nicole L. Kovacic, Pharm.D. Maine Medical Center Department of Pharmacy Portland, Maine Simon W. Lam, Pharm.D., FCCM, BCPS, BCCCP Cleveland Clinic Department of Pharmacy Cleveland, Ohio Ishaq Lat, Pharm.D., FCCP, FCCM, BCPS Rush University Medical Center Department of Pharmacy Chicago, Illinois John J. Lewin III, Pharm.D., MBA, FASHP, FCCM, FNCS The Johns Hopkins Hospital Department of Pharmacy Baltimore, Maryland Robert MacLaren, Pharm.D., MPH, FCCP, FCCM University of Colorado Department of Clinical Pharmacy Aurora, Colorado

Stephanie Mallow Corbett, Pharm.D, FCCM University of Virginia Health System Department of Pharmacy Charlottesville, Virginia Kali Martin, Pharm.D. Ferris State University College of Pharmacy Grand Rapids, Michigan Steven J. Martin, Pharm.D., BCPS, FCCP, FCCM Ohio Northern University Rudolph H. Raabe College of Pharmacy Ada, Ohio Kathryn R. Matthias, Pharm.D., BCPS-AQ ID University of Arizona Department of Pharmacy Practice and Science Tucson, Arizona Joseph E. Mazur, Pharm.D., BCPS Medical University of South Carolina Department of Pharmacy Services Charleston, South Carolina Ali McBride, Pharm.D., M.S., BCPS, BCOP The University of Arizona Cancer Center

Department of Pharmacy Tucson, Arizona M. Claire McManus, Pharm.D. St. Elizabeth’s Medical Center Department of Pharmacy Boston, Massachusetts Cristian Merchan, Pharm.D., BCCCP NYU Langone Medical Center Department of Pharmacy New York, New York Scott T. Micek, Pharm.D., FCCP, BCPS St. Louis College of Pharmacy Department of Pharmacy Practice St. Louis, Missouri Kathryn Morbitzer, Pharm.D. UNC Eshelman School of Pharmacy School of Pharmacy Chapel Hill, North Carolina Claire V. Murphy, Pharm.D., BCPS Ohio State University Wexner Medical Center Department of Pharmacy Columbus, Ohio

Michelle Nadeau, Pharm.D., BCPS Yale–New Haven Hospital Department of Pharmacy New Haven, Connecticut Melissa Nestor, Pharm.D., BCPS University of Kentucky HealthCare College of Pharmacy Lexington, Kentucky Komal Pandya, Pharm.D., BCPS University of Kentucky College of Pharmacy Lexington, Kentucky John Papadopoulos, B.S., Pharm.D., FCCM, BCNSP, BCCCP NYU Langone Medical Center Department of Pharmacy New York, New York Keith M. Olsen, Pharm.D., FCCP, FCCM University of Nebraska Medical Center College of Pharmacy Omaha, Nebraska Kate Oltrogge Pape, Pharm.D., BCPS University of Iowa Hospitals and Clinics

Department of Pharmaceutical Care Iowa City, Iowa Lance J. Oyen, Pharm.D., FCCM, FCCP, BCPS Mayo Clinic Department of Pharmacy Rochester, Minnesota Steven E. Pass, Pharm.D., FCCP, FCCM, FASHP, BCPS Texas Tech University HSC School of Pharmacy Dallas, Texas Asad E. Patanwala, Pharm.D. University of Arizona Department of Pharmacy Practice and Science Tucson, Arizona Sajni Patel, Pharm.D., BCPS University of Chicago Medicine Department of Pharmacy Chicago, Illinois Heather Personett, Pharm.D., BCPS Mayo Clinic Department of Pharmacy Rochester, Minnesota

Gregory Peitz, Pharm.D., BCPS University of Nebraska Medical Center Department of Pharmaceutical and Nutrition Care Omaha, Nebraska Brent N. Reed, Pharm.D., FAHA, BCPS-AQ Cardiology University of Maryland Department of Pharmacy Practice and Science Baltimore, Maryland Denise H. Rhoney, Pharm.D., FCCP, FCCM, FNCS UNC Eshelman School of Pharmacy Department of Practice Advancement and Clinical Education Chapel Hill, North Carolina A. Josh Roberts, Pharm.D., BCPSAQ Cardiology University of California, Davis Department of Pharmacy Sacramento, California Jo E. Rodgers, Pharm.D., FCCP, BCPS-AQ Cardiology University of North Carolina School of Pharmacy Division of Pharmacotherapy and Experimental Therapeutics Chapel Hill, North Carolina Andrew M. Roecker, Pharm.D., BCPS Ohio Northern University

Rudolph H. Raabe College of Pharmacy Ada, Ohio Carol J. Rollins, M.S., RD, Pharm.D., FASHP, FASPEN, BCNSP Banner University Medical Center Tucson and University of Arizona Department of Pharmacy Practice and Science Tucson, Arizona A. Shaun Rowe, Pharm.D., BCPS University of Tennessee Department of Clinical Pharmacy Knoxville, Tennessee Curtis N. Sessler, M.D., FCCP, FCCM Virginia Commonwealth University Health System Department of Internal Medicine Richmond, Virginia Mazda Shirazi, M.D., Ph.D. University of Arizona Department of Emergency Medicine; Department of Pharmacy Practice Tucson, Arizona Colgan T. Sloan, Pharm.D., BCPS University of Arizona Department of Pharmacy Practice

Tucson, Arizona Curtis L. Smith, Pharm.D., BCPS Ferris State University Department of Pharmacy Practice Lansing, Michigan Zachary A. Stacy, Pharm.D., M.S., FCCP, BCPS St. Louis College of Pharmacy Division of Acute Care; Department of Pharmacy Practice St. Louis, Missouri Paul M. Szumita, Pharm.D., FCCM, BCCCP, BCPS Brigham and Women’s Hospital Department of Pharmacy Boston, Massachusetts Robert L. Talbert, Pharm.D. University of Texas Pharmacotherapy Education and Research Center San Antonio, Texas Eljim P. Tesoro, Pharm.D., BCPS University of Illinois at Chicago Department of Pharmacy Practice Chicago, Illinois

James E. Tisdale, Pharm.D., FCCP, FAPhA, FAHA, BCPS Purdue University Department of Pharmacy Practice Indianapolis, Indiana Toby C. Trujillo, Pharm.D., FCCP, FAHA, BCPS-AQ Cardiology University of Colorado Skaggs Pharmaceutical Sciences

School

of

Pharmacy

Department of Clinical Pharmacy Aurora, Colorado Cory M. Vela, Pharm.D. Moffitt Cancer Center Department of Pharmacy Tampa, Florida Amber Verdell, Pharm.D., BCPS, BCNSP West Coast University Department of Pharmacy Practice Los Angeles, California Stacy Voils, PharmD, M.Sc., BCPS University of Florida Department of Pharmacotherapy and Translational Research Gainesville, Florida Robert J. Weber, Pharm.D., M.S., FASHP, BCPS The Ohio State University Wexner Medical Center

and

Department of Pharmacy College of Pharmacy Pharmacy Practice and Science Columbus, Ohio David Williamson, B. Pharm, M.Sc., Ph.D., BCPS University of Montreal Faculty of Pharmacy Montreal, Quebec Amanda Zomp, Pharm.D., BCPS University of Virginia Department of Pharmacy Charlottesville, Virginia

REVIEWERS The American College of Clinical Pharmacy, Dr. Erstad, and the authors would like to thank the following individuals for their careful chapter review. Earnest Alexander, Pharm.D. Tampa General Hospital Department of Pharmacy Tampa, Florida William L. Baker, Pharm.D., FCCP, FACC, BCPS-AQ Cardiology University of Connecticut Department of Pharmacy Practice Storrs, Connecticut Elizabeth Beltz, Pharm.D. University of Iowa Department of Pharmacy Iowa City, Iowa Christopher Bland, Pharm.D., BCPS, FIDSA University of Georgia Department of Clinical and Administrative Pharmacy Savannah, Georgia

Mary Beth Bobek, Pharm.D., CPP New Hanover Regional Medical Center Wilmington, North Carolina Kevin Box, Pharm.D. University of California, San Diego Department of Pharmacy San Diego, California Trisha Branan, Pharm.D., BCCCP University of Georgia Department of Clinical and Administrative Pharmacy Athens, Georgia Lisa Burry, Pharm.D. Mount Sinai Hospital Department of Pharmacy and Medicine Toronto, Ontario Josh Caraccio, Pharm.D., BCPS Utah Valley Regional Medical Center Department of Pharmacy Provo, Utah Amber Castle, Pharm.D., BCPS, BCCCP Yale–New Haven Hospital Department of Pharmacy

New Haven, Connecticut Alexandra Cheung, Pharm.D. Mount Sinai Hospital Department of Pharmacy Toronto, Ontario Henry Cohen, Pharm.D., FCCM, BCPP Kingsbrook Jewish Medical Center Department of Pharmacy Services Brooklyn, New York Aaron Cook, Pharm.D., BCPS University of Kentucky Department of Pharmacy Services Lexington, Kentucky Amanda Corbett, Pharm.D., BCPS, FCCP University of North Carolina Division of Pharmacotherapy and Experimental Therapeutics Chapel Hill, North Carolina Cheryl D. Cropp, Pharm.D., Ph.D. University of Arizona College of Pharmacy Department of Pharmacy Research Institute (TGen)

Practice/Translational

Genomics

Phoenix, Arizona Roland Dickerson, Pharm.D., BCNSP, FCCP University of Tennessee Department of Clinical Pharmacy Memphis, Tennessee Jeremiah Duby, Pharm.D., BCPS University of California, Davis, Medical Center Department of Pharmacy Services Davis, California Sandy Estrada, Pharm.D., BCPS Lee Memorial Hospital Department of Pharmacy Fort Myers, Florida Stacey Folse, Pharm.D., MPH Emory University Hospital Department of Pharmaceutical Services Atlanta, Georgia Lisa L. Forsyth, Pharm.D., FCCM Beaumont Hospital, Royal Oak Department of Pharmaceutical Services Royal Oak, Michigan

Erin R. Fox, Pharm.D., FASHP University of Utah Health Care Drug Information Service Salt Lake City, Utah Anthony T. Gerlach, PharmD, BCPS, FCCM, FCCP The Ohio State University Department of Pharmacy Columbus, Ohio Katherine Gharibian, Pharm.D. University of Michigan Department of Clinical Pharmacy Ann Arbor, Michigan Myke Green, Pharm.D., BCOP University of Arizona Department of Pharmacy Services Tucson, Arizona Bonnie C. Greenwood, Pharm.D. University of Massachusetts Medical School Clinical Pharmacy Services Shrewsbury, Massachusetts John Horn, Pharm.D., FCCP University of Washington

Department of Pharmacy Seattle, Washington Yvonne Huckleberry, Pharm.D., BCPS Banner University Medical Center Medical Intensive Care Unit (Pharmacy) Tucson, Arizona Theresa Human, Pharm.D., BCPS Barnes-Jewish Hospital, Washington University Department of Pharmacy St. Louis, Missouri Brian Kopp, Pharm.D., BCPS, FCCM Banner University Medical Center Department of Pharmacy Services Tucson, Arizona Seung Joo Lee, Pharm.D. University of Toronto Department of Pharmacy Toronto, Ontario Courtney McKinney, Pharm.D., BCPS Intermountain Medical Center Department of Pharmacy Services Salt Lake City, Utah

Charles Medico, Pharm.D., BCPS Geisinger Medical Center Department of Enterprise Pharmacy Danville, Pennsylvania Wenya Miao, Pharm.D. Mount Sinai Hospital Department of Pharmacy Toronto, Ontario John Murphy, Pharm.D., FCCP University of Arizona Department of Pharmacy Practice and Science Tucson, Arizona David Nix, Pharm.D. University of Arizona Department of Pharmacy Practice and Science Tucson, Arizona Erin M. Nystrom, Pharm.D., BCNSP Mayo Clinic Department of Pharmacy Rochester, Minnesota Christopher Paciullo, Pharm.D., BCCCP, FCCM Emory University Hospital

Department of Pharmaceutical Services Atlanta, Georgia William Peppard, Pharm.D., BCPS Froedtert and the Medical College of Wisconsin Department of Pharmacy Milwaukee, Wisconsin Hanna Phan, Pharm.D., BCPS University of Arizona Department of Pharmacy Practice and Science; Department of Pediatrics Tucson, Arizona Asia N. Quan, Pharm.D., BCPS Maricopa Integrated Healthcare System The Arizona Burn Center Phoenix, Arizona John Radosevich, Pharm.D., BCCCP, BCPS St. Joseph’s Hospital and Medical Center Department of Pharmacy Phoenix, Arizona Hal Richards, Pharm.D., BCNSP St. Joseph’s Candler Health System Department of Pharmacy Savannah, Georgia

Garrett Schramm, Pharm.D., BCPS Mayo Clinic Department of Pharmacy Rochester, Minnesota Susan Skledar, RPh, MPH, FASHP University of Pittsburgh Department of Pharmacy and Therapeutics Pittsburgh, Pennsylvania Maria Stubbs, RPh, BCPS VA San Diego Healthcare System Department of Pharmacy Carlsbad, California Scott Taylor, Pharm.D., M.Sc., BCPS Via Christi Hospitals Department of Pharmacy Wichita, Kansas Michael C. Thomas, Pharm.D., BCPS, FCCP Western New England University Department of Pharmacy Practice Springfield, Massachusetts Sarah Todd, Pharm.D., BCPS Emory University Hospital

Department of Pharmacy Atlanta, Georgia Todd Sorensen, Pharm.D. University of Minnesota Department of Pharmaceutical Care and Health Systems Minneapolis, Minnesota Sara Stahle, Pharm.D., BCPS The University of Chicago Medicine Department of Pharmacy Chicago, Illinois Zachariah Thomas, Pharm.D. Director, Global Health Science The Medicines Company New York, New York Velliyur Viswesh, Pharm.D., BCPS Roseman University of Health Sciences Department of Pharmacy Practice Henderson, Nevada Sol Atienza Yoder, Pharm.D., BCOP Aurora Health Care Department of Pharmacy Milwaukee, Wisconsin

Dinesh Yogaratnam, Pharm.D., BCPS, BCCCP Massachusetts College of University

Pharmacy and Health Sciences

Department of Pharmacy Practice Worcester, Massachusetts

Index Note: Page numbers followed by b, f, or t indicate material in boxes, figures, or tables, respectively.

A AACE. See American Association of Clinical Endocrinologists AAG. See α1-acid glycoprotein AANS. See American Association of Neurological Surgeons AASLD. See American Association for the Study of Liver Diseases AB5000 Circulatory Support System ABA. See American Burn Association ABCDE, for trauma ABCDEF, for delirium abciximab abdominal compartment syndrome ABG. See arterial blood gas ABO compatibility absolute neutrophil count (ANC) absorption ALF and DDIs and AC. See adrenal crisis Academy of Nutrition and Dietetics ACAG. See albumin-corrected AG

ACC. See American College of Cardiology ACCM/SCCM. See American College Medicine/Society of Critical Care Medicine

of

ACE. See angiotensin-converting enzyme ACEIs. See angiotensin-converting enzyme inhibitors acetaminophen acetazolamide acetoacetate acetone acetylcholine acetylcholine inhibitors acetylcholinesterase inhibitors acetylcysteine α1-acid glycoprotein (AAG) acid-base disorders bicarbonate and case studies for clinical findings for clinical syndromes intravenous fluids and PEA and potassium and secondary responses to stepwise diagnosis of Stewart model for acidemia acidosis. See also metabolic acidosis

Critical

Care

AF and agitation and ALF and coagulopathy and lactic liver and malignant hyperthermia and potassium and respiratory TIC and Acinetobacter spp. ACLS. See advanced cardiac life support ACOS. See asthma-COPD overlap syndrome acquired immunodeficiency syndrome (AIDS). See HIV/AIDS ACS. See acute coronary syndrome ACT. See activated clotting time ACTH. See adrenocorticotropic hormone activated clotting time (ACT) activated partial thromboplastin time (aPTT) ACT and anti-Xa and for bivalirudin for DTIs inhalation injury and MCS and morbid obesity and TEG and

VTE and activated prothrombin complex concentrate (aPCC) active surveillance Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) acute coronary syndrome (ACS) anticoagulants for antithrombotics for β-blockers for cardiac biomarkers for CCB for chest pain with ECG for GPIIb/IIIa inhibitors for hypertensive crisis and oxygen therapy for P2Y inhibitors for pathophysiology of PCI for platelet transfusions and risk scores for acute decompensated heart failure (ADHF) cardiac transplantation for clinical presentation of hemodynamic subsets for hemodynamic support for inotropes for

laboratory testing for loop diuretics for LVADs for MCS for PCWP and thiazide diuretics for vasodilators for volume management for Acute Decompensated Heart Failure National Registry (ADHERE) Acute Dialysis Quality Initiative (ADQI) acute ischemic stroke (AIS) classification, risk factors, and diagnosis for hyperglycemia and hypertension and pathophysiology of seizures and treatment of acute kidney disease, vs. CKD acute kidney injury (AKI) ADEs and AF and assessment of biomarkers for drug clearance and drug dosing in drug-induced ECMO and

etiology of hypomagnesemia and incidence and prognosis for intrarenal laboratory testing for from normal saline pathophysiology of postrenal prevention and treatment of rhabdomyolysis and RRT for scoring systems for severity staging of sodium chloride solutions and trauma and Acute Kidney Injury Network (AKIN) acute liver failure (ALF) absorption and classifications of clinical presentation of CTP for epidemiology of etiology of management of nonpharmacologic therapy for pathophysiology of PK for

prognosis for scoring systems for acute lung injury (ALI) acute lymphoblastic leukemia acute myocardial infarction (AMI) bradycardia and hypertensive crisis and hypomagnesemia and SCA and shock and VT and Acute Physiology and Chronic Health Evaluation (APACHE II) ALF and antimicrobials and delirium and GCS and glucose management and hypophosphatemia and β-lactam antibiotics and nutrition and for pancreatitis PN and Acute Physiology Score (APS) acute postoperative hypertension (APH) acute respiratory distress syndrome (ARDS) histoplasmosis and MCS for

NMBAs for omega-3 fatty acids for Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND) acute tubular necrosis (ATN) acyclovir ADA. See American Diabetes Association Addison disease ADE Prevention Study adenosine adenosine diphosphate (ADP) adenosine triphosphate (ATP) ALF and malignant hyperthermia and ticagrelor and adenovirus ADEs. See adverse drug events ADH. See antidiuretic hormone ADHERE. See Acute Decompensated Heart Failure National Registry ADHF. See acute decompensated heart failure adipose tissue, metabolic acidosis and adjusted body weight (AdjBW) ADP. See adenosine diphosphate ADQI. See Acute Dialysis Quality Initiative adrenal crisis (AC) adrenal disorders adrenal insufficiency

α2-adrenergic agonists adrenergic blockers β-adrenergic blockers adrenergic-receptor antagonists adrenocorticotropic hormone (ACTH) adrenal insufficiency and stress response and β2-adrenoreceptors Adrogue-Madias equation advanced cardiac life support (ACLS), for SCA advanced trauma life support, for trauma adverse drug events (ADEs) active surveillance for defined epidemiology of medication safety and MEs and pharmacogenomics and systems analysis of Adverse Event Reporting System, of FDA AEDs. See automated external defibrillators Aerosolized Iloprost Randomized Study (AIR) AF. See atrial fibrillation AG. See anion gap Agency for Healthcare Research and Quality agitation clinical significance of

cocaine and defined delirium with etiology of incidence of nonpharmacologic therapy for opioids for sedatives for alternative for assessment of traditional for α2-agonists β-agonists AHA. See American Heart Association AIR. See Aerosolized Iloprost Randomized Study air leak syndromes AIS. See acute ischemic stroke; ASIA Impairment Scale AKI. See acute kidney injury AKIN. See Acute Kidney Injury Network alanine aminotransferase (ALT) ALBIOS. See Albumin Italian Outcome Sepsis albumin for aSAH for burns calcium and cefotaxime and DDIs and

for ECMO for hemorrhagic shock MAP and nutrition and for peritonitis plasmapheresis and for PPH randomized trials for for sepsis for shock uses of Vss and albumin and lactate corrected AG (ALCAG) Albumin in Subarachnoid Hemorrhage (ALISAH) Albumin Italian Outcome Sepsis (ALBIOS) albumin-corrected AG (ACAG) albuterol ALCAG. See albumin and lactate corrected AG alcohol abuse acetaminophen-ALF and agitation and aSAH and frostbite and hypophosphatemia and Mallory-Weiss tears from withdrawal from

hypertensive crisis and phenobarbital for alcoholic hepatitis aldosterone ALF. See acute liver failure ALF Study Group ALI. See acute lung injury ALISAH. See Albumin in Subarachnoid Hemorrhage ALIVE trial alkalemia alkalosis metabolic overshoot respiratory allergic rhinitis allopurinol ALT. See alanine aminotransferase alteplase altered mental status ALF and aSAH and with encephalitis hypothyroidism and SVC and amantadine Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy (ARIES)

American Academy of Pediatrics American Association for the Study of Liver Diseases (AASLD) American Association of Clinical Endocrinologists (AACE) American Association of Neurological Surgeons (AANS) American Burn Association (ABA) American College of Cardiology (ACC) American College of Chest Physicians American College of Critical Care Medicine/Society of Critical Care Medicine (ACCM/SCCM) American College of Obstetricians and Gynecologists American College of Surgeons American Diabetes Association (ADA) American Heart Association (AHA) American Psychiatric Association American Society for Parenteral and Enteral Nutrition (ASPEN) American Society of Health-System Pharmacists (ASHP) American Spinal Injury Association (ASIA) American Stroke Association (ASA) American Thoracic Society AMI. See acute myocardial infarction amikacin α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) γ-aminobutyric acid (GABA) baclofen and benzodiazepines and

delirium and NMBAs and propofol and SE and treprostinil and volatile anesthetics and aminoglutethimide aminoglycosides AKI from ECMO and extended-interval drug dosing for hypomagnesemia and for morbid obesity NMBAs and PD of aminophylline aminorex amiodarone for AF antiretrovirals and bradycardia from delirium from myxedema coma and P-glycoprotein and plasmapheresis for for PSVT for SCA

ticagrelor and for VT amitriptyline amlodipine ammonia ammonium chloride amoxicillin amoxicillin/clavulanic acid AMPA. See α-amino-3-hydroxy-5-methylisoxazole-4-propionate amphetamines amphotericin B AKI from for Aspergillus for Candida for Cryptococcus neoformans delirium from for FN hypomagnesemia and pregnancy and properties of ampicillin amrinone amyl nitrite amyloidosis amyotrophic lateral sclerosis anal fissures analgesics. See also opioids

analgosedation approach to delirium from ECMO and multimodal with non-opioids nonpharmacologic therapy for in pregnancy for procedural pain for respiratory alkalosis therapeutic options in in transition from ICU to ward analgosedation approach, to analgesia anaphylactic shock ANC. See absolute neutrophil count andexanet androgens anemia ADP and aSAH and endothelin receptor antagonists and hypertensive crisis and MCS and riociguat and anesthetics ALF from bradycardia from NMBAs and

for SE TdP from aneurysmal subarachnoid hemorrhage (aSAH) DCI and DVT and early brain injury and epidemiology of fever and grading scales for hydrocephalus and hypertensive crisis and hyponatremia and initial stabilization of management and complication prevention for multidisciplinary team for paroxysmal sympathetic hyperactivity and pathophysiology of pharmacotherapy for rebleeding and risk factors for seizures and subarachnoid spaces and thermoregulation for treatment of angioedema angiotensin II angiotensin receptor blockers (ARBs)

angiotensin-converting enzyme (ACE) angiotensin-converting enzyme inhibitors (ACEIs) angiotensinogen anion gap (AG) metabolic acidosis and antacids α1-antagonists anthropometry antiarrhythmics antibacterials antiretrovirals and as concentration-dependent drugs as time-dependent drugs antibiograms antibiotics. See also antimicrobials; β-lactam antibiotics agitation and ALF from for COPD at endotracheal intubation for MCS MIC for for morbid obesity for myxedema coma NMBAs and PD of resistance to, strategies to minimize

for respiratory acidosis for SSIs TdP from anticancer drugs anticholinergics anticoagulants for ACS ADEs and for AF for BCVIs complications with DDIs with for DIC GI bleeding and, reintroduction of hemorrhage with for HIT IHD and for invasive procedures in ischemia-driven strategy laboratory testing for ACT for anti-Xa for aPTT for chromogenic factor X and D-dimer for dTT for ecarin clotting time for

Hemoclot thrombin inhibitor for Heptest and Heptest-Stat for methods for PiCT for platelet reactivity tests for regulatory requirements for reptilase time for ROTEG for samples for TEG for thrombin generation assays for Mallory-Weiss tears from MCS and for morbid obesity for NSTE peptic ulcer disease from in pregnancy for respiratory acidosis reversal of, for drug-induced coagulopathies for GI bleeding for ICH for STEMI for VTE anticonvulsants, antidepressant discontinuation syndrome antidepressants

antidiuretic hormone (ADH). See also syndrome of inappropriate antidiuretic hormone antiemetics antiepileptics antifibrinolytics antifungals ALF from antiretrovirals and for burns for Candida CYP and drug dosing of ECMO and for FN liver drug clearance and MIC for for mucormycosis PD and PK of P-glycoprotein and prophylaxis with QT interval and resistance to TdP from antihistamines Antihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) antihypertensives antimicrobial stewardship programs (ASPs)

antimicrobials ALF from ARC for ASPs for biomarkers for for burns clinical decision support systems for for COPD CrCl for DDIs with de-escalation of for donor-derived infections drug dosing of drug shortages of duration of ECMO and for FN for GNB, de-escalation of for hepatic encephalopathy MDR to MIC for for morbid obesity PD of for burns drug dosing of goals for limitations of

for sepsis and septic shock PK of alterations in critical illness for burns changes in drug absorption drug clearance for drug dosing of half-life of limitations of protein binding and Vss for in pregnancy prolonged infusions of prophylaxis with for CIEDs drug dosing of ECMO and for HCT ICP and for MCS at mechanical ventilation for nasal packing for neurosurgery for neutropenia principles of for spontaneous bacterial peritonitis for SSIs

for subdural grids for TAH for VADs for VAP protocolized management of rapid diagnostics for resistance to to clarithromycin to metronidazole SSIs and selection of for severe sepsis and septic shock TDM for timing of administration of underdrug dosing of for VAP antioxidants antiplatelets for ACS CYP and DAPT DDIs with GI bleeding and, reintroduction of in ischemia-driven strategy platelet transfusions for reversal of, for ICH antiprotozoal

antipsychotics antipyretics antipyrine antiretrovirals. See also highly active antiretroviral therapy antithrombin (AT) antithrombotics for ACS for BCVIs with fibrinolysis MCS and for STEMI AntithromboticTrialists’ Collaboration α2-antitrypsin antivirals, . See also highly active antiretroviral therapy for EBV for influenza for VHFs anti-Xa for apixaban LMWH and MCS and morbid obesity and for rivaroxaban anxiety ANZICS. See Australian and New Zealand Intensive Care Society aortic dissection aortic regurgitation/insufficiency

APACHE II. See Acute Physiology and Chronic Health Evaluation aPCC. See activated prothrombin complex concentrate APH. See acute postoperative hypertension apixaban anti-Xa for for GI bleeding P-glycoprotein and APOE. See apolipoprotein E apolipoprotein E (APOE) apoptosis APS. See Acute Physiology Score aPTT. See activated partial thromboplastin time arbovirus ARBs. See angiotensin receptor blockers ARC. See augmented renal clearance ARDS. See acute respiratory distress syndrome area under the curve (AUC) area under the receiver operating characteristic curves (aROCs) argatroban arginine arginine vasopressin (AVP) ARIES. See Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy ARISE. See Australasian Resuscitation in Sepsis Evaluation Arizona Center for Education and Research on Therapeutics (AZCERT)

aROCs. See area under the receiver operating characteristic curves ARREST trial arrhythmias. See cardiac arrhythmias arterial blood gas (ABG) ASA. See American Stroke Association aSAH. See aneurysmal subarachnoid hemorrhage ASCEND. See Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure ascorbic acid. See vitamin C ASHP. See American Society of Health-System Pharmacists ASIA. See American Spinal Injury Association ASIA Impairment Scale (AIS) aspartate transaminase (AST) ASPEN. See American Society for Parenteral and Enteral Nutrition Aspergillus spp. aspirin asthma and GI bleeding from for NSTE peptic ulcer disease from ASPs. See antimicrobial stewardship programs AST. See aspartate transaminase asthma anaphylactic shock and clinical presentation of epidemiology of management of

NIV for NMBAs for oxygen therapy for in pregnancy treatment for asthma-COPD overlap syndrome (ACOS) asynchronous defibrillation asystole AT. See antithrombin; atrial tachycardia ATACH. See Antihypertensive Hemorrhage

Treatment

in

Acute

Cerebral

atherosclerosis Atlanta classification, for pancreatitis ATN. See acute tubular necrosis ATOLL. See STEMI Treated with Primary Intravenous Lovenox or Unfractionated Heparin atorvastatin ATP. See adenosine triphosphate atracurium atrial fibrillation (AF) AT and drugs for treatment algorithm for atrial flutter atrial tachycardia (AT) atrioventricular node block (AV block) ECG for

Angioplasty

and

pacemakers for atrioventricular node reciprocating tachycardia (AVNRT) atrioventricular reciprocating tachycardia (AVRT) atropine AUC. See area under the curve AUC0-24/MIC. See ratio of the 24-hour area under the serum concentration versus time curve to pathogen MIC augmented renal clearance (ARC) Australasian Resuscitation in Sepsis Evaluation (ARISE) Australian and New Zealand Intensive Care Society (ANZICS) autoimmune hepatitis automated external defibrillators (AEDs) autoregulation AV block. See atrioventricular node block average A-weighted energy-equivalent sound pressure in decibels (dBA LAeq) AVNRT. See atrioventricular node reciprocating tachycardia AVP. See arginine vasopressin AVRT. See atrioventricular reciprocating tachycardia AZCERT. See Arizona Center for Education and Research on Therapeutics azithromycin azoles

B B lymphocytes Bacille-Calmette-Guérin (BCG)

baclofen bacteremia BAL. See bronchoalveolar lavage Balthazar grading system, for pancreatitis barbiturate coma barbiturates base excess (BE) basic life support Baux formula BCAAs. See branched-chain amino acids BCG. See Bacille-Calmette-Guérin BC-GN. See gram-negative blood culture test BC-GP. See gram-positive blood culture test B-CONVINCED. See Beta-Blocker Continuation versus Interruption in Patients with Congestive Heart Failure Hospitalized for a Decompensation Episode BCVIs. See blunt cerebrovascular injuries BE. See base excess Bedside Index of Severity in Acute Pancreatitis (BISAP) Behavioral Pain Scale (BPS) benfluorex benzodiazepines for endotracheal intubation in children GABA and for hypertensive crisis for nicotine withdrawal pregnancy and

for SE benzoylecgonine benztropine benzyl alcohol Bernard-Soulier disease Beta-Blocker Continuation versus Interruption in Patients with Congestive Heart Failure Hospitalized for a Decompensation Episode (B-CONVINCED) Better Bladder Bhaskar, E bicarbonate. See also sodium bicarbonate Bickell, WH Bickford, A Biffl, WL bilirubin biomarkers for ACS for AKI for antimicrobials for PAH for TBI BIS. See bispectral index BISAP. See Bedside Index of Severity in Acute Pancreatitis bismuth subsalicylate bispectral index (BIS) bisphosphonate bivalirudin

for ACS MCS and for STEMI black cohosh blastomycosis Blatchford score, for rebleeding α-blockers β-blockers for ACS for ADHF for AF for aortic dissection for burns for HF for pheochromocytoma for PSVT VT and blood glucose (BG). See glucose blood pressure. See also diastolic blood pressure; hypertension; hypotension; systolic blood pressure aSAH and COPD and hypertensive crisis and ICH and pheochromocytoma SCI and blood transfusions

for anemia aSAH and DTIs and for GI bleeding for hypovolemic shock blood urea nitrogen (BUN) bloodstream infections, aSAH and bloody vicious triad blunt cerebrovascular injuries (BCVIs) BMI. See body mass index BNP. See brain natriuretic peptide body mass index (BMI) cefazolin and fondaparinux and hypertensive crisis and morbid obesity and nutrition and UFH and underweight patients and Bordetella pertussis Borg dyspnea score bortezomib bosentan BPS. See Behavioral Pain Scale BPS-Non-intubated (BPS-NI) Bradley, MJ bradycardia

syncope and bradykinin brain natriuretic peptide (BNP) Brain Trauma Foundation (BTF) branched-chain amino acids (BCAAs) breast cancer BREATHE Brilinta. See cyclopentyltriazolopyrimidine Brill-Edwards method bromfenac bromocriptine bronchoalveolar lavage (BAL) bronchodilators Brunkhorst, FM BTF. See Brain Trauma Foundation Budd-Chiari syndrome bumetanide (Bumex) BUN. See blood urea nitrogen bupropion Burke, JF Burkitt lymphoma burns antimicrobials for arginine and ascorbic acid for carbon monoxide and chemical

crystalloids and colloids for cyanide and depth of from electrical injuries fluid resuscitation for glucose and hyperglycemia and hypovolemic shock and inhalation injury with mortality risk factors with NMBAs and nutrition and nutrition for renal failure from sepsis and severity assessment of SIRS and VTE and

C CABG. See coronary artery bypass graft cachexia Cairo, MS calcineurin inhibitors (CNIs) calcitonin calcitriol calcium. See also hypercalcemia; hypocalcemia

HCM and hemostasis and respiratory alkalosis and sodium bicarbonate and TdP and TLS calcium channel blockers (CCB) for aSAH bradycardia from NMBAs and pregnancy and calcium chloride calcium gluconate calcium phosphate CALORIES trial CAM. See complementary and alternative medicine CAM-ICU. See confusion assessment method for the intensive care unit cAMP. See cyclic adenosine monophosphate Canadian Clinical Practice Guidelines cancer. See also specific organs and types HCM and MSCC and SIADH and SVC and TLS and underweight patients with

VTE and Candida albicans Candida spp. ALF and antibiotic de-escalation for antifungals for HCT and MDR of MIC for PNA-FISH for triazoles for in vitro interpretative criteria for cangrelor CAPD. See continuous ambulatory peritoneal dialysis capillary leak syndrome carbamazepine carbapenem carbapenem-resistant Enterobacteriaceae (CRE) carbon dioxide (CO2) asthma and COPD andH. pylori and metabolic acidosis and respiratory acidosis and sodium bicarbonate and carbon monoxide carbonic acid carboplatin

carboprost carboxyhemoglobin cardiac arrest. See sudden cardiac arrest Cardiac Arrhythmia Suppression Trial (CAST) cardiac arrhythmias. See also specific types asthma and from electrical injuries hypokalemia and malignant hyperthermia and metabolic acidosis and respiratory alkalosis and supraventricular ventricular VHFs and cardiac index (CI) cardiac output (CO) aSAH and burns and in children MCS and phenylephrine and cardiac tamponade cardiac transplantation cardiogenic shock cardiomyopathy cardiopulmonary bypass surgery cardiopulmonary resuscitation (CPR)

for children for SCA Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) cardiovascular implantable electronic devices (CIEDs) β-carotene carotid sinus hypersensitivity CARRESS-HF. See Cardiorenal Decompensated Heart Failure

Rescue

Study

in

Acute

caspofungin CAST. See Cardiac Arrhythmia Suppression Trial catecholamines burns and pheochromocytoma respiratory alkalosis and for septic shock SRMD and catheter-related bloodstream infections CATIS. See China Antihypertensive Trial in Acute Ischemic Stroke CCB. See calcium channel blockers CCPD. See continuous cycler-assisted peritoneal dialysis CD4 CDC. See Centers for Disease Control and Prevention CDS. See clinical decision support cefazolin cefepime cefmetazole

cefotaxime cefotiam ceftazidime ceftobiprole ceftriaxone cefuroxime Centers for Disease Control and Prevention (CDC) Centers for Medicare & Medicaid Services (CMS) central cord syndrome central nervous system (CNS) cocaine and hypercalcemia and hypocalcemia and hyponatremia and hypothyroidism and metabolic acidosis and neurosurgical infections and nitroprusside and opioids and respiratory acidosis and respiratory alkalosis and VTE and VZV and central venous catheters (CVC) central venous oxygen saturation (Scvo2) central venous pressure (CVP) CentriMag

cephalexin cephalosporin cerebral blood flow cerebral edema cerebral perfusion pressure (CPP) cerebral vasospasm cerebrospinal fluid (CSF) shunting devices cerivastatin cervical cancer cervical spine fractures CG. See Cockcroft-Gault equation cGMP. See cyclic guanosine monophosphate Chagas disease chain of survival CHAMPION PHOENIX Chan, AL Chawla LS chemical burns chemotherapy drug shortages of hypomagnesemia and SIADH and SVC and CHEST. See Crystalloid versus Hydroxyethyl Starch Trial chest pain chikungunya

child abuse. See nonaccidental trauma Child-Pugh score (CTP), for ALF children asystole in CPR for CRRT for DVT in endotracheal intubation for Haemophilus influenzae in hypoglycemia in hypothermia in hypovolemic shock in MV for organ dysfunction criteria for physiologic differences of, respiratory distress in retinal hemorrhages in RSV in SA in SE in sepsis in septic shock in severe sepsis in shock in SIRS in SRMD in TBI in

thrombosis in VF in vital signs for China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) Chiu, HM Chlamydia pneumoniae Chlamydia trachomatis chloride chlorothiazide (Diuril) chlorpromazine chlorthalidone (Hygroton) cholestyramine cholinesterase inhibitors chromogenic factor X chronic kidney disease (CKD) vs. acute kidney disease chronic lymphocytic leukemia chronic obstructive pulmonary disease (COPD) clinical presentation of epidemiology of management of MV for NIV for oxygen therapy for triggers of Chung, CY Chvostek sign

CI. See cardiac index cidofovir CIEDs. See cardiovascular implantable electronic devices cilastatin cimetidine CIP/M. See critical illness polyneuropathy and myopathy ciprofloxacin AKI from for burns drug-nutrient interactions with ECMO and for FN pregnancy and cirrhosis cisatracurium cisplatin citalopram CK. See creatine kinase CK-BB CKD. See chronic kidney disease CK-MM CL. See clot lysis Clarification of Optimal Anticoagulation Through Genetics (COAG) clarithromycin CLARITY-TIMI. See Clopidogrel as Adjunctive Reperfusion TherapyThrombolysis in Myocardial Infarction Classen, DC

clavulanic acid clazosentan Clazosentan to Overcome Neurological Ischemia and Infarct Occurring After Subarachnoid Hemorrhage (CONSCIOUS) clevidipine CLIA. See Clinical Laboratory Improvement Amendments Clichy’s criteria, for ALF clindamycin clindamycin/primaquine clinical decision support (CDS) Clinical Laboratory Improvement Amendments (CLIA) Clinical & Laboratory Standards Institute (CLSI) Clinical Pharmacogenetics Implementation Consortium (CPIC) clonazepam clonidine clopidogrel (Plavix) Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT– OASIS) Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction (CLARITY-TIMI) Clopidogrel for the Reduction of Events During Observation (CREDO) Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Clostridium difficile clot lysis (CL) clotting factors acidosis and

fibrinogen and hemostasis and INR and INR for liver and PT and PTT and TEG and CLSI. See Clinical & Laboratory Standards Institute Cmax/MIC. See ratio of maximum serum drug concentration to MIC CMS. See Centers for Medicare & Medicaid Services CMV. See cytomegalovirus CNIs. See calcineurin inhibitors CNS. See central nervous system; Congress of Neurological Surgeons CO. See cardiac output CO2. See carbon dioxide COAG. See Clarification of Genetics coagulopathy ALF and Dengue fever and fluid resuscitation and hypovolemic shock and MCS and reversal or prevention of TIC

Optimal Anticoagulation Through

trauma and cocaine hypertensive crisis and coccidioidomycosis Cochrane group Cockcroft-Gault equation (CG) codeine Cohn, Edwin colistin College of American Pathologists colloids for AKI for burns for critically ill patients crystalloids and, equivalency chart for electrolyte composition of for hemorrhage for hemorrhagic shock oncotic pressure, osmolality, osmolarity, and tonicity and overview of for shock studies in critical patients for for trauma Vss and Colloids versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) colonoscopy

colorectal cancer coma barbiturate hypermagnesemia and myxedema SVC and COMMIT. See Clopidogrel and Metoprolol in Myocardial Infarction Trial compartment syndrome frostbite and complementary and alternative medicine (CAM) complete blood count comprehensive pharmacy service computed tomography (CT) for aortic dissection for aSAH for hemorrhagic shock for nutrition for PN for TBI TPA and for VZV confusion assessment method for the intensive care unit (CAM-ICU) congenital heart disease congestive heart failure Congress of Neurological Surgeons (CNS) conivaptan

conjugated estrogen CONSCIOUS. See Clazosentan to Overcome Neurological Ischemia and Infarct Occurring After Subarachnoid Hemorrhage CONSENSUS II. See Cooperative New Scandinavian Enalapril Survival Study II Consensus Statement on Malnutrition continuous ambulatory peritoneal dialysis (CAPD) continuous cycler-assisted peritoneal dialysis (CCPD) continuous renal replacement therapy (CRRT) continuous venovenous hemodiafiltration (CVVHDF) continuous venovenous hemodialysis (CVVHD) continuous venovenous hemofiltration (CVVH) CONTROL trial convection, in drug clearance Cooperative New (CONSENSUSII)

Scandinavian

Enalapril

Survival

Study

COPD. See chronic obstructive pulmonary disease copper Cori cycle coronary artery bypass graft (CABG) coronary artery disease coronary perfusion pressure (CPP) coronavirus corrected QT interval (QTc) correctional insulin Corticosteroid Randomisation After Significant Head Injury (CRASH) Corticosteroid Therapy for Septic Shock (CORTICUS)

II

corticosteroids for ACOS for ADHF cardiac transplantation anaphylactic shock and for COPD delirium from for EBV for HSV for MSCC for myxedema coma peptic ulcer disease from for PJP in pregnancy for RSV for SA in children for septic shock for TBI treprostinil and withdrawal from CORTICUS. See Corticosteroid Therapy for Septic Shock cortisol Costantini, TW Cothren, CC COX-1. See cyclooxygenase-1 COX-2. See cyclooxygenase-2 Cp. See plasma concentration CPIC. See Clinical Pharmacogenetics Implementation Consortium

CPOT. See Critical-Care Pain Observation Tool CPP. See cerebral perfusion pressure; coronary perfusion pressure CPR. See cardiopulmonary resuscitation Cpss. See plasma concentration at steady state CRASH. See Corticosteroid Randomisation After Significant Head Injury CrCl. See creatinine clearance CRE. See carbapenem-resistant Enterobacteriaceae C-reactive protein creatine kinase (CK) creatinine creatinine clearance (CrCl)s CREDO. See Clopidogrel for the Reduction of Events During Observation Creon CRISTAL. See Colloids versus Crystalloids for the Resuscitation of the Critically Ill critical illness polyneuropathy and myopathy (CIP/M) Critical-Care Pain Observation Tool (CPOT) Crohn disease CRRT. See continuous renal replacement therapy crush injuries cryoprecipitate cryptococcosis Cryptococcus neoformans Crystalloid versus Hydroxyethyl Starch Trial (CHEST) crystalloids

acid-base disorders and adverse effects of for AKI for burns colloids and, equivalency chart for for critically ill patients electrolyte composition of for hemorrhage oncotic pressure, osmolality, osmolarity, and tonicity and overview of for severe sepsis and septic shock for shock studies in critical patients for for trauma Vss and Crystalloids Morbidity Associated with Severe Sepsis (CRYSTMAS) CS. See Cushing syndrome CSF. See cerebrospinal fluid CT. See computed tomography CT angiography CT severity index (CTSI) CTP. See Child-Pugh score CTSI. See CT severity index Cullen, DJ CURB-65 CURE. See Clopidogrel in Unstable Angina to Prevent Recurrent Events Curling ulcers

CURRENT–OASIS. See Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes Cushing syndrome (CS) Cushing ulcers CVC. See central venous catheters CVP. See central venous pressure CVVH. See continuous venovenous hemofiltration CVVHD. See continuous venovenous hemodialysis CVVHDF. See continuous venovenous hemodiafiltration cyanide cyanosis cyclic adenosine monophosphate (cAMP) cyclic guanosine monophosphate (cGMP) cyclooxygenase-1 (COX-1) cyclooxygenase-2 (COX-2) cyclopentyltriazolopyrimidine (Brilinta) cyclophosphamide cyclosporine CYP. See cytochrome P450 cystatin C Cystic Fibrosis Foundation cytochrome P450 (CYP) AC and acetaminophen and antifungals and carbamazepine and

cirrhosis and clopidogrel and DDIs and, disease states and drug clearance and endothelin receptor antagonists and hemodialysis and nicardipine and nimodipine and P-glycoprotein and phenytoin and PK and PPIs and TdP and TE and ticagrelor and underweight patients and valproic acid and cytokines burns and SRMD and cytomegalovirus (CMV) cytotoxic T lymphocytes

D dabigatran

anticoagulant reversal for for GI bleeding DAD-HF. See Dopamine in Acute Decompensated Heart Failure Dagan, O DAH. See diffuse alveolar hemorrhage dalbavancin dalteparin damage control Danish Verapamil Infarction Trial (DAVITII) dantrolene DAPT. See dual antiplatelet therapy daptomycin dasatinib DAVIT-II. See Danish Verapamil Infarction Trial dBA LAeq. See average A-weighted energy-equivalent sound pressure in decibels DBP. See diastolic blood pressure DCC. See direct current cardioversion DCI. See delayed cerebral ischemia D-dimer (fibrin degradation product) for anticoagulant testing hypertensive crisis and DDIs. See drug-drug interactions De Orbe Novo (Martyr d’Anghiera) decompressive craniectomy, for TBI in children decongestants deep venous thrombosis (DVT)

delayed cerebral ischemia (DCI) delayed ischemic neurological deficit delayed PN delirium ABCDEF for agitation and assessment of, sedatives and dexmedetomidine for from drugs I-C-U-D-E-L-I-R-I-U-M-S mnemonic for pathophysiology of risk factors for TdP and treatment for Demadex. See torsemide demeclocycline demyelinating disease Dengue fever denosumab desmopressin desmoteplase Devine, BJ dexamethasone CYP and for MSCC dexfenfluramine dexmedetomidine

for delirium pregnancy and dextrans dextrose (1,3)-β-d-glucan (1,3)-β-D-glucan diabetes aortic dissection and CS and diagnosis of nutrition and diabetes insipidus diabetes mellitus diabetes with neuropathy diabetic ketoacidosis (DKA) Diagnostic and Statistical Manual of Mental Disorders dialysis with convection and ultrafiltration for hyperphosphatemia DIAS-3 diastolic blood pressure (DBP) diazepam DIC. See disseminated intravascular coagulation diclofenac DiCocco, JM didanosine dietary reference intakes (DRIs)

dietary supplements diffuse alveolar hemorrhage (DAH) diffusion, in drug clearance digital subtraction angiography digitalis digoxin for ADHF for AF bradycardia from DDIs with drug-nutrient interactions with for PAH for PSVT succinylcholine and toxicity dihydropyridine DILI. See drug-induced liver injury diltiazem for AF antiretrovirals and for PSVT diluted thrombin time (dTT) dimorphic fungi diphenhydramine DIPS. See Drug Interaction Probability Scale dipyridamole direct current cardioversion (DCC)

direct thrombin inhibitors (DTIs) ACT for activated clotting time for aPTT for chromogenic factor X and for GI bleeding for HIT TEG for for VTE direct-acting oral anticoagulants (DOACs) Disability Rating Score, for aSAH disaccharides disseminated intravascular coagulation (DIC) distribution volume distributive shock disulfiram Diuretic Optimization Strategies Evaluation (DOS) diuretics. See also loop diuretics; thiazide diuretics nitroprusside and for PAH Diuril. See chlorothiazide diverticulosis DKA. See diabetic ketoacidosis D-lactate DO2. See oxygen delivery DOACs. See direct-acting oral anticoagulants

dobutamine (Dobutrex) for ADHF for aSAH for PAH for septic shock dofetilide donor-derived infections dopamine for ADHF for AKI for aSAH cocaine and for PAH for septic shock in children Dopamine in Acute Decompensated Heart Failure (DAD-HF) dopaminergics doripenem DOS. See Diuretic Optimization Strategies Evaluation doxapram doxycycline DRHC. See drug-related hazardous condition DRIs. See dietary reference intakes DRIVE. See Drug Interaction Evidence Evaluation dronedarone drotrecogin alfa drug clearance antibiotics

of anticoagulants in CRRT with ECMO ECMO and liver and plasmapheresis and with RRT drug dosing in AKI in ALF for aminoglycosides of antifungals of antimicrobials of antivirals for EN for fluid resuscitation MARS and for morbid obesity obesity and PD for PK for for PPH in pregnancy in special populations therapeutic plasma exchange and for underweight patients Drug Interaction Evidence Evaluation (DRIVE)

Drug Interaction Probability Scale (DIPS) drug shortages causes of impact of management strategies for drug-drug interactions (DDIs) absorption and with anticoagulants with antiplatelets with antiretrovirals CYP and, displacement in evaluation of PD and P-glycoprotein and PK of protein binding and QT interval and renal system and drug-induced AKI drug-induced liver injury (DILI) drug-nutrient interactions drug-related hazardous condition (DRHC) DTIs. See direct thrombin inhibitors dTT. See diluted thrombin time dual antiplatelet therapy (DAPT) dual mechanism block

durable implantable VADs Dutch Pharmacogenetics Working Group DVT. See deep venous thrombosis dysoxia dyspepsia dysphagia dyspnea

E Early Albumin Resuscitation in Septic Shock (EARSS) early brain injury Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation Acute Coronary Syndrome (EARLY-ACS) Early Goal-Directed Therapy (EGDT) Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) EARSS. See Early Albumin Resuscitation in Septic Shock Eastern Association for Surgery of Trauma Ebola virus EBV. See Epstein-Barr virus ecarin clotting time ECASS. See European Cooperative Acute Stroke Study ECF. See enterocutaneous fistula; extracellular fluid ECG. See electrocardiogram echinocandins echocardiography for electrical injuries for PAH

TEE for thrombosis TTE ECLIPSE. See Evaluation of Clevidipine in the Perioperative Treatment of Hypertension Assessing Safety Events ECLS. See extracorporeal life support ECMO. See extracorporeal membrane oxygenation E-Codes ECPR. See extracorporeal cardiopulmonary resuscitation ecstasy eczema ED95 EDD. See extended daily hemodialysis EDEN study edoxaban Edwards, NM EEG. See electroencephalography efavirenz effective SID Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q wave Coronary Events (ESSENCE) Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) Effient. See thienopyridine efflux pumps EG-1962

EGDT. See Early Goal-Directed Therapy eicosanoids EKOS catheters electrical injuries electrocardiogram (ECG) for ACS for AF for AV block for electrical injuries IABP and for PAH potassium and for SCA electroencephalography (EEG) for cerebral vasospasm for SE electrolyte disorders. See also calcium; magnesium; phosphorus; potassium; sodium agitation and asthma and bradycardia and Dengue fever and malignant hyperthermia and replacement protocols for TLS and VT and electroneutrality

ELISA. See enzyme-linked immunoassay Elsharnouby, NM emphysema EN. See enteral nutrition enalaprilat encainide encephalitis endocarditis endocrine disorders. See also pheochromocytoma adrenal disorders thyroid endophthalmitis endoscopy, for GI bleeding endothelial growth factor endothelial nitric oxide synthase (eNOS) endothelin receptor antagonists endothelin type A (ETA) endothelin type B (ETB) endothelin-1 endothelin-1 antagonists endothelium, hypertensive crisis and endotracheal intubation antibiotics and for children for hypermagnesemia for SA in children for SCA for trauma

VAP and Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) energy expenditure, guidelines for eNOS. See endothelial nitric oxide synthase enoxaparin for ACS for GI bleeding for NSTE ENT-1. See equilibrative nucleoside transporter 1 enteral nutrition (EN) for burns drug dosing for glutamine in pancreas and RDA with SRMD and for TBI Enterobacter spp. Enterobacteriaceae Enterococcus spp. VRE enterocutaneous fistula (ECF) enterovirus enzyme-linked immunoassay (ELISA) EPaNIC. See Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients

EPIC II. See Extended Prevalence of Infection in Intensive Care epinephrine AMI and for anaphylactic shock for asthma cocaine and EN and myocardial ischemia and in pregnancy ROSC and for SCA for septic shock epistaxis epoprostenol Epstein-Barr virus (EBV) eptifibatide equilibrative nucleoside transporter 1 (ENT-1) ergot alkaloids ertapenem erythrocyte sedimentation rate erythromycin ESBL. See extended-spectrum beta lactamase ESC. See European Society of Cardiology ESCAPE. See Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke; Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness Escherichia coli

esmolol esomeprazole esophageal varices ESPEN. See European Society for Parenteral and Enteral Nutrition ESSENCE. See Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events estrogen eszopiclone ETA. See endothelin type A ETB. See endothelin type B ethylene glycol etodolac EU-PACT. See Therapy

European

Pharmacogenetics

of

Anticoagulant

European Cooperative Acute Stroke Study (ECASS) European Medicines Agency, PH and European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) European Society for Parenteral and Enteral Nutrition (ESPEN) European Society of Cardiology (ESC) euvolemia euvolemic hypernatremia Evaluation of Clevidipine in the Perioperative Treatment Hypertension Assessing Safety Events (ECLIPSE)

of

Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) EVEREST. See Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan excretion, of drugs

exercise testing, for PAH extended daily hemodialysis (EDD) Extended Prevalence of Infection in Intensive Care (EPIC II) extended-spectrum beta lactamase (ESBL) extended-spectrum penicillins Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intraarterial (EXTEND-IA) extracellular fluid (ECF) ECMO and hyperphosphatemia and hypophosphatemia and sodium bicarbonate and extracorporeal cardiopulmonary resuscitation (ECPR) extracorporeal life support (ECLS) extracorporeal membrane oxygenation (ECMO) AKI and analgesia and antimicrobials and MCs and for PAH PK and RRT and Vd and extra-NMJ actions, of NMBAs extrinsic pathway ezetimibe

F T>MIC. See time during which unbound/free drug concentration remains above the pathogen MIC factor eight inhibitor bypassing inhibitor activity (FEIBA) FACTT. See Fluids and Catheters Treatment Trial FACTT Lite. See Fluid and Catheter Treatment Trial Lite famotidine Fanconi syndrome Faraklas, I fasciculations, NMBAs and FAST. See focused assessment with sonography for trauma fatty liver of pregnancy FDA. See Food and Drug Administration FEAST. See Fluid Expansion as Supportive Therapy febrile neutropenia (FN) FEIBA. See factor eight inhibitor bypassing inhibitor activity FENa. See fractional excretion of sodium fenfluramine fenoldopam fentanyl delirium from ECMO and in pregnancy FEV1. See forced expiratory volume in 1 second fever aSAH and

Dengue Lassa rheumatic TBI in children and VHFs yellow FFP. See fresh frozen plasma fibrin degradation product. See D-dimer fibrinogen fibrinolysis GPIIb/IIIa inhibitors and ICH and for PE for STEMI Figge-Stewart approach Finsterer, U flecainide Flolan fluconazole for burns for Candida CYP and for neutropenia pregnancy and flucytosine fludrocortisone Fluid and Catheter Treatment Trial Lite (FACTT Lite)

fluid creep Fluid Expansion as Supportive Therapy (FEAST) fluid resuscitation. See also colloids; crystalloids acid-base disorders and for AKI for ARDS for aSAH for burns coagulopathy and CVP and distribution by body compartment drug dosing for future directions for for GI bleeding for hemorrhage for hemorrhagic shock for hyperglycemic emergencies for hypernatremia for hypovolemic shock for influenza MAP and for metabolic acidosis monitoring of for obstructive shock peripheral line administration for RCT for reviews and guidelines for

for rhabdomyolysis for SA in children for septic shock for shock for stroke for TBI in children for TIC for TLS TTE for for underweight patients vasopressors and Vss and Fluids and Catheters Treatment Trial (FACTT) flumazenil fluoroquinolones DDIs with ECMO and for morbid obesity pregnancy and thrombocytopenia and fluoxetine fluvoxamine FN. See febrile neutropenia focused assessment with sonography for trauma (FAST) fondaparinux anticoagulant reversal for for STEMI

Food and Drug Administration (FDA) acetylcysteine and Adverse Event Reporting System of antibiotics and anticoagulant testing and antimicrobial drug dosing and antipsychotics and DDIs and drug shortages and ecarin clotting time and endothelin receptor antagonists and epoprostenol and ertapenem and fondaparinux and GHB and glucose management and hemodialysis and gentamicin and hydroxycobalamin and iloprost and NephroCheck and nimodipine and omega-3 fatty acids and pancreatic enzymes and PCR and PH and recombinant human activated protein and on ribavirin

riociguat and sildenafil and simvastatin and teduglutide and TPA and VADs and forced expiratory volume in 1 second (FEV1) forced vital capacity (FVC) foscarnet fosfomycin fosphenytoin FOUR. See Full Outline of Unresponsiveness fractional excretion of sodium (FENa) frank hematemesis Frank-Starling curve free radicals free thyroxine (FT4) FREEDOM C fresh frozen plasma (FFP) for ALF for anticoagulant reversal for cirrhosis DTIs and for GI bleeding for hemorrhagic shock in MTP VKA and

frostbite FT4. See free thyroxine Full Outline of Unresponsiveness (FOUR) fungal infections AF and dimorphic fusariosis molds mucormycosis rapid diagnostic tools for scedosporiosis yeasts furosemide (Lasix) fusariosis FVC. See forced vital capacity

G GABA. See γ-aminobutyric acid gabapentin galactomannan galactomannan antigen detection assays ganciclovir ganglionic blockade, with NMBAs gangliosides Garnacho-Montero, J gastroesophageal reflux

gastrointestinal system (GI) acid-base disorders and antibiotic drug absorption and antifungals and bleeding anticoagulant reversal for anticoagulants and, reintroduction of antiplatelets and, reintroduction of with clopidogrel colonoscopy for diagnosis of endoscopy for hemostatic agents for with hypovolemic shock initial management for lower Mallory-Weiss tears and NSAIDs and from peptic ulcer disease prevention of rebleeding with spontaneous bacterial peritonitis and SRMd and stress ulcer prophylaxis for upper CRE and FN and

hypercalcemia and hypokalemia and hypomagnesemia and hypophosphatemia and hypothyroidism and metabolic alkalosis and mixed acid-base disorders and nutrition and opioids and SCI and TBI and gate control theory GBS. See Guillain-Barré syndrome GCS. See Glasgow Coma Scale GDMT. See guideline-directed medical therapy Geerts, WH gemtuzumab genetics ACOS and aSAH and coagulopathy and MDR and pheochromocytoma SE and TdP and GeneXpert, for methicillin-susceptible Staphylococcus aureus genome-wide association studies (GWAS)

gentamicin GFR. See glomerular filtration rate GH. See growth hormone GHB. See γ-hydroxybutyrate GI. See gastrointestinal system Gibbon, J., Jr. GINA. See Global Initiative for Asthma GLA. See γ-linolenic acid Glanzmann disease Glasgow Coma Scale (GCS) for aSAH BCVIs and for ICH for TBI Glasgow Outcomes Scale-Extended Global Initiative for Asthma (GINA) Global Initiative for Chronic Obstructive Lung Disease (GOLD) Global Registry of Acute Coronary Events (GRACE) Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) glomerular filtration rate (GFR) GLP. See glucagon-like peptide; Good Laboratory Practices glucagon glucagon-like peptide (GLP) glucocorticosteroids Glucontrol study glucose. See also hyperglycemia; hypoglycemia

aSAH and burns and hypernatremia and ICH and management of clinical management team in guidelines for hyperglycemic emergency management insulin for medications for monitoring in multidisciplinary steering committee in primary literature summary for RCT for future team approach to metabolic acidosis and nutrition and shock and stress response and stroke and GLUT-4 glutamate glutamine glutathione glycemic variability glycine glycoprotein (GP)

glycoprotein IIb/IIIa (GPIIb/IIIa) ACS and ACT and inhibitors of thrombocytopenia and GNB. See gram-negative bacilli GOLD. See Global Initiative for Chronic Obstructive Lung Disease Goldstein, B Good Laboratory Practices (GLP) Goodpasture syndrome GP. See glycoprotein GPIIb/IIIa. See glycoprotein IIb/IIIa GRACE. See Global Registry of Acute Coronary Events gram stains gram-negative bacilli (GNB) antimicrobials for as donor-derived infection neurosurgical infections and peptic ulcer disease from vancomycin and VAP from gram-negative blood culture test (BC-GN) gram-positive bacteria gram-positive blood culture test (BC-GP) Griffith, Harold growth hormone (GH) rhGH

guanfacine guanylate cyclase guideline-directed medical therapy (GDMT) Guillain-Barré syndrome (GBS) Gunnerson, KJ GUSTO. See Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries GWAS. See genome-wide association studies

H H1N1 H2RBs. See histamine-2 receptor antagonists HAART. See highly active antiretroviral therapy habitus Haemophilus influenzae hairy leukoplakia (HLP) HAIs. See health-care associated infections haloperidol CYP and delirium and halothane Hamburger, Hartog HAP. See hospital-acquired pneumonia haptoglobin Harris-Benedict equations Hartford nomogram

Hartman, ME Hartmann, Alexis Hartmann’s solution HBO. See hyperbaric oxygen HCAP. See health care-associated pneumonia HCM. See hypercalcemia of malignancy HCT. See hematopoietic cell transplantation headache with aSAH endothelin receptor antagonists and hypertensive crisis and pheochromocytoma riociguat and health care-associated pneumonia (HCAP) health-care associated infections (HAIs) heart block heart failure (HF). See also acute decompensated heart failure AF and bradycardia and congestive hypertensive crisis and metabolic acidosis and renal failure from SCA and succinylcholine and VT and VTE and

heart failure with reduced ejection fraction (HFrEF) heart-lung transplantation HeartMate II HeartWare Helicobacter pylori heliox HELLP syndrome. See hemolysis, elevated liver enzymes, low platelets hematochezia hematopoietic cell transplantation (HCT) hematopoietic growth factors hemochromatosis Hemoclot thrombin inhibitor hemodialysis CYP and for HCM for hyperkalemia for TdP hemodilution, for aSAH hemoglobinuria hemolysis, elevated liver enzymes, low platelets (HELLP syndrome) hemorrhage. See also specific types with anticoagulants with cirrhosis fluid resuscitation for hemostatic agents for in pregnancy

with surgery trauma and hemorrhagic conversion hemorrhagic shock hemorrhagic stroke hemorrhoids hemostasis measuring hemostatic agents for GI bleeding for hemorrhage hemothorax Henderson-Hasselbalch equation heparin. See also low-molecular weight-heparin; unfractionated heparin for BCVIs for inhalation injury MCS and heparin-induced thrombocytopenia (HIT) DTIs for IHD and in pregnancy hepatic encephalopathy hepatic insufficiency hepatic system. See liver hepatitis A virus hepatitis B virus hepatitis C virus

hepatitis E virus hepatocytes Heptest Heptest-Stat herbal preparations Herget-Rosenthal, S herpes simplex virus (HSV) herpes zoster HES. See hydroxyethyl starch Heshmati, F Hespan Hessels, L Hextend HF. See heart failure HFrEF. See heart failure with reduced ejection fraction HHS. See hyperglycemic hyperosmolar state hiatal hernia, Mallory-Weiss tears from HIE. See hyperinsulinemia-euglycemia highly active antiretroviral therapy (HAART) His-Purkinje system histamine histamine-2 receptor antagonists (H2RAs) for SRMD in children histoplasmosis HIT. See heparin-induced thrombocytopenia HIV/AIDS CMV and Cryptococcus neoformans and

defining conditions of EBV and HAART for HSV and immunosuppression in MAC and PAH and PJP and prophylaxis for TE and thrombocytopenia and underweight patients with VZV and HLA. See human leucocyte antigens HLA-B*1502 HLA-B*5701 HLP. See hairy leukoplakia Hodgkin lymphoma homocysteine horny goat weed hospital-acquired pneumonia (HAP) HSV. See herpes simplex virus Human Genome Project human immunodeficiency virus (HIV). See HIV/AIDS human leucocyte antigens (HLA) Hunt and Hess score, for aSAH hydralazine

hydrocephalus hydrochloric acid hydrochlorothiazide (Microzide) hydrocortisone hydrogen ion acidosis hydromorphone hydrophilic drugs hydrophobia hydroxocobalamin β-hydroxybutyrate γ-hydroxybutyrate (GHB) hydroxycobalamin. See vitamin B12 hydroxycut hydroxyethyl starch (HES) hydroxymethylglutaryl coenzyme A reductase hydroxyzine Hygroton. See chlorthalidone hyperaldosteronism hyperammonemia hyperbaric oxygen (HBO) hypercalcemia hypercalcemia of malignancy (HCM) hypercapnia hypercarbia hyperchloremic metabolic acidosis hyperglycemia

AIS and aSAH and burns and causes of hypernatremia and hypomagnesemia and ICH and metabolic acidosis and nutrition and SSIs and stress response and hyperglycemic emergencies hyperglycemic hyperosmolar state (HHS) hyperinsulinemia-euglycemia (HIE) hyperkalemia bradycardia and lactated Ringer and management of MCS and SCA and from succinylcholine succinylcholine and TLS and treatment for hyperlactatemia hypermagnesemia hypernatremia

hyperosmolarity hyperparathyroidism hyperphosphatemia hypertension. See also pulmonary arterial hypertension AF and AIS and APH aSAH and cocaine and CS and intra-abdominal PH portal PPHN hypertensive crisis aSAH and blood pressure and clinical presentation of diagnosis of end-organ damage from epidemiology of ICH and laboratory testing for pathophysiology of in pregnancy pregnancy and retinopathy and

special considerations with treatment for hypertensive encephalopathy hyperthermia baclofen withdrawal and malignant SCI and hypertonic hypertonic hyponatremia hypertonic saline for SIADH for TBI ICP in children hypertonic sodium chloride hypertriglyceridemia hyperuricemia hyperventilation hypervolemia hypoalbuminemia hypoaldosteronism hypocalcemia hypocaloric feeding hypoglycemia ALF and aSAH and in children cocaine and

ICH and myxedema coma and SCA and stroke and hypokalemia SCA and VT and hypomagnesemia hyponatremia aSAH and assessment of clinical manifestations of etiology of management of ODS and overcorrection of severely symptomatic SIADH and vasopressin receptor antagonists in hypoparathyroidism hypophosphatemia hypotension ADEs and AF and ALF and anaphylactic shock and Dengue fever and

DKA and hypermagnesemia and hypocalcemia and malignant hyperthermia and metabolic acidosis and nitroglycerin and propofol and refractory riociguat and SCI and severe sepsis and septic shock and shock and SRMD and TBI in children and VHFs and hypothermia. See also therapeutic hypothermia bradycardia and in children coagulopathy and CYP and with hypovolemic shock for ICH malignant hyperthermia and myxedema coma and SCA and SCI and TBI in children and

TIC and hypothyroidism hypotonic hypotonic hyponatremia hypovolemia hypovolemic hypernatremia hypovolemic shock in children plasmapheresis and renal failure from hypoxanthine hypoxemia COPD and hypothyroidism and influenza and SCI and succinylcholine and hypoxia

I IABP. See intra-aortic balloon pump IABP-SHOCK II. See Intraaortic Balloon Pump in Cardiogenic Shock Ibrahim, RB ibuprofen ibutilide IBW. See ideal body weight ICDSC. See Intensive Care Delirium Screening Checklist

ICF. See intracellular fluid ICH. See intracranial hemorrhage ICP. See intracranial pressure ICS. See inhaled corticosteroids ICUAW. See intensive care unit-acquired weakness I-C-U-D-E-L-I-RI-U-M-S mnemonic idarucizumab ID/AST system ideal body weight (IBW) IDSA. See Infectious Diseases Society of America IgA. See immunoglobulin A IgE. See immunoglobulin E IGFBP-7. See insulin-like growth factor binding protein 7 IgG. See immunoglobulin G IgM. See immunoglobulin M IHD. See intermittent hemodialysis IHI. See Institute for Healthcare Improvement IL. See interleukins iloprost imipenem immune reconstitution inflammatory syndrome (IRIS) immunoglobulin A (IgA) immunoglobulin E (IgE) immunoglobulin G (IgG) immunoglobulin M (IgM) immunosuppression. See also HIV/AIDS; tumor lysis syndrome CNI neurotoxicity and

in DAH donor-derived infections and in FN in HIV in PERDS IMPACT-HF. See Initiation Management Predischarge Process for Assessment of Carvedilol Therapy in Heart Failure Impella IMPROVE. See International Medical Prevention Registry on Venous Thromboembolism Infectious Diseases Society of America (IDSA) inferior vena cava (IVC), filters inflammatory bowel disease influenza inhalation injury inhaled corticosteroids (ICS) inhaled nitric oxide Initiation Management Predischarge Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) Injury Severity Score (ISS) innate immune system inodilators inotropes INR. See international normalized ratio Institute for Healthcare Improvement (IHI) insulin for burns

DKA and potassium and resistance, stress response and insulin-like growth factor binding protein 7 (IGFBP-7) Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) Intensive Care Delirium Screening Checklist (ICDSC) intensive care unit–acquired weakness (ICUAW) INTERACT. See Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) interferon-α interferon-β interferon-γ interleukins (IL) IL-1 IL-1b IL-6 IL-10 INTERMACS. See Interagency Registry for Mechanically Assisted Circulatory Support intermittent hemodialysis (IHD) International Medical Prevention Thromboembolism (IMPROVE) international normalized ratio (INR) ALF and for anticoagulant testing

Registry

on

Venous

chromogenic factor X and clotting factors and coagulopathy and for DTIs PAH and PCCs and for TIC VKA and for warfarin International SCI Pain Basic Data Set international sensitivity index (ISI) International Society for Heart & Lung Transplantation (ISHLT) International Society for Pharmaceutical Engineering (ISPE) International Subarachnoid Aneurysm Trial (ISAT) intra-abdominal hypertension intra-aortic balloon pump (IABP) Intraaortic Balloon Pump in Cardiogenic Shock (IABP-SHOCK II) intra-arterial catheters intracellular fluid (ICF) Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) intracranial hemorrhage (ICH) ALF and anticoagulant reversal for antiplatelet reversal for blood pressure and DAPT and

fibrinolysis and hypernatremia and hypertensive crisis and seizures and thermoregulation for TPA and VKA for VTE and intracranial pressure (ICP) ALF and antimicrobial prophylaxis and aSAH and bradycardia and CSF shunting devices and ICH and NMBAs for respiratory alkalosis and TBI and in children and hyperosmolarity and intrarenal (intrinsic) AKI intravenous immunoglobulins (IVIG) Intravenous Nimodipine West European Stroke Trial (INWEST) intrinsic pathway intrinsic positive end-expiratory pressure (PEEPi) invasive fungal infections (IFIs). See fungal infections INWEST. See Intravenous Nimodipine West European Stroke Trial

IRIS. See immune reconstitution inflammatory syndrome iron, antioxidants and ISAR-REACT. See Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment ISAT. See International Subarachnoid Aneurysm Trial isavuconazole ischemia-driven strategy ischemic colitis ischemic penumbra ISHLT. See International Society for Heart & Lung Transplantation ISI. See international sensitivity index isoflurane isoniazid isotonic isotonic hyponatremia ISPE. See International Society for Pharmaceutical Engineering ISS. See Injury Severity Score itraconazole IVC. See inferior vena cava IVIG. See intravenous immunoglobulins

J James equation Janmahasatian, S Japanese encephalitis Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7)

Joint Section on Disorders of the Spine and Peripheral Nerves

K Kahn, SA Kane-Gill, SL Kcentra KCH. See King’s College Hospital criteria KCNH2 KDIGO. See Kidney Disease Improving Global Outcomes ketamine bradycardia from CYP and for SE ketoacidosis ketoconazole ketones ketorolac Kew, KM kidney. See also acute kidney injury; chronic kidney disease ALF and ammonium and cirrhosis and drug clearance and hyperphosphatemia and respiratory acidosis and volatile anesthetics and

Kidney Disease Improving Global Outcomes (KDIGO) kidney failure King’s College Hospital (KCH) criteria, for ALF Kiser, TH Klebsiella pneumoniae Klebsiella spp. Korotkoff sounds Kress, JP Kruse, JA Kuf. See ultrafiltration coefficient Kurtz, I Kussmaul respirations

L LABAs. See long-acting β-agonists labetalol laboratory testing for ADHF for AKI for anticoagulants chromogenic factor X and Heptest and Heptest-Stat for methods for regulatory requirements for samples for ASPs for

for hypertensive crisis for SE laboratory TLS (LTLS) lacosamide β-lactam antibiotics for burns ESBL for morbid obesity PBPs and pregnancy and TDM for thrombocytopenia and lactate metabolic acidosis and shock and lactate dehydrogenase (LDH) lactated Ringer for burns for hyperchloremic metabolic acidosis for hypovolemic shock lactic acidosis lactulose LAMB. See liquid formulations of amphotericin B lamivudine lansoprazole Lasix. See furosemide Lassa fever

laudanosine Lazarus-Barlow, WS LBBB. See left bundle branch block LBW. See lean body weight LDH. See lactate dehydrogenase lean body weight (LBW) left bundle branch block (LBBB) left ventricle (LV) failure hypertrophy left ventricular assist devices (LVADs) Legionella pneumophila length of stay (LOS) AF and arginine and aSAH and methadone and omega-3 fatty acids and PN and lethal triad leucovorin leukemia leukopenia leukotriene inhibitors leukotriene receptor antagonists Leuven MICU trial Leuven SICU trial

levalbuterol levetiracetam levocarnitine levodopa levofloxacin levosimendan levothyroxine Leykin, Y lidocaine for SCA for VT ligament of Treitz LightCycler SeptiFast Test Lillehei, C. Walton LiMAx test Lin, H linezolid for burns ECMO and for FN for morbid obesity for MRSA P-glycoprotein and for serotonin syndrome thrombocytopenia and γ-linolenic acid (GLA) lipophilic drugs

liquid formulations of amphotericin B (LAMB) LIS. See lung injury score lithium carbonate liver acid-base disorders and anticoagulants and cirrhosis and coagulopathy and drug clearance and nitrogen and NMBAs and nutrition and potassium in stress response and volatile anesthetics and warfarin and liver failure. See also acute liver failure agitation and SE and SRMD and VTE and liver transplantation. See orthotopic liver transplantation LMWH. See low-molecular weight-heparin lofexidine log P lomefloxacin long QT syndrome (LQTS)

long-acting β-agonists (LABAs) loop diuretics for ADHF pregnancy and loop of Henle lopinavir/ritonavir lorazepam LOS. See length of stay lovastatin low-molecular weight-heparin (LMWH) for ACS coagulant reversal for for GI bleeding INR for for morbid obesity in pregnancy for underweight patients for VTE LQTS. See long QT syndrome LTLS. See laboratory TLS L-tryptophan Ludwig, KP Lugol solution lung ALI cancer transplantation

lung injury score (LIS) LV. See left ventricle LVADs. See left ventricular assist devices lymphoma lymphopenia

M MA. See maximum amplitude MAC. See Mycobacterium avium complex macitentan macrolides macronutrients macrophages magnesium. See also hypermagnesemia; hypomagnesemia for aSAH for SA in children Magnesium for Aneurysmal Subarachnoid Hemorrhage (MASH-2) magnesium sulfate magnetic resonance imaging (MRI) for aortic dissection for aSAH for cerebral vasospasm for HSV for ICH for MSCC for SVC

for VZV Ma-Huang maintenance fluid administration MALDI-TOF MS. See matrix-assisted laser desorption ionization time of flight mass spectrometry malignant hyperthermia malignant spinal cord compression (MSCC) Mallory-Weiss tears malnutrition manganese mannitol MAOIs. See monamine oxidase inhibitors MAP. See mean arterial pressure Maquet Bioline Maquet Cardiopulmonary AG Maquet Safeline Maquet Softline Marburg virus Marfan syndrome MARS. See molecular adsorbent recirculating system Martyr d’Anghiera, Peter MASH-2. See Magnesium for Aneurysmal Subarachnoid Hemorrhage massage massive transfusion protocols (MTPs) for PPH for TIC for trauma

MATE1. See multidrug and toxin extrusion transporter 1 matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) MATTERs. See Military Application of Tranexamic Acid in Trauma Emergency Resuscitation maximum amplitude (MA) maximum clot firmness (MCF) MCA. See middle cerebral artery McDonald, M MCF. See maximum clot firmness McGill Pain Questionnaire MCS. See mechanical circulatory support MDI. See metered dose inhaler MDR. See multidrug-resistant bacteria MDRD. See Modified Diet in Renal Disease mean arterial pressure (MAP) aSAH and EN and IABP for phenylephrine and stroke and TBI in children and vasopressors and mean pulmonary artery pressure (mPAP) measles mechanical circulatory support (MCS) for ADHF anticoagulants and antithrombotics and

coagulopathy and comorbidities and complications of devices hemolysis and indications for infection treatment and prevention for landmarks in pharmacological challenges with PK of thrombosis and mechanical ventilation (MV) acid-base disorders and AF and agitation and antibiotic drug clearance and antimicrobial prophylaxis at for aSAH for asthma for children CMV and for COPD for coronavirus CVP and delirium and for hypovolemic shock iloprost and

for myxedema coma NMBAs and nutrition and in pregnancy for respiratory acidosis for SCI TPA and medical intensive care unit (MICU) medication errors (MEs) active surveillance for epidemiology of medication safety and systems analysis of medication withdrawal. See withdrawal Medtronic Carmeda Medtronic Trillium melanoma MELD. See Model for End-Stage Liver Disease melphalan MELT. See middle cerebral artery embolism Melzack, R MEN 2. See multiple endocrine neoplasia type 2 meningitis meperidine meropenem MERS. See Middle East respiratory syndrome MEs. See medication errors

mesenchymal stem cell transplantation mesenteric ischemia meta-analysis metabolic acidosis AG and respiratory alkalosis and delirium and hyperkalemia and hypertensive crisis and hypoalbuminemia and nitroprusside and Plasma-Lyte for rhabdomyolysis and SBE and secondary responses to serum bicarbonate and metabolic alkalosis metanephrines, for pheochromocytoma METAPLUS trials metered dose inhaler (MDI) methadone methamphetamines methanol methemoglobinemia methicillin-resistant Staphylococcus aureus (MRSA) antimicrobials resistance and as donor-derived infection

HCT and SSIs and methicillin-susceptible Staphylococcus aureus (MSSA) methimazole methotrexate methoxamine methyldopa methylergonovine methylprednisolone for COPD for DAC for PERDS in pregnancy for SCI methylxanthines metoclopramide metolazone (Zaroxolyn) metronidazole antiretrovirals and CYP and for H. pylori for hepatic encephalopathy metyrapone Meyhoff, CS MIC. See minimum inhibitory concentration micafungin Micrococcus spp.

microdialysis micronutrients Microzide. See hydrochlorothiazide MICU. See medical intensive care unit midazolam antiretrovirals and ECMO and for endotracheal intubation in children for rabies for SE middle cerebral artery (MCA) middle cerebral artery embolism (MELT) Middle East respiratory syndrome (MERS) midodrine mifepristone Mifflin equations Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Miller, JT milrinone (Primacor) miltefosine Milwaukee protocol, for rabies minimum inhibitory concentration (MIC) for aminoglycosides for antibacterials for antibiotics for antifungals

for antimicrobials for fluoroquinolones for β-lactam antibiotics for vancomycin mini-stroke. See transient ischemic stroke minocycline mitotane mitral regurgitation mivacurium mixed acid-base disorders Mobidiag Prove-It Sepsis modafinil Model for End-Stage Liver Disease (MELD) Modified Diet in Renal Disease (MDRD) MODS. See Multiple Organ Dysfunction Score molds molecular adsorbent recirculating system (MARS) molecular weight monamine oxidase inhibitors (MAOIs) Moraxella catarrhalis morbid obesity antibiotics for anticoagulants for antimicrobials for drug dosing for NMBAs for sedatives for

moricizine morphine for ACS ECMO and pharmacologic properties of in pregnancy Morrison, JJ mortality probability model (MPM) Morton, RP motor vehicle collisions (MVCs) Moviat, M moxifloxacin mPAP. See mean pulmonary artery pressure MPM. See mortality probability model MR CLEAN MRI. See magnetic resonance imaging MRSA. See methicillin-resistant Staphylococcus aureus MSCC. See malignant spinal cord compression MSSA. See methicillin-susceptible Staphylococcus aureus MTPs. See massive transfusion protocols mucormycosis Multidisciplinary Consensus Conference multidrug and toxin extrusion transporter 1 (MATE1) multidrug-resistant bacteria (MDR) to antimicrobials mechanisms of mutations and

P. aeruginosa as threats of multimodal analgesia multiple endocrine neoplasia type 2 (MEN 2) multiple myeloma Multiple Organ Dysfunction Score (MODS) multiple organ failure syndrome mumps mupirocin Murphy, GS muscarinic receptors muscle relaxation techniques muscular dystrophy mushroom poisoning music therapy MV. See mechanical ventilation MVCs. See motor vehicle collisions Mycobacterium avium complex (MAC) Mycobacterium tuberculosis mycophenolic acid Mycoplasma pneumoniae myocardial infarction. See acute myocardial infarction; ST-segment elevation myocardial infarction myocardial ischemia myocarditis myoglobin myotonic muscular dystrophy

myxedema coma NABIS:H II. See National Acute Brain Injury Study: Hypothermia II N-acetyl-p-benzoquinone imine (NAPQI) N-acetyltransferase nAChR. See nicotinic cholinergic receptor nafcillin Na-K-ATPase pump naloxone NAPQI. See N-acetyl-p-benzoquinone imine Narcotrend Index Narotam, PK nasal packing NASCIS. See National Acute Spinal Cord Injury Study nasogastric tube (NG) NAT. See nonaccidental trauma National Acute Brain Injury Study: Hypothermia II (NABIS: H II) National Acute Spinal Cord Injury Study (NASCIS) National Center for Shake Baby Syndrome National Comprehensive Cancer Network (NCCN) National Confidential Enquiry into Patient Outcome and Death (NCEPOD) National Coordinating Council for Medication Error Reporting and Prevention National Healthcare Safety Network National Heart, Lung, and Blood Institute (NHLBI) National Institute for Health and Care Excellence (NICE) National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health Stroke Scale (NIHSS)

National Quality Forum (NQF) National Spinal Cord Injury Statistical Center National Stroke Association National Traumatic Coma Data Bank Natrecor. See nesiritide natriuretic peptides NCCN. See National Comprehensive Cancer Network NCEPOD. See National Confidential Enquiry into Patient Outcome and Death NCS. See Neurocritical Care Society NCSE. See non-convulsive status epilepticus necrosis ALF and retinal hemorrhages and nefazodone nelfinavir neomycin neostigmine NephroCheck nephrosis nephrotoxins nesiritide (Natrecor) neuraminidase inhibitors neurocardiac syncope Neurocritical Care Society (NCS) neurofibromatosis (NF) neuromuscular blocking agents (NMBAs)

for ARDS for asthma CIP/M and cross-reactivity of for DAC depolarizing for endotracheal intubation in children extra-NMJ actions of fasciculations and ganglionic blockade with histamine and hypersensitivity and for ICP ICUAW from interactions with for intra-abdominal hypertension malignant hyperthermia and mechanism of action of monitoring of for morbid obesity muscarinic receptors and ND NMJ and obesity and pharmacologic effects of PK of pregnancy and

priming of rapid sequence intubation and RCT for reversal of for SA in children for sepsis for surgical procedures sympathetic stimulation by for TBI ICP for temperature management after cardiac arrest vagolytic actions of neuromuscular junction (NMJ) neuropathic pain neuropeptide Y neurosurgery, antimicrobial prophylaxis for neutral protamine Hagedorn (NPH) neutropenia neutrophils nevirapine New York Heart Association (NYHA) NEWTON. See Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage NF. See neurofibromatosis NF-κB. See nuclear factor kappa B NG. See nasogastric tube NHLBI. See National Heart, Lung, and Blood Institute

nicardipine NICE. See National Institute for Health and Care Excellence NICE-SUGAR. See Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation nicotine nicotine replacement therapy (NRT) nicotinic cholinergic receptor (nAChR) nicotinic receptors nifedipine NIHSS. See National Institutes of Health Stroke Scale nimodipine Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage (NEWTON) NINDS. See National Institute of Neurological Disorders and Stroke Nipride. See nitroprusside nitrates nitric oxide cGMP and eNOS inhaled nitroglycerin and nitrofurantoin nitrogen nitroglycerin nitroprusside (Nipride) for ADHF for aortic dissection

DKA and for hypertensive crisis pregnancy and for septic shock in children nitrous oxide, aSAH and NIV. See noninvasive ventilation NKCC. See sodium-potassium-chloride cotransporter NMBAs. See neuromuscular blocking agents N-methyl-d-aspartate (NMDA) NMJ. See neuromuscular junction NOACs. See nonvitamin K antagonist oral anticoagulants Nogo-A nonaccidental trauma (NAT) non-convulsive status epilepticus (NCSE) non-Hodgkin lymphoma noninvasive positive pressure ventilation noninvasive ventilation (NIV) non-opioids nonpharmacologic therapy for agitation for ALF for analgesia for delirium prevention for SCA for SE non-preventable ADE nonresponsiveness

non-small cell lung cancer nonsteroidal anti-inflammatory drugs (NSAIDs) AKI from ALF from for aSAH asthma and CYP and delirium from GI bleeding from Mallory-Weiss tears from peptic ulcer disease from for procedural pain SIADH and non-ST-segment elevation (NSTE) antithrombotics for nonvitamin K antagonist oral anticoagulants (NOACs) norepinephrine for aSAH cocaine and for PAH for septic shock in children for shock for underweight patients norfloxacin normal saline Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation (NICE-SUGAR)

NOR-TEST Norwood, SH NPH. See neutral protamine Hagedorn NQF. See National Quality Forum NRS. See numeric rating scale NRT. See nicotine replacement therapy NRTIs. See nucleotide/nucleoside reverse transcriptase inhibitors NSAIDs. See nonsteroidal anti-inflammatory drugs NSTE. See non-ST-segment elevation nuclear factor kappa B (NF-κB) nucleic acid testing nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs) numeric rating scale (NRS), for pain assessment NUTRIC. See Nutrition Risk in the Critically Ill nutrition assessment of for burns burns and diabetes and drug-nutrient interactions glucose and hyperglycemia and liver and macronutrients and malnutrition and micronutrients and MV and

pancreas and renal system and respiratory system and for SCI stress response and for TBI timing and route of support for underfeeding vs. full nutrition Nutrition Risk in the Critically Ill (NUTRIC) NYHA. See New York Heart Association O OASIS. See Organization to Assess Strategies in Acute Ischemic Syndromes OATP1B1. See organic anion transporting polypeptide 1B1 OATs. See organic anion transporters obesity. See also morbid obesity AF and antimicrobials and CS and drug dosing and fondaparinux and NMBAs and PK and SE and UHF and Vss and VTE and obstructive shock

Octaplex octreotide OCTs. See organic cation transporters ODS. See osmotic demyelination syndrome odynophagia ofloxacin OI. See opportunistic infection oliguria OLT. See orthotopic liver transplantation omega-3 fatty acids omeprazole oncotic pressure ondansetron Operational Classification (ORCA) opiate antagonists opioids for ACS for agitation agitation and in analgosedation approach to analgesia CYP and NMBAs and pharmacologic properties of in pregnancy SIADH and withdrawal from opportunistic infection (OI)

dimorphic fungi OPTIMIZE-HF. See Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure oral antidiabetic medications oral contraceptives ORCA. See Operational Classification Orenitram. See treprostinil organic anion transporters (OATs) organic anion transporting polypeptide 1B1 (OATP1B1) organic cation transporters (OCTs) Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS) Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) oritavancin Orrell equation orthostatic hypotension orthotopic liver transplantation (OLT) oseltamivir osmolality osmolarity osmotic demyelination syndrome (ODS) osteoporosis ovarian cancer overshoot alkalosis oxandrolone oxazepam

oxcarbazepine Oxepa oxygen consumption (VO2) oxygen delivery (DO2) oxygen therapy for ACS for asthma and COPD for respiratory acidosis for respiratory distress in children for SA in children oxyhemoglobin oxyiminoalkanoic acid oxytocin

P P selectin P waves P2Y inhibitors PAC. See pulmonary arterial catheters pacemakers packed red blood cells (PRBCs) Paco2 DKA and metabolic acidosis and metabolic alkalosis and respiratory acidosis and

respiratory alkalosis and PAD. See pain, agitation, and delirium Paget disease PAH. See pulmonary arterial hypertension PAI-1. See plasminogen activator inhibitor-1 pain with ACS with aSAH assessment of for communicative patients for noncommunicative patients gate control theory of hypertensive crisis and with SCI pain characteristics in low back pain syndrome (PQRST) pain, agitation, and delirium (PAD) palivizumab pamidronate pancreas pancreatic cancer pancreatitis Pancreaze pancuronium pantoprazole papilledema paradoxical breathing paradoxical worsening

parasympathetic nervous system parathyroid hormone (PTH) HCM and parenteral nutrition (PN) Parikh, AA Parkland formula paroxetine paroxysmal supraventricular tachycardia (PSVT), paroxysmal sympathetic hyperactivity partial thromboplastin time (PTT) parvovirus B19 Patient Registry for Primary Pulmonary Hypertension Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) PBP2a transpeptidase PBPs. See penicillin-binding proteins PCCs. See prothrombin complex concentrates PCI. See percutaneous coronary intervention PCR. See polymerase chain reaction PCT. See procalcitonin PCWP. See pulmonary capillary wedge pressure PD. See pharmacodynamics PDE-5. See phosphodiesterase type 5 PE. See pulmonary embolism PEA. See pulseless electrical activity peak expiratory flow rate (PEFR) pediatrics. See children

PEEP. See positive end-expiratory pressure PEEPi. See intrinsic positive end-expiratory pressure PEFR. See peak expiratory flow rate penicillin extended-spectrum penicillin-binding proteins (PBPs) Penn State equations pentobarbital peptic ulcer disease peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) peramivir percutaneous coronary intervention (PCI) PERDS. See peri-engraftment respiratory distress syndrome pericarditis peri-engraftment respiratory distress syndrome (PERDS) peripheral line administration peripheral nerve stimulation/train-of-four (PNS/TOF) peripherally inserted central catheter (PICC) peristalsis peritoneal dialysis peritonitis permanent AF permanent pacemaker devices (PPDs) perphenazine persistent inflammation-immunosuppression catabolism syndrome (PICS) persistent pulmonary hypertension (PPHN) personal protective equipment (PPE)

Pertzye PGI2. See prostaglandin I2 P-glycoprotein PH. See pulmonary hypertension Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM) pharmacodynamics (PD) in ADHF of aminoglycosides of antibacterials of antibiotics of antifungals of antimicrobials for burns drug dosing of goals for limitations of for sepsis and septic shock of antiprotozoal of antivirals basic principles of of clopidogrel DDIs and for drug dosing of fluoroquinolones of β-lactam antibiotics, prolonged and continuous infusions of of linezolid

pharmacogenomics and with plasmapheresis of vancomycin pharmacoeconomics pharmacogenomics CYP polymorphisms and HLA and incorporating into patient care KCNH2 and N-acetyltransferase and PK and SLCO1B1 genotype and TNF-α and VKOR and Pharmacogenomics Knowledgebase Pharmacogenomics Research Network pharmacokinetics (PK) in ADHF in ALF of aminoglycosides of antibacterials of antifungals of antimicrobials alterations in critical illness of antimicrobials, changes in drug absorption for burns drug clearance for drug dosing of half-life of

limitations of protein binding and for sepsis and septic shock Vss for of antiprotozoal of antivirals of cefazolin for chronic kidney disease CYP polymorphisms and of DDIs for drug dosing ECMO and of fluoroquinolones of linezolid of MCS of NMBAs obesity and pharmacogenomics and for SCA underweight patients and of vancomycin pharmacy services management hospital and justification for leadership in medication costs and optimization of

personnel management in pharmacoeconomics in privileging in strategic planning in phencyclidine phenelzine phenobarbital phenoxybenzamine phentolamine phenylalkylamines phenylephrine for aSAH for HSV for PAH for SCA phenylpropanolamine phenytoin ALF from for aSAH CYP and DDIs with drug-nutrient interactions with for SE therapeutic plasma exchange and thrombocytopenia and pheochromocytoma phosphate

phosphodiesterase type 5 (PDE-5) inhibitors of phosphorus. See also hyperphosphatemia; hypophosphatemia Physician Quality Reporting System (PQRS) PI. See pulsatility index PICC. See peripherally inserted central catheter PICS. See persistent inflammation-immunosuppression catabolism syndrome PiCT. See prothrombinase-induced clotting time piperacillin piperacillin/tazobactam pirbuterol pituitary adenoma PJP. See Pneumocystis jiroveci pneumonia PK. See pharmacokinetics Plan-Do-Check-Act plasma. See also fresh frozen plasma therapeutic plasma exchange, drug dosing and plasma concentration (Cp) plasma concentration at steady state (Cpss) Plasma-Lyte plasmapheresis plasminogen activator inhibitor-1 (PAI-1) Platelet Glycoprotein IIb-IIIa in Unstable Angina: Suppression Using Integrilin Therapy (PURSUIT) Platelet Inhibition and Patient Outcomes (PLATO) platelet reactivity tests

Receptor

Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) platelet-derived growth factor platelets ALF and for cirrhosis enhancing function of function measurement of mapping of, TEG for MCS and in MTP optimization of thrombocytopenia and transfusions of PLATO. See Platelet Inhibition and Patient Outcomes Plavix. See clopidogrel PN. See parenteral nutrition PNA-FISH. See peptide nucleic acid fluorescence in situ hybridization Pneumocystis jiroveci, HIV and Pneumocystis jiroveci pneumonia (PJP) pneumomediastinum pneumonia. See also ventilator-associated pneumonia aSAH and asthma and COPD and from Candida as donor-derived infection HAP

HCAP HSV and from inhalation injury PERDS and PJP SCI and scoring systems for from VZV Pneumonia Severity Index (PSI) pneumothorax tension PNS/TOF. See peripheral nerve stimulation/train-of-four POCT. See point-of-care testing point-of-care testing (POCT) POISE-2 polycystic kidney disease polymerase chain reaction (PCR) for Dengue fever for HSV for PJP for VZV polyvinyl chloride (PVC) portal hypertension posaconazole positive end-expiratory pressure (PEEP) positive predictive value (PPV) posterior reversible leukoencephalopathy syndrome (PRES)

postpartum hemorrhage (PPH) postrenal AKI potassium. See also hyperkalemia; hypokalemia supplementation of TdP and TLS and potassium chloride PPDs. See permanent pacemaker devices PPE. See personal protective equipment PPH. See postpartum hemorrhage PPHN. See persistent pulmonary hypertension PPIs. See proton pump inhibitors PPV. See positive predictive value PQRS. See Physician Quality Reporting System PQRST. See pain characteristics in low back pain syndrome PR interval Pragmatic Randomized (PROPPR)

Optimal

Platelet

and

Plasma

Ratios

prasugrel PRBCs. See packed red blood cells PREDICT-1. See Prospective Randomized Evaluation of DNA Screening in a Clinical Trial prednisone pregnancy aortic dissection and asthma in drug dosing in

hemorrhage in hypertensive crisis in SE in VTE and prekallikrein PRES. See posterior reversible leukoencephalopathy syndrome Present Pain Index preventable ADE Primacore. See milrinone priming thrombin PRIS. See propofol-related infusion syndrome PRISM-PLUS. See Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms privileging, in pharmacy services management PROACT II. See Prolyse in Acute Cerebral Thromboembolism II probiotics procainamide procaine procalcitonin (PCT) procedural pain ProCESS. See Protocolized Care for Early Septic Shock prochlorperazine progesterone Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) progressive multifocal leukoencephalopathy prokinetics Prolyse in Acute Cerebral Thromboembolism II (PROACT II)

ProMISe. See Protocolised Management in Sepsis PROMMTT. See Prospective, Observational, Multicenter, Major Trauma Transfusion propafenone propofol bradycardia from CYP and for endotracheal intubation in children pregnancy and for SE propofol-related infusion syndrome (PRIS) PROPPR. See Pragmatic Randomized Optimal Platelet and Plasma Ratios propranolol propylene glycol propylthiouracil Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Prospective Randomized Evaluation of DNA Screening in a Clinical Trial (PREDICT-1) prostacyclin prostaglandin E prostaglandin I2 (PGI2) prostate cancer protease inhibitors ProTECT. See Progesterone for the Treatment of Traumatic Brain Injury protein binding

ALF and antimicrobials and DDIs and ECMO and plasmapheresis and protein C proteins burns and stress response and proteinuria prothrombin prothrombin complex concentrates (PCCs) for GI bleeding in MTP VKA and warfarin and prothrombin time (PT) for ALF for apixaban prothrombinase-induced clotting time (PiCT) Protocolised Management in Sepsis (ProMISe) Protocolized Care for Early Septic Shock (ProCESS) proton pump inhibitors (PPIs) CYP and DDIs with for GI bleeding rebleeding with

for SRMD in children pseudoephedrine Pseudomonas aeruginosa PSI. See Pneumonia Severity Index PSVT. See paroxysmal supraventricular tachycardia psychotropics PT. See prothrombin time PTH. See parathyroid hormone PTT. See partial thromboplastin time Puhringer, FK pulmonary arterial catheters (PAC, Swan-Ganz catheter) pulmonary arterial hypertension (PAH) diagnosis of epidemiology of monitoring of obstructive shock and pathophysiology of treatment for vasodilators for WHO and pulmonary capillary wedge pressure (PCWP) pulmonary edema pulmonary embolism (PE) fibrinolysis for hypertensive crisis and MCS for SCA and

pulmonary function tests pulmonary hypertension hypertension

(PH).

See

also

pulmonary

arterial

pulmonary vascular resistance (PVR) pulsatility index (PI) pulse oximetry pulseless electrical activity (PEA) pulseless ventricular tachycardia (PVT) pulsus paradoxus PURSUIT. See Platelet Glycoprotein IIbIIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy PVC. See polyvinyl chloride PVR. See pulmonary vascular resistance PVT. See pulseless ventricular tachycardia pyrazinamide pyridostigmine pyrimethamine pyruvate pyruvate dehydrogenase

Q QRS complex QT interval QTc. See corrected QT interval Quadrox D oxygenator quetiapine QuickFISH

quinidine quinine quinolones

R RAAS. See renin-angiotensin-aldosterone system rabies radiation enteritis radiation therapy for MSCC for SVC radiographic contrast media Ralib, AM Ramsay sedation scale randomized controlled trials (RCTs) for fluid resuscitation for glucose management for HSV for NMBAs Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) ranitidine RANK. See receptor activator of nuclear factor-κB RANKL. See receptor activator of nuclear factor-κB ligand Ranson criteria, for pancreatitis rapeseed oil rapid sequence intubation (RSI)

ketamine for NMBAs and for trauma RAS. See reticular activating system rasburicase RASS. See Richmond Agitation-Sedation Scale ratio of maximum serum drug concentration to MIC (Cmax/MIC) ratio of the 24-hour area under the serum concentration versus time curve to pathogen MIC (AUC0-24/MIC) RBCs. See red blood cells RCTs. See randomized controlled trials RDA. See recommended dietary allowance real-time PCR rebleeding aSAH and with GI bleeding receiver operating characteristic (ROC) receptor activator of nuclear factor-κB (RANK) receptor activator of nuclear factor-κB ligand (RANKL) recombinant activated factor VIIa (rFVIIa) for ALF for cirrhosis in MTP for PPH recombinant human activated protein C recombinant human growth hormone (rhGH) recommended dietary allowance (RDA)

with EN for potassium red blood cells (RBCs) for anemia for hemorrhagic shock for PPH PRBCs REDOXs trials REE. See resting energy expenditure refeeding syndrome refractory hypotension refractory seizures refractory status epilepticus (RSE) Registry to Evaluate Early- and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) Rehm, M Reinelt, P Reiter syndrome REMATCH. See Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure remifentanil Remodulin. See treprostinil REMS. See Risk Evaluation and Mitigation Strategies renal cell carcinoma renal failure AF and electrical injuries and

hypertensive crisis and metabolic acidosis and from NSAIDs from septic shock from severe sepsis SRMD and renal insufficiency Renal Optimization Strategies Evaluation (ROSE) renal replacement therapy (RRT) advantages and disadvantages of for AKI drug clearance with ECMO and for metabolic acidosis outcomes of for rhabdomyolysis for TLS types of typical conditions in renal system. See also kidney anticoagulants and DDIs and nutrition and opioids and renal tubular acidosis (RTA) renin-angiotensin-aldosterone system (RAAS) ACS and

reptilase time respiratory acidosis respiratory alkalosis respiratory failure respiratory quotient (RQ) respiratory syncytial virus (RSV) respiratory system. See also lung acid-base disorders and metabolic acidosis and nutrition and viral infections respiratory tract infections resting energy expenditure (REE) Resuscitation Outcomes Consortium (ROC) reteplase reticular activating system (RAS) retinal hemorrhages retinitis retinopathy return of spontaneous circulation (ROSC) Revatio. See sildenafil REVEAL. See Registry to Evaluate Early-and Long-term Pulmonary Arterial Hypertension Disease Management Revised Trauma Score rFVIIa. See recombinant activated factor VIIa rhabdomyolysis RHC. See right heart catheterization

rheumatic fever rheumatoid arthritis rhGH. See recombinant human growth hormone rhinovirus ribavirin ribosomal RNA (rRNA) Richmond Agitation-Sedation Scale (RASS) rifampin CYP and P-glycoprotein and thrombocytopenia and rifaximin RIFLE. See risk, injury, failure, loss of kidney function, and end-stage kidney disease right heart catheterization (RHC) right ventricle (RV) ADHF and afterload, PVR and PAH and Ringer, Sydney riociguat risk, injury, failure, loss of kidney function, and end-stage kidney disease (RIFLE) Risk Evaluation and Mitigation Strategies (REMS) risperidone ritonavir rituximab

rivaroxaban anti-Xa for for GI bleeding P-glycoprotein and Rivers, E ROC. See receiver operating characteristic; Resuscitation Outcomes Consortium Rockall score, for rebleeding rocuronium Rodrigo, G ROSC. See return of spontaneous circulation ROSE. See Renal Optimization Strategies Evaluation Rosenberg, RS rosuvastatin rotational TEG (ROTEG) Rotondo, MF Royal Dutch Pharmacists Association RQ. See respiratory quotient rRNA. See ribosomal RNA RRT. See renal replacement therapy RSE. See refractory status epilepticus RSI. See rapid sequence intubation RSV. See respiratory syncytial virus RTA. See renal tubular acidosis Rumack-Matthew nomogram RV. See right ventricle

S SA. See status asthmaticus SABA. See short-acting β-agonist SAFE. See Saline versus Albumin Fluid Evaluation salbutamol salicylate Saline versus Albumin Fluid Evaluation (SAFE) SAPS. See Simplified Acute Physiology Score saquinavir sarcoidosis sarcoma SARS. See severe acute respiratory syndrome SAS. See sedation-agitation scale SBE. See standard base excess SBP. See spontaneous bacterial peritonitis; systolic blood pressure SBS. See short bowel syndrome SCA. See sudden cardiac arrest SCCM. See Society of Critical Care Medicine scedosporiosis schistosomiasis SCI. See spinal cord injury SCIP. See Surgical Care Improvement Project scleroderma SCr. See serum creatinine SCUF. See slow continuous ultrafiltration Scvo2. See central venous oxygen saturation

SE. See status epilepticus sedation-agitation scale (SAS) sedatives delirium and interruption of for morbid obesity for nicotine withdrawal NMBAs and in pregnancy for respiratory alkalosis strategies for traditional withdrawal from seizures. See also status epilepticus AIS and aSAH and hypernatremia and hypertensive crisis and hypomagnesemia and hyponatremia and ICH and refractory SVC and TBI and selective serotonin reuptake inhibitors (SSRIs) selenium self-extubation

sepsis. See also severe sepsis; systemic inflammatory response syndrome AF and agitation and AKI and albumin for antioxidants and arginine and burns and in children CYP and delirium and glucose and MCS and metabolic acidosis and mixed acid-base disorders and NMBAs for PCT for procalcitonin for SRMD and TNF-α and underweight patients with septic arthritis septic shock AF and antibiotic de-escalation for antimicrobials for

burns and in children crystalloids and colloids for diagnosis of fluid resuscitation for host response in management bundle for PAH and pathophysiology of PCT for procalcitonin for renal failure from supportive therapies for tissue perfusion impairment in treatment pathways for underweight patients with Sequential Organ Failure Assessment (SOFA) SERAPHIN. See Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome serotonergics serotonin serotonin and norepinephrine reuptake inhibitors (SNRIs) serotonin syndrome sertraline serum bicarbonate serum creatinine (SCr) severe acute respiratory syndrome (SARS)

severe sepsis AF and antibiotic de-escalation for antimicrobials for ARDS and burns and in children crystalloids and colloids for diagnosis of fluid resuscitation for host response in management bundle for pathophysiology of PCT for procalcitonin for renal failure from supportive therapies for tissue perfusion impairment in treatment pathways for severely symptomatic hyponatremia sexually transmitted infections (STIs) SGA. See subjective global assessment sGC. See soluble guanylate cyclase shaken baby syndrome SHEA. See Society for Healthcare Epidemiology of America Shekar, K shock. See also specific types

albumin for assessment of catecholamines for in children colloids for crystalloids for CVC for differentiation of states of dopamine and epinephrine for fluid resuscitation for hemodynamic markers and perfusion for influenza and inotropes for intra-arterial catheters for metabolic acidosis and mixed acid-base disorders and norepinephrine for PAC for phenylephrine for vasopressors for shock liver short bowel syndrome (SBS) short-acting β-agonist (SABA) shortness of breath SIADH. See syndrome of inappropriate antidiuretic hormone sick sinus syndrome

sickle cell disease SICU. See surgical intensive care unit SID. See strong ion difference SIG. See strong ion gap sildenafil (Revatio, Viagra) Silverman, RA Simplified Acute Physiology Score (SAPS) simvastatin Simvastatin in Aneurysmal Subarachnoid Hemorrhage (STASH) single nucleotide polymorphisms (SNPs) sinus bradycardia sinusitis sirolimus SIRS. See systemic inflammatory response syndrome skin infections of, testing for normal structure and function of SLCO1B1 genotype SLCO1B1 genotype and SLEAP study SLED. See sustained low-efficiency hemodialysis sleep apnea slow continuous ultrafiltration (SCUF) small cell lung cancer smoking. See also nicotine aSAH and asthma and

COPD and SNPs. See single nucleotide polymorphisms SNRIs. See serotonin and norepinephrine reuptake inhibitors Society for Healthcare Epidemiology of America (SHEA) Society of Critical Care Medicine (SCCM) arginine and delirium and glutamine and PAD and on pain assessment probiotics and TBI in children and Society of Thoracic Surgeons (STS) sodium. See hypernatremia; hyponatremia sodium acetate sodium bicarbonate sodium chloride sodium homeostasis sodium iodide sodium nitrite sodium nitroprusside. See nitroprusside sodium oxybate (Xyrem) sodium thiosulfate sodium-potassium-chloride cotransporter (NKCC) SOFA. See Sequential Organ Failure Assessment soluble guanylate cyclase (sGC) somatostatin

somnolence Sort, P sotalol spinal cord injury (SCI) blood pressure and epidemiology and pathophysiology of management of MV for neuroprotective therapy for NMBAs and succinylcholine and thermoregulation for VTE and splenomegaly spontaneous bacterial peritonitis (SBP) SRMD. See stress-related mucosal disease SSC. See Surviving Sepsis Campaign SSIs. See surgical site infections SSRIs. See selective serotonin reuptake inhibitors St. John’s wort standard base excess (SBE) Staphylococcus aureus. See also methicillin-resistant Staphylococcus aureus; methicillin-susceptible Staphylococcus aureus CIEDs and COPD and influenza and nasal packing and

neurosurgical infections and PAC and SSIs from Staphylococcus epidermidis Staphylococcus spp. Starling, EH STASH. See Simvastatin in Aneurysmal Subarachnoid Hemorrhage statins ALF from antiretrovirals and for aSAH SLCO1B1 genotype and status asthmaticus (SA) status epilepticus (SE) children with diagnosis of EEG for emergent treatment for epidemiology of etiology of genetics and HSV and kidney failure and laboratory testing for liver failure and obesity and pathophysiology of

in pregnancy prophylaxis for RSE treatment for, urgent treatment for stavudine STEMI. See ST-segment elevation myocardial infarction STEMI Treated with Primary Angioplasty and Intravenous Lovenox or Unfractionated Heparin (ATOLL) steroids for DAC for PERDS for PJP for TBI Stevens-Johnson syndrome Stewart model, for acid-base disorders STIs. See sexually transmitted infections Streptococcus pneumoniae Streptococcus pyogenes Streptococcus spp. stress response stress ulcers stress-related mucosal disease (SRMD) stroke. See also acute ischemic stroke AF and assessment of BCVIs and

classification, risk factors, and diagnosis for clinical presentation of epidemiology of fluid resuscitation for glucose and hemorrhagic hypertensive crisis and hypoglycemia and hypomagnesemia and hypovolemia and NMBAs and pathophysiology of TIA TPA for treatment of stroke volume strong ion difference (SID) intravenous fluids and metabolic alkalosis and respiratory acidosis and THAM and strong ion gap (SIG) strong ions STS. See Society of Thoracic Surgeons ST-segment depression ST-segment elevation myocardial infarction (STEMI) Study of the Neuroprotective Activity of Progesterone in Severe

Traumatic Brain Injuries (SYNAPSE) Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) subarachnoid hemorrhage. hemorrhage

See

subarachnoid spaces subdural grids subjective global assessment (SGA) substance abuse agitation and ALF from frostbite and substance P succinylcholine sucralfate sudden cardiac arrest (SCA) ACLS for algorithm for antiarrhythmics for asystole and basic life support for causes and interventions for CPR for drug administration in ECG for epidemiology of etiology and clinical presentation of

aneurysmal

subarachnoid

evidence-based recommendations for general management of magnesium for nonpharmacologic therapy for PEA and PVT and sodium bicarbonate for TH for thrombolysis for vasopressin for vasopressors for VF and sudden cardiac death (SCD). See sudden cardiac arrest sulfadiazine sulfamethoxazole/trimethoprim. See trimethoprim/sulfamethoxazole sulfonamides superior vena cava syndrome (SVC) Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) superoxide dismutase support stockings supraventricular arrhythmias supraventricular tachyarrhythmias Surgical Care Improvement Project (SCIP) surgical intensive care unit (SICU) surgical site infections (SSIs) antimicrobial prophylaxis for

neurosurgical infections and risks for Surviving Sepsis Campaign (SSC) on catecholamines management bundle of underweight patients and sustained low-efficiency hemodialysis (SLED) SVC. See superior vena cava syndrome SVO2. See venous oxygen saturation SVR. See systemic vascular resistance Swan-Ganz catheters. See pulmonary arterial catheters sympathetic nervous system sympathomimetics SYNAPSE. See Study of the Neuroprotective Progesterone in Severe Traumatic Brain Injuries

Activity

of

syncope AF and bradycardia and respiratory alkalosis and syndrome of inappropriate antidiuretic hormone (SIADH) SYNERGY. See Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors systemic inflammatory response syndrome (SIRS) burns and in children systemic lupus erythematosus systemic vascular resistance (SVR)

systolic blood pressure (SBP) aSAH and cirrhosis and hypertensive crisis and IABP for iloprost and sepsis and severe sepsis and septic shock and shock and VT and

T T cell-mediated immune response T waves T3. See triiodothyronine T4. See thyroxine tachycardia AT aSAH and AVRT cocaine and COPD and DKA and GI bleeding and malignant hyperthermia and nitroglycerin and

PSVT, PVT SIRS and VT tachyphylaxis tachypnea TACO. See transfusion-associated cardiac overload tacrolimus TAH. See total artificial heart takotsubo cardiomyopathy TandemHeart TARGET. See Treatment Approaches in Renal Cancer Global Evaluation Trial Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY-ACS) target-specific oral anticoagulants (TOACs) tazobactam TBI. See traumatic brain injury TBSA. See total body surface area TBW. See total body water; total body weight TCD. See transcranial Doppler TDM. See therapeutic drug monitoring TdP. See torsades de pointes TE. See thromboembolism; Toxoplasma encephalitis tedizolid teduglutide TEE. See transesophageal echocardiogram

TEG. See thromboelastography telavancin temazepam tenecteplase tension pneumothorax terbinafine terbutaline terlipressin Terumo Cardiovascular Systems Terumo X Coating tetracycline TH. See therapeutic hypothermia THAM. See tris-hydroxymethyl aminomethane; tromethamine theophylline therapeutic drug monitoring (TDM) for aminoglycosides for antifungals for antimicrobials for β-lactam antibiotics for tacrolimus for vancomycin therapeutic hypothermia (TH) Therapeutic Intervention Scoring System (TISS) therapeutic plasma exchange, drug dosing and thermoregulation for AIS for aSAH

for ICH for SCI thermoslim thiazide diuretics thienopyridine (Effient) thiocyanate thiopentone thiosulfate thrombin generation assays thrombin time (TT) thrombocytopenia. See also heparin-induced thrombocytopenia ADEs and coronavirus and Dengue fever and hypertensive crisis and IABP and valproic acid and thromboelastography (TEG) thromboembolism (TE) Thrombolysis in Myocardial Infarction (TIMI) thrombolytics thrombophlebitis thrombosis. See also thromboembolism in children MCS and SVC and

deep

venous

thrombosis;

venous

thromboxane A2 (TXA2) thyroid disorders thyroid function tests thyroid storm (thyroid crisis) thyroid-stimulating hormone (TSH) thyroxine (T4) TIA. See transient ischemic stroke TIC. See trauma-induced coagulopathy ticagrelor ticarcillin tigecycline time during which unbound/free drug concentration remains above the pathogen MIC ( T>MIC) TIMI. See Thrombolysis in Myocardial Infarction TIMP-2. See tissue inhibitor of metalloproteinase 2 tinzaparin TIPS. See transjugular intrahepatic portosystemic shunts tirilazad mesylate tirofiban TISS. See Therapeutic Intervention Scoring System tissue inhibitor of metalloproteinase 2 (TIMP-2) tissue plasminogen activator (tPA) tizanidine TLS. See tumor lysis syndrome T-lymphocytes TNF-α. See tumor necrosis factor-α TOACs. See target-specific oral anticoagulants tobacco. See smoking

tobramycin TOF. See train-of-four tolvaptan Tomlinson, BE tonic-clonic seizures tonicity topiramate torsades de pointes (TdP) dofetilide and KCNH2 and QT interval and torsemide (Demadex) total artificial heart (TAH) total body surface area (TBSA) total body water (TBW) total body weight (TBW) total parenteral nutrition (TPN) toxic shock syndrome (TSS) Toxoplasma encephalitis (TE) tPA. See tissue plasminogen activator TPN. See total parenteral nutrition train-of-four (TOF) TRALI. See transfusion-related acute lung injury tranexamic acid transcranial Doppler (TCD) transcutaneous pacing transesophageal echocardiogram (TEE)

transferrin transforming growth factor β transfusion. See blood transfusions; massive transfusion protocols transfusion-associated cardiac overload (TACO) transfusion-related acute lung injury (TRALI) transfusion-related immunomodulation (TRIM) transient ischemic stroke (TIA) transjugular intrahepatic portosystemic shunts (TIPS) transthoracic echocardiography (TTE) transthyretin trauma ABCDE for advanced trauma life support for airway maintenance for AKI and antioxidants and arginine and BCVIs coagulopathy and crystalloids and colloids for DVT and hemorrhage and hemorrhagic shock and NMBAs and renal failure from scoring systems for VTE and

Trauma Score and Injury Severity Score (TRISS) trauma-induced coagulopathy (TIC) traumatic brain injury (TBI) aSAH and biomarkers for in children CYP and ECF and epidemiology and pathophysiology of hyperventilation and ICP and hyperosmolarity and nutrition for SAFE and SBS and seizures from, prophylaxis for VTE and Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) treprostinil (Orenitram, Remodulin, Tyvaso) Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) triamterene triazoles triiodothyronine (T3) TRILOGY-ACS. See Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary

Syndromes TRIM. See transfusion-related immunomodulation trimethoprim/sulfamethoxazole ALF from for PJP pregnancy and for TE thrombocytopenia and triple-H therapy tris-hydroxymethyl aminomethane (THAM) TRISS. See Trauma Score and Injury Severity Score TRITON-TIMI 38. See Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis In Myocardial Infarction troglitazone tromethamine (THAM) troponin Trousseau sign TSH. See thyroid-stimulating hormone TSS. See toxic shock syndrome TT. See thrombin time TTE. See transthoracic echocardiography tuberculosis tubocurarine tumor lysis syndrome (TLS) hyperphosphatemia and management of

risk factors for tumor necrosis factor-α (TNF-α) ALF and sepsis and TBI and trauma and TXA2. See thromboxane A2 Tyvaso. See treprostinil

U UA. See uric acid UAG. See urinary anion gap UCr. See urine creatinine UFH. See unfractionated heparin ulcerative colitis ultrafiltration ultrafiltration coefficient (Kuf) ultrasonography, for AKI Ultresa UNa. See urine sodium concentration underweight patients, drug dosing for unfractionated heparin (UFH) for ACS ACT for activated clotting time for for AF

anti-Xa for aPTT for fibrinolysis and INR for in ischemia-driven strategy for NSTE in pregnancy for STEMI TT for for VTE United States Pharmacopeia (USP) UNLOAD. See Patients Hospitalized for Acute Decompensated Congestive Heart Failure unmasking unstable angina urea uric acid (UA) urinary anion gap (UAG) urinary tract infections (UTIs) urine antigen testing urine creatinine (UCr) urine microscopy urine output urine sodium concentration (UNa) USP. See United States Pharmacopeia UTIs. See urinary tract infections

V VADs. See ventricular assist devices valacyclovir valganciclovir valproate valproic acid Van den Berghe, G vancomycin AKI from for burns for CSF shunting devices drug clearance of ECMO and for FN GNB and for hepatic encephalopathy for morbid obesity for MRSA pregnancy and TDM for thrombocytopenia and vancomycin-resistant Enterococcus (VRE) VAP. See ventilator-associated pneumonia varenicline varicella zoster virus (VZV) VAS. See Visual Analog Scale

vasoconstrictors Vasodilation in the Management of Acute CHF (VMAC) vasodilators for ADHF for hypertensive crisis for septic shock in children vasopressin EN and for GI bleeding for PAH for PEA for SCA for septic shock in children vasopressin receptor antagonists vasopressin receptors. See antidiuretic hormone vasopressors for ADHF cardiac transplantation for aSAH for hypermagnesemia MAP and for myxedema coma for PAH for PEA for shock for underweight patients VTE and vasoreactivity challenge

Vd. See volume of distribution vecuronium Veletri venlafaxine venous oxygen saturation (SVO2) shock and venous thromboembolism (VTE) AIS and anticoagulants for aPTT and burns and DTIs for ICH and prevention of SCI and TBI and thrombolytics for trauma and in underweight patients ventilator-associated pneumonia (VAP) antibiotic de-escalation for antimicrobials for resistance to endotracheal intubation and from GNB minimizing testing for

tigecycline for ventricular arrhythmias ventricular assist devices (VADs) antimicrobial prophylaxis for classification of durable implantable extracorporeal or paracorporeal MCS and percutaneous SSIs and ventricular fibrillation (VF) ventricular tachycardia tachycardia

(VT).

See

also

verapamil Verigene test VF. See ventricular fibrillation VHFs. See viral hemorrhagic fevers VHL. See von Hippel-Lindau syndrome Viagra. See sildenafil vinblastine Vincent, JL vincristine Viokace viral hemorrhagic fevers (VHFs) viral infections. See also specific infections ALF from COPD and

pulseless

ventricular

in respiratory acidosis of respiratory system Virchow triad VISEP. See Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis Visual Analog Scale (VAS) vitamin B12 (hydroxycobalamin) vitamin C (ascorbic acid) vitamin D burns and HCM and hypophosphatemia and PTH and vitamin E vitamin K ALF and DTIs and vitamin K antagonists (VKA) vitamin K epoxide reductase (VKOR) vitamin K-dependent factor VKA. See vitamin K antagonists VKOR. See vitamin K epoxide reductase VMAC. See Vasodilation in the Management of Acute CHF VO2. See oxygen consumption volatile anesthetics volume of distribution (Vd) ECMO and

volume of distribution at steady state (Vss) antimicrobial half-life and of fluconazole of hydrophilic drugs for β-lactam antibiotics Voluven von Hippel-Lindau syndrome (VHL) von Willebrand disease von Willebrand factor (vWF) voriconazole for Aspergillus CYP and for FN for fusariosis pregnancy and for scedosporiosis VRE. See vancomycin-resistant Enterococcus Vss. See volume of distribution at steady state VT. See ventricular tachycardia VTE. See venous thromboembolism vWF. See von Willebrand factor VZV. See varicella zoster virus

W Wahl, WL Wall, PD

warfarin for BCVIs CYP and DDIs with drug-nutrient interactions with for GI bleeding for HIT INR for liver and for PAH pregnancy and VKORC and water homeostasis weak ions Weil, MH West, Ranyard West Nile virus (WNV) white blood cells WHO. See World Health Organization Wilson disease withdrawal from α2-adrenergic agonists from alcohol hypertensive crisis and phenobarbital for from antidepressants from baclofen from corticosteroids

from nicotine from opioids from sedatives from SNRIs from SSRIs WNV. See West Nile virus Wolff-Parkinson-White syndrome (WPW) Women’s Health Initiative World Federation of Neurological Surgeons World Health Organization (WHO) on aSAH BMI and endothelin receptor antagonists and epoprostenol and iloprost and on influenza PAH and riociguat and WPW. See Wolff-Parkinson-White syndrome Wright, Lewis H.

X Xa inhibitors xanthine Xyrem. See sodium oxybate

Y yeasts yellow fever virus Yunos, NM

Z zafirlukast zanamivir Zaroxolyn. See metolazone Zenpep zinc zoledronic acid

Disclosure of Potential Conflicts of Interest Consultancies: Erik Abel (Revo Biologics); Jeffrey Barletta (Hospira; Cubist); Christopher Bland (Theravance Pharmaceuticals; Cubist Pharmaceuticals); Kevin Box (Dignity Health Care); Amanda Corbett (Food and Drug Administration); Joseph Dasta (Abbvie; AcelRx; Hospira; Jannsen Scientific Affairs; Mallinckrodt Pharmaceuticals; Medicines Company; Otsuka America Pharmaceuticals; Pacira Pharmaceuticals; Phillips Visicu); John Devlin (Society of Critical Care Medicine); Roland Dickerson (Fresenius Kabi Global); Paul Dobesh (AstraZeneca; The Medicines Company; Daiichi Sankyo, Inc.); Brian Erstad (Critical Path Institute); Elizabeth Farrington (BPS Pediatric Specialty Council); Douglas Fish (Bayer Healthcare; Cempra, Inc.); Curtis Haas (Excellus Blue Cross/Blue Shield; KJT Group); Martina Holder (CMS); Theresa Human (Cumberland Pharmaceutical; UCB Pharma); Thomas Johnson (American Society of Health-System Pharmacists; Society of Critical Care Medicine); Melanie Joy (Boehringer Ingelheim Pharmaceuticals, Inc.; Eli Lilly; Janssen Pharmaceuticals); Sandra Kane-Gill (Agency for Healthcare Research and Quality); David Kaufman (Vital Therapies, Inc.); Marin Kollef (Accelerate; Cubist; Merck); Robert MacLaren (GSK); Stephanie Mallow Corbett (American College of Critical Care Medicine; Center for Academic Partnerships for Interprofessional Research and Education; Thomas Jefferson Medical Reserve Corps Advisory Board); Ali McBride (Sanofi); David Nix (Critical Path Institute); Hanna Phan (Vertex Pharmaceuticals; Pediatric Pharmacy Advocacy Group; Cystic Fibrosis Foundation Data Safety Monitoring Board); Hal Richards (Board of Pharmacy Specialties); Jo Rodgers (Amgen; Novartis); Carol Rollins (American Society of Health-System Pharmacists; American Society for Parenteral and Enteral Nutrition; National Home Infusion Association); Todd Sorensen (Board of Pharmacy Specialties); Zachary Stacy ( Janssen Pharmaceuticals); Robert Talbert (U.S. Pharmacopeial

Convention; Expert Exchange; McGraw-Hill); Eljim Tesoro (Philips VISICU); James Tisdale (National Institutes of Health; American College of Clinical Pharmacy; American Heart Association; American College of Cardiology) Grants: Erik Abel (Extracorporeal Life Support Organization; American Society of Health-Systems Pharmacists); Kevin Box (American Society of Health-System Pharmacists Foundation); Lisa Burry (Technology Evolution in the Elderly); Amanda Corbett (Gilead; NIH); John Devlin (AstraZeneca; NHLBINIH); Paul Dobesh (AstraZenekaDaiichi Sankyo); Thomas Dowling (MediBeacon, LLC); Brian Erstad (Mallinckrodt; American Society of Health-System Pharmacists); Douglas Fish (Merck Pharmaceuticals); Katherine Gharibian (Astellas Pharma Inc.; Theravance Biopharma Inc.; NxStage Medical Inc.); Katja Gist (American Heart Association; Children’s Hospital Colorado Research Institute); Theresa Human (Astellas); Stephanie Mallow Corbett (Health Resources and Services Administration; University of Virginia Colligan Quality Improvement Grant; Paragon Biomedical; NIH ROI); Steven Martin (Health Resources and Services Administration); Kathryn Matthias (ASHP Foundation; University of Arizona Foundation; ADVANCE Grant, University of Arizona); Ali McBride (Sanofi); Courtney McKinney (American Society of Health-System Pharmacists); Scott Micek (Pfizer, Cubist, Forest, Astellas, Optimer, Astra Zeneca, and Merck); David Nix (Valley Fever Solutions); Asad Patanwala (American College of Clinical Pharmacy; Mallinckrodt Pharmaceuticals); Hanna Phan (American Society of Health-System Pharmacists Research and Education Foundation; Cystic Fibrosis Foundation); Denise Rhoney (Otsuka); James Tisdale (Indiana Clinical and Translational Sciences Institute; American Health Association Midwest Affiliate); David Williamson (Hospira) Lecture Services: Christopher Bland (Cubist Pharmaceuticals; Merck Pharmaceuticals); Bradley Boucher (The Medicines Company); John Devlin (AstraZeneca); Erin Fox (University of Illinois College of Pharmacy; American Society of Health-System Pharmacists;

Association of Surgical Technologists; National Association of EMS Physicians; American Medical Association; National Association of State EMS Officials; American Bar Association; International Pharmaceutical Federation; St. Jude Hospital; Healthcare Supply Chain Association; American College of Clinical Pharmacy); Myke Green (Merck); Melanie Joy (Pri-Med); Sandra Kane-Gill (SCCM and CRRT meeting); Marin Kollef (Cubist; Merck); Stephanie Mallow Corbett (Society of Critical Care Medicine; Virginia Society of Health-System Pharmacists; University Health System Consortium); Zachary Stacy (AstraZeneca; Janssen Pharmaceuticals); James Tisdale (Indiana Chapter of the American College of Cardiology; American Heart Association; American Society of Health-System Pharmacists; American College of Cardiology; American College of Clinical Pharmacy; University of Manitoba; Canadian Society of Hospital Pharmacists; Nova Southeastern University); David Williamson (Pfizer) Stock Ownership; Relationships with Companies or Vendors: Joseph Dasta (Abbott; Bristol Meyer Squibb; Eli Lilly; Express Scripts ; Merck Pharmaceuticals; Pfizer); David Feliciano (McGraw-Hill); Thomas Johnson ( Jones and Bartlett Learning); Melanie Joy (Katharos, Inc.); Zachariah Thomas (The Medicines Company); James Tisdale (American Society of Health-System Pharmacists)

WORLD HEADQIJARTERS American College of Clinical Pharmecy 13000 West & 7th Street Pgrkway, Suite 100 Lenene, KSW215 PHONE : (913) 492- 3311 FAX: (913) 492- 0000 vvww.accp.coim WASHINGTON OFFICE American College of Oinical Phenmecy 14S 5 Pennsyluania Avenue NW, Suite 400 Washington, D.C. 20004 PHONE : (202) 621 1020 FAX : ( 202) 621 1019

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