Critical Care Pharmacotherapy 9781939862204

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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.

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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:

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 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

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.

Figure 3.6 Example of protocol-driven electrolyte replacement.

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Crit Care 2004;19:54-64. 140. Forsythe RM, Wessel CB, Billiar TR, et al. Parenteral calcium for intensive care unit patients. Cochrane Database Syst Rev 2008;4:CD006163. 141. Dickerson RN. Treatment of hypocalcemia in critical illness – part 2. Nutrition 2007;23:436-7. 142. Vincent JL, Bredas P, Jankowski S, et al. Correction of hypocalcemia in the critically ill: what is the hemodynamic benefit? Intensive Care Med 1995;21:838-41. 143. Zaloga GP. Hypocalcemic crisis. Crit Care Clin 1991;7:191-200. 144. Body JJ, Bouillon R. Emergencies of calcium homeostasis. Rev Endocr Metab Disord 2003;4:167-75. 145. Reber PM, Heath H. Hypocalcemic emergencies. Med Clin North Am 1995;79:93-106. 146. Dickerson RN, Morgan LM, Cauthen AD, et al. Treatment of acute hypocalcemia in critically ill multiple-trauma patients. JPEN 2005;29:436-41. 147. Dickerson RN, Morgan LM, Croce MA, et al. Treatment of moderate to severe acute hypocalcemia in critically ill trauma patients. JPEN 2007;31:228-33. 148. Forster J, Querusio L, Burchard KW, et al. Hypercalcemia in critically ill surgical patients. Ann Surg 1985;202:512-8. 149. Hijazi M, Al-Ansari M. Protocol-driven vs. physician-driven electrolyte replacement in adult critically ill patients. Ann Saudi Med 2005;25:105-10. 150. Kanji Z, Jung K. Evaluation of an electrolyte replacement protocol in an adult intensive care unit: a retrospective before and after analysis. Intensive Crit Care Nurs 2009;25:181-9. 151. Todd SR, Sucher JF, Moore LJ, et al. A multidisciplinary protocol improves electrolyte replacement and its effectiveness. Am J Surg 2009;198:911-15.

152. Couture J, Letourneau A, Dubuc A, et al. Evaluation of an electrolyte repletion protocol for cardiac surgery intensive care patients. Can J Hosp Pharm 2013;66:96-103.

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

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

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

ALI = acute lung injury; HR = hazard ratio

Although 25(OH)D is measured to determine vitamin D status, 1,25dihydroxyvitamin D is the compound that has physiologic activity. Vitamin D refers to either ergocalciferol (vitamin D2), which is consumed in the diet, or cholecalciferol (vitamin D3), which is synthesized in the skin. The RDA for vitamin D was increased in 2010 from 200 international units to 400–800 international units, depending on age.93 Cholecalciferol and ergocalciferol are generally considered interchangeable, and oral supplements are available in both forms. However, some evidence suggests that cholecalciferol better increases vitamin D serum concentrations.93 No individual parenteral vitamin D product is available in the United States, and the adult parenteral multivitamin products contain only 200 international units. However, pediatric parenteral multivitamin products contain 400 international units per standard dose. With diligent attention to total amounts of all vitamins provided, use of a pediatric parenteral multivitamin could be considered for patients at high risk of complications from a true vitamin D deficiency (i.e., concentrations not influenced by systemic inflammatory response) when oral supplementation of vitamin D will not be possible for weeks to months. Prospective studies evaluating vitamin D supplementation and patient outcomes in critically ill patients are rare. The VITdAL-ICU study evaluated 475 critically ill patients with 25(OH)D concentrations less than 20 ng/mL (50 nmol/L).97 This single-center double-blind study randomized patients to either placebo or vitamin D3 orally or by nasogastric tube at a dose of 540,000 international units once,

followed by monthly doses of 90,000 international units for 5 months. There was no difference in the primary outcome of hospital LOS, nor was there any difference in secondary outcomes. The authors found a statistically significant decrease in hospital mortality among the subgroup of patients with 25(OH)D concentrations less than 12 ng/mL (30 nmol/L), but this disappeared at 6 months. Data are insufficient to recommend vitamin D supplementation in critically ill patients. Vitamins C and E Decreased concentrations of vitamins C and E have been found in patients with burns, sepsis, trauma, and major surgery.98,99 With many vitamins, systemic inflammation is known to decrease vitamin concentrations, but unfortunately, few studies on vitamins C and E evaluate the presence of inflammation concomitantly. Supplementation of vitamins C and E is most often delivered as part of an antioxidant “cocktail” with selenium, or included in an immune-modulating enteral formula. However, the 2015 update of the Canadian Clinical Practice Guidelines added a new section regarding intravenous vitamin C, although evidence was insufficient to make a recommendation on supplementation of vitamin C in critically ill patients.37 The supplementation of antioxidants in critical illness is discussed later. Selenium Selenium is a trace element that is essential in many metabolic processes, including the enzymes glutathione peroxidase and selenoprotein P.94 Both enzymes are necessary for oxidative defense. Because selenium is classified as an essential trace element, it is added to enteral formulas and is included in five-ingredient multitrace additives for PN. Because of selenium’s role in antioxidant defense, it has also been studied at a supraphysiologic dose to improve outcomes in critically ill patients. Patients with sepsis and systemic inflammatory response have high selenium-dependent glutathione peroxidase activity and low selenium concentrations.100 Older guidelines recommend

intravenous selenium, primarily because of a small study published in 2007 and a meta-analysis from 2005, which showed potential benefit from doses of 500–1,000 mcg/day.32,37,69 The SIC (Selenium in Intensive Care) trial evaluated 249 patients with systemic inflammatory response, sepsis, and septic shock. Patients were randomized to receive 1,000 mcg intravenously of sodium selenite followed by 14 daily infusions of 1,000 mcg or placebo.100 The intention-to-treat analysis showed no significant difference in the primary outcome of 28day mortality; however, the 92 per-protocol patients showed reduced mortality (p=0.49; OR 0.56; CI, 0.32–1.0). A meta-analysis published in 2005 aggregated seven studies with 186 patients and reported that selenium supplementation (alone and in combination with other antioxidants) was associated with a trend toward lower mortality (RR 0.59; 95% CI, 0.32, 1.08 p=0.09).101 For higher doses of selenium, one trial evaluating 60 patients with septic shock found no benefit in time to vasopressor withdrawal when 4,000 mcg was given on the first day and 1,000 mcg was given daily afterward for 9 days.102 A metaanalysis from 2012 aggregated 16 studies of critically ill patients and compared different dosing schemes used for selenium supplementation. Overall, the analysis found no mortality benefit to selenium in critically ill patients. When comparing selenium dosed at greater than 500 mcg, equal to 500 mcg, and less than 500 mcg daily, no dose achieved a statistically significant improvement in mortality.103 A separate meta-analysis from 2013 evaluated nine trials with 792 patients with sepsis only and found lower mortality (OR 0.73; 95% CI, 0.54, 0.98; p=0.03; I2 = 0%) with selenium supplementation than with placebo.104 In conclusion, given the available data, there appears to be no consistent benefit to supplementing supraphysiologic doses of selenium, and it cannot be recommended to routinely supplement selenium in critically ill patients.

Other Substances Glutamine

Glutamine is an amino acid that has been studied in critically ill patients for more than 20 years. It is classified as conditionally essential in catabolic states. In critically ill patients, the main consumers of glutamine are macrophages and lymphocytes, which deplete glutamine stores in muscle tissues.105,106 Consequently, plasma glutamine concentrations fall.80,82 When this occurs, glutamine may be unavailable for immune cells and other rapidly dividing cells or the synthesis of glutathione, renal ammonia, and glycogen.105,107 The practice of supplementing glutamine in critically ill patients has changed substantially as new studies have been published, which may serve as a cautionary tale for interpreting small studies. A small prospective cohort trial associated low plasma glutamine concentrations at ICU admission with increased hospital mortality in 2001.105 As a result, some clinicians began supplementing glutamine in critically ill patients. This was done either enterally (in doses of 0.16– 0.5 g/kg of body weight per day) or parenterally (in doses of 0.18–0.57 g/kg/day), usually in combination with nutrition support. A meta-analysis of smaller studies from 2002 found that critically ill patients given glutamine supplementation had a reduction in complication and mortality rates; the greatest benefit occurred in patients receiving high-dose, parenteral glutamine.108 The initial Canadian Clinical Practice Guidelines published in 2003 recommended supplementation of PN with parenteral glutamine, when available, but data were inadequate to make a recommendation on intravenous supplementation for patients receiving EN.33 Enteral glutamine was regarded as appropriate to consider in burn and trauma patients, but data were inadequate in other critically ill patients to suggest routine use. The nutrition guidelines for critically ill patients from SCCM/ASPEN, published in 2009, give a grade B and C recommendation to consider enteral and parenteral gluta-mine supplementation.32 However, two subsequent larger trials failed to find a benefit to intravenous glutamine supplementation.109,110 The most recent and largest trials to date, the REDOXs111 and the METAPLUS112 trials, have actually found a signal of harm in supplementing glutamine to the

most critically ill patients. The REDOXs trial supplemented glutamine as 0.35 g/kg of ideal body weight per day intravenously and 30 g enterally per day. Patients enrolled in this trial were required to receive mechanical ventilation and have at least two organ system failures. The patients who received glutamine had a statistically significant increase in in-hospital and 6-month mortality.111 The METAPLUS study, in contrast, used enteral glutamine at a dose of 0.3–0.5 g/kg/day as part of an immune-modulating enteral product that also contained omega-3 fatty acids and antioxidants. These patients were mechanically ventilated with a maximum SOFA score of 12. In this trial, there was also a statistically significant increase in 6-month mortality for the patients who received glutamine supplementation.112 These two studies differed in the route of administration and the dose of glutamine supplemented, but both found evidence of harm. The benefit seen previously was present in small single-center trials that were under-powered to detect an increase in mortality.113 After these studies were published, the Canadian Clinical Practice Guidelines 2013 updates added a caution for use of any glutamine in patients with shock or multiorgan failure.69 By the 2015 Canadian Clinical Practice Guidelines update, use of enteral glutamine was not recommended in critically ill patients.37 In conclusion, given the available evidence, it cannot be recommended to routinely supplement glutamine in critically ill patients. Arginine Arginine is another amino acid that has been studied for supplementation in critically ill patients. Soon after trauma or surgery, plasma arginine concentrations drop and remain low for days to weeks after the injury.114 Arginine is a substrate for nitric oxide production in several cell types, including T lymphocytes and myeloid cells. Physical injury causes myeloid-derived suppressor cells to appear; these cells express arginase-1, which leads to arginine deficiency and Tlymphocyte dysfunction.114-116 A recent meta-analysis that included about 3,000 patients found a treatment effect of arginine therapy, at doses delivered in immune-modulating enteral formulas of around 12

g/day, after major surgery; arginine treatment reduced risk of infection by 40% and overall LOS versus standard EN.115 However, the same may not be true in patients with sepsis. Most trials show very little benefit or, more commonly, harm when arginine is supplemented in patients with sepsis.117-119 The explanation for this effect may be the supraphysiologic supplement dose (8–20 g/day vs. 3–5 g/day normally ingested) promotes excessive nitric oxide, which worsens hypotension and may increase mortality.114,119,120 The 2009 SCCM/ASPEN guidelines recommended argi-nine supplementation as part of an immune-modulating enteral formula for patients with major GI surgery, trauma, burns, and head and neck cancers and for critically ill patients who were not severely septic.32 However, the Canadian Clinical Practice Guidelines have never recommended the use of arginine for critically ill mechanically ventilated patients.33,37,69,121 Because of the lack of high-quality studies supporting the use of arginine and the potential harm, it is not recommended to supplement arginine in critically ill patients. Antioxidants Antioxidants have been studied together with glutamine and/or arginine as part of an immune-modulating or immune-enhancing diet, but they have also been studied separately. Under normal physiologic conditions and inspiration of 21% oxygen, there are adequate defenses against reactive oxygen species and reactive nitrogen-oxygen species, commonly known as free radicals.122 Cellular injury occurs when the overproduction of free radicals overwhelms endogenous antioxidant defenses such as glutathione, superoxide dismutase, and antioxidant vitamins. Data have shown that in surgery, trauma, and sepsis, antioxidant levels are decreased and that the more severe the injury, the more depleted the antioxidant defenses become.101 The body’s antioxidant defense mechanisms depend on selenium, zinc, manganese, and iron, which are cofactors for antioxidant enzymes and the vitamins C, E, and beta-carotene. A recent meta-analysis pooled 21 randomized controlled trials with around 2,500 patients that

evaluated antioxidant supplementation in critically ill patients.123 Of note, this analysis excluded trials that also combined glutamine or arginine with antioxidant vitamins and trace elements. The authors found a decrease in overall mortality of 18% in the antioxidant-treated group (RR 0.82; 95% CI, 0.72–0.93; p=0.002). The analysis also noted a decrease in ventilator-days from a small group of included studies, and in the subgroup analysis of enterally versus parenterally supplied antioxidants, only the enteral route achieved a statistically significant benefit. Many of the studies performed with antioxidant supplementation have used slightly different doses of each antioxidant, though most include vitamins C and E and selenium, and the therapy ranges from 7 to 28 days, which should be considered when making a recommendation. Previous guidelines have recommended supplemental antioxidants for critically ill patients.32,37,69 Although the results from smaller studies and aggregated results from meta-analyses are promising, we do not yet know the optimal composition, dose, or route for supplementing antioxidants. Because of these unknowns, routine supplementation of antioxidants in critically ill patients cannot be recommended.

Omega-3 Fatty Acids Another nutrient with the potential to affect immune function is the omega-3 fatty acids. Omega-6 fatty acids are metabolized into eicosanoids that tend to be proinflammatory; omega-3 fatty acids are metabolized into a different series of prostaglandins, leukotrienes, and thromboxanes that do not promote inflamation and thrombosis, and may be referred to as anti-inflammatory. In addition, when omega-3 fatty acids are incorporated into membrane phospholipids of immune cells, they alter membrane fluidity, which affects secondary messengers, transporters, receptors, and enzymes.124,172 Many studies have found a benefit with an omega-3–supplemented enteral formula (Oxepa) in patients with ALI or acute respiratory distress syndrome (ARDS) when compared to high-fat formulas, not typical ICU formulas.125-127 Use of omega-3–supplemented formulas will be

discussed in greater detail later. In addition, a recent meta-analysis concluded that critically ill patients who received enteral formulas with a high percentage of omega-3 fatty acids had decreased infectious rates, hospital LOS, and mortality.128 Although data suggest that parenteral omega-3 fatty acids are also beneficial, no products are currently approved for use in the United States. However, European intravenous omega-3 products can be obtained if an Investigational New Drug (IND) application is authorized for each patient by the U.S. Food and Drug Administration (FDA). Omega-3–containing enteral formulas are recommended for patients with ALI/ARDS, and recommendations for omega-3 fatty acid in other forms will change as products become available in the United States.

Probiotics Probiotics have the potential to treat gut and immune disturbances in the critically ill population through competitively inhibiting the growth of pathogenic organisms, enhancing the mucosal barrier, and modulating the host inflammatory response. Understanding and modifying the human gut microbiome is still a developing area of research, and unfortunately, trials of probiotics in the critically ill population have not shown comprehensive benefit. Some studies have shown benefit, whereas others have shown no difference, likely because of differences between ICU populations and strains of probiotics used. The 2009 SCCM/ASPEN guidelines do not recommend providing probiotics to the general ICU population, but they do recommend probiotics for patients with transplantation, major abdominal surgery, and severe trauma (grade C).32 However, in light of conflicting evidence, the potential for harm, and the legal issues of providing non– FDA-approved products to hospitalized patients, use of probiotics in the critically ill population remains controversial.

ORGAN-SPECIFIC CONSIDERATIONS Renal

Renal dysfunction is a common diagnosis in the ICU. Both acute kidney injury (AKI) and chronic kidney disease (CKD) affect a patient’s nutritional requirements and tolerance. To assess nutritional status, it is recommended to evaluate a patient’s weight and inflammatory status in setting nutritional goals.129 Indirect calorimetry is preferred to determine caloric needs in renal dysfunction. Protein goals, electrolyte provision, and vitamin/mineral needs depend on whether the patient is receiving renal replacement therapy and the type of therapy. Acute Kidney Injury Patients with AKI are both hypermetabolic and hypercatabolic as a result of the inflammatory response associated with acute injury.130 Metabolic complications that may occur in AKI include loss of glucose homeostasis, muscle wasting, protein catabolism, electrolyte imbalance, and development of metabolic acidosis.130 Protein catabolism causes accumulation of protein metabolism byproducts resulting in azotemia. Tissue catabolism also releases intracellular electrolytes such as potassium, phosphorus, magnesium, and proteinbound acids such as sulfuric acid and hydrochloric acid.131 This, combined with decreased renal clearance, leads to electrolyte imbalance and metabolic acidosis. Continuous Renal Replacement Therapy Continuous renal replacement therapy (CRRT) uses specialized filtration membranes that are highly permeable and that remove solutes by convection with or without diffusion. To discuss the implications of fluids used during CRRT, we will first discuss CRRT modalities. Continuous venovenous hemofiltration (CVVH), the most commonly used modality, uses convection to remove solutes and water. To prevent hypovolemia, water removed during hemofiltration must be returned to the patient as replacement fluid in the CRRT circuit. Conversely, continuous venovenous hemodialysis (CVVHD) uses dialysate to remove solutes. If the concentration in the dialysate is lower than the blood concentration, the solute is removed by diffusion;

if the opposite is true, the solute will be delivered to the patient. Continuous venovenous hemodialysis does not use replacement fluids in the circuit. Finally, continuous venovenous hemodiafiltration (CVVHDF) uses both dialysate and replacement fluids. Depending on the modality, CRRT dialysate fluids contain dextrose and either bicarbonate or lactate, and they may contain additional electrolytes. Dextrose amounts can vary in commercial CRRT dialysate solutions. Using a dialysate that contains just 1.5% dextrose at a flow rate of 1 L/hour can result in the patient’s receiving 500 dextrose calories from the CRRT alone.132 There are also disadvantages to using a dialysate with very low dextrose. Glucose losses may occur in the ultrafiltrate fluid removed during CRRT. Glucose losses into the dialysate are dependent on and are equal to the serum blood glucose concentration they are dialyzed against.133 Another source of calories from CRRT solutions is citrate, which is being used more commonly for anticoagulation during CRRT. In one study, a mean caloric load of citrate anticoagulation during CRRT was 1,323 calories per day.134 At a CVVHDF flow rate of 2 L/hour, another study found a caloric load of 63 calories/hour with a 2.2% citrate solution, 20 calories/hour with a 4% trisodium citrate solution, and 60 calories/hour with heparin anticoagulation.135 Continuous renal replacement therapy dialysate solutions may contain electrolytes, and all replacement fluids should contain dextrose, sodium, chloride, potassium, calcium, and magnesium. Occasionally, dialysate fluids are also used as replacement fluids. Of special note, phosphorus cannot be added to a calcium-containing CRRT solution, so frequent monitoring and replacement of phosphorus is prudent. Protein needs are elevated for patients with AKI receiving CRRT, largely because of the severity of their illness and the accompanying inflammatory response. In addition, small proteins and amino acids are lost through CRRT. Studies have shown that at least 1.5 g/kg/day of protein is needed daily, and up to 2.5 g/kg/day may be required for positive nitrogen balance.129 An amino acid solution is available for use in PN formulas for patients with AKI; however, evidence is insufficient to support its use, and current guidelines recommend a standard amino

acid solution.129 Patients receiving CRRT do not usually require fluid restriction, so concentrated enteral or parenteral formulas are not necessary. If a patient receiving CRRT requires enteral feeding, the recommendation is to start with a standard enteral formula and to follow standard ICU calorie and protein requirements. If significant electrolyte disturbances occur, a formula designed for renal failure with lower electrolyte provision may be considered.129 However, high hemofiltration rates increase the removal rate for small molecules like electrolytes, so patients receiving CRRT do not typically require lower amounts of electrolytes while the CRRT is being used. If a patient is receiving PN while on CRRT, electrolytes may require frequent adjustment, so clinicians may prefer to minimize electrolytes in the PN solution and adjust by CRRT fluids or replace outside the PN. Chronic Kidney Disease Patients with preexisting CKD may require nutrition support in the ICU. Patients with CKD develop protein energy wasting as a result of neuroendocrine factors that include reduced protein synthesis and increased protein breakdown. Many patients also have glucose intolerance and hypertriglyceridemia. Altered calcium/phosphorus metabolism and anemia should be considered when prescribing nutrition. Finally, because of decreased renal clearance, patients with CKD will also have impaired clearance of electrolytes, metabolic acidosis, and altered fluid status. Restricted protein diets have long been used and advocated for delaying the progression to dialysis.133,136-138 These studies typically targeted a protein goal of 0.6 g/kg/day or less of protein. However, while these patients are acutely ill and hospitalized, catabolism will increase protein requirements, and patients may require dialysis to aid in removal of metabolic wastes.129 Patients should be prescribed protein that meets their needs according to degree of critical illness. Hemodialysis

Energy requirements for patients receiving hemodialysis are similar to those for patients without renal failure. The current protein recommendation for patients with CKD on maintenance hemodialysis is 1.2 g/kg/day; however, in critical illness, protein should be provided according to critical care guidelines, 1.0–2.5 g/kg/day, to meet increased metabolic demands.129 Vitamin status is an additional concern. Hemodialysis removes water-soluble vitamins, including vitamin C, pyridoxine (B6), cyanocobalamin (B12), thiamine (B1), and folic acid, as well as vitamin D.129 A standard oral renal vitamin may be used to replace these if the patient has oral or enteral access. Peritoneal Dialysis Calories from the dextrose-containing peritoneal dialysis solutions may be as high as 500–1,000 calories per day and should be accounted for when designing the nutrition prescription.130 Wideroe et al. have developed a system to estimate the amount of absorbed glucose from the perito-neal dialysis solution.139 As with other CRRT modalities, calorie and protein goals in critical illness should be set to goals according to the patient’s level of catabolism.

Respiratory In the past, high lipid feedings were recommended for patients with respiratory compromise. The theory behind this practice was that using lipids for calories produces less carbon dioxide than carbohydrates or protein and therefore will aid in weaning from the ventilator or improving respiratory status. This is represented as a respiratory quotient (RQ) equal to carbon dioxide production (Vco2) divided by oxygen consumption (Vo2), with an RQ from lipid oxidation being 0.85, protein 0.82, and carbohydrates 1. However, early reports of respiratory dysfunction and failure with high-carbohydrate feedings provided excessive calories overall.140 A study by Talpers et al. shows this; 20 mechanically ventilated patients received a low, medium, or high proportion of carbohydrates in enteral feeding or 1.0, 1.5, or 2.0 times

their basal energy expenditure in total calories. There was no difference in Vco2 between the different carbohydrate feedings, but the Vco2 significantly increased as total calories increased.141 This classic study supports the argument, and current practice, that limiting total calories will do more to prevent ventilatory adverse effects than limiting carbohydrates or increasing lipids. Both ALI and ARDS have an inflammatory component. In both conditions, eicosanoid-mediated neutrophil migration into the alveolar space causes lung damage.127,142 The type and activity of eicosanoids can be modified by omega-6 or omega-3 fatty acids. In addition, γlinolenic acid (GLA) decreases neutrophil leukotriene synthesis and increase prostaglandin E1, which may be beneficial in ALI/ARDS.141 Table 4.5 compares studies evaluating omega-3–supplemented EN in patients with ALI/ARDS. Many clinical trials using an enteral formula supplemented with omega-3 fatty acids, GLA, and antioxidants (Oxepa) have shown benefit in patients with ALI/ARDS.125-127,143 One study found a mortality benefit in the supplemented group compared with the group receiving the high-fat control formula.143 Limitations of these studies include small patient numbers, use of a high-fat comparator, and heterogeneous etiology/severity of ALI/ARDS in included patients, although patients with a diagnosis of ALI/ARDS are inherently heterogeneous. The largest study to date found no benefit to supplementing with omega-3s, GLA, and antioxidants; this study used a twice-daily enteral supplement (not the commercially available Oxepa formula) to bolus the nutrients and used a high-carbohydrate control formula, unlike previous studies.142 Further large studies using typical ICU formulas rather than high-fat formulas are needed to determine whether these nutrients can be bloused separately from the enteral formula or whether they need to be given continuously to be beneficial. No studies have shown increased adverse events with omega-3– supplemented EN compared with the control formula.125-127,142,143 With the mixed data available, some clinicians choose to recommend an enteral formula supplemented with omega-3 fatty acids, GLA, and antioxidants Oxepa for patients with ALI/ARDS, whereas others do not.

Hepatic Patients with advanced hepatic failure represent a challenge in nutritional assessment and delivery. Many patients with chronic liver disease are malnourished, but available tools for assessment may be inaccurate. Malnutrition occurs in most patients with alcoholic liver disease, but it may be less common in patients with non-alcoholic steatohepatitis.144 Body weight and fluid distribution is altered in patients with cirrhosis, and many patients have hypoalbuminemia and decreased concentrations of other blood proteins. Providing nutrition support to patients with liver disease is challenging. The liver is responsible for the metabolism of proteins, carbohydrates, and lipids. Altered protein metabolism is a well-known sign of advanced liver disease. These patients have low plasma concentrations of the branched-chain amino acids (BCAAs); leucine, valine, and isoleucine; and high concentrations of aromatic amino acids. In healthy patients, BCAAs are taken up by skeletal muscle to create glutamine, a carrier for ammonia, or are transported to the liver for gluconeogenesis. In patients with cirrhosis, excessive glutamine is produced in the muscle while the liver is unable to convert ammonia to urea, resulting in increased concentrations of ammonia.145 Patients with cirrhosis also have glucose intolerance and insulin resistance. This is associated with the early use of protein and lipid for fuel.145 Finally, patients with advanced liver disease also have impaired lipid metabolism. Altered absorption is caused by decreased concentrations of intraluminal bile salts, concurrent pancreatic or intestinal disease, and mucosal edema. In addition, there is an imbalance between triglyceride synthesis and catabolism, which depletes lipid stores.145

Table 4.5 Comparison of Studies Evaluating Omega-3– Supplemented EN in Patients with ALI/ARDS

ARDS = acute respiratory distress syndrome; BID = twice daily; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; Fio2 = fraction of inspired oxygen; ITT = intention-totreat analysis; LIS = lung injury score; PEEP = positive end-expiratory volume; PP = perprotocol analysis; RR = relative risk; SOFA = Sequential Organ Failure Assessment (score).

Caloric requirements for these patients may be difficult to ascertain. The Harris-Benedict equation is inaccurate in patients with cirrhosis.146 Anthropometry, 24-hour uri-nary creatinine collection, and SGA will yield more accurate information about the patient’s nutritional status.147 Although there may be a theoretical basis to consider restricting protein in patients with liver disease, this is not necessary. A study by Cordoba et al. showed that hepatic encephalopathy developed at a similar rate

in patients given either a low-protein or a standard-protein formula.148 In addition, Gheorghe et al. found that when patients with cirrhosis were given an oral diet with standard calories and protein, their hepatic encephalopathy improved, with the greatest improvement occurring in the most severe patients.149 Critically ill patients should receive the amount of protein that meets their catabolic needs (1.5–2.0 g/kg/day). Stable or less critically ill patients with liver disease require 1–1.5 g/kg/day of protein. The preferred route for nutrition support in patients with liver disease is the enteral route. Enteral supplementation in these patients improves nutritional status and, in some cases, markers of hepatic function.149152 The enteral route is preferred because of the infection risk with a central vascular line and preservation of gut mucosa and accompanying decreased risk of bacterial translocation.145 In addition, PN can cause liver damage in the long term and, in some cases, with short-term use. Fear of bleeding in patients with esophageal varices may delay placement of nasoenteric feeding tubes. However, small-bore softtipped nasally or orally placed tubes have a low risk of causing bleeding in non-bleeding varices, and placement should not be delayed or deferred.153 After variceal hemorrhage, however, it may be advisable to wait 48 hours after bleeding has been stopped before resuming feeding.153 Standard enteral formulas should be used for critically ill patients with liver disease. Some outpatient studies suggest that oral supplementation with BCAAs delays progression of liver disease. No studies show that short-term supplementation has any benefit in the critically ill population. The current guidelines recommend reserving formulas with BCAAs for the rare patient with hepatic encephalopathy who is refractory to medical treatment.32 Other nutritional considerations for patients with liver disease include vitamins and electrolytes. Vitamin D deficiency is common in patients with liver disease, especially cholestatic liver disease, so monitoring and replacement is important in these patients.145 Thiamine deficiency and refeeding syndrome may be common in patients with liver disease who continue to consume alcohol.145,154 Another important

consideration is to restrict sodium to 2 g daily in patients with ascites. In summary, it may be difficult to assess critically ill patients with acute or chronic liver disease for malnutrition, but malnutrition is common in these patients. Calorie and protein goals should be provided to meet the catabolic needs of critical illness, with care not to restrict protein. Special amino acid preparations containing high amounts of branched chain amino acids are not necessary, except for patients with hepatic encephalopathy refractory to lactulose and luminal antibiotics. Vitamin D and electrolytes should be monitored.

Pancreatic Nutrition support may be required for patients who have either acute pancreatitis or a history of chronic pancreatitis. The main nutritional considerations in acute pancreatitis are hypermetabolic/hypercatabolic state, hyperglycemia, hypertriglyceridemia, and hypocalcemia. Nutritional considerations for chronic pancreatitis include anorexia, weight loss, exocrine insufficiency, and malabsorption. We will discuss the primary issues in patients with pancreatic disease, including timing and type of nutrition support initiation and pancreatic enzyme replacement. Route and Type of Feeding The discussion of pancreatic rest in acute pancreatitis and its implications for nutrition support has changed dramatically in the past 20 years. In the past, many clinicians considered pancreatic rest synonymous with bowel rest, and patients were placed on PN in an effort to decrease complications. Providing pancreatic rest as a sole management strategy does not improve patient outcome.155 Enteral nutrition is superior to PN, especially in patients with severe acute pancreatitis.156-159 In one study where 100% of the enrolled patients had severe acute pancreatitis, overall and septic complications were significantly reduced.159 Evidence is still insufficient to show the superiority of EN to a standard oral diet, although smaller studies suggest it.160 Many trials evaluating the safety of EN in severe acute

pancreatitis used jejunal tube placement to avoid gastric stimulation.161 Although fewer studies support gastric feeding over jejunal feeding, the American College of Gastroenterology and SCCM/ASPEN guidelines recommend gastric and jejunal feeding equally.32,162 Standard polymeric formulas should be the first choice for enteral feeding.155 If the patient has increased nausea or increased abdominal pain, the tube position should be checked or advanced distally to the jejunum, the patient switched to continuous enteral feeding, or the feeding changed to a semi-elemental or elemental formula.32 Increased nausea is not a contraindication to continuing EN. If a patient develops persistent ileus or bowel obstruction, PN may be considered after 5 days of admission. Because intravenous lipids do not worsen symptoms of pancreatitis, they can be safely used when serum triglyceride is below 400 mg/dL.155 Standard guidelines apply to formulating PN for patients with acute pancreatitis. Enzyme Replacement Pancreatic enzyme replacement will be necessary for many patients with chronic pancreatitis. Recently, the FDA required all manufacturers of pancreatic enzyme supplements to submit an NDA by April 2010 or to stop distributing their products. Before this, there were around 25 pancreatic enzyme products, and because this deadline has passed, there are six pancreatic enzymes on the U.S. market: Creon, Zenpep, Pancreaze, Ultresa, Viokace, and Pertzye. Each product has several strengths with differing amounts of amylase, lipase, and protease. Viokace is the only product without an enteric coating and is labeled to take with a proton pump inhibitor. Labeled dosing for all products recommends dosing according to the Cystic Fibrosis Foundation, beginning with 500 units of lipase per kilogram per meal and titrating to a maximum of 2,500 lipase units per kilogram per meal. Many other dosing schemes are available.155 Although none of the available products are labeled for administration through gastrostomy or distal feeding tubes, dosing and administration methods have been reported in the literature. One method is to provide 1,000 lipase units for each gram of fat provided by the enteral feed and dose this every 3 hours

for continuous feeding.163 For gastric tubes, it is recommended to suspend enteric-coated microspheres (all products except Viokace) in a nectar thick acidic liquid and administer by syringe into the feeding tube.163 For distal feeding tubes, the enteric-coated spheres must be mixed with sodium bicarbonate to activate the enzymes, which may take more than 30 minutes.163,164 The only products found to dissolve completely in sodium bicarbonate within 30 minutes, dosed in lipase units, are Creon 24,000, Ultresa 23,000, and Zenpep 20,000 and 40,000.164 Water, carbonated beverages, or sweetened beverages should not be used to dilute pancreatic enzymes because this increases the adhesiveness of the enteric coating, which can cause tube obstruction. Crushing the microspheres is not recommended because this causes coagulation of the formula, and the powder can potentially be inhaled or come into contact with the eyes. It is not recommended to add pancreatic enzymes directly to the enteral feeding because this may compromise sterility and will cause coagulation of the formula, which may cause clogging. Table 4.6 summarizes information on pancreatic enzyme administration with EN. In conclusion, patients with severe acute pancreatitis should receive nutrition support by the enteral route whenever possible. Enteral feeding is associated with not only an improvement in nutritional status but also a reduction in complication rates. Patients with acute pancreatitis may be fed by either the gastric or the jejunal route. If a critically ill patient requires pancreatic enzyme replacement, the pharmacist should be aware of new formulations and dosing strategies.

DISEASE-SPECIFIC CONSIDERATIONS Diabetes/Glucose Control A recent survey of U.S. hospitals reported that hyperglycemia occurred in 46% of critically ill patients.165 Hyperglycemia has been associated with many poor outcomes in critically ill patients, including infections, septic shock, poor wound healing, and increased ICU stay.166 Both hyper- and hypoglycemia should be avoided in critically ill patients.

Current ASPEN guidelines recommend a blood glucose target of 140– 180 mg/dL in adult critically ill patients receiving nutrition support.165 This recommendation is in line with the current AACE/ADA (American Association of Clinical Endocrinologists/American Diabetes Association) recommendations for critically ill patients. Avoiding overfeeding is critical in patients with hyperglycemia; excess calories can contribute to hyperglycemia and associated poor outcomes. All sources of calories should be included in the nutritional assessment, including propofol and dextrose-containing intravenous fluids. Either standard or specialized diabetes/hyperglycemia enteral formulas are appropriate for critically ill patients with hyperglycemia.165 Many clinicians choose specialized formulas because of a lower provision of glucose and a relatively high provision of protein, which is needed for critical illness. Continuous enteral feeding is more commonly tolerated with less variation in serum glucose. Serum glucose should be monitored as enteral feeding is advanced to goal rate, and intravenous insulin infusions may be necessary. If PN is necessary in a patient with hyperglycemia, it is prudent to begin insulin therapy before or concurrently with PN and/or to reduce dextrose in the PN. Parenteral nutrition is associated with greater hyperglycemia than EN.166 Initially, intravenous insulin infusion that may be titrated separately from the PN infusion is recommended; if the infusion is to be discontinued, 80% of the daily dose from the infusion may be added to the PN. Another strategy for estimating the insulin requirements to be added to PN is to add 0.05–0.1 unit of regular human insulin per gram of dextrose in the PN. It is best to be conservative when estimating insulin requirements in PN because most facilities prepare PN solutions 12–24 hours before they are administered, and changing insulin requirements can be difficult to predict. Additional subcutaneous insulin may be needed for unexpected hyperglycemia.

Table 4.6 Pancreatic Enzyme Administration with EN

Fr = French; q = every.

Thermal Injury Burn injuries result in a hypermetabolic state similar to trauma or sepsis. The degree to which patients with severe burns are hypermetabolic and hypercatabolic is much greater, however. Because of the hypermetabolic nature of burn injuries, the resting energy expenditures of pediatric patients with severe burns have been reported to be up to 150% greater than expected and up to 160% greater in adults.167 In addition, patients with burns may oxidize amino acids at a rate 50% higher than fasting controls, leading to a significant protein deficit.168 This significant calorie and protein hyper-metabolism may continue for up to 2 years post-injury.166 If nutritional interventions are not made, significant weight loss can occur. A 10% loss of total body mass in patients with burns leads to immune dysfunction; 20%, to impaired wound healing; 30%, to severe infections; and 40%, eventually to death.167 Time to receipt of EN is critical to lessen the impact of the hypermetabolic state through modulation of catecholamine concentrations and maintaining gut mucosal integrity. Early enteral feeding initiated less than 24 hours after injury is recommended.167 Parenteral nutrition should only be used if the patient has a non-functional GI tract; it is unclear whether PN should be used

in addition to EN when calorie and protein goals cannot be met with EN alone. Indirect calorimetry is the most reliable way to measure caloric needs in patients with severe burns. If indirect calorimetry is not available, predictive equations may be used. Some authors suggest the Galveston, Curreri, or Toronto equations,167 whereas others suggest that the Milner and Carlson equations are most accurate.169 Overall, it can be expected that the caloric requirements of these patients will be higher than in patients without burns. The next nutritional consideration is the balance of substrates to provide. Patients with severe burns will have high caloric requirements, so it is important to provide glucose at less than the maximum glucose oxidation rate (7 mg/kg/hour). High-carbohydrate formulas are typically provided to patients with burns because this has been associated with improved outcomes.168 Conversely, insulin therapy is used at some burn centers for purposes other than glucose control. Typically, this is done with continuous infusions of insulin and dextrose titrated to euglycemia. Insulin therapy in patients with burns stimulates muscle protein synthesis, increases lean body mass, and is associated with improved wound healing, without increasing hepatic triglyceride production.167 Immediately after burn injury, fat metabolism and use are altered. There is an increase in peripheral fat breakdown and use by the liver. About 30% of the available free fatty acids are used for fuel through beta-oxidation; the rest undergoes reesterification and potential accumulation in the liver.167 Some centers may therefore limit fat administration to the minimal amount needed to prevent essential fatty acid deficiency. Increased proteolysis is an important metabolic implication of burns. Protein requirements are estimated at 1.5–2 g/kg/day in adults with burns and at 2.5–4.0 g/kg/day in children with burns.32,167 Some clinicians advocate the use of the amino acid glutamine for patients with burns. The 2009 SCCM/ASPEN guidelines recommend immunemodulating enteral formulas that contain glutamine for patients with burns, as well as enteral supplementation.32

Certain vitamins and minerals are also recommended for patients with burns. Decreased vitamin and mineral concentrations are associated with poor outcome; however, further research is needed to determine the dosages for these micronutrients. An older study recommends the following daily for patients with greater than 20% total body surface area burns: one multivitamin, 500 mg of ascorbic acid twice daily, 10,000 international units of vitamin A, and 45–50 mg of zinc.170 European guidelines recommend supplementation of vitamin C, copper, selenium, and zinc.171 Recently, low vitamin D concentrations were reported in children with burns despite supplementation, but the significance of this is not yet known. In summary, patients with severe burns are highly catabolic. These patients will have high caloric and protein needs immediately post-burn and potentially long after the initial injury. Protein requirements are estimated at up to 2 g/kg/day for adults and up to 4 g/kg/day for children with severe burns. Early enteral feeding is preferred; a formula with a high carbohydrate to fat proportion is a reasonable choice. Patients with severe burns should receive the RDA of necessary vitamins and minerals at a minimum and may require additional supplementation.

SUMMARY Critically ill patients are characterized by an inflammatory response that results in a failure to adapt energy and protein use to restore homeostasis, as occurs in simple starvation. The complexities of nutrition support are many in this population, and there are several controversies with few definitive answers regarding the optimal nutrition therapy for best outcomes. However, nutrition support therapy in critically ill patients is a rapidly evolving aspect of patient care with many new studies being conducted. Practitioners must remain cognizant of emerging data, and 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. Until more robust data are available, clinical practice guidelines will

continue to guide clinicians in their selection of nutrition support therapy but cannot determine the most appropriate therapy for any individual patient.

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167. Rodriguez NA, Jeschke MG, Williams FN, et al. Nutrition in burns: Galveston contributions. J Parenter Enteral Nutr 2011;35:704-14. 168. Abdullahi A, Jeschke MG. Nutrition and anabolic pharmacotherapies in the care of burn patients. Nutr Clin Pract 2014;29:621-30. 169. Shields BA, Doty KA, Chung KK, et al. Determination of resting energy expenditure after severe burn. J Burn Care Res 2013;34:22-8. 170. Gottschlich MM, Warden GD. Vitamin supplementation in the patient with burns. J Burn Care Rehabil 1990;11:275-9. 171. Rousseau A, Losser M, Ichai C, et al. ESPEN endorsed recommendations: nutritional therapy in major burns. Clin Nutr 2013;32:497-502. 172. Stapleton RD, Martin JM, Mayer K. Fish oil in critical illness: mechanisms and clinical applications. Crit Care Clin 2010;26(3):501-514, ix. 173. Grau-Carmona T, Morán-García V, García-de-Lorenzo A, et al. Effect of an enteral diet enriched with eicosapentaenoic acid, gamma-linolenic acid and anti-oxidants on the outcome of mechanically ventilated, critically ill, septic patients. Clin Nutr 2011;30(5):578-84.

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

LEARNING OBJECTIVES 1. Describe sources of hyperglycemia in critically ill patients. 2. Critique primary literature and multidisciplinary guidelines on glucose management in the intensive care unit. 3. Analyze medication therapy options for glucose management in a critically ill patient. 4. Categorize and construct treatment plans for patients with hyperglycemic emergencies (diabetic ketoacidosis and hyperglycemic hyperosmolar state). 5. Formulate a plan for an institution-wide multidisciplinary approach to glucose management.

ABBREVIATIONS IN THIS CHAPTER BG

Blood glucose

DKA

Diabetic ketoacidosis

HHS

Hyperglycemic hyperosmolar state

ICU

Intensive care unit

MICU

Medical intensive care unit

POCT

Point-of-care testing

RCT

Randomized controlled trial

SICU

Surgical intensive care unit

STS

Society of Thoracic Surgeons

TPN

Total parenteral nutrition

INTRODUCTION Management of blood glucose (BG) in critically ill patients is one of the key facets of supportive care. Retrospective analyses have shown increased mortality and morbidity with dysglycemia.1-5 In this chapter, we will review the causes of hyperglycemia in the critically ill population as well as in the primary literature focused on glucose management in the intensive care unit (ICU) population. We will also evaluate medication therapy options for patients with hyperglycemia, as well as for patients undergoing a hyperglycemic emergency such as diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar state (HHS).

PATHOPHYSIOLOGY/CAUSES OF HYPERGLYCEMIA Several mechanisms are responsible for acute hyperglycemia in ICU patients. These include insufficient antihyperglycemic therapy in patients with a known history of diabetes because many patients with diabetes on oral agents have their oral agents discontinued on admission, which are not replaced with an effective inpatient antihyperglycemic regimen.6 Critically ill patients also commonly have increased insulin resistance among peripheral tissue, and increases in both hepatic and renal gluconeogenesis.7 Acute hyperglycemia related

to critical illness, also called stress hyperglycemia, is caused by release of the hormones norepinephrine, epinephrine, cortisol, and growth hormone and increases in the inflammatory mediators that lead to insulin resistance.8 Hyperglycemia can increase proinflammatory cytokines, prothrombotic mediators, and oxidative stress.9 External factors potentially contributing to hyperglycemia are the use of dextrose-containing intravenous admixtures and maintenance fluids as well as nutrition with high-carbohydrate tube feedings.6 Hyperglycemia can also impair blood flow and cause decreased perfusion in patients with acute coronary syndromes.10 The deleterious effects of hyperglycemia are well documented in many organ systems throughout the body, and as such, it is important to address glucose status in all ICU patients. We will discuss the benefits to glucose management shown in the primary literature later in this chapter.

RANDOMIZED CONTROLLED TRIALS: TIGHT VS. MODERATE GLUCOSE MANAGEMENT Ideal goal BG concentrations for critically ill patients remain a topic of controversy. In this section, we will review the primary literature comparing “tight” BG control with “moderate” BG control in the ICU.

Leuven SICU A 2001 Belgian single-center, nonblinded, randomized controlled trial (RCT) of 1,548 patients, known as the Leuven SICU trial by Van den Berghe et al., compared treatment of surgical intensive care unit (SICU) patients with intensive or conventional glycemic control.11 Most patients in this analysis were post-cardiac surgery (63% in the conventional arm and 62% in the intensive arm). This was the first large trial to show a decrease in morbidity and mortality associated with tight glycemic control in the ICU. The intensive arm aimed for a goal glucose of 80–110 mg/dL, whereas the conventional glycemic control arm treated patients to a goal glucose of 180–200 mg/dL. For the primary

end point of mortality, a significant reduction was noted in the intensive arm (4.6% vs. 8%; p 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

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

In the absence of significant organ dysfunction, critically ill patients often have increased renal perfusion, increased glomerular filtration rates and creatinine clearance, and subsequently increased clearance of hydrophilic antibiotics.77-79 Further evidence suggests that critically ill patients have higher creatinine clearances even in the presence of normal plasma creatinine concentrations.80-85 The recognition of augmented renal clearance (ARC), defined as a creatinine clearance greater than 130 mL/minute/1.73 m2, in many critically ill patients adds

yet another measure of uncertainty in the evaluation of renal function and drug clearance for purposes of antimicrobial dosing. Augmented renal clearance occurs at highly variable rates and has been reported to occur in 30%–86% of patients in ICUs.80,83,84,86-88 Specific risk factors have not been identified, although several factors have consistently been reported among various studies; these include younger age (50 years or younger), male, trauma, traumatic brain injury, mechanical ventilation, and lesser severity of illness.80,83,85 However, the occurrence of ARC is highly unpredictable and has also been reported among 40% of patients with sepsis, in older patients, and in patients with high severity of illness.84-88 Although the timing of onset and duration of ARC have not been well characterized, it may already be present on ICU admission and last for 1 week or more.84-88 The presence of ARC is a significant problem for antimicrobial dosing in critically ill patients because, if unrecognized, use of improperly adjusted drug doses may result in underdosing of antimicrobials, subtherapeutic drug concentrations, and therapeutic failure in the treatment of infections.81,86-90 Among specific types of patients, trauma patients have commonly been reported to have increased clearance of renally eliminated drugs. However, actual studies have provided mixed results with respect to renal clearance and dosing requirements of various antibiotics in this population.14 Despite the apparently high incidence of ARC in this population, studies have nevertheless noted a high degree of variability in drug clearance among trauma patients.14 Medical and surgical ICU patients are likewise highly variable with respect to alterations in renal clearance. A review of literature reporting antibiotic PK in medical and surgical patients concluded that, although some patients did in fact have increased renal clearance, a similar number of patients had no changes or even reduced renal clearance of antibiotics.14 The high degree of variability in drug clearance among medical and surgical ICU patients likely mirrors the high degree of patient heterogeneity found among this population with respect to patient demographics, underlying comorbidities, and reason for admission to the ICU.14 Patients with burn injuries have also been often reported to have

increased renal clearance of antibiotics. Similar to trauma patients, patients with burn injuries tend to be younger, have fewer baseline comorbidities, are initially hypermetabolic, and receive large volumes of resuscitation fluids.14 Many studies of this population have shown increased renal clearance compared with normal patients not in ICUs, but patients with burn injuries also tended to have a high degree of variability with respect to both increased and decreased clearance. Antimicrobials such as aminoglycosides, vancomycin, ciprofloxacin, and fluconazole usually have increased clearance, whereas individual βlactam agents are more variable in the effects of their injuries.14,91-96 Clinicians should remember that patients with burn injuries often require higher daily doses of antimicrobials in order to meet desired PK/PD targets, but that such aggressive dosing may also place patients at greater risk of drug-related toxicities if patients do not actually have increased renal clearance.14 This is a potentially problematic finding, because drug concentrations that are much more variable than in normal subjects could result in a higher incidence of subtherapeutic or toxic concentrations. Although toxic concentrations in a patient may be detected by adverse events that manifest as clinical or laboratory abnormalities, the risk of subtherapeutic drug concentrations from rapid clearance is largely undetectable at the bedside and is compounded by the increased volume of distribution commonly seen in these patients.

Changes in Plasma Protein Binding and Antibiotic Penetration to Tissues The effects of altered protein binding on Vss and hepatic drug clearance have already been described. Drugs with reduced binding to albumin or other plasma proteins may have increased fu of antibiotic, which could potentially have therapeutic implications. Because timedependent antibiotics rely on free drug concentrations to be consistently above the pathogen MIC (f T>MIC being the key PD parameter for these agents), it is possible that increased fu of these drugs may actually contribute to enhanced therapeutic efficacy. However, decreased protein binding produces mixed effects on PK

parameters, including both Vss and clearance, which may offset the theoretical advantages. As previously discussed, decreased protein binding is often associated with increased Vss and may result in reduced concentrations of hydrophilic drugs in plasma, interstitial fluids, and other tissues through a dilutional effect. This alteration in Vss may therefore have adverse effects on concentration-dependent drugs unless doses are correspondingly increased. Protein binding alterations are not usually clinically relevant for hepatically cleared drugs because clearance of high EH drugs is not limited by protein binding and, for low EH drugs, changes in fu are often quickly offset by corresponding increases in hepatic clearance. The most relevant effect of decreased protein binding for most antimicrobials, particularly those that are renally cleared, is that increasing fu values often result in more rapid renal drug elimination.97 However, hypoalbuminemia and other causes for altered protein binding are only likely to significantly influence antibiotic clearance when the agent is highly protein bound (90% or greater) and has an intrinsically low Vss.98 Protein binding is sufficiently low for most antimicrobials that alterations in fu are not likely to pose a problem with respect to altered drug clearance (Table 12.3). The foregoing discussion regarding the PK effects of altered protein binding largely assumes that patients have otherwise normal hepatic and renal function and will follow well-established models of PK disposition of drugs. This is obviously not the case for critically ill patients in whom significant renal and hepatic impairment is common, as well as hemodynamic changes that may alter normal processes related to Vss and clearance. Although the protein binding of antimicrobials in critically ill patients is known to be altered, the true clinical significance of these alterations is not well understood and likely varies considerably among individual patients. Antimicrobial penetration into infection sites is also an important consideration related to the PK/PD properties of the drugs. The ability of antibiotics to penetrate to tissue sites is related to the type of antibiotic, protein binding, tissue characteristics, and method of antibiotic administration. The disposition of antibiotics has traditionally been studied by comparing tissue to serum concentration ratios in

infected and non-infected tissues. However, these studies have also shown high variability in estimates of tissue distribution. In vitro and in vivo studies suggest that high intravascular protein binding restricts the penetration of antibiotics into extravascular tissue sites.98-101 Microdialysis is an in vivo sampling technique that is being increasingly used to characterize antimicrobial tissue penetration, particularly in critically ill patients.102-106 Several studies using microdialysis techniques have shown quite good correlations between degree of protein binding and drug concentrations in interstitial fluids. However, free drug concentrations in plasma are often not representative of drug concentrations being achieved at actual infection sites because of physiological shunting or otherwise impaired tissue perfusion. Data analyses suggest that antibiotic penetration into tissues of patients with septic shock is impaired because of hemodynamic instability and regional perfusion abnormalities. Antibiotic concentrations in tissues of patients with septic shock may be 5- to 10-fold lower than in healthy volunteers or patients with less severe sepsis.102-106 Aggressive dosing of antibiotics is probably required to maximize antibiotic penetration into infected tissue, particularly in patients with shock states, although data to support this are currently lacking, and even administration of very high doses may be insufficient to overcome tissue perfusion abnormalities, which may be present in various pathophysiological processes. For highly bound antimicrobials that undergo primarily renal elimination, aggressive dosing may likewise be required to overcome potentially enhanced renal clearance in patients without renal impairment.

Changes in Antibiotic Half-Life The elimination half-life of a drug is directly related to its clearance and Vss characteristics. The half-life is mathematically represented by the following equation:

The half-life of a drug is directly related to changes in both Vss and clearance; increased Vss and/or decreased clearance will increase the half-life, whereas decreased Vss and/or increased clearance will decrease the half-life. An increase in Vss that prolongs the half-life might be therapeutically advantageous for time-dependent antimicrobials from a PK/PD perspective but a potential disadvantage for concentration-dependent agents that are dependent on achieving adequate Cmax concentrations. The same considerations could apply to reductions in drug clearance, which would also potentially be advantageous for time-dependent antimicrobials because of the reduced elimination rates and maintenance of drug concentrations over longer periods. However, such generalizations do not adequately represent the complexities of the many patho-physiological processes that influence Vss and clearance (often simultaneously), the dynamic nature of critically ill patients in whom PK properties of drugs may be changing on a daily (if not hourly) basis because of therapeutic interventions and evolving pathophysiological processes, or the significant difficulties in adequately assessing and characterizing the potential PK alterations that may be present in an individual patient. Although it is predictable that PK alterations are occurring in many critically ill patients, it is also extremely difficult for clinicians to make informed dosing decisions on the basis of accurate estimates of the magnitude of these changes.

General Strategies for Dosing Adjustments Based on PK Alterations A general strategy for assessing the need for potential dose adjustments of antimicrobials in critically ill patients is first to determine whether the specific drug is primarily cleared through hepatic metabolism or renal excretion. As previously discussed, antimicrobials that are hepatically metabolized do not generally require dosage adjustments in ICU patients unless significant hepatic dysfunction is present. For drugs that are renally cleared, reduction in total daily doses may be considered in the presence of renal impairment, whereas the presence of certain other conditions (Table 12.2) should

prompt clinicians to consider increasing total daily doses. Clinicians should also consider increasing doses of hydrophilic drugs in the presence of conditions that are associated with increased Vss values of these agents (Table 12.2). Beyond these simple considerations, determining if and how antimicrobial regimens should be appropriately adjusted in ICU patients becomes much more difficult. Because of the severity of infections encountered in critically ill patients and because of the variability in PK, tissue penetration, presence of obesity, pathogen MICs, and other factors relating to the efficacy of antimicrobials, the general recommendation for antimicrobials in ICU patients is to use high, aggressive initial doses. Aggressive dosing of antimicrobials (at least during empiric therapy in high-risk patients) should be a standard practice in ICUs to optimize the PD performance of the drugs. Use of high initial doses (until pathogens and susceptibilities are determined and/or patients show favorable clinical response) potentially compensates for PK variability that may be present and helps ensure that patients are receiving enough drug to successfully achieve the PD goals of antimicrobial use. Reliable attainment of key PK/PD targets (AUC0-24/MIC, Cmax/MIC, and f T>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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164. Wiederhold NP. Using antifungal pharmacodynamics to improve patient outcomes. Curr Fungal Infect Rep 2010;4:70-7. 165. Pfaller MA, Diekema DJ, Rex JH, et al. Correlation of MIC with outcome for Candida species tested against voriconazole: analysis and proposal for interpretive breakpoints for gramnegative aerobic bacteria based. J Clin Microbiol 2006;44:819-26. 166. Rodrıguez-Tudela JL, Almirante B, Rodrıguez-Pardo D, et al. Correlation of the MIC and dose/MIC ratio of fluconazole to the therapeutic response of patients with mucosal candidiasis and candidemia. Antimicrob Agents Chemother 2007;51:3599-604. 167. Pai MP, Turpin RS, Garey KW. Association of fluconazole area under the concentration-time curve/MIC and dose/MIC ratios with mortality in nonneutropenic patients with candidemia. Antimicrob Agents Chemother 2007;51:35-9. 168. Baddley JW, Patel M, Bhavnani SM, et al. Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrob Agents Chemother 2008;52:3022-8. 169. Smith J, Safdar N, Knasinski V, et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 2006;50:1570-2. 170. Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 2008;46:201-11. 171. Hong Y, Shaw PJ, Nath CE, et al. Population pharmacokinetics of liposomal amphotericin B in pediatric patients with malignant diseases. Antimicrob Agents Chemother 2006;50:935-42. 172. Gumbo T. Impact of pharmacodynamics and pharmacokinetics on echinocandin dosing strategies. Curr Opin Infect Dis 2007;20:58791. 173. Wiederhold NP, Kontoyiannis DP, Chi J, et al. Pharmacodynamics of caspofungin in a murine model of invasive pulmonary aspergillosis: evidence of concentration-dependent activity. J Infect Dis 2004;190:1464-71.

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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

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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

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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 70% isolates), C. pelliculosa, C. rugosa, and C. valida (> 70% isolates). cInducible

fluconazole resistance has been reported for C. utilis.

dCases

of itraconazole-resistant isolates have been reported for Candida spp. including C. guilliermondii, C. haemulonii (> 90% isolates), C. pelliculosa (> 70% isolates), C. rugosa, and C. utilis (> 50% isolates). eCases

of voriconazole-resistant isolates have been reported for Candida spp. including C. dubliniensis, C. famata, C. guilliermondii, C. haemulonii, and C. valida.

Table 16.6 Resistance Patterns for Candida spp. with Polyene, Echinocandin, and Miscellaneous Antifungal Agents29-31

aCases

of amphotericin B–resistant isolates have been reported for Candida spp. including C. haemulonii (> 70%) and C. krusei. bCases

of flucytosine-resistant isolates have been reported for Candida spp. including C. haemulonii, C. krusei (> 70%), C. pelliculosa, and C. utilis (> 50%).

Most Aspergillus spp. are reported to have low MIC values for commonly used therapy such as voriconazole and amphotericin B agents, but recent increases in resistance have been reported for specific species. A. terreus isolates tend to have high amphotericin B MIC values, whereas A. calidostus and A. lentulus isolates have reduced susceptibility to a variety of antifungal agents. Certain isolates of A. fumigatus have been reported to be resistant to voriconazole (TR46/Y121F/T289A mutation), itraconazole, and/or posaconazole, and higher mortality rates have been reported in patients infected with these isolates.59 Posaconazole, itraconazole, and isavuconazole all have potential efficacy for the treatment of invasive aspergillosis. In a noninferiority trial that compared isavuconazole with voriconazole, all-cause mortality rates through day 42 were 18.6% and 20.2%, respectively.60 Combination salvage therapy with an echinocandin and voriconazole or amphotericin B has been reported. The mortality rates of 47 patients

with invasive aspergillosis were significantly lower in patients who received voriconazole plus caspofungin than in those who received voriconazole mono-therapy (OR 0.28; 95% CI, 0.28–0.92).61 Aspergillosis Treatment Voriconazole is recommended as monotherapy as first line because of a multicenter, randomized unblinded, clinical trial that compared the use of voriconazole with that of amphotericin B deoxycholate in patients with invasive aspergillosis.2 The voriconazole and amphotericin B group survival rates at 12 weeks were 70.8% and 57.9%, respectively (hazard ratio 0.59; 95% CI, 0.4–0.88).62 In critically ill patients with suspected invasive aspergillosis, initial use of an amphotericin B agent has been recommended to cover for both mucormycosis and aspergillosis until Aspergillus spp. infection has been confirmed, especially if the patient had recently received voriconazole.2,3

Mucormycosis The rapidly growing organisms that cause mucormycosis (previously known as zygomycosis) include Absidia, Apophysomyces, Cunninghamella, Mucor, Rhizomucor, Rhizopus, and Saksenaea spp.3 The most common infection sites are rhino-orbital-cerebral or pulmonary in patients who are immunocompromised, received a diagnosis of diabetes, are intravenous drug users, or are receiving deferoxamine therapy for iron overload (enhanced growth of organisms). Although invasive Candida infection rates have decreased in patients with hematologic malignancies, rates of mucormycosis have increased. The use of voriconazole in this patient population has been associated as being an independent risk factor for disease (OR 10.4; 95% CI, 2.1–39).63

Table 16.7 Rapid Diagnostic Tools for Fungal Infections5,41-50

aResearch

use only.

bLightCycler

SeptiFast test not available in the United States.

MALDI-TOF = matrix-assisted laser desorption/ionization time-of-flight (mass spectrometry); PNA FISH = peptide nucleic acid fluorescence in situ hybridization.

Mucormycosis Treatment Primary treatment of mucormycosis is surgical intervention with early antifungal therapy together with decreasing immunosuppression or other risk factors, if possible.3 Appropriate early antifungal therapy within 6 days of diagnosis for mucormycosis is associated with decreased mortality rates (49% vs. 83%).64 Lipid formulations of amphotericin B are used for initial therapy. Double coverage with posaconazole or isavuconazole is controversial because of the high mortality rate for patients with mucormycosis who receive amphotericin B monotherapy and the potential antagonism with triazole therapy. Before FDA approval of the labeled uses of the delayed-release tablet and intravenous formulations of posaconazole together with the oral and intravenous formulation of isavuconazole, the oral suspension formulation of posaconazole was used for the treatment of mucormycosis.

According to posaconazole 24-hour area under the curve comparison, the bioavailability of the delayed-release formulation of posaconazole is higher than that of the oral suspension, so the tablet formulation may be preferred for mucormycosis treatment.18 Isavuconazole has an FDA-approved indication for the treatment of invasive mucormycosis. In an open-label study of isavuconazole for patients with probable or proven mucormycosis, the all-cause mortality rate was 47% at day 180.65 Echinocandin agents in combination with amphotericin B products have been reported.66 Echinocandin agents have no in vitro activity against the organisms that cause mucormycosis. One retrospective study evaluated 41 patients with rhino-orbital or rhino-orbital-cerebral mucormycosis. Six of the 41 patients received a combination of caspofungin and amphotericin B agents, whereas the remaining patients received monotherapy with amphotericin B.66 Using multivariate logistic regression analysis with an end point of success at 30 days after hospital discharge, the combination therapy patient group had higher success rates (OR 10.9; 95% CI, 1.3–∞).

Scedosporiosis Scedosporiosis is associated with high mortality rates in immunocompromised patients, and infection outcomes are associated with the immune function of patients and surgical interventions.56 Scedosporiosis Treatment Antifungal susceptibility testing is recommended because of variable reported resistance to Scedosporium spp.55 Voriconazole is often used as the primary antifungal agent for infections caused by S. apiospermum (asexual form of Pseudallescheria boydii). Therapy options are limited for S. prolificans because high antifungal MIC (amphotericin B, flucytosine, triazole agents) and minimum effective concentration (echinocandin) values have been reported for most isolates. Combination therapy of voriconazole with micafungin,

miltefosine, or terbinafine based on in vitro synergy testing has been reported.

Fusariosis Certain Fusarium spp. have been reported to cause IFIs with high mortality rates in immunocompromised patients, especially those with a T-cell immunodeficiency or severe neutropenia.57 Treatment successes are associated with improved outcomes with immune reconstitution. Agents such as interferon-γ and granulocyte colony-stimulating factor have been prescribed to patients with invasive fusariosis, but efficacy rates with these types of agents are not fully understood. Fusariosis Treatment High MIC values have been reported for a variety of anti-fungal agents including echinocandin and amphotericin B agents with Fusarium spp. and triazole agents, specifically with F. solani and F. verticillioides.57 Despite in vitro results, lipid formulations of amphotericin B and/or voriconazole have been used to treat invasion fusariosis, with 90-day survival rates reported as 28%–53% with amphotericin B agents and 60% with voriconazole.57 Posaconazole has been used as salvage therapy, whereas combinations of amphotericin B agents with caspofungin, terbinafine, or voriconazole have been reported.

DIMORPHIC FUNGI—OPPORTUNISTIC ENDEMIC FUNGAL INFECTIONS Some fungi are dimorphic because these organisms can grow as either a mold or a yeast, depending on growth conditions. Many of the dimorphic fungi that cause IFIs in critically ill patients are considered endemic to certain geographic locations. Blastomyces dermatitidis, Coccidioides spp., and Histoplasma capsulatum may be causative organisms of IFIs, depending on a patient’s exposure history in the United States.67-69 Treatment of endemic IFIs depends on the site and

severity of disease together with patient characteristics. Amphotericin B or triazole (including fluconazole or itraconazole) is commonly used as first-line therapy.

Treatment of Blastomycosis Pulmonary blastomycosis is commonly treated with itraconazole or amphotericin B, as recommended by the 2008 Infectious Diseases Society of America guideline statement.67 Therapy recommendations start with amphotericin B agents rather than itraconazole for severe disseminated blastomycosis.

Treatment of Coccidioidomycosis Endemic to the U.S. Southwest, Coccidioides spp. infections often need no treatment.68 Most patients will be asymptomatic after initial exposure. Pulmonary or disseminated disease can develop in some infected patients. Amphotericin B agents are often used first line for symptomatic critically ill patients, with fluconazole or other triazole agents used as stepdown therapy or as initial therapy for less severe disease. If a patient is given a diagnosis of meningitis, fluconazole or alternative triazole therapy is normally recommended to be continued for the duration of the patient’s life because of high relapse rates if triazole therapy is discontinued. For refractory cases, other triazole agents have been prescribed, but comparison data are limited. Interferon-γ has been used in salvage therapy in combination with antifungal therapy for patients with interferon-γ receptor 1 deficiency.70

Treatment of Histoplasmosis Infection with H. capsulatum is often asymptomatic, but certain critically ill patients, especially if immunocompromised, may require antifungal therapy.69 As discussed in the 2007 Infectious Diseases Society of America guideline statement, amphotericin B is often used as first-line therapy for moderate to severe pulmonary histoplasmosis, and

methylprednisolone can be prescribed in combination if the patient develops acute respiratory distress syndrome. Itraconazole can be used as outpatient therapy.

PROPHYLAXIS FOR IFIs As shown in Table 16.8, patients in a critical care setting can have a variety of risk factors that have been associated with the increased invasive Candida infection rates, including degree of immunosuppression, exposure to broad-spectrum antibiotics, parenteral nutrition, and use of devices including dialysis and extracorporeal life support.21,33,71-74 The use of antifungal prophylaxis and screening tests such as (1,3)-beta-d-glucan or galactomannan antigen detection assays has been evaluated for patients with certain risk factors for the prevention and detection of IFIs.75-78 Please see chapter 13, “Laboratory Testing Considerations”; chapter 18, “Antimicrobial Prophylaxis”; and chapter 50, “Care of Immunocompromised Patient,” for specific information regarding fungi screening assays and antifungal prophylaxis in critically ill patients.

CONCLUSION Specialists with a knowledge of antifungal therapy pharmacology and pharmacokinetics together with interpretive susceptibility breakpoints can influence the appropriate use of these agents in patients with IFIs in critical care settings. As yeast and mold rapid diagnostic detection advances, practitioners’ ability to develop antifungal therapy algorithms and protocols for drug selection and monitoring on the basis of therapy outcomes, patient characteristics, and known resistance patterns will become important to decrease the time to appropriate antifungal therapy.

Table 16.8 Risk Factors for Invasive Candida Infections21,33,71-73

Infection Site General risk factors for invasive infection

Associated Risk Factors Include Immunocompromised state (hematologic malignancies, HSCT, solid organ transplantation, corticosteroids), central venous catheters, parenteral nutrition, exposure to broad-spectrum antibiotics, renal dysfunction (acute), diabetes, surgical procedures Specific risk factors based on diagnosis:

Bloodstream infection (candidemia)

• ICU admission

Empyema

• Candidemia

Endocarditis

• Prosthetic heart values, intravenous drug use, central venous catheters, prolonged candidemia

Meningitis

• Candidemia

Pericarditis

• Candidemia, thoracic surgery

Peritonitis

• Peritoneal dialysis, GI perforation, anastomotic leaks, acute necrotizing pancreatitis

HSCT = hematopoietic stem cell transplantation; ICU = intensive care unit.

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exposure to micafungin and caspofungin in a BM transplant unit. Bone Marrow Transplant 2015;50:158-60. 55. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010;50:291-322. 56. Troke P, Aguirrebengoa K, Arteaga C, et al. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob Agents Chemother 2008;52:1743-50. 57. Nucci M, Marr KA, Vehreschild MJ, et al. Improvement in the outcome of invasive fusariosis in the last decade. Clin Microbiol Infect 2014;20:580-5. 58. Sipsas NV, Kontoyiannis DP. Invasive fungal infections in patients with cancer in the Intensive Care Unit. Int J Antimicrob Agents 2012;39:464-71. 59. Gregson L, Goodwin J, Johnson A, et al. In vitro susceptibility of Aspergillus fumigatus to isavuconazole: correlation with itraconazole, voriconazole, and posaconazole. Antimicrob Agents Chemother 2013;57:5778-80. 60. Kontoyiannis D, Giladi M, Lee M, et al. A Phase 3, Randomized, Double-blind, Non-inferiority Trial to Evaluate Efficacy and Safety of Isavuconazole versus Voriconazole in Patients with Invasive Mold Disease (SECURE): Outcomes in Invasive Aspergillosis Patients. Available at idsa.confex.com/idsa/2014/webprogram/Paper46236.html. Accessed July 6, 2015. 61. Marr KA, Boeckh M, Carter RA, et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004;39:797-802. 62. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-15. 63. Kontoyiannis DP, Lionakis MS, Lewis RE, et al. Zygomycosis in a

tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis 2005;191:1350-60. 64. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis 2008;47:503-9. 65. Marty FM, Perfect JR, Cornely OA, et al. An Open-label Phase 3 Study of Isavuconazole (VITAL): Focus on Mucormycosis. Available at idsa.confex.com/idsa/2014/webprogram/Paper45645. html. Accessed July 6, 2015. 66. Reed C, Bryant R, Ibrahim AS, et al. Combination polyenecaspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis 2008;47:364-71. 67. Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis 2008;46:1801-12. 68. Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005;41:1217-23. 69. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-25. 70. Vinh DC, Masannat F, Dzioba RB, et al. Refractory disseminated coccidioidomycosis and mycobacteriosis in interferon-γ receptor 1 deficiency. Clin Infect Dis 2009;49:e62-5. 71. Serefhanoglu K, Timurkaynak F, Can F, et al. Risk factors for candidemia with non-albicans Candida spp. in intensive care unit patients with end-stage renal disease on chronic hemodialysis. J Formos Med Assoc 2012;111:325-32. 72. Montagna MT, Caggiano G, Lovero G, et al. Epidemiology of

invasive fungal infections in the intensive care unit: results of a multicenter Italian survey (AURORA Project). Infection 2013;41:645-53. 73. Wisplinghoff H, Ebbers J, Geurtz L, et al. Nosocomial bloodstream infections due to Candida spp. in the USA: species distribution, clinical features and antifungal susceptibilities. Int J Antimicrob Agents 2014;43:78-81. 74. Gardner AH, Prodhan P, Stovall SH, et al. Fungal infections and antifungal prophylaxis in pediatric cardiac extracorporeal life support. J Thorac Cardiovasc Surg 2012;143:689-95. 75. Timsit JF, Azoulay E, Cornet M, et al. EMPIRICUS micafungin versus placebo during nosocomial sepsis in Candida multicolonized ICU patients with multiple organ failures: study protocol for a randomized controlled trial. Trials 2013;14:399-408. 76. Prattes J, Hoenigl M, Rabensteiner J, et al. Serum 1,3-betadglucan for antifungal treatment stratification at the intensive care unit and the influence of surgery. Mycoses 2014;57:679-86. 77. Fontana C, Gaziano R, Favaro M, et al. (1-3)-β-D-glucan vs galactomannan antigen in diagnosing invasive fungal infections (IFIs). Open Microbiol J 2012;6:70-3. 78. Krause R, Zollner-Schwetz I, Salzer HJ, et al. Elevated levels of interleukin 17A and kynurenine in candidemic patients, compared with levels in noncandidemic patients in the intensive care unit and those in healthy controls. J Infect Dis 2015;211:445-51.

Chapter 17 Invasive Viral Infections

in the Intensive Care Unit P. Brandon Bookstaver, Pharm.D., FCCP, BCPSAQ ID, AAHIVP; and Caroline B. Derrick, Pharm.D., BCPS

LEARNING OBJECTIVES 1. Describe and familiarize the reader with viral infections that may be present in the intensive care unit (ICU). 2. Discuss typical patient presentations of these viral infections. 3. List standard diagnostic tools used to differentiate typical viral infections in ICU patients. 4. Recommend appropriate pharmacologic therapy for common viral infections in the ICU.

ABBREVIATIONS IN THIS CHAPTER CDC

Centers for Disease Control and Prevention

CMV

Cytomegalovirus

CoV

Coronavirus

CSF

Cerebrospinal fluid

EBV

Epstein-Barr virus

HAART

Highly active antiretroviral therapy

HSV

Herpes simplex virus

ICU

Intensive care unit

IRIS

Immune reconstitution inflammatory syndrome

IVIG

Intravenous immunoglobulin

MERS

Middle East respiratory syndrome

PCR

Polymerase chain reaction

RSV

Respiratory syncytial virus

SARS

Severe acute respiratory syndrome

VHF

Viral hemorrhagic fever

VZV

Varicella zoster virus

WNV

West Nile virus

INTRODUCTION Viruses play a predominant role in many infectious-related hospital admissions ranging from mild gastroenteritis to life-threatening meningoencephalitis. Intensive care unit (ICU) admissions are also commonplace both in acute viral infections (e.g., respiratory, encephalitis) and among those with chronic infections including HIV and hepatitis. The emergence of viral hemorrhagic fevers (VHFs) and vaccine-preventable diseases such as measles is becoming more prevalent in recent times, requiring new therapeutic advances and renewal of once-forgotten therapies. Many patients admitted to the ICU with viral infections will require mechanical ventilation, vasopressor support, and further invasive management.1 Although viral pathogens are probably community acquired, there are several reports of hospital

acquisition of enteric pathogens such as rotavirus and norovirus, influenza, and cytomegalovirus (CMV).2,3 Many hospital-acquired infections can be limited through proper education combined with continued hand hygiene, appropriate employee vaccination, and early recognition of a potential outbreak.3-5 Although significant, morbidity and mortality vary depending on the viral pathogen and the underlying immune status of the host. The increasing burden of viral disease in hospitalized patients, especially among immunocompromised hosts, has concurrently increased the need for and value of early diagnosis.6,7 Molecular-based rapid diagnostics such as nucleic acid amplification tests, which are becoming more readily available, allow for early identification of viral pathogens.8,9 Although causality cannot always be established because of the limitations of such tests, they can help direct targeted pharmacotherapy and promote antimicrobial stewardship in combination with additional laboratory assessment and clinical correlation. Pharmacologic therapy includes not only direct antiviral therapy, but also supportive care measures including hemodynamic management, corticosteroids, and management of common sequelae such as seizures, acute kidney injury, and post-viral bacterial infections. Despite their effectiveness, many antivirals are associated with significant adverse drug events and require careful monitoring. Continuing of home medications for chronic viral infections, specifically HIV, is essential to avoid the development of resistance and an iatrogenic nonadherence.10 In addition, challenges in drug administration and dosing are created with ICU patients, with frequent interruptions in oral access, intravenous compatibility issues, dynamic renal function, and altered pharmacokinetics.10 This chapter discusses the clinical presentation, diagnoses, and management of both the common and emerging viral infections seen in the ICU.

HUMAN HERPES VIRUS The Herpesviridae is a family of double-stranded DNA viruses with eight distinct varieties identified as human pathogens. Exposure to

these endemic viruses is common, and transmission is often through sexual contact such as with herpes simplex virus (HSV) or casual contact with Epstein-Barr virus (EBV).11 Although infections in immunocompetent hosts are common, underlying immunocompromise from malignancy, solid-organ or blood and marrow transplantation, or HIV places patients at a heightened risk of invasive herpes infections.12 In addition to HSV-1 and HSV-2 infections, other important invasive human herpes viruses in hospitalized patients include CMV and varicella zoster virus (VZV).

Herpes Simplex Virus Types 1 and 2 Herpes simplex virus exposure in the general population occurs commonly at an early age with an 80%–90% seropositivity rate.13 Herpes simplex virus type 1 preferentially establishes latency in the trigeminal ganglion near the ear, typically causing oral lesions, whereas HSV-2 primarily establishes latency in the sacral ganglion at the base of the spine, leading to genital infections. Transmission is through direct contact, by the oral or genital route.14 Although many infections secondary to HSV are often superficial, HSV is responsible for invasive diseases including meningoencephalitis and, less commonly, pneumonia. Herpes simplex virus is the most prevalent pathogen in encephalitis, identified in 40%–50% of encephalitis cases with a known cause and in about 20% overall.1,15,16 Table 17.1 provides an overview of viral causes of encephalitis. Although HSV-2 may cause aseptic meningitis, HSV-1 is the predominant type in encephalitis cases. The incidence does not appear to change significantly on the basis of age or sex.1,13

Table 17.1 Viral Etiologies of Encephalitis with Diagnostic Testinga Viral Pathogen

Proportion of Total Cases

Diagnostic Endocrine and

Metabolic Disorders Testing Method Herpes simplex virus (HSV-1)

11%–22%

PCR (CSF)

Varicella zoster virus (VZV)

4%–14%

PCR (CSF)

Enterovirus

1%–4%

PCR (CSF)

Arboviruses

Varies by location and season

PCR (CSF)

(Japanese encephalitis virus; West Nile virus [WNV]; tickborne encephalitis virus [TBEV]; Murray Valley encephalitis virus; St. Louis encephalitis virus; La Crosse encephalitis virus [LCEV]) Other herpes viruses

North America: WNV and LCEV Europe: TBEV, WNV

Rare, except in immunocompromised hosts

PCR (CSF)

Serology

(EBV, HHV-6, CMV) JC virus (PML)

Serology (blood and CSF)

Only in immunocompromised

PCR (CSF)

Serology Respiratory viruses

Rare, except during outbreaks

PCR (respiratory samples, CSF)

Rare

PCR saliva, CSF; serology

(influenza, adenovirus) Rabies

Brain biopsy Mumps, measles

Rare

Serology

(blood)

aUnknown

cause in 37%–70% of cases.

CMV = cytomegalovirus; EBV = Epstein-Barr virus; HHV = human herpes virus; PML = progressive multifocal leukoencephalopathy.

Universally, patients with viral encephalitis present with altered mental status, although coma is less common, occuring in about 25% of patients with HSV. For coma to occur, there must be significant cerebral edema raising intracranial pressure or disruption of the ascending reticular activating system (RAS), a neuronal network responsible for wakefulness.17 Disruption of the RAS is especially common with the temporal lobe involvement seen with HSV encephalitis. Fever occurs in more than 75% of patients. Overt seizures have been reported in up to 65% of patients; however, encephalitis in general is among the most common cause of nonconvulsive status epilepticus, which can only be reliably diagnosed with electroencephalogram (EEG). Seizures are an independent predictor of worse outcomes, and chronic epilepsy is common after treatment.18,19 Diagnosis is achieved through radiology, cerebrospinal fluid (CSF) examination after lumbar puncture, and CSF polymerase chain reaction (PCR) for HSV. Magnetic resonance imaging (MRI) is abnormal in 90% of cases, whereas computed tomography (CT) scans are abnormal more than 50% of the time. On CSF examination, patients typically have a predominance (80%) of lymphocytes with elevated protein. The presence of red blood cells or xanthochromia may be caused by hemorrhagic inflammation secondary to HSV. Serologic testing is unhelpful, and the test of choice is PCR on the CSF. The sensitivity, which is about 100%, may decrease slightly over time if obtaining CSF is delayed for several days. Viral culture has a low sensitivity and is not commonly performed in standard laboratories.20,21 According to several randomized controlled trials (RCTs), antiviral therapy with intravenous acyclovir should be initiated empirically if HSV is in the diagnostic differential (Table 17.2).22,23 Acyclovir is activated

by the viral enzyme thymidine kinase, present in essentially all strains of HSV. Therapy delays beyond 2 days have been associated with poorer outcomes, and initiation within the first 48 hours of suspicion has resulted in reduced mortality rates below 10%.24 Acyclovir is typically dosed on ideal body weight, although this recommendation is based on very limited data.25 Associated toxicities commonly include nephrotoxicity and, less commonly, headache, gastrointestinal (GI) effects, altered mental status, and bone marrow suppression. The mechanism of nephrotoxicity is thought to be obstructive secondary to the crystallization of acyclovir in the renal tubules exceeding maximium solubility. Intravenous hydration is an important mechanism of prevention and should be initiated in critically ill patients. Rapid administration may also contribute to the development of acute kidney injury.10 Therapy duration is typically 14–21 days, despite the original RCTs targeting 10 days of therapy,24 because of the long-term neuropyschological effects commonly seen among survivors. A recent trial of extended 3-month therapy with oral valacyclovir showed no improved outcomes compared with placebo; however, the rate of neuropyschological decline in this population was less than 15%, lower than in previous reports.26 Oral valacyclovir, a prodrug of acyclovir, has excellent bioavailability and, at doses of 1,000 mg every 8 hours, has shown sustained CSF concentrations above target during a 20-day treatment period.27,28 Although treatment data are limited, this may be a potential option when intravenous access or intravenous acyclovir is unavailable. Rarely, HSV has tolerance or resistance to acyclovir, primarily because of deficiency or mutations in thymidine kinase. In these cases, alternative antiviral therapies, including foscarnet or less commonly cidofovir, should be considered. Ganciclovir, a thymidine kinase–dependent antiviral, should not be used routinely in suspected acyclovir resistance or clinical failures.11 Foscarnet and cidofovir dosing is available in Table 17.2 and discussed in more detail in the Cytomegalovirus section. Comprehensive symptomatic care is also important for these patients to prevent secondary brain injury, including management of hypotension, hypoxemia, intracranial hypertension, hyperthermia, hypo-

and hyperglycemia, anemia, and seizures.1 Adjunctive use of corticosteroids, specifically dexamethasone, was studied in a limited fashion in a single study of 45 patients with HSV encephalitis.29 Although corticosteroids were a predictor of improved outcomes in combination with acyclovir, they are not routinely recommended at this time. Management of status epilepticus in accordance with current national guidelines is initially with intravenous lorazepam and establishment of a second agent to prevent recurrence, which may include one of several intravenous options including phenytoin, fosphenytoin, valproate, levetiracetam, and lacosamide.30

Cytomegalovirus Cytomegalovirus is a large double-stranded type 5 β-herpesvirus most closely related to human herpesviruses 6 and 7.6 Viral replication takes place in human fibroblasts and can be found in an array of cell types including hematopoietic cells, epithelial cells, endothelial cells, fibroblasts, and smooth muscle cells.31 Similar to other herpesviruses, CMV remains latent in the human body after primary infection and may reactivate throughout a host’s life span, causing severe disease in immunocompromised individuals. Asymptomatic viral shedding (urine, saliva, semen, breast milk, and cervical secretions) continues after primary infection; the virus is passed from the infected host through direct contact with body fluids, including sexual contact, blood transfusions, and transplanted organs, with oral and respiratory secretions being the primary route of transmission.32,33

Table 17.2 Antiviral Properties and Dosing

AMS = altered mental status; BMS = bone marrow suppression; CrCl = creatinine clearance; HA = headache; HCV = hepatitis C virus; HPV = human papillomavirus; HSV = herpes simplex virus (types 1 and 2); IBW = ideal body weight; IM = intramuscular; IV = intravenous; IVIG = intravenous immunoglobulin; PO = by mouth; RSV = respiratory syncytial virus; VZV = varicella zoster virus.

Cytomegalovirus causes complications in the fetus, neonate, and immunocompromised host but rarely in the healthy adult.34,35 The Centers for Disease Control and Prevention (CDC) reports that 50%– 80% of all adults within the United States are infected with CMV by age 40.33 About 1% of infants are congenitally infected in the United States.33 Cannon and colleagues found a higher seroprevalence of 45%–100% among women of reproductive ability. Seronegativity within this population places patients at risk of primary infection while pregnant. Variation exists in seropositive percentages across the United States.34 In the immunocompetent host, children and adults may be asymptomatic. However, CMV often presents similar to a mononucleosis-like syndrome, comparable with that caused by EBV.12 Cytomegalovirus causes host-dependent diseases, resulting in immunocompromised hosts developing invasive disease.6 Specifically in the immunocompromised host, CMV often presents with end-organ damage (e.g., colitis, esophagitis, and neurologic diseases). Solidorgan transplant recipients may have CMV-associated leukopenia, and bone marrow recipients often present with interstitial pneumonitis or pneumonia. In severely immunocompromised patients with AIDS, disease manifestations include gastroenteritis and chorioretinitis leading to potential blindness.12 Cytomegalovirus retinitis is the most common HIV-associated CMV infection and usually presents at CD4 counts below 100 cells/mm3. Acute flares may be associated with initiating

highly active antiretroviral therapy (HAART) against HIV correlating with an immune reconstitution syndrome. Cytomegalovirus viremia is detected primarily by PCR, although antigen assays and culture are also available. End-organ disease should not be diagnosed by CMV antigen because of the potential for false-negative tests.7 Antibody presence in breast milk does not confer protective immunity but may defend against serious disease in the newborn. Antibody titers during acute and chronic illness are usually performed with enzyme immunoassays and indirect and anticomplement immunofluorescence assays. The CMV-immunoglobulin (Ig)M test is highly sensitive but is restricted because of the crossreaction of acute EBV and the presence of rheumatoid factors.9 A 4fold increase in serologies is used to assist in diagnosing infection; however, false positives may occur, and serology testing should not be used alone. Cytomegalovirus may be detected in a blood, urine, throat, and lung culture (from bronchoalveolar lavage or washing) as well as in a lung biopsy. The tissue culture method (shell vial assay) involves centrifugation and an immunocytochemical detection, which uses monoclonal antibodies directed at early CMV antigen.36 In the solid-organ transplant recipient, CMV is one of the most important pathogens causing significant morbidity and mortality posttransplantation. More than 50% of solid-organ transplant recipients show evidence of CMV infection. The serostatus of the recipient and donor determines the response after transplantation. The patient with the strongest risk of infection and invasive disease is a serologically negative recipient receiving an organ from a serologically positive donor. However, CMV infection in hematopoietic stem cell transplant recipients is primarily through reactivation of a latent virus of a seropositive recipient.12,35 Infection can occur if the recipient or donor is serologically positive; however, the disease severity is lessened. The T cell–mediated immune response primarily controls CMV replication, placing immunodeficient hosts at higher infection rates. Cytomegalovirus pneumonitis is rare together with pneumonia, but it represents the most troublesome infection in this patient population, which presents with fever, cough, and infiltrates on chest radiography.

Clinicians prefer to see diagnostic “owl’s-eye” inclusion bodies on lung biopsy for confirmation.7,35 The widespread use of HAART in the United States against HIV has led to a decreased prevalence of CMV retinitis within this population. Retinitis is still the most common CMV-associated end-organ disease and often presents unilaterally. Bilateral progression occurs without appropriate therapy or recovery of the immune system.7 Cytomegalovirus retinitis affects populations discordantly; men who have sex with men have a higher rate of latent infection, with estimates as high as above 90%.37 Therapy for CMV-associated infections should be individualized.38 Location and severity of infection should be considered before initiating therapy. Primary treatment with ganciclovir (or valganciclovir) is indicated in patients with confirmed, invasive disease. Foscarnet and cidofovir are alternative therapeutic regimens. Patients with HIV infection remain on secondary prophylaxis until CD4 counts recover to greater than 100 cells/mm3 for 3–6 months.7,38 Patients receiving solidorgan or bone marrow transplants usually receive prophylaxis for about 3 months. Ganciclovir requires triphosphorylation to a substrate that competitively inhibits viral DNA synthesis by inhibiting the binding of deoxyguanosine triphosphate to DNA polymerase. The first phosphorylation is known as the rate-limiting step and is induced by enzymes produced by CMV. This unique mechanism renders acyclovir inactive against CMV. The oral prodrug of ganciclovir, valganciclovir, is commonly used in CMV infections. Valganciclovir is rapidly converted to ganciclovir and has about 60% bioavailability. Both agents are renally dose adjusted and require close monitoring.7,39,40 The predominant adverse effects are moderate to severe neutropenia followed by thrombocytopenia and central nervous system (CNS) events such as confusion and dizziness. Fever and GI adverse events are also documented. Valganciclovir adverse drug events include hypertension, headache, insomnia, and tremor, which are more associated with the use of valganciclovir than with ganciclovir. Cerebrospinal fluid concentrations of ganciclovir are about 50% of serum concentrations.

This agent should be continued and monitored closely as maintenance therapy after induction is complete, given the high relapse rates if prematurely discontinued. Ganciclovir may also be administered intraocularly every 5–8 months for CMV retinitis.7,39,40 Foscarnet is a pyrophosphate analog that acts as a non-competitive inhibitor of many viral RNA and DNA polymerases as well as HIV reverse transcriptase. Foscarnet is a highly toxic agent causing considerable nephrotoxicity and electrolyte disturbances (hypomagnesemia, hypokalemia, hypocalcemia). Aggressive hydration is used to decrease renal toxicity, and appropriate dose adjustments must be made in patients with preexisting renal dysfunction. An infusion pump, at a rate not to exceed 1 mg/kg/minute, is necessary for administration. Other documented adverse events are genital ulcers, dysuria, nausea, and paresthesia. This agent does not require phosphorylation to be active; therefore, it can be used to treat ganciclovir-resistant isolates.7,41 Cidofovir acts through inhibition of viral DNA synthesis by incorporating cidofovir into replicating viral DNA. Infusion must take place over 1 hour with 1 L of 0.9% normal saline administered intravenously before cidofovir infusion. A second liter may be administered over 1–3 hours immediately after infusion, if tolerated. Serum creatinine (SCr) must be monitored for dose adjustments, and contraindications to cidofovir include SCr values greater than 1.5 mg/dL, creatinine clearance greater than 55 mL/minute/1.73 m2, history of clinically severe hypersensitivity to probenecid or other sulfacontaining medications, and use of nephrotoxic agents within 7 days. Although renal toxicity is the primary adverse effect of cidofovir administration, GI, hematologic (black box warning for neutropenia), and CNS effects have been reported.42,43

Varicella Zoster Virus Varicella zoster virus is a human neurotropic DNA virus. Primary varicella infection or chickenpox was once commonplace in children in the United States until the vaccine was licensed in 1995. The causative

agent, VZV, remains latent in the cranial nerve, dorsal root, and autonomic ganglia along the entire neuroaxis. More than 90% of adults are latently infected with VZV.44 With the decline in VZV cell-mediated immunity, reactivation occurs in older adults, especially those older than 85 years, and in those with severe immunocompromise, including organ transplantation, malignancy, and HIV.1,44 Reactivation may occur at any point during the immunocompromised state, although it has been the presenting condition before an HIV diagnosis. On reactivation, herpes zoster presents classically as a vesicular rash after dermatomes with sharp, radiating pain exacerbated by touch. Varicella zoster virus is also the most common cause of viral encephalitis in immunocompromised hosts. Other systemic manifestations include cerebellitis, meningoencephalitis, myelopathy, and ocular disease. Ocular involvement usually manifests as acute retinal necrosis or progressive outer retinal necrosis, of which VZV is the most common cause. This typically occurs in patients with HIV and a CD4 count less than 10 cells/mm3. Varicella zoster virus infection in the cerebral arteries often leads to ischemic or hemorrhagic stroke.45-47 Postherpetic neuralgia is also extremely common. Vasculopathy is a common theme in patients with systemic varicella CNS disease, and some investigators have argued that most VZV CNS infections represent vasculopathy as opposed to encephalitis. Patients may have both small and large vessel involvement. Although most patients will develop CNS involvement after zoster, up to 33% of patients will develop encephalitis in the absence of rash.45,46,48 In addition, MRI scans are abnormal in most cases; however, some changes on CT and MRI can be seen in patients with rash in the absence of neurological changes. Patients who present with transient ischemic attack or ischemic stroke, chronic headaches, or severe altered mental status with a history of zoster should be evaluated for VZV CNS disease. In addition, those with severe immunocompromise with or without preceding zoster should be evaluated for VZV disease when other common causes of altered mental status have been ruled out. Compared with HSV encephalitis, however, milder CNS-specific symptoms and fever should be expected.1,44

Together with imaging findings, patients with confirmed disease will have a CSF pleocytosis in approximately 66% of cases. Angiography has revealed abnormal findings in 70% of patients. With a high specificity, VZV PCR on CSF may be the initial diagnostic test, but with a low sensitivity, a negative PCR can be seen in up to 70% of patients.1,44 Anti-VZV IgG in the CSF is present in more than 90% of patients with active CNS infection and should be considered the optimal diagnostic test. Patients in the ICU are less likely to have VZV optic disease because of the protracted disease course; however, it may occur concomitantly with CNS disease.48 Recommended management of invasive VZV disease is intravenous acyclovir 10–15 mg/kg every 8 hours.1,24,49 Compared with HSV, higher doses of acyclovir may be required because targeted concentrations against VZV are relatively higher in some strains. Controlled trials supporting this recommendation are limited; however, reduction in disease severity and recovery time has been shown. Therapy should not be delayed because of lack of confirmed diagnostics from CSF if suspicion of VZV is high. Many patients will have concomitant immunocom-promising states (e.g., malignancy and HIV) that require management of these conditions. Toxicities associated with acyclovir, which are often dose-dependent, remain significant and may be exacerbated in immunocompromised patients with underlying renal dysfunction. Therapy duration should be 14 days; however, 21 days should be strongly considered in patients with underlying immunocompromise.1,24,48 Use of oral agents such as valacyclovir has not been studied and cannot be recommended at this time. Because of the accompanying vasculitis, adjunct corticosteroids are recommended by many experts. A prednisone equivalent dose of 1 mg/kg/day should be considered. Limited use in varicella pneumonia has had some beneficial effects.2 No definite duration for prednisone has been established, although some have recommended 3–5 days of therapy.1,50,51 Shortcourse therapy may still be associated with significant adverse drug events and should be evaluated and managed as required. In patients with VZV optic disease—specifically, progressive outer retinal necrosis —acyclovir monotherapy has produced suboptimal results. Ganciclovir

or foscarnet, or in combination, should be considered first-line therapy. Dosage is consistent with that of other invasive viral diseases (Table 17.2). Because of the immunocompromised state of many of these patients, specialist management, including infectious diseases consultation, is recommended. Although many patients recover from the VZV infection itself, full recovery is highly dependent on disease manifestations (e.g., stroke) and the patient’s immune status.44

Epstein-Barr Virus Epstein-Barr virus is commonly known as the causative pathogen of infectious mononucleosis. Although it can rarely be responsible for other invasive viral syndromes in immuncompetent hosts, including encephalitis, most patients at risk of EBV disease are severely immuno-compromised. Epstein-Barr virus is primarily transmitted through saliva.52 In immunocompetent hosts, EBV preferentially infects circulating B lymphocytes and the epithelium in the oropharynx and of the cervix. These infected B lymphocytes lead to infiltration of other organs. The lymphocytosis seen with EBV infection is primarily that of T lymphocytes, indicative of the extreme immune response mounted against infected B cells.52,53 In immunocompromised hosts, especially those with HIV/AIDS and those after solid-organ or blood and marrow stem cell transplantation, EBV is responsible for many infections including hairy leukoplakia (HLP), lymphoproliferative syndromes, and several associated malignancies. In HLP, EBV replicates at high numbers in associated lesions; however, EBV remains in a latent state in other associated syndromes and malignancies.53 Treatment of these patients is targeted at restoring T-cell (and Bcell) immune function and supportive care. Antiviral therapy, including acyclovir, has activity in vitro; however, clinical trials have failed to show morbidity or mortality benefit.54,55 This may be because of a lack of phosphorylation, and thus activation, of the antivirals by viral enzymes. In addition, failure to concentrate in circulating infected B lymphocytes and inability to target the virus in the latent state may be contributing factors. Corticosteroids are used in the acute phase of these infections

by some experts, although clinical data to support outcomes are lacking.1,55

HUMAN IMMUNODEFICIENCY VIRUS Establishment of HIV infection depletes the T lymphocytes and therefore promotes an immunosuppressive state. About 3–6 weeks after an initial HIV infection, more than half of infected individuals experience an acute HIV infection syndrome.56 The term acute refers to the time during which the virus is detectable within the blood and serum but antibodies have not yet formed.57 Symptoms vary in severity but resemble an acute infectious mononucleosis. The decrease in CD4 T lymphocytes and the perpetual increase in viral load lead to the acute HIV response. After this response, described in further detail in the following text, an immune response will mount from the host in an attempt to fight the infection. The immunity formed from the host does not completely hinder viral replication, and the decrease in viremia does not persist.58,59 Immunity is decreased by the infected CD4 T lymphocytes, and opportunistic infections are most common at CD4 Tcell counts less than 200/mm3. To prevent this progressive decrease in immune function, the mainstay of treatment is initiating antiretroviral therapy.60 During initial HIV infection, patients often present with fever, pharyngitis, lymphadenopathy, headache, muscle pain, fatigue, weight loss, and GI symptoms (nausea, vomiting, and diarrhea). Patients may also have a maculopapular rash on the trunk and extremities and/or genital ulcers. Presentation with sexually transmitted infections (HSV, gonorrhea, syphilis, hepatitis viruses) is common, and coinfection rates are high. This nonspecific syndrome leads to a diagnostic challenge for clinicians. Antibody formation is undetectable on initial infection and may not be present during the acute infectious stage. Acute HIV is therefore often undiagnosed, leading to negative patient outcomes and necessitating high clinical suspicion.58,59 On entry into the health care system, it is recommended that all patients be tested for HIV with an opt-out setting. Initial HIV infection

presents with a high viral load, and patients may not know they are infected. Rosenberg and colleagues found that early treatment with antiretrovirals increased HIV-1–specific CD4 and CD8 T-cell responses, boosting host immunity.60 Initiating HAART may precipitate an immune reconstitution inflammatory syndrome (IRIS), often called immune reconstitution disease if not stemming from an autoimmune process.56 Variations in epidemiologic statistics exist, but early retrospective data showed that about 30% of patients who are at risk of IRIS develop the clinical syndrome. More recent data support a lower incidence overall, about 15%, with higher percentages of almost 38% for patients with CMV retinitis specifically.61 Opportunistic infections that have not been treated may reactivate, causing an exacerbation of clinical symptoms. Cytomegalovirus retinitis, tuberculosis, Mycobacterium avium complex, Pneumocystis jiroveci pneumonia, cryptococcosis, progressive multifocal leukoencephalopathy, and herpes zoster infection represent most of the causative opportunistic infections outlined by Walker and colleagues detailing HIV-associated IRIS specifically. Previously undiagnosed infection is termed unmasking, and exacerbation or recurrence of symptoms is termed paradoxical worsening.62 Risk factors for IRIS consist of a lower CD4 count (less than 100 cells/mm3), high viral load, and suboptimal treatment of opportunistic infections before initiating HAART.63 Immune reconstitution, which may occur days to months after HAART, is accompanied by an increase in CD4 cells. The pathophysiology of the response is not clearly defined and cannot completely be explained by this increase. Cytokines as well as innate and adaptive immune responses, together with the host immune functional capacity, have been proposed as important factors. Patients may have symptoms of inflammation—specifically, fever, malaise, and lymphadenitis. If an opportunistic infection was not previously treated, the symptoms specific to this infection may present.64 Shel-bourne et al. performed a retrospective chart review of patients with HIV infection with Mycobacterium tuberculosis, M. avium complex, or Cryptococcus neoformans and evaluated risk factors for IRIS.65 When the opportunistic infection was diagnosed, affected

patients were more likely to have started HAART close to diagnosis, to have been antiretroviral naive, and to have had a more rapid initial fall in HIV-1 RNA levels in response to HAART. Cytomegalovirus retinitis– associated IRIS has sight-threatening implications; therefore, patients with HIV infection having a history of CMV retinitis should have a dilated ophthalmologic examination every 3 months for the first year after initiation of ARV therapy or if visual acuity changes or floaters develop. Wiselz and colleagues detail three case reports of acute respiratory failure after introducing HAART to patients with severe P. jiroveci pneumonia. In the ICU, this clinical picture may present as a therapeutic challenge. Reintroducing steroids or suspending HAART was necessary for these patients to recover.65 In all cases, appropriate diagnostics must be performed to identify whether an opportunistic infection has activated. If identified, the opportunistic infection must be treated appropriately. Overall, symptomatic treatment is the mainstay of therapy. If the IRIS is severe, steroids may be administered for 1–2 weeks and tapered to discontinuation. Doses have not been standardized; however, some experts recommend 1–2 mg/kg of prednisone daily. For mild IRIS, nonsteroidal anti-inflammatory agents can be used for fever and inflammation; if pulmonary inflammation presents, inhaled steroids are therapeutic options. In general, a delay in, or holding of, antiretroviral therapy is not currently recommended because of the life-saving nature of the therapy.66 However, if life-threatening symptoms occur or if permanent sequelae may result, HAART should be deferred. Dheda and colleagues evaluated patients coinfected with tuberculosis and HIV and concluded that initiating HAART reduced immediate and long-term risk of death and AIDS-defining illnesses.67 In addition, patients with a CD4+ cell count less than 100 cells/mm3 are at higher risk of death or new AIDS-defining illnesses during the early phase of tuberculosis treatment and more prone to immune reconstitution. Treating opportunistic infections before HAART will assist in preventing IRIS and decreasing bacterial burden.7,30,67 Patients with long-standing HIV infection are often admitted to the ICU for noninfectious causes.45 It is imperative to consider reinitiating

antiretroviral therapy as soon as clinically feasible. Failure to reinitiate antiretroviral therapy may lead to an iatrogenic nonadherence. Antiretroviral errors are very common in the hospitalized setting and may occur in up to 70% of inpatients.68 In the ICU specifically, high rates of acute kidney injury and use of acid-suppressing agents may lead to dosing errors and drug-drug interactions, respectively. In addition, knowledge of crushable administration is important in the ICU, and maintaining available formulations of solutions and suspensions will help ensure the continuity of antiretroviral therapy.69

RESPIRATORY VIRUSES Viral infections may play a prominent role in respiratory disease in the ICU, both community acquired and less commonly through nosocomial acquisition.2,70 Community-acquired viruses such as influenza, specifically H1N1, have resulted in significant acute respiratory diseases prompting ICU admission (Table 17.3).7 This is more likely to occur in the older adult or immunocompromised population and is often associated with community outbreaks. Reactivation of endogenous viruses including HSV and CMV can also occur in immunocompromised patients. Histologic assessment and open lung biopsy of previously healthy intubated patients with suspected ventilatorassociated pneumonia have revealed that almost 30% had findings compatible with CMV lung disease, whereas only 3% had HSV.71 Patients with documented CMV infections have had increased duration of mechanical ventiliation and longer ICU and overall hospital length of stay; these infections were inconsistently associated with increased mortality.71,72 In addition, these patients had higher rates of bacterial and fungal superinfections, which may also be reflected in the immunocompromised state of most of these patients. Herpes simplex virus appears less likely to be associated with a true pneumonia or bronchopneumonitis, as opposed to a tracheobronchitis.2,73 Patients with HSV often have outcomes similar to those with nonviral infections. If active CMV infection is suspected, management with ganciclovir is appropriate; however, consultation with infectious diseases specialists

is recommended.74 Preemptive or prophylactic management of viral infections in acute respiratory distress syndrome is limited to a single prospective study of intravenous acyclovir showing no clinical benefit in ventilated patients. Despite the unknown contribution of CMV and HSV as viral pathogens in respiratory disease in the ICU, these patients are susceptible to nosocomial outbreaks of viruses including influenza.75 Both patients and health care workers may serve as potential vectors. Procalcitonin has been investigated specifically in patients with concurrent influenza to determine the presence or absence of bacterial infection. The available data suggest that in patients with concurrent respiratory viral disease, procalcitonin is helpful to determine the need for antibiotics; however, it should not be used as a stand-alone test.76,77 The availability of rapid diagnostics outside conventional antigen testing with influenza and respiratory synctial virus (RSV) using nucleic acid amplification tests and PCR technologies is becoming more prevalent.9 Commerically available multiplex testing allows for simultaneous investigation of not only several viruses but also atypical bacteria. Use of multiplex PCR for viral pathogens specifically offers several potential advantages in the ICU population: optimizing treatment with both antibacterials and antivirals, limiting the overuse of antibiotics and the subsequent development of resistance, reducing the need for superfluous diagnostic testing, and allowing for proper isolation. Installing multiplex PCR has shown a reduction in the use of antibiotics, primarily in a hematology-oncology population.9,32,49 Data for use in a medical or surgical ICU are limited to date; however, this is a quickly evolving area of study and development. Several other viral pathogens including RSV, adenovirus, parainfluenza, metapneumovirus, and rhinovirus have been implicated in causing primarily respiratory disease. Although most of these pathogens are typically associated with self-limiting infections, serious, life-threatening disease is not uncommon, especially in children younger 1 year and older adults, often with accompanying immunocompromise. Management of these viruses is primarily symptomatic care, and identification by PCR, including commercially available multiplex PCR, is increasingly common for high-volume institutions. The clinical relevance of identifying these

pathogens in the presence of respiratory disease remains debatable, although a growing body of evidence supports their causality of lower respiratory tract infections in immunocompromised adults. Viruses, including virulent strains of coronavirus (CoV) and enterovirus, although naturally common, have been associated with severe outbreaks globally and in the United States, respectively.

Influenza Influenza types A and B are known to cause serious infection in humans and are typically associated with seasonal outbreaks, typically peaking in the winter months. Unlike influenza B, influenza A can be further subtyped by the surface proteins hemagglutinin and neuraminadase. There are 18 different hemagglutinin (H1–H18) and 11 different neuraminidase (N1–N11) subtypes.78 Viruses are named in accordance with the internationally accepted World Health Organization (WHO) nomenclature originally published in 1980.79 Each year, 5%–20% of the U.S. population will be infected with influenza, resulting in more than 200,000 hospitalizations.78 Most of these hospitalizations do not result in critical illness except in patients of extreme age or with immunocompromise. However, since 2009, with the emergence of the endemic H1N1 (an influenza type A) strain, young and middle-aged adults have more commonly been admitted to the ICU with severe acute respiratory distress syndrome.80 This may be because of the relatively lower immunization rate in this population (less than 50% nationally) and the prior immunity acquired in older patients from exposure to antigenic similar strains.54,80 This 2009 strain has now replaced the previously circulating H1N1 virus in humans. The annual deaths associated with influenza range from 3,000 to up to 35,000 annually, and most recently, most are associated with the H1N1 strain.78 Patients with obesity (body mass index greater than 30 kg/m2) and pregnant women are among the higher-risk populations for critical illness with influenza infection. Proinflammatory cytokines occur at a high rate in the lungs of influenza-positive patients and are responsible for much of the significant morbidity associated with the disease.7,81

Table 17.3 Causes of Viral Respiratory Disease in the Intensive Care Unit Virus Community

Endogenous HSV, CMV

Nosocomial HSV, CMV

Exogenous Influenza, parainfluenza, adenovirus, rhinovirus, CoV, metapneumovirus, enterovirus Mimivirus, CMV (transfusion), influenza (H1N1), CoV

CoV = coronavirus.

Rapid diagnosis is important because many patients will deteriorate 4–5 days after onset of illness, which is associated with typical flu-like symptoms including fever, fatigue, cough, rhinorhea, and myalgias.8 Although the historic gold standard for influenza diagnosis is viral cell culture, delays in diagnosis and required laboratory resources make this impractical for routine patient diagnosis, especially during influenza season.82 The use of rapid diagnostics, specifically molecular-based PCR testing, is recommended for hospitalized patients. Reversetranscriptase PCR testing is available in both single and multiplex design. Table 17.4 lists commonly available testing methods. The sensitivity of rapid diagnostic tests is typically 50%–70% but ranges from 10% to 80%, depending on the viral replication and specimen collection, storage, and transport.82,83 Testing within 3–4 days of onset of influenza infection is more likely to yield positive test results. Specificity is quite high (more than 95%), and false positives are unlikely.83,84 A false positive may be achieved if a patient has received the live attenuated virus vaccine within 7 days and an upper respiratory tract sample is used. In addition, if a patient tests positive to both influenza A and influenza B, the unlikely result of having both viruses simultaneously should prompt additional testing at a reference laboratory. False negatives are more common during peak season, and of importance, a negative test should not preclude targeted antiviral

therapy during peak season and in the setting of high pretest probability. In an outbreak, testing several patients will significantly increase the sensitivity.83 On deterioration, patients will develop hypoxemia, shock, and multiorgan dysfunction. Careful monitoring of hemodynamics is required for prompt and timely intubation. Patients may also present with concomitant bacterial pneumonia, especially Staphylococcus aureus, including methicillin-resistant S. aureus, Streptococcus pneumoniae, or Streptococcus pyogenes.85 The acute respiratory distress syndrome associated with influenza requires low-tidal volume lung-protective ventilation and an open-lung approach with increased positive endexpiratory pressure. Appropriate fluid management is also essential to recovery. Many patients may not respond to conventional management and may require advanced care to include extracorporeal membrane oxygenation, neuromuscular blockade, nitric oxide, and lung recruitment maneuvers.7 Outcomes with these interventions are inconsistent and should be considered on a patient-specific basis.

Table 17.4 Commonly Available Influenza Diagnostic Testing Methods83

ET = endotracheal; NP = nasopharyngeal.

Adapted from: Centers for Disease Control and Prevention (CDC). Guidance for Clinicians on the Use of Rapid Influenza Diagnostic Tests. Available at www.cdc.gov/flu​ /professionals/diagnosis​/clinician_gu​idance_ridt.htm. Accessed October 9, 2015.

Antiviral therapy is recommended for all hospitalized patients with influenza.78 Neuramindase inhibitors, including oseltamivir, zanamavir, and most recently peramivir, are recommended for both influenza A and influenza B.78,86,87 Oral oseltamivir is recommended by the CDC as first-line therapy for hospitalized, critically ill patients. Zanamavir is available as inhaled version and may be difficult to administer in critically ill patients, especially if intubated. Zanamavir is also contraindicated in patients with underlying respiratory disease such as asthma or chronic obstructive pulmonary disease.86,88 Intravenous zanamavir is currently under investigation and available on limited access.78 Oseltamivir is orally adminstered as a prodrug that is rapidly converted to the active form. Oral bioavailability is high and reaches peak concentrations within 1 hour of administration. Standard dosing (75 mg twice daily) for a minimum of 5 days is recommended (Table 17.2), although longer durations should be considered in critically ill patients, depending on clinical response.78,86,88 Higher doses of 150 mg twice daily have also been suggested in critically ill patients, although limited data suggest that serum concentrations are adequate with conventional dosing.89 Limited pharmacokinetic studies in morbid obesity and pregnancy also suggest that standard doses provide adequate concentrations, despite some clinician practices to increase the dosing to 150 mg.90 In critically ill patients, oseltamivir administered by oro- or nasogastric tube was well absorbed, including in those on continuous renal replacement therapy and extracorporeal membrane oxygenation.90-92 If absorption is questioned or oral access is not established, intravenous peramivir is recommended.78,87 Although intravenous peramivir compared with standard of care had no clinical benefit in hospitalized patients during clinical trials, it was well tolerated.87 Treatment should be 600 mg daily for at least 5 days.78 A small subset of patients with influenza A may have resistance to oseltamivir. Zanamavir often maintains activity against oseltamivir-

resistant strains, and its use should be strongly considered.54,88 Despite the recommendations and widespread use of the neuraminidase inhibitors for influenza, there are questions regarding their effectiveness. In a 2014 Cochrane review, data from 46 clinical trials showed a modest 14.4- to 16.8-hour reduction in time to first symptom alleviation for oseltamivir and zanamivir.93 However, complications of influenza were not carefully examined in most studies, and lack of consistent definitions did not allow for full assessment if a reduction occurred in these influenza-related complications including pneumonia. Prophylactic oseltamivir appeared to reduce symptomatic influenza but did not reduce hospitalizations.93 De-spite the relative lack of effectiveness shown and general lack of good outcomes data in hospitalized patients, our treatments are limited to aggressive antiviral therapies and supportive care. Ultimate recovery is variable and dependent on the total care of the patient beyond antiviral therapies. Prevention is likely to be the best mode of treatment for most patients. Patients with influenza are more susceptible to bacterial pathogens, as mentioned previously. Postinfluenza S. aureus, including methicillinresistant S. aureus (MRSA), pneumonia is often common.94 In patients with a recent history of influenza infection or severe viral pneumonia, MRSA pneumonia should be considered in the differential and may direct empiric therapy, even in community-acquired infections. Prevention through vaccination is primarily the responsibility of health care workers, including pharmacists. Many hospitals have introduced mandated vaccine protocols for workers with direct patient care responsibilities.95 Despite the limitations in viral coverage associated with the recent available vaccine therapy, use has been shown to reduce influenza infections and prevent health care worker-to-patient transfer and thus the potential for associated outbreaks.

Respiratory Syncytial Virus Respiratory syncytial virus is an RNA virus in the Pneumovirus genus that is responsible for more than 50,000 hospitalizations each year in children younger than 5 years.96 An additional 175,000 hospitalizations

with almost 15,000 deaths in adults older than 65 years are reported in the United States.97 Infants younger than 1 year are at highest risk. By age 3, virtually all children have been infected. Respiratory syncytial virus is a seasonal virus peaking between October and May in the United States.97 Respiratory syncytial virus may be responsible for up to 2% of nursing home deaths in older adults. The disease manifestations range from common cold symptoms to severe lower respiratory tract disease.98 The air trapping that results leads to a rapid respiratory rate, a palpable spleen and liver, and typical radiographic findings of hyperinflation and diffuse atelectasis. Bronchiolitis may lead to respiratory failure requiring mechanical ventilation. Around 1%–2% of patients will require admission to the ICU.96,98 Treatment of these patients is primarily supportive care, although many treatments have been studied. Most clinical data remain in pediatric patients.96 Bronchodilators and corticosteroids have not been shown to improve clinical outcomes and are not currently recommended. Bronchodilators may be used on a trial basis and continued if there is objective improvement.96,99,100 Ribavirin is U.S. Food and Drug Administration (FDA) approved for the management of RSV, despite large controlled studies showing a lack of benefit in clinical end points. The aerosolized form has been used anecdotally with some success and is recommended in pediatric patients with severe, clinical disease and potentially underlying immunocom-promise. Administration is continuous or intermittent for 8–24 hours daily for 3–5 days and requires a special device for aerosol delivery (Table 17.2).52 Ribavirin is also considered a hazardous agent according to the National Institute for Occupational Safety and Health. Precautions during preparation and administration are required.101 Ribavirin is category X and is contraindicated in pregnancy.28 Exposure to ribavirin has been seen by health care workers administering the drug, with minor adverse effects including headaches and nausea. Although improvements in delivery continue, pregnant health care workers should be cautioned in delivering the aerosolized drug. On rare occasions, it can worsen bronchospasms for the patient.28 Palivizumab, a humanized

monoclonal antibody derived from murine samples, and polyclonal immunoglobulins have been used in adults and children with mixed results in a treatment modality.102 Palivizumab is FDA approved for the prophylaxis of RSV in high-risk pediatric patients. The American Academy of Pediatrics updates recommendations on the basis of additional evidence.102 The most recent update in the summer of 2014 included premature infants (younger than 29 weeks) who are younger than 12 months at the start of the RSV season, especially those with congenital heart or lung disease.

Coronavirus Coronavirus infections are caused by one of six serotypes, four of which are extremely common, and most adults have been infected with one or more during their lifetime.103,104 Typically, these are responsible for mild, self-limiting upper respiratory tract diseases. Two strains in particular, SARSCoV and MERS-CoV, are responsible for global outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), respectively.94 In 2002, an outbreak of SARS, which began in China, was responsible for almost 8,100 infections and more than 750 deaths. Since 2004, however, there have been no documented cases of SARS worldwide.94,105 The SARS-CoV strain disproportionally infects adults and carries a case fatality rate of almost 10%.5 Most patients present with 5–7 days of fever, dyspnea, cough, malaise, and other generalized respiratory symptoms. About 25% will have diarrhea, and of concern, 20% will develop severe respiratory distress requiring mechanical ventilation. Transmission occurs from human-to-human contact and peaks during the second week of illness (day 10) concurrently with peaks in viral load. Management is primarily symptomatic care, although several agents have been studied in humans.5,106 Ribavirin, interferon, and lopinavir/ritonavir have all shown antiviral activity in vitro.103,107 Clinical studies, however, do not support the routine use of these agents. Corticosteroids and intravenous immunoglobulin (IVIG) also failed to

show improved outcomes.5,103 Patients who received ribavirin or corticosteroids also had higher rates of significant adverse drug events, and those who received pulse-dose methylprednisolone specifically had higher rates of 30-day mortality, which should be considered before administration.5 Proper isolation and infection control measures are essential to prevent patient-to-health care worker or patient-to-patient transmission in an institutional setting. The MERS-CoV strain was responsible for a recent outbreak, which began in 2012 in Jordan. Since then, as of June 2015, about 1,200 cases have been reported to WHO.107 Outside the Middle East, where most cases have been reported, South Korea has also had a significant outbreak of almost 200 cases. Only two cases have been reported in the United States, both from international travelers from the Middle East.108 Like with SARS-CoV, bats are thought to be the primary vector of infection.109 However, unlike with SARS-CoV, humanto-human transmission, although possible and documented, appears to be somewhat less of a concern. Adults are primarily affected (in more than 90% of cases), and the median age is around 50.94,109 Most patients with MERS-CoV infection, about 75%, have had associated comorbidities, and more than 75% of patients have required hospitalization. Respiratory failure is common, requiring mechanical ventilation. Patients often have laboratory abnormalities including leukopenia, lymphopenia, thrombocytopenia, and elevated lactate dehydrogenase. The case fatality rate appears to be 35%– 45%.94,108,109 Table 17.5 offers a detailed comparison of SARS-CoV and MERS-CoV. Early recognition and diagnosis remains difficult in patients with MERS infection. The primary method of diagnosis is MERS-CoV PCR testing and is available on respiratory, blood, and stool samples. There are reports of false negatives, especially on inadequate upper respiratory tract samples early in the disease process. Retesting of patients with high pre-test probability may be required at this time.109 Most state reference laboratories in the United States are equipped to handle specimen testing; however, contact with the CDC for suspected cases is required. Treatment of these patients is primarily symptomatic care, recognizing the aggressive and virulent

nature of this virus. Interferon, ribavirin, cyclosporine A, and mycophenolic acid have shown effects in vitro; however, none has shown positive clinical outcomes to date.106,109 Limited knowledge of the viral kinetics currently limits targeted therapies. Convalescent serum from survivors may be considered in the absence of other proven therapies.106,107

Table 17.5 Comparison of Common Characteristics Between SARS and MERS94 Characteristic First reported case Incubation period Age group affected Mortality Sex

MERS-CoV

SARS-CoV

April 2012 – Jordan

November 2002 – China

5.2 days (2–13 days)

4.6 days (2–14 days)

Adults > 90%

Adults > 90%

~35%

~10%

Male: ~65%

Male: ~43%

Fever 98%

99%–100%

Chills/rigors 87%

15%–73%

Cough 83%

62%–100%

Hemoptysis 17%

0%–1%

Myalgia 32%

45%–61%

Shortness of breath 72%

40%–42%

Chest radiograph abnormalities 100%

94%–100%

Leukopenia 14%

25%–35%

Lymphopenia 32%

68%–85%

Symptoms

Laboratory results

Thrombocytopenia 36%

40%–45%

Elevated LDH 48%

50%–71%

Elevated ALT/AST 11%–14%

20%–30%

Ventilatory support required 80%

14%–20%

LDH = lactate dehydrogenase; MERS = Middle East respiratory syndrome; SARS = systemic acute respiratory syndrome. Adapted from: Hui DS, Memish ZA, Zumla A. Severe acute respiratory syndrome vs. the Middle East respiratory syndrome. Curr Opin Pulm Med 2014;20:233-41.

Enterovirus In 2014, a nationwide outbreak of enterovirus infection occurred in the United States, infecting almost 1,200 people, primarily infants and young children.110,111 This population is primarily affected because of the lack of natural immunity acquired from exposure to related viruses. The virus strain in this particular outbreak of severe disease, enterovirus D68 (EV-D68), is only one of almost 100 identified nonpolio enteroviruses. Patients present with severe hypoxemia, wheezing, and difficulty breathing. Many of these patients have underlying asthma (75%). Very few (about 25%) patients have fever on initial presentation.110 Consideration of enterovirus diagnosis is important to prevent human-to-human transmission, which may occur through droplets. Management of underlying lung disease and acute respiratory decline is essential, which may often include corticosteroids.110,112 There is no conclusive evidence of the effectiveness of pharmacologic interventions, aside from symptomatic care of acute respiratory syndrome. The death rate appears to be about 1%. During the 2014 outbreak, about 100 patients were also given a diagnosis of an acute flaccid myelitis, first reported in Colorado.112 Although it has not been conclusively proven, evidence suggests and experts agree that this is a unique presentation of EV-D68. Many of these patients have remained symptomatic, and only a small percentage of patients have fully recovered. Therapeutic interventions including corticosteroids, IVIG,

and convalescent serum have been tried, but no evidence supports their benefit at this time.110,112

VIRAL HEMORRHAGIC FEVERS Viral hemorrhagic fevers represent a group of viruses from four distinct families: arenaviruses, filoviruses, bunyaviruses, and flaviviruses. All are RNA viruses enveloped in a lipid bilayer that require an animal or insect as the vector. Outbreaks of these infections are primarily relegated to the geographic areas where the natural hosts live.22 However, in the example of Marburg virus, the first reported cases in 1978 were in Marburg and Frankfurt, Germany, and Yugoslavia secondary to exposure to infected monkeys from the host region.113 Transmission may occur from human-to-human contact for some VHFs, including Ebola, Marburg, and Lassa. Recent outbreaks of Ebola virus disease in 2014 that affected the United States and other Western countries have increased the sensitivity and need for preparedness for VHFs.22,61 Global transportation has brought the world much closer, shrinking once-distinct geographic regions for disease. Patients often present with typical, generalized viral illness symptoms including fatigue, fever, weakness, and muscle aches. Severe disease is associated with bleeding, although this is not necessarily present in most patients, and patients often die secondary to severe hypovolemia and multiorgan failure. Treatment is primarily symptomatic care, although emerging antiviral and convalescent serum therapies are under development or have some limited experimental data. Ribavirin has been used effectively in patients with Lassa fever and hemorrhagic fever renal syndrome.114 The CDC has developed practical, institutional guidelines for managing and preventing VHFs.61 Guidelines are often updated on the emergence of new outbreaks and availability of new data. Understanding and management of these infections is limited in part because of the relative youth in discovery of many of these VHFs as well as because much of the burden of disease has been isolated to the developing world in Sub-Saharan Africa. Ebola virus disease, highlighted in detail in the following text, can serve as an

example in management and prevention for other VHFs. Ebola virus, a member of the flavivirus family, was first identified in 1976 near the Ebola River in the present-day Democratic Republic of the Congo. Although a vector has not been fully confirmed, many experts agree that the fruit bat is the most likely host. The virus affects both humans and primates. Several outbreaks have been reported historically, localized primarily to Central Africa and the eastern coastline. The most recent outbreak, which began in March 2014 in Guinea, has resulted in almost 28,000 infected individuals and more than 11,000 deaths.115 In June 2015, at least several small pockets of disease remain in Sierra Leone. The incubation period can be as short as 2 days and as long as 3 weeks; however, the average onset of symptoms is typically 8–10 days from infection.115 Trans-mission can be directly from the infected primate or the vector or between humans through contact with infected body fluids including blood, sweat, urine, and saliva. Viral RNA typically peaks 3–5 days after infection and is higher among fatal cases than among survivors. Like with many other VHFs, patients often present with generalized symptoms including fever, fatigue, malaise, generalized weakness, hiccups, and muscle aches.22,116,117 Gastrointestinal symptoms typically appear in the first 5 days and are common. Diarrhea is very severe, with volumetric losses mimicking those of severe cholera. Severe hypovolemia preempting additional sequelae (e.g., acute kidney injury) is often the primary reason for ICU admission. Despite volume losses of up to 10 L/day, patients have increased body weights of 15– 20 kg because of extreme third spacing. Electrolyte abnormalities including hyponatremia, hypokalemia, and hypocalcemia are severe and require prompt attention. In severe cases, patients have multiorgan failure and other effects including seizures and arrhythmias.22,116,118 Prompt diagnosis, followed by isolation, is the first and most important intervention to prevent further exposure and limit spread of disease. Diagnosis is based initially on appropriate travel history and corresponding symptoms. Ebola PCR testing is available but, because it is not routinely available in institutions, requires a delay for send-out testing at a reference laboratory.22,61,119 Rapid diagnostic testing is not

currently commercially available but is under investigation. To prevent transmission, a level 4 biocontainment facility setup is required. In general, the patient requires 24 hours/day, 7 days/week one-to-one or two-to-one nursing care using strict isolation and appropriate personal protection equipment (PPE).22,61 Staff must be specially trained on the donning and doffing of PPE. Laboratory specimens for testing require point-of-care testing or designated equipment in a centralized laboratory. Although medication transfer and administration are managed by the nurse, medication safety checks and balances such as bar scanning should be maintained, whenever possible. The CDC outlines the appropriate development of a biocontainment team and isolation ward.61 Treatment of these patients is primarily symptomatic care because no antiviral agents have shown effectiveness on a large scale. Some experts recommend the use of lactated Ringer solution (20 mL/kg) boluses with aggressive intravenous electrolyte replacement.22,118 Sequelae such as disseminated intravascular coagulation, hypotension, arrhythmias, and/or seizures should be managed like in other critically ill patients. Antibiotics are not indicated unless a secondary bacterial infection develops.22,118 Experimental antivirals have been used with success, and several are currently under development. Without controlled trials, little is currently known about the safety and effectiveness of these antivirals in humans. Convalescent serum from survivors has also been used with success.120 Antibodies that develop to Ebola virus disease are thought to remain for about 10 years.62 At least one reinfection case has been documented.115

ARBOVIRUSES Arboviruses represent a broad group of viruses with arthropod vectors, most commonly mosquitoes and ticks. The most common arboviruses and their characteristics are listed in Table 17.6.1,121,122 Knowledge and discovery of these viruses varies significantly because the first reports of Dengue fever date to AD 992 in the Encyclopedia of Chinese Medicine.123 West Nile virus (WNV) was first identified in 1937, since

being recognized in the United States at the turn of the 20th century.124 Throughout history, these viruses have caused sporadic epidemics globally, but rarely have they caused a significant burden of disease in the United States. Globalization with enhanced international travel during the past 3–4 decades has increased the spread of the disease and emergence in new parts of the world. The incubation period ranges from 2 days to 2 weeks in most patients.124 Many infected patients have self-limiting disease; however, severe infections requiring hospitalization result in a subset of patients. Symptoms range from general “flu-like” illness to severe respiratory distress, multiorgan failure, and shock. Symptomatic care is the hallmark of treatment with no active antiviral therapies available. In some instances, IVIG has been used on a limited basis with mixed results. In a pediatric population in Nepal with Japanese encephalitis, IVIG at 400 mg/kg/day for 5 days resulted in higher antibodies and interleukin (IL)-4 and IL-6 levels in treated patients than in those receiving standard of care.125 Clinical outcomes, however, remained the same in both groups. Sporadic case reports show mixed results on the effectiveness in WNV encephalitis.1 Immunoglobulin lots obtained from endemic areas are likely to have higher viral titers specific to many of these viral infections and potentially enhanced effects. In viral encephalitis, some experts suggest using intrathecal or intraventricular administration to enhance antibody exposure across the blood-CSF barrier. Although IVIG may be considered in many of the flavivirus infections with progression despite aggressive symptomatic care, caution should be used with untoward effects. The optimal dosing and route of administration for a suspected CNS infection are unknown.1,124

Table 17.6 List of Common Arboviruses and Corresponding Properties

N/V = nausea and vomiting.

Dengue Fever Dengue fever is the most common arbovirus infection, only behind malaria for infection-related sequelae in the tropics. The mosquito in the genus Aedes is the primary vector, and human-to-human transfer of disease is not confirmed. Infection occurs with one of four serotypes, DEN 1–4, and infection with one serotype does not offer protection against the others.123 Subsequent infections, in fact, with different

serotypes may increase the severity of disease and the likelihood of associated hemorrhagic fever or shock. The infection rate worldwide has increased 30-fold in the past 50 years.123 Dengue fever worldwide is primarily a disease of infants and children, although disease in a returning traveler from an area where Dengue fever is endemic may occur in adults as well. Diagnosis is based on travel history, together with fever and two of the following criteria: nausea/vomiting, rash, aches and pains, positive tourniquet test, leukopenia, or one of the warning signs for severe disease. Viral serologies are also available for Dengue, which are often used for confirmation. The hemagglutination inhibition assay and the IgG and IgM enzyme immunoassays are available, with the IgM enzyme immunoassay test being the most commonly used. Rapid PCR testing is also available that can diagnose the disease early in the infection window (less than 48 hours), but it requires a reference laboratory for most institutions.124,126 Dengue infection occurs in three distinct phases over an average 10-day period: febrile, critical, and recovery.123,126 The hallmark of the clinical course is an increase in capillary permeability and a resultant plasma leakage and increase in hematocrit. Plasma leakage peaks over a 24to 48-hour period during the critical phase. This is accompanied by a significant decrease in white blood cell and platelet counts. The severity of the plasma leakage may lead to other sequelae including shock and multiorgan failure, although this is rare. Other laboratory abnormalities seen in the critical phase include hypoalbuminemia, elevated liver enzymes, thrombocytopenia and leukopenia, and abnormal coagulation profile.1,126 Management of severe Dengue fever is primarily symptomatic care and focused on appropriate fluid balance. Repeated boluses may be needed in severe plasma leak; however, maintenance fluids should be carefully balanced and adjusted according to patient requirement.126 Further management of resultant hypotension beyond intravenous fluids may be required in rare situations. Electrolyte shifts are also common. Antibiotics are not indicated unless a secondary bacterial infection occurs. The mortality rate is less than 1%, and many patients can be treated as outpatients, with proper education and knowledge of

immune status. Prevention is a primary focus with the lack of anti-viral therapies. Avoiding mosquito acquisition is the best current strategy. Vaccine development is under investigation, although no timeline is available.1,123

Other Zoonotic Infections The rabies virus is an RNA virus transmitted through the saliva of an infected animal vector. In the United States, bats, raccoons, skunks, and foxes are the primary sources of infection, depending on the geographic region. Each year in the United States, about 6,000 animals, 92% of which are nondomestic, and two or three humans are infected with rabies. Worldwide, however, almost 75,000 cases occur annually.127 The case fatality rate is 100%, and only three survivors who have not received postexposure prophylaxis with immunoglobulin or the rabies vaccine have been reported.128 After exposure to an infected animal, the average incubation period is 20–90 days, although time to presentation is quite variable.41,129 Patients often have localized symptoms after the initial bite has healed, including localized pain, numbness, tingling, and paresthesias together with generalized viral syndrome of fatigue, malaise, and fever. The two distinct forms of rabies are encephalitic in 80% of patients and paralytic in 20% of patients. It is not clearly understood why and how each may manifest. The encephalitic form has a greater burden of disease involving the spinal cord and peripheral nerves. Patients have episodes of hyperexcitability separated by lucid periods. Autonomic dysfunction is common. The hallmark feature is hydrophobia, which involves diaphragmatic spasms lasting 5–15 seconds on attempts to swallow. This can also be triggered by the sight of liquids and draft of air. Patients quickly progress to coma and multiorgan failure. Paralytic rabies typically begins at the bite location with spread to quadriparesis and bilateral facial weakness. Hydrophobia does not typically occur in this form of rabies, although progression to coma and organ failure is imminent but often delayed compared with progression with the encephalitic form.41,130

Early presentation after a bite but before the onset of symptoms will trigger a proactive response to determine the necessary prophylaxis. Animal testing can be done quickly using direct fluorescent antibody testing on the brain tissue. If it is determined that a high-risk exposure has occurred, the previously unvaccinated patient will receive a single dose of human rabies immunoglobulin (HRIG) infiltrated into the wound and surrounding areas.128,129 Patients will also receive a four-dose series of rabies vaccine, with the first dose beginning the same day and subsequent doses given on days 3, 7, and 14. The vaccine should be administered intramuscularly in the deltoid area at a site distant from the HRIG. If the entire volume of the HRIG cannot be administered local to the bite, the remaining volume can be administered intramuscularly at a site distant from the vaccine. This is to reduce the potential inactivation of the rabies vaccine. Patients who were previously vaccinated should receive two doses of the vaccine, but HRIG is not indicated.128 Among the three survivors known to date who did not receive postexposure prophylaxis, a 15-year-old girl who survived was placed in a therapeutic coma with intravenous midazolam and supplemental phenobarbital for a burst-suppression pattern on EEG. In addition, she was maintained on continuous infusion ketamine and provided antiviral therapy with ribavirin and amantadine. This protocol, based on very limited evidence, has been labeled the “Milwaukee protocol.”128,131 Despite success in this patient, at least 20 failures have been documented using a similar approach since its publication.132 Although these agents are under investigation, no evidence currently suggests that this pharmacologic approach promotes clearance of rabies or resolution of symptoms.

SUMMARY Pharmacists contribute daily to improving patient care in the ICU through improving medication safety, promoting evidence-based practice, optimizing medication delivery, and reducing unnecessary costs. For many critical care pharmacists, managing infectious

diseases is a primary function of day-to-day patient care activities.10 Viral infections play a critical role in the burden of infectious diseases in the ICU. Although many of these are acquired in the community, the risk of nosocomial viral infections is increasingly prevalent. Pharmacists should always practice and promote appropriate infection control measures, abiding by institutional guidelines. Good hand hygiene is a simple but proven effective measure for reducing the transmission of nosocomial pathogens from health care workers to patients or between patients.4 The continued development of rapid diagnostics and the availability of new testing platforms for viral pathogens such as multiplex PCR provide an additional, integral role for pharmacists. Knowledge and interpretation of such tests are important for properly managing unnecessary antibiotics, discussing the potential need for targeted antiviral therapy, or communicating the need for infection control measures. Supportive care is the cornerstone of management for many invasive viral infections; however, some of the more prevalent viral infections in the ICU have proven, available, evidence-based, antiviral therapies. For antivirals, which are usually much less commonly used than antibacterials, knowledge of appropriate dosing, administration, and adverse effects is limited to a select few members of the treatment team. Many of these patients will also have accompanying immunocompromised states, requiring a working knowledge of immunomodulators and immunodeficiencies. Research is significantly lacking in the management of many invasive viral infections, priming pharmacists for an opportunity to help lead efforts to enhance the clinical investigation of these patients.

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119. Hill CE, Burd EM, Kraft CS, et al. Laboratory test support for ebola patients within a high-containment facility. Lab Med 2014;45:e109-11. 120. World Health Organization (WHO). Use of Convalescent Whole Blood or Plasma Collected from Patients Recovered from Ebola Virus Disease for Transfusion, as an Empirical Treatment During Outbreaks. Version 1.0, September 2014. Available at http://www.searo.who.int/​entity/emerging_diseases/​ ebola/who_his_​sds_2014.8_eng.pdf. Accessed November 25, 2015. 121. Go YY, Balasuriya UB, Lee CK. Zoonotic encephalitides caused by arboviruses: transmission and epidemiology of alphaviruses and flaviviruses. Clin Exp Vaccine Res 2014;3:58-77. 122. Weaver SC, Forrester NL. Chikungunya: evolutionary history and recent epidemic spread. Antiviral Res 2015;120:32-9. 123. Halstead SB, Cohen SN. Dengue hemorrhagic fever at 60 years: early evolution of concepts of causation and treatment. Microbiol Mol Biol Rev 2015;79:281-91. 124. Weaver SC, Reisen WK. Present and future arboviral threats. Antiviral Res 2010;85:328-45. 125. Rayamajhi A, Nightingale S, Bhatta NK, et al. A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal. PLoS One 2015;10:e0122608. 126. Ranjit S, Kissoon N. Dengue hemorrhagic fever and shock syndromes. Pediatr Crit Care Med 2011;12:90-100. 127. Centers for Disease Control and Prevention (CDC). Rabies. Available at www.cdc.gov/rabies/. Accessed September 7, 2015. 128. Jackson AC. Current and future approaches to the therapy of human rabies. Antiviral Res 2013;99:61-7. 129. Jackson AC. Rabies. Neurol Clin 2008;26:717-26.

130. Fu ZF, Jackson AC. Neuronal dysfunction and death in rabies virus infection. J Neurovirol 2005;11:101-6. 131. Zimmerman RF, Belanger ES, Pfeiffer CD. Skin infections in returned travelers: an update. Curr Infect Dis Rep 2015;17:467. 132. Caicedo Y, Paez A, Kuzmin I, et al. Virology, immunology and pathology of human rabies during treatment. Pediatr Infect Dis J 2015;34:520-8.

Chapter 18 Antimicrobial

Prophylaxis Keith M. Olsen, Pharm.D., FCCP, FCCM; and Gregory Peitz, Pharm.D., BCPS

LEARNING OBJECTIVES 1. Determine the correct use of antibiotics during surgical prophylaxis pertaining to indication, dose, duration, and timing. 2. Identify risk factors for surgical site infections (SSIs) and the unique risks faced by critically ill patients. 3. Identify differences in the causative pathogens for SSIs among intensive care unit (ICU) patients. 4. Synthesize an antibiotic prophylactic approach for the ICU patient receiving antibiotics for a concomitant infection. 5. Describe which procedures performed at the ICU bedside warrant antibiotic prophylaxis and the preferred regimen.

ABBREVIATIONS IN THIS CHAPTER AASLD American Association for the Study of Liver Diseases ANC

Absolute neutrophil count

BMI

Body mass index

CIED

Cardiovascular implantable electronic device

CMS

Centers for Medicare & Medicaid Services

CSF

Cerebrospinal fluid

ECMO

Extracorporeal membrane oxygenation

HCT

Hematopoietic stem cell transplantation

ICU

Intensive care unit

ISHLT

International Society for Heart & Lung Transplantation

LVAD

Left ventricular assist device

MRSA

Methicillin-resistant Staphylococcus aureus

PPDs

Permanent pacemaker devices

PQRS

Project and Physician Quality Reporting System

SBP

Spontaneous bacterial peritonitis

SSI

Surgical site infection

TAH

Total artificial heart

VAD

Ventricular assist device

VAP

Ventilator-associated pneumonia

INTRODUCTION: BASICS OF SURGICAL PROPHYLAXIS Surgical site infections (SSIs) precipitate a cascade of events that often result in significant morbidity, increased mortality, and substantial costs to health care systems and patients. Prevention of these SSIs is fundamental to clinical practice whether the patient originates in the intensive care unit (ICU), hospital ward, skilled nursing facility, or is admitted from home. Antimicrobial prophylaxis plays an important role in the prevention of infections, but their administration is only one step in a comprehensive infection prevention program. Basic infection control practices are the core of preventing SSIs and should include

controllable factors such as targeted temperature control, blood glucose control, hair clipping versus shaving, venous thromboembolism prophylaxis, and perioperative β-blocker administration. Equally important are controllable factors of antimicrobial administration that include which surgical cases may benefit antibiotic selection, antibiotic dosing, timely administration before surgical incision, and duration of postoperative prophylaxis. Pharmacists have been involved in collaborative improvement efforts on the national, state, local, and institutional level to improve antimicrobial use during the perioperative period. Major national initiatives developed by the Centers for Medicare & Medicaid Services (CMS), including the Surgical Care Improvement Project and Physician Quality Reporting System (PQRS), have resulted in dramatic improvements in standardizing antimicrobial administration and infectious control practices centered on the surgical procedure. For example, CMS requires collection and reporting of administration of antibiotic prophylaxis through the PQRS, which is shown electronically on public access websites to allow the consumer to compare performance among hospitals on specific surgical procedures. Many questions remain unanswered with perioperative antimicrobial prophylaxis. An area that is largely absent in recommendations from CMS and SSI prevention guidelines is the decision-making process for patients receiving antibiotics for other infections, including patients residing in the ICU. The pharmacist and surgeon are often left without guidance regarding the correct approach to antimicrobial prophylaxis among these patients. Very few answers to these questions are found in the literature; however, a basic understanding of antimicrobial prophylaxis and the targeted organisms that cause these infections provides evidence for best practices. These are important considerations for patient safety, potential antimicrobial resistance, burden of antimicrobial use, and ties to CMS reimbursement policies. This chapter will examine the fundamentals of antimicrobial surgical prophylaxis, review surgical procedures in the ICU and surgical suite, and address antibiotic administration in patients receiving active treatment for infection.

Principles of Prophylaxis Surgical Site Infections The National Healthcare Safety Network has defined the criteria for determining an SSI. Infections can be classified in three categories: superficial incisional site SSI, deep incisional SSI, and organ space SSI.1,2 Superficial infections usually occur within 30 days of the operative procedure and involve the skin and/or surrounding subcutaneous tissue of the incision site plus the clinical findings of purulent wound drainage, aseptically isolated organisms from the wound, and at least one sign of infection: pain or tenderness, or localized swelling, redness, or heat. Additionally, any culture positive or noncultured superficial incision that is deliberately opened by or determined by a surgeon or another clinician as an incisional SSI, is classified as a superficial infection. Deep incisional infections also occur within 30 days, or if an implant is left in place, the period is extended to 1 year, and the SSI appears related to the procedure. Deep tissue infections involve the fascial and muscle layer and/or deep soft tissue. An SSI is confirmed if the surgical site has purulent drainage or the incision spontaneously dehisces or is opened by the surgeon and is culture positive. If not cultured, the patient must have other signs of infection that include fever (temperature greater than 38°C), localized pain or tenderness, abscess, or other evidence of infection found on examination or during reoperation, histopathologic or radiologic evidence, or visual diagnosis by the clinician. Organ space SSIs may occur in a part of the body excluding infections isolated to superficial or deep tissues (e.g., those of the skin incision, fascia, or layers of muscle) and is more likely to result in systemic culture of infecting pathogens. Organ space infections follow the same 30-day and 1-year criteria of deep incisional SSIs and meet the criteria of purulent drainage from a drain placed through the wound, organism isolated aseptically, abscess or radiologic or histopathologic evidence, or direct examination with evidence of infection. Complete descriptions of these criteria are found elsewhere.3

Surgical Site Pathogens Common pathogens associated with SSIs are usually associated with skin flora that include Staphylococcus aureusand coagulase-negative organisms such as Staphylococcus epidermidis. In procedures that penetrate areas harboring other pathogens (e.g., intra-abdominal, colon), the pathogens associated with SSI also include Enterococcus sp., enteric gram-negative rods (e.g., Escherichia coli, Proteus sp.), and anaerobes (e.g., Bacteroides sp.). There is an increasing understanding of pathogen access to the surgical wound by hematogenous spread, through drains, or through slow-healing wounds.4 In addition to preoperative risk factors, postoperative factors that have been associated with SSIs may include prolonged hospital stay or ICU admission, admission from a long-term care facility, poor wound healing, anticoagulation, respiratory insufficiency, and prolonged antimicrobial administration beyond the first postoperative 24 hours. Antimicrobial Resistance Antibiotic resistance is an increasing cause of SSIs that has led to increased morbidity and mortality and associated costs of care for these complicated infections.5 The incidence of methicillin-resistant S. aureus (MRSA) and S. epidermidis has gradually risen and is now a major cause of SSIs in some health centers. Awad and colleagues showed a greater than 45% rise in MRSA isolates from 288 surgical cases requiring surgical debridement.6 A comparison of SSIs caused by methicillin-sensitive S. aureus (MSSA) and MRSA showed a 90-day postoperative mortality rate of 6.7% versus 20.7% (p 14% SSIs

None

No differences between antibiotics including cephalosporin generations

Orthopedic Clean; no implants Spinal Hip fracture

Cefazolin Cefazolin Cefazolin

Total joint replacement Transplantation Heart

Cefazolin

Cefazolin; same as

cardiovascular procedures Lung and heart-lung

Cefazolin

First-generation cephalosporin if negative donor cultures

Liver

Piperacillin/tazobactam or cefotaxime + ampicillin

Modify regimen on the basis of isolated pathogens from donor; gram-negative aerobes, staphylococci, enterococci most common

Pancreas and pancreaskidney

Cefazolin ± fluconazole

A wide range of pathogens including gram-negative may necessitate broader coverage

Kidney

Cefazolin or ceftriaxone

Two separate studies with single-dose cefazolin or ceftriaxone resulted in 0% SSI

Cefazolin or ampicillin/sulbactam

Clean procedures without risk factors do not require prophylaxis

Plastic Clean or clean contaminated

aClindamycin

or vancomycin may be administered in β-lactam allergy for gram-positive

coverage. bAztreonam,

aminoglycoside, and, occasionally, a fluoroquinolone may be added for additional gram-negative coverage or gram-negative coverage with β-lactam allergy. SSI = surgical site infection. Adapted from: Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013;70:195-283.

The authors did not mention whether a second dose of antibiotic was administered intraoperatively in prolonged surgical procedures. However, they did conclude that high-quality evidence showed that antibiotics targeting both aerobic and anaerobic pathogens were more effective. Ertapenem is the only U.S. Food and Drug Administration label-approved antibiotic for single-dose prophylaxis in colorectal

surgical procedures. Few studies have compared a short duration of prophylaxis in cardiovascular surgical procedures. A study of more than 2,800 patients undergoing prolonged cardiovascular surgical procedures compared the SSI rate of 48 hours or less with more than 48 hours of antimicrobial prophylaxis. The results showed no difference in the SSI rate between the two durations; however, with the longer duration, when an infection did occur, it was more likely (odds ratio 1.6% [95% confidence interval, 1.1–2.6]) caused by an antimicrobialresistant pathogen.17 Repeat Dosing Antibiotics with short half-lives require repeated dosing in prolonged surgical procedures to ensure adequate tissue concentrations at the surgical site. If the surgery exceeds 2 half-lives of the antibiotic, repeat dosing is necessary.3 For example, cefazolin with a half-life of 2 hours should be redosed if the time from the start of antibiotic administration and the surgical procedure exceeds 4 hours. Antibiotics with a longer half-life (e.g., ceftriaxone with an 8-hour half-life) generally do not require repeat dosing. With repeated dosing guidance now available, institutions should consider developing additional guidelines for the frequency of intraoperative dosing to avoid excessive under- and overdosing of antimicrobials. Dose To achieve adequate tissue concentration preoperatively, the antimicrobial dose should be chosen on the basis of the type of surgery, antibiotic pharmacokinetics, and individual characteristics of the patient. Early studies of antimicrobial prophylaxis used fixed dosing; however, weight-based dosing is increasingly recognized as ensuring adequate drug concentration at the incision site. Standardized fixed doses do have merit because they avoid the common pitfalls of calculations that lead to dosing errors and compromise patient safety.3 Obesity rates have been rising in the United States, with estimates of more than 66% of adult Americans classified as overweight or obese,

which may affect tissue concentrations of antibiotics at the point of incision.19 The most recent guidelines for surgical prophylaxis recommend intravenous cefazolin 2 g for patients weighing more than 80 kg and 3 g for those weighing more than 120 kg.3 However, only a few studies have addressed dosing in the patient with obesity, most of which have been directed toward the patient with morbid obesity undergoing bariatric surgery. Nonetheless, the clinician should be aware of the potential impact of obesity on antimicrobial penetration into fat tissue and to the surgical incision site. The pharmacokinetics of a single dose of cefazolin were examined in 25 patients (body mass index [BMI] range 43.7–55.7 kg/m2) undergoing elective surgical procedures. Patients were divided into four groups according to their BMI and then assigned to receive cefazolin 2 g intravenous push, 2 g by 30-minute infusion (two different groups), and 3 g by 30-minute infusion. Serum cefazolin concentrations were determined in sequential format before surgery through 360 minutes after initiating the infusion. At all BMIs and doses, the cefazolin pharmacokinetics exhibited similar mean concentrations at 30 minutes after the dose and displayed concentrations of 67.1–84.8 mcg/mL and 22.9–40.8 mcg/mL at 120 and 360 minutes post-dose, respectively. The authors concluded that a single 2-g cefazolin dose provided adequate serum concentrations regardless of BMI for surgical procedures of less than 5 hours.20 In contrast, 38 patients undergoing Rouxen-Y gastric bypass for morbid obesity were given cefazolin 2 g intravenously followed by a second dose 3 hours later. Patients were assigned to one of three groups according to their BMI (40–49, 50–59, 60 kg/m2 or greater). Serum cefazolin concentrations were inadequate in 52%, 68%, and 73%, with therapeutic tissue concentrations achieved in only 48.1%, 28.6%, and 10.2%, respectively.21 Pharmacists responsible for dosing antibiotics in surgical prophylaxis should be knowledgeable of pharmacokinetics and pharmacodynamics in applying weight-based dosing, and weight-based dosing, versus standard dosing, should be the new standard of practice. Aminoglycosides and vancomycin are examples of antibiotics used in surgical prophylaxis with the dose based on weight.

Traditionally, a 1-g dose of vancomycin has been administered for surgical prophylaxis. In a study of 216 patients who screened positive for MRSA before elective total joint or spine surgical procedures, a vancomycin 1-g dose was compared with a weight-based dose of 15 mg/kg. A total of 149 patients (69%) were determined to be underdosed, and an additional 22 patients (10%) were overdosed. The predicted vancomycin value was less than 15 mg/L in 60% of patients receiving the 1-g dose.22 Antibiotic dosing should be appropriately adjusted for renal dysfunction. In single-dose administration, the dose usually needs no adjustment for renal impairment; however, multidose regimens may need the dose reduced or the interval extended, depending on the estimated glomerular filtration rate and antibiotic renal clearance. ICU Patients Many ICU patients receive antibiotics for other infections before their surgical procedure. This scenario often raises the question of whether additional antibiotics are required before the procedure. Unfortunately, there are no randomized trials to guide the clinician in this decision. Rather, the decision must be made considering the antibiotics being used to treat the infection, their antimicrobial coverage, the length of hospital stay, and the most recent dose in proximity to the surgical procedure. If the antibiotics used for the infection are substantially different in coverage from what would be used for surgical prophylaxis, the recommended dose of the antibiotic commonly used in the procedure should be administered at the appropriate time and duration. However, if the antibiotics being used for the existing infection consistently cover the potential pathogens associated with the procedure, a prudent approach would be to adjust the time of administration to coincide with the usual administration of prophylaxis, or if the times are considerably different from what would be required for the procedure, an additional dose may be given within 1 hour before the incision.

ICU Specifics and Risks of SSIs Many factors, including several comorbidities, depressed host defenses, the presence of invasive devices, prolonged antibiotic courses, immunosuppressive therapy, and exposure to resistant bacteria, make infectious complications in the critically ill population of concern. Specifically, infectious insults in the ICU environment are more common than infectious complications in non-ICU patients, with at least twice the risk of mortality as in patients who are not affected by an infection.23,24 These increases in prevalence and suboptimal outcomes are a result of several variables encountered by critically ill patients.23,25 Many patients admitted to the ICU have comorbidities or acute syndromes that precipitate an immunocom-promised state. This transient state of depressed immune function predisposes critically ill patients to infection. Even previous immunocompetent hosts who are exposed to surgical or traumatic procedures are particularly susceptible to a bacterial insult because of an excessive inflammatory response affecting cell-mediated immunity.26 In addition to acute changes in immune status, other challenges faced by the critically ill population include perioperative glucose management. Hyperglycemia (blood glucose greater than 150 mg/dL), which can impair macrophage chemo-taxis and function, has been shown to occur in patients in the perioperative setting and to increase the likelihood of postoperative infections.27 Colonization with virulent pathogens also carries an increased risk of infectious complications in the ICU. Nasal colonization of MRSA in medically ICU patients has been shown to have a significant increase in subsequent MRSA infections over that in patients not colonized with the bacteria.28,29 Many critically ill patients also receive foreign devices such as central venous catheters, ventricular assist devices (VADs), cardiovascular implantable electronic devices (CIEDs), and neurosurgical devices,30,31 which may be prone to the formation of biofilm. Although data are sparse regarding the ability of perioperative prophylaxis to affect biofilm development in all device implantation,

using effective preoperative antibiotics may be important to minimize the risk of any inoculum propagating biofilm after surgery.31,32 Although critically ill patients are perhaps at a greater risk of infection related to surgical procedures, this population is also susceptible to other infectious complications because of patients’ various risk factors. Prophylactic antibiotic regimens in this population have been shown to reduce infectious complications. This review is intended to focus on specific ICU indications for antimicrobial prophylaxis and, in addition to ICU procedures, the need for antimicrobial prophylaxis that has not been fully elucidated in previous literature or guidelines. It is not intended to be fully comprehensive in addressing all potential ICU infections.

ANTIBIOTIC PROPHYLAXIS IN ICU PATIENT POPULATIONS Prophylaxis in Nonsurgical ICU Patients Spontaneous Bacterial Peritonitis Prophylaxis Spontaneous bacterial peritonitis (SBP) is a common complication of cirrhotic ascites that causes inflammation and infection of the abdominal cavity membrane. It affects more than 10% of patients admitted with cirrhotic ascites33-35 and has an attributable mortality rate of up to 50%,36 with a higher risk of death if the infection occurs within 48 hours of a variceal bleeding event.34 Patients with cirrhosis who present with suspected SBP are recommended to be promptly initiated on appropriate antibiotic therapy, but the outcomes associated with empiric antibiotic initiation have been more compelling in the resolution of infection than in having an impact on mortality.35 Empiric antibiotic therapy for SBP is warranted if at least one risk factor is present, including (1) temperature greater than 37.8°C, (2) abdominal pain or tenderness, (3) acute mental status changes, or (4) polymorphonuclear leukocytes greater than 250 cells/mm3 in the ascitic

fluid.35,37 Patients with cirrhosis having no outward indication for empiric SBP treatment should be evaluated for the inclusion of SBP prophylaxis. Spontaneous bacterial peritonitis prophylaxis has not only been shown to reduce the risk of infections by 30%,38 but has also delayed the development of hepatorenal syndrome,39 reduced variceal rebleeding,40 and improved patients’ hemodynamics41 and has shown a mortality benefit.38,39,42 Because of concerns that the widespread use of antibiotics in all patients with cirrhosis may lead to subsequent colonization with multidrug-resistant organisms, the AASLD (American Association for the Study of Liver Diseases) guidelines have provided specific indications for the provision of SBP prophylaxis. Their recommendations and level of support can be seen in Table 18.2.35 The most common isolated organisms during cirrhotic bleeding events are aerobic gram-negative bacilli of enteric origin including E. coli and Klebsiella sp., but gram-positive organisms have also been isolated.39,43 Few studies have evaluated various antibiotics and regimens regarding prophylaxis against SBP. Norfloxacin was once the preferred agent for SBP prophylaxis,44 but ceftriaxone (1 g daily) has been proven superior in the setting of cirrhosis complicated by gastrointestinal (GI) bleeding39 and is recommended as initial intravenous prophylaxis.35 Prophylaxis for SBP should continue for 7 days in patients who present with an acute GI bleed, but once the patient can take oral medications, transitioning to an oral twice-daily norfloxacin regimen would be appropriate. Norfloxacin is not available in the United States; thus, ciprofloxacin 500 mg daily orally can be used. In summary, ceftriaxone 1 g daily or ciprofloxacin 500 mg daily for 7 days is recommended for SBP prophylaxis. Fungal Prophylaxis Although a relatively rare occurrence, the development of an invasive fungal infection in the ICU portends high mortality, particularly with delays in effective treatment.45,46 Overall mortality may reach 60%,

with outcomes worse in medical patients than in surgical patients.45,47,48 Preexisting diabetes mellitus, concurrent immunosuppression, mechanical ventilation, and temperatures greater than 38.2°C are associated with increased mortality.49 In ICU patients without neutropenia, the incidence of fungemia is less than 0.5%, with most cases attributable to Candida spp.48,49 Because of the considerably poor outcomes observed in these infectious insults, initiating early appropriate antifungal therapy is of paramount importance for success. To aid in identifying patients at risk of fungal infections, research efforts have investigated the use of clinical prediction tools to identify patients who may empirically benefit from antifungal prophylaxis.50-54 These clinical prediction tools have collated various risk factors for invasive candidiasis found in ICU patients without neutropenia. Common risk factors identified by these studies include colonization with Candida spp.,53,55 con-current antibiotic use,52,55 surgical procedures,53 the presence of a foreign device,55 acute kidney injury or dialysis,52,55 prolonged intubation,50 and increased severity of illness,56 among others. Each prediction tool is different because each incorporates different variables into its risk assessment; thus, each tool has variations in both sensitivity and specificity to predict the critically ill patients who would benefit from antifungal prophylaxis.50-54,56 Several of these prediction tools have not been validated in prospective multicenter trials. In addition, several have failed to consistently predict infection, and their potential role as standard surveillance for the general critically ill population remains undetermined.

Table 18.2 Indications for Spontaneous Bacterial Peritonitis Prophylaxis in Patients with Cirrhosis Recommendation Patients with concurrent GI bleeding

Level of Evidence Class I, Level A

Patients having ≥ 1 episode of SBP Patients with concurrent ascites AND aseitic fluid protein > 1.5 g/dL with concurrent renal dysfunction (creatinine > 1.2 mg/dL; BUN > 25 mg/dL or serum sodium < 130 mEq/L) or liver failure (Child-Pugh score > 9 and bilirubin > 3 mg/dL)

Class I, Level A Class I, Level A

Adapted from: Runyon BA, AASLD. Introduction to the revised American Association for the Study of Liver Diseases practice guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology 2013;57:1651-3.

Eight major prospective studies have evaluated fungal prophylaxis in the critically ill population. Although specific trials and subsequent metaanalyses have shown a reduction in the incidence of Candida infections after fungal prophylaxis in the ICU,57-61 survival benefits have been equivocal and have mainly been shown in surgical/trauma ICU patients.59 High-risk surgical patients, particularly those with intestinal perforations or anastomotic leaks, have benefited from empiric prophylactic antifungal therapy.57 A small study evaluated 49 patients with recurrent GI perforations or anastomotic leakage treated with intravenous fluconazole 400 mg/day or placebo.62 The investigators showed a significant decrease in Candida peritonitis (4% vs. 35%) and Candida infections (9% vs. 35%) in the fluconazole arm of the study.62 In addition to these high-risk surgical patients, routine prophylaxis is beneficial in these patients after solid organ transplantation, or in patients with neutropenia.63,64 Otherwise, routine prophylaxis in the ICU is only recommended if a patient’s risk is presumed to be greater than 10%.65 Fluconazole dosed at 400 mg daily is the preferred prophylactic agent of choice as described by the 2009 Infectious Diseases Society of America (IDSA) guidelines, but there is evidence that fluconazole resistance may be emerging (these guidelines are currently under

revision).66 In an effort to curb Candida resistance to azole therapy and optimize the benefits of fungal prophylaxis, there may be utility in analyzing institution-specific risk factors for invasive fungal infections and applying necessary prophylactic antifungals according to local culture data including albicans and nonalbicans Candida spp. A study of prophylaxis showed a favorable outcome with oral fluconazole versus placebo in 260 critically ill surgery patients with greater than a 3-day expected length of stay. The patients who received fluconazole had a statistically lower rate of Candida infections; however, this did not occur until day 14, when only 20 patients remained in the study.61 A more recent study examined the impact of caspofungin prophylaxis versus placebo followed by preemptive therapy for invasive candidiasis in high-risk adults in the ICU. A total of 222 patients who were in the ICU for at least 3 days; who were mechanically ventilated; who received antibiotics, with central line present; and who had at least one other risk factor were included in the study. The primary end point was proven or probable invasive candidiasis. The caspofungin arm of the study had lower or proven invasive candidiasis, but this was not statistically significant, nor was the overall mortality of 16.7% and 14.3% in the two study arms.67 At this time, prophylactic, presumptive, or even empiric therapy cannot be routinely recommended in the ICU patient. For patients with GI leakage into the abdominal cavity or those with an overall calculated fungemia risk of 10% or higher, fluconazole 400 mg intravenously daily can be recommended for prophylaxis. Hematopoietic Cell Transplantation Hematopoietic cell transplantation (HCT) is a therapeutic option for many bloodborne syndromes including lymphoma, leukemia, myelodysplastic syndrome, myeloproliferative disorders, and 68 autoimmune conditions, among others. Transplanted hematopoietic stem cells can be obtained from the recipient patient (autologous HCT) or from another donor (allogenic HCT). Hematopoietic cell transplantation is often preceded by either a myeloablative or a nonmyeloablative conditioning regimen that is facilitated to eradicate malignant cells of the offending disease process

and prevent rejection of an allogenic stem cell transplant. Myeloablative and nonmyeloablative therapies differ in their chemotherapeutic intensity depending on the specific type of conditioning regimen and respective malignant disorder. Consequently, these regimens vary in their degree of cytotoxicity and bone marrow suppression. Substantial pancytopenia is commonly precipitated by these conditioning regimens, placing patients at an increased risk of infection. In addition to neutropenia, these immunosuppressive regimens can cause damage to normal mucosal barriers and further increase the infectious risks of HCT recipients.69 After a patient’s initial conditioning therapy and subsequent HCT, the infectious pathogenic risks change as each patient’s immune system recovers and specific immune-regulating cell lines are regenerated. Early after the conditioning phase, patients are at the highest risk of an infection caused by gram-negative bacteria or Candida spp. Compelling factors that may contribute to infectious threats include the type of transplant (autologous HCT vs. allogenic HCT), severity of the patient’s underlying malignant disorder, degree of donor matching, and time from conditioning therapy to the patient’s stem cell transplant. As patients recover from their neutropenia and progress further from transplantation, their infectious risk profile shifts from predominant bacterial causes to viral and invasive fungal pathogens as the cellularmediated immunity remains deficient.68 The long-term prophylactic regimens necessary for managing these risks will be discussed elsewhere in this book, and the prophylactic strategies described in this chapter will focus on the immediate posttransplant period. Immediately after stem cell infusion, patients should receive an antibiotic with gram-negative coverage. Levofloxacin 500 mg orally daily is recommended and should continue until a patient’s neutropenia has resolved.68,70 Evidence does not support the inclusion of broadspectrum gram-positive agents to the initial prophylactic regimen. The understanding and application of local bacterial resistance patterns should be used when deciding on a prophylactic strategy. If a patient has had recurrent MRSA infections, mupirocin has been used to reduce the MRSA burden by applying the ointment twice daily for 5 days

directly to the nares or to any visible wounds for up to 2 weeks, but this strategy has insufficient evidence to recommend universally.68 Anti-infective Prophylaxis After Neutropenia Neutropenia is defined as a reduction in the absolute neutrophil count (ANC) in a patient’s peripheral blood. Although neutropenia can occur secondary to autoimmune disorders,71,72 the focus of this section will be directed at neutropenia experienced in patients with cancer, which can be defined as an ANC less than 500 cells/m3.73 After a course of chemotherapy or a bone marrow transplant, patients are at an increased risk of life-threatening infectious complications, particularly when profound neutropenia (ANC less than 100 cells/m3) exists. Bodey and colleagues showed that in patients with leukemia having an ANC less than 100 cells/m3, there was an overall risk of 43 infectious episodes per 1,000 patient-days.74 During neutropenia, infectious insults are often recognized by observing a patient’s temperature because fever continues to be detectable early in a neutropenic infection.75 Fever, defined as a single temperature of 38.3°C or greater for 1 hour by the Infectious Diseases Society of America (IDSA)73 and the National Comprehensive Cancer Network (NCCN) guidelines,70 can be realized in up to 50% and greater than 80% of patients who receive chemotherapy for solid tumors and hematologic malignancies, respectively.73 Despite the high rates of febrile episodes, less than 30% of these patients will have a verified clinical infection during the period of febrile neutropenia.73 Gram-positive organisms, particularly coagulasenegative staphylococci, have become the most common organisms isolated in bloodstream infections in patients with neutropenia.76 Gramnegative pathogens including E. coli, Klebsiella sp., Enterobacter sp., and other Enterobacteriaceae are isolated less commonly but are associated with a higher mortality rate than are gram-positive bacterial infections in the neutropenic population.73 Although the definitive yield of infectious cause may be poor, prompt and appropriate treatment of patients who develop febrile neutropenia

is imperative to improve outcomes, with improvements in mortality observed with early antibiotic initiation on detection of fever in the patient with neutropenia.77 Although early initiation of antibiotics is critical in a patient with neutropenia and fever, preventing infection during the neutropenic phase after chemotherapy is also important. Antibiotic prophylaxis in the patient with neutropenia is recommended by the NCCN and IDSA guidelines with considerations given to low- and high-risk populations for infection. Antibiotic prophylaxis is recommended by both organizations, specifically in high-risk populations. High-risk patients are identified as those with an ANC less than 100 cells/m3 or an anticipated duration of neutropenia of greater than 7 days. The NCCN guidelines70 also encourage prophylactic antibiotics for patients being treated for multiple myeloma or chronic lymphocytic leukemia and in those who are receiving a purine analog as their chemotherapeutic agent.70 Fluoroquinolones are the preferred antibacterial prophylactic agents for these patients during their high-risk period of neutropenia. Levofloxacin 500 mg daily orally has shown a reduced rate of infection and hospitalization in two randomized prospective clinical trials, but it had no mortality benefits.78,79 Adding gram-positive prophylaxis is not recommended in the initial regimen for patients with neutropenia. Fungal prophylaxis with fluconazole 400 mg daily either intravenously or orally is warranted as well in high-risk patients with neutropenia, particularly in those who are receiving allogeneic HCT or being treated with intense chemo-therapy for remission or salvage therapy in acute leukemia.73 Prophylaxis should continue throughout neutropenia. Prophylaxis with the antiviral agent acyclovir is recommended for patients who test positive for herpes simplex virus and have undergone induction therapy for allogenic HCT or leukemia. Viral prophylaxis after HCT is dependent on the presence of specific viral findings in pretransplant serum testing. Prophylaxis for cytomegalovirus (CMV) infection after HCT is determined by the patient’s and donor’s serum CMV status in allogeneic HCT. For any patients who require CMV prophylaxis (CMV-seropositive HCT recipients or CMVseropositive donors), available prophylactic options

include high-dose acyclovir therapy (500 mg/m2 intravenously three times daily or 800 mg orally four times daily), valacyclovir (2 g three or four times daily), or intravenous ganciclovir. For patients who receive ganciclovir therapy, it is recommended to include induction therapy of 5 mg/kg twice daily for 5–7 days; this should be initiated when HCT occurs and then continued daily for 100 days post-HCT.68 To prevent reactivation of herpes simplex virus, prophylactic acyclovir is recommended for all individuals who test seropositive before transplantation. Acyclovir 400– 800 mg orally twice daily or 250 mg/m2 per dose every 12 hours intravenously should commence during the initial conditioning phase and be continued until the patient has appropriate engraftment or resolution of mucositis.68 Fluconazole 400 mg orally or intravenously daily is recommended as prophylaxis for all patients receiving allogeneic HCT and for those with autologous HCT who have had intense conditioning regimens or who are experiencing mucositis. Fungal prophylaxis should ensue until at least 7 days after the ANC is greater than 1,000 cells/mm3.

Prophylaxis in Cardiac Critical Care Procedures Ventricular Assist Devices The rate and precision of VAD implantation has dramatically increased since the first report of an artificial ventricle in 1963. As the placement of these devices has become more common, efforts have continued to improve their longevity in addition to minimizing the associated complications. One specific improvement of note is the increasing prevalence of the implantation of continuous-flow devices such as the HeartMate II, which have shown more favorable outcomes, including infectious complications, than pulsatile-flow left ventricular assist devices (LVADs).80 Although data from the 2014 Interagency Registry for Mechanically Assisted Circulatory Support report indicate that infection rates for VADs have decreased, infection remains a common complication associated with VAD placement.81 Despite this information, there is a lack of consensus on the management of these

patients’ infectious prophylaxis, particularly in the perioperative setting. The main infectious risks immediately after VAD implementation are driveline infections, pump pocket infections, bacteremia, and endocarditis.82 The pathogenic insults to these patients may include gram-positive organisms, gram-negative bacilli, and fungi.83,84 The principal source of inoculum comes from the skin surface, which is a primary source of staphylococcal species. These isolates have a high capacity to adhere to foreign device material and form biofilm and evade the immunological system, thereby becoming very difficult to eradicate,32,85,86 making antistaphylococcal prophylaxis of paramount importance in the perioperative period. Although staphylococcal coverage is deemed of utmost importance for VAD perioperative prophylaxis, coverage for other pathogens remains common in most VAD centers. In addition to driveline infections, surgical pocket infection is common. Because of a high mortality rate associated with fungemia, fungal prophylaxis often joins the perioperative antibiotic prophylactic regimen. In addition, coverage of gram-negative pathogens is often added. Several studies have evaluated various perioperative antibiotic regimens in the setting of VAD placement, but inconsistent choice, timing, and duration of prophylactic antimicrobial therapy and differing definitions of LVAD infection make a direct comparison of stated infection rates difficult.87 Unfortunately, large prospective trials are lacking regarding the appropriateness of perioperative antibiotic management in VAD transplantation, and recommendations in the International Society for Heart & Lung Transplantation (ISHLT) guidelines are largely based on expert opinion. The 2013 update on perioperative management recommends broad-spectrum gram-positive and gram-negative coverage within 60 minutes of the first incision before implantation. Because of the high rate of staphylococcal driveline infections, the opinion expressed in the document calls for patients to undergo nasal swab screening for MRSA preoperatively with the desire for topical treatment with mupirocin to be incorporated if positive. Gram-negative and fungal coverage inclusion should be tailored according to institution-specific epidemiologic data, colonization

rates, and other high-risk patient-specific data. Fungal coverage may be warranted in regions known to have higher risks of virulent fungal pathogens. There are no specific recommendations on which antibiotics to choose or address toward antifungal coverage, but there is evidence that advocates against using prolonged vancomycin in high-risk general cardiac surgery patients.18,88 The recommended therapy duration is 24–48 hours, but the evidence with the longer duration is scarce.83 The optimal regimen for antibiotic prophylaxis in patients undergoing LVAD placement is not known. Guidelines indicate that a single dose of cefazolin or cefuroxime can be used before LVAD transplantation,3 but the 2013 ISHLT guidelines83 advocate for MRSA coverage with 24–48 hours of antimicrobial coverage. Many centers use a combination of vancomycin (15 mg/kg intravenously 1 hour before surgery; then every 12 hours), rifampin (600 mg orally 1–2 hours before surgery; then every 24 hours), levofloxacin (500 mg intravenously 1 hour before surgery; then every 24 hours), and fluconazole (200 mg intravenously 1 hour before surgery; then every 24 hours) for a total of 48 hours postoperatively as recommended in the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial.89,90 Data analyses on the use of alternative MRSA prophylactic strategies other than vancomycin are scarce in LVAD transplantation, but if a contraindication to vancomycin exists, daptomycin may be an alternative prophylactic strategy. Artificial Heart Implantation The availability of total artificial heart (TAH) implantation has improved short-term survival rates in patients who do not meet the criteria for VAD placement or who do not have an opportunity for an immediate heart transplant.91 Postoperative complications, including infections, are major deterrents to the success after TAH placement. Infectious complications can occur in more than 80% of TAH recipients, potentially delaying the patient’s ability to receive a heart transplant.91,92 At least half of all infections occur within the first 30 days post-implantation,93

but most documented infectious complications originate from pulmonary or urinary sources.92,93 In addition to these infectious insults, patients with TAH are predis-posed to bacteremia, driveline infections, and superficial sternal infections, potentially because of exposure to organisms during the perioperative period. These infectious risks are notably higher than in other patients, potentially because of the nature of the mechanical device itself. A TAH system is composed of metals and polymers that are in contact with tissues and hemodynamic surfaces. These surfaces pose a medium susceptible to biofilm development that is believed to promote bacterial colonization and predicate biomaterial-centered infections.85 Unfortunately, prophylactic antibiotic regimens are poorly described in the literature, and there are no specific recommendations for the choice of antimicrobial agent or duration of prophylaxis in the perioperative management of TAH. Because of the nature of the surgical procedure necessary for a TAH placement, antibiotic administration with agents similar to those used in other cardiac surgical procedures such as intravenous cefazolin of cefuroxime for 24 hours would be advocated. Patients with penicillin allergies should receive vancomycin or clindamycin as surgical prophylaxis. Extracorporeal Membrane Oxygenation Cannulation The prevalence of extracorporeal membrane oxygenation (ECMO) initiation has continually increased during the past 2 decades in both the neonatal and the adult critical care populations. As more adult patients have acute needs for ECMO initiation, it is evident that coinciding management strategies will have to continue evolving to improve delivery and minimize complications. Currently, infectious complications during ECMO management are the second most frequent setback after hemorrhagic issues.94 Potential issues that pose infection risks to patients initiated on ECMO therapy are the presence of several large-bore catheters that are exposed to the environment after surgical placement. In addition, depending on the selection of site of the ECMO cannulation that is chosen, infectious risks differ. Venovenous ECMO therapy typically uses a femoral access site that

may carry an additional infectious risk because of higher contamination rates similar to the placement of femoral central lines.95 Several studies have investigated potential infections related to ECMO initiation. In a study by Aubron et al., the investigators found that 14.4% of 146 patients had a bloodstream infection related to ECMO cannulation within 8 days of the procedure.95 Although they showed that the only independent risk of perioperative infection was related to the patient’s present severity of illness, this is not in accordance with all studies as a risk factor. The independent relationship between patient severity before ECMO initiation and bloodstream infection occurrence is controversial, possibly because of the variations in design between studies, including differences in periods and methods used for assessing severity and patient populations. Similar to TAH, there are no published standardized prophylactic antibiotic strategies or associated infectious outcomes with their use during the initiation of ECMO therapy, but using cefazolin or cefuroxime (or vancomycin or clindamycin in penicillin-allergic patients) would be appropriate, especially in the setting of central cannulation. Cardiac Implantable Electronic Devices Cardiovascular implantable devices, including both PPDs (permanent pacemaker devices) and ICDs (implantable cardioverter-defibrillators), have increased in prevalence by at least 19% and 60%, respectively, since 1999,96 with more procedures being done in older patients with more comorbidities.96,97 As the overall patient age and acuity of these device recipients continues to increase, there is an increasing probability that critical care practitioners will provide care to this population after a new cardiac event while these patients are in the ICU. Two primary categories of infections are seen after CIED implantation: pocket infection and deeper infections. Pocket infection is a particular risk during CIED implantation and is most consistent with gram-positive bacteria, specifically S. aureus.98 Overall, infectious complications after CIEDs are relatively low in the perioperative

window, but infections after the implantation of these devices portend high morbidity, costs, and mortality up to 18% at 6 months.98 Like other cardiovascular devices, CIEDs have the risk of biofilm development, which can contribute antibiotic resistance.98 These devices can also become infected secondary to bacteremia or intraoperative contamination. To minimize the risk of perioperative infection with CIED placement, it is recommended to administer a parenteral antibiotic within 1 hour of the procedure. This is supported by findings from a double-blind randomized trial in which preoperative cefazolin had a postoperative infection rate of 0.63% compared with 3.28% without prophylaxis.99 Additional support for preoperative antibiotics can be seen in two multivariate analyses,100,101 both of which have shown preoperative antibiotics to have a protective effect against infections after CIED. A one-time dose of cefazolin or cefuroxime (vancomycin or clindamycin for β-lactam allergy) given within 1 hour of the procedure is sufficient prophylaxis before CIED placement.

Prophylaxis in Neurocritical Care Procedures Neurosurgical procedures are stratified into one of five categories according to a neurosurgical classification score investigated by Narotam and colleagues (Table 18.3).102 The classification system delineates variation in infectious risks according to the type of neurosurgical procedure. Clean neurosurgical procedures carry the lowest infection risk (1.9%–5.8%)102-104 if perioperative antimicrobial prophylaxis is used. The absence of antibiotic prophylaxis has been shown to increase the risk of postoperative infections by up to 10% in this patient population.103,104 Specific risk factors can compound the likelihood of postoperative infections in neurosurgical patients. Diabetes mellitus, emergency surgery, prolonged procedural times, cerebrospinal fluid (CSF) leaks, or the surgical placement of a foreign body increases the infection risk. Neurosurgical infectious complications are typically attributed to either superficial SSIs or the development of deeper central nervous system

(CNS) infectious such as meningitis, epidural abscesses, or subdural empyemas.105,106 Antimicrobial prophylaxis has resulted in lower postoperative infections when perioperative antibiotics are included in low-risk neurosurgical procedures. The American Society of HealthSystem Pharmacists and Society for Healthcare Epidemiology of America (SHEA) guidelines for surgical guidelines for antibiotic prophylaxis recommend a single dose of antibiotic within 60 minutes before the incision.3 There is no overall consensus on the choice of antibiotics in the neurosurgical population.107 Perioperative antibiotics should be directed at gram-positive organisms such as S. aureus and coagulase-negative staphylococcus, which account for most infectious insults.108,109 Gram-negative organisms are less commonly reported but are indicated in up to 20% of cases. Pseudomonas aeruginosa and other resistant gram-negative organisms’ prevalence is indicated in less than 5% of cases.104 Antibiotic selection should include an agent active against gram-positive organisms and ideally tailored to local resistant and susceptibility patterns. A common antimicrobial used for prophylaxis in neurosurgical procedures includes cefazolin, or vancomycin if severe allergy or if MRSA resistance rates are high at the individual institution.

Table 18.3 Narotam Classification of Neurosurgical Procedures Clean

Elective procedure under ideal operative conditions

Clean with foreign body implantation

All other criteria for a clean procedure with the placement of permanent or temporary foreign material, including shunt, intracranial monitory, reservoirs, or ventricular draining device

Cleancontaminated

Procedure with entry into the paranasal sinuses, cranial base fracture, surgery for greater than 2 hr, or breach in standard procedures

Contaminated

Contamination of operative site, compound skull fractures, open lacerations for greater than 4 hr, CSF leakage, or operation within the same incision site within the previous 4 wk

Dirty

Procedure occurring during sepsis at the time of operation; confounding infection including abscess, subdural empyema, ventriculitis, osteitis, or skin infection

Adapted from: Narotam PK, van Dellen JR, du Trevou MD, et al. Operative sepsis in neurosurgery: a method of classifying surgical cases. Neurosurgery 1994;34:409-15; discussion 415-6.

In addition to clean neurosurgical procedures, surgical procedures that involve the placement of foreign devices for intracranial monitoring or CSF shunting are common in the critically ill population.110 These devices have been indicated as specific risks of postoperative infection in the neurosurgical population.109,111,112 Intracranial Pressure (ICP) Monitoring and CSF Shunting Devices External ventricular drains are commonly used for CSF diversion from the cranial space as well as for intracranial pressure (ICP) monitoring in the setting of traumatic brain injury, intracranial hemorrhage, or hydrocephalus. Although these devices are used for monitoring and management, they portend infectious complications cumulating around 10%,113 with the incidence of infection increasing with prolonged ventricular catheterization.112,113 Similar to the microbiologic sources seen in the clean procedural infections, most pathogenic organisms are gram-positive cocci.113 Studies supporting the routine use of prophylactic antibiotics in these populations are equivocal. Retrospective analyses have shown no benefit with prophylactic antibiotics over no prophylaxis after ICP placement in infectious outcomes.112,114 The provision of broad-spectrum perioperative antibiotics (ceftriaxone or ciprofloxacin) has also not been advantageous versus narrow-spectrum antibiotics (cefazolin or vancomycin) after ICP placement.115 In addition, it has been shown that either broad-spectrum antibiotics or prolonged use of antibiotics may expose patients to resistant gram-negative organisms in future infections.114,115 To contrast these findings, however, two meta-

analyses have shown a reduction in infection rates using antibiotic prophylaxis in CSF shunting procedures.116,117 Antibiotic-impregnated shunts are available for use, but further data may be needed before universal use.3 Because of the high risk of complications associated with a CSF-related infection and available data, the SHEA surgical antibiotic guidelines committee gave a level A recommendation for a one-time preoperative dose of cefazolin before shunting procedures.3 Clindamycin and vancomycin are recommended for patients allergic to penicillin. Subdural Grids Subdural grid placement may occur in a select set of patients with a history of intractable antiepileptic medication-resistant epilepsy,118 which often requires close observation, possibly in a neuro-ICU. Placement of a subdural grid with depth electrodes for seizure foci identification is done by craniectomy. By definition, this is a clean procedure with a foreign body implantation and carries more than a minimal risk of perioperative infection as classified by Narotam et al.102 There currently are no guidelines or specific recommendations for antibiotic coverage during the placement and period of subdural grid. A meta-analysis involving 21 studies (20 retrospective) indicated that although the overall prevalence of neurologic infections is relatively low, they are the most commonly identified complication in these cases. Particular infectious insults were described as superficial surgical infections (3%), pyogenic neurologic infections (2.3%), and CSF bacterial colonization (7.1%). Thirteen of the 21 studies indicated that systemic antibiotics were administered, but the choice of antibiotics and duration of use were variable, with cephalosporins being the most likely used antibiotic class. Prophylaxis is extended for the duration of the subdural grid placement in most cases. Because of the paucity of randomized trials of antibiotic prophylaxis, a standard recommendation cannot be made at this time, but antibiotics with adequate CNS penetration that target superficial gram-positive flora such as cefazolin or cefotaxime would be reasonable while the subdural grid is in place.

Prophylaxis in Unique ICU Procedures Antibiotics at Intubation Patients who are intubated during their ICU stay have an increased risk of developing pneumonia. Ventilator-associated pneumonia (VAP) may occur in up to 15% of ventilated patients and portends worse outcomes such as longer length of stay, increased costs, and higher mortality rates.119 The estimated mortality associated with VAP may be as high as 10%.120 Identified risk factors for VAP include concurrent organ failure, age older than 60, prior antibiotic exposure, and failure to elevate the head of the bed after intubation.121 Although the inoculum responsible for VAP commonly comes from pathogens that are colonized in the oropharynx and upper GI tract, targeted bacteria should be based on a patient’s medical history, prior antibiotic exposure, and institutional microbial patterns.122 Specifically recommended prophylactic measures for VAP include the coordination of daily interruption of sedation and spontaneous breathing trials, incorporation of early mobility measures, use of noninvasive mechanically ventilation when possible, and changing of the ventilator circuit only when necessary.123 Although there is moderate evidence for using both prophylactic probiotics and chlorhexidine-based oral care in mechanically ventilated patients, evidence remains sparse describing the utility of prophylactic antibiotics during intubation or mechanical ventilation. Some trials have investigated the benefit of prophylactic antibiotics post-intubation. Cefuroxime given as prophylaxis for two doses after intubation had a protective effect against early-onset VAP in patients with head injury.124 Another prospective trial that studied the impact of a single dose of ceftriaxone, ertapenem, or levofloxacin given before intubation showed a reduction in the incidence of early-onset VAP. However, it showed no benefit regarding late-onset VAP, tracheobronchitis, or mortality.125 Neither of these single-center trials assessed the impact on developing resistant pathogens, possibly

overlooking any ramification on antimicrobial stewardship efforts. The SHEA guidelines do not address the utility of prophylactic antibiotics in VAP.123 Because of the absence of larger multicenter randomized trials, the delivery of prophylactic antibiotics at intubation cannot be recommended. Nasal Packing Although epistaxis is a relatively normal occurrence at some point in a patient’s lifetime, only 6% of these events result in the need for medical attention,126 and many bleeding events occurring in the anterior septum are self-limiting. For the patients who have bleeding events that require nasal packing, however, there may be a need for more aggressive management and closer observation, occasionally in the ICU. Complications that can ensue after nasal packing include aspiration, angina, myocardial infarction, respiratory distress, and hypoxia.126-128 Patients with nasal packing are also at an increased risk of toxic shock syndrome (TSS), an insult that is rapidly precipitated after toxin production by colonized S. aureus in the nasal membranes. Although the rate of TSS is reportedly low in postoperative nasal packing (16 per 100,000 packings), antibiotics are routinely prescribed to these patients.129 However, there has been no clear evidence that using antibiotics reduces the rate of S. aureus infection, rates of nasal colonization, or episodes of TSS.130-132 Antimicrobial prophylaxis may not be necessary for TSS prophylaxis in the setting of nasal packing, but if used, agents that have antistaphylococcal activity such as amoxicillin/clavulanate 500 mg orally three times daily or cephalexin 500 mg orally twice daily could be considered for the duration of the nasal packing.

SUMMARY Because of the increased risk of adverse events attributed to SSIs, adherence to antimicrobial prophylactic strategies in the critically ill population is of paramount importance and should be directed by best practices. Pharmacists practicing in an ICU environment should be

aware of the surgical risks and necessary precautions to minimize poor outcomes in many unique surgical and non-surgical scenarios. Various recommendations have been provided throughout this chapter according to the available evidence and guidelines, but the chapter does not provide insight into all potential ICU procedures or infectious events. However, this chapter can serve as a guide to the ICU clinician when fully elucidated recommendations may not be available in other available guidelines.

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48. Nolla-Salas J, Sitges-Serra A, Leon-Gil C, et al. Candidemia in non-neutropenic critically ill patients: analysis of prognostic factors and assessment of systemic antifungal therapy. study group of fungal infection in the ICU. Intensive Care Med 1997;23:23-30. 49. Leroy O, Gangneux JP, Montravers P, et al. Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005-2006). Crit Care Med 2009;37:1612-8. 50. Michalopoulos AS, Geroulanos S, Mentzelopoulos SD. Determinants of candidemia and candidemia-related death in cardiothoracic ICU patients. Chest 2003;124:2244-55. 51. Dupont H, Bourichon A, Paugam-Burtz C, et al. Can yeast isolation in peritoneal fluid be predicted in intensive care unit patients with peritonitis? Crit Care Med 2003;31:752-7. 52. Paphitou NI, Ostrosky-Zeichner L, Rex JH. Rules for identifying patients at increased risk for candidal infections in the surgical intensive care unit: approach to developing practical criteria for systematic use in antifungal prophylaxis trials. Med Mycol 2005;43:235-43. 53. Leon C, Ruiz-Santana S, Saavedra P, et al. Usefulness of the “candida score” for discriminating between Candida colonization and invasive candidiasis in non-neutropenic critically ill patients: a prospective multicenter study. Crit Care Med 2009;37:1624-33. 54. Ostrosky-Zeichner L, Sable C, Sobel J, et al. Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting. Eur J Clin Microbiol Infect Dis 2007;26:271-6. 55.. Wey SB, Mori M, Pfaller MA, et al. Risk factors for hospitalacquired candidemia. A matched case-control study. Arch Intern Med 1989;149:2349-53. 56. Pittet D, Monod M, Suter PM, et al. Candida colonization and subsequent infections in critically ill surgical patients. Ann Surg

1994;220:751-8. 57. Eggimann P, Francioli P, Bille J, et al. Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients. Crit Care Med 1999;27:1066-72. 58. Playford EG, Webster AC, Sorrell TC, et al. Antifungal agents for preventing fungal infections in non-neutropenic critically ill and surgical patients: systematic review and meta-analysis of randomized clinical trials. J Antimicrob Chemother 2006;57:62838. 59. Cruciani M, de Lalla F, Mengoli C. Prophylaxis of Candida infections in adult trauma and surgical intensive care patients: a systematic review and meta-analysis. Intensive Care Med 2005;31:1479-87. 60. Shorr AF, Chung K, Jackson WL, et al. Fluconazole prophylaxis in critically ill surgical patients: a meta-analysis. Crit Care Med 2005;33:1928-35; quiz 1936. 61. Pelz RK, Hendrix CW, Swoboda SM, et al. Double-blind placebocontrolled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg 2001;233:542-8. 62. Eggimann P, Francioli P, Bille J, et al. Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients. Crit Care Med 1999;27:1066-72. 63. Bow EJ, Evans G, Fuller J, et al. Canadian clinical practice guidelines for invasive candidiasis in adults. Can J Infect Dis Med Microbiol 2010;21:e122-50. 64. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48:503-35. 65. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis

2009;48:503-35. 66. Kanafani ZA, Perfect JR. Antimicrobial resistance: resistance to antifungal agents: mechanisms and clinical impact. Clin Infect Dis 2008;46:120-8. 67. Ostrosky-Zeichner L, Shoham S, Vazquez J, et al. MSG-01: a randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting. Clin Infect Dis 2014;58:1219-26. 68. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009;15:1143-238. 69. Metzger KE, Rucker Y, Callaghan M, et al. The burden of mucosal barrier injury laboratory-confirmed bloodstream infection among hematology, oncology, and stem cell transplant patients. Infect Control Hosp Epidemiol 2015;36:119-24. 70. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: prevention and treatment of cancer-related infection. Updated 2015. Available at http://www.nccn.org/​professionals/physician_gls/​pdf/infecti​ ons.pdf. Accessed October 22, 2015. 71. Akhtari M, Curtis B, Waller EK. Autoimmune neutropenia in adults. Autoimmun Rev 2009;9:62-6. 72. Nossent JC, Swaak AJ. Prevalence and significance of haematological abnormalities in patients with systemic lupus erythematosus. Q J Med 1991;80:605-12. 73. 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. 74. Bodey GP, Buckley M, Sathe YS, et al. Quantitative relationships

between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966;64:328-40. 75. Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993;328:1323-32. 76. Wisplinghoff H, Seifert H, Wenzel RP, et al. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis 2003;36:1103-10. 77. 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. 78. Bucaneve G, Micozzi A, Menichetti F, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med 2005;353:977-87. 79. Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med 2005;353:988-98. 80. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361:2241-51. 81. Kirklin JK, Naftel DC, Pagani FD, et al. Sixth INTERMACS annual report: a 10,000-patient database. J Heart Lung Transplant 2014;33:555-64. 82. Gordon RJ, Quagliarello B, Lowy FD. Ventricular assist devicerelated infections. Lancet Infect Dis 2006;6:426-37. 83. Feldman D, Pamboukian SV, Teuteberg JJ, et al. The 2013 International Society for Heart and Lung Transplantation guidelines for mechanical circulatory support: executive summary. J Heart Lung Transplant 2013;32:157-87. 84. Gordon SM, Schmitt SK, Jacobs M, et al. Nosocomial bloodstream infections in patients with implantable left ventricular

assist devices. Ann Thorac Surg 2001;72:725-30. 85. Gristina AG, Dobbins JJ, Giammara B, et al. Biomaterialcentered sepsis and the total artificial heart. Microbial adhesion vs tissue integration. JAMA 1988;259:870-4. 86. Shoham S, Miller LW. Cardiac assist device infections. Curr Infect Dis Rep 2009;11:268-73. 87. Acharya MN, Som R, Tsui S. What is the optimum antibiotic prophylaxis in patients undergoing implantation of a left ventricular assist device? Interact Cardiovasc Thorac Surg 2012;14:209-14. 88. Eyler RF, Butler SO, Walker PC, et al. Vancomycin use during left ventricular assist device support. Infect Control Hosp Epidemiol 2009;30:484-6. 89. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001;345:1435-443. 90. Holman WL, Park SJ, Long JW, et al. Infection in permanent circulatory support: experience from the REMATCH trial. J Heart Lung Transplant 2004;23:1359-65. 91. Copeland JG, Smith RG, Arabia FA, et al. Cardiac replacement with a total artificial heart as a bridge to transplantation. N Engl J Med 2004;351:859-67. 92. Roussel JC, Senage T, Baron O, et al. CardioWest (jarvik) total artificial heart: a single-center experience with 42 patients. Ann Thorac Surg 2009;87:124-9; discussion 130. 93. Copeland JG, Copeland H, Gustafson M, et al. Experience with more than 100 total artificial heart implants. J Thorac Cardiovasc Surg 2012;143:727-34. 94. Aubron C, Cheng AC, Pilcher D, et al. Factors associated with outcomes of patients on extracorporeal membrane oxygenation support: a 5-year cohort study. Crit Care 2013;17:R73. 95. Aubron C, Cheng AC, Pilcher D, et al. Infections acquired by

adults who receive extracorporeal membrane oxygenation: risk factors and outcome. Infect Control Hosp Epidemiol 2013;34:2430. 96. Zhan C, Baine WB, Sedrakyan A, et al. Cardiac device implantation in the united states from 1997 through 2004: a population-based analysis. J Gen Intern Med 2008;23(suppl 1):13-9. 97. Uslan DZ, Tleyjeh IM, Baddour LM, et al. Temporal trends in permanent pacemaker implantation: a population-based study. Am Heart J 2008;155:896-903. 98. Baddour LM, Epstein AE, Erickson CC, et al. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation 2010;121:458-77. 99. de Oliveira JC, Martinelli M, Nishioka SA, et al. Efficacy of antibiotic prophylaxis before the implantation of pacemakers and cardioverter-defibrillators: results of a large, prospective, randomized, double-blinded, placebo-controlled trial. Circ Arrhythm Electrophysiol 2009;2:29-34. 100. Klug D, Balde M, Pavin D, et al. Risk factors related to infections of implanted pacemakers and cardioverter-defibrillators: results of a large prospective study. Circulation 2007;116:1349-55. 101. Sohail MR, Uslan DZ, Khan AH, et al. Risk factor analysis of permanent pacemaker infection. Clin Infect Dis 2007;45:166-73. 102. Narotam PK, van Dellen JR, du Trevou MD, et al. Operative sepsis in neurosurgery: a method of classifying surgical cases. Neurosurgery 1994;34:409-15; discussion 415-6. 103. Barker FG II. Efficacy of prophylactic antibiotics against meningitis after craniotomy: a meta-analysis. Neurosurgery 2007;60:887-94; discussion 887-94. 104. Korinek AM, Golmard JL, Elcheick A, et al. Risk factors for neurosurgical site infections after craniotomy: a critical reappraisal

of antibiotic prophylaxis on 4,578 patients. Br J Neurosurg 2005;19:155-62. 105. Borges LF. Infections in neurologic surgery. host defenses. Neurosurg Clin North Am 1992;3:275-8. 106. McClelland S III, Hall WA. Postoperative central nervous system infection: incidence and associated factors in 2111 neurosurgical procedures. Clin Infect Dis 2007;45:55-9. 107. Hosein IK, Hill DW, Hatfield RH. Controversies in the prevention of neurosurgical infection. J Hosp Infect 1999;43:5-11. 108. Korinek AM, Baugnon T, Golmard JL, et al. Risk factors for adult nosocomial meningitis after craniotomy: role of antibiotic prophylaxis. Neurosurgery 2006;59:126-33; discussion 126-33. 109. Lietard C, Thebaud V, Besson G, et al. Risk factors for neurosurgical site infections: an 18-month prospective survey. J Neurosurg 2008;109:729-34. 110. Curry WT Jr, Butler WE, Barker FG II. Rapidly rising incidence of cerebrospinal fluid shunting procedures for idiopathic intracranial hypertension in the United States, 1988-2002. Neurosurgery 2005;57:97-108; discussion 97-108. 111. Korinek AM, Baugnon T, Golmard JL, et al. Risk factors for adult nosocomial meningitis after craniotomy: role of antibiotic prophylaxis. Neurosurgery 2008;62(suppl 2):532-9. 112.. Rebuck JA, Murry KR, Rhoney DH, et al. Infection related to intracranial pressure monitors in adults: analysis of risk factors and antibiotic prophylaxis. J Neurol Neurosurg Psychiatry 2000;69:381-4. 113. Lozier AP, Sciacca RR, Romagnoli MF, et al. Ventriculostomyrelated infections: a critical review of the literature. Neurosurgery 2008;62(suppl 2):688-700. 114. Alleyne CH Jr, Hassan M, Zabramski JM. The efficacy and cost of prophylactic and perioprocedural antibiotics in patients with

external ventricular drains. Neurosurgery 2000;47:1124-7; discussion 1127-9. 115. May AK, Fleming SB, Carpenter RO, et al. Influence of broadspectrum antibiotic prophylaxis on intracranial pressure monitor infections and subsequent infectious complications in head-injured patients. Surg Infect (Larchmt) 2006;7:409-17. 116. Langley JM, LeBlanc JC, Drake J, et al. Efficacy of antimicrobial prophylaxis in placement of cerebrospinal fluid shunts: metaanalysis. Clin Infect Dis 1993;17:98-103. 117. Haines SJ, Walters BC. Antibiotic prophylaxis for cerebrospinal fluid shunts: a meta-analysis. Neurosurgery 1994;34:87-92. 118. Hedegard E, Bjellvi J, Edelvik A, et al. Complications to invasive epilepsy surgery workup with subdural and depth electrodes: a prospective population-based observational study. J Neurol Neurosurg Psychiatry 2014;85:716-20. 119. Klompas M, Branson R, Eichenwald EC, et al. Strategies to prevent ventilator-associated pneumonia in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014;35:915-36. 120. Melsen WG, Rovers MM, Koeman M, et al. Estimating the attributable mortality of ventilator-associated pneumonia from randomized prevention studies. Crit Care Med 2011;39:2736-42. 121. Kollef MH. Ventilator-associated pneumonia. A multivariate analysis. JAMA 1993;270:1965-70. 122. Park DR. The microbiology of ventilator-associated pneumonia. Respir Care 2005;50:742-63; discussion 763-5. 123. Klompas M, Branson R, Eichenwald EC, et al. Strategies to prevent ventilator-associated pneumonia in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014;35:915-36. 124. Sirvent JM, Torres A, El-Ebiary M, et al. Protective effect of intravenously administered cefuroxime against nosocomial pneumonia in patients with structural coma. Am J Respir Crit Care

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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

LEARNING OBJECTIVES 1. Identify risk factors for seizures in critically ill patients. 2. Recommend appropriate dosing and monitoring of urgent and emergent therapy. 3. Compare and contrast antiepileptic agents used in the management of status epilepticus (SE). 4. Customize drug therapy management in special populations with altered pharmacokinetic parameters. 5. Develop a patient-specific treatment algorithm for the management of refractory SE in intubated and non-intubated patients.

ABBREVIATIONS IN THIS CHAPTER cEEG

Continuous electroencephalogram

EEG

Electroencephalogram

GABA

γ-Aminobutyric acid

ICU

Intensive care unit

NCSE

Non-convulsive status epilepticus

NMDA

N-methyl-d-aspartate

RSE

Refractory status epilepticus

SE

Status epilepticus

TH

Therapeutic hypothermia

INTRODUCTION Seizures are a serious medical complication of the central nervous system (CNS) that can lead to considerable morbidity and mortality. They can occur along a spectrum of syndromes, from the focal seizure to status epilepticus (SE), which in turn can evolve into refractory status epilepticus (RSE) and super-refractory status epilepticus. Most isolated seizures are self-resolving, but any seizure that persists beyond 5 minutes or a series of seizures between which a patient does not regain consciousness should be considered SE.1 In intensive care units (ICUs), this diagnosis may be difficult to make because of severe underlying neurological disease or drugs that may mask outward signs of seizures. Although outcomes are improved with faster identification and timely pharmacologic treatment, clinicians are still challenged by the hemodynamic instability, numerous drug interactions, and end-organ dysfunction often seen in critically ill patients. Several guidelines have been published to help promote evidence-based practice,2,3 but the ICU remains a challenging area. Use of published algorithms and pathways and development of institutional protocols can expedite treatment to terminate SE. This chapter will focus on the treatment of SE in critically ill patients with a brief discussion of the role of seizure prophylaxis. The goals of therapy for SE are to (1) rapidly terminate seizure activity, both

physiologic and electrographic; (2) identify and treat the cause, if possible; and (3) prevent future seizures, if needed, with the appropriate use of anticonvulsants.

EPIDEMIOLOGY A recent study described the epidemiology of SE in the United States over 12 years.4 Although an increase in incidence was seen (3.5–12.5 per 100,000), there was no change for in-hospital mortality. This increased incidence may have occurred partly because of the change in definition of SE as well as increased use of electroencephalogram (EEG) monitoring and, therefore, SE diagnosis during the past decade.5 A higher incidence of SE was seen at each end of the age spectrum (younger than 10 years and older than 50 years), but inhospital mortality was much higher for older adults than for children (20.2% vs. 2.6%). Men have higher incidence and mortality rates than do women; men also have SE at a younger age. Racial disparities are seen in SE, with a higher incidence among blacks (13.7 per 100,000) than among whites (6.9 per 100,000), although in-hospital mortality rates are higher for whites (10%; 95% CI, 9.8–10) than for blacks (7.4%; 95% CI, 7.3–7.6). The number of patients discharged to home declined over time, whereas discharge to long-term care facilities almost doubled. Most seizures occurring in ICU patients are convulsive in nature— around 90% in a recent series of medical and surgical patients,6 although 50% of these patients had a history of epilepsy. Hospital mortality was reported to be 21% and was highly predicted by age, lower Glasgow Coma Scale score at baseline, and severity of SE. Treatment of SE in a neuro-ICU versus a medical ICU did not result in decreased mortality or morbidity or a shorter length of stay,7 although the use of continuous electroencephalogram (cEEG) monitoring was greater in the neuro-ICU. Mortality for SE has been reported to be around 4% for inpatients with generalized tonic-clonic SE.8 Additional mortality risk factors include mechanical ventilation, female sex, comorbidity index, and

anoxic brain injury. Other cohort studies report higher case fatality rates of around 22%, but they include all types of SE. Increasing age and anoxic brain injury continue to be driving contributors for death after SE and are commonly seen in ICU patients. Status epilepticus after CNS infection also confers a poor prognosis. Patients without epilepsy who develop SE tend to have worse outcomes.9

ETIOLOGY Seizures in the ICU can arise from existing neurological conditions or as a complication of systemic illness (see Table 19.1). Neurotrauma, stroke, CNS infections or tumors, and epilepsy are common neurological etiologies of SE. Hypoxia, substance abuse/toxicity, drugdrug interactions, renal or hepatic dysfunction, and acute metabolic disturbances may also lead to the development of SE in the critically ill patient. Electrolyte imbalances are common in ICU patients, and acute fluctuations in sodium, calcium, and magnesium can lead to seizure activity.10 Drugs may also be implicated in acute seizures. Bupropion, diphenhydramine, tricyclic antidepressants, tramadol, amphetamines, isoniazid, and venlafaxine have all been implicated in seizures or SE in overdose cases.11 A clinical tool was recently developed to aid clinicians in evaluating potential etiologies in patients with SE,12 which may result in more timely treatment and resolution. The most common determinants for SE included subtherapeutic anticonvulsant concentrations, brain tumors, acute intracerebral hemorrhage, history of epilepsy, infection (both CNS and systemic), traumatic brain injury, alcohol withdrawal/intoxication, and benzodiazepine withdrawal.

Table 19.1 Etiology and Selected Prevalence and Mortality in Status Epilepticus

aData

from: Dham BS, Hunter K, Rincon F. The epidemiology of status epilepticus in the United States. Neurocrit Care 2014;20:476-83. bData

from: Rowe AS, Goodwin H, Brophy GM, et al. Seizure prophylaxis in neurocritical care: a review of evidence-based support. Pharmacotherapy 2014;34:396-409. AED = antiepileptic drug.

PATHOPHYSIOLOGY Traditionally, the cause of SE has been described as an imbalance of excitatory and inhibitory neurotransmitter activity in the CNS. It may be a condition of excess excitation, insufficient inhibition, or a combination of both. Clinically, it is difficult to differentiate, but current treatments focus on increasing overall inhibitory activity. Glutamate, substance P, and neurokinin B are the more common excitatory neurotransmitters, whereas γ-aminobutyric acid (GABA) and neuropeptide Y moderate neuronal inhibition. Most isolated seizures occur when inhibitory

mechanisms are transiently overwhelmed. Glutamate normally produces depolarization of neurons through its effects on postsynaptic N-methyl-d-aspartate (NMDA) and α-amino-3hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptors. γaminobutyric acid mediates postsynaptic hyperpolarization through the opening of chloride channels. More recent literature has shed light on additional mechanisms and potential treatment strategies.13 An alteration in GABA activity over time may explain the refractoriness of GABA-ergic drugs as SE progresses.14,15 Internalization of synaptic GABAA receptors has been reported to increase with ongoing seizure activity, resulting in the decreased efficacy of benzodiazepines as well as other GABA-ergic drugs.16 Clinically, this pharmacoresistance begins soon after seizures begin, persists beyond 30 minutes, and may contribute to increased morbidity in these patients because of delayed diagnosis and proper intervention. Use of benzodiazepines early on in SE may be successful, but response quickly declines as time progresses between onset and treatment.17 This highlights the importance of rapidly identifying seizure activity with immediate administration of benzodiazepines to optimize control, followed by urgent and refractory treatments as necessary. Distinct physiological phases are seen with classic generalized tonicclonic SE. Within 10 minutes of seizure activity (early or phase I), increases in serum concentrations of norepinephrine and epinephrine as well cortisol can be seen, leading to cardiovascular hyperactivity (e.g., hypertension, tachycardia, and arrhythmias), fever, and hyperglycemia.18 Prolonged muscle contraction from uncontrolled tonicclonic convulsions results in lactic acid production, and subsequent acidosis can be severe. Normally, this resolves once convulsions stop, but in critically ill patients with an underlying acidosis from other conditions or compromised tissue perfusion, it may persist and warrant further therapy. After 30 minutes of continuous seizing (late or phase II), systems begin to fail as compensatory mechanisms are overwhelmed. Hypotension, bradycardia, and hypoglycemia can be seen; cerebral perfusion pressure is compromised as mean arterial pressure falls,

whereas cerebral demand remains high because of unrelenting electrical activity. In critically ill patients with poor reserve or unrecognized SE, this phase may occur earlier and require emergent treatment. Unrelenting tonic-clonic activity can lead to rhabdomyolysis and subsequent renal failure.19

DIAGNOSIS Timely clinical identification of SE is important because of the timesensitive response of treatment strategies. Most generalized seizures in the ICU are well recognized,20 but it can be difficult to detect subtle seizure types such as non-convulsive status epilepticus (NCSE) where the traditional tonic-clonic movements of the extremities are not visibly apparent (Table 19.2). A cEEG is a useful tool in these cases to help identify such patients and direct therapy. Any unexplained acute changes in mental status should be investigated with EEG for evidence of seizure activity. Patients who lack response to drug therapy will also benefit from EEG monitoring. Figure 19.1 and Figure 19.2 represent EEG findings in patients with convulsive and non-convulsive seizures, respectively.

Table 19.2 Clinical Features of Seizures Seizure Type

Physical Findings

Sensorium

Focal motor

Focal facial or limb twitching

No alteration

Complex partial

Automatisms/involuntary activity

Disturbed

Generalized tonic-clonic

Generalized convulsions

Loss of consciousness

Non-convulsive status epilepticus

No twitching/convulsions

Altered sensorium or loss of consciousness

PROPHYLAXIS For patients with known risk factors for seizures, prophylactic therapy can reduce the risk of SE. In patients with provoked SE, it is essential to treat both the seizure and the underlying cause. For some ICU patients, it may be difficult to assess the cause of the SE because of several risk factors and difficulty in identifying the exact onset of the seizure activity. Some etiologies such as anoxic brain injury, most commonly seen after cardiac arrest, are more difficult to treat and tend to have poorer outcomes.20 Certain ICU patients at high risk of seizures should receive shortterm prophylaxis (e.g., traumatic brain injury and aneurysmal subarachnoid hemorrhage; see Table 19.1). Guidelines have been published to identify high-risk populations, describe the risk of seizures after brain injury, and recommend suitable timing of therapy.21 Seizures, and potentially SE, may occur in these patients if dosing is not optimized, prophylaxis is not initiated in a timely manner, or therapy is interrupted or inadvertently altered (e.g., drug interactions). Prophylaxis should only be provided during the high-risk period and discontinued afterward unless actual seizures occur because these agents are not without considerable adverse effects. ICU patients who are pharmacologically sedated and paralyzed should remain on seizure prophylaxis until these agents are cleared systemically because of the possible masking of any physiologic signs of seizures unless cEEG monitoring can confirm the absence of seizure activity.

TREATMENT The treatment of SE is complex, often requiring the use of multiple agents, drugs with narrow therapeutic indexes, aggressive dosing targeting higher serum concentrations, and frequent titrations to a goal of seizure cessation. Although a variety of treatment options are available, evidence is lacking to support one treatment strategy over another. Many of the current treatment data are from non-randomized, retrospective studies that have small sample sizes and lack standardized dosing strategies and treatment durations. Newer

anticonvulsants have easier, non–weight-based dosing, fewer drug interactions, and better adverse event profiles. Although they may be more desirable, the data surrounding their use, particularly as first-line agents, are less robust than for historical agents. These agents were also excluded from many of the earlier comparator trials.22 Regardless of which drugs are selected, the primary treatment goal remains the same: cessation of seizures, including clinical and subclinical (electrographic) seizures. Management of airway, breathing, and circulation should occur simultaneously with targeted treatment for SE. Other goals include achievement of therapeutic drug concentrations, liberation from mechanical ventilation (particularly if the initial treatment required respiratory support), identification and treatment of the underlying cause, and selection of regimens that produce acceptable adverse effect profiles. Emergent therapy should be initiated within the first 5 minutes of seizure onset and urgent control treatment, immediately after or within the first 10 minutes of seizure onset.3

Figure 19.1 EEG of patient with tonic-clonic seizures. Normal brain waves are seen initially followed by evidence of seizure activity.

It is important to be familiar with all available agents so that an individualized, stepwise approach to the treatment of SE can be selected. Pharmacologic options may be classified as emergent, urgent, and refractory and are generally initiated in this order, although sometimes, the addition of a drug or the titration of a continuous infusion occurs simultaneously. Table 19.3 describes the most commonly used drugs for SE.

Emergent Initial Treatment: Benzodiazepines Benzodiazepines, GABA receptor agonists, are considered first-line agents in the treatment of SE. Lorazepam, midazolam, and diazepam are the most commonly used benzodiazepines, and all are available intravenously. When used emergently for SE, intravenous benzodiazepine administration is preferred; however, nasal, buccal, or rectal routes are acceptable alternative routes of administration.3 Historically, drugs such as midazolam and diazepam were preferred for their ability to quickly cross the blood-brain barrier; however, they carry a risk of rebound seizures because of their rapid redistribution out of the brain and into adipose tissue.23 Intravenous lorazepam, a less lipophilic benzodiazepine than diazepam, is the preferred first-line treatment for SE.3,22,24 A randomized trial comparing lorazepam (2–4 mg), diazepam (5–10 mg), and placebo for out-of-hospital SE found an SE termination rate of 59%, 43%, and 21%, respectively. Although the only statistically significant difference was between both benzodiazepines and the placebo group, there was a trend toward faster termination and better control of SE in the lorazepam group.25 Another study found numerically better success rates with lorazepam 2 mg over diazepam 5 mg (78% vs. 58% seizure termination after one dose), but the results were not statistically significant. Similar results were seen after two doses of each drug; a total of 4 mg of lorazepam and 10 mg of diazepam terminated seizures in 89% and 76%, respectively.26 The VA Cooperative Trial compared four different treatment regimens (lorazepam, phenobarbital, diazepam plus

phenytoin, and phenytoin) and found that lorazepam was more successful than phenytoin in overt status cases (64.9% vs. 43.6%; p=0.002). Because of the formulation of lorazepam and diazepam with propylene glycol, midazolam is the preferred agent when given intramuscularly. In a randomized controlled trial, midazolam 10 mg intramuscularly was found as effective as lorazepam 4 mg intravenously for prehospital seizure control.27 Diazepam is preferred for rectal administration, although this route should only be used when intravenous and intramuscular options are unavailable or contraindicated.3 Although respiratory depression is a concern with benzodiazepine administration, studies have shown no difference in respiratory depression compared with placebo and nonbenzodiazepines when administered for SE.22,25

Urgent Control Treatment Urgent treatment uses non-benzodiazepine anticonvulsants. Drugs are initiated in a stepwise fashion and quickly titrated to therapeutic doses. No prospective, comparative data past the first benzodiazepine and non-benzodiazepine drug combination suggest the superiority of any third-line agent. Because of the suboptimal success rate with second and third anticonvulsants, some prescribers opt to skip urgent control treatment and move directly to continuous infusions, whereas others may initiate anticonvulsants concurrently with continuous infusions. Regardless, most prescribers will at least administer one anticonvulsant after the initial benzodiazepine before ordering a continuous infusion.28 This option is especially desirable in nonintubated patients who may benefit from a trial of anticonvulsants in order to avoid the intubation required for most anesthetic infusions. Urgent therapy with anticonvulsants often requires bolus dosing, rapid and aggressive titration, and, at times, addition of several drugs concomitantly or in rapid succession. Dose adjustments for renal or hepatic dysfunction are not required for loading doses. Because treatment delays of greater than 30 minutes are associated with a delayed response, the initiation and titration of urgent therapy should

occur rapidly.29 Commonly used agents are detailed in the following sections and are listed in descending order according to the amount of data surrounding their use.

Figure 19.2 EEG of non-convulsive status epilepticus.

Table 19.3 Treatment Summary Chart

CI = continuous infusion; ICP = intracranial pressure; IM = intramuscular(ly); IV = intravenous(ly); NS = normal saline; PgP = p-glycoprotein; PO = oral(ly); PRIS = propofolrelated infusion syndrome; q = every; TDC = target drug concentration. Adapted from: Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3-23; Tanaka E. Clinically significant pharmacokinetic drug interactions with benzodiazepines. J Clin Pharm Ther 1999;24:347-55. Tanaka E. Clinically significant pharmacokinetic drug interactions between antiepileptic drugs. J Clin Pharm Ther 1999;24:87-92; Limdi NA, Shimpi AV. Faught E. et al. Efficacy of rapid IV administration of valproic acid for status. Neurology 2005;64:353-5.

Phenytoin/Fosphenytoin Phenytoin is one of the most commonly studied drugs in the treatment of SE. Phenytoin is a substrate of cytochrome P450 (CYP) 2C19 (major), 2C9 (minor), and 3A4 (minor) as well as a potent CYP3A4, CYP2C19, and CYP2C9 PgP inducer. Because of its interference with major metabolic enzymes, phenytoin is associated with several drug interactions and can decrease concentrations of drugs that are

commonly coadministered in the ICU such as quetiapine, midazolam, methadone, nimodipine, and atorvastatin. Additional interactions occur with other highly protein-bound agents. Co-administration with warfarin may result in increased serum concentration of each drug. Because of its effects on sodium channels, phenytoin is considered a class 1B antiarrhythmic, and it can lead to arrhythmias and hemodynamic instability. It is formulated with propylene glycol, which further potentiates its risk of hypotension, especially with faster administration rates. Thus, the rate of administration is limited to 50 mg/minute or less. Fosphenytoin, a prodrug of phenytoin, is often preferred to phenytoin because it is not stabilized with propylene glycol and can be administered at a faster maximum rate of 150 mg/minute. The less basic pH of the formulation decreases the risk of purple glove syndrome and phlebitis compared with phenytoin and allows for intramuscular administration. Whereas phenytoin is only compatible with normal saline, fosphenytoin is compatible with many diluents, including 5% dextrose. Phenytoin and fosphenytoin both carry other significant adverse effects including thrombocytopenia, leukopenia, and hepatotoxicity. Phenytoin follows Michaelis-Menten kinetics, which requires thoughtful dose titration because small increases in dose may result in large, nonlinear increases in serum concentrations. For example, a simple doubling of the dose may lead to an exponentially higher-thanexpected drug concentration, increasing the risk of toxicity. In addition, high serum concentrations may take days or weeks to return to the therapeutic or desired range because of phenytoin’s long half-life, which is concentration-dependent. Phenytoin is highly protein bound, and free serum concentrations may be needed to properly assess phenytoin concentrations in patients who are critically ill or otherwise hypoalbuminemic. Although correction equations exist to adjust for low albumin, studies have found conflicting results regarding their accuracy in estimating true free concentrations.30,31 Valproic Acid

Although less commonly used than phenytoin, valproic acid is another commonly studied second-line anticonvulsant. Valproic acid has shown efficacy comparable with phenytoin in SE.32,33 A meta-analysis of benzodiazepine-resistant SE assessed the relative efficacy of anticonvulsants in patients who did not respond to benzodiazepines and found the mean efficacy of valproate to be 75.5% compared with phenytoin (50.2%), levetiracetam (68.5%), and phenobarbital (73.6%).34 Valproic acid has many adverse effects, including hepatotoxicity, pancreatitis, hyperammonemia, and thrombocytopenia, but it lacks the cardiac toxicity associated with phenytoin. It affects the metabolism of other CYP substrates through its inhibition of CYP2C9, resulting in increased concentrations of CYP2C9 substrates. Valproic acid can displace phenytoin from protein binding sites as well as inhibit its hepatic metabolism,35 warranting a close follow-up with free serum concentrations of both drugs to optimize efficacy. Several drugs may also affect valproate acid concentrations through interactions not directly related to the CYP hepatic enzymes. Of note, carbapenems can significantly decrease valproic acid concentrations, often making it challenging to reach therapeutic targets. This combination should be avoided whenever possible when treating SE. Valproic acid concentrations should be monitored routinely, particularly at initiation of therapy, with dosage changes, and when interacting drugs are concomitantly used. Free concentrations of phenytoin are more readily available than for valproic acid, which is also known to be highly protein bound. In these cases, it is helpful to assess the serum albumin concentration as well as the free phenytoin to total phenytoin fraction (for patients receiving both agents) to help interpret total valproic acid concentrations. For instance, a patient with low albumin, a subtherapeutic total phenytoin concentration, and a therapeutic free phenytoin concentration may be expected to have a higher free valproic acid concentration (active drug) than generally observed. This may help prevent unnecessary rebolusing and dose escalations for patients with resolving SE in whom dose de-escalation is warranted.

Phenobarbital Phenobarbital is a barbiturate that exerts an effect by its actions on GABA receptors, but at a different subunit from where benzodiazepines act. In the VA Cooperative Trial, its efficacy was similar to that of lorazepam; however, it is rarely administered as a first-line agent.22 Its long half-life, drug interactions, and adverse effect profile (i.e., sedation) make it less desirable than the alternatives for urgent control treatment. Accumulation of phenobarbital can occur after repeated doses, making it difficult to assess a patient’s neurological examination, even after doses have been tapered or weaned off completely. Phenobarbital is a reasonable option for patients who require third-line therapy but are not yet eligible for a continuous infusion, such as patients without ventilator support or those who are outside an ICU setting. Levetiracetam The use of levetiracetam for SE has grown in recent years because of the availability of an intravenous formulation. It offers advantages over historical agents in being easy to dose (non–weight-based dosing) and free of significant drug interactions. It does not require therapeutic drug concentration monitoring, has very low protein binding, and does not cause respiratory depression. Some laboratories will report drug concentrations for levetiracetam; although a therapeutic range has been recommended, it has not been correlated with therapeutic outcomes in SE.36 Thus, the role of levetiracetam monitoring is unclear in the general population; however, it may be considered in patients with pharmaco-kinetic alterations such as obesity and continuous renal replacement therapy. In addition, levetiracetam concentrations may be helpful in assessing adherence in patients who were prescribed levetiracetam and present with breakthrough seizures. Levetiracetam can be titrated quickly, and doses higher than those used in chronic epilepsy have been safely used in SE. For these reasons, it has become a staple of urgent control treatment regimens.3 One study randomized 44 patients with SE to phenytoin intravenously (20 mg/kg)

or levetiracetam intravenously (20 mg/kg) after administration of lorazepam 0.1 mg/kg intravenously. In patients receiving phenytoin versus levetiracetam, there was no difference in clinical termination of seizure activity within 30 minutes (68.2% vs. 59.1%), seizure recurrence within 24 hours (72.7% vs. 59.1%), adverse effects (9.1% vs. 0%), need for mechanical ventilation (27.3% vs. 18.2%), or mortality (9.1% vs. 9.1%).37 Another study retrospectively compared phenytoin, valproic acid, and levetiracetam as second-line agents for SE. In 167 patients, 198 seizure episodes were identified, and treatment failures were reported in 25%, 41%, and 48% of valproic acid, phenytoin, and levetiracetam patients, respectively (p=0.032 with valproic acid as the comparator). After adjusting for SE severity and etiology, levetiracetam was associated with a higher risk of treatment failure than was valproic acid (OR 2.7; 95% CI, 1.2–6.1), but not phenytoin, and there was no difference in mortality between the three groups.38 Levetiracetam is not as well studied as phenytoin, valproic acid, and phenobarbital; however, its pharmacokinetic profile makes it an attractive adjunctive agent in the treatment of SE. Lacosamide Like with levetiracetam, lacosamide’s intravenous availability, ease of dosing, lack of major drug interactions, and well-tolerated adverse effect profile have led to its off-label use in SE. Lacosamide can cause changes on electrocardiogram (ECG) (i.e., PR prolongation), which may warrant ECG monitoring when used at the higher doses for SE, especially in patients with underlying cardiac abnormalities. One analysis of 19 RSE studies of patients treated with lacosamide reported an overall success rate of 56% in 136 cases. Lacos-amide was generally well tolerated (dose range 50–600 mg), with sedation being the most common adverse effect (25%) and one patient who developed third-degree atrioventricular block.39 One study compared two loading-dose regimens of lacosamide in 25 patients with RSE. The overall response rate was 36% for both groups, with a numerically higher overall response in the 400-mg group versus the 200-mg group (50% vs. 18%, p=0.2). The maintenance dose of 200 mg every 12

hours was the same in both groups.40 The use of lacosamide as an adjunctive treatment for status has also increased during the past few years; however, more data are needed to confirm its place in SE algorithms.

RSE Treatment Status epilepticus that is unresponsive to first-line (emergent) or second-line (urgent) therapies is considered RSE. Treatment of RSE uses anesthetics and continuous intravenous infusions. The results of studies evaluating these treatment modalities are difficult to interpret, partly because of the heterogeneous patient populations, nonstandardized treatment regimens, and variable dosing strategies. Given the lack of superiority data establishing a standard of care, patientspecific characteristics, such as hemodynamic stability as well as physician preference and institutional algorithms, generally guide agent selection. Continuous infusions may be implemented as refractory treatment, after failure of initial anticonvulsants, or earlier to allow the traditional anticonvulsants enough time to be initiated and to reach therapeutic concentrations. When continuous infusions are titrated, they should be rebolused with every increase in the continuous infusion rate. Commonly, 24–48 hours of seizure control is recommended before continuous infusions and drugs are tapered; however, practices varies widely among clinicians, particularly in super-refractory status epilepticus treatment.3 Several anticonvulsants may be used adjunctively, particularly when trying to wean off the anesthetic infusions. Propofol Propofol is a very short-acting anesthetic that acts on GABA receptors and may have an effect on NMDA receptors. It causes significant hypotension at treatment doses for SE, which are often higher than that required for continuous sedation, necessitating the use of vasopressors. The risk of propofol-related infusion syndrome (PRIS) associated with higher doses and long durations of propofol makes it

less ideal for treatment of RSE, where high doses are often needed for extended periods. Triglycerides (TG) should be evaluated every 48–72 hours in patients receiving propofol, with TG concentrations greater than 400 mg/dL necessitating a potential dose reduction, discontinuation, or change to alternative therapy. One prospective, randomized study of 23 patients with RSE randomized patients to barbiturates (pentobarbital 5-mg/kg bolus and thiopental 2-mg/kg bolus) or propofol (2 mg/kg bolus) titrated to burst suppression. The median doses for each agent were propofol 5.5 mg/kg/hour (range 2– 10.9), thiopental 7 mg/kg/hour (range 4–20), and pentobarbital 2.5 mg/kg/hour (range 2–3). Investigators of this study found no difference in mortality between propofol and barbiturates, but they did find a longer duration of mechanical ventilation with barbiturates and a nonsignificant increase in RSE control with propofol (43% vs. 22%). One patient in the propofol group was determined to have PRIS.41 Midazolam Continuous Infusion Continuous infusion midazolam is the benzodiazepine of choice for RSE treatment because of its lack of propylene glycol diluent, which allows it to be administered at high doses for long durations without risk of toxicity and metabolic acidosis. Midazolam is a CYP3A4 substrate and is affected by CYP3A4 inducers and inhibitors (including other concomitantly used anticonvulsants). Although the parent drug undergoes hepatic metabolism, it has an active metabolite that is renally eliminated; thus, its half-life is prolonged in older adult patients or those with renal failure. After prolonged infusions, midazolam distributes into adipose tissues and can prolong sedative effects. Midazolam causes respiratory depression requiring intubation, and high doses often cause hypotension requiring vasopressors, although generally less so than propofol. A retrospective study of 20 patients found no difference in clinical seizure suppression (64% vs. 67%) or electrographic seizure suppression (78 vs. 67%) between propofol and midazolam, respectively, as well as no difference in infection, duration of mechanical ventilation, or hemodynamic compromise. Mortality was nonsignificantly higher in the propofol group (57% vs. 17%), although

patients receiving propofol had a longer duration of SE before treatment. Propofol was administered as a bolus (1–3 mg/kg) in some, but not all, patients, followed by a continuous infusion range of 1–10 mg/kg/hour. Midazolam was administered as a bolus (2–12 mg) and continuous infusion of 0.05–0.8 mg/kg/hour.42 Another study identified 33 patients with continuous EEG monitoring who received midazolam (0.1- to 0.2-mg/kg bolus, followed by an infusion at 0.05–0.4 mg/kg/hour) for RSE. Seizure termination was seen within the first hour in 82% of patients, and breakthrough seizures were seen in 56% of patients who were treated for more than 6 hours. Midazolam did not control RSE in 18% of cases and required switching to an alternative continuous infusion anesthetic.43 Pentobarbital Pentobarbital is a long-acting barbiturate that can be used in place of propofol or midazolam for RSE. Pentobarbital is known to cause significant cardiovascular depression and hypotension, leading to cardiovascular collapse and the requirement of vasopressors in order to maintain therapeutic infusion rates. Mechanical ventilation is required before initiation due to respiratory depression. Pentobarbital has a halflife of 15–48 hours, but it may take days to weeks for complete elimination. Its long half-life complicates neurological examinations and prognostication. For patients evaluated for brain death, pentobarbital may confound the examination, and serum concentrations typically come back elevated for significant periods after the drug has been discontinued. In addition, adverse effects are noted even after the infusion has been discontinued, leading to possible prolonged mechanical ventilation and hypotension, higher risk of infections, and reduced gastrointestinal motility. One systematic review that assessed pentobarbital, propofol, and midazolam for the treatment of RSE in 193 patients and 28 studies found no difference in mortality between the three treatments. Pento-barbital was associated with less short-term treatment failure and fewer breakthrough seizures than the other agents; however, fewer patients received cEEG monitoring than in the propofol and midazolam groups, making it possible to have missed

some breakthrough seizures. Pentobarbital was more frequently titrated to burst suppression rather than seizure termination, and titration to EEG suppression was associated with fewer breakthrough seizures (4 vs. 53%, p 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 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

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

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

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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.

Figure 22.1 Location of aneurysm responsible for subarachnoid hemorrhage in the “circle of Willis.” Most (85%) saccular aneurysms arise in the vessels that constitute the circle of Willis at the base of the brain. The anterior circulation comprises the anterior cerebral

arteries that are joined by a single anterior communicating artery that is paired with the internal carotid arteries. Most aneurysms are within the anterior circulation. The posterior circulation is composed of the posterior communicating arteries that are paired with the posterior cerebral arteries that originate at the bifurcation of the basilar terminus of the basilar artery. Early brain injury starts with the initial response of increased ICP because of the blood in the subarachnoid space and sometimes the cerebral ventricle and brain parenchyma. The quantity of the initial bleed drives the degree of ICP elevation the patient experiences. With this increase in ICP, the cerebral perfusion pressure (CPP) decreases, causing cerebral ischemia through a reduction in cerebral blood flow because cerebral autoregulation may be disturbed. The presence of blood and its degraded products in the cerebral ventricles produces obstructive hydrocephalus, which also results in an increase in ICP. As a result, global ischemia may occur, which produces oxidative damage to neural tissue and then neuronal death. Oxidative mediators can also disrupt the blood-brain barrier and lead to the production of cytotoxic cerebral edema, which results in more ischemia.27 The global ischemia experienced varies in severity, with about 30% of patients having necrosis throughout the brain and the remainder, a degree of ischemia not as severe but in which both apoptosis and necrosis may be present. Overall, brain injury occurs from transient global ischemia and from the direct effects of the intracranial blood. The ischemic insults to the brain after aSAH stimulate several complex pathways that can lead to stimulation of apoptotic mechanisms in the hippocampus, blood-brain barrier, and vasculature, resulting in early brain injury. Some of the proposed different mechanisms for early brain injury include nitric oxide dysregulation, oxidative injury, generation of matrix metalloproteinase-9, modulation of nuclear factor erythroid-2 related factor 2 and antioxidant-response element pathway, interleukin-1 beta activation, vascular endothelial

growth factor, activation of c-Jun N-terminal kinase pathway, mitogenactivation protein kinase, and iron overload.29-33 Currently, interventions targeting early brain injury are mainly experimental, but they deserve further investigation because the cerebral infarction that occurs in aSAH not only occurs after vasospasm but also as a result of the physiologic changes that occur with the initial bleed.

Delayed Neurological Deterioration Neurological worsening that occurs days after aSAH can be ascribed to DCI (see Figure 22.2). Throughout the literature, various terms are used that may be confused as being interchangeable: symptomatic vasospasm, DCI, and angiographic vasospasm. Delayed cerebral ischemia is a clinical syndrome that encompasses symptomatic deterioration in the neurological examination together with radiographic evidence of ischemia or infarction.34 Not all patients with DCI have angiographic vasospasm, and not all patients with angiographic spasm have DCI. Delayed cerebral ischemia occurs in about 30% of patients 3–14 days after the initial hemorrhage and is the most important cause of mortality and morbidity in the patients who survive the initial bleed.35 Angiographic vasospasm occurs within 3–14 days after aneurysm rupture in almost 70% of patients, 30% of whom develop significant global or focal neurological deficits.36 The severity and duration of vasospasm are related to the thickness, density, location, and persistence of the subarachnoid blood.37 The most likely mechanism for development is an inflammatory reaction in the blood vessel wall. Extravasated blood and its by-products in the cerebrospinal fluid (CSF) are thought to be responsible for this complication. Many spasmogens such as oxyhemoglobin, histamine, eicosanoids, endothelin, nitrous oxide, and 2-hydrosy-3-methylglutarylcoenayme have been implicated in the development of vasospasm. These spasmogenic substances cause endothelial damage and smooth muscle contraction and can result in cerebral hypoperfusion, DCI, and infarction.38 The true connection between vasospasm and DCI is under question because interventions have shown that significant reductions in angiographic

vasospasm do not improve outcome.39 Clinical and physiological factors that influence whether angiographic vasospasm causes cerebral infarction include genetic variations (APOE [apolipoprotein E] alleles, polymorphisms of eNOS [endothelial nitric oxide synthase] and plasminogen activator inhibitor-1), epigenetic variations, DNA polymorphisms, cerebral metabolic demand, autoregulation, variations in collateral and anastomotic blood flow, cardiac output, and ICP.27

Figure 22.2 Pathophysiology of early brain injury and delayed cerebral ischemia after aSAH. The etiology starts with early brain injury as a result of the initial bleeding event, leading to transient global cerebral ischemia. This process starts a complex cascade of pathophysiological changes leading to secondary brain injury. aSAH = aneurysmal subarachnoid hemorrhage; BBB = blood-brain barrier; CBF = cerebral blood flow; CBV = cerebral blood volume; CPP = cerebral perfusion pressure; ET-1 = endothelin-A; ICP = intracranial pressure; NO = nitric oxide; NOS = nitric oxide synthase; TF = tissue factor.

Angiographic vasospasm may be associated with DCI, but other pathophysiological factors may also play a role in DCI development such as microthrombosis, cortical spreading ischemia, microcirculatory constriction, and apoptosis.27 Nimodipine is currently the only pharmacologic agent that has shown an improvement in outcome after aSAH, and it is indicated for use by the U.S. Food and Drug Administration (FDA). In clinical trials, nimodipine did not show a significant improvement in angiographic vasospasm, which led to other theories surrounding the benefit of this agent. It is proposed that nimodipine slightly attenuates vasospasm but also inhibits cortical spreading ischemia and reduces microthrombi through its fibrinolytic activity.27

Systemic Effects The extent of injury after aSAH also affects other organ systems like the heart and lung. There is an increase in sympathetic nervous system activity that can contribute to the development of acute lung injury, pulmonary edema, and cardiac dysfunction (takotsubo cardiomyopathy, stunned myocardium, ECG changes).40 The most prevalent systemic response that occurs in up to 60% of patients with aSAH is a systemic inflammatory response characterized by increased or decreased body temperature, tachypnea, tachycardia, and leukocytosis or leukopenia.41

CARE SETTINGS AND MULTIDISCIPLINARY TEAM Aneurysmal subarachnoid hemorrhage is a complex disease with a prolonged course that requires expertise from a multidisciplinary team. Ideally, the management of patients with aSAH should take place in a neuro-ICU or an ICU similarly equipped that treats a high volume of patients with aSAH. The available data analyses show that high-volume centers (defined as greater than 60 cases per year) had the best outcomes and that low-volume centers with less than 20 cases per

year had the worst outcomes.42,43 The most recent guidelines by both the Neurocritical Care Society (NCS) Multidisciplinary Consensus Conference and the American Heart Association/American Stroke Association (AHA/ASA) recommend that patients with aSAH be treated at high-volume centers and that low-volume hospitals consider early transfer of these patients to high-volume centers.44,45 A multidisciplinary neurocritical care team in a specialized neuro-ICU is independently associated with improved hospital discharge disposition for patients with aSAH.46 This improved outcome may not be a result of the single addition of any type of personnel; rather, it may be the overall impact of a consistent and organized approach to patient management that contributes to improved outcomes.

INITIAL STABILIZATION IN EMERGENCY DEPARTMENT Clinical Features The clinical presentation of aSAH can vary dramatically from what is described as “the worst headache of my life” to coma or death. Often, patients have nausea, vomiting, neck stiffness, and photophobia in addition to the sudden-onset severe headache. With more severe presentations, patients may have an altered level of consciousness with states of confusion, lethargy, or coma. Furthermore, focal neurological deficits such as motor weakness, aphasia, special neglect, or cranial nerve palsies may be present. Commonly, patients may have had a severe headache similar in nature several days before presentation, which has been termed a sentinel bleed.

Diagnostic Approaches to aSAH The diagnosis of aSAH must be considered when patients present with the classic symptoms; however, because many of the symptoms are nonspecific, the diagnosis is commonly missed on initial presentation to a medical provider.47 Because patients who are initially misdiagnosed have a higher rate of complications, an accurate and sensitive workup

must be initiated at presentation.48 The sensitivity for noncontrast head CT has been validated and is 98%–100% within 12 hours from onset and 93% at 24 hours.49,50 After 3 days, however, the sensitivity decreases to 73% and after 7 days, to 50%, which results in a high likelihood of a false-negative study.49,50 If the clinical suspicion is high, a lumbar puncture to evaluate for xanthochromia is warranted. This should be done at least 12 hours after the onset of headache for a negative study to be valid because it takes this amount of time for xanthochromia to develop from red blood cell breakdown.47 Magnetic resonance imaging (MRI) is up to 100% sensitive in the detection of aSAH and can be considered as an alternative to lumbar puncture; however, it is not available at many hospitals and is not cost-effective.51 For patients in whom the diagnosis of aSAH has not been effectively ruled out, a further imaging study is required. Computed tomography angiography, a high-resolution CT scan of the cerebral arteries that is obtained after intravenous contrast injection, is comparable with the gold standard procedure, digital subtraction angiography of the cerebral blood vessels.52 When an aneurysm is not identified in this circumstance, repeat imaging in a delayed fashion after 1–2 weeks is supported, given that an undetected untreated aneurysm has high morbidity and mortality.53

Clinical Severity Scores Many scoring algorithms have been developed with the aim of predicting the outcome and risk of neurological complications after aSAH (Table 22.1). The most widely used clinical scoring systems to predict outcome include the Hunt and Hess score and the World Federation of Neurological Surgeons score. With both scales, the higher the score, the higher the likelihood of a poor outcome.54,55 The Hunt and Hess score is an ordinal scale from 1 to 5 that is based on the level of consciousness as well as focal neurological deficits. Patients who score a 1 are asymptomatic or have a mild headache, whereas those who score a 5 are comatose with reflexive motor response only. The World Federation of Neurological Surgeons score is

based on two components: the overall neurological status according to the Glasgow Coma Scale (GCS), range 3–15, and the absence or presence of motor deficits. Patients with a normal GCS of 15 and no neurological deficits are given a score of I, whereas those with a GCS score of 3–6 with or without motor deficits are given a V. The Fisher grade was developed to predict the risk of cerebral vasospasm after aSAH according to the amount of blood revealed on head CT at presentation.37 Patients with no hemorrhage or with a hemorrhage of minimal thickness have a very low rate of vasospasm, whereas those with a hemorrhage greater than 1 mm in thickness have a high rate of developing clinical vasospasm and a worse outcome.37,56

MANAGEMENT AND PREVENTION OF NEUROLOGICAL COMPLICATIONS The primary strategies used in the management of aSAH are to provide initial supportive therapy and to prevent both neurological and medical complications (see Table 22.2 and Table 22.3).

Rebleeding Recurrent bleeding of an aneurysm after the initial hemorrhage is often fatal, and early measures should be in place to reduce this risk.57 The highest risk is within the first 24 hours; therefore, treatment of the underlying aneurysm should be completed on an emergency basis.44,45 Furthermore, medical management should include therapies aimed at risk reduction, including strict blood pressure control and the consideration of antifibrinolytics. Other important supportive interventions include the use of bed rest, stool softeners to prevent straining, and pain management because pain is associated with a transient elevation in blood pressure, which can increase the risk of rebleeding.

Table 22.1 Aneurysmal Subarachnoid Hemorrhage

Grading Scales

GCS = Glasgow Coma Scale; WFNS = World Federation of Neurological Surgeons continued on page 425

Table 22.2 General Overview of Patient Management for Aneurysmal Subarachnoid Hemorrhage

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

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 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

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

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

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

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

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

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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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.

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.

Figure 25.5 Creation of goal aPTT targets and titration algorithms according to the correlation between anti-Xa and activated partial thromboplastin time results.

Figure 25.6 Discordance between activated partial thromboplastin time and anti-Xa measurement. Unfractionated heparin resistance can also be identified by failure to obtain a therapeutic aPTT despite escalating doses of UFH (e.g., greater than 25 units/kg/hour). If this occurs, evaluation of antithrombin III activity may need to be considered. However, the low response to heparin may be because of increased clearance, increased binding to heparin-binding proteins, or increases in acute-phase reactants such as factor VIII or fibrinogen.8 The aPTT is the most common test used for monitoring parenteral DTI therapy (e.g., argatroban or bivalirudin). Although the aPTT is used to monitor DTIs, the dose-response is not linear, and the aPTT reaches a ceiling threshold with high concentrations of the drug in plasma. The goal therapeutic aPTT range for parenteral DTIs is not the same as the heparin-calibrated curve by the anti-Xa regression analysis. Many

centers simply use the DTI package insert–recommended aPTT goals and create an individualized goal aPTT range on the basis of the patient’s baseline aPTT (goal aPTT 1.5–3 times baseline aPTT for argatroban or 1.5–2.5 times baseline aPTT for bivalirudin). Alternative options are to create a titration algorithm that is based on the mean of the normal aPTT range (or, in some cases, the upper end of the normal range) to create a standard aPTT goal for all patients (Figure 25.7).11,12 Given that many critically ill patients do not have a normal aPTT at baseline, this approach may be limited. Laboratories can also create a therapeutic range that is based on spiked normal plasma with known concentrations of each DTI. This may allow for detecting different reagent lot sensitivities to the DTIs. However, the concentration versus aPTT regression line is curvilinear, and little evidence is currently available linking a goal range of DTI plasma concentrations to therapeutic and safety outcomes. Other options include the development of aPTT range using ecarin chromogenic or dilute thrombin time or plasma diluted thrombin time (dTT) assays, but these require a clinical laboratory to perform significant validation steps throughout the process and are more cumbersome than the methods mentioned earlier. The timing of aPTT monitoring varies between institution, DTI, and organ function and expected time to steady state (extended time to steady state would be expected for argatroban in patients with hepatic impairment and bivalirudin in patients with renal impairment). When developing an aPTT monitoring plan for parenteral DTIs, an aPTT should be monitored within 2–4 hours of initiation or after any dosing change. After this, the aPTT can be monitored every 4–6 hours until at least two consecutive aPTTs are within the goal range. Once this occurs, the frequency can be extended to once daily.8,11,12

ANTI-Xa MONITORING The anti-Xa can be measured using a functional assay to determine anticoagulation intensity for anticoagulants that directly or indirectly affect factor Xa. The test is performed by adding patient plasma to a

reagent factor Xa and measuring factor Xa activity using a substrate that releases a color compound when cleaved. The premise of the assay depends on the fact that the factor Xa activity is proportional to the amount of anticoagulant in the plasma. The most common anti-Xa activity assays currently used are chromogenic because clot-based assays may underestimate activity.

Figure 25.7 Example of a monitoring and titration algorithm for direct thrombin inhibitor therapy.

Institutions may use a single hybrid anti-Xa curve for UFH and LMWH, or create separate titration curves. Anti-Xa assays are typically calibrated using UFH. It is important to verify that the correct calibrated anti-Xa curve is being used for the anticoagulant being tested. Of note, use of the UFH-derived curve to evaluate LMWH can underestimate the LMWH effect, whereas use of the LMWH curve for measuring UFH can overestimate the UFH effect. Because of these differences in calibration, target anti-Xa levels may vary between laboratories. In addition, the activity of fondaparinux and the directacting oral anticoagulants (DOACs) requires a separate anti-Xa calibration before the results can accurately be interpreted. The anti-Xa goal range was originally established using protamine sulfate titration. Variability in assay performance can occur because of different lots of heparin, the addition of exogenous antithrombin, or variations in the process of creating the standard curve. Antithrombin supplementation or the administration of antithrombin either directly or indirectly (e.g., through the administration of fresh frozen plasma) may result in altered anti-Xa results. Other outside influences listed as having a potential to interfere with the reagent include plasma concentrations greater than 1.5 g/L hemoglobin (0.15 g% or greater plasma free hemoglobin), greater than 288 mg/L conjugated bilirubin (28.8 mg% or greater direct bilirubin), greater than 138 mg/L unconjugated bilirubin (13.8 g% or greater indirect bilirubin), and greater than 6.9 g/L triglycerides (690 mg% or greater triglycerides). Despite the potential effects of outside influences, the anti-Xa provides a potentially more accurate measurement of UFH therapy. For this reason, many institutions have moved to monitoring UFH by anti-Xa rather than aPTT. The anti-Xa may be preferred to the aPTT for monitoring UFH in patients with suspected heparin resistance, lupus anticoagulant, or antiphospholipid antibodies or when the aPTT results do not appear to correlate with UFH dosing adjustments. In general, anti-Xa monitoring of UFH results in fewer variations in results, reduced testing, fewer dose changes, and more time within the therapeutic range. However, limited data are available regarding the use of anti-

Xa– based titration and clinical outcomes, and as mentioned in the aPTT section within this chapter, discordance between the anti-Xa result and aPTT may be a predictor for risk of bleeding or thrombosis.10 Monitoring of both the anti-Xa activity and the aPTT may be prudent in certain critically ill patients, such as those with hepatic disease, prolonged baseline clotting time, and significant thrombosis or risk of bleeding and those with factor inhibitors. However, there is little guidance on what clinicians should do if the aPTT and anti-Xa results are discordant. Ultimately, a decision on which assay to use will have to be made according to which laboratory test appears to be correlating best with the patient’s clinical scenario. The anti-Xa assay can be used similarly to the aPTT when dose adjusting heparin. The anti-Xa activity (heparin level) should be drawn at intervals similar to those recommended for the aPTT (e.g., every 6 hours initially and then at least daily after two consecutive levels in goal are achieved). Heparin nomograms can be used for titrating heparin in a fashion similar to those derived from the aPTT (Figure 25.8). The anti-Xa assay is the preferred measurement for LMWH; however, monitoring is typically needed only in special populations. Such critical care populations include those with extremes of body weight (e.g., less than 50 kg or more than 150 kg), those with reduced creatinine clearance (e.g., less than 30 mL/minute), pediatric patients, trauma patients, patients with a potential for altered sub-cutaneous absorption (e.g., significant edema), pregnant patients with mechanical valves, or those with unexpected bleeding or thrombosis during therapy. Unlike UFH, where an anti-Xa level can be monitored anytime during the infusion, timing is important when monitoring LMWHs. A peak concentration should be drawn 4 hours after the subcutaneous dose of the LMWH. The goal anti-Xa varies depending on whether once- or twice-daily dosing is used, which LMWH is being administered, treatment versus prophylactic dosing, and the calibration of the assay by the laboratory. For example, the goal concentration for 1 mg/kg of twice-daily enoxaparin may be 0.6–1 IU/mL, and the goal concentration for 200 units/kg of once-daily dalteparin may be 1–2 IU/mL.8 A peak concentration of 0.2–0.4 IU/mL or a trough

concentration greater than 0.1 IU/mL has been suggested as a target for prophylactic dosing strategies.13-15 Of note, a specifically calibrated assay must be used for monitoring fondaparinux. Goal concentrations for fondaparinux are not well established, but anti-Xa peak levels are about 0.39–0.5 mg/L for 2.5-mg/ day doses and about 1.2 mg/L for 7.5-mg/day dosing. Clinicians should consult with their laboratory to determine the therapeutic ranges for the LMWH and dosing strategy used in their patient. The heparin-calibrated chromogenic anti-Xa assay can also be used to quantitate the newer DOACs.16 Currently, calibration kits for rivaroxaban and apixaban are available for research use only. However, hospitals may choose to calibrate their standard anti-Xa assay to measure these DOACs. Of note, the returned values for the DOAC will be significantly higher than those reported for UFH, and dilution of the sample may be required to fit the results within the laboratory’s testing range. Although the PT may provide a quick qualitative assessment of the presence of a DOAC in the patient, the correlation with drug concentration is much higher with the anti-Xa assay than with the PT.16 See Figure 25.9 through Figure 25.14.

Figure 25.8 Example of an anti-Xa monitoring and titration algorithm for unfractionated heparin therapy.

HEPTEST AND HEPTEST-STAT The Heptest and Heptest-Stat are clot-based assays that measure heparin or LMWHs and fondaparinux in human plasma, respectively. The assay consists of incubating plasma samples with an equal volume of factor Xa. This mixture is then recalcified by adding a reagent containing optimal concentrations of calcium chloride and brain cephalin in a bovine plasma fraction rich in factor V and fibrinogen. The amount of anticoagulant present in the sample is interpolated from a standard curve of clotting times versus known heparin levels. The Heptest has a high correlation with the anti-Xa chromogenic

assay for heparin and LMWH and may more accurately measure the anticoagulant effects of heparins than the aPTT because it is less influenced by high factor VIII levels and lupus anticoagulant.17 The Heptest-Stat is most likely to be useful for low-dose heparin monitoring, including dialysis and pediatric patients. The Heptest-Stat has been used for monitoring VTE prophylaxis in pregnant women with and without prosthetic valves because it is unaffected by the hormonal changes common in these patients.18

ACTIVATED CLOTTING TIME The activated clotting time (ACT) is one of the few point-of-care methods used for monitoring anticoagulant therapy in critically ill patients. The ACT is performed by adding an activating agent (e.g., kaolin) to a sample of freshly drawn whole blood and measuring the time to clot formation. The results for time to clot are presented in seconds. The ACT devices use a low- and high-range cassette, which provide different responses depending on the heparin level present. Because the aPTT becomes infinitely prolonged when heparin levels exceed 1 unit/mL, the ACT is typically used to monitor high-dose UFH or DTI therapy during cardiopulmonary bypass or other invasive intravascular procedures such as cardiac angiography and intervention, extracorporeal membrane oxygenation, vascular surgery, or carotid endarterectomy. The ACT is capable of showing a graded response to heparin levels at 1–5 units/mL. Low- and high-dose cartridges are available depending on the dose of anticoagulation and type of procedure being performed.

Figure 25.9 Correlation between STA liquid heparin hybrid anti-Xa activity and apixaban concentration in spiked samples.

Figure 25.10 Correlation between STA liquid heparin hybrid anti-Xa activity and rivaroxaban concentration in spiked samples.

Figure 25.11 Correlation between prothrombin time and apixaban concentration in treated patient samples. The ACT results can be affected by many factors including platelet count, platelet function, lupus anticoagulants, factor deficiencies, blood volume, temperature, and hemodilution (Figure 25.15). The presence of other anticoagulants (e.g., warfarin) or antiplatelet agents (e.g., glycoprotein IIb/IIIa inhibitors) can also increase the ACT. The optimal goal range for the ACT is not well established, which therefore leads to variability in goals among various procedures and settings. A linear relationship between ACT and thrombosis and bleeding outcomes in percutaneous coronary intervention has not been established; however, increased rates of death, myocardial infarction, and target vessel revascularization have been observed in patients with ACTs of 300 seconds or less.19 In patients undergoing cardiopulmonary bypass, a minimal ACT goal may range from greater than 350 to greater than 500 seconds; however, many institutions target a value between 400 and 480 seconds.20 The ACT correlates well with heparin level only after the initial bolus of UFH in patients undergoing cardiopulmonary bypass. This correlation decreases significantly during cardiopulmonary bypass, potentially because of hemodilution, hypothermia, and platelet dysfunction (Figure 25.15).21 Adding normal

plasma to the patient sample may improve the correlation.22 Reduced heparin sensitivity (e.g., heparin resistance) can also be picked up on if the ACT does not increase as expected with a given UFH dose (Figure 25.16). An arbitrary cut-point of failure to achieve an ACT of greater than 480 seconds despite 500 units/kg of UFH has been a common definition of heparin insensitivity.23,24 The clinical importance of identifying heparin resistance is unknown, and considerable debate exists about whether patients should simply be given higher doses of UFH or whether exogenous antithrombin III should be administered.

ECARIN CLOTTING TIME OR ECARIN CHROMOGENIC ASSAY The ecarin clotting time test uses a known quantity of ecarin (thrombin activatable snake venom) and adds this to the plasma of a patient treated with a DTI. Ecarin activates prothrombin through a specific proteolytic cleavage, which produces meizothrombin, a prothrombinthrombin intermediate that retains the full molecular weight of prothrombin but possesses a low level of procoagulant enzymatic activity. This activity is inhibited by DTIs, but not by heparin. The ecarin clotting time is also unaffected by prior treatment with warfarin or the presence of phospholipid-dependent anticoagulants, such as lupus anticoagulant. Thus, the ecarin clotting time is prolonged in a specific and linear fashion with increasing concentrations of DTIs. An enhancement of the ecarin clotting time is the ecarin chromogenic assay in which diluted sample is mixed with an excess of purified prothrombin, and the generated meizothrombin is measured with a specific chromogenic substrate. This assay shows no interference from prothrombin or fibrinogen in the sample and is suitable for measuring all DTIs.25,26 Unfortunately, this test is not yet FDA approved for use in the United States. Even if the test becomes available, many questions remain regarding the optimal drug concentration and correlation of the ecarin chromogenic assay to patient outcomes.

THROMBIN TIME AND DTT The thrombin time (TT) measures the conversion of fibrinogen to fibrin, the final step in the clotting pathway. The test measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant after an excess of thrombin has been added. It is typically used to diagnose blood coagulation disorders and to assess the effectiveness of fibrinolytic therapy. The TT compares the rate of clot formation with that of a sample of normal pooled plasma. Thrombin is added to the samples of plasma. If the time it takes for the plasma to clot is prolonged, a quantitative (fibrinogen deficiency) or qualitative (dysfunctional fibrinogen) defect is present. Thrombin time can be prolonged by anticoagulants (e.g., heparin or DTIs), fibrin degradation products, and fibrinogen deficiency or abnormality. The assay can be affected by fibrinogen concentrations, with fibrinogen concentrations greater than 600 mg/dL causing as much as a 5%–20% decrease in expected dTT compared with samples with normal fibrinogen values.27 The TT has a high sensitivity to anticoagulants, particularly DTIs.27 For example, if used to monitor DTIs, this unmodified TT will provide results above the threshold for the assay (e.g., greater than 200 seconds). Therefore, the assay is typically diluted with pooled normal patient plasma by a 1:4 ratio yielding a dTT. The dTT may provide an alternative to the aPTT for monitoring UFH or DTIs, but because of the availability of other laboratory options for UFH, its use is more common with DTIs.28 Potential advantages of the assay compared with the aPTT are avoidance of interference by lupus inhibitors, deficiency in vitamin K–dependent factor levels, or elevated D-dimer concentrations. Although the dTT can be run by automated machines, additional work must be done at individual institutions to dilute the patient samples and calibrate the assay according to DTI plasma concentrations (Figure 25.17). Additional considerations are the appropriateness of choosing the target therapeutic range for the dTT test because the goal therapeutic concentrations for DTIs vary depending on the source. For example, published argatroban goal concentrations equivalent to an aPTT of about 1.5–3 times baseline aPTT have been reported as 0.5– 1.5 mcg/mL, 1–2 mcg/mL, and 0.4–1.1 mcg/mL.29-31 The

predominance of pharmacokinetic information with bivalirudin is in patients undergoing percutaneous coronary intervention or coronary artery bypass grafting, which uses significantly higher doses and yields concentrations of 1–15 mcg/mL.32 This range is even less well defined for bivalirudin in patients with heparin-induced thrombocytopenia and is approximated to be anywhere from 0.25 to 1.5 mcg/mL.27 To account for this, some institutions have decided to truncate the goal range to a mean of the concentrations reported in the literature (e.g., 0.8–1.2 mcg/ mL). However, more data are needed linking therapeutic concentrations to clinical outcomes before a specific goal can be recommended. Furthermore, individual ICU patient considerations, treatment goals, and risk-benefit of thrombosis and bleeding should be considered when designing a patient’s therapeutic goal. Use of the test for DTIs should likely be reserved for patients with altered baseline aPTT values (e.g., patients with lupus anticoagulant) or those with an unexpected aPTT response in concordance with usual DTI dosing strategies.

Figure 25.12 Correlation between prothrombin time and rivaroxaban concentration in treated patient samples.

Figure 25.13 Correlation between STA liquid heparin hybrid anti-Xa activity and apixaban concentration in treated patient samples.

Figure 25.14 Correlation between STA liquid heparin hybrid anti-Xa activity and rivaroxaban concentration in treated patient samples.

Figure 25.15 Factors affecting the activated clotting time result. Factors prolonging the activated clotting time independent of heparin effects. Low

coagulation factors, low platelets, and low fibrinogen can all prolong the activated clotting time (ACT). Additional confounders that cause the ACT not to correlate well with heparin levels include hypothermia (less a problem when small sample sizes are used), excess protamine, and the presence of antiphospholipid antibodies (typically found in patients with lupus).21

PROTHROMBINASE-INDUCED CLOTTING TIME ASSAY The prothrombinase-induced clotting time (PiCT) assay is a clotting assay that is sensitive to factor Xa and IIa. The assay adds factor Xa and Russell viper venom to platelet-poor plasma. After incubation, the plasma is recalcified, and the clotting time is determined. The PiCT is a relatively new test that has mainly been studied ex vivo. A mostly linear dose response is observed when evaluating UFH, LMWHs, argatroban, and fondaparinux.33 A study comparing the PiCT assay with the ecarin chromogenic and dTT tests for monitoring argatroban, bivalirudin, and dabigatran showed greater variations in results with the PiCT test.11 More studies are needed of critically ill patients before recommendations can be made to use the PiCT test in clinical practice.

HEMOCLOT THROMBIN INHIBITOR ASSAY The Hemoclot thrombin inhibitor assay is a chronometric assay used for the quantitative measurement of both parenteral (argatroban) and oral (dabigatran) DTIs. During the Hemoclot thrombin inhibitor test, the patient’s plasma is first diluted with normal pooled human plasma. Clotting is then initiated by adding a constant amount of highly purified human thrombin. The clotting time measured is directly related to the concentration of the DTI in plasma. Preliminary studies have shown a higher correlation between the Hemoclot thrombin inhibitor test and DTI concentrations in plasma than in the aPTT; however, little is known about the use of this test in clinical practice.34,35 The test is relatively new in the United States and currently has no calibrators for bivalirudin.

THROMBIN GENERATION TEST

Thrombin generation assays measure the ability of a plasma sample to generate thrombin after activation of coagulation with tissue factor or another trigger. Thrombin generation assays also probe the propagation and termination phases. The thrombin generation curve shows and integrates all procoagulant and anticoagulant reactions that regulate the formation and inhibition of thrombin. Currently, there is poor standardization for the assay among institutions, which significantly limits its application in clinical practice.36

REPTILASE TIME Reptilase is an enzyme similar to thrombin. It is different from thrombin because it resists inhibition by heparin through antithrombin. In addition, it is unaffected by DTIs. Reptilase time is useful for detecting abnormalities in fibrinogen and in detecting whether heparin or DTIs are causing a prolongation of the TT.

THROMBOELASTOGRAPHY Thrombelastography (TEG) is a common method of performing pointof-care monitoring of coagulation. It provides clinicians with real-time results of whole blood coagulation status and is applicable at the bedside. More specifically, the TEG device provides graphic representation of the rate of fibrin polymerization, platelet function, and clot strength and stability through in vivo interactions of the coagulation system with platelets and red blood cells at the patient’s actual temperature.

Figure 25.16 Dose-response graph for initial heparin bolus as measured by the activated clotting time. Dose-response graph for initial heparin bolus as measured by the activated clotting time. (A) Before commencing cardiopulmonary bypass (CPB), the relationship of an intravenous heparin bolus and the resulting ACT is relatively linear. This relationship does not continue during CPB. (B) The heparin sensitivity index (HSI) is the dose-response slope. It is calculated by subtracting the baseline ACT measurement from the ACT obtained after the loading dose (both measured in seconds) and dividing that by the loading dose of heparin given (in units per kilogram).21

TERMINOLOGY Thromboelastography was first described in 1948 as a research device to assess global viscoelastic changes in coagulation of a single blood sample.37 In 1996, thromboelastograph and TEG became registered trademarks of the Haemoscope Corporation (Niles, IL) and now describe the assay performed using Haemoscope instrumentation only. Rotational thromboelastography (ROTEM) also measures the viscoelastic properties of coagulation and differs from TEG in proprietary components and coagulation activators but has similar graphic results.

Figure 25.17 Correlation of the direct thrombin inhibitor plasma concentration to dilute thrombin time.

PRINCIPLES OF THROMBELASTOGRAPHY The TEG/ROTEM devices both assess the viscoelastic physical properties of clotting whole blood, but they do so in a blood sample cup; this negates the high shear forces otherwise found in the vessels of the circulatory system. Because the TEG measures coagulation status under a no-flow (static) state in a blood sample cup (in vitro), it is important to emphasize that the results should be interpreted in context of the clinical scenario.38 The TEG device uses a stationary cylindrical blood sample cup and oscillates through an angle of 4° 45’ with each rotation lasting 10 seconds.6 An immersed pin is suspended in the blood by a torsion wire and is monitored for motion. Torque is generated between the oscillation of the blood sample cup and the pin only after fibrin-platelet bonding has linked the cup and pin together. The graphic output of the rotational movement is related to the magnitude of strength of these fibrin-platelet bonds for the immersed pin. The TEG device may graphically represent robust or weak fibrinplatelet bond interactions depending on the level of coagulation and fibrinolysis the sampled blood is experiencing.38 The ROTEM device uses modified technology compared with the TEG device using an optical detector rather than a torsion wire, and the mechanical oscillation originates from the pin, not the blood sample cup. Furthermore, the ROTEM instrument uses different plastic for the pin and cup that enhances contact activation with the sample; it also is equipped with an automatic pipette device and has proprietary formulas for coagulation activators different from those of the TEG system.37,38 Table 25.2 describes the TEG/ROTEM viscoelastic measurements and the variable nomenclature that represent the different stages of

developing and resolving clot. The time until initial fibrin formation is the reaction (R) time (TEG) or clotting time (CT) (ROTEM); the kinetics of fibrin formation and clot development is the kinetic (K) or alpha angle (α) (TEG) or the clot formation time or alpha angle (α) (ROTEM); the strength and stability of the fibrin clot is the maximum amplitude (MA) (TEG) or maximum clot firmness (MCF) (ROTEM) and clot lysis (CL) (TEG) or clot lysis (LY) (ROTEM).

USE OF TEG FOR MONITORING ANTICOAGULANT THERAPY Thromboelastography produces a tracing that depicts parameters measured throughout the life span of a clot (Figure 25.18). Alterations because of anticoagulation therapy or coagulopathies result in alteration of the tracing. Interpretation of the tracing (Figure 25.19) or output results (Table 25.3) can provide insight into the contributions of anticoagulant therapy versus those of other contributors to alterations in the clotting cascade that may be present in critically ill patients on anticoagulation.

Table 25.2 Nomenclature and Reference Values of Thromboelastography and Thromboelastometry6 TEG Clotting time (period to 2 mm amplitude)

Clot kinetics (period from 2 to 20 mm amplitude)

Clot strengthening (α angle)

ROTEM

R (reaction time)

CT (clotting time)

N (WB) 4–8 min

N (Cit, in-TEM) 137–246 s

N (Cit, kaolin) 3–8 min

N (Cit, ex-TEM) 42–74 s

K (kinetic time)

CFT (clot formation time)

N (WB) 1–4 min

N (Cit, in-TEM) 40–100 s

N (Cit, kaolin) 1–3 min

N (Cit, ex-TEM) 46–148 s

α (slope between r

α (slope of tangent at 2 mm

and k) N (WB) 47°–74°

amplitude) N (Cit, in-TEM) 71°–82° N (Cit, ex-TEM) 63°–81°

Amplitude (at set time) A

A

A

Maximum strength

N (WB) 55–73 mm

MCF (maximum clot firmness)

MA (maximum amplitude)

N (Cit, in-TEM) 52–72 mm

N (Cit, kaolin) 51– 69 mm

N (Cit, fib-TEM) 9–25 mm

CL30, CL60

LY30, LY60

Lysis (at fixed time)

N (Cit, ex-TEM) 49–71 mm

TEG (thromboelastography): N = normal values for kaolin activated TEG in native whole blood (WB) or citrated and recalcified blood samples (Cit) (Haemoscope Corp.) or ROTEM using contact (partial thromboplastin phospholipids, in-TEM), tissue factor (exTEM), and tissue factor plus platelet inhibitor cytochalasin D (fib-TEM) activated citrated and recalcified blood samples. Reference value depends on reference population, blood sampling technique, and other re-analytic factors and coagulation activator.

Thromboelastography can be used to evaluate the effect of heparin, either exogenous or endogenous, by placing the sample into cups coated with heparinase. This enzyme, unlike protamine, will antagonize the effects of heparin without affecting TEG/ROTEM variables. The heparinase-coated cup samples can be analyzed in parallel with noncoated cup samples to determine whether heparin is still present (e.g., in the case of protamine reversal)39 or to monitor coagulation in the presence of full-dose heparin therapy. The difference in R time between the simultaneously performed TEG with and without heparinase provides a linear relationship between heparin level and R time and allows for the determination of heparin dosing in patients.40 The test times of TEG and ROTEM are typically 20 minutes or less, which offers a convenient point-of-care option if the machine is located near the patient. The downside to the TEG for monitoring heparin is the lack of clinical outcomes associated with the results provided. This makes it difficult to establish the goal R time and an appropriate

recommendation for dosage adjustment that is based on the result. Although the use of the TEG for monitoring heparin therapy is a plausible option, it still becomes a distant alternative to the aPTT and anti-Xa assay for routine monitoring of heparin therapy. In addition to monitoring UFH, TEG can detect the anticoagulant effects of LMWHs. Thromboelastography has been compared with anti-Xa activity using a variety of end points including R time, α angle, and maximum amplitude. Most, but not all, studies have shown a good correlation between the anti-Xa results and TEG R time or change in R time.41-43 The goal R time or change in R time is unknown, but a study of coronary care unit patients showed that every 10% increase in milligram per kilogram dose of enoxaparin resulted in an increase in R time of 2.7 (95% confidence interval, 0.6–4.7).41 Almost all patients had an R time of more than 8 minutes when peak levels were drawn 4 hours after a 1-mg/kg subcutaneous enoxaparin dose. Most studies to date are too small to correlate TEG results to clinical outcomes in patients on LMWH. A study of 87 trauma and general surgery patients used TEG-guided enoxaparin dosing to increase the R time by 1–2 minutes. They compared this TEG-adjusted regimen with a standard 30-mg twice-daily regimen. Thromboelastography-guided therapy resulted in increased LMWH dosing and anti-Xa levels, but no decrease in VTE.44 Therefore, at this time, TEG may be considered an additional tool for monitoring LMWH when the anti-Xa assay is not readily available or there is a question about the accuracy of the reported results.

Figure 25.18 Thromboelastography tracing and measured parameters. Normal viscoelastic tracing of TEG/ROTEM. Upper side: Thromboelastography (TEG) tracing: α = slope between R and K; CL = clot lysis; K time = kinetic time; MA = maximum amplitude; MA60 = maximum amplitude 60 min after initial maximum amplitude; R = reaction time. Lower side: Rotation thromboelastography (ROTEM) tracing: α = slope of tangent at 2 mm amplitude; CFT = clot formation time; CT = clotting time; LY = lysis; MCF = maximum clot formation firmness.

Figure 25.19 Examples of abnormal TEG/ROTEM tracings. Thromboelastography assays using ecarin can be used as an alternative method to monitor DTIs.45-47 Adding ecarin to the TEG initiates coagulation, and the effect of bivalirudin is measured by the change in R time. Compared with the ACT, correlation of the ecarin TEG with bivalirudin concentration was significantly higher with the TEG (r2 = 0.75) versus the ACT (r2 = 0.31) [p 90%) -Reflects fibrinolysis LY30 (< 7.5%)

-The rate of amplitude reduction 30 minutes after MA

-Reflects fibrinolysis

FFP = fresh frozen plasma; LY = lysed; MA = maximum amplitude; PCC = prothrombin complex concentrate; rFVIIa = recombinant factor VIIa.

The need for platelet monitoring is based on the premise that it will improve patient outcomes. However, data analyses to date are mixed regarding any clinical outcome improvements.60-63 A recent randomized multicenter study of 2,440 patients scheduled for coronary stenting was unable to show any significant improvements in clinical outcomes with platelet function monitoring with dose adjustment compared with standard antiplatelet therapy without monitoring.61 Given the lack of a clear benefit in most patients, point-of-care monitoring of platelet activity should likely be reserved for patients with significant drug interactions with their antiplatelet medications, those with concerns about oral antiplatelet absorption, and those with a significant risk of bleeding.

Table 25.4 Disorders Associated with Increased Plasma Concentrations of Fibrin D-dimer Arterial thromboembolic disease Myocardial infarction Stroke Acute limb ischemia Atrial fibrillation Intracardiac thrombus Venous thromboembolic disease Deep venous thrombosis Pulmonary embolism Disseminated intravascular coagulation Preeclampsia and eclampsia Abnormal fibrinolysis; use of thrombolytic agents

Cardiovascular disease, congestive failure Severe infection/sepsis/inflammation Surgery/trauma (e.g., tissue ischemia, necrosis) Systemic inflammatory response syndrome Vasoocclusive episode of sickle cell disease Severe liver disease (decreased clearance) Malignancy Renal disease Nephrotic syndrome (e.g., renal vein thrombosis) Acute renal failure Chronic renal failure and underlying cardiovascular disease Normal pregnancy Venous malformations

FUTURE DIRECTIONS IN LABORATORY ANTICOAGULATION TESTING Despite the many tests available and the vast experience with antithrombotic agents, bleeding and thrombosis are still substantial contributors to morbidity and mortality in the ICU. The problem with many anticoagulant laboratory tests is their evaluation of only a portion of the coagulation process and their susceptibility to outside influences. Many tests may be a good surrogate for an anticoagulant’s contribution to a specific portion of thrombus generation, but they may lead to a lack of understanding of the entire hemostatic process that places a patient at risk of unintended outcomes. Many believe that global assays of hemostasis (e.g., TEG) are more reflective of likely clinical outcomes such as VTE, bleeding, length of stay, and mortality. However, their lack of standardization and limited data showing their sensitivity and specificity for predicting clinically important outcomes preclude their use as a standard of care for most ICU patients. Novel global assays in development build on currently available tests and include thrombin and plasmin generation, thrombodynamics, and flow perfusion chambers.64 Despite the potential advantages of these new

options, most of these tests are in their infancy. Large patient cohorts will be necessary to determine whether they offer any clinically meaningful advantage over current laboratory options. Given that the data generated will have to show both a statistically and a clinically meaningful difference, clinicians are likely to have to choose a monitoring strategy from the currently available laboratory tests for the near future.

CONCLUSION Routine anticoagulant laboratory tests, including the PT, aPTT, and antiXa, are commonly ordered to assess clotting function in critically ill patients. Many variables commonly present in critically ill patients must be considered when interpreting the results of coagulation laboratory tests. Newer laboratory tests are available that may be more specific for monitoring certain anticoagulants; however, data correlating results to clinical outcomes are limited. Many assays are performed on several platforms using different reagents between institutions, making standardization difficult to accomplish. Critical care clinicians should have a close working relationship with the anticoagulation laboratory and hematologists to ensure appropriate use of coagulation testing and interpretation.

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with extracorporeal circulation. Best Pract Res Clin Anaesthesiol 2015;29:189-202. 22. Koster A, Despotis G, Gruendel M, et al. The plasma supplemented modified activated clotting time for monitoring of heparinization during cardiopulmonary bypass: a pilot investigation. Anesth Analg 2002;95:26-30, table of contents. 23. Staples MH, Dunton RF, Karlson KJ, et al. Heparin resistance after preoperative heparin therapy or intraaortic balloon pumping. Ann Thorac Surg 1994;57:1211-6. 24. Williams MR, D’Ambra AB, Beck JR, et al. A randomized trial of antithrombin concentrate for treatment of heparin resistance. Ann Thorac Surg 2000;70:873-7. 25. Lange U, Nowak G, Bucha E. Ecarin chromogenic assay—a new method for quantitative determination of direct thrombin inhibitors like hirudin. Pathophysiol Haemost Thromb 2003;33:184-91. 26. Nowak G. The ecarin clotting time, a universal method to quantify direct thrombin inhibitors. Pathophysiol Haemost Thromb 2003;33:173-83. 27. Love JE, Ferrell C, Chandler WL. Monitoring direct thrombin inhibitors with a plasma diluted thrombin time. Thromb Haemost 2007;98:234-42. 28. Lind SE, Boyle ME, Fisher S, et al. Comparison of the aPTT with alternative tests for monitoring direct thrombin inhibitors in patient samples. Am J Clin Pathol 2014;141:665-74. 29. Ahmad S, Ahsan A, George M, et al. Simultaneous monitoring of argatroban and its major metabolite using an HPLC method: potential clinical applications. Clin Appl Thromb Hemost 1999;5:252-8. 30. Fenyvesi T, Jorg I, Harenberg J. Monitoring of anticoagulant effects of direct thrombin inhibitors. Semin Thromb Hemost 2002;28:361-8.

31. Harenberg J, Jorg I, Fenyvesi T, et al. Treatment of patients with a history of heparin-induced thrombocytopenia and anti-lepirudin antibodies with argatroban. J Thromb Thrombolysis 2005;19:65-9. 32. Koster A, Chew D, Grundel M, et al. Bivalirudin monitored with the ecarin clotting time for anticoagulation during cardiopulmonary bypass. Anesth Analg 2003;96:383-6, table of contents. 33. Calatzis A, Peetz D, Haas S, et al. Prothrombinase-induced clotting time assay for determination of the anticoagulant effects of unfractionated and low-molecular-weight heparins, fondaparinux, and thrombin inhibitors. Am J Clin Pathol 2008;130:446-54. 34. Samos M, Stanciakova L, Ivankova J, et al. Monitoring of dabigatran therapy using Hemoclot((R)) Thrombin Inhibitor assay in patients with atrial fibrillation. J Thromb Thrombolysis 2015;39:95-100. 35. Guy S, Kitchen S, Maclean R, et al. Limitation of the activated partial thromboplastin time as a monitoring method of the direct thrombin inhibitor argatroban. Int J Lab Hematol 2015. 36. Castoldi E, Rosing J. Thrombin generation tests. Thromb Res 2011;127(suppl 3):S21-5. 37. Luddington RJ. Thrombelastography/thromboelastometry. Clin Lab Haematol 2005;27:81-90. 38. Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 2008;106:1366-75. 39. Levin AI, Heine AM, Coetzee JF, et al. Heparinase thromboelastography compared with activated coagulation time for protamine titration after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2014;28:224-9. 40. Schaden E, Jilch S, Hacker S, et al. Monitoring of unfractionated heparin with rotational thrombelastometry using the prothrombinase-induced clotting time reagent (PiCT(R)). Clin Chim

Acta 2012;414:202-5. 41. White H, Sosnowski K, Bird R, et al. The utility of thromboelastography in monitoring low molecular weight heparin therapy in the coronary care unit. Blood Coagul Fibrinolysis 2012;23:304-10. 42. Klein SM, Slaughter TF, Vail PT, et al. Thromboelastography as a perioperative measure of anticoagulation resulting from low molecular weight heparin: a comparison with anti-Xa concentrations. Anesth Analg 2000;91:1091-5. 43. Carroll RC, Craft RM, Whitaker GL, et al. Thrombelastography monitoring of resistance to enoxaparin anticoagulation in thrombophilic pregnancy patients. Thromb Res 2007;120:367-70. 44. Louis SG, Van PY, Riha GM, et al. Thromboelastogram-guided enoxaparin dosing does not confer protection from deep venous thrombosis: a randomized controlled pilot trial. J Trauma Acute Care Surg 2014;76:937-42; discussion 42-3. 45. Solbeck S, Meyer MA, Johansson PI, et al. Monitoring of dabigatran anticoagulation and its reversal in vitro by thrombelastography. Int J Cardiol 2014;176:794-9. 46. Carroll RC, Chavez JJ, Simmons JW, et al. Measurement of patients’ bivalirudin plasma levels by a thrombelastograph ecarin clotting time assay: a comparison to a standard activated clotting time. Anesth Analg 2006;102:1316-9. 47. Engstrom M, Rundgren M, Schott U. An evaluation of monitoring possibilities of argatroban using rotational thromboelastometry and activated partial thromboplastin time. Acta Anaesthesiol Scand 2010;54:86-91. 48. Dias JD, Norem K, Doorneweerd DD, et al. Use of thromboelastography (TEG) for detection of new oral anticoagulants. Arch Pathol Lab Med 2015;139:665-73. 49. Craft RM, Chavez JJ, Bresee SJ, et al. A novel modification of the Thrombelastograph assay, isolating platelet function,

correlates with optical platelet aggregation. J Lab Clin Med 2004;143:301-9. 50. Katori N, Szlam F, Levy JH, et al. A novel method to assess platelet inhibition by eptifibatide with thrombelastograph. Anesth Analg 2004;99:1794-9, table of contents. 51. Kettner SC, Panzer OP, Kozek SA, et al. Use of abciximabmodified thrombelastography in patients undergoing cardiac surgery. Anesth Analg 1999;89:580-4. 52. Khurana S, Mattson JC, Westley S, et al. Monitoring platelet glycoprotein IIb/IIIa-fibrin interaction with tissue factor-activated thromboelastography. J Lab Clin Med 1997;130:401-11. 53. Aschwanden M, Labs KH, Jeanneret C, et al. The value of rapid D-dimer testing combined with structured clinical evaluation for the diagnosis of deep vein thrombosis. J Vasc Surg 1999;30:929-35. 54. Lennox AF, Delis KT, Serunkuma S, et al. Combination of a clinical risk assessment score and rapid whole blood D-dimer testing in the diagnosis of deep vein thrombosis in symptomatic patients. J Vasc Surg 1999;30:794-803. 55. Wells PS, Anderson DR, Bormanis J, et al. Application of a diagnostic clinical model for the management of hospitalized patients with suspected deep-vein thrombosis. Thromb Haemost 1999;81:493-7. 56. Le Gal G, Righini M, Roy PM, et al. Value of D-dimer testing for the exclusion of pulmonary embolism in patients with previous venous thromboembolism. Arch Intern Med 2006;166:176-80. 57. Righini M, Le Gal G, De Lucia S, et al. Clinical usefulness of Ddimer testing in cancer patients with suspected pulmonary embolism. Thromb Haemost 2006;95:715-9. 58. Dornia C, Philipp A, Bauer S, et al. D-dimers are a predictor of clot volume inside membrane oxygenators during extracorporeal membrane oxygenation. Artif Organs 2015.

59. Lubnow M, Philipp A, Dornia C, et al. D-dimers as an early marker for oxygenator exchange in extracorporeal membrane oxygenation. J Crit Care 2014;29:473 e1-5. 60. Steinhubl SR, Kottke-Marchant K, Moliterno DJ, et al. Attainment and maintenance of platelet inhibition through standard dosing of abciximab in diabetic and nondiabetic patients undergoing percutaneous coronary intervention. Circulation 1999;100:197782. 61. Collet JP, Cuisset T, Range G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012;367:2100-9. 62. Steinhubl SR, Talley JD, Braden GA, et al. Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study. Circulation 2001;103:2572-8. 63. Tamberella MR, Bhatt DL, Chew DP, et al. Relation of platelet inactivation with intravenous glycoprotein IIb/IIIa antagonists to major bleeding (from the GOLD study). Am J Cardiol 2002;89:1429-31. 64. Lipets EN, Ataullakhanov FI. Global assays of hemostasis in the diagnostics of hypercoagulation and evaluation of thrombosis risk. Thromb J 2015;13:4.

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

LEARNING OBJECTIVES 1. Describe the basic etiology, common causes, and prognosis of acute kidney injury (AKI). 2. Differentiate prerenal azotemia, intrinsic AKI, and postrenal causes of AKI. 3. Explain how laboratory tests are used to differentiate between various types of AKI. 4. Discuss approaches to prevent and treat AKI. 5. Explain measures the critical care pharmacist may use to predict, prevent, and manage drug-induced AKI.

ABBREVIATIONS IN THIS CHAPTER ACEI

Angiotensin-converting enzyme inhibitor

AKI

Acute kidney injury

AKIN

Acute Kidney Injury Network

ARB

Angiotensin receptor blocker

ATN

Acute tubular necrosis

BUN

Blood urea nitrogen

FENa

Fractional excretion of sodium

GFR

Glomerular filtration rate

ICU

Intensive care unit

KDIGO Kidney Disease Improving Global Outcomes NSAID

Nonsteroidal anti-inflammatory drug

RIFLE

Risk, injury, failure, loss of kidney function, end-stage kidney disease

RRT

Renal replacement therapy

INTRODUCTION Monitoring kidney function and hemodynamics is a mainstay of intensive care medicine. Acute kidney injury (AKI), previously called acute renal failure, is characterized by a rapid decline in glomerular filtration rate (GFR) and excretory function in the kidneys. The traditional assumptions about acute changes in kidney function have been challenged within the past decade, with a renewed focus on earlier, mild injury associated with adverse clinical outcomes, particularly in the critically ill population. This chapter will review the most recent approaches to preventing, defining, staging, and managing AKI with an emphasis on patient care.

Incidence and Prognosis Acute kidney injury reportedly affects almost 500 people per 1 million each year, including 5% of all hospitalized patients,1 with around 40% of these requiring acute renal replacement therapy (RRT).2 The timeline for developing AKI after an acute insult ranges from hours to

days or weeks and has been reported to occur in up to 20% of hospital admissions.3 The reported incidence of AKI in post-surgical populations ranges from 0.8% (minor surgery) to 36.7% (major surgery), with mortality (90 day and 5 year) increasing 2- to 3-fold in the presence of AKI.4 The incidence of AKI in intensive care unit (ICU) patients is even higher, approaching 50% in patients with early AKI.5 The prognosis of patients with AKI is associated with the degree of reduced urine output and the duration and severity of AKI. For example, it is widely reported that a urine output of less than 0.5 mL/kg/hour for 6 hours is associated with increased mortality even in the absence of changes in serum creatinine.6 However, lower thresholds for urine output have been associated with worse outcomes. In a critical care cohort study, Ralib et al. reported that a urine output below 0.3 mL/kg/hour for 6 hours was associated with a marked increase in mortality.7 The length of time serum creatinine remains elevated, or the duration of AKI, has also been associated with worse outcomes. Long-term survival was associated with the duration of AKI in patients post-cardiac surgery8 and in patients with diabetes noncardiac surgery,9 where the mortality for patients with 3–6 days of initial AKI was greater than 2 or fewer days of more advanced stages of AKI.

Etiology Acute kidney injury is highly preventable and usually reversible, with recovery taking days to weeks. If prolonged, AKI can progress to endstage kidney disease requiring chronic RRT. Thus, identifying risk factors for AKI (see Table 26.1) is critical to prevent it from developing. According to NCEPOD (the UK National Confidential Enquiry into Patient Outcome and Death), around 20%– 30% of all AKI events are predictable and avoidable. In reviewing more than 1,500 AKI-related deaths, this expert advisory group found that only 50% of patients receiving care for AKI met acceptable medical practice standards (defined as “good”).10 A likely contributor to inadequate care for patients with AKI is failure to recognize and manage the condition. For

example, azotemia, defined as a nonspecific elevation in serum urea nitrogen concentration, is common in patients with gastrointestinal bleeding, severe catabolism, oliguria, intravascular volume depletion, and after administering drugs that alter renal hemodynamics. Other confounding factors include nonspecific elevations in serum creatinine, as noted in patients with increased muscle mass, associated with increased dietary protein intake, or after severe muscle injury or rhabdomyolysis. Thus, a complete clinical assessment is needed before an accurate diagnosis of AKI can be made. Regardless of the etiology of AKI, both ischemic injury and directly toxic injury to the kidney can ultimately lead to AKI, including acute tubular necrosis (ATN). Acute kidney injury in the ICU population is often complicated by several organ system failures occurring simultaneously. These critically ill patients may be receiving pharmacologic and life-support treatments, including RRT to maintain adequate homeostasis.

PATHOPHYSIOLOGY The two fundamental mechanisms contributing to AKI are hypoxia and cellular injury. The kidneys receive almost 20% of cardiac output to meet the high tissue oxygen demands. The tubular regions in the loop of Henle have the highest oxygen extraction ratio (relative to O2 delivery) of any cell in the human body, with almost 80% of delivered oxygen being used.11 Most of the oxygen consumption is related to ATP-dependent sodium transporters that drive the major fluid homeostasis mechanism of the body. This activity is coupled with GFR, where increased ultrafiltrate delivery leads to higher sodium reabsorption and greater oxygen consumption. The three primary mechanisms of AKI are conventionally classified according to relative hemodynamics and vascular anatomy.

Prerenal Azotemia Azotemia classified as “prerenal” indicates that an acute decrease in GFR has occurred in an otherwise normal kidney, in response to

hypovolemia or hypoperfusion. As an initial response to hypoperfusion, blood flow is redistributed to the hypoxic regions of the kidney (medulla). Renal ischemia and tissue hypoperfusion, if present for a prolonged duration, can ultimately lead to loss of renal cellular integrity and tissue necrosis. In severe ischemia, tubular sodium reabsorption is compromised, leading to urinary sodium loss and activation of the renin-angiotensin-aldosterone system (RAAS). This leads to heightened afferent arteriolar tone and a decrease in GFR. Without this RAASmediated negative feedback mechanism, the GFR would remain unchanged, and severe dehydration and death would rapidly ensue. The reduced GFR and urine output (oliguria) in the face of AKI serves as a mechanism that sacrifices GFR to maintain life. This functional feedback loop is often called “acute renal success” as opposed to renal failure.

Table 26.1 Examples of Risk Factors Associated with AKI35,125-127 Preexisting liver disease Preexisting renal disease Concomitant nephrotoxins (i.e., amphotericin B, aminoglycosides) Advanced age Impaired renal vasoconstriction/vasodilation

Hypovolemic states (hemorrhage, volume depletion, burns, cardiovascular shock) Low cardiac output (heart failure) Anaphylaxis Severity of illness

Obesity Cardiovascular disease ACEIs/ARBs Surgery or trauma Multiple comorbidities Respiratory disease Vasopressors Diuretics

ACEI = angiotensin-converting enzyme inhibitor; AKI = acute kidney injury; ARB = angiotensin receptor blocker.

Intrarenal (Intrinsic) AKI Intrinsic renal causes are important sources of AKI and are usually categorized by the mechanism of direct injury that typically occurs in each condition. The most common forms of intrinsic AKI likely to be seen in ICU settings include sepsis, ATN, ischemia/vascular, and endogenous nephrotoxins. Sepsis Sepsis is the most common form of AKI occurring in the ICU population (greater than 30%). The exact mechanism is not fully understood, but it likely involves a complex interplay between initial reduction in vascular resistance, hypoperfusion, ischemia/reperfusion, and apoptosis.12,13 Acute Tubular Necrosis Acute tubular necrosis is the leading cause of non-sepsis AKI in the ICU. Because of the close association of ATN with pre-renal azotemia, it is important to distinguish the two forms using clinical signs, medical history, and laboratory criteria (see Table 26.2). The time course of ATN is often described by a three-part series of events: initiation, maintenance, and recovery. The initiation phase is characterized by an acute decline in GFR, followed by a rapid rise in serum creatinine and blood urea nitrogen (BUN) concentrations. The maintenance phase is characterized by a sustained reduction in GFR, continuing for up to 2 weeks. Because GFR is severely compromised during this phase, serum creatinine and BUN continue to rise. During the recovery phase, tubular function is restored, leading to an increase in urine output and a return of the BUN and serum creatinine concentrations to their preinjury levels. The extent of tubule cell damage and nephrotoxicity in ATN depends on the kidneys’ capacity to recover from the initial insult, intrarenal vasoconstriction, and any intratubular obstruction. Ischemia/Vascular Ischemic ATN is often closely related to prerenal azotemia, given that

both conditions are caused by similar insults. Ischemic ATN occurs after prolonged hypoperfusion, where the initial autoregulatory responses in the kidney are overwhelmed. Here, severe hypoperfusion leads to cell injury and cell death. Endogenous Nephrotoxins Conditions associated with traumatic injury or muscle toxicity can lead to rhabdomyolysis-induced AKI. Extensive hemolysis caused by severe blood transfusion reactions can lead to myoglobin-induced AKI. Acute crystal-induced nephropathy is another endogenous form of AKI, caused by myeloablative cancer treatments associated with high cell turnover (and release of uric acid crystals), but it may also be caused by acute ingestions of ethylene glycol or high-dose vitamin C. Exogenous Nephrotoxins Many nephrotoxic drugs that are associated with ATN are commonly used in the ICU. Individual nephrotoxic drugs are rarely the sole cause of AKI, unless given in high doses over a long period. Nephrotoxic drugs used in high-risk patients with preexisting conditions such as chronic kidney disease, sepsis, dehydration, or hypotension, or the use of vasopressors, can increase the likelihood of AKI in the ICU. Examples of drug-induced ATN include the following: Aminoglycoside-related toxicity occurs in 10%–30% of patients receiving aminoglycosides, even when serum drug concentrations are within the typical therapeutic range. This is the result of direct toxicity in proximal tubular cells, where uptake is mediated by megalin receptors.14 Amphotericin B nephrotoxicity is often dose-related, where risk is related to the maximum daily dose (greater than 3 g) and therapy duration. The mechanism is likely related to the combined effects of sterol binding in cell membranes and direct vasoconstriction. The increased membrane permeability can lead to the renal wasting of electrolytes, such as

potassium and magnesium, as well as a back-leak of hydrogen ions in the collecting duct, causing distal renal tubular acidosis. Direct vasoconstriction at the afferent arteriole can further contribute to acute changes in GFR and alterations in the tubuloglomerular feedback mechanism. Radiographic contrast media can cause contrast-induced nephropathy or radiocontrast nephropathy. These agents cause renal medullary vasoconstriction, decreased renal blood flow, and direct tubular toxicity.15 Radiocontrast nephropathy is associated with several risk factors, including preexisting chronic kidney disease, diabetic nephropathy, heart failure, volume depletion and drugs (i.e., diuretics, nonsteroidal anti-inflammatory drugs [NSAIDs], angiotensinconverting enzyme inhibitors [ACEIs], and angiotensin receptor blockers [ARBs]). Nonsteroidal anti-inflammatory drugs can have adverse renal effects that are explained by two distinct pathological processes. The first mechanism of AKI is the result of reduced renal plasma flow caused by a decrease in prostaglandin synthesis, which regulates vasodilation at the glomerular level. Nonsteroidal anti-inflammatory drugs block the compensatory vasodilation response of renal prostaglandins, leading to unopposed vasoconstriction. A second mechanism of AKI is an acute allergic reaction, also known as acute interstitial nephritis. This typically occurs after short-term exposure (less than 7 days) and is characterized by the presence of an inflammatory cell infiltrate in the interstitium of the kidney. Calcineurin inhibitors (such as cyclosporin and tacrolimus) often cause acutely severe afferent arteriolar vasoconstriction that impairs glomerular blood flow, leading to decreased GFR. Chronic exposure to these drugs can lead to tubulointerstitial fibrosis, further increasing the risk of AKI when combined with other risk factors, including vasopressors

such as norepinephrine, which are commonly used in ICU settings.

Table 26.2 Common Clinical Laboratory Evaluation of AKI

aOften seen in acute interstitial nephritis. FENa = fractional excretion of sodium; SCr = serum creatinine.

Postrenal AKI Postrenal AKI is often caused by an obstruction in the urinary tract downstream from the kidneys, disrupting normal urine outflow. It occurs less often than intrinsic AKI or ATN in ICU settings. Conditions that may lead to postrenal AKI include kidney stones, an enlarged prostate, and neurological conditions leading to incomplete bladder emptying. For example, urinary calculi can be caused by metabolic abnormalities induced by loop diuretics, carbonic anhydrase inhibitors, and laxatives or supersaturation/crystallization with ciprofloxacin, triamterene, and sulfonamide antibiotics. In most cases, normal kidney function is regained if the etiology is identified and corrected promptly.

DISEASE ASSESSMENT

History and Physical Examination A detailed and accurate medical history is critical for understanding the cause(s) of AKI in a given patient. This information is needed to distinguish acute from chronic kidney disease, where symptoms of fatigue, weight loss, anorexia, and pruritus are more common. Findings in the medical history that may predispose an individual to AKI include significant fluid or blood loss (i.e., gastroenteritis, recent surgery), trauma, and exposure to nephrotoxic drugs or heavy metals (mercury, lead, cadmium) that are considered an occupational hazard for welders and miners. Certain preexisting conditions can place patients at an elevated risk of developing AKI, including hypertension, chronic heart failure, diabetes, and autoimmune disorders. The physical examination may provide evidence of intravascular hypovolemia depending on cardiovascular signs (heart rate, blood pressure) and peripheral edema. The presence of skin lesions may indicate trauma or acute allergic/immune reactions. Abdominal examination may help identify bladder obstruction caused by cancer or an enlarged prostate. Estimating urine output for the past 3–5 days together with recent hourly fluid intake and output can yield important information about the time of onset and severity of AKI. Oliguria, defined as a urine output less than 400 mL/day, commonly occurs in prerenal and intrinsic AKI, whereas abrupt anuria (less than 50 mL/day) suggests acute urinary obstruction. A slower rate of urine output decline may indicate urethral or bladder outlet obstruction related to prostate hypertrophy.

Serum and Urinary Measures The criteria most widely used to define AKI are based on (1) rate of rise of serum creatinine and (2) urine output. Until recently, there were no clear guidelines, definitions, or terminology related to AKI, making it difficult to directly compare ICU populations and outcomes in clinical studies. In 2004, the RIFLE approach to categorizing and staging AKI according to risk, injury, failure, loss of kidney function, and end-stage kidney disease was introduced by the ADQI (Acute Dialysis Quality

Initiative) to grade the severity of AKI in the ICU.16 In 2007, a set of uniform standards for describing and classifying AKI was proposed by the Acute Kidney Injury Network (AKIN).17 In 2012, a third set of criteria was introduced by the Kidney Disease Improving Global Outcomes (KDIGO) group that incorporates parts of both the RIFLE and the AKIN definitions.18 A comparison of these approaches is shown in Table 26.3. The AKIN criteria include a shorter time interval for the rise of serum creatinine (within 48 hours) and include an absolute increase in serum creatinine of 0.3 mg/dL or greater or 50% or greater from baseline. Both RIFLE and AKIN criteria include a reduction in urine output of less than 0.5 mL/kg per hour for more than 6 hours. The KDIGO group further simplified the approach to include a basic definition of AKI, together with severity criteria (similar to AKIN), to provide a single definition that could be applied to practice, research, and public health. Cystatin C is another surrogate marker used to detect acute changes in kidney function. It has been suggested that the rise in serum cystatin C from baseline occurs earlier than for serum creatinine and is a better early indicator of AKI. Herget-Rosenthal et al. reported that an increase in cystatin C of 50% occurred almost 2 days earlier than a similar rise in serum creatinine.19 Nejat et al. studied more than 400 ICU patients and reported that changes in urinary cystatin C were detected earlier than for creatinine in patients with AKI, and urinary cystatin C was independently associated with AKI, sepsis, and death within 30 days.20 In addition to measuring urine output and classifying/ staging AKI according to the criteria given previously, measuring the fractional excretion of sodium (FENa) provides an index of the percentage of filtered sodium excreted in the urine that can be used to distinguish prerenal from intrarenal (ATN) causes of AKI (Table 26.1). This nonspecific index of tubular function should not be used alone to evaluate AKI because many other conditions can alter FENa values, including renal salt wasting and diuretic therapy. The FENa is included as part of the comprehensive evaluation of AKI, including medical history, clinical and laboratory evaluation, and urine microscopy.

Table 26.3 Common Criteria Used for AKI Severity Staging

aWithin the past 7 days. bRecommended to use MDRD (Modification of Diet in Renal Disease) with estimated GFR of 75–100 mL/minute/1.73m 2 to estimate baseline creatinine when missing. cStage 3 also includes any patients with at least stage 1 AKI requiring RRT (renal replacement therapy). AKIN = Acute Kidney Injury Network; KDIGO = Kidney Disease Improving Global Outcomes; RIFLE = risk, injury, failure, loss of kidney function, and end-stage kidney disease.

Calculating FENa requires measuring the filtered sodium load, which is the product of the creatinine clearance [urine creatinine (UCr) × urine volume (V) divided by serum creatinine (SCr)] and the serum sodium

concentration (SNa). The urinary sodium excretion is equal to the product of the urine sodium concentration (UNa) and the urine volume (V). This results in the following equation:

Although no definitive tests predict AKI, measuring urine output in response to a diuretic challenge has been proposed. For example, a furosemide stress test, consisting of a single dose of furosemide 1 mg/kg in naive patients or 1.5 mg/kg in previously exposed patients, in early AKI (defined as AKIN stage I or II) significantly predicts the patients who will progress to a higher AKI stage.21 After receiving the furosemide dose, patients were significantly more likely to progress if their subsequent urine output in 2 hours was less than 200 mL (100 mL/hour). The sensitivity and specificity of this test are 87.1% and 84.1%, respectively. Adding other renal biomarkers did not improve the predictive quality of the test.

Urine Microscopy Urine microscopy is readily available and inexpensive and is an important part of the differential diagnosis of AKI. Evaluating the urinary sediment is most useful to distinguish between ATN and prerenal AKI. Urinary microscopy in patients with ATN often reveals renal tubular epithelial cells, cellular casts, granular casts, and muddy brown or mixed cellular casts. In a study of 267 consecutive patients with AKI, a urinary sediment scoring system was a strong predictor of ATN.22 In the absence of pyelonephritis, the presence of leukocytes, red blood cells (RBCs), and white blood cell (WBC) casts in the urine of patients with AKI can indicate drug-induced acute interstitial nephritis. In contrast, patients with prerenal AKI may have no abnormal findings on microscopy, or occasional hyaline casts.

Renal Imaging and Biopsy Studies Renal ultrasonography is particularly important for identifying postrenal causes of AKI. For example, the presence of residual postvoiding urine volumes greater than 100 mL can indicate a urine outflow obstruction. Other extrarenal causes of obstruction, such as tumors, can be detected using computed tomography or magnetic resonance imaging. Kidney biopsies are usually reserved for when pre- and postrenal causes of AKI have been excluded and the cause of intrinsic renal injury is unclear. Renal biopsy can be used to confirm acute glomerular and interstitial nephritis (acute interstitial nephritis) that may be related to drug-induced AKI.

Novel Biomarkers Many novel urinary protein biomarkers have been shown to predict the occurrence and severity of AKI in ICU settings. Haase et al. compiled the results of several studies and found that neutrophil gelatinaseassociated lipocalin (NGAL), across different time points, predicted the need for dialysis and death.23 Similarly, Koyner et al. reported that urine NGAL, measured post-cardiac surgery, was a strong predictor of stage 3 AKI and that preoperative urine KIM-1 (kidney injury molecule 1) levels were less predictive.24 Parikh et al. reported that urine IL-18 (inter-leukin-18) was significantly associated with mortality in a subgroup of ICU patients within the ARDS (Acute Respiratory Distress Syndrome) Network trial.25 More recent studies have evaluated novel combinations of biomarkers for their ability to predict AKI. Prowle et al. studied a group of 93 high-risk patients undergoing cardiopulmonary bypass together with combinations of biomarkers to predict RIFLE-R (see Table 26.3) within 5 days after surgery.26 Of the 25 patients who developed AKI, the ratio of urinary NGAL to creatinine measurement postoperatively, followed by urinary hepcidin to creatinine at 24 hours, best identified the patients in the high-, intermediate-, and low-risk AKI groups. In 2013, a combination test was introduced that measures urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and urinary insulin-like growth factor binding protein 7 (IGFBP-7). The rationale for

studying these two biomarkers is that they are both involved in the G1 cell cycle arrest of renal tubular cells during the early period of cell injury. Derivation and validation of the “TIMP-2 × IGFBP-7” biomarker algorithm in more than 500 patients accurately predicted AKI after cardiac surgery in high-risk patients,27,28 resulting in the FDA approval of NephroCheck (Astute Medical, San Diego, CA) as a urinary diagnostic device for AKI in September 2014.29

PREVENTION AND TREATMENT General Approaches Because of limited treatment options, preventing AKI is essential. Patients at risk of AKI should be identified early, with steps taken to avoid potential renal insults (see Table 26.4). Patient characteristics associated with a greater risk of AKI are included in Table 26.1. Once high-risk patients are identified, instituting general measures lessens the occurrence of AKI. These measures include maintaining appropriate fluid status and, when possible, avoiding diuretics; maintaining adequate blood pressure; and minimizing the use of potential nephrotoxins, including drugs. Loop diuretics are used in many patients with AKI to either treat or prevent renal failure.30 Because data regarding the use of loop diuretics in AKI are usually from observational or small clinical trials, often with conflicting results, several meta-analyses have clarified their role.31,32 These meta-analyses conclude that loop diuretics have little to no impact on the outcome of AKI. Whether loop diuretics were used to prevent renal deterioration or treat AKI, there was no effect on mortality or the requirement for RRT. The results were mixed regarding number of dialysis sessions and urine output, with one analysis concluding that loop diuretics shorten the duration of RRT and increase urine output, and the other showing no difference. One of the analyses showed a significantly greater incidence of ototoxicity in the loop diuretic group. Loop diuretics also have not proven beneficial in renal recovery after the completion of AKI-related RRT.33 Overall, using loop

diuretics in AKI remains controversial. There are no definitive trials of critically ill patients, and at this time, the benefit or harm of loop diuretics in AKI is unsubstantiated. The soon-to-be-published SPARK (Furosemide in Early Acute Kidney Injury) study may provide more definitive guidance.34

Hypovolemia Hypovolemia and volume depletion are significant risk factors for AKI.35 Although no clinical trials substantiate the use of fluids in preventing and treating AKI, their importance in this setting is well accepted. In addition, no large randomized controlled trials analyze the amount of fluid that should be administered to prevent or treat AKI. In the large trials that have compared colloids (e.g., albumin, hetastarches) with crystalloids (e.g., 0.9% saline, lactated Ringer solution) and chlorideliberal with chloride-restricted fluids, the amount of fluid given was at the discretion of the treating clinician. Many trials have compared colloids with crystalloids for volume depletion in ICU patients. The SAFE (Saline versus Albumin Fluid Evaluation) trial compared the administration of albumin with that of crystalloids (normal saline) in patients who required fluid administration to maintain intravascular volume.36 Although the number of patients who subsequently developed AKI was not specifically delineated in the trial, there were no differences in the number of patients with new single or multiorgan failure. Another study that looked at adding albumin to crystalloid resuscitation in patients with septic shock found similar results.37 Patients received albumin infusions on a daily basis for 28 days, and crystalloids were given according to sepsis guidelines and at the discretion of the clinician. No differences existed in the number of patients who developed AKI or required RRT at 28 days. The CRISTAL (Colloids versus Crystalloids for the Resuscitation of the Critically Ill) trial compared crystal-loids with several different colloids (albumin, gelatins, dextrans, hydroxyethyl starches) in patients with hypovolemic shock.38 Results showed no difference in the percentage of patients requiring RRT within 7 or 28 days. Of interest, using hydroxyethyl

starches for resuscitation in this trial did not increase the requirement for RRT as it had in other trials.39 In fact, a meta-analysis has shown that the use of hydroxyethyl starches for resuscitation increases the risk of AKI and the need for RRT.40 These data suggest that other than hydroxyethyl starches, which may increase the risk of AKI, the choice of resuscitation fluid, colloid or crystalloid, does not affect the subsequent development of AKI. Early goal-directed therapy in sepsis is designed to administer fluids to achieve a central venous pressure of 8–12 mm Hg; mean arterial pressure of 65 mm Hg or greater; urine output of 0.5 mL/kg/hour or greater; superior vena cava oxygenation saturation (Scvo2) or mixed venous oxygen saturation (Svo2) of 70% or 65%, respectively; and normalization of lactate concentrations.41,42 The results of the original trial showing mortality benefits with goal-directed therapy did not specifically evaluate the benefits related to AKI.41 However, several organ functioning scores were improved with the therapy. Subsequent trials evaluating the impact of early goal-directed therapy in sepsis did not find any benefit in the fluid strategy for either mortality or AKI.43,44 The number of patients requiring RRT and the duration of RRT were not statistically different between groups. There is also concern that fluid accumulation, which may occur in early goal-directed therapy in patients who are volume depleted or hypotensive, may actually increase the risk of AKI.45 In this trial, patients with fluid overload had greater mortality at 30 days and less recovery of renal function after AKI. In the FACTT study (Fluids and Catheters Treatment Trial), which evaluated conservative versus liberal fluid management of patients with acute lung injury, there was no difference in the incidence of AKI in the two fluid management groups.46

Table 26.4 General AKI Prevention/ Treatment Strategies General interventions

• Identify at-risk patients • Maintain appropriate fluid status

• Avoid diuretics • Maintain adequate blood pressure • Minimize nephrotoxic medications • Use alternative, less nephrotoxic agents when possible • Discontinue the offending agent as soon as possible • Provide general supportive measures including fluids and RRT, if necessary Loop diuretics

• Minimize use to prevent AKI • Little to no benefit in preventing or treating AKI

Crystalloids

• Equal in efficacy to colloids at preventing AKI in volume-depleted patients. • Recommended over colloids (KDIGO) • Use chloride-restricted fluids

RRT = renal replacement therapy.

Another important factor related to fluid resuscitation is choosing between chloride-liberal and chloride-restricted fluids. Excess chloride is believed to have a negative impact on renal perfusion. Therefore, administering large volumes of chloride-rich fluids may increase the risk of AKI. Most patients who receive crystalloids for shock receive normal saline (0.9% sodium chloride), which contains 154 mEq of chloride per liter. Chloride-restricted fluids include Ringer lactate and PlasmaLyte (109 and 98 mEq of chloride per liter, respectively). In a large trial of almost 3,000 patients, the use of a chloride-restricted fluid resuscitation strategy resulted in fewer patients with moderate to severe AKI and a lower requirement for RRT.47 The fluids used were either crystalloids or colloids, but the chloride-restricted fluids all had chloride concentrations less than 110 mEq/L. An even larger retrospective study of more than 7,000 patients matched patients receiving normal saline for resuscitation with patients receiving a chloride-restricted crystalloid approach (combination of Ringer lactate and normal saline).48 Although in-hospital mortality was significantly lower in the balanced fluid group, there were no differences in the

percentage of patients experiencing AKI with or without the need for dialysis. A meta-analysis of perioperative and critical care fluid resuscitation with chloride-liberal versus chloride-restricted fluids found no difference in mortality between the different crystalloids.49 However, chloride-restricted resuscitation decreased the incidence of acute renal failure and hyperchloremic metabolic acidosis. In this analysis, the significant effect was mostly driven by the results of the Yunos et al. trial, which was the only trial in the analysis that included colloids.47 The KDIGO AKI guidelines recommend crystal-loids for expanding intravascular volume over albumin or starches.50 They do not address the issue of hyperchloremic crystalloids, but most of the literature in this area was published after publication of the KDIGO guidelines. The Kidney Disease Outcomes Quality Initiative (KDOQI) commentary related to the KDIGO AKI guidelines does address the issue of harm related to hyperchloremic fluids but suggests that better prospective data are still warranted before advocating the preferential use of these fluids.18 Both KDIGO and KDOQI recommend that vasopressors be used with fluids to prevent AKI in patients with hypovolemic shock, with KDOQI commentators recommending cautious use of dopamine as a first-line vasopressor. Finally, the KDIGO guidelines recommend using a protocol to manage hemodynamic instability (e.g., early goal-directed therapy). However, because the original early goal-directed therapy trial in sepsis did not specifically assess the incidence of AKI and because more recent trials have not shown a benefit to early goaldirected therapy at preventing AKI, the KDOQI commentators do not endorse management by a protocol. It should be noted that the lack of benefit with early goal-directed therapy in more recent trials may be related to an overall improvement in the standard of care (the comparative arm in these trials) for the fluid management of sepsis. Given all of this, to prevent AKI in hypovolemic patients, it seems prudent to use chloride-restricted crystalloids with vasopressors when necessary, as part of a fluid management protocol.

Drug-Induced AKI

Specific recommendations for preventing or treating drug-induced AKI are limited (see Table 26.5). For most drugs, understanding the risk and using alternative, less nephrotoxic agents in patients at high risk of renal failure is the best preventive strategy. Treatment involves supportive care and discontinuing the offending agent as soon as possible. Fortunately, most drug-related causes of AKI are reversible if caught early, with subsequent discontinuation of the nephrotoxin. Medications most associated with renal failure include NSAIDs and selective cyclooxygenase 2 inhibitors; ACEIs and ARBs; vasopressors; β-lactam, sulfonamide, aminoglycoside, and glycopeptide antibiotics; amphotericin B; acyclovir and cisplatin; carboplatin and oxaliplatin; cyclosporine and tacrolimus; and radio-contrast agents. Drug classes with specific recommendations are listed in the paragraphs that follow with the data supporting prevention or treatment strategies. ACEIs and ARBs Although there are no specific prevention or treatment recommendations for ACEI- or ARB-induced AKI, two important points should be stressed. First, ACEI- or ARB-induced AKI is more likely to occur in patients receiving NSAIDs or diuretics, or in patients who are volume depleted.51 These risk factors reduce renal perfusion pressure and exacerbate the ACEI or ARB effect on the kidneys. In patients with these risk factors, ACEIs and ARBs should be initiated at low doses and titrated slowly. Even when someone is stabilized on an ACEI/ ARB, volume depletion or adding an NSAID or diuretic can increase the likelihood of decreasing GFR.51

Table 26.5 Drug-Induced AKI Prevention/Treatment Strategies Medication ACEIs and ARBs

• Avoid concomitant use with NSAIDs and diuretics, if possible • Maintain adequate volume status

• Start at low doses and titrate slowly Aminoglycosides

• Avoid prolonged courses, elevated trough concentrations, hypovolemia, concurrent nephrotoxic agents, and overdiuresis • Use high-dose extended-interval dosing, if possible Vancomycin • Close monitoring when targeting higher trough concentrations • Close monitoring when used concomitantly with either aminoglycosides or piperacillin/tazobactam

Amphotericin B

• Use a lipid formulation • Liberalize sodium intake, including normal saline boluses before and after administration

Sulfonamides, acyclovir, methotrexate (crystalluria) Cisplatin

• Adequate fluid (e.g., normal saline) to achieve a urine output of 100–150 mL/hr • For sulfonamide or methotrexate crystalluria, alkalinize the urine • Adequate fluid (e.g., normal saline) to achieve a urine output of 100–150 mL/hr • Begin fluid administration 12 hr before infusion and continue for 24 hr • In ovarian cancer, may consider administering amifostine before each dose • Reduce the dose or use carboplatin instead

Calcineurin inhibitors (cyclosporine, tacrolimus) Radiocontrast agents

• Monitor therapeutic drug concentrations closely • Avoid drug interactions that increase serum concentrations • Use lower doses and minimize diagnostic tests requiring radiocontrast agents • Normal saline or sodium bicarbonate infusions up to 12 hr before and 12 hr after administration • Moderate- or high-dose statins (for cardiac procedures using contrast) • Ascorbic acid (for cardiac procedures using contrast)

NSAID = nonsteroidal anti-inflammatory drug.

Second, an increase in serum creatinine after administering ACEIs/ARBs is not a reason to discontinue therapy. An increase in creatinine of up to 30% is common in the first few weeks after initiating an ACEI/ARB.51 This increase will remain but will stabilize in the first month of therapy. Only if a patient’s creatinine increases greater than 30% over baseline when initiating an ACEI/ARB should the dose be reduced or the drug discontinued altogether. Aminoglycosides Nephrotoxicity is a well-known complication of aminoglycoside therapy. Fortunately, this adverse event is reversible after discontinuation because renal cells can regenerate.52 Controversy exists regarding the risk factors associated with aminoglycoside nephrotoxicity. Various controlled studies relate certain factors to subsequent toxicity, including a prolonged course or recent course, persistently elevated trough concentrations, hypovolemia, advanced age, liver disease, concurrent nephrotoxic agents, and overdiuresis.52,53 No specific interventions consistently prevent amino-glycoside nephrotoxicity. General measures (e.g., hydrating the patient and avoiding concomitant nephrotoxins) are important. Maintaining appropriate serum concentrations is also recommended; however, no data correlate nephrotoxicity with specific serum concentrations or with therapeutic drug monitoring.54 In an effort to decrease toxicity and improve efficacy, high-dose extended-interval (“once daily”) aminoglycoside dosing is recommended. Many studies have evaluated the nephrotoxicity of once-daily dosing compared with traditional dosing, and many meta-analyses have subsequently tried to aggregate the results.55-62 In two of eight of these meta-analyses, once-daily dosing was associated with less nephrotoxicity, a 26%–40% relative risk reduction. In the others, there was no difference between the two dosing strategies. Although controversial, it seems prudent to use once-daily dosing whenever possible and to institute other general preventive strategies, including therapeutic drug monitoring, when using

aminoglycosides. Vancomycin The understanding of vancomycin nephrotoxicity has changed over the years. Early in its use, vancomycin contained many impurities that were believed to lead to nephrotoxicity. Once the clinical formulation was purified, the incidence of nephrotoxicity was 5%–17% in various clinical trials.63–68 This rate increased to as high as 35% of patients when vancomycin was combined with aminoglycosides. In guidelines published in 2009, higher vancomycin trough values (10–20 mcg/mL) were recommended to decrease resistance, enhance tissue penetration, and improve clinical outcomes, especially in serious MRSA (methicillin-resistant Staphylococcus aureus) infections.69 After these recommendations, several studies and a meta-analysis of a variety of hospitalized patients with gram-positive infections showed an increased nephrotoxicity of vancomycin to as high as 34% of patients.70-73 A few other factors were related to this high level, including ICU residence and longer lengths of therapy, but higher trough concentrations had the biggest impact. As with aminoglycosides, no specific interventions definitively prevent or treat vancomycin nephrotoxicity. Because recent studies suggest that higher vancomycin trough concentrations increase the risk of nephrotoxicity, closer monitoring is advised when targeting trough concentrations above 15 mcg/mL. Certain infections may require these higher concentrations because of the location or the MIC (minimum inhibitory concentration) of the causative organism. In these situations, using an alternative antibiotic may be the most appropriate method to prevent AKI. The incidence of nephrotoxicity is also significantly higher when vancomycin is combined with aminoglycosides63,67 or piperacillin/tazobactam.68,74,75 Because these are antibiotic combinations commonly used in the ICU patient, diligence is warranted in monitoring serum concentrations, maintaining adequate volume status, and avoiding any other nephrotoxins.

Amphotericin B Amphotericin B nephrotoxicity occurs commonly, with the GFR falling within the first few weeks of initiating therapy.76 Most patients stabilize at 20%–60% of normal renal function, but acute renal failure can occur.77 The exact mechanism of nephrotoxicity is uncertain but is probably related to decreases in renal blood flow and amphotericin binding to cholesterol in the tubular epithelium, causing tubular necrosis. The decrease in function is also believed to be the result of a feedback mechanism in the kidney where the ion load created by amphotericin in the urine causes vasoconstriction of the afferent arteriole.77 Newer lipid formulations of amphotericin significantly decrease the incidence of renal toxicity, with rates decreasing from 40%–50% to 8%–20%.78–81 This lower incidence is believed to be because of a slower release of amphotericin B in the bloodstream and less of the drug available to interact directly with the renal tubules. Because there is no specific treatment for amphotericin renal toxicity, prevention is key. Treatment usually consists of interrupting amphotericin therapy, which is problematic in patients with certain resistant fungal infections. Newer antifungals, such as the azoles and echinocandins, are not considered nephrotoxic and are appropriate alternatives for certain fungal infections (e.g., candidiasis and aspergillosis) in patients at risk of nephrotoxicity.82 Lipid formulations of amphotericin should be used whenever possible to decrease the risk of nephrotoxicity. One of the best nephrotoxicity prevention strategies for either amphotericin deoxycholate or one of the lipid formulations is salt loading.77,83 Because of the proposed renal feedback mechanism for nephrotoxicity, maintaining an adequate osmolality in the blood decreases the renal response to the high ionic load in the renal tubules. Liberalizing salt intake and using normal saline for maintenance fluid and intravenous medications is beneficial. In addition to increasing sodium intake, 500 mL of normal saline should be administered over the 30 minutes immediately before and immediately after the amphotericin infusion.77 Ideally, the goal is to induce a urinary sodium excretion of 250–300 mmol per day. If not instituted preventively, sodium loading may be beneficial as a treatment to allow for continued

amphotericin B administration. The only other method with data supporting its effectiveness in preventing nephrotoxicity is continuous infusion amphotericin.84 Acetylcysteine and mannitol are not beneficial in preventing amphotericin toxicity.85,86 Sulfonamides, Acyclovir, and Methotrexate Certain medications cause AKI by crystallizing in the urine and causing tubular obstruction. Examples of these drugs include sulfonamides, acyclovir, and methotrexate. This crystallization can be prevented by administering adequate fluids. Patients should receive fluid to maintain a urine output of 100–150 mL/hour while on these agents.87 For crystallization secondary to sulfonamides and methotrexate, giving sodium bicarbonate to alkalinize the urine increases crystal solubility. Cisplatin Because of its efficacy as a cancer chemotherapeutic agent, cisplatin is still commonly used, even though it causes significant direct cellular toxicity in the proximal tubule. Many agents have been evaluated for their potential protection against this nephrotoxicity.88 At this time, the best method appears to be administering fluid, starting at least 12 hours before cisplatin. This fluid volume should achieve a urine output of at least 100–125 mL/hour. In addition, cisplatin should be infused in normal saline. Fluid administration should then continue for 24 hours after cisplatin administration. Data on administering diuretics such as furosemide or mannitol do not consistently support their effectiveness over saline alone.89 In ovarian cancer, administering amifostine before each cisplatin dose may be considered to prevent renal oxidative stress and subsequent cisplatin-related nephrotoxicity.90 Amifostine cost and adverse events, especially hypotension, may limit its use. Finally, cisplatin dose reduction or use of the less nephrotoxic platinum drug carboplatin decreases the risk of nephrotoxicity. Calcineurin Inhibitors

The calcineurin inhibitors, cyclosporine and tacrolimus, are both acutely and chronically nephrotoxic.91 This can add to the complexity of their therapeutic use, especially when used to prevent renal transplant rejection. Acutely, these agents cause vasoconstriction of afferent arterioles, leading to nephrotoxicity that is reversed with dosage alterations. Chronically, they cause an irreversible tubular toxicity and progressive, ischemic glomerulosclerosis.92 Patients receiving these agents should take the standard precautions for preventing toxicity (i.e., avoid other nephrotoxic agents, maintain appropriate fluid volume, etc.). Both medications should have drug concentrations monitored closely and doses adjusted accordingly. Concomitant medications should be used carefully to avoid drug interactions that may increase concentrations and associated nephrotoxicity. Radiocontrast Agents Whether radiocontrast agents are nephrotoxic is controversial. Studies with control groups are rare (all nonrandomized) and have found no difference in AKI between those that do and do not receive these agents.93 The proposed mechanism of nephrotoxicity associated with radiocontrast agents is unknown but is believed to be the result of a combination of decreased renal blood flow and direct tubular toxicity. Many studies have evaluated strategies for preventing nephrotoxicity, primarily focusing on normal saline, sodium bicarbonate, acetylcysteine, and statins. Several meta-analyses and guidelines have been developed using these studies. As with amphotericin, an effective preventive strategy appears to be sodium loading.94 Recommendations include using normal saline at a rate of 100 mL/hour 6–12 hours before and 4–12 hours after administering radiocontrast agents. Obviously, in emergency cases, the pre-administration salt loading may not be possible. Studies have also shown that sodium bicarbonate infusions are more effective than normal saline at preventing radiocontrastinduced AKI, and most subsequent meta-analyses have confirmed this superior benefit.95-99 Acetylcysteine has been studied to prevent radiocontrast-induced AKI in several clinical trials with subsequent meta-analyses. These meta-analyses have generally not supported this

intervention because of inconsistent results, but using higher doses may be beneficial.100-103 Many studies have evaluated the use of statins in either moderate or high doses to prevent contrast-induced nephropathy after coronary angiography and percutaneous coronary intervention. Several meta-analyses of these trials have shown a consistent benefit of statins in preventing AKI.104-107 Ascorbic acid is also effective at preventing AKI after contrast use for coronary angiography.108 Theophylline has shown benefit in preventing contrastinduced nephrotoxicity, but primarily in patients with normal serum creatinine.109 Other agents that have been tried without success in this setting are mannitol, furosemide, and fenoldopam.110 Nonpharmacologic measures such as using lower doses of contrast, minimizing diagnostic tests with contrast, or spacing out these tests can also be used to prevent toxicity. Ineffective Agents for Renal Protection For years, low- or renal-dose dopamine was used to maintain renal perfusion and prevent AKI. At doses of 0.5–5 mcg/kg/minute, dopamine has preferential effects on the kidney, causing increased renal perfusion. Many meta-analyses and a large clinical trial have looked at several different outcomes when using low-dose dopamine, including mortality, increases in serum creatinine, development of acute renal failure, need for RRT, and hospital and ICU lengths of stay.111-114 Urine output increases in the first 24 hours after adding low-dose dopamine, but that effect diminishes within 48 hours.114 Low-dose dopamine is therefore no longer recommended for renal protection.42 Fenoldopam, a D1-specific dopamine agonist, has also been suggested as an agent to prevent or treat AKI in critical care patients. A meta-analysis of studies in cardiac surgery patients found that the incidence of AKI was significantly decreased by fenoldopam.115 Patients receiving fenoldopam had a higher incidence of hypotension and vasopressor use, and there was no difference in the use of RRT, length of hospital or ICU stay, or mortality. A subsequent, large, randomized, placebo-controlled clinical trial using fenoldopam in cardiac

surgery patients found no differences in use of RRT or mortality.116 Hypotension was greater in the fenoldopam group. Although another meta-analysis that included both postoperative and critically ill patients found that fenoldopam decreased the incidence of AKI, use of RRT, ICU length of stay, and in-hospital mortality, no large clinical trials have confirmed these results.117 The renal-protective effects of nesiritide have been evaluated in patients with acute decompensated heart failure or in those undergoing high-risk cardiac surgeries. In patients with diminished renal function and decompensated heart failure, several studies show no significant effect of nesiritide on measures of renal function (urine output, GFR, changes in creatinine or cystatin C, etc.).118-120 Studies using nesiritide to prevent renal dysfunction in patients undergoing high-risk cardiac surgery have yielded mixed results. One prospective trial found no difference in short- or long-term survival or need for dialysis, although there was a lower incidence of AKI in the nesiritide group.121,122 Another prospective trial of patients undergoing coronary artery bypass grafting found that perioperative nesiritide resulted in lower rises in creatinine, greater urine output, shorter hospital stays, and lower mortality in the nesiritide group.123 The Perioperative Ischemic Evaluation 2 (POISE-2) trial studied aspirin and clonidine perioperatively for patients undergoing noncardiac surgery.124 Although the primary outcomes of POISE-2 were death or nonfatal MI, a substudy evaluated the impact of the two drugs on AKI. Neither drug decreased the risk of AKI perioperatively; however, there was an increased risk of major bleeding and hypotension as the result of aspirin and clonidine, respectively. Patients who had either a major bleed or hypotension had a higher risk of subsequent AKI.

CONCLUSION In summary, AKI often occurs in ICU settings. It is rarely attributed to a single factor, and most critically ill patients who develop AKI do so as a result of several renal insults occurring simultaneously or in sequence (hemodynamic, septic, and nephrotoxic). The clinical picture is further

complicated in patients with underlying kidney disease and in those receiving nephrotoxic medications. Because many forms of AKI are preventable, patients at risk should be identified early and steps taken to avoid potential renal insults. Treatment of established AKI involves fluids, drug dose adjustment or discontinuation, and supportive care.

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29. U.S. Food and Drug Administration (FDA). FDA Allows Marketing of the First Test to Assess Risk of Developing Acute Kidney Injury. September 5, 2014. Available at www.fda.gov/NewsEvents​ /Newsroom/Press​Announcement​s/ucm412910.htm. Accessed February 28, 2015. 30. Uchino S, Doig GS, Bellomo R, et al.; Beginning and Ending Supportive Therapy for the Kidney (B.E.S.T. Kidney) Investigators. Diuretics and mortality in acute renal failure. Crit Care Med 2004;32:1669-77. 31. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ 2006;333:420. 32. Bagshaw SM, Delaney A, Haase M, et al. Loop diuretics in the management of acute renal failure: a systematic review and metaanalysis. Crit Care Resusc 2007;9:60-8. 33. van der Voort PH, Boerma EC, Koopmans M, et al. Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: a double blind randomized controlled trial. Crit Care Med 2009;37:533-8. 34. Bagshaw SM, Gibney RT, McAlister FA, et al. The SPARK study: a phase II randomized blinded controlled trial of the effect of furosemide in critically ill patients with early acute kidney injury. Trials 2010;11:50. 35. Piccinni P, Cruz DN, Gramaticopolo S, et al.; NEFROINT Investigators. Prospective multicenter study on epidemiology of acute kidney injury in the ICU: a critical care nephrology Italian collaborative effort (NEFROINT). Minerva Anestesiol 2011;77:1072-83. 36. Finfer S, Bellomo R, Boyce N, et al.; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56. 37. Caironi P, Tognoni G, Masson S, et al.; ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis

or septic shock. N Engl J Med 2014;370:1412-21. 38. Annane D, Siami S, Jaber S, et al.; CRISTAL Investigators. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA 2013;310:1809-17. 39. Myburgh JA, Finfer S, Bellomo R, et al.; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012;367:1901-11. 40. Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA 2013;309:678-88. Erratum in: JAMA 2013;309:1229. 41. Rivers E, Nguyen B, Havstad S, et al.; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77. 42. Dellinger RP, Levy MM, Rhodes A, et al.; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580-637. 43. ARISE Investigators; ANZICS Clinical Trials Group, Peake SL, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496-506. 44. ProCESS Investigators; Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-93. 45. Bouchard J, Soroko SB, Chertow GM, et al.; Program to Improve Care in Acute Renal Disease (PICARD) Study Group. Fluid accumulation, survival and recovery of kidney function in critically

ill patients with acute kidney injury. Kidney Int 2009;76:422-7. 46. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network; Wiedemann HP, Wheeler AP, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354:2564-75. 47. Yunos NM, Bellomo R, Glassford N, et al. Chloride-liberal vs. chloride-restrictive intravenous fluid administration and acute kidney injury: an extended analysis. Intensive Care Med 2015;41:257-64. 48. Raghunathan K, Shaw A, Nathanson B, et al. Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis. Crit Care Med 2014;42:1585-91. 49. Krajewski ML, Raghunathan K, Paluszkiewicz SM, et al. Metaanalysis of high- versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg 2015;102:24-36. 50. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl 2012;2:1-138. 51. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitorassociated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 2000;160:685-93. 52. Lietman PS, Smith CR. Aminoglycoside nephrotoxicity in humans. Rev Infect Dis 1983;5(suppl 2):S284-S292. 53. Appel GB. Aminoglycoside nephrotoxicity. Am J Med 1990;88:16S-20S; discussion 38S-42S. 54. McCormack JP, Jewesson PJ. A critical reevaluation of the “therapeutic range” of aminoglycosides. Clin Infect Dis 1992;14:320-39. 55. 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. 56. 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. 57. Ferriols-Lisart R, Alós-Almiñana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health Syst Pharm 1996;53:1141-50. 58. Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. Ann Intern Med 1996;124:717-25. 59. 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. 60. Barza M, Ioannidis JP, Cappelleri JC, et al. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996;312:33845. 61. Blaser J, König C. Once-daily dosing of aminoglycosides. Eur J Clin Microbiol Infect Dis 1995;14:1029-38. 62. Galløe AM, Graudal N, Christensen HR, et al. Aminoglycosides: single or multiple daily dosing? A meta-analysis on efficacy and safety. Eur J Clin Pharmacol 1995;48:39-43. 63. Farber BF, Moellering RC Jr. Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981. Antimicrob Agents Chemother 1983;23:138-41. 64. Mellor JA, Kingdom J, Cafferkey M, et al. Vancomycin toxicity: a prospective study. J Antimicrob Chemother 1985;15:773-80. 65. Sorrell TC, Collignon PJ. A prospective study of adverse reactions associated with vancomycin therapy. J Antimicrob Chemother 1985;16:235-41. 66. Cimino MA, Rotstein C, Slaughter RL, et al. Relationship of serum

antibiotic concentrations to nephrotoxicity in cancer patients receiving concurrent aminoglycoside and vancomycin therapy. Am J Med 1987;83:1091-7. 67. Downs NJ, Neihart RE, Dolezal JM, et al. Mild nephrotoxicity associated with vancomycin use. Arch Intern Med 1989;149:177781. 68. Meaney CJ, Hynicka LM, Tsoukleris MG. Vancomycin-associated nephrotoxicity in adult medicine patients: incidence, outcomes, and risk factors. Pharmacotherapy 2014;34:653-61. 69. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis 2009;49:325-7. Erratum in: Clin Infect Dis 2009;49:1465. 70. Lodise TP, Patel N, Lomaestro BM, et al. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients. Clin Infect Dis 2009;49:507-14. 71. Bosso JA, Nappi J, Rudisill C, et al. Relationship between vancomycin trough concentrations and nephrotoxicity: a prospective multicenter trial. Antimicrob Agents Chemother 2011;55:5475-9. 72. van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother 2013;57:73444. 73. Carreno JJ, Jaworski A, Kenney RM, et al. Comparative incidence of nephrotoxicity by age group among adult patients receiving vancomycin. Infect Dis Ther 2013;2:201-8. 74. Burgess LD, Drew RH. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with

and without concomitant piperacillin-tazobactam. Pharmacotherapy 2014;34:670-6. 75. Gomes DM, Smotherman C, Birch A, et al. Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime. Pharmacotherapy 2014;34:662-9. 76. Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical experience. Rev Infect Dis 1990;12:308-29. 77. Branch RA. Prevention of amphotericin B-induced renal impairment. A review on the use of sodium supplementation. Arch Intern Med 1988;148:2389-94. 78. Falci DR, da Rosa FB, Pasqualotto AC. Comparison of nephrotoxicity associated to different lipid formulations of amphotericin B: a real-life study. Mycoses 2015;58:104-12. 79. Cannon JP, Garey KW, Danziger LH. A prospective and retrospective analysis of the nephrotoxicity and efficacy of lipidbased amphotericin B formulations. Pharmacotherapy 2001;21:1107-14. 80. Wade RL, Chaudhari P, Natoli JL, et al. Nephrotoxicity and other adverse events among inpatients receiving liposomal amphotericin B or amphotericin B lipid complex. Diagn Microbiol Infect Dis 2013;76:361-7. 81. Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs 2013;73:919-34. 82. Limper AH, Knox KS, Sarosi GA, et al.; American Thoracic Society Fungal Working Group. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-128. 83. Karimzadeh I, Farsaei S, Khalili H, et al. Are salt loading and prolonging infusion period effective in prevention of amphotericin B-induced nephrotoxicity? Expert Opin Drug Saf 2012;11:969-83.

84. Falagas ME, Karageorgopoulos DE, Tansarli GS. Continuous versus conventional infusion of amphotericin B deoxycholate: a meta-analysis. PLoS One 2013;8:e77075. 85. Karimzadeh I, Khalili H, Farsaei S, et al. Role of diuretics and lipid formulations in the prevention of amphotericin B-induced nephrotoxicity. Eur J Clin Pharmacol 2013;69:1351-68. 86. Karimzadeh I, Khalili H, Dashti-Khavidaki S, et al. N-acetyl cysteine in prevention of amphotericin-induced electrolytes imbalances: a randomized, double-blinded, placebo-controlled, clinical trial. Eur J Clin Pharmacol 2014;70:399-408. 87. Perazella MA. Crystal-induced acute renal failure. Am J Med 1999;106:459-65. 88. dos Santos NA, Carvalho Rodrigues MA, Martins NM, et al. Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update. Arch Toxicol 2012;86:1233-50. 89. Santoso JT, Lucci JA III, Coleman RL, et al. Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity: a randomized trial. Cancer Chemother Pharmacol 2003;52:13-8. 90. Hensley ML, Hagerty KL, Kewalramani T, et al. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 2009;27:127-45. 91. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009;4:481-508. 92. Nankivell BJ, Borrows RJ, Fung CL, et al. The natural history of chronic allograft nephropathy. N Engl J Med 2003;349:2326-33. 93. McDonald JS, McDonald RJ, Comin J, et al. Frequency of acute kidney injury following intravenous contrast medium administration: a systematic review and meta-analysis. Radiology 2013;267:11928. 94. Weisbord SD, Palevsky PM. Prevention of contrast-induced

nephropathy with volume expansion. Clin J Am Soc Nephrol 2008;3:273-80. 95. Jang JS, Jin HY, Seo JS, et al. Sodium bicarbonate therapy for the prevention of contrast-induced acute kidney injury – a systematic review and meta-analysis. Circ J 2012;76:2255-65. 96. Trivedi H, Nadella R, Szabo A. Hydration with sodium bicarbonate for the prevention of contrast-induced nephropathy: a metaanalysis of randomized controlled trials. Clin Nephrol 2010;74:28896. 97. Kunadian V, Zaman A, Spyridopoulos I, et al. Sodium bicarbonate for the prevention of contrast induced nephropathy: a metaanalysis of published clinical trials. Eur J Radiol 2011;79:48-55. 98. Zoungas S, Ninomiya T, Huxley R, et al. Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Ann Intern Med 2009;151:631-8. 99. Navaneethan SD, Singh S, Appasamy S, et al. Sodium bicarbonate therapy for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. Am J Kidney Dis 2009;53:617-27. 100. Sun Z, Fu Q, Cao L, et al. Intravenous N-acetylcysteine for prevention of contrast-induced nephropathy: a meta-analysis of randomized, controlled trials. PLoS One 2013;8:e55124. 101. Nallamothu BK, Shojania KG, Saint S, et al. Is acetylcysteine effective in preventing contrast-related nephropathy? A metaanalysis. Am J Med 2004;117:938-47. 102. Gonzales DA, Norsworthy KJ, Kern SJ, et al. A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity. BMC Med 2007;5:32. 103. Trivedi H, Daram S, Szabo A, et al. High-dose N-acetylcysteine for the prevention of contrast-induced nephropathy. Am J Med 2009;122:874.e9-15.

104. Zhang BC, Li WM, Xu YW. High-dose statin pretreatment for the prevention of contrast-induced nephropathy: a meta-analysis. Can J Cardiol 2011;27:851-8. 105. Ukaigwe A, Karmacharya P, Mahmood M, et al. Meta-analysis on efficacy of statins for prevention of contrast-induced acute kidney injury in patients undergoing coronary angiography. Am J Cardiol 2014;114:1295-302. 106. Giacoppo D, Capodanno D, Capranzano P, et al. Meta-analysis of randomized controlled trials of preprocedural statin administration for reducing contrast-induced acute kidney injury in patients undergoing coronary catheterization. Am J Cardiol 2014;114:541-8. 107. Gandhi S, Mosleh W, Abdel-Qadir H, et al. Statins and contrastinduced acute kidney injury with coronary angiography. Am J Med 2014;127:987-1000. 108. Sadat U, Usman A, Gillard JH, et al. Does ascorbic acid protect against contrast-induced acute kidney injury in patients undergoing coronary angiography: a systematic review with meta-analysis of randomized, controlled trials. J Am Coll Cardiol 2013;62:2167-75. 109. Dai B, Liu Y, Fu L, et al. Effect of theophylline on prevention of contrast-induced acute kidney injury: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2012;60:360-70. 110. Kelly AM, Dwamena B, Cronin P, et al. Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med 2008;148:284-94. 111. Kellum JA, M Decker J. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med 2001;29:1526-31. 112. Marik PE. Low-dose dopamine: a systematic review. Intensive Care Med 2002;28:877-83. 113. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care

Society (ANZICS) Clinical Trials Group. Lancet 2000;356:213943. 114. Friedrich JO, Adhikari N, Herridge MS, et al. Meta-analysis: lowdose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005;142:510-24. 115. Zangrillo A, Biondi-Zoccai GG, et al. Fenoldopam and acute renal failure in cardiac surgery: a meta-analysis of randomized placebocontrolled trials. J Cardiothorac Vasc Anesth 2012;26:407-13. 116. Bove T, Zangrillo A, Guarracino F, et al. Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial. JAMA 2014;312:2244-53. 117. Landoni G, Biondi-Zoccai GG, Tumlin JA, et al. Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials. Am J Kidney Dis 2007;49:56-68. 118. Chen HH, Anstrom KJ, Givertz MM, et al.; NHLBI Heart Failure Clinical Research Network. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013;310:2533-43. 119. Witteles RM, Kao D, Christopherson D, et al. Impact of nesiritide on renal function in patients with acute decompensated heart failure and pre-existing renal dysfunction a randomized, doubleblind, placebo-controlled clinical trial. J Am Coll Cardiol 2007;50:1835-40. 120. Wang DJ, Dowling TC, Meadows D, et al. Nesiritide does not improve renal function in patients with chronic heart failure and worsening serum creatinine. Circulation 2004;110:1620-5. 121. Ejaz AA, Martin TD, Johnson RJ, et al. Prophylactic nesiritide does not prevent dialysis or all-cause mortality in patients undergoing high-risk cardiac surgery. J Thorac Cardiovasc Surg 2009;138:959-64.

122. Lingegowda V, Van QC, Shimada M, et al. Long-term outcome of patients treated with prophylactic nesiritide for the prevention of acute kidney injury following cardiovascular surgery. Clin Cardiol 2010;33:217-21. 123. Mentzer RM Jr, Oz MC, Sladen RN, et al.; NAPA Investigators. Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery: the NAPA trial. J Am Coll Cardiol 2007;49:716-26. 124. Garg AX, Kurz A, Sessler DI, et al.; POISE-2 Investigators. Perioperative aspirin and clonidine and risk of acute kidney injury: a randomized clinical trial. JAMA 2014;312:2254-64. 125. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 2006;10:R73. 126. Bagshaw SM, George C, Dinu I, et al. A multi-centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008;23:1203-10. 127. Taber SS, Mueller BA. Drug-associated renal dysfunction. Crit Care Clin 2006;22:357-74.

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

LEARNING OBJECTIVES 1. Understand how solute transfer occurs between different modes of intermittent and continuous renal replacement. 2. Compare the advantages and disadvantages of intermittent hemodialysis and continuous renal replacement therapy. 3. List anticoagulation options used for extracorporeal dialytic therapies. 4. Understand how renal replacement therapy fluids affect the transfer of electrolytes during therapy. 5. List filter characteristics that affect solute movement during renal replacement therapies. 6. Identify pharmacokinetic alterations in patients with critical illness. 7. Understand the drug characteristics that promote clearance by continuous renal replacement therapies. 8. Appreciate the impact of diffusion versus convection on drug clearance.

9. Understand how to develop drug dosing regimens using pharmacokinetic data in patients receiving continuous renal replacement strategies. 10. Understand the drug characteristics that promote clearance by plasmapheresis. 11. Appreciate how different components and conditions of the plasmapheresis procedure can affect drug clearance. 12. Know when to dose drugs in patients receiving plasmapheresis. 13. Describe the components of the extracorporeal membrane oxygenation (ECMO) circuit. 14. Identify the factors responsible for alterations in drug pharmacokinetics in patients on ECMO. 15. Recognize the drugs known or predicted to be sequestered by the ECMO circuit.

ABBREVIATIONS IN THIS CHAPTER AUC

Area under the plasma concentration time curve

Cl

Total body clearance

Cp

Concentration in the plasma

Cpss

Concentration in the plasma at steady state

CVVH

Continuous venovenous hemofiltration

CVVHD

Continuous venovenous hemodialysis

CVVHDF Continuous venovenous hemodiafiltration E

Extraction of a drug across an organ or device

ECMO

Extracorporeal membrane oxygenation

EDD

Extended daily hemodialysis

IHD

Intermittent hemodialysis

ICU

Intensive care unit

Q

Flow rate determining delivery of a drug to the extracting organ or device

SCUF

Slow continuous ultrafiltration

SLED

Sustained low-efficiency hemodialysis

Vd

Volume of distribution

INTRODUCTION Renal replacement therapy comprises a group of techniques that provide dialytic and fluid removal support either alone or in combination. It is estimated that 6% of patients admitted to the intensive care unit (ICU) will receive renal replacement therapy during their hospitalization.1 In addition to patients with a history of dialysisdependent chronic kidney disease, patients in the ICU are at increased risk of requiring renal replacement therapy because of acute kidney injury induced by drugs, sepsis, exacerbation of autoimmune diseases, and so forth.2 The primary goals of renal replacement therapy in ICU patients are to reduce kidney injury and complications related to decreased kidney function.2 Prescribed renal replacement therapies can be intermittent or continuous in duration. Intermittent therapies include conventional intermittent hemodialysis (IHD), sustained low-efficiency hemodialysis (SLED) or extended daily hemodialysis (EDD), and intermittent peritoneal dialysis. Continuous renal replacement therapies include two forms of peritoneal dialysis (CAPD [continuous ambulatory peritoneal dialysis] and CCPD [continuous cycler-assisted peritoneal dialysis]) and several forms of dialysis and ultrafiltration (slow continuous ultrafiltration [SCUF], continuous venovenous hemofiltration [CVVH],

continuous venovenous hemodialysis [CVVHD], and continuous venovenous hemodiafiltration [CVVHDF]). A discussion of each technique will follow later in this chapter. An excellent review that discusses the various continuous renal replacement therapies has been published.3 In general, renal replacement therapy techniques are capable of removing water and metabolic waste products (often called solute) by transport across a semipermeable membrane. What differentiates each technique is the method in which water and solute are removed. Ultrafiltration is the process of water removal without the appreciable loss of solutes. Hypervolemic conditions (e.g., heart failure) are indications for isolated ultrafiltration or SCUF. When ultrafiltration flow rates are increased (usually greater than 1,000 mL per hour), solute is removed as water carries it across a semipermeable membrane in response to a transmembrane pressure gradient. The process of removing solute with water from blood is termed hemofiltration. When it is performed in a continuous mode (e.g., CVVH), replacement fluid is adjusted at either the prefilter or the postfilter location. Ultrafiltration through CVVH can remove larger molecular weight solutes than diffusion alone (e.g., CVVHD). Because CVVHD uses diffusion to remove solutes, a dialysate is needed to create a concentration gradient. To effectively remove both solute and fluid, several extracorporeal techniques, including IHD, SLED/EDD, and CVVHDF, can be used. Choosing a modality is controversial and is usually determined by the ICU physician and/or nephrologist depending on the clinical needs of the patient. However, continuous forms of renal replacement therapy are preferred over IHD in patients who are hemodynamically unstable or who have increased intracranial pressure or brain edema (e.g., acute brain injury).2

Outcomes with Renal Replacement Therapy Patients developing acute kidney injury tend to have prolonged ICU and hospital stays and have in-hospital mortality rates of 50%–70%.4-8 For survivors, health-related quality of life is reduced compared with the

general population.9 For ICU survivors with and without acute kidney injury, the health-related quality of life is similar at 6 months; however, it is still lower than in the general population.10 There is considerable interest in determining the effect of different renal replacement therapies on long-term kidney function recovery. Studies evaluating short-term kidney function recovery have not found a difference between continuous renal replacement therapy and IHD.11,12 For longterm recovery comparisons, observational and cohort studies have suggested that patients receiving continuous renal replacement therapy compared with intermittent therapies are less likely to progress to chronic kidney disease requiring maintenance hemodialysis.13-15 Although a cause and effect has not been determined, it is believed that less hemodynamic instability occurs during continuous renal replacement therapy.16,17 Many patients regaining kidney function after acute kidney injury will have advanced kidney disease compared with their baseline kidney function.18,19

RENAL REPLACEMENT THERAPY Of the available forms of renal replacement therapy, IHD and continuous therapies are used most commonly in adult critically ill patients in developed countries. Peritoneal dialysis is infrequently used because of its inability to effectively and rapidly remove metabolic waste products in hypercatabolic critically ill patients. In addition, it has a relative contraindication in patients with recent intra-abdominal surgery and pathologies.20 Pediatric and neonatal patients with acute kidney injury often receive peritoneal dialysis, but controversy remains regarding the most appropriate therapy.21 In developing countries, peritoneal dialysis provides a means for renal replacement therapy when other, more technical procedures may not be feasible.20

COMPONENTS OF THERAPIES Filters and Dialyzers

Technologies to improve the biocompatibility and permeability of filters used in IHD and continuous renal replacement therapies have evolved over several decades, from cellulosic membranes primary used in early IHD to synthetic polymers (e.g., polysulfone, polyamide, polymethylmethacrylate, polyacrylonitrile) used most often today. Other important features of newer filter membranes include a larger, more uniform pore size, increased hydrophobicity, and greater biocompatibility. Binding to these filters has been described for select drugs (e.g., aminoglycosides)22 and cytokines.23 Attempts at removing cytokines during continuous renal replacement therapies have been investigated using both hemodialysis and hemofiltration. Cytokine removal during CVVH would likely require a highly permeable membrane with production of a large amount of filtrate. Cytokines may also adsorb to these membranes. However, because the surface area of these filters quickly becomes saturated, frequent filter changes may be required. Cole et al. investigated the adsorption of several interleukins and tissue necrosis factor to a polyacrylonitrile membrane (AN69) using donated blood from six healthy volunteers in an ex vivo model of CVVHD and CVVH. Cytokine adsorption was only minor.24 Several studies have failed to show a correlation between cytokine removal and improved outcomes.25,26 The permeability of a filter directly correlates with the ability of water to cross and is described as the ultrafiltration coefficient (Kuf ). The Kuf is determined by the volume of fluid that crosses the membrane in milliliters per hour per millimeter of mercury. If the membrane Kuf is low, its permeability to water is also low, and a higher transmembrane pressure is required to generate an ultra-filtrate. Membranes with a higher Kuf produce a greater amount of ultrafiltrate at equivalent or lower transmembrane pressures. Small solutes (e.g., urea) are primarily removed by diffusion. In addition to size, the ability of solutes to cross a membrane is a function of the thickness and porosity and is expressed as the diffusion coefficient. To remove larger solutes, convection is needed. The rate of convection is related to how fast water crosses the membrane, size of the solute, and pore size of the membrane. The ability of solutes to

cross a membrane during convection is determined by the solute’s sieving coefficient. A solute with a sieving coefficient of 1.0 crosses the membrane, whereas a solute with a value of zero is impermeable. For IHD, filters with a greater urea clearance are required because of the short therapy duration. For continuous renal replacement therapies, however, lower urea clearance is acceptable because of the continuous duration. For convection (CVVH), the Kuf must be greater than 6–8 mL/hour/mm Hg to produce an ultrafiltration rate of 15–20 mL/minute. For diffusive clearance (IHD, CVVHD, or CVVHDF), solutes must pass through the membrane quickly to prevent equilibration between the plasma and the dialysate.

Anticoagulation Activation of the intrinsic and extrinsic coagulation pathway occurs, in addition to platelet activation, when blood contacts the surface of an extracorporeal circuit. Because of this blood-circuit interface, anticoagulation is needed for most patients. In patients who are critically ill, this may be problematic because many have an increased tendency for bleeding given concomitant hepatic impairment. The need for anticoagulation must be balanced with the increased risk of bleeding. One advantage of peritoneal dialysis over IHD and continuous renal replacement therapy is that no anticoagulation is required. Anticoagulation during IHD usually consists of a heparin bolus given at the beginning of treatment with an additional bolus dose or infusion given during treatment. For patients at high risk of bleeding, a “noheparin” or minimum-dose heparin option is usually chosen. Other anticoagulation options include trisodium citrate dialysate or regional anticoagulation with trisodium citrate or prostacyclin. In heparin-induced thrombocytopenia, a no-heparin approach is preferred with a direct thrombin inhibitor as the anticoagulant of choice. The choice of an anticoagulant and its dose should be patient-specific to reduce the likelihood of bleeding events. Several agents have been used to anticoagulate the extracorporeal circuit in continuous renal replacement therapy including unfractionated heparin, low-molecular-weight heparin, trisodium citrate, direct

thrombin inhibitors, and prostacyclin. Regional trisodium citrate is generally preferred in the absence of a contraindication (e.g., severe liver failure). Although trisodium citrate has the advantage of reduced bleeding, metabolic acidosis and hypocalcemia can occur in patients with reduced liver function. Other complications include alkalosis, hypernatremia, and hypercalcemia. The largest disadvantage of trisodium citrate is its complexity of administration and monitoring. However, with the use of a specific protocol, it can safely be used. Unfractionated heparin has several advantages over trisodium citrate including its wide availability, familiarity, and easy of monitoring. The disadvantages of unfractionated heparin include increased risk of bleeding, unpredictable kinetics, risk of heparin-induced 2 thrombocytopenia, and heparin resistance. Regardless of the anticoagulant selected for use, each institution should have a protocol in place to reduce the possibility of unwanted adverse effects.

Composition of Dialysate and Replacement Fluids In general, dialysate fluids for IHD, peritoneal dialysis, and continuous renal replacement therapies mimic physiological consistency. However, they can be modified to enhance the elimination of electrolytes. For example, if hypercalcemia is present, the dialysate will contain a lower amount of calcium. Replacement fluids can also be tailored to ensure that blood solutes have a composition that is physiologic. Although there are several choices for commercial premade solutions, Table 27.1 gives examples of the different types of dialysate and replacement fluids used in IHD, peritoneal dialysis, CVVH, and CVVHD.

TYPES OF RENAL REPLACEMENT Intermittent Techniques Intermittent Hemodialysis Solute removal during IHD and CVVHD occurs primarily by diffusion.

The principal differences between CVVHD and IHD are the duration and frequency of treatment and the flow rates for blood and dialysate. Table 27.2 lists flow rate characteristics (blood, dialysate, and ultrafiltration), mechanisms for solute removal, and therapy durations for both continuous and intermittent renal replacement therapies. Several advantages and disadvantages are associated with each of these therapies (Table 27.3). An advantage of IHD is the rapid removal of solutes and water. This is most important in the setting of hyperkalemia, certain intoxications, and severe fluid overload. However, hypotension is a common cause for interrupting or stopping IHD and occurs during 20%–30% of treatments. Patients with acute kidney injury are often intolerant of IHD, and it is estimated that up to 10% of these patients cannot tolerate this form of therapy.27 Sustained Low Efficiency Dialysis and Extended Daily Dialysis Sustained low-efficiency dialysis and EDD are performed using conventional hemodialysis machines, but with modified blood and dialysate flow rates. A typical blood flow rate is 200 mL/minute during SLED/EDD versus up to about 450 mL/minute with conventional IHD. Dialysate flow rate is about 300 mL/minute during SLED/EDD versus up to 800 mL/minute with conventional IHD sessions. The therapy duration is longer during SLED/EDD (6–12 hours) than during conventional IHD (4 hours), but it is shorter than during continuous renal replacement therapy. Longer treatment duration allows for better hemodynamic stability than with IHD. In addition, because of its intermittent nature, SLED/EDD enables time away from therapy to perform various tests and procedures without affecting solute clearance and fluid management treatment goals.

Table 27.1 Composition of Dialysate and Replacement Fluids

CVVHD = continuous venovenous hemodialysis; CVVH = continuous venovenous hemofiltration; IHD = intermittent hemodialysis; PD = peritoneal dialysis.

Table 27.2 Typical Conditions During Renal Replacement Therapies40,119

aDialysate

flow rates are in milliliters per minute for intermittent and milliliters per hour for continuous therapies. bBecause

of the slow rate at which fluid is removed during CVVHD, ultrafiltration has no impact on solute removal. CVVH = continuous venovenous hemofiltration; EDD = extended daily dialysis; SLED = sustained low-efficiency dialysis; IHD = intermittent hemodialysis; CWHD = continuous venovenous hemodialysis; CVVHDF = continuous venovenous hemodiafiltration

Peritoneal Dialysis (intermittent or continuous) Peritoneal dialysis differs from intermittent or continuous renal

replacement therapies because it uses the lining of the abdominal cavity to act as a dialysis membrane. However, dialysate is also needed for peritoneal dialysis in order to create a concentration gradient to enable solute and water removal. Several commercial dialysate solutions are available for peritoneal dialysis, and all contain a mixture of electrolytes, lactate, and glucose.

Continuous Renal Replacement Techniques Slow Continuous Ultrafiltration Ultrafiltration uses pressure to force plasma water across a semipermeable membrane. The driving force for flow is dependent on the difference between the positive pressure that is created on the blood side of the membrane and the negative pressure that is created on the opposite side of the membrane. Although the hydrostatic pressure has a large impact on removal of fluid, there is a minimal effect on solute removal. When isolated ultrafiltration is provided in a continuous mode, it is typically termed SCUF. Figure 27.1 represents a typical SCUF circuit. Continuous Venovenous Hemodialysis Diffusion occurs when a solute moves across a semipermeable membrane in response to a concentration gradient. The ability to transverse the membrane depends on membrane porosity and the molecular weight of the solute. The ability to diffuse is inversely proportional to the solute molecular weight. For diffusion, the greatest impact on solute clearance is for low-molecular-weight molecules (less than 500 g/mol). Other factors that influence solute clearance are membrane characteristics (e.g., surface area and thickness) and solution temperature.28 For diffusion to occur, a concentration gradient must be maintained. Blood (containing a high-solute concentration) flows across the hollow fiber membranes, whereas dialysate (containing an absent or low-solute concentration) flows countercurrent on the other side of the dialyzer membrane. If the dialysate contains a

higher concentration of solute than blood, diffusion will occur in the opposite direction (e.g., from dialysate to blood). In general, this “backward flow” is undesirable. One exception may be the backward flow of bicarbonate in metabolic acidosis. In 2004, an ISMP Canada Safety Bulletin reported the deaths of two patients who inadvertently received dialysate containing about 57 mEq per liter of potassium chloride.29 Because dialysate fluid is not under a condition of recirculation, equilibrium is not obtained. Figure 27.2 shows the diffusion process as it occurs in IHD (and CVVHD). However, although conventional IHD usually occurs over 4 hours, CVVHD is a form of continuous renal replacement therapy. Figure 27.3 is a graphical depiction of CVVHD.

Table 27.3 Advantages and Disadvantages of Renal Replacement Therapies Therapy Advantages and Disadvantages IHD

Advantages • Less expensive than SLEDD and CRRT • Rapid control of hyperkalemia Disadvantages • Can cause hemodynamic compromise in critically ill patients • May require frequent treatments (e.g., daily for several days) early in therapy course

SLEDD

Advantages • Better hemodynamic stability than IHD • Less expensive than CRRT • Allows for out-of-unit test and procedures Disadvantages • Requires two nurses (ICU and dialysis) for the treatment duration at most institutions • Limited drug dosing recommendations

CRRT

Advantages

• Can be used in most hemodynamically unstable critically ill patients • Several options to choose from (i.e., CVVH, CVVHD, CVVHDF) • Allows for full nutritional support • May be safer for patients with brain injuries • May have a beneficial effect in patients in septic shock • May increase the likelihood of renal recovery Disadvantages • Requires the purchase of specific devices • Higher cost for supplies • Requires a dedicated ICU nurse • Usually requires continuous anticoagulation • Can cause hypothermia • Can cause life-threating depletion of several electrolytes if not monitored closely and replaced

Figure 27.1 Slow continuous ultrafiltration (SCUF) circuit. For slow continuous ultrafiltration (SCUF), blood is filtered through a semipermeable membrane under pressure, producing an ultrafiltrate. Because fluid removal is minimal, a replacement solution is not needed. The primary indication for SCUF is volume overload.

Continuous Venovenous Hemofiltration The ability to remove medium- and high-molecular-weight solutes (up to

15,000 g/mol) using extracorporeal techniques requires convection. Convection occurs when solutes are transported across a semipermeable membrane with the flow of water under the influence of a pressure gradient. The hemofilter membranes have enhanced permeability to enable removal of higher molecular weight solutes.30,31 Figure 27.4 shows the blood, water, and ultra-filtration components of convection. The clearance of solute shown during convection occurs though solvent drag. Hemofiltration differs from ultrafiltration in that the flow across the filter is increased. To provide adequate hemofiltration, at least 1 L of water per hour should cross the membrane.32 Figure 27.5 provides an example of a typical CVVH circuit showing both pre- and postfilter replacement fluid administration. Continuous Venovenous Hemodiafiltration Continuous venovenous hemodiafiltration uses both diffusion and convection to remove water and solute (Figure 27.6).

Box 27.1. Characteristics of Drugs That Enhance Dialytic Clearance ↓ Molecular weight/size ↑ Hydrophilicity ↓ Protein binding ↓ Volume of distribution ↑ Percentage of clearance by kidneys ↑ Percentage of clearance by nonrenal routes significantly altered by critical illness

DRUG-RELATED CHARACTERISTICS AND CLEARANCE BY CONTINUOUS EXTRACORPOREAL DIALYTIC TECHNIQUES The removal of drugs by continuous as well as intermittent dialytic techniques is dependent on the physicochemical characteristics of the drugs and the characteristics of the dialytic procedure. The primary physicochemical characteristics that predict whether a drug will be removed by a dialytic technique are its molecular weight, degree of hydrophilicity, protein binding, volume of distribution (Vd), and whether the kidneys represent the primary clearance pathway (Box 27.1).

Molecular Weight A drug with a molecular weight of less than 500 g/mol is readily removed by extracorporeal clearance methods that use diffusion. The clearance of drugs with higher molecular weights is enhanced with techniques that use high-flux membranes.

Hydrophilicity vs. Lipophilicity Drugs are classified by their lipophilic to hydrophilic status by log P values. The log P is a partition coefficient defined as the log of the ratio of the concentration of nonionized drug between oil (lipophilic) and aqueous (hydrophilic) phases. It is often necessary to adjust the pH of the aqueous phase to optimize for the presence of the nonionized form of the drug when determining partition coefficients. A lower log P value indicates that the drug is more hydrophilic, whereas higher log P values indicate improved lipophilicity. Drugs that are more hydrophobic have a greater ability to diffuse through lipid bilayers of cells. Hydrophilic drugs, because of their charges, require transporters to move across cellular membranes.

Figure 27.2 Intermittent hemodialysis circuit. Diffusion occurs when solute moves from an area of higher concentration to an area of lower concentration. Renal replacement therapies that use diffusion do not allow for equilibrium. To prevent equilibrium, these therapies use a countercurrent dialysate solution (e.g., a dialysate). Diffusion is responsible for removing small molecular weight molecules.

Figure 27.3 Continuous venovenous hemodialysis (CVVHD) circuit.

Continuous venovenous hemodialysis (CVVHD) uses the principle of diffusion and is given continuously, ideally over 24 hours.

The hydrophilic/hydrophobic characteristics can influence the absorption, distribution, and excretion of drugs. Drugs and metabolites that are cleared by the kidney are typically hydrophilic. They are typically cleared by dialytic techniques because of their presence in the intravascular compartment (the eliminating compartment for dialytic techniques). For hydrophilic compounds, charges (positive or negative) can result in interactions with extra-corporeal membranes that can lead to drug adsorption. Determination of adsorption requires the assessment of drug concentrations in the effluent and not just arterial and venous port measurements. Gentamicin (log P -3.1) is an example of a drug that is documented to adsorb to the polyacrylonitrile extracorporeal filter membrane.22,33 A recent publication showed adsorption of teicoplanin by polysulfone and polymethylmethacrylate membranes.34

Figure 27.4 Continuous venovenous hemofiltration circuit demonstrating movement of blood flow and solutes. Convection occurs when solutes are transported across a semipermeable membrane with the flow of water and under the influence of pressure. As flow increases, so does the movement of solutes. This movement is called “solute drag.” Convection can remove middle to large molecular weight molecules.

Figure 27.5 Continuous venovenous hemofiltration (CVVH) circuit incorporating pre- and post-filter replacement fluids. Continuous venovenous hemofiltration (CVVH) uses the principle of convection. Because CVVH requires the production of a large ultrafiltrate, replacement fluids are added either prefilter (predilution) or postfilter (postdilution), or both. Convection removes middle to large molecular weight molecules.

Figure 27.6 Circuitry of continuous venovenous hemodiafiltration ( CVVHDF) with pre- and post-filter fluid replacement. Circuitry of continuous venovenous hemodiafiltration with pre- and postfilter fluid replacement. Continuous venovenous hemodiafiltration (CVVHDF) uses both diffusive and convective clearance. Therefore, both dialysate and replacement fluids are required. CVVHDF removes both small and middle molecules.

Protein Binding The extent of protein binding is important for determining the Vd and exposure of a drug to its tissue sites compared with the intravascular compartment. The clearance of drugs by dialytic methods, as with filtration clearance by the endogenous kidney, is dependent on the fraction of unbound drug. Drugs that are more highly protein bound (e.g., greater than 80% protein bound) are less likely to be removed by dialytic techniques. Bound drugs are complexed with high-molecularweight proteins, with albumin (69,000 g/mol) being a common protein for binding acidic drugs. It is customary to consult common drug dosing references and product literature to ascertain the reported unbound fraction of a drug. However, the sieving coefficient can also be determined experimentally under conditions of isolated ultrafiltration35 or referenced from the literature. The sieving coefficient is the ratio of drug concentration in the ultrafiltrate to the prefilter plasma concentration. Either the sieving coefficient or the unbound fraction is necessary for estimating drug clearance during continuous renal replacement therapy. Sieving coefficients typically, but not always, correspond to the unbound fraction. The degree of protein binding can be decreased by competitive displacers in the plasma including other concomitant highly protein bound drugs and uremic toxins.36,37 Decreased albumin concentrations in kidney and hepatic diseases can also reduce protein binding. Increased protein binding can result from increased α1-acid glycoprotein concentrations found in acute care and inflamed patients.38

Because α1-acid glycoprotein binds basic drugs, increased binding will not be observed for acidic drugs. The systemic pH can also influence the protein binding of drugs in critical care patients.

Volume of Distribution The Vd of a drug is defined as a theoretical volume that the total amount of administered drug would have to occupy, if uniformly distributed, to provide the same concentration as blood plasma. It is most influenced by protein binding and log P. Drugs that have high plasma protein binding have small Vd values. Drugs that have high tissue protein binding and low plasma protein binding typically have large Vd values. Factors described earlier (under Protein Binding) will also influence the Vd of drugs. Because extracorporeal techniques remove solutes from blood or plasma, drugs with smaller Vd values (e.g., less than 1 L/ kg) are more likely to be removed by dialytic techniques. The duration of the dialytic technique will also affect the degree of influence of Vd on drug clearance. The likelihood of clearance for drugs with large Vd values increases as the duration of the dialytic procedure increases. The increased time allows drugs to transfer between tissue and vascular compartments. This is particularly important for drugs with larger Vd values. Moxifloxacin (Vd 1.7–2.7 L/kg) is an example whereby clearance is 95 mL/minute with conventional IHD and 33 mL/minute with extended daily dialysis.39 However, the moxifloxacin half-life is shorter on extended dialysis (6 hours) than on IHD (12 hours).39 Readers are referred to a recent review on antibiotic dosing during extended dialysis.40

Clearance Pathways The clearance pathway for a drug is also important for determining the impact of dialytic clearance on total body clearance. In acute and chronic kidney diseases, dialytic modalities are important for enhancing the clearance of drugs that undergo a significant percentage of clearance by the renal route. As kidney function declines, the total body

clearance of drugs that are excreted primarily by the renal route declines significantly. The contribution of clearance by extracorporeal techniques, renal pathways, and non-renal pathways to total body clearance is determined by equation 27.1:

The terms in this equation are total body clearance (clearancetotal), nonrenal clearance (clearancenonrenal), renal clearance (clearanceresidual renal), and extracorporeal clearance (clearanceextracorporeal). The equation shows that clearance processes are additive. Several clinical cases require particular attention with respect to clearance. Special consideration is required in drug conditions where nonrenal clearance can also decline as kidney function declines since the drug product literature values for unaltered nonrenal clearance may not be valid under this condition. As an example, cyto-chrome P450 (CYP) 3A expression and function is significantly reduced in chronic kidney disease.41 Patients receiving drugs that undergo predominant nonrenal clearance through CYP3A will likely have reductions in this clearance pathway necessitating drug dosing adjustments. Another special consideration is the case of drug combinations. In this scenario, one compound may have a predominant renal clearance pathway, whereas the other compound is predominantly cleared through nonrenal routes. Another consideration is the contribution of residual renal function to total body clearance. It is often assumed that patients in the ICU who require dialytic techniques have a drug clearanceresidual renal of 0 mL/minute. However, some patients can have significant kidney function that can result in a drug clearance that is considerably higher than predicted. In these circumstances, it is important to remember to add the estimated residual renal clearance to the clearance by nonrenal and extracorporeal pathways to avoid drug underdosing.

CLEARANCE PROCESSES OF DRUGS DURING

EXTRACORPOREAL TECHNIQUES Diffusion Drug clearance during continuous renal replacement therapies using a dialysis component occurs through diffusion. Several equations can be used to estimate this clearance. In the body or by extracorporeal devices, clearance is calculated as Q × E, where Q is a flow rate, and E is the extraction of the drug across the organ or device. The extraction across the dialyzer is governed by the unbound fraction of the drug. Extraction can be measured by the difference between the prefilter (arterial) concentration and the postfilter (venous) concentration divided by the prefilter concentration: E = (arterial – venous)/arterial. The clearance can be estimated either by the unbound fraction or by E multiplied by the dialysate flow rate (equation 27.2). Dialytic clearance estimates by this approach are amenable for use in the clinical environment.

The dialytic clearance can also be measured during the continuous renal replacement procedure, but this requires more laborious methods that are usually reserved for research studies. These methods are analogous to the calculations used to measure drug clearance by the renal route. For these assessments, the dialysate effluent is collected at intervals, the volume is measured, and the concentration of drug is determined by an analytic method. After multiplying dialysate volumes by their respective concentrations, drug amount determinations are obtained. The amounts are then summed over the intervals and divided by the area under the plasma concentration time curve (AUC) that corresponds to this total time period; this is shown in equation 27.3. Determination of the AUC requires serial blood sampling over the collection period.

Convection/Ultrafiltration Drug clearance during continuous renal replacement therapies using an ultrafiltration component occurs through convection. Several clearance equations can be used to estimate convection clearance. Clearance is calculated as Q × E; where Q is the ultrafiltration flow rate, and E is the extraction of the drug across the filter. The extraction across the filter is governed by the available unbound fraction of the drug. Extraction is measured by the ratio of drug in the ultrafiltrate to the prefilter concentration: E = [ultrafiltrate]/[arterial]. This determination of E is also called the sieving coefficient. A value of 1 indicates free passage of the solute across the membrane under the condition of isolated ultrafiltration. The clearance can be estimated either by the unbound fraction or by E multiplied by the ultrafiltration flow rate (equation 27.4). Equation 27.4 is used when fluids are administered postdilution.

If fluids are administered in the predilution mode, equation 27.5 should be used.

Clearance estimates by these approaches can be used in the clinical environment. The ultrafiltration clearance, like the dialysate clearance, can also be measured during continuous renal replacement therapy. For these assessments, the ultrafiltration effluent is collected at intervals, the volume measured, and the concentration of drug determined by an analytic method. After multiplying ultrafiltrate volumes by their respective concentrations, drug amount results are obtained. These amounts are then summed over the intervals and divided by the AUC that corresponds to this total time period; this is shown in equation 27.6. Determination of the AUC requires serial blood sampling over the collection period.

Combined Dialysis with Convection/Ultrafiltration It is now common in the ICU to use a combination of dialysis and ultrafiltration during continuous renal replacement therapy. Therefore, the clinician needs to know how to account for clearance through this combination. The clearance by the combination of dialysis and ultrafiltration can be estimated by multiplying the unbound fraction by the total effluent rate, which is composed of the combination of dialysate flow rate and ultrafiltration flow rate (equation 27.7). Clearance estimates by this approach are used in the clinical environment.

For measuring clearance through the combination of dialysis and ultrafiltration, the total effluent is collected at intervals, the volume is measured, and the concentration of drug is determined through an analytic method. After multiplying effluent volumes by their respective concentrations, drug amounts result. These amounts are then summed over the intervals and divided by the AUC that corresponds to this total time; this is shown in equation 27.8.

As mentioned at the beginning of this section, to adequately determine drug clearance, an assessment of determinants of total clearance is required. Therefore, the nonrenal clearance and residual renal clearance of the drug must be added to the clearance estimated or measured from the continuous renal replacement therapy (equation 27.1). Box 27.2 summarizes the clearance equations discussed in this section. Table 27.4 provides the abstracted clearance data for drugs during various continuous renal replacement therapies.

ACUTE VS. CHRONIC KIDNEY DISEASE AND PHARMACOKINETIC ALTERATIONS There is a considerable body of literature to show the influence of chronic kidney disease on the pharmacokinetics of drugs.42-44 However, there is a paucity of comparable data in patients with acute kidney injury. According to the available data, it is reasonable to assume similar changes in acute and chronic kidney diseases. However, there are differences that require consideration (Table 27.5), which are discussed in the following sections. Patients with acute kidney disease typically receive continuous versus intermittent dialytic techniques. The longer treatment duration will affect drugs with a large Vd secondary to more time for net transfer from tissue to vascular compartments. The incorporation of convection with high-flux membranes in continuous renal replacement therapy will enhance the removal of drugs with high molecular weights. Drug pharmacokinetics can be altered in critical care patients secondary to the physiological changes induced by organ alterations such as acute kidney injury, hepatic disease, cardiac failure, or generalized inflammatory states, occurring alone or in combination. Changes to drug absorption, distribution, metabolism, and excretion processes are reported and are reviewed.

Absorption Because many medications are administered by the intravenous route to patients in the ICU, changes to oral bioavailability secondary to alterations in absorption may be less problematic. However, medication administered by other extravascular routes, including subcutaneous and intramuscular, can result in alterations in absorption and for subsequent bioavailability. Several processes are responsible changes to the systemic bioavailability of medications in the critical care population and are described.

Box 27.2. Equations for Clearance Determination in Continuous Renal Replacement Therapies Diffusion Eq. 2: Clearance = fub (or E) × Qdialysate Eq. 3: Clearancedialysis = [ (concentrationdialysate × volume)]/AUCover collection time Convection Eq. 4: Clearance = fub (or E) × Qultrafiltration (if using predilution fluids) Eq. 5: Clearance = fub (or E) × Qultrafiltration × [Qblood/(Qblood + QReplacement)] (if using postdilution fluids) Eq. 6: Clearanceultrafiltration = [ (concentrationultrafiltrate × volume)]/AUCover collection time Diffusion + Convection Eq. 7: Clearance = fub × (Qdialysate + Qultrafiltration) Eq. 8: Clearanceeffluent = [ (concentrationeffluent × volume)]/AUCover collection time

Table 27.4 Drug Clearance Data During Continuous Renal Replacement Therapies

ClTB = total body clearance; ClRRT = renal replacement therapy clearance; DFR = dialysate flow rate; MW = molecular weight; NR = not reported; PB = protein binding; REF = reference; SA = surface area; UFR = ultrafiltration flow rate; Vd = volume of distribution.

Slowing of gastric emptying, or gastroparesis, is common in the ICU patient and can decrease the rate of drug absorption, resulting in a prolonged time (Tmax) to reach the maximum plasma concentration (Cmax). In addition, patients may have concomitant diseases such as diabetes mellitus or be prescribed medications (e.g., opiates, tricyclic antidepressants, phenothiazines, and calcium channel blockers) that can slow gastric emptying. Metabolic acidosis is common in critical care patients and can change the fraction of drug in the ionized versus nonionized state, resulting in changes to bioavailability. In addition, critical care patients are often prescribed ulcer prophylaxis and/or treatment regimens that contain drugs that can increase gastric pH, resulting in changes to the systemic bioavailability of prescribed medications. Concomitant use of proton pump inhibitors will reduce the absorption of iron, calcium, magnesium, and vitamin B12. The pH can also influence the availability of active pharmaceuticals from prodrug formulations. Binding of medications in the gut, such as the interaction between sucral-fate and fluoroquinolones, can reduce oral bioavailability. Reduction in first-pass metabolism can occur in critically ill patients secondary to decreases in the function of CYP metabolizing enzymes in the gut and liver. This can result in increases in the systemic bioavailability of CYP substrates. Other conditions such as edema of the gut and impaired small bowel function can also change the bioavailability of medications in the critical care population.

Distribution Distribution volume is related to plasma protein binding and tissue binding. Two common plasma proteins are albumin (which binds acidic drugs) and α1-acid glycoprotein (which binds basic drugs). Although chronic kidney disease is associated with reduced plasma protein

concentrations, acute care patients can have increased protein binding of basic drugs secondary to increased α1-acid glycoprotein concentrations.38 This scenario would predict a potential increase in the removal of acid drugs and a decrease in the removal of basic drugs during continuous renal replacement therapies. Patients with acute illness can also have redistribution of albumin from the intravascular to the extravascular compartments secondary to capillary leak syndrome, resulting in significant changes to the Vd of hydrophilic drugs.45 Common antibiotic examples include ceftriaxone, ertapenem, daptomycin, and aztreonam.46 It is often recommended to consider using loading doses of hydrophilic drugs in critical care patients. Alterations in drug to albumin binding have recently been extensively reviewed.46 Increases in body water that occur with volume overload in acute kidney disease can result in increases in the distribution volume of hydrophilic drugs (e.g., aminoglycoside antibiotics).

Table 27.5 Differences Between Acute and Chronic Kidney Diseases That May Impact Drug Pharmacokinetics Acute

Chronic

Use of continuous RRT

Use of intermittent RRT

Redistribution of plasma proteins

Decreased plasma proteins

↑ Vd for hydrophilic drugs

↓ Vd for hydrophilic drugs

↑ Residual renal clearance

↓ Residual renal clearance

Addition of ECMO

Metabolism and transport alterations

RRT = renal replacement therapy.

Metabolism

Cytochrome P450 enzymes can be decreased up to 35%, according to studies using experimental models of chronic kidney disease, and decreased up to 63%, according to clinical studies.41-44 In addition, in patients with chronic kidney disease, the function of CYP3A4 can be improved immediately after hemodialysis.41 The function of metabolic pathways in acute kidney injury and other representative diseases in critically ill patients is not well defined. Reductions in the nonrenal clearance of imipenem and vancomycin have been reported in patients with acute kidney injury.47 The clearance reduction was reported to be less severe than in patients with chronic kidney disease requiring IHD: 90 mL/minute versus 50 mL/minute, respectively, for imipenem and 15 mL/minute versus 5 mL/minute, respectively, for vancomycin.47 The duration of acute kidney injury can also influence the reduction in nonrenal clearance. Macias et al. reported that as the length of continuous renal replacement therapy increased, the nonrenal clearance was more significantly affected.48

Excretion Drugs that undergo excretion primarily through the kidneys (aminoglycosides, penicillins) will have significant reductions in total body clearance through decreases in renal clearance. The Dettli method49-51 is used to predict the fraction of clearance of a patient with chronic kidney disease relative to the expected clearance in a healthy individual (e.g., Q factor). It can be used to predict changes in the dose, interval, or combination of dose and interval in patients with chronic kidney disease. However, it has not been tested under acutely changing kidney function conditions. Endogenous clearance (both renal and nonrenal) can be different in acute versus chronic kidney diseases. It is generally recognized that residual renal clearances will be higher in the setting of acute versus chronic kidney disease. In addition, clearance can be increased in critically ill patients secondary to concomitant drugs prescribed to maintain adequate perfusion pressure.52 Mechanical ventilation can also contribute to increased clearance.53 A recent review provides

additional discussion of the potential for augmented renal clearance in critical care patients.54 Several transport proteins (e.g., P-glycoprotein, organic anion and cation transporters) contribute to drug secretion in the kidney tubules and can be affected by chronic kidney disease. The effects of critical illness on transport processes have not been evaluated. In addition, the influence of metabolic by-products (e.g., uremic toxins) on transporters in acute kidney injury is currently unknown.36,37,42,44

DRUG DOSING STRATEGIES/ PHARMACOKINETICS A previous section of this chapter reviewed the basic equations for estimating and measuring clearance during continuous renal replacement techniques. However, in addition to clearance determinations, clinicians must be able to recommend appropriate medication doses according to the clearance values, pharmacodynamic goals, and other individual concerns. This is important because the available drug dosing references are not written to be personalized for the patient in your care. Individual patients may have specific therapeutic goals or may be receiving different dialytic techniques or concomitant medications that could affect the plasma and tissue concentrations of drugs. The following sections will review drug dosing equations that use the clearance determinations from continuous renal replacement modalities (Table 27.6). These equations can also be used for dosing drugs in patients with chronic kidney disease. Additional information for drug clearance and dosing in chronic kidney disease can be found in several manuscripts and reviews.49,51,55-58 The equations will empower the clinician to calculate the plasma concentrations likely to result under given administration scenarios. In addition, the equations can be rearranged to solve for dose to enable the dosing revisions required to reach targeted plasma concentrations. The equations described in the following sections are applicable to drugs that are described by a one-compartment model.

Intravenous Bolus

Intravenous bolus administration implies an instantaneous administration of drug into the central compartment of the body. Many drugs (e.g., morphine, diphenhydramine) are administered as a direct intravenous bolus in the critical care unit. In addition, intravenous bolus administration can be used to provide a loading dose of medications and will be followed by an intravenous infusion. The maximal plasma concentration (Cp) after intravenous bolus administration is described by the dose and Vd (equation 27.9).

Table 27.6 Equations for Drug Dosinga IV Bolus Eq. 9

Cp = dose/Vd

IV Infusion Eq. 10 (during infusion):

Cp = Ko/Cl × [1 – e -ke*t]

Eq. 11 (at steady state):

Cpss = Ko/Cl

Eq. 12 (at end of infusion):

Cp = Ko/Cl × [1 – e -ke*T]

Eq. 13 (after end of infusion):

Cp = Cpat time= T e -ke*[time-T]

Extravascular Eq. 14:

Cp = [F × dose × Ka]/[Vd (Ka – Ke)] × [e-ke*t – e–ka*t]

Eq. 15:

Dose = (Cpss × Cl × tau)/(S × F)

aThe equations are representative of one-compartment models. IV = intravenous.

As shown in the equation, a good estimation of the Vd for the drug in the critically ill patient will suffice for determining concentration without respect to clearance. If the concentration is less than expected,

the Vd of the drug in the patient was higher than predicted by literature values. The equation can be rearranged to inform about the Vd in the particular patient. Subsequent intravenous bolus doses can be modified according to the actual Vd to achieve a targeted peak plasma concentration. The decline of the plasma concentration after intravenous bolus administration will suggest whether the drug follows a one-, two-, or three-compartment model.

Intravenous Infusion (during infusion) Although an intravenous bolus is straightforward, infusions are more complicated. For intravenous infusions, it must be realized that clearance processes during the infusion will affect the obtained concentration in the plasma. The plasma concentration (Cp) can be computed at any time point (t) during the intravenous infusion according to equation 27.10, considering the rate of infusion (Ko), total body clearance (Cl), and amount remaining as defined by the term 1 – e-ke*t.

As suggested earlier, the total body clearance should be the sum of the residual renal, nonrenal, and renal replacement therapy clearance. The duration of the renal replacement therapy will further affect the clearance. This condition (equation 27.10) does not represent steady state. Equation 27.10 will be helpful to use to determine where the plasma concentrations fall during an infusion and to calculate the infusion rates needed to achieve a targeted drug concentration.

Intravenous Infusion (at steady state) The plasma concentration at steady state (Cpss) can be computed for drug therapy that requires an intravenous infusion according to equation 27.11, considering the rate of infusion (Ko) and total body clearance (Cl). Note that the amount remaining term is not included because, by definition, steady state would imply that the rate in equals the rate out.

This method can also be useful to determine rates of infusion needed given a known clearance and targeted Cpss.

Intravenous Infusion (at end of infusion) The plasma concentration at the end of an infusion (time is T) can be computed according to equation 27.12, considering the rate of infusion (Ko), total body clearance (Cl), and amount remaining term (1 – e-ke*T) that incorporates the end of infusion time term (T).

This equation will be helpful to determine where the plasma concentrations fall at the end of one infusion rate in order to guide changes to infusion rates for subsequent doses to achieve a targeted drug concentration.

Intravenous Infusion (after end of infusion) Finally, the plasma concentration at any time point after the end of an intravenous infusion (time) can be computed according to equation 27.13, considering the concentration at the end of the infusion (Cp at T) and the loss of drug between the end of the infusion and T (e-ke*[time-T]).

Extravascular Route The calculation of the plasma concentration after administration of a drug by the extravascular route is more complicated (equation 27.14). It requires the bioavailability term (F), dose, Vd, and rate constants for elimination (Ke) and absorption (ka).

If the usual condition of the absorption rate being faster than the elimination rate is not met, the drug is said to have flip-flop pharmacokinetics. Given the potential absorption issues in critical care patients, clinical scenarios whereby flipflop pharmacokinetics are shown are highly likely. At steady state, an extravascular dose can be calculated as shown in equation 27.15.

In equation 27.15, the numerator is the product of the concentration in plasma at steady state (Cpss), total body clearance (Cl), and dosing frequency (Tau), whereas the denominator is the product of the salt form of the drug (S) and bioavailability (F). More advanced pharmacokinetic modeling and simulation using population approaches are warranted to fully understand the differences in pharmacokinetics in discrete populations within the ICU. In addition, population modeling techniques enable the determination of patient, clinical, and renal replacement therapy covariates that could affect pharmacokinetic parameters and interindividual variability.59

IMPLICATIONS OF DRUG DOSING ON PHARMACODYNAMIC EFFECTS It has been suggested that despite attention to adjustments of drugs in patients receiving renal replacement therapies, patients with infections who are receiving antibiotics often have inadequate outcomes.60,61 Because of variations in drug clearance by renal replacement therapies, it is highly recommended that clinicians treat infections aggressively, especially during the early phase of treatment, using loading doses to reach targeted plasma concentrations sooner. For antibiotics, the targeted plasma concentrations should consider the

desired concentrations at the infection site. It is necessary for clinicians to consult their local laboratory to obtain susceptibility data (minimum inhibitory concentrations [MICs]) for antibiotics to ensure that targeted concentrations are adequate. Clinicians also need to identify whether the selected antibiotics have time- or concentration-dependent killing.62 For drugs that have time-dependent killing, previous data analyses have suggested that maximal bactericidal effects occur when concentrations above the MIC are obtained for a defined percentage of the dosing interval: for cephalosporins, about 60%–70%; penicillins, 50%; and carbapenems, 40%.63 These targeted times have been used as pharmacodynamic measures for therapy outcomes.64 In the study by Seyler et al., 90% of patients receiving antibiotic therapy (meropenem, piperacillin/tazobactam, cefepime, or ceftazidime) had plasma concentrations deemed adequate for concentration breakpoints of Enterobacteriaceae, but inadequate for most other 64 microorganisms. According to Seyler et al., the dosing ranges suggested for the antibiotics mentioned previously in critical care patients receiving renal replacement therapies would have resulted in poor pharmacodynamic responses given the percentage of the antibiotic dosing interval in which drug concentrations are greater than the MIC.64 These data analyses suggest that clinicians should use the combined pharmacokinetic-pharmacodynamic simulation tools available in many commercial pharmacokinetics software packages to more accurately estimate how dosing recommendations may affect pharmacodynamic outcomes. Strategies proposed during continuous renal replacement therapies to optimize the attainment of adequate concentrations of antibiotics with time-dependent killing include continuous or prolonged infusions, shorter dosing intervals, supplemental dosing, and weight-based dosing.65 For antibiotics that have concentration-dependent dosing (e.g., aminoglycosides, colistin, daptomycin, fluoroquinolones, linezolid, macrolides, metronidazole, vancomycin), strategies such as loading doses, extended dosing intervals, and weight-based dosing have been proposed to optimize pharmacodynamic outcomes.65 A paucity of literature exists for other

classes of drugs and pharmacodynamic outcomes in patients undergoing continuous renal replacement therapies.

CLINICIAN DOSING AND OUTCOMES Despite clinicians providing dosing consultations for drugs in patients receiving renal replacement therapies, there are limited publications that show outcomes. One publication reported more than 180 recommendations for dosing adjustment of antimicrobials in critical care patients.66 Changing continuous renal replacement therapy conditions was reportedly the most common reason for dosing errors, showing the need to adequately monitor for these changes and incorporate them into clearance and drug dosing equations. Of importance, clinician dosing recommendations had positive clinical outcomes, including reduced length of stay in the ICU by 3 days as compared with a control group not receiving targeted recommendations.66 Another recent publication evaluated prescribing patterns of antimicrobials in patients receiving sustained low-efficiency dialysis.67 Results indicated that antimicrobial under-dosing was a predominant problem, with failures to reach clinical cures. These data show the potential for the positive impacts clinicians can have on outcomes in patients receiving renal replacement therapies.

ONGOING CONSIDERATIONS FOR CONTINUOUS RENAL REPLACEMENT THERAPIES According to the available published data for the pharmacokinetics of drugs during continuous renal replacement therapy, it is clear that most evaluated drugs have been antibiotics. Given the polypharmacy in the ICU population, future studies should assess pharmacokinetic alterations and dosing guidance for other classes of drugs. Most published research evaluating drug pharmacokinetics during renal replacement has focused on adults. However, given the increased frequency of these therapies in the pediatric population and the inherent pharmacokinetic differences between adult and pediatric

patients, future research should include this patient subgroup as well. Continuous renal replacement therapies have been in clinical use since the 1990s. However, the therapy conditions have evolved over time with new hemofilters composed of different materials and higher effluent rates. It is necessary to note the therapy conditions in published research in order to determine the relevance to individual patients today. It may be necessary to recalculate the expected clearance for a drug of interest according to the differences in effluent rates in the past versus the present. Pharmacokineticpharmacodynamic modeling and simulation can assist with achieving targeted concentrations and clinical outcomes. Finally, given the widespread use of continuous renal replacement therapies, it is now necessary to provide education and experiential training to students and clinicians who train or practice in the critical care setting.

PLASMAPHERESIS Plasmapheresis is a continuous flow procedure that involves the extracorporeal separation of plasma from other blood components through intravenous access. The plasma is discarded and exchanged with a physiological replacement fluid that varies depending on the clinical scenario and typically contains albumin or fresh frozen plasma. Replacement fluid is necessary to maintain oncotic pressure and intravascular blood volume in order to avoid hypovolemic shock. Replacement fluid in conjunction with the patient’s blood and cellular components is returned to the patient through the intravenous access. There are many clinical indications for the use of plasma-pheresis. Disease indications include thrombotic thrombocytopenic purpura, myasthenia gravis, acute/chronic inflammatory demyelinating polyneuropathy, acute antibody-mediated rejection related to a variety of solid organ transplant types, and other autoimmune processes. In addition, plasmapheresis has been reported to be effective for the treatment of medication overdoses and venomous exposures.68-70 Apart from the intended use of plasmapheresis for the treatment of

medical conditions and toxicological problems, there is an unintended effect of plasmapheresis on the loss of prescribed medications. The impact of plasmapheresis on the pharmacokinetics of medications commonly prescribed in the ICU setting is not insignificant. There continues to be a paucity of evidence-based guidelines on the impact of plasmapheresis on drug clearance. Limited studies in the literature report formal pharmacokinetic evaluations of drugs during plasmapheresis.71 In 2007, Ibrahim et al. described the existing limitations of the available published literature on this topic including (1) heterogeneity of plasma exchange procedures with respect to the duration, volume, and type of replacement fluid used; (2) lack of uniformity in plasma sampling times for pharmacokinetic evaluation among studies, and the relationship of this sampling to initiation of plasmapheresis; (3) use of different analyses to ascertain removal such as declines in drug plasma concentration versus the total quantity of drug removed during plasmapheresis; (4) statistical flaws; and (5) inappropriate extrapolations between patient populations (e.g., adult data extrapolated to neonates).71

DRUG CHARACTERISTICS FOR CLEARANCE BY PLASMAPHERESIS There are specific drug- and plasmapheresis-dependent factors that influence the likelihood of a drug being cleared by this extracorporeal technique72 (Table 27.7). To provide a framework for the extent of solute removal during plasmapheresis, one study reported that a single exchange of 1 plasma volume (about 3 L in a 70-kg adult patient) removes around 63% of all solutes in the plasma, and an increase to a 1.5 exchange volume removes about 78% of solutes.73 Solute elimination by plasma exchange is passive and described by linear kinetics.73 The time between the drug administration and plasmapheresis initiation is considered to be the most important and critical factor affecting drug removal.74 Several early studies evaluating the disposition and removal of ceftriaxone, ceftazidime, phenobarbital, vancomycin, gentamicin, thyroxine, and aspirin reported increased drug

removal when plasmapheresis was initiated immediately or shortly after drug administration. These data are consistent with more recent findings such as those described for cefepime removal by plasmapheresis.74-81 Ibrahim et al. also reported data showing that 75% of mycophenolate mofetil was recovered in the volume of plasma removed when it was concurrently administered by intravenous infusion during the plasmapheresis procedure.72

Table 27.7 Important Determinants of the Effectiveness of Plasmapheresis in Removal of Drugs72 Drug-Dependent Time between dose administration and plasmapheresis initiation The higher the drug plasma concentration at the time of plasmapheresis initiation, the more likely it will be removed (a function of the drug’s distribution half-life) Protein binding The lower a drug’s protein binding, the less likely it will be removed Volume of distribution The higher the drug’s volume of distribution, the less likely it will be removed Plasmapheresis-Dependent Duration of plasmapheresis Successive plasmapheresis sessions Volume of plasma removed Plasmapheresis replacement fluid (equivocal)

Reprinted with permission. Adapted from: Ibrahim RB, Balogun RA. Medications in patients treated with therapeutic plasma exchange: prescription dosage, timing and drug overdose. Semin Dial 2012;25:176-89.

Drugs with a higher degree of protein binding have enhanced removal during plasmapheresis. In general, a drug whose protein binding is greater than 80% will be removed by plasmapheresis.71,72 It

is suggested that for a drug bound to albumin, a linear relationship exists between the fraction eliminated during the plasmapheresis session and the fraction of the drug present in the extracellular fluid.82 Plasma proteins and bound drugs are removed in tandem with fluid in plasmapheresis. Of importance, this scenario is contrary to what is known about drug protein binding and clearance during extracorporeal dialysis techniques. During dialysis procedures (intermittent or continuous), drugs with increased protein binding are not significantly removed. The unbound fraction of drugs is cleared through dialysis procedures (as described earlier in this chapter). Drugs with a lower Vd (less than 0.2 L/kg) are more likely to be removed by plasmapharesis.72 This is intuitive because drugs must be in the plasma compartment to be eliminated by plasmapheresis. A drug with increased Vd has reduced clearance by plasma exchange. Calculating patient-specific Vd values for medications will enable an estimate of total body drug stores. This method is the most stringent for determining the drug fraction eliminated during plasmapheresis.83 Single-dose drug studies of plasmapheresis are limited because the Vd after a single dose may vary from the Vd at steady state and is one of the limitations of many of the published studies.84 Hydrophilic drugs with small volumes of distribution and high protein binding would be predicted to be cleared, especially if administered around the time of the plasmapheresis procedure. However, lipophilic drugs have large Vd and would not be expected to have significant clearance by plasmapheresis.72 For example, voriconazole, a lipophilic drug with a large Vd (4 L/kg) and moderate protein binding (58%), was not significantly removed by plasmapheresis.85

PLASMAPHERESIS CONDITIONS AND DRUG CLEARANCE Several plasmapheresis-specific factors are implicated in drug clearance including the duration of the plasmapheresis procedure, need for successive plasmapheresis sessions, volume of plasma removed, and type of replacement fluid used (Table 27.8).71,72

Table 27.8 Drug Characteristics for Removal by Plasmapheresisa

aThis

is not a comprehensive list of medications. A more comprehensive list can be found in Ibrahim RB, Balogun RA. Medications in patients treated with therapeutic plasma exchange: prescription dosage, timing and drug overdose. Semin Dial 2012;25:176-89. t½ = half-life.

Most commonly, plasmapheresis sessions last 1–3 hours. The duration of the sessions can vary depending on the patient’s hemodynamics during exchange of the desired plasma volume and the overall therapeutic goals. Although some drugs have a large Vd and will not be removed by plasmapheresis, others that are highly protein bound will have increased removal, as previously discussed. An extended duration of each session may result in increased drug removal. It is, however, important to realize that although some drugs such as β-blockers are heavily removed by plasmapheresis, blood concentrations do not correlate with their biologic effect. As such, removal by plasmapheresis may not always predict changes in pharmacodynamics. However, out of an abundance of caution, it is

recommended that drugs with a small Vd and high degree of protein binding be administered after the plasmapheresis session. In some clinical scenarios, several plasmapheresis sessions may be required, often on a daily basis, depending on the intended outcome. As discussed previously, waiting to dose drugs with small distribution volumes and increased protein binding until after the plasmapheresis session is complete may allow for enhanced benefits from the therapies. Because dilution of plasma occurs secondary to the administration of replacement fluid, the targeted substances of interest cannot completely be removed from the circulation. For example, for each 1– 1.5 plasma volume exchanged, about 60%–70% of the substances present in the plasma at the start of that plasma volume will be removed. As additional plasma volumes are exchanged, the absolute amount removed becomes lower, although the removal of a fixed 60%– 70% still occurs. For this reason, routine practice is to exchange only 1–1.5 plasma volumes during a single plasmapheresis session. Plasmapheresis volumes beyond 1.5 plasma volumes remove smaller, less clinically important amounts of pathologic substances present in the plasma while prolonging the procedure and exposing patients to more replacement fluid with an increasing risk of complications.86 Similar to the removal of pathologic substances, plasma volume can also affect the removal of drug solutes. The composition of the replacement fluid influences the effects of plasmapheresis on the patient. It is known that about one-third of the replacement fluid administered at the beginning of a session will be present by the end, with the other two-thirds removed. Administering plasma as a replacement fluid at the beginning of a session exposes the patient to blood products without additional clinical benefit. The most commonly used replacement fluid is 5% albumin in physiological saline. This fluid mixture has several advantages because it decreases the risk of disease transmission from the use of blood products and transfusion-related reactions such as acute lung injury. This specific replacement fluid has a higher oncotic pressure than plasma and thus may result in expansion of the intravascular volume. The albumin

concentrations in the replacement fluids may affect drug clearance through protein binding.

DRUG PHARMACODYNAMICS WITH PLASMAPHERESIS As mentioned previously, plasma concentrations of drugs and therapeutic proteins do not always correlate with clinical effects. Therefore, plasmapheresis may not alter the biologic effect of a drug despite reducing the plasma concentration. This scenario has been shown for rituximab, a monoclonal antibody used for the treatment of a variety of conditions. Rituximab has a moderate Vd (3.1 L), no protein binding, and a half-life of 9–70 days. Despite these pharmacokinetic parameters, significant removal of rituximab is seen when it is dosed within 24 hours of a plasmapheresis session. The main mechanism for rituximab removal by plasmapheresis is unknown but is thought to be related to the removal of the therapeutic antibody or antibody complexes and resulting inflammatory cytokines, or the transient depletion of complement.68 However, an assessment of pharmacodynamic markers (peripheral CD19 B cells and ADAMST12 immunoglobulin G, and increased ADAMST13 activity) has suggested that the drug response was unaltered.87 Given this example, it can be concluded that the removal of therapeutic proteins by plasmapheresis does not necessarily translate to a loss of pharmacologic effects. The optimal timing between drug administration and plasmapheresis initiation for different drugs remains ill defined, and the correlation between drug pharmacokinetics and clinical outcomes requires further study. Plasmapheresis may have effects on drugs because of the clearance of other circulating components necessary for drug effectiveness. Plasmapheresis is known to reduce levels of antithrombin III,71 and can therefore have an effect on achieving therapeutic anticoagulation. A study evaluating anti-factor 10a activity during plasmapheresis found decreased anti-factor 10a and a 40% loss in a patient receiving low-molecular-weight heparin. This is thought to be related to the extraction of antithrombin III alone or the complex

of heparin and antithrombin III.88 Patients on plasmapheresis who require simultaneous anticoagulation with heparin may require higher doses to achieve therapeutic effects. Patients receiving plasmapheresis often have other comorbidities that can influence the pharmacokinetics of drugs. For example, acute renal or hepatic failure can alter pharmacokinetics, independent of plasmapheresis. Clinicians should review the characteristics of prescribed drugs (protein binding, Vd) before plasmapheresis initiation so that they can be aware of the medications that should be closely monitored for decreased efficacy secondary to increased clearance.89 Ibrahim et al. have published two excellent reviews from the literature (case reports and randomized studies) on the impact of plasmapheresis on drug removal.71,72 Table 27.8 is a summary of drug clearance by plasmapheresis. Finally, if the pharmacokinetic and pharmacodynamic effects of plasmapheresis on the drug are not well described, administration of drugs after a plasmapheresis session remains a viable and conservative approach. Therapeutic drug monitoring should also be considered when available.

EXTRACORPOREAL MEMBRANE OXYGENATION Extracorporeal membrane oxygenation (ECMO) is a type of extracorporeal life support and, depending on its configuration, can be used to provide oxygenation, carbon dioxide removal, and/or perfusion to vital organs for days to weeks in critically ill patients with lung and/or cardiac dysfunction. Its use spans a wide variety of populations, including neonates, children, adolescents, and adults. The first successful use of ECMO was in 1972, but initial enthusiasm was dampened when a randomized controlled trial of ECMO for adult acute respiratory distress syndrome (ARDS) was terminated because of futility.90 Al-though there have been some advances in technology, enthusiasm for this technique in adults has been renewed because of recent randomized and cohort studies of patients with severe ARDS, and in particular H1N1-related ARDS where reductions in mortality were reported.91,92

The two separate modes of ECMO are venovenous and venoarterial. Venovenous ECMO is used for isolated respiratory failure, and its use increased dramatically in adults during the H1N1 influenza outbreak.91 In this mode, systemic blood flow and pressure are the result of native cardiac function unrelated to extracorporeal flow. Venoarterial ECMO is used for isolated cardiac failure or combined cardiopulmonary failure. Systemic flow is a combination of that established by the extracorporeal circuit plus the amount of blood passing through the native heart and lungs. Systemic oxygen and carbon dioxide concentrations are determined by a mix of blood passing through the lungs and heart and oxygenated blood that is reinfused from the circuit into the arterial circulation.

ECMO Components Several circuit components are known to affect drug pharmacokinetics. A clear understanding of each of the circuit components, including the tubing, oxygenator, type of circuit (roller vs. centrifugal pump), and venous reservoir, is necessary to understand how they may affect drug pharmacokinetics. Several excellent reviews have been published that describe these components and their function.93-96 Figure 27.7 depicts the standard ECMO circuit setup.94 The purpose of the pump is to push blood through the oxygenator and back to the patient. Flow in the centrifugal pump is dependent on the blood volume from the patient, systemic vascular resistance, size of the cannula, and pump speed. The main advantage of the centrifugal pump is that it creates less negative pressure on the blood, and therefore less hemolysis. Flow in the roller pump depends on the size of the tubing in the raceway, occlusion pressures of the rollers, pump speed, and blood volume. One of the major disadvantages of the roller pump is increased hemolysis and continued rotation of the pump independent of blood volume or air entrapment.93,97 The two main devices used for gas exchange in the ECMO circuit are the silicone membrane oxygenator and the hollow fiber oxygenator. The hollow fiber oxygenator has major advantages, including priming

that is easy and fast, presence of a coating that reduces the risk of clot formation, smaller surface area to reduce platelet activation and inflammation, and lower pressure gradient across the membrane to reduce shear stress on the red blood cells and subsequent hemolysis. Different types of ECMO tubing exist, each with different components, and are beyond the scope of this chapter. However, remember that each of these tubing types can influence drug pharmacokinetics in patients on ECMO. An ECMO circuit may also include a venous reservoir or bladder located on the venous line before the pump and serves as an air bubble trap and volume buffer as it sits at the lowest point on the ECMO circuit. Clot formation in the reservoir poses a significant risk. Pooling of medications may occur in the venous reservoir, especially if the specific gravity of the medication is less than that of blood. For this reason, it is recommended that medications be administered in the circuit at a location after the reservoir.98 Many centers no longer use a venous reservoir as part of the ECMO circuit.

Factors Responsible for Alterations in Drug Pharmacokinetics in ECMO Extracorporeal membrane oxygenation can alter the pharmacokinetics and pharmacodynamics of medications for a variety of reasons in a population (e.g., critically ill patients) already known to have altered drug pharmacokinetics. The addition of ECMO increases the degree of systemic inflammation because of the interaction between the patient’s blood and the artificial membranes, hemodilution, transfusions, organ dysfunction, and renal replacement therapy.99,100 Extracorporeal membrane oxygenation treatment can lead to drug sequestration and changes to Vd and clearance. The addition of continuous renal replacement therapy to the ECMO circuit (Figure 27.7) can result in further changes to drug pharmacokinetics (as described earlier in this chapter). Although the body of literature on the effects of ECMO on drug clearance is growing, data are currently insufficient to make meaningful recommendations for drug dosing adjustments.101 Ongoing

studies continue to investigate altered pharmacokinetics and related outcomes for a variety of drugs commonly administered to patients requiring ECMO.102,103 These studies fall into three general categories: in vitro studies related to the physiochemical properties of drugs (e.g., drug binding to ECMO circuitry), classical pharmacokinetic studies, and clinical trials evaluating outcomes.89

Figure 27.7 Standard extracorporeal membrane oxygenation (ECMO) circuit. Venous blood drains from the patient and passes through a venous saturation sensor and a bladder before being pumped to the oxygenator/heat-exchanger device. The oxygenated warmed blood passes the ECMO circuit bridge before infusing back into the patient into the arterial (venoarterial) or venous (venovenous) system. There are many infusion and access ports, as well as pressure and flow monitors, along the way. CRRT = continuous renal replacement therapy.

Reprinted with permission from: Lequier L, Horton SB, McMullan DM, et al. Extracorporeal membrane oxygenation circuitry. Pediatr Crit Care Med 2013;14:S7-12.

Drug Sequestration and Influence of ECMO Circuit Components and Drug Characteristics Drug sequestration on ECMO is well known but poorly characterized. It is influenced by specific drug properties, including molecular size, degree of ionization, lipophilicity, and plasma protein binding.104 Sequestration is a function of binding to a biosynthetic surface. The most common biosynthetic surface is the standard polyvinyl chloride tubing. In addition, there are a variety of other coated tubing types, including Maquet Safeline (synthetic immobilized albumin), Maquet Softline (heparin-free biopassive polymer), Maquet Bioline (recombinant human albumin plus heparin) by Maquet Cardiopulmonary AG (Hirrlingen, Germany), Terumo X Coating (poly2methoxylacrylate) by Terumo Cardiovascular Systems Corporation (Ann Arbor, MI), and Medtronic Carmeda (covalently bonded heparin) and Medtronic Trillium (covalently bonded heparin) by Medtronic (Minneapolis, MN). Sequestration can vary depending on the circuit components (pump, oxygenator, tubing, venous reservoir), circuit priming, and age of the circuit.105,106 Most of the available data on drug disposition have been derived from neonatal studies using older-generation ECMO circuits.107 In these studies, significant sequestration by the ECMO circuit was observed and was dependent on the physiochemical properties of drugs and the type and age of the circuits used.104,107,108 In an adult ex vivo model of ECMO using contemporary circuitry, Shekar et al. hypothesized that lipophilic and protein bound drugs have enhanced sequestration in ECMO circuits.109 The authors used four identical ECMO circuits comprising centrifugal pumps and polymethylpentene oxygenators to investigate the influence of plasma protein binding on drug disposition. Drug recovery was defined as the amount of drug recovered from the ex vivo circuit at the end of the study and after accounting for sequestration. Ceftriaxone, ciprofloxacin, linezolid, fluconazole, caspofungin, and thiopentone were selected for

evaluation on the basis of lipophilicity and protein binding values. Lipophilicity (log P) and protein binding values for these drugs appear in Table 27.9. The circuit conditions (oxygen tension, temperature, activated clotting times, pH) were kept stable in order to discern differences in sequestration related to drug characteristics. Study drugs were injected post-oxygenator as a single bolus dose, with doses selected on the basis of producing concentrations that were similar to expected clinical concentrations. Larger doses were chosen for drugs having high protein binding in order to achieve concentrations that were similar to clinical concentrations. Equivalent doses of drugs were injected into four polypropylene jars containing fresh human whole blood in order to serve as study controls and for stability testing. Serial blood samples were collected from the ECMO circuits and control reservoirs over 24 hours. Drugs with a significant decrease in plasma concentration at 24 hours had a high degree of protein binding (greater than 80%), were highly lipophilic (log P greater than 2.3), or both, with a recovery of less than 20%.109 However, meropenem, a drug with a low degree of protein binding (2%) and hydrophilic (log P -0.6), had a very low plasma concentration remaining at 24 hours, which was attributed to its instability at physiological temperature. This situation highlights the need to study and identify the impact of ECMO on the sequestration of thermolabile medications.108110,111 Despite this robust study, it remains unclear whether protein binding and lipophilicity definitively have an additive effect on drug sequestration in the circuit. In addition, drugs with a similar lipophilicity but different protein binding can have variable recovery from the circuit, suggesting that protein binding determines circuit drug sequestration.109

Table 27.9 Lipophilicity (log P) and Percent (%) Protein Binding of Drugs Prone to Sequestration in ECMO Drug Ciprofloxacin

Lipophilicity (log P) 2.3

Protein Binding (%) 20–40

Fluconazole

0.4

12

Linezolid

0.9

31

Ceftriaxone

-1.7

95

Caspofungin

0.1

80

Fentanyl

3.9

85

Midazolam

3.9

92

Meropenem

-0.6

2

Vancomycin

-3.1

55

Morphine

0.8

30

Thiopentone

2.3

80

A significant loss of ampicillin, a hydrophilic drug (log P -2.0) with low protein binding (15%–25%), was reported in ex vivo blood primed circuits compared with crystalloid primed circuits.111 This suggests that ECMO circuits can bind blood proteins and drugs, and it is unclear whether there is a competitive binding between them, and if so, whether this phenomenon is concentration-dependent. The mechanisms that lead to circuit sequestration of highly protein bound drugs are unclear. In ex vivo neonatal circuits, 80% of fentanyl (85% protein bound, log P 3.9) was sequestered in the absence of an oxygenator, and an additional 6% sequestration occurred when the oxygenator was added.112 It has been postulated that circuit sites that bind albumin and other proteins on priming or after the passage of blood lead to binding of administered drugs that have high protein binding. In a recent study evaluating different circuit types, there were significant differences in drug recovery rates between roller and centrifugal pumps, respectively, for fentanyl (0.4% vs. 34%) and midazolam (0.6% vs. 63%).108,113 Similar to fentanyl, midazolam is 92% protein bound and has a log P value of 3.9. Age of the ECMO

circuit can also influence drug sequestration. Midazolam sequestration in the first 10 minutes in a used ECMO circuit was lower than in a new ECMO circuit (4.1% vs. 26.1%, p = 0.0004), but this difference disappeared after 180 minutes.106 For both midazolam and fentanyl, there was a failure to reach steady state, and ongoing drug losses suggest the presence of a greater amount of binding sites within the ECMO circuit for these drugs than for other evaluated compounds. This study, however, did not identify where the loss of drugs occurred.106 Although all drugs are clinically administered before the oxygenator in the circuit to decrease the risk of air embolus, given the results, it can be hypothesized that fentanyl and perhaps other highly lipophilic drugs have less therapeutic effectiveness when administered pre-oxygenator in the ECMO circuit. Hence, these drugs should be administered directly to the patient to minimize sequestration.106 It is known that drug adsorption by polymers (silicone and rubber) is related to lipophilicity.113 As the total adsorptive capacity is linked to total surface area, ECMO circuits with larger membrane oxygenators and longer tubing may result in more adsorption. It has been reported that polyvinyl chloride tubing with newer surface coatings such as the Maquet tubing (including Bioline) led to a decrease in morphine concentration in the circuit to 51% of baseline compared with 35% of baseline in other types of tubing, suggesting that adsorption by certain tubing types is significantly reduced.113 Several unanswered questions remain regarding sequestration of drugs during ECMO. Controversy currently exists over whether new or old circuits have more drug sequestration, with studies showing significant variability.106,108,114 It remains unclear how fast saturation occurs for the protein and drug-binding sites in the ECMO circuit. The impact of competitive binding to blood proteins and circuit components from administration of concomitant drugs also remains unknown. When dye was administered to the venous limb of the circuit, it pooled at the loop of the reservoir.98 Newer types of reservoirs such as the collapsible Better Bladder (Circulatory Technology, Oyster Bay, NY), which is vertically oriented, may decrease this pooling by regulating forward flow through the ECMO pump.

In summary, the circuit loss of a drug through sequestration may represent a balance between the binding to the circuit components and the extent of drug protein binding. In addition, critically ill patients can have reductions in serum proteins that can influence protein binding of drugs in addition to the effects of binding to the circuit. Sequestration of drugs in the circuit may have implications in both choice and dosing of particular drugs during ECMO. The circuit may also release the sequestered molecules once a drug infusion is ceased. This situation is unpredictable and may prolong the pharmacologic effect in an undesirable manner. Interpatient variability inherent to critically ill children and adult patients contributes to altered pharmacokinetics observed on ECMO. Therefore, therapeutic drug monitoring is highly recommended, when available. It is also recommended to refer to routine drug dosing handbooks and recent ECMO literature for information pertaining to drug protein binding and Vd information and factors responsible for ECMO clearance.103,109,115

VOLUME OF DISTRIBUTION Volume of distribution is the theoretical volume of fluid into which the total drug administered will have to be diluted to produce a concentration equal to that observed in plasma. It has been suggested that ECMO represents another pharmacokinetic compartment, similar to extra-corporeal dialysis techniques. Extracorporeal membrane oxygenation can lead to a SIRS (systemic inflammatory response syndrome) that increases the Vd, resulting in low serum concentrations and therapeutic failure (Figure 27.8).101 The inflammatory response can down-regulate CYP enzymes in the liver and increase the Vd within the extracellular fluid. Extracorporeal membrane oxygenation alters the Vd of medications (Table 27.10).101 The circuit may lead to a doubling in the patient’s extracellular fluid volume. This effect is much more pronounced with drugs that have a small Vd and for smaller patients. Extracorporeal membrane oxygenation circuit priming volumes in a child varies from 200 to 400 mL, and the circulating blood volume of an infant is 80–85

mL/kg. The dilutional effect of the circuit prime is exacerbated by the ongoing intravenous fluid requirements in the critically ill patient and by requirements for repeat blood and blood product transfusions. The degree to which ECMO itself expands the extracellular fluid compartment is debatable, and an increased drug Vd may be the result of the disease process rather than or in addition to ECMO. The prime and multiple transfusions dilute the plasma proteins and can result in decreased drug binding, increased free concentration of drug, and an apparent increase in Vd. Additional effects on plasma proteins during ECMO include binding of protein by heparin and potential denaturation of proteins passing through the membrane oxygenator. The large surface area of oxygenators can affect the Vd and drug concentrations. Dagan et al. examined circuits and showed that there was a significant decrease in drug concentration after flow through the oxygenator.114 They found that phenytoin concentrations in the circuit decreased by 43%, whereas vancomycin and morphine decreased by 36%, phenobarbital by 17%, and gentamicin by 10%. In circuits that had been used for 5 days, the drug concentrations decreased much less: morphine by 16%, vancomycin by 11%, and phenobarbital by 6%. This suggests saturation of the binding sites over several days.114

Figure 27.8 Impact of critical illness, inflammation and ECMO on drug pharmacokinetics. Impact of critical illness, inflammation, and extracorporeal membrane oxygenation on drug pharmacokinetics. CO = cardiac output; ECMO = extracorporeal membrane oxygenation; SIRS = systemic inflammatory response syndrome. Reprinted with permission from: Shekar K, Fraser JF, Smith MT, et al. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care 2012;27:741 e9-18.

Table 27.10 Impact of Pharmacokinetic (PK) Changes During ECMO and Clinical Implications

Reprinted with permission from: Shekar K, Fraser JF, Smith MT, et al. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care 2012;27:741 e9-18.

Several other important factors are known to increase drug Vd, including hemodilution from priming solutions at ECMO initiation, ongoing blood product transfusions, pH alterations that affect protein binding and therefore distribution, and administration of volume to maintain circuit flows.107 Although hemodilution can often enhance the pharmacokinetic effect of highly protein bound drugs by increasing the unbound fraction, redistribution of free drug into the tissues may result in a lower serum concentration.107 Much of the ECMO data evaluating Vd originate from the neonatal population. This population has a higher proportion of total body water and less adipose tissue. As a result, neonates will have a higher Vd for hydrophilic drugs (β-lactams and aminoglycosides) and a lower Vd for lipophilic drugs (fluoroquinolones and macrolides) relative to adults. There is also decreased protein binding in neonates, resulting in increased unbound drug concentrations and Vd.116 These physiological alterations limit the use of neonatal pharmacokinetic data to guide drug

dosing in critically ill adults requiring ECMO. Table 27.10 summarizes the pharmacokinetic changes during ECMO and clinical implications.101

DRUG CLEARANCE Several indirect mechanisms lead to decreased drug clearance during ECMO. Preceding hypoxia and hypoperfusion may lead to a kidney insult and decrease in renal clearance. Extracorporeal membrane oxygenation can result in altered organ perfusion most prominently by the lack of pulsatility, even though tissue oxygen delivery may be adequate. However, a comparison of the half-life for gentamicin in infants who received either venoarterial ECMO or venovenous ECMO was no different.117 Alterations in regional liver blood flow may also affect the clearance of drugs, especially those with a high extraction ratio. Decreased pulmonary blood flow during venoarterial ECMO may affect the sequestration and metabolism of many sedative and analgesic drugs by the lungs.118 Drug removal by the ECMO circuit may reduce the bioavailability of the first dose as well as the overall clearance.108 Decreased clearance predisposes the patient to drug toxicity, especially for drugs with a narrow therapeutic window. The clearance of a drug is also directly affected by ECMO. Clearance can be influenced by the degree to which ECMO affects bound or unbound drug concentrations. Drug adsorption to the pump/tubing and oxygenator can also result in clearance alterations. When the ECMO circuit is changed, there can be a rapid alteration in drug concentration because the binding sites are no longer saturated, which can affect clearance. Another consideration is whether the drug is administered in the circuit or directly to the patient. When drugs are administered directly in the circuit, there can be differences in drug concentration depending on whether dosing location is before or after the oxygenator.

RENAL REPLACEMENT THERAPY Discussion of renal replacement therapy during ECMO is complex

because of the variability in techniques, including where the renal replacement circuit is located in relation to the oxygenator. This high degree of variability in techniques emphasizes the need for therapeutic drug monitoring where available, especially because adding another extracorporeal circuit can further affect the Vd, sequestration, and clearance of drugs.

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120. Robert R, Rochard E, Malin F, et al. Amikacin pharmacokinetics during continuous veno-venous hemofiltration. Crit Care Med 1991;19:588-9. 121. Armendariz E, Chelluri L, Ptachcinski R. Pharmacokinetics of amikacin during continuous veno-venous hemofiltration. Crit Care Med 1990;18:675-6. 122. Lawless S, Restaino I, Azin S, et al. Effect of continuous arteriovenous haemofiltration on pharmacokinetics of amrinone. Clin Pharmacokinet 1993;25:80-2. 123. Shearer ES, O’Sullivan EP, Hunter JM. Clearance of atracurium and laudanosine in the urine and by continuous venovenous haemofiltration. Br J Anaesth 1991;67:569-73. 124. Isla A, Arzuaga A, Maynar J, et al. Determination of ceftazidime and cefepime in plasma and dialysate-ultrafiltrate from patients undergoing continuous veno-venous hemodiafiltration by HPLC. J Pharm Biomed Anal 2005;39:996-1005. 125. Isla A, Gascon AR, Maynar J, et al. Cefepime and continuous renal replacement therapy (CRRT): in vitro permeability of two CRRT membranes and pharmacokinetics in four critically ill patients. Clin Ther 2005;27:599-608. 126. Malone RS, Fish DN, Abraham E, et al. Pharmacokinetics of cefepime during continuous renal replacement therapy in critically ill patients. Antimicrob Agents Chemother 2001;45:3148-55. 127. Evers J, Borner K, Koeppe P. Cefotiam during continuous haemofiltration. Eur J Clin Pharmacol 1993;44:509-10. 128. Davies SP, Lacey LF, Kox WJ, et al. Pharmacokinetics of cefuroxime and ceftazidime in patients with acute renal failure treated by continuous arteriovenous haemodialysis. Nephrol Dial Transplant 1991;6:971-6. 129. Traunmuller F, Schenk P, Mittermeyer C, et al. Clearance of ceftazidime during continuous venovenous haemofiltration in critically ill patients. J Antimicrob Chemother 2002;49:129-34.

130. Matzke GR, Frye RF, Joy MS, et al. Determinants of ceftazidime clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis. Antimicrob Agents Chemother 2000;44:1639-44. 131. Mariat C, Venet C, Jehl F, et al. Continuous infusion of ceftazidime in critically ill patients undergoing continuous venovenous haemodiafiltration: pharmacokinetic evaluation and dose recommendation. Crit Care 2006;10:R26. 132. Isla A, Gascon AR, Maynar J, et al. In vitro AN69 and polysulphone membrane permeability to ceftazidime and in vivo pharmacokinetics during continuous renal replacement therapies. Chemotherapy 2007;53:194-201. 133. Matzke GR, Frye RF, Joy MS, et al. Determinants of ceftriaxone clearance by continuous venovenous hemofiltration and hemodialysis. Pharmacotherapy 2000;20:635-43. 134. Weiss LG, Cars O, Danielson BG, et al. Pharmacokinetics of intravenous cefuroxime during intermittent and continuous arteriovenous hemofiltration. Clin Nephrol 1988;30:282-6. 135. Vossen MG, Gattringer KB, Jager W, et al. Single-dose pharmacokinetics of cidofovir in continuous venovenous hemofiltration. Antimicrob Agents Chemother 2014;58:1952-5. 136. Keller E, Fecht H, Bohler J, et al. Single-dose kinetics of imipenem/cilastatin during continuous arteriovenous haemofiltration in intensive care patients. Nephrol Dial Transplant 1989;4:640-5. 137. Vos MC, Vincent HH, Yzerman EP. Clearance of imipenem/ cilastatin in acute renal failure patients treated by continuous hemodiafiltration (CAVHD). Intensive Care Med 1992;18:282-5. 138. Davies SP, Azadian BS, Kox WJ, et al. Pharmacokinetics of ciprofloxacin and vancomycin in patients with acute renal failure treated by continuous haemodialysis. Nephrol Dial Transplant 1992;7:848-54. 139. Wallis SC, Mullany DV, Lipman J, et al. Pharmacokinetics of

ciprofloxacin in ICU patients on continuous veno-venous haemodiafiltration. Intensive Care Med 2001;27:665-72. 140. Lindsay CA, Bawdon R, Quigley R. Clearance of ticarcillinclavulanic acid by continuous venovenous hemofiltration in three critically ill children, two with and one without concomitant extracorporeal membrane oxygenation. Pharmacotherapy 1996;16:458-62. 141. Markou N, Fousteri M, Markantonis SL, et al. Colistin pharmacokinetics in intensive care unit patients on continuous venovenous haemodiafiltration: an observational study. J Antimicrob Chemother 2012;67:2459-62. 142. Vilay AM, Grio M, Depestel DD, et al. Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis. Crit Care Med 2011;39:19-25. 143. Cirillo I, Vaccaro N, Balis D, et al. Influence of continuous venovenous hemofiltration and continuous venovenous hemodiafiltration on the disposition of doripenem. Antimicrob Agents Chemother 2011;55:1187-93. 144. Nicolau DP, Crowe H, Nightingale CH, et al. Effect of continuous arteriovenous hemodiafiltration on the pharmacokinetics of fluconazole. Pharmacotherapy 1994;14:502-5. 145. Yagasaki K, Gando S, Matsuda N, et al. Pharmacokinetics and the most suitable dosing regimen of fluconazole in critically ill patients receiving continuous hemodiafiltration. Intensive Care Med 2003;29:1844-8. 146. Muhl E, Martens T, Iven H, et al. Influence of continuous venovenous haemodiafiltration and continuous veno-venous haemofiltration on the pharmacokinetics of fluconazole. Eur J Clin Pharmacol 2000;56:671-8. 147. Gattringer R, Meyer B, Heinz G, et al. Single-dose pharmacokinetics of fosfomycin during continuous venovenous haemofiltration. J Antimicrob Chemother 2006;58:367-71.

148. Boulieu R, Bastien O, Bleyzac N. Pharmacokinetics of ganciclovir in heart transplant patients undergoing continuous venovenous hemodialysis. Ther Drug Monit 1993;15:105-7. 149. Zarowitz BJ, Anandan JV, Dumler F, et al. Continuous arteriovenous hemofiltration of aminoglycoside antibiotics in critically ill patients. J Clin Pharmacol 1986;26:686-9. 150. Lehman ME, Kolb KW. Gentamicin elimination in a patient undergoing continuous ultrafiltration. Clin Pharm 1985;4:327-30. 151. Ernest D, Cutler DJ. Gentamicin clearance during continuous arteriovenous hemodiafiltration. Crit Care Med 1992;20:586-9. 152. Mueller BA, Scarim SK, Macias WL. Comparison of imipenem pharmacokinetics in patients with acute or chronic renal failure treated with continuous hemofiltration. Am J Kidney Dis 1993;21:172-9. 153. Fish DN, Teitelbaum I, Abraham E. Pharmacokinetics and pharmacodynamics of imipenem during continuous renal replacement therapy in critically ill patients. Antimicrob Agents Chemother 2005;49:2421-8. 154. Kraft MD, Pasko DA, DePestel DD, et al. Linezolid clearance during continuous venovenous hemodiafiltration: a case report. Pharmacotherapy 2003;23:1071-5. 155. Meyer B, Kornek GV, Nikfardjam M, et al. Multiple-dose pharmacokinetics of linezolid during continuous venovenous haemofiltration. J Antimicrob Chemother 2005;56:172-9. 156. Fiaccadori E, Maggiore U, Rotelli C, et al. Removal of linezolid by conventional intermittent hemodialysis, sustained low-efficiency dialysis, or continuous venovenous hemofiltration in patients with acute renal failure. Crit Care Med 2004;32:2437-42. 157. Mauro LS, Peloquin CA, Schmude K, et al. Clearance of linezolid via continuous venovenous hemodiafiltration. Am J Kidney Dis 2006;47:e83-6.

158. Leblanc M, Raymond M, Bonnardeaux A, et al. Lithium poisoning treated by high-performance continuous arteriovenous and venovenous hemodiafiltration. Am J Kidney Dis 1996;27:365-72. 159. van Bommel EF, Kalmeijer MD, Ponssen HH. Treatment of lifethreatening lithium toxicity with high-volume continuous venovenous hemofiltration. Am J Nephrol 2000;20:408-11. 160. Hansen E, Bucher M, Jakob W, et al. Pharmacokinetics of levofloxacin during continuous veno-venous hemofiltration. Intensive Care Med 2001;27:371-5. 161. Guenter SG, Iven H, Boos C, et al. Pharmacokinetics of levofloxacin during continuous venovenous hemodiafiltration and continuous venovenous hemofiltration in critically ill patients. Pharmacotherapy 2002;22:175-83. 162. Isla A, Maynar J, Sanchez-Izquierdo JA, et al. Meropenem and continuous renal replacement therapy: in vitro permeability of 2 continuous renal replacement therapy membranes and influence of patient renal function on the pharmacokinetics in critically ill patients. J Clin Pharmacol 2005;45:1294-304. 163. Ververs TF, van Dijk A, Vinks SA, et al. Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration. Crit Care Med 2000;28:3412-6. 164. Valtonen M, Tiula E, Backman JT, et al. Elimination of meropenem during continuous veno-venous haemofiltration and haemodiafiltration in patients with acute renal failure. J Antimicrob Chemother 2000;45:701-4. 165. Langgartner J, Vasold A, Gluck T, et al. Pharmacokinetics of meropenem during intermittent and continuous intravenous application in patients treated by continuous renal replacement therapy. Intensive Care Med 2008;34:1091-6. 166. Robatel C, Decosterd LA, Biollaz J, et al. Pharmacokinetics and dosage adaptation of meropenem during continuous venovenous

hemodiafiltration in critically ill patients. J Clin Pharmacol 2003;43:1329-40. 167. Krueger WA, Neeser G, Schuster H, et al. Correlation of meropenem plasma levels with pharmacodynamic requirements in critically ill patients receiving continuous veno-venous hemofiltration. Chemotherapy 2003;49:280-6. 168. Hirata K, Aoyama T, Matsumoto Y, et al. Pharmacokinetics of antifungal agent micafungin in critically ill patients receiving continuous hemodialysis filtration. Yakugaku Zasshi 2007;127:897901. 169. Bolon M, Bastien O, Flamens C, et al. Midazolam disposition in patients undergoing continuous venovenous hemodialysis. J Clin Pharmacol 2001;41:959-62. 170. Fuhrmann V, Schenk P, Jaeger W, et al. Pharmacokinetics of moxifloxacin in patients undergoing continuous venovenous haemodiafiltration. J Antimicrob Chemother 2004;54:780-4. 171. Cussonneau X, Bolon-Larger M, Prunet-Spano C, et al. Evaluation of MPA and MPAG removal by continuous venovenous hemodiafiltration and continuous venovenous hemofiltration. Ther Drug Monit 2008;30:100-2. 172. Fuhrmann V, Schenk P, Mittermayer C, et al. Single-dose pharmacokinetics of ofloxacin during continuous venovenous hemofiltration in critical care patients. Am J Kidney Dis 2003;42:310-4. 173. Lau AH, Kronfol NO. Effect of continuous hemofiltration on phenytoin elimination. Ther Drug Monit 1994;16:53-7. 174. Bauer SR, Salem C, Connor MJ Jr, et al. Pharmacokinetics and pharmacodynamics of piperacillin-tazobactam in 42 patients treated with concomitant CRRT. Clin J Am Soc Nephrol 2012;7:452-7. 175. Valtonen M, Tiula E, Takkunen O, et al. Elimination of the piperacillin/tazobactam combination during continuous venovenous

haemofiltration and haemodiafiltration in patients with acute renal failure. J Antimicrob Chemother 2001;48:881-5. 176. Mueller SC, Majcher-Peszynska J, Hickstein H, et al. Pharmacokinetics of piperacillin-tazobactam in anuric intensive care patients during continuous venovenous hemodialysis. Antimicrob Agents Chemother 2002;46:1557-60. 177. Awissi DK, Beauchamp A, Hebert E, et al. Pharmacokinetics of an extended 4-hour infusion of piperacillin-tazobactam in critically ill patients undergoing continuous renal replacement therapy. Pharmacotherapy 2015;35:600-7. 178. Davies JG, Greenwood EF, Kingswood JC, et al. Quinine clearance in continuous venovenous hemofiltration. Ann Pharmacother 1996;30:487-90. 179. Armstrong DK, Hidalgo HA, Eldadah M. Vancomycin and tobramycin clearance in an infant during continuous hemofiltration. Ann Pharmacother 1993;27:224-7. 180. Thomson AH, Grant AC, Rodger RS, et al. Gentamicin and vancomycin removal by continuous venovenous hemofiltration. DICP 1991;25:127-9. 181. Matzke GR, O’Connell MB, Collins AJ, et al. Disposition of vancomycin during hemofiltration. Clin Pharmacol Ther 1986;40:425-30. 182. Santre C, Leroy O, Simon M, et al. Pharmacokinetics of vancomycin during continuous hemodiafiltration. Intensive Care Med 1993;19:347-50. 183. Reetze-Bonorden P, Bohler J, Kohler C, et al. Elimination of vancomycin in patients on continuous arteriovenous hemodialysis. Contrib Nephrol 1991;93:135-9. 184. DelDot ME, Lipman J, Tett SE. Vancomycin pharmacokinetics in critically ill patients receiving continuous venovenous haemodiafiltration. Br J Clin Pharmacol 2004;58:259-68.

185. Robatel C, Rusca M, Padoin C, et al. Disposition of voriconazole during continuous veno-venous haemodiafiltration (CVVHDF) in a single patient. J Antimicrob Chemother 2004;54:269-70. 186. Quintard H, Papy E, Massias L, et al. The pharmacokinetic profile of voriconazole during continuous high-volume venovenous hemofiltration in a critically ill patient. Ther Drug Monit 2008;30:117-9. 187. Fuhrmann V, Schenk P, Jaeger W, et al. Pharmacokinetics of voriconazole during continuous venovenous haemodiafiltration. J Antimicrob Chemother 2007;60:1085-90.

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

LEARNING OBJECTIVES 1. Define acute liver failure (ALF) and describe the epidemiology of ALF. 2. Describe the pathophysiology of ALF. 3. Describe and contrast etiologies of ALF including acetaminophen, idiosyncratic drug-induced ALF, and viral infections. 4. Explain different prognostic indicators used in ALF. 5. Describe clinical presentation of patients presenting with ALF. 6. Define the mechanism of action of acetylcysteine in the management of acetaminophen toxicity. 7. Summarize the four grades of encephalopathy. 8. Compare agents used in the treatment of hepatic encephalopathy. 9. Identify the most common infectious pathogen classes in patients with ALF. 10. Describe nonpharmacologic interventions in the management of ALF. 11. Describe general principles of hepatic drug clearance and

potential mechanisms of altered drug disposition in ALF. 12. Apply principles of altered drug disposition in ALF in selecting and modifying pharmacotherapy in a patient with ALF.

ABBREVIATIONS IN THIS CHAPTER AASLD American Association for the Study of Liver Diseases ALF

Acute liver failure

CLint

Intrinsic hepatic drug clearance

CPP

Cerebral perfusion pressure

CTP

Child-Pugh (Child-Turcotte-Pugh) (score)

DILI

Drug-induced liver injury

EH

Hepatic extraction ratio

ICP

Intracranial pressure

KCH

King’s College Hospital (criteria)

MELD

Model for End-Stage Liver Disease

NAPQI

N-acetyl-p-benzoquinone imine

OLT

Orthotopic liver transplantation

QH

Hepatic blood flow

INTRODUCTION Acute liver failure (ALF) is a rare form of severe liver disease, characterized by a rapid deterioration of liver function in individuals without known preexisting liver disease.1,2 ALF is associated with

substantial morbidity and mortality, often resulting in the need for lifesustaining therapies and potential liver transplantion for definitive treatment. Further, ALF can impact the pharmacokinetics of numerous drugs. In this chapter, the pathophysiology of ALF is reviewed, followed by an overview of ALF management, and general recommendations for drug dosing in ALF.

DEFINITIONS Acute liver failure represents a syndrome, rather than a specific disease, and can have several causes that vary in outcome.3 In the past, ALF has also been called fulminant hepatic failure or fulminant hepatitis. A widely used definition for ALF is acute onset (illness less than 26 weeks in duration) of coagulation abnormalities (commonly, an international normalized ratio [INR] of 1.5 or greater) and any degree of hepatic encephalopathy (which can be defined as any change in mental status) in a patient without preexisting hepatic disease.1 Other definitions have characterized ALF as development of hepatic encephalopathy within 8 weeks of the first symptoms of liver disease (of note, the key features of the definition are the same: hepatic encephalopathy and symptoms of hepatic failure [jaundice, coagulopathy] in the absence of chronic hepatic disease).4,5 Acute liver failure can further be subdivided into categories on the basis of the length of illness (Table 28.1); this subclassification can be useful in identifying the etiology of ALF.4 More recently, the term acute liver injury has been used to describe patients with severe liver injury (INR of 2 or greater and AST [aspartate transaminase] greater than 10 times the upper limit of normal) with no evidence of encephalopathy.6 It is important to differentiate ALF from “acute on chronic” liver failure because the treatment and prognosis of each disease can differ substantially. Acute on chronic liver failure is generally regarded as an acute deterioration of preexisting, chronic liver disease that is usually related to an identifiable precipitating event that may be unrelated to the original cause of liver disease.7 Acute on chronic liver failure will not be discussed at length in this chapter; however, the care of patients

with acute on chronic liver failure resembles that of patients with ALF.

EPIDEMIOLOGY Acute liver failure is relatively uncommon in developed countries, with about 2,000–3,000 cases in the United States per year, and is most commonly seen in young adults in their third decade.1,4,8 The ALF Study Group collected data related to ALF epidemiology for almost a decade; during this time, 67% of ALF cases were in women, and the mean age was 38 years (range 17–79 years).3 Of note, the etiology of ALF has a geographic distribution: in North America and Western Europe, the primary causes are acetaminophen toxicity and idiosyncratic drug hepatotoxicity, whereas in Asia and developing nations, the primary causes are infectious (particularly hepatitis B virus and hepatitis E virus). Acute liver failure is often associated with a poor outcome. The mortality rate associated with ALF can exceed 40%– 50%, depending on the etiology and type of care provided, and overall 1-year survival including patients receiving a transplant is about 65%.1,9,10 The primary causes of death in ALF are cerebral edema (as a result of increased intracranial pressure [ICP]), sepsis, and shock/multiorgan failure.9 Ultimately, orthotopic liver transplantation (OLT) is the only definitive therapy proved to be of benefit in patients with ALF who are unable to regenerate sufficient hepatocyte mass.1,9

PATHOPHYSIOLOGY Specific mechanisms of disease vary for different ALF causes. However, common to most etiologies is the presence of massive hepatocyte loss resulting in rapid loss of hepatic metabolic and immune function.2,8 The liver has the capacity to regenerate lost mass; however, ALF occurs when loss of hepatic cells exceeds the liver’s ability to regenerate.11 Precipitating factors for hepatocyte loss vary by etiology (see text that follows) and include both direct injury and immunologic injury.12 With respect to immunologic injury, innate immunemediated injury is triggered early, which may be followed by adaptive

immune responses.12

Table 28.1 Classifications of Acute Liver Failure4 Term

Symptom Durationa

Hyperacute

< 7 days

Acute

7–21 days

Subacute

> 21 days and < 26 weeks

aSymptom

duration from onset of jaundice to hepatic encephalopathy.

The pattern of hepatocyte death may follow a pattern of necrosis, apoptosis, or both.11 Necrosis involves depletion of adenosine triphosphate (ATP), leading to cell lysis and secondary inflammation, whereas apoptosis is an ATP-dependent programmed cell death.11 Although once thought to be separate entities in ALF, necrosis and apoptosis may share initiating factors and signaling pathways and may thus occur as alternating patterns of hepatocyte destruction.11 Mitochondrial permeability transition (a process leading to mitochondrial swelling) may be a common event causing both patterns of hepatocyte destruction, where the pattern of death depends on whether ATP is depleted (necrosis) or preserved (apoptosis).11 Apoptosis may be the predominant mode of hepatocyte destruction in ALF caused by viral and toxic etiologies.12 Necrosis is often related to metabolic injury (leading to ATP depletion) and can be caused by ischemia/reperfusion and acute drug-induced hepatotoxicity.13 The acute and massive loss of hepatocytes in ALF leads to the release of ammonia, alanine, lactate, and pro-inflammatory cytokines from the splanchnic circulation, including tumor necrosis factor alpha, interleukin (IL)-1 beta, and IL-6.10,12 This inflammatory response is likely key to the systemic inflammation associated with ALF. Furthermore, the systemic inflammation can contribute to cerebral

edema by decreasing cerebrovascular tone.10,12 Release of intracellular materials from hepatocytes may lead to the polymerization of proteins that impairs hepatic microcirculation.10 Increased gut permeability may lead to increased absorption of luminal endotoxin, which, in conjunction with reduced hepatic endotoxin clearance, can further propagate the condition of systemic inflammation.10 Acute liver failure leads to a syndrome that may include many physiologic derangements, including hepatic encephalopathy, cerebral edema, coagulopathy, oliguria/ acute renal failure, portal hypertension, acidosis, systemic vasodilation with hypotension, hypoglycemia, respiratory failure, and impaired platelet and white blood cell function.5,10 More than half of patients with ALF meet the criteria for systemic inflammatory syndrome.5 In short, the profound hepatic dysfunction associated with ALF often precipitates the development of multiple organ dys-function syndrome.10 As indicated previously, the primary causes of death in ALF are cerebral edema, sepsis, and shock/multiorgan failure.3,14 Other causes of death include cardiac arrhythmia/arrest, respiratory failure, and infection (bacterial and fungal).3,14 Of note, despite the high prevalence of coagulopathy in ALF, mortality secondary to hemorrhage is rare in ALF.3

ETIOLOGY The causes of ALF include several toxic, infectious, metabolic, and vascular insults to the liver.10 As indicated previously, the frequency of the various etiologies of ALF follows a geographic distribution. The most common etiology of ALF in North America and Western Europe is acetaminophen toxicity. In the ALF Study Group registry, acetaminophen accounted for almost 40% of all cases of ALF.14 Idiosyncratic drug reactions (nonacetaminophen, 13% of cases) and viral hepatitis (hepatitis A virus infections and hepatitis B virus infections, collectively 11% of cases), were the next most common causes.14 In contrast, viral infections (hepatitis A virus, hepatitis B virus, and hepatitis E virus) are the most predominant causes of ALF in the developing world.2 In up to 15% of ALF cases, there is no determinate

cause.3 Determining the etiology of ALF is important because this assists in determining the appropriate therapy, helps rule out contraindications to transplantation, and can help predict prognosis.15

Acetaminophen As indicated earlier, acetaminophen is the most common cause of ALF in developed countries, accounting for greater than 25,000 hospitalizations and 400–500 deaths per year in the United States.3,16 It is likely that some cases of ALF with no recognizable cause may also be attributed to acetaminophen toxicity because acetaminophen adducts (produced by the binding of an active acetaminophen metabolite to cysteine residues) have been detected in some of these cases.17,18 Acetaminophen-related ALF is dose related. At therapeutic doses, greater than 90% of an acetaminophen dose is metabolized in the liver by a combination of glucuronidation and sulfonation (with the resulting metabolites excreted in the urine), about 2% of a dose is excreted unchanged in the urine, and 5%–10% of the dose is metabolized by cytochrome P450 (CYP) 2E1.16 The metabolism of acetaminophen by CYP2E1 results in the formation of N-acetyl-pbenzoquinone imine (NAPQI), an extremely reactive metabolite.19 At normal acetaminophen doses, the small amount of NAPQI that is formed is rapidly conjugated by hepatic glutathione and excreted in the urine. At supratherapeutic doses, sulfation and glucuronidation pathways become saturated, and more acetaminophen is metabolized to NAPQI by CYP2E1, eventually resulting in the depletion of hepatic glutathione.16,19 When hepatic glutathione stores are depleted by about 70%–80%, NAPQI begins to form protein adducts through covalent binding to cysteine residues, leading to hepatocyte injury.13 Glutathione depletion may contribute to additional injury because of oxidative stress, and hepatocyte death stimulates the innate immune system, which can also exacerbate hepatic injury.16,19 In addition to acetaminophen dose, other factors that may increase the risk of acetaminophen-related ALF after acetaminophen overdose include malnutrition, advanced age, concomitant use of CYP2E1 inducers,

concomitant use of drugs that deplete glutathione stores (e.g., sulfamethoxazole/ trimethoprim), and chronic alcoholism (chronic ethanol ingestion can induce CYP2E1; in contrast, acute ethanol ingestion may offer some protection against acetaminophen-induced ALF).19 Acetaminophen toxicity can occur as a result of both intentional and unintentional overdoses. In the United States, around 37% of acetaminophen ALF cases are caused by intentional overdose, whereas 57% are caused by accidental toxicity.14 Patients with unintentional overdose are more likely to have used multiple acetaminophen-containing products.20 A single acute ingestion (total consumption within 8 hours) of 7.5–10 g or greater in adults or 150 mg/kg in children younger than 6 years may result in hepatotoxicity (although these estimates may be conservative).18,19 In data collected by the ALF Study Group on acetaminophen-related ALF, the median acetaminophen dose ingested was 13.2 g/day (range 2.6–75 g/day); 83% of the patients had ingested greater than 4 g/day, which is considered the toxic breakpoint.14

Idiosyncratic Drug-Induced ALF (Non-acetaminophen) Drug-induced liver injury (DILI) is a recognized complication of more than 1,000 drugs and supplements and has an annual incidence of 1 in 10,000–100,000.21 Drug-induced liver injury is the second most common cause of ALF in the United States, representing about 11-13% of all ALF cases.14,22 However, less than 10% of all DILI progresses to ALF; for example, in a study conducted by the Drug-Induced Liver Injury Network, only 6% of all DILI cases resulted in transplantation or death.2,23 In a more recent study from the same network that evaluated 660 patients with idiosyncratic DILI, almost 10% of all patients died or required a transplant (5% and 4.5%, respectively) within 6 months of DILI.24 The incidence of DILI-related ALF is about one or two cases per 1 million people per year, or 1 in 30,000–100,000 prescriptions.2,25 Drug-induced liver injury–related ALF is idiosyncratic and unpredictable and can vary in both severity and time course.2,25

Furthermore, DILI-related ALF can be independent of the dose, route, or duration of therapy with the offending agent.25 It often follows a subacute course and can progress to ALF despite discontinuation of the precipitating drug.2 Mechanistically, it is possible that many causes of DILI-related ALF are a result of individual differences in drug metabolism (e.g., because of genetic differences) that lead to the formation of a toxic metabolite.20 Acute liver failure can be caused by either the offending agent itself or a metabolite. Damage may result from direct injury or stress, initiation of an immune response, or changes in mitochondrial function, ultimately leading to mitochondrial permeability transition and necrosis/apoptosis.26 Conventional hypersensitivity is seen in less than one-third of patients with DILI, and the liver can show either cholestatic or hepatocellular patterns of injury (the latter is associated with a worse prognosis).2 In general, the onset of DILI-associated ALF evolves more slowly than the onset observed with acetaminophen.25 Spontaneous recovery is often slow with DILIrelated ALF. Overall transplant-free survival rates are around 27%, and up to 42% of patients require a transplant.25 Transplant-free survival may be predicted by the degree of liver dysfunction (serum bilirubin, INR, and prognostic scores [see Prognostic Indicators in ALF section]); other factors that may be related to outcome include presence of jaundice, elevated serum aminotransferases, and advanced age.2,22 A wide variety of drugs can cause DILI-related ALF, and geographic differences exist in causative agents. In Western nations, conventional medications are commonly implicated, whereas in Asian countries, natural products and dietary supplements are commonly implicated.26 In the ALF Study Group registry, more than 60 individual agents were identified as potential causes of ALF (Box 28.1).22 The most commonly reported drug classes associated with ALF are antimicrobials (representing almost half of all cases), followed by nonsteroidal antiinflammatory drugs, antiretroviral drugs, anticancer drugs/biologics, and dietary supplements/illicit substances.20

Viral Infections

Viral infections are a relatively infrequent cause of ALF in developed nations and have gradually been declining as a cause of ALF.2 In the United States, hepatitis A virus and hepatitis B virus are the most common viral etiologies of ALF; about 7% of ALF cases are caused by hepatitis B virus and 4% of cases by hepatitis A virus.14 Only 1% of cases of hepatitis A virus and hepatitis B virus infections ultimately progress to ALF.20 Prognostic factors that may predict a poor outcome for ALF caused by hepatitis A virus or hepatitis B virus include ALT (alanine amino-transferase) less than 2,600 U/L, serum creatinine greater than 2 mg/dL, and need for intubation, vasopressors, or both.20 Hepatitis B–related ALF is probably initiated by an immune response and can manifest as either a primary infection or a secondary reactivation in chronic carriers (reactivation can be spontaneous or occur after immunosuppression/cancer chemotherapy).15,20 The liver damage related to hepatitis A virus infection is likely a result of an excessive immune response associated with a dramatic decrease in viral load.15 Hepatitis B–related ALF is often associated with a poor prognosis and results in death or transplantation in up to 80% of cases.3,15 In contrast, hepatitis A virus-related ALF is generally associated with a better prognosis than is hepatitis B virus.3,15 In developing countries, hepatitis E virus is an important cause of ALF, particularly in pregnant women. Hepatitis E virus is spread through enteric transmission, and large waterborne epidemics are possible in developing regions.15,20 Other less common viral causes of ALF are possible, particularly during immunosuppression, including herpes simplex viruses 1 and 2, adenovirus, varicella zoster virus, and parvovirus B19.15,20

Other Causes In addition to the more common etiologies of ALF described earlier, there are many miscellaneous causes of ALF. These include ischemic hepatitis (i.e., “shock liver”), autoimmune hepatitis, Wilson disease, specific toxic insults (e.g., because of mushroom poisoning), the HELLP syndrome (hemolysis, elevated liver enzymes, low plate-

lets)/fatty liver of pregnancy, and the Budd-Chiari syndrome (acute hepatic vein thrombosis).14,27 Finally, in many ALF cases, there is no definite etiology; in the ALF Study Group registry, around 17% of all ALF cases were described as having an indeterminate etiology.14

PROGNOSTIC INDICATORS IN ALF Estimating a patient’s prognosis in ALF can be important because this may relate to the decision to proceed with OLT. However, in contrast to chronic liver diseases, the relative infrequency of ALF in conjunction with the heterogeneity of disease associated with ALF has made it difficult to develop prognostic indicators. As a result, to date, there is no single reliable prognostic scoring system used to grade the severity or prognosis of ALF, although several prognostic scoring systems have been used to help predict the need for OLT.1 The most commonly used prognostic models include Clichy’s criteria, the King’s College Hospital (KCH) criteria, and the Model for End-Stage Liver Disease (MELD) (Table 28.2). The Child-Pugh (Child-Turcotte-Pugh; CTP) score is not used for prognostic determinations in ALF, but it may assist in drug dosing in ALF (see text that follows).32 Clichy’s criteria considers plasma factor V concentrations, encephalopathy grade, and patient age; use of Clichy’s criteria is restricted in part because of the limited availability of factor V concentration measurement, the fact that the model was developed from patients with ALF with hepatitis B virus infection, and evidence that Clichy’s criteria may be less accurate than KCH criteria.33 The KCH criteria are more widely used than are the Clichy criteria and have separate approaches for patients with either acetaminophen or non–acetaminophen-related ALF. The KCH criteria consider both the etiology and the clinical parameters of ALF.29 Although the KCH criteria have a high specificity and positive predictive value (70%–100%) for identifying patients likely to have a poor prognosis, they have a low negative predictive value for poor outcome (25%–94%) (i.e., not meeting the criteria does not necessarily predict survival).1,34,35 The MELD score was originally developed to predict the survival of patients undergoing TIPS (transjugular intrahepatic

portosystemic shunts) and is used in some centers to identify patients who should be listed for transplantation.33,36 The MELD is a continuous score that incorporates serum creatinine, serum bilirubin, and INR (Table 28.2). Although MELD has performed better than KCH and Clichy’s criteria in some studies comparing MELD with KCH and/or Clichy’s criteria in ALF, this has not consistently been the case.33,37-39 Furthermore, it is unclear what, if any, MELD score should serve as the cutoff value indicating the need for transplantation in ALF (although scores of 30–35 are often reported as cutoffs, MELD scores can fluctuate substantially in ALF, and patients with higher MELD scores may survive without transplantation).33,39-41

Box 28.1. Drugs Associated with Drug-Induced ALFa I. Antimicrobial Agents A. Antituberculosis drugs 18.8% Isoniazid alone 11.3% Isoniazid combined with two of three: rifampin, pyrazinamide, and ethambutol 4.5% Rifampin and pyrazinamide with or without ethambutol 2.3% Dapsone 0.075% B. Sulphur-containing drugs 9.0% Trimethoprim/sulfamethoxazole alone 4.5% Trimethoprim/sulfamethoxazole in combination with azithromycin, statin, or antiretroviral drugs 2.3% Sulfasalazine 2.3% C. Other antibiotics 14.3% Nitrofurantoin alone 8.3% Nitrofurantoin with a statin 0.75% Misc: amoxicillin, doxycycline, ciprofloxacin, clarithromycin, cefepime 5.3%

D. Antifungal agents 4.5% Terbinafine 2.3% Itraconazole 0.75% Ketoconazole alone 0.75% Ketoconazole with ezetimibe 0.75% E. Antiretroviral drugs 3.0% Stavudine with didanosine 1.5% Lamivudine with stavudine and nelfinavir 0.75% Abacavir 0.75% II. Central Nervous System Drugs A. Antiepileptic drugs 8.3% Phenytoin 6.0% Carbamazepine 2.3% Valproic acid 1.5% B. Psychotropic agents Quetiapine 0.75% Nefazodone 0.75% Fluoxetine 0.75% Venlafaxine 0.75% D. Anesthetics 1.5% Halothane 0.75% Isoflurane 0.75% III. Other Agents A. Antimetabolites and enzyme inhibitors 8.3% Disulfiram 3.0% Propylthiouracil 3.8% Allopurinol 0.75%

Melphalan 0.75% B. Nonsteroidal anti-inflammatory drugs (NSAIDs) 5.3% Bromfenac 3% Diclofenac 1.5% Etodolac 0.75% C. Biological agents and leukotriene inhibitors 3.0% Gemtuzumab 0.75% Zafirlukast 0.75% Interferon beta 0.75% Bacille-Calmette-Guérin (BCG) 0.75% D. Statins and ezetimibe 4.5% Cerivastatin 1.5% Simvastatin (± ezetimibe) 1.5% Atorvastatin 1.5% E. Other drugs 6.0% Troglitazone 3.0% Oxyiminoalkanoic acid derivative 0.75% Methyldopa 3.0% Hydralazine 0.75% IV. Complementary and Alternative Medicine (CAM) and Illicit Substances Unspecified herbal preparations 2.3% Usnic acid 1.5% Thermoslim (contains saw palmetto) 0.75% Herbal mixture (contains blue-green algae) 0.75% Ma-Huang 0.75% Horny goat weed 0.75%

Black cohosh 0.75% Hydroxycut 0.75% Uva-ursi 0.75% Cocaine 0.75% Ecstasy 0.75% aCases

were identified over a 10.5-year period by the ALF Study Group. Numbers

represent the proportion of drug-induced ALF cases caused by individual agents/classes (out of 133 total cases of drug-induced ALF). Adapted from:Reuben A, Koch DG, Lee WM. Acute Liver Failure Study Group. Druginduced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010;52:2065-76.

Clinical predictors of poor outcome in patients with ALF are likely as important as (if not more important than) prognostic scoring systems in predicting prognosis and guiding treatment decisions. These include etiology (specifically, idiosyncratic drug injury, acute hepatitis [and other non-hepatitis A virus infections], autoimmune hepatitis, mushroom poisoning, Wilson disease, and Budd-Chiari syndrome) and encephalopathy grade on admission (grade III or IV, see Table 28.3).1 Similarly, in some studies, common intensive care prognostic models (e.g., the Acute Physiology and Chronic Health Evaluation [APACHE] II and APACHE III) have been better predictors of prognosis in ALF than have the liver-specific models mentioned previously.30,42,43 Ultimately, no single scoring system has been shown to perform reliably as an indicator of prognosis in ALF, and both methodological flaws and reporting limitations are common in existing studies.44 Therefore, the American Association for the Study of Liver Diseases (AASLD) does not recommend relying entirely on scoring systems to guide decisions regarding prognosis and need for transplantation in ALF.1

CLINICAL PRESENTATION Initial clinical presentation of ALF is multifactorial, varying according to the underlying etiology of the organ compromise and the time of presentation to the health care system. Early signs of ALF may include malaise, nausea, vomiting, anorexia, abdominal pain, dehydration, and fever. Initial signs of ALF are often nonspecific.9,45 As the metabolic and detoxification function of the liver becomes compromised in the later stages of ALF, it is anticipated that the patient will have consistent clinical features of acute loss of hepatocellular function, systemic inflammatory response, and multiorgan system failure (acute renal failure is a common manifestation of ALF).1 Clinical manifestations of ALF can be classified into three groups, based on time from the development of jaundice to the evolvement of hepatic encephalopathy. Stages may be classified as hyperacute (less than 7 days), acute (7– 21 days), and subacute (3–26 weeks) (Table 28.1).9

MANAGEMENT OF ALF General Considerations The foundation for the management and treatment of ALF is largely supportive care with an emphasis on prevention or progression of secondary complications. Unfortunately, no single therapy is available to improve, reverse, or prevent further evolution of ALF from all etiologies. Hospitalization with transfer to the intensive care unit is often an appropriate escalation in care for those admitted with significant hepatocellular insufficiency because rapid deterioration in neurologic status may occur, prompting the need for rapid interventions by the medical team.46 If treatment exists for the specific etiology of ALF, initiation of therapy should be prompt, followed by close monitoring of fluid status, hemodynamics, and metabolic abnormalities and surveillance of infection— considerations appropriate for all presentations of ALF. Laboratory monitoring for all patients should include evaluation of prothrombin time/INR, complete blood cell counts,

electrolytes, lactate, creatinine, blood urea nitrogen, ammonia, acetaminophen concentration, toxicology screen, viral hepatitis serologies, and autoimmune markers. Serum aminotransferases and total bilirubin should also be included in the monitoring of these patients; however, there is poor correlation between changes in these liver-specific laboratory values and prognosis.1

Pharmacologic Treatment Acetylcysteine Acetylcysteine, a hepatoprotective agent, is an established antidote for acetaminophen toxicity. Acetylcysteine exerts its effects by restoring hepatic glutathione stores through the replenishment of cysteine, enhancing the sulfation pathway of acetaminophen elimination, and may result in a reduction reaction of NAPQI back to acetaminophen.19 Acetylcysteine is available in both intravenous and oral preparations. The oral formulation of acetylcysteine undergoes extensive first-pass metabolism by the liver, resulting in a low yield of available drug. However, acetylcysteine undergoes deacetylation in the liver to produce cysteine, which may be of benefit given that cysteine is the rate-limiting factor in glutathione production. In contrast, intravenous administration of acetylcysteine bypasses first-pass metabolism and may subsequently result in lower glutathione concentrations than oral administration.47 The U.S. Food and Drug Administration (FDA)approved recommendations for oral administration of acetylcysteine require a minimum treatment duration of 72 hours. The oral dosage regimen consists of a 140-mg/kg loading dose followed by maintenance dosing of 70 mg/kg every 4 hours for 18 doses or a total cumulative dose of 1330 mg/kg. Intravenous administration of acetylcysteine is provided over a minimum of 21 hours in three doses. Administration should include an initial loading dose of 150 mg/kg (maximum of 15 g) infused over 60 minutes, followed by a dose of 50 mg/kg (maximum of 5 g) infused over 4 hours, and ending with a third dose of 100 mg/kg (maximum of 10 g) infused over 16 hours.18 The

most commonly reported adverse effects of the intravenous form include the dose-dependent anaphylactoid reactions of tachycardia, hypotension, edema, rash, pruritus, nausea, vomiting, bronchospasms, and angioedema. The incidence of adverse events noted with the intravenous form is reduced substantially when acetylcysteine is administered orally.47 Although a systematic review did not provide conclusive evidence to support one route of acetylcysteine administration over another, the intravenous route of administration remains the preferred route for most acute ingestions.48

Table 28.2 Prognostic Models for ALF Prognostic Model Clichy’s criteria28

Model Parameters Indicating Poor Prognosis (i.e., need for liver transplantation) Poor prognosis in patients with grade 3 or grade 4 encephalopathy and: • Factor V concentrations < 20% for patients < 30 years • Factor V concentrations < 30% for patients > 30 years

King’s Hospital criteria1,29,30

Acetaminophen-induced ALF Poor prognosis • Arterial pH < 7.3 (regardless of stage of hepatic encephalopathy) (according to AASLD, consider arterial pH < 7.3 OR arterial lactate > 3.0 mmol/L after adequate fluid resuscitation)1 • OR • PTT > 100 s (INR > 6.5) AND serum creatinine > 3.4 mg/dL in patients with grade 3 or 4 hepatic encephalopathy Non–acetaminophen-induced ALF Poor prognosis

Comments • Derived from patients with ALF with hepatitis B infection • May be limited by availability of factor V concentrations • Good positive predictive value or poor outcome, but poor negative predictive value

• PTT > 100 s (INR > 6.5) regardless of stage of hepatic encephalopathy) • OR • Any THREE of the following criteria: • Age < 10 or > 40 years • Jaundice for > 7 days before development of hepatic encephalopathy • PTT > 50 s (INR > 3.5) • Serum bilirubin ≥ 17 mg/dL • AND serum creatinine > 3.4 mg/dL • According to AASLD, also consider unfavorable etiology such as Wilson disease, idiosyncratic drug reaction, seronegative hepatitis 1 Model for EndStage Liver Disease (MELD)31

• MELD = 3.78 × ln[serum bilirubin (mg/dL)] + 11.2 × ln[INR] + 9.57 × ln[serum creatinine (mg/dL)] + 6.43 × etiology (0: cholestatic or alcoholic, 1: otherwise) • If patients have had dialysis twice per week in the previous 7 days, the serum creatinine value is set at 4.0 mg/dL

• Unclear what cutoff value should be used to determine candidates for transplantation, not developed or validated for ALF

• Laboratory values < 1.0 are set as 1.0 (to avoid negative values)

AASLD = American Association for the Study of Liver Diseases; ALF = acute liver failure; PTT = partial thromboplastin time.

Greatest success with administration of acetylcysteine for the prevention of hepatic toxicity and subsequent ALF is seen when administration occurs within 8 hours of toxic acetaminophen ingestion. As the delay in acetylcysteine therapy extends beyond 8 hours of acetaminophen poisoning, antidotal effects decrease, and risk of ALF increases. Despite decreased efficacy when acetylcysteine is administered further from the time of an acute toxic acetaminophen ingestion, initiation of acetylcysteine regardless of post-ingestion time

is typically favored because the potential benefit of administration outweighs the risk associated with its use. Hepatotoxicity risk after acetaminophen ingestion can be assessed by plotting the serum acetaminophen concentration and the corresponding hours postingestion on the Rumack-Matthew nomogram (Figure 28.1).18 To use this tool effectively, a random serum acetaminophen concentration must be obtained between 4 hours and 24 hours of ingestion. If the time of ingestion is unknown, the Rumack-Matthew nomogram cannot be used to assess the need for treatment and the potential risk of hepatotoxicity. Therefore, an elevated serum acetaminophen concentration is typically treated regardless of post-ingestion time because the benefits of acetylcysteine vastly outweigh the risk of administration. If a serum acetaminophen concentration is obtained, the hour of ingestion is known, and the post-ingestion time fits within the targeted time interval of 4–24 hours, the concentration can be plotted on the Rumack-Matthew nomogram to assess the need for initiating acetylcysteine. The treatment line, also known as the parallel line at 150 mcg/mL 4 hours post-ingestion on the nomogram, is the most commonly used guideline for acetylcysteine initiation after toxic ingestion of acetaminophen.18

Table 28.3 Grades of Encephalopathy1,38 Grade I II III

IV

Definition Changes in behavior with minimal change in level of consciousness Gross disorientation, drowsiness, possible asterixis, inappropriate behavior Marked confusion; incoherent speech, sleeping most of the time but arousable to vocal stimuli Comatose, unresponsive to pain, decorticate or decerebrate posturing

Figure 28.1 Rumack-Matthew nomogram. Reprinted with permission from Hodgman MJ, Garrard AR. A review of acetaminophen poisoning. Crit Care Clin 2012;28:499516.

Administering acetylcysteine may also provide beneficial effects after hepatic injury in non–acetaminophen-induced ALF and alcoholic hepatitis.47 Efficacy of acetylcysteine administration in these clinical presentations is unrelated to detoxification. Presumed beneficial mechanisms of action in these clinical scenarios include scavenging of free radicals and replenishment of glutathione stores during oxidative stress, production of nitric oxide resulting in vasodilation and hepatic

perfusion, and anti-inflammatory properties through inhibition of proinflammatory factors.18,47 In the treatment of non–acetaminopheninduced ALF, administration of oral and intravenous acetylcysteine has shown increased transplant-free survival rates and decreased length of hospitalization. For the treatment of severe alcoholic hepatitis, acetylcysteine has also shown theoretical benefits secondary to the antioxidant and anti-inflammatory effects. Again, despite varying data regarding benefit for acetylcysteine in non–acetaminophen-induced ALF and alcoholic hepatitis, initiation of acetylcysteine is typically favored because the potential benefits of administration outweigh the risks associated with its use.

Management of Secondary Complications Hepatic Encephalopathy The hallmark complication of ALF, hepatic encephalopathy, is related to cerebral edema and intracranial hemorrhage (ICH). As the severity of hepatic encephalopathy increases, denoted by grade (see Table 28.3), the rate of cerebral edema and ICH increases. These detrimental effects of hepatic encephalopathy are a result of hyperammonemia. Pharmacologic management of hepatic encephalopathy and less invasive medical interventions (excluding electroencephalogram, mechanical ventilation, and artificial liver systems) can typically bridge patients with grade I and II hepatic encephalopathy. As patients progress to grade III and IV hepatic encephalopathy, intubation and subsequent mechanical ventilation become mandatory to provide supportive care until the symptoms improve or resolve.1 Pharmacologic therapies for the management of hepatic encephalopathy mitigate their action through lowering of ammonia, with a focus on the ammonia-producing bacteria of the colon. Disaccharides are considered the first-line pharmacologic agents of choice for lowering the production and absorption of ammonia, with lactulose being the most commonly used agent. Lactulose is metabolized by the gut flora into acetic and lactic acids, producing an acidic, non-survival

environment for the bacteria. In addition, the metabolism of lactulose inhibits the diffusion of ammonia into the systemic circulation and the subsequent conversion of ammonia to ammonium. Lactulose for hepatic encephalopathy can be administered by enteral access or per rectum and is typically titrated to 2–4 semisoft stools per day. Despite mechanistic belief of efficacy, conflicting data exist regarding substantial benefit in the treatment of hepatic encephalopathy compared with placebo. Currently, there is insufficient evidence to dispute the initiation of lactulose therapy; therefore, lactulose (or other laxative agents discussed in the following text) should be administered to all patients with hepatic encephalopathy.49 Despite the long-standing use of disaccharide therapy in hepatic encephalopathy, recent evidence is challenging its role as the first-line treatment option for hepatic encephalopathy. Polyethylene glycol, an osmotic laxative with gut catharsis activity, was hypothesized to resolve hepatic encephalopathy more effectively than lactulose in the Hepatic Encephalopathy: Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution (HELP) study. Efficacy was evaluated by an improvement in one or more grades of hepatic encephalopathy at 24 hours after the administration of pharmacologic intervention. Therapies evaluated include lactulose 20–30 g orally or 300 g per rectum for a minimum of three doses in 24 hours compared with polyethylene glycol 4 L orally over 4 hours. Patient demographics were similar in each treatment group, including severity of liver failure. A statistically significant improvement in one or more grades of hepatic encephalopathy was noted in the polyethylene glycol treatment arm compared with the lactulose therapy treatment arm (91% vs. 52%; p 0.6)

Acetaminophen

Amiodarone

Buspirone

Alprazolam

Amitriptyline

Chlorpromazine

Carbamazepine

Atorvastatin

Cyclosporine

Ceftriaxone

Azathioprine

Doxepin

Chlordiazepoxide

Carvedilol

Fluvastatin

Clarithromycin

Ciprofloxacin

Imipramine

Clindamycin

Clomipramine

Isosorbide dinitrate

Diazepam

Clozapine

Labetalol

Diphenhydramine

Codeine

Lovastatin

Flurazepam

Diltiazem

Metoprolol

Glipizide

Erythromycin

Midazolam

Isoniazid

Felodipine

Morphine

Lamotrigine

Fluphenazine

Nicardipine

Lansoprazole

Haloperidol

Nitroglycerine

Lansoprazole

Itraconazole

Perphenazine

Levetiracetam

Lidocaine

Propranolol

Lorazepam

Nifedipine

Quetiapine

Methadone

Nortriptyline

Sertraline

Methylprednisone

Olanzapine

Sirolimus

Metoclopramide

Omeprazole

Tacrolimus

Metronidazole

Paroxetine

Trimipramine

Mycophenolate mofetil

Pravastatin

Venlafaxine

Oxazepam

Ranitidine

Verapamil

Phenobarbital

Simvastatin

Zaleplon

Phenytoin Prednisolone Prednisone Rifampin Risperidone Temazepam Theophylline Tiagabine Tolbutamide Topiramate

Trazadone Triazolam Valproic acid Zolpidem

aTable

is intended to provide examples of EH for some commonly encountered drugs and is not an exhaustive list. EH = hepatic extraction ratio. Adapted from: Delco F, Tchambaz L, Schlienger R, et al. Dose adjustment in patients with liver disease. Drug Saf 2005;28:529-45.

Alterations in Drug Distribution Alterations in plasma protein concentrations in ALF can affect the volume of distribution of drugs that are highly protein bound (i.e., drugs with 90% or greater protein binding).62 Potential mechanisms for decreased plasma protein binding include impaired hepatic protein synthesis, accumulation of exogenous compounds that can inhibit protein binding (e.g., bilirubin), and potential qualitative changes in albumin.58,60 Reductions in plasma albumin in ALF can lead to higher concentrations of free drug for agents that are highly bound to albumin.58 This may be clinically important because the unbound drug is generally responsible for generating a pharmacologic effect.61 Furthermore, changes in the concentration of unbound drug resulting in changes in volume of distribution may lead to alterations in clearance.62 Simultaneous increases in unbound fraction and decreases in metabolism (see text that follows) of highly bound drugs cleared by the liver can result in toxicity.62 Because the time course of ALF is variable and the half-life of albumin is relatively long (i.e., about 21 days), reductions in plasma albumin are not as predictable in ALF as in chronic liver diseases. Volume of distribution may also be influenced by third spacing (because of ascites, edema, or both); this may be particularly important for hydrophilic drugs (e.g., aminoglycosides).60

Table 28.5 Child-Pugh (CTP) Scorea,32

aA (mild):

5–6 points; B (moderate): 7–9 points; C (severe): 10–15 points.

Alterations in Drug Metabolism and Clearance In general, hepatic drug metabolism is likely impaired in patients with ALF, although most available data come from chronic liver diseases. Hepatic metabolism may be impaired because of several mechanisms. Hepatic transporters mediate the transport of some drugs in or out of hepatocytes and into the bile canaliculus. Transporter expression and activity may be altered in acute and chronic liver diseases; however, a detailed discussion of transporter alterations is beyond the scope of this chapter.60 Alterations in hepatic enzymatic capacity (including alterations in hepatic enzyme expression and loss of hepatocytes) can substantially affect hepatic drug metabolism.60 The effect of ALF on drug metabolism may partly depend on whether the drug is a high, intermediate, or low extraction drug.60 As indicated earlier, EH describes the efficiency of drug removal by the liver and is dependent

on Q H, CLint, and plasma protein binding.61 Intrinsic drug clearance is an indication of the liver’s ability to clear unbound drug from the blood and depends on hepatic metabolic enzyme activity and the function of hepatic transporters.58 Therefore, ALF may result in a reduction in EH because of a reduction in the expression and activity of drugmetabolizing enzymes and may further affect metabolism as a result of changes in Q H.60 The hepatic drug clearance of low EH drugs tends to be sensitive to changes in enzyme activity and protein binding.60 High EH drugs are more sensitive to alterations in Q H.60 Although specific data regarding hepatic enzyme activity in ALF are lacking, data in chronic liver diseases such as cirrhosis can offer insight into probable alterations. Cytochrome P450 enzymes are likely more affected in cirrhosis than are phase II metabolizing enzymes.63,64 The extent to which liver disease affects drug metabolism depends on several factors, including the metabolic pathway involved, extent of injury, and time course of injury.59 Results of studies in cirrhosis have been variable; however, in general, the activity and expression of CYP3A, CYP1A2, and CYP2C19 appear to be most susceptible to the effects of chronic liver disease, whereas CYP2D6 and CYP2C9 may be more preserved.59,64 In a study evaluating CYP3A activity in cirrhosis, CYP3A activity was correlated with CTP and MELD scores.65 In this study of patients with severe cirrhosis (CTP class C or MELD of 15 or higher), the unbound clearance of midazolam (a CYP3A substrate) was 14% of the corresponding midazolam clearance in control subjects.65 Although caution should be used in extrapolating these results to ALF, it is likely that ALF is associated with a reduction in CYP function and expression, given the extensive hepatocyte necrosis and apoptosis that is characteristic of ALF. In one of the few pharmacokinetic studies conducted in ALF, the plasma half-life of antipyrine was significantly prolonged in patients after acetaminophen overdose (antipyrine is a substrate for several CYP enzymes, including CYP1A2, CYP2C9, and CYP3A4).66,67 Similarly, in a study that included eight subjects with acute hepatitis (out of 18 total subjects with liver disease), antipyrine clearance was decreased compared with controls, and this was most pronounced in patients with encephalopathy.68 Of note, an in vivo test

of CYP1A2 as a measure of liver function (LiMAx test) showed decreased CYP1A2 function in patients with ALF, with lower function in patients with ALF without spontaneous recovery than in patients with ALF with spontaneous recovery.69 For low EH drugs, changes in protein binding can also affect metabolism (see earlier text). Specifically, low EH drugs with high protein binding may be sensitive to alterations in protein binding that may be present in ALF.60

Table 28.6 Examples of Drugs with Dosing Guidelines Based on CTP Scorea,b

aThis

is an abbreviated list and does not contain all drugs with dosing guidelines based on Child-Pugh (CTP) score. bCTP

score was not designed for use in ALF and has not been validated in ALF. Proposed approaches for patients with ALF include calculating an individual patient’s CTP score or assuming that the patient has severe disease (CTP class C, score 10–15). Adapted from: Budingen FV, Gonzalez D, Tucker AN, et al. Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments. Ther Adv Infect Dis 2014;2:17-42; and Spray JW, Willett K, Chase D, et al. Dosage adjustment for hepatic dysfunction based on Child-Pugh scores. Am J Health Syst Pharm 2007;64:690, 2-3.

Phase II enzymes may also be affected by ALF, although they are

generally thought to be less affected than phase I enzymes in chronic liver diseases.60 For example, the metabolism of benzodiazepines eliminated by phase II reactions (e.g., oxazepam, temazepam, lorazepam) may be less likely to have reduced clearance than benzodiazepines metabolized by phase I reactions (e.g., midazolam, diazepam).70 In general, sulfonation reactions are more affected than glucuronidation.60 Acute liver failure is often associated with renal dysfunction, which affects the renal clearance of drugs, and should be accounted for when selecting a dosing regimen.

Guidelines for Drug Dosing in ALF The relative paucity of data regarding pharmacokinetic changes in ALF, in combination with the variability in the presentation of ALF, limits the ability to develop specific dosing guidelines. However, several generalizations may be made. First, when available, serum drug concentrations should be monitored to assist in drug dosing in ALF, and when possible, monitoring of free drug concentrations may be preferred (to monitoring of total concentrations).62 Un-fortunately, serum concentration monitoring is available for only a minority of drugs used clinically. For some drugs, dosing recommendations based on the CTP score may be available; however, these recommendations are generally based on chronic liver diseases, not ALF.62 The CTP classification assigns points according to the presence of ascites and encephalopathy, as well as serum bilirubin, albumin, and prothrombin time (Table 28.5).32 The patient is classified as having mild, moderate, or severe disease. Although the CTP score was not developed for the intent of drug dosing, the FDA has included its use in a guidance statement for pharmacokinetic studies in hepatic impairment, and dosing guidelines based on the CTP score are included in the labeling of some drugs (see Table 28.6 for examples). In the absence of dosing recommendations specific to ALF, guidelines based on the CTP score may be used as an initial guide to dose drugs in ALF (i.e., either using patient characteristics to calculate a CTP score or assuming the

patient has severe disease). For drugs with no dosing guidelines based on CTP scores, doses may be adjusted on the basis of a drug’s EH and protein binding (see Table 28.7).70,71

Table 28.7 Summary of Potential Pharmacokinetic Changes in Acute Liver Failure Pharmacokinetic Parameter

Potential Change

Enteral bioavailability

• May be increased, particularly with high EH drugs

Recommendation

• Consider parenteral formulation if available • Consider lower dose - A conservative approach is to assume 100% bioavailability of high EH drugs, and dose using the formula: adjusted initial dose = (normal dose × bioavailability in normal liver function)/100a

Volume of distribution

• Increases in free concentrations of drugs highly bound to albumin • Potential increases in volume of distribution of hydrophilic drugs in the setting of ascites/edema

Clearance

• Impaired hepatic drug metabolism by CYP enzymes • High EH drugs are more sensitive to alterations in hepatic blood flow (e.g., during shock) • Low EH drugs are more sensitive to alterations in CYP

• Consider monitoring free drug concentrations, if available • Account for changes in protein binding when interpreting total drug concentrations • Consider higher loading doses for hydrophilic drugs (e.g., aminoglycosides) in the setting of ascites • Consider therapeutic drug monitoring, if available • For drugs with guidelines based on CTP score, consider using clinical characteristics to estimate a CTP score and follow guidelines for severe diseaseb • In the absence of dosing guidelines based on CTP score, the following guidelines may be considered:

activity and protein binding

- For high EH drugs administered orally: initial maintenance dose = (normal dose × bioavailability in normal liver function)/100a - For high EH drugs administered intravenously: initial maintenance dose = normal dosea - For low EH drugs with low binding to albumin (< 90% binding): initial dose = normal initial dose,a maintenance dose should be reduced to 50% of normal in patients with calculated CTP class A, reduced to 25% of normal dose in calculated CTP class B; for calculated CTP class C, avoid drugs without proven safety in this population, or initiate low dose and monitor therapy closelya - For low EH drugs with high binding to albumin (≥ 90% binding): monitor therapy closelya - For intermediate EH drugs, initial dose is the low range of normal dose; maintenance dose should be adjusted on the basis of guidelines for low EH drugs • Closely monitor patients for efficacy and signs of toxicity • Adjust doses as necessary on the basis of renal function

aAdapted

from: Delco F, Tchambaz L, Schlienger R, et al. Dose adjustment in patients with liver disease. Drug Saf 2005;28:529-45; and Perianez-Parraga L, Martinez-Lopez I, Ventayol-Bosch P, et al. Drug dosage recommendations in patients with chronic liver disease. Rev Esp Enferm Dig 2012;104:165-84. bThe

CTP (Child-Pugh) score was not developed for use in acute liver failure.

EH = hepatic extraction ratio.

It is likely that drugs with a high EH will have an increased enteral

bioavailability in ALF; in these cases, administering lower doses (and gradually titrating doses on the basis of response and toxicity) or using parenteral administration may be warranted. If enteral administration of a drug with high EH is required, a conservative approach is to assume 100% bioavailability of these agents and to dose on the basis of the following formula: adjusted initial dose = (normal dose × bioavailability in normal liver function)/100.70 Acute liver failure is often associated with acute renal failure, which may warrant a dose adjustment of drugs that are cleared through the kidneys. Furthermore, management of ALF and acute renal failure may require the use of extracorporeal support systems (e.g., molecular adsorbent recirculating systems, renal replacement therapy). Information regarding drug dosing in renal failure and during use of extracorporeal support systems is found in Chapter 41, “Drug Dosing in Special ICU Populations.” In all cases, patients should be closely monitored for signs of both efficacy and toxicity. A summary of the guidelines for drug dosing in ALF is presented in Table 28.7.

REFERENCES 1. Lee WM, Larson AM, Stravitz RT. AASLD Position Paper: The Management of Acute Liver Failure: Update 2011. 2011:1-79. Available at www.aasld.org/sites​/default/files/​ guideline_documents/​alfenhanced.pdf. Accessed June 2015. 2. Bernal W, Auzinger G, Dhawan A, et al. Acute liver failure. Lancet 2010;376:190-201. 3. Lee WM, Squires RH Jr, Nyberg SL, et al. Acute liver failure: summary of a workshop. Hepatology 2008;47:1401-15. 4. Bernal W, Wendon J. Acute liver failure. N Engl J Med 2013;369:2525-34. 5. Whitehouse T, Wendon J. Acute liver failure. Best Pract Res Clin Gastroenterol 2013;27:757-69. 6. Acute Liver Failure Study Group [homepage on the Internet].

Available at www.utsouthwestern.edu​/labs/acute-liver/​clinicaltrials/patient​-enrollment.html. Accessed August 27, 2015. 7. Olson JC, Kamath PS. Acute-on-chronic liver failure: concept, natural history, and prognosis. Curr Opin Crit Care 2011;17:165-9. 8. Sundaram V, Shaikh OS. Acute liver failure: current practice and recent advances. Gastroenterol Clin North Am 2011;40:523-39. 9. Wang DW, Yin YM, Yao YM. Advances in the management of acute liver failure. World J Gastroenterol 2013;19:7069-77. 10. Larsen FS, Bjerring PN. Acute liver failure. Curr Opin Crit Care 2011;17:160-4. 11. Rutherford A, Chung RT. Acute liver failure: mechanisms of hepatocyte injury and regeneration. Semin Liver Dis 2008;28:16774. 12. Chung RT, Stravitz RT, Fontana RJ, et al. Pathogenesis of liver injury in acute liver failure. Gastroenterology 2012;143:e1-e7. 13. Malhi H, Gores GJ, Lemasters JJ. Apoptosis and necrosis in the liver: a tale of two deaths? Hepatology 2006;43:S31-44. 14. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947-54. 15. Ichai P, Samuel D. Epidemiology of liver failure. Clin Res Hepatol Gastroenterol 2011;35:610-7. 16. Chun LJ, Tong MJ, Busuttil RW, et al. Acetaminophen hepatotoxicity and acute liver failure. J Clin Gastroenterol 2009;43:342-9. 17. Khandelwal N, James LP, Sanders C, et al.; Acute Liver Failure Study G. Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure. Hepatology 2011;53:567-76. 18. Hodgman MJ, Garrard AR. A review of acetaminophen poisoning. Crit Care Clin 2012;28:499-516.

19. Bunchorntavakul C, Reddy KR. Acetaminophen-related hepatotoxicity. Clin Liver Dis 2013;17:587-607, viii. 20. Lee WM, Seremba E. Etiologies of acute liver failure. Curr Opin Crit Care 2008;14:198-201. 21. Grant LM, Rockey DC. Drug-induced liver injury. Curr Opin Gastroenterol 2012;28:198-202. 22. Reuben A, Koch DG, Lee WM. Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010;52:2065-76. 23. Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN Prospective Study. Gastroenterology 2015;148:1340-52 e7. 24. Fontana RJ, Hayashi PH, Gu J, et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology 2014;147:96-108 e4. 25. Lee WM. Drug-induced acute liver failure. Clin Liver Dis 2013;17:575-86, viii. 26. Suk KT, Kim DJ. Drug-induced liver injury: present and future. Clin Mol Hepatol 2012;18:249-57. 27. Taylor RM, Tujios S, Jinjuvadia K, et al. Short and long-term outcomes in patients with acute liver failure due to ischemic hepatitis. Dig Dis Sci 2012;57:777-85. 28. Bernuau J, Goudeau A, Poynard T, et al. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 1986;6:648-51. 29. O’Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439-45. 30. Cox NR, Mohanty SR. Acute liver failure. Hosp Physician 2009:715.

31. Ge PL, Du SD, Mao YL. Advances in preoperative assessment of liver function. Hepatobiliary Pancreat Dis Int 2014;13:361-70. 32. U.S. Food and Drug Administration (FDA). Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. Available at www.fda.gov/downloads​/drugs/guidancecompli​ anceregulatoryinformation/​guidances/ucm072123.pdf. Accessed August 27, 2015. 33. Polson J. Assessment of prognosis in acute liver failure. Semin Liver Dis 2008;28:218-25. 34. Shakil AO, Kramer D, Mazariegos GV, et al. Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria. Liver Transpl 2000;6:163-9. 35. Anand AC, Nightingale P, Neuberger JM. Early indicators of prognosis in fulminant hepatic failure: an assessment of the King’s criteria. J Hepatol 1997;26:62-8. 36. Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864-71. 37. Lee HS, Choi GH, Joo DJ, et al. Prognostic value of model for end-stage liver disease scores in patients with fulminant hepatic failure. Transplant Proc 2013;45:2992-4. 38. Conn HO, Leevy CM, Vlahcevic ZR, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 1977;72:573-83. 39. Dhiman RK, Jain S, Maheshwari U, et al. Early indicators of prognosis in fulminant hepatic failure: an assessment of the Model for End-Stage Liver Disease (MELD) and King’s College Hospital criteria. Liver Transpl 2007;13:814-21. 40. Yantorno SE, Kremers WK, Ruf AE, et al. MELD is superior to King’s College and Clichy’s criteria to assess prognosis in

fulminant hepatic failure. Liver Transpl 2007;13:822-8. 41. Parkash O, Mumtaz K, Hamid S, et al. MELD score: utility and comparison with King’s College criteria in non-acetaminophen acute liver failure. J Coll Physicians Surg Pak 2012;22:492-6. 42. Fikatas P, Lee JE, Sauer IM, et al. APACHE III score is superior to King’s College Hospital criteria, MELD score and APACHE II score to predict outcomes after liver transplantation for acute liver failure. Transplant Proc 2013;45:2295-301. 43. Guler N, Unalp O, Guler A, et al. Glasgow coma scale and APACHE-II scores affect the liver transplantation outcomes in patients with acute liver failure. Hepatobiliary Pancreat Dis Int 2013;12:589-93. 44. Wlodzimirow KA, Eslami S, Chamuleau RA, et al. Prediction of poor outcome in patients with acute liver failure—systematic review of prediction models. PLoS One 2012;7:e50952. 45. Pyleris E, Giannikopoulos G, Dabos K. Pathophysiology and management of acute liver failure. Ann Gastroenterol 2010;23:257-65. 46. Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med 2007;35:2498-508. 47. Bass S, Zook N. Intravenous acetylcysteine for indications other than acetaminophen overdose. Am J Health Syst Pharm 2013;70:1496-501. 48. Brok J, Buckley N, Gluud C. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev 2006;2:CD003328. 49. Sharma P, Sharma BC. Management of overt hepatic encephalopathy. J Clin Exp Hepatol 2015;5:S82-7. 50. Rahimi RS, Singal AG, Cuthbert JA, et al. Lactulose vs polyethylene glycol 3350—electrolyte solution for treatment of

overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA Intern Med 2014;174:1727-33. 51. Patidar KR, Bajaj JS. Antibiotics for the treatment of hepatic encephalopathy. Metab Brain Dis 2013;28:307-12. 52. XIFAXAN(R) oral tablets, rifaximin oral tablets [product information]. Morrisville, NC: Salix Pharmaceuticals, 2010. 53. Sharma BC, Sharma P, Lunia MK, et al. A randomized, doubleblind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol 2013;108:1458-63. 54. Vaquero J. Therapeutic hypothermia in the management of acute liver failure. Neurochem Int 2012;60:723-35. 55. Faybik P, Krenn CG. Extracorporeal liver support. Curr Opin Crit Care 2013;19:149-53. 56. Alqahtani SA. Update in liver transplantation. Curr Opin Gastroenterol 2012;28:230-8. 57. Findlay JY. Patient selection and preoperative evaluation for transplant surgery. Anesthesiol Clin 2013;31:689-704. 58. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008;64:1147-61. 59. Rodighiero V. Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokinet 1999;37:399-431. 60. Budingen FV, Gonzalez D, Tucker AN, et al. Relevance of liver failure for anti-infective agents: from pharmacokinetic alterations to dosage adjustments. Ther Adv Infect Dis 2014;2:17-42. 61. Lin S, Smith BS. Drug dosing considerations for the critically ill patient with liver disease. Crit Care Nurs Clin North Am 2010;22:335-40. 62. Nguyen HM, Cutie AJ, Pham DQ. How to manage medications in the setting of liver disease with the application of six questions. Int

J Clin Pract 2010;64:858-67. 63. McLean AJ, Morgan DJ. Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet 1991;21:42-69. 64. Villeneuve JP, Pichette V. Cytochrome P450 and liver diseases. Curr Drug Metab 2004;5:273-82. 65. Albarmawi A, Czock D, Gauss A, et al. CYP3A activity in severe liver cirrhosis correlates with Child-Pugh and model for end-stage liver disease (MELD) scores. Br J Clin Pharmacol 2014;77:160-9. 66. Engel G, Hofmann U, Heidemann H, et al. Antipyrine as a probe for human oxidative drug metabolism: identification of the cytochrome P450 enzymes catalyzing 4-hydroxyantipyrine, 3hydroxymethylantipyrine, and norantipyrine formation. Clin Pharmacol Ther 1996;59:613-23. 67. Forrest JA, Roscoe P, Prescott LF, et al. Abnormal drug metabolism after barbiturate and paracetamol overdose. Br Med J 1974;4:499-502. 68. Andreasen PB, Ranek L. Liver failure and drug metabolism. Scand J Gastroenterol 1975;10:293-7. 69. Lock JF, Kotobi AN, Malinowski M, et al. Predicting the prognosis in acute liver failure: results from a retrospective pilot study using the LiMAx test. Ann Hepatol 2013;12:556-62. 70. Delco F, Tchambaz L, Schlienger R, et al. Dose adjustment in patients with liver disease. Drug Saf 2005;28:529-45. 71. Perianez-Parraga L, Martinez-Lopez I, Ventayol-Bosch P, et al. Drug dosage recommendations in patients with chronic liver disease. Rev Esp Enferm Dig 2012;104:165-84.

Chapter 29 Acute Gastrointestinal

Bleeding: Prophylaxis and Treatment Salmaan Kanji, Bsc. Pharm, Pharm.D.; and David Williamson, B. Pharm, M. Sc., Ph.D., BCPS

LEARNING OBJECTIVES 1. Differentiate between the typical presentation of upper and lower gastrointestinal (GI) bleeding. 2. Identify risk factors for clinically relevant GI bleeding in the intensive care unit. 3. Identify measures for the primary prevention of both upper and lower GI bleeding. 4. Individualize the reversal of drug-associated bleeding according to the likely offending agent. 5. Understand the role of acid-suppressive therapy and other hemostatic agents in the acute management of clinically significant GI bleeding. 6. Identify strategies for the secondary prevention of GI bleeding using risk stratification tools. 7. Understand the role of Helicobacter pylori screening and treatment in the setting of peptic ulcer disease. 8. Consider the risks and benefits of reintroducing anticoagulation, antiplatelet therapies, and NSAIDs.

ABBREVIATIONS IN THIS CHAPTER COX-2

Cyclooxygenase-2

FFP

Fresh frozen plasma

H2RB

Histamine-2 receptor blocker

ICU

Intensive care unit

LMWH

Low-molecular-weight heparin

NSAID

Nonsteroidal anti-inflammatory drug

PCC

Prothrombin complex concentrate

PPI

Proton pump inhibitor

SRMD

Stress-related mucosal disease

INTRODUCTION Acute upper and lower gastrointestinal bleeding (GI) are common conditions that require admission to the intensive care unit (ICU) or complicate the stay of patients admitted for other ailments. Despite advances in endoscopic and pharmacologic therapies, morbidity and mortality associated with upper and lower GI bleeding remain significant.1,2 In addition, the epidemiology of GI bleeding is evolving, given that a decrease in the incidence of upper GI bleeding and an increase in the incidence of lower GI bleeding have occurred in recent years.3 Peptic ulcer disease remains the most common cause of GI bleeding. Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin use as well as Helicobacter pylori infection are the primary causes.4,5 Lower GI bleeding is not as well studied as upper GI bleeding and remains likely underreported because many patients with bleeding remain without medical evaluation.6 Three levels of bleeding, ranging

from occult to moderate to severe, show the gravity of the disease.7 Diverticular disease is the most common cause of lower GI bleeding. In the critically ill, mesenteric ischemia and ischemic colitis are also common. Admission to the ICU for upper and lower GI bleeding is determined by the presence of hypotension, respiratory failure, cardiac ischemia, and new neurological dysfunction.

CLINICAL PRESENTATION AND PATHOPHYSIOLOGY Upper GI Bleeding Upper GI bleeding is defined as bleeding originating from the esophagus, stomach, or duodenum.7 Clinically important upper GI bleeding has been defined as macroscopic bleeding causing hemodynamic instability or necessitating blood transfusions. The most common presentations for upper GI bleeding are hematemesis, vomiting of fresh blood or coffee ground–like matter, and melena, which are black and tarry stools. Hematochezia, the passage of fresh blood with stools, may also be present in upper GI bleeding, most often when the bleeding is clinically significant. Common causes of upper GI bleeding include duodenal and gastric ulcer disease, erosive gastritis, esophageal variceal hemorrhage, and Mallory-Weiss tears (Box 29.1). In critically ill patients, stress-related mucosal disease (SRMD) is a common cause of ICU-acquired GI bleeding. Because significant bleeding reduces intravascular volume, it commonly presents with systemic symptoms such as resting tachycardia and hypotension or postural changes in blood pressure.8 The pathophysiology of upper GI bleeding varies according to cause. Peptic ulcer disease is mainly caused by H. pylori infection.9 This gram-negative bacteria causes inflammation of the gastric and duodenal mucosa, which renders the mucosa more vulnerable to ulceration that can progress to the submucosa and damage arterial walls.7,10 The NSAIDs inhibit cyclooxygenase and modify prostaglandin production, thereby reducing the protection provided by the mucosa. In much the same way as H. pylori, NSAID use enables the formation of

mucosal ulcerations. Whereas H. pylori is responsible for more duodenal than gastric ulcers, NSAIDs have a more predominant effect on the stomach than on the duodenum.7 In the presence of both pathologic factors, the risk of ulceration seems to be additive.11 In addition, drugs that inhibit platelet aggregation (e.g., selective serotonin reuptake inhibitors or the coagulation cascade) increase the risk of GI bleeding in patients with preexisting mucosal damage.12 Stress-related mucosal disease develops when critical illness induces a reduction in cardiac output, catecholamine-induced vasoconstriction, and proinflammatory cytokine release. The ensuing splanchnic hypoperfusion induces an imbalance between oxygen delivery and demand, inducing mucosal ischemia and a reduction in the capacity to neutralize hydrogen ions. A reduction in motility as well as a reduction in protective mucus production also contribute to the development of SRMD (Figure 29.1).13 The initial mucosal injury can remain superficial and lead to occult blood loss from the bleeding of mucosal capillaries. In certain cases, the injury can evolve to larger vessels and cause severe bleeding. Mallory-Weiss tears are longitudinal lacerations to the mucosa of the stomach cardia or at the gastroesophageal junction that are caused by a sudden increase in intra-abdominal pressure, which is most often caused by vomiting.14 Initially described in patients with acute alcohol ingestion, Mallory-Weiss tears are often described in other conditions associated with repeated vomiting (i.e., chemotherapy, gastroenteritis). Esophageal varices develop as the result of portal hypertension secondary to liver cirrhosis and can be life threatening. Because the management and outcomes are different from those for other causes of upper GI bleeding, this subject is beyond the scope of this chapter and will be covered with liver diseases (Chapter 28). Lower GI Bleeding Lower GI bleeding is defined as bleeding from the gut distal to the ligament of Treitz. Hematochezia is the most common feature, but melena can also be present, especially in patients with bleeds originating from the distal small bowel and colon. The most common

causes of lower GI bleeding are colonic diverticulosis, colorectal malignancy, inflammatory bowel disease, anorectal disease, mesenteric ischemia, and ischemic colitis.2,15,16 Colonic diverticulosis develops with age as the colonic wall weakens, creating protrusions, usually at the insertion of the vasa recta artery.17 Bleeding is secondary to the rupture of this artery and spontaneously resolves in many cases. However, in 3%–5% of cases, bleeding can be important.18 Clinically significant bleeding secondary to diverticular disease has been associated with diabetes, hyper-tension, anticoagulation, and ischemic heart disease.18 Mesenteric ischemia and ischemic colitis arise from an imbalance between oxygen supply and demand in the small bowel and colon. Thrombosis, emboli, and vasoconstriction caused by medications such as vasopressors are responsible for mesenteric ischemia.7 The main causes of mesenteric ischemia are arterial embolism, arterial thrombosis, small vessel occlusion, and venous thrombosis. Atherosclerosis and cardiac disease (valvular disease, atrial arrhythmias, ventricular dilatation) are important risk factors.19 A hypercoagulable state, hypovolemia, and previous arterial emboli are also associated with mesenteric ischemia.20 Ischemic colitis is caused by reduced perfusion to the colon, and bleeding occurs as the result of mucosal necrosis. Colon carcinomas represent an important proportion of rectal bleeding in older patients. These tumors tend to bleed much more slowly.21 Crohn disease, ulcerative colitis, hemorrhoids, and anal fissures are other common causes of lower GI bleeding.

Box 29.1. Causes of Upper GI Bleeding Common Peptic ulcer disease (gastric and duodenal ulcers) (28%–59%) Variceal bleeding (6%–14%) Gastritis/duodenitis (9%–31%) Esophagitis (4%–18%)

Mallory-Weiss tears (4%–7%) Less common Malignancy (2%–4%) No diagnosis (8%–25%) Others Adapted from: van Leerdam ME. Epidemiology of acute upper gastrointestinal bleeding. Best Pract Res Clin Gastroenterol 2008;22:209-24.

Epidemiology The reported incidence of upper GI bleeding leading to hospitalization varies from 37 to 172 per 100,000 adults.1,22 Differences in reported incidents are attributable to variations in studied populations and study periods. Duodenal and gastric ulcers represent the most common etiologies of upper GI bleeds, followed by Mallory-Weiss tears and esophagitis.22 The reported incidence of lower GI bleeding in the general population varies from 22 to 87 per 100,000 adults.2,22

Peptic Ulcer Disease The hospitalization rates for peptic ulcer bleeding have been declining in recent years because of reduced H. pylori infection rates and increased use of proton pump inhibitors (PPIs).23,24 In the United States, the age/sex-adjusted incidence of peptic ulcer bleeding decreased from 41.8 to 35.7 per 100,000 between 2001 and 2009.25 In Spain, the incidence of hospitalization for upper GI bleeding decreased from 54.6 in 1996 to 25.8 per 100,000 person-years in 2006.23

Stress-Related Mucosal Disease

Endoscopic studies suggest that most critically ill patients develop gastric erosions related to SRMD during the ICU stay.26 However, the incidence of clinically important upper GI bleeding, defined as the presence of hematemesis, bloody GI aspirate, or melena, is 1.5%– 2.8% in the critically ill.27,28 In patients with risk factors such as mechanical ventilation and coagulopathy, the incidence increases to 3.7%.28 Nevertheless, these data were published 15–20 years ago, and because the treatment of critically ill patients has evolved during the past decades, the incidence of SRMD is declining.29 Contemporary studies tend to suggest a decline in the incidence of clinically important upper GI bleeding.29,30

Mallory-Weiss Syndrome Mallory-Weiss tears are a common cause of upper GI bleeding and represent 3%–12% of cases.14,22 However, most cases resolve spontaneously, and clinically significant bleeding is rare.14

Lower GI Bleeding The incidence of lower GI bleeding requiring hospitalization, for both acute and occult bleeding, is reported to be 20–33 per 100,000 in studies from the United States and Spain.2,31 A recent populationbased study of patients undergoing colonoscopy in Iceland reported a crude incidence of 87 per 100,000 per year.15

RISK FACTORS The risk of upper GI bleeding is significantly increased in older age. Studies have reported a 4-fold increase in the risk in patients 75 years and older.32 Nonsteroidal anti-inflammatory drugs are a major risk factor for upper GI bleeding caused by peptic ulcers. Although all NSAIDs are associated with an increased risk of upper GI bleeding, traditional NSAIDs are associated with a greater risk of upper GI bleeding than are cyclooxygenase-2 (COX-2) selective inhibitors.33

Among the traditional NSAIDs, ibuprofen seems to have the best safety profile, whereas ketorolac has the worst.33 As previously mentioned, H. pylori also plays an important role in the pathogenesis and risk of developing upper GI bleeding. In patients with GI bleeding, risk factors identifiable on admission that are associated with an increased risk of developing acritical illness include coagulopathy, hypo-tension, neurologic dysfunction, and an Acute Physiology and Chronic Health Evaluation II (APACHE II) score greater than 15.34 When comparing upper and lower GI bleeding, male sex and NSAID use have been associated with an increased risk of upper GI bleeding, whereas the number of comorbidities and a recent diagnosis were associated with an increased risk of lower GI bleeding.31

Peptic Ulcer Disease H. pylori and NSAIDs are the two main causes of peptic ulcer disease. As rates of H. pylori–associated peptic ulcer disease have declined, some studies have reported an increase in low-dose-aspirin– associated disease.35 Several demographic and lifestyle risk factors have been associated with complicated peptic ulcer disease. Older age, male sex, significant alcohol consumption, tobacco use, comorbidi-ties, and psychological stress have been linked, although not always consistently across studies, to an increased risk of complicated peptic ulcer disease.36,37 Serotonin reuptake inhibitors have also been associated with a modest increase in upper GI bleeding, which significantly increases in the presence of NSAID use.38 Patients at high risk of NSAID-associated GI bleeding are those with a history of complicated ulcer and two other risk factors (age older than 65 years, high-dose NSAID therapy, and concurrent use of aspirin, corticosteroids, or anticoagulants).39 Patients with one risk factor or a history of uncomplicated ulcer are considered at moderate risk.

Stress-Related Mucosal Disease

Historically, SRMD has been associated with head trauma (Cushing ulcers) and major burns (Curling ulcers). In the critically ill, the risk of SRMD has been associated with respiratory failure and coagulopathy. The presence of both factors has been associated with a 3.7% incidence of GI bleeding compared with 0.1% in patients without these risk factors.28 Other factors commonly associated with SRMD include hypotension, sepsis, surgery, hepatic failure, and renal failure.13,27 Receiving enteral nutrition is an independent protective factor, even in the presence of ranitidine.27

Mallory-Weiss Syndrome Mallory and Weiss first described the condition in 1929 in the setting of acute alcohol ingestion.40 Other factors that have been associated with Mallory-Weiss tears include NSAID use, anticoagulation, and the presence of hiatal hernia.41

Lower GI Bleeding As the incidence of diverticulosis and ischemia increases with age, so does the incidence of lower GI bleeding.2 In a recent study, the agestandardized incidence rate of acute lower GI bleeding increased from 18 per 100,000 per year in patients 25–39 years of age to 187 and 690 per 100,000 per year in patients 60–79 and 80–105 years of age, respectively.15 Male sex has been inconsistently associated with an increased risk of lower GI bleeding.2,31 The presence of comorbidities and the use of NSAIDs, antiplatelet agents including aspirin, and anticoagulants have also been associated with an increased risk of lower GI bleeding.42 Rebleeding occurs more often in older patients and those exposed to NSAIDs and nonaspirin antiplatelet agents.13 Finally, independent risk factors for clinically significant (compared with nonsignificant) bleeding include age, non-hemorrhoidal bleeding, and combined use of aspirin and warfarin.15

OUTCOMES The consequences and complications associated with upper and lower GI bleeding are broad and include anemia, emergency surgery, cardiac ischemia, and hospitalization, as well as an increased risk of death.43 The mortality associated with upper GI bleeding has been declining in recent years.9 A recent database study from the United States reported a 2.45% case fatality for upper GI bleeding.25 Intensive care unit–acquired GI bleeding in mechanically ventilated patients has been associated with an increased risk of death.43 Clinically important upper GI bleeding in critically ill patients has also been associated with an increase in length of stay secondary to bleeding of 3.8–7.9 days.43 Many risk factors are associated with unfavorable outcomes in patients with an upper GI bleed, including increasing age, APACHE II score, comorbid conditions, liver disease, hypotension or shock on presentation, hospitalization, and rebleeding.1,32,44,45 Rebleeding occurs in 7%–16% of patients after endoscopic treatment and has a major influence on the outcomes of upper GI bleeding.1,10 The reported mortality rate in patients with recurrent bleeding is greater than 30%.46 The mortality risk appears to be similar when comparing peptic ulcer disease with non-ulcer causes of upper GI hemorrhage.47,48 In the specific case of Mallory-Weiss syndrome, age older than 65 years and comorbidities are independently associated with an increased risk of mortality.48 In patients with lower GI bleeding, the reported mortality is 2.2%– 8.8%.16,31,49,50 When patients with lower GI bleeding were compared with those with upper GI bleeding, one study reported a greater risk of mortality (8.8% vs. 5.5%) and an increased length of hospitalization (11.6 vs. 7.7 days).31 Risk factors for unfavorable outcomes in patients with a lower GI bleed include advanced age, hemodynamic instability, comorbid conditions, already being hospitalized, and use of certain drugs such as aspirin and NSAIDs.2

PREVENTION OF GI BLEEDING

Stress Ulcer Prophylaxis Although clinically significant GI bleeding rarely occurs in critically ill patients, strategies to prevent stress ulcers have long been advocated in high-risk patients.51,52 Stress ulcer prophylaxis is aimed at reducing the risk of clinically important upper GI bleeding and consequently improving outcomes such as length of stay in critically ill patients. Stress ulcer prophylaxis is recommended in patients with risk factors for SRMD, notably coagulopathy and mechanical ventilation for more than 48 hours.51,52 Several pharmacologic agents have been advocated for preventing stress ulcers, including antacids, sucralfate, histamine-2 receptor blockers (H2RBs), and PPIs.53 Antacids, titrated to obtain a gastric pH above 3.5, reduced GI bleeding.54 Frequent administration and the risk of drug interactions significantly limit antacid use. Sucralfate, which protects the gastric mucosa by forming a cytoprotective barrier, reduces ulcerations compared with placebo.26 Histamine-2 receptor blockers reduce gastric acid and secretions by competitively inhibiting hista-mine binding to parietal cell receptors. In a pivotal clinical trial, H2RBs reduced the relative and absolute risks of clinically important GI bleeding by 66% and 2.1%, respectively, compared with sulcralfate.55 Proton pump inhibitors increase gastric pH by inactivating the parietal cell H+/K+ ATPase enzyme. Although no large and adequately powered studies compare PPIs with H2RBs, a recent meta-analysis suggests that PPIs are more effective at reducing the risk of clinically significant GI bleeding.56 In North America, observational studies have shown that PPIs are the most commonly used agents in critically ill patients.57 Although H2RBs and PPIs reduce the risk of clinically significant GI bleeding, a corresponding impact on mortality has not been shown.58 The use of stress ulcer prophylaxis is not without risks. Using H2RBs and PPIs in critically ill patients may be associated with infectious complications, particularly Clostridium difficile–associated diarrhea and nosocomial pneumonia. Given that gastric acid contents are protective against bacterial survival in the stomach, there is evidence that alkalizing agents such as PPIs and H2RBs promote bacterial

overgrowth.59,60 However, evidence from randomized controlled trials supporting these associations is limited because nosocomial infections, and especially C. difficile infections, are rarely reported. In a recent meta-analysis comparing PPIs with H2RBs, investigators of eight trials reported on the risk of ventilator-associated pneumonia and found no difference in the risk of nosocomial pneumonia.10 However, no studies reported on the risk of C. difficile infections. Several observational studies have assessed the association between PPI or H2RB use and the risk of developing nosocomial pneumonia and C. difficile– associated diarrhea. Some studies of critically ill patients have reported an independent increased risk of nosocomial pneumonia with PPI use, whereas others have not found this association.61-65 Different patient populations, differing definitions of nosocomial pneumonia, and residual confounding may account for these different findings. The risk of C. difficile–associated diarrhea is increased with PPI use in several observational studies, but not in others.66-71 Variations in endemicity, susceptibility of populations, and presence of other risk factors such as the use of broad-spectrum antibiotics may explain these contrasting results.72 In addition, patients taking H2RBs seem to be at lower risk of contracting C. difficile–associated diarrhea compared with those taking PPIs.73 Because using H2RBs and PPIs for stress ulcer prophylaxis has been questioned for efficacy and safety reasons, enteral nutrition alone has been suggested as a potential alternative to acid-suppressive therapies.74 Studies have suggested that enteral nutrition improves mucosal blood flow and may increase gastric pH.75 Because of observational data, some authors suggest using enteral nutrition as the only stress ulcer prophylaxis in most critically ill patients (excluding trauma and burn patients).74 However, no randomized controlled trials have directly compared enteral nutrition with H2RBs or PPIs.

Prevention of Drug-Induced/Associated GI Bleeding Because NSAID, COX-2 inhibitor, and aspirin users have an increased risk of GI bleeding, mucosal protection strategies are used to prevent

the development of peptic ulceration. Proton pump inhibitors, high-dose H2RBs, and misoprostol all reduce the risk of peptic ulcers.75 The COX-2 inhibitors are associated with a lower incidence of peptic ulcers than are the NSAIDs. However, the combined use of low-dose aspirin and COX-2 inhibitors is associated with the same risk of GI bleeding as the use of NSAIDs. In addition, this protective effect of COX-2 inhibitors is undermined by an increased risk of myocardial infarction.76 Hence, recent recommendations for preventing NSAID-related ulcer complications consider both the GI risk (low, moderate, or high) and the cardiovascular risk (requirement of aspirin for preventing serious cardiovascular events). Risk factors for NSAID GI toxicity include age older than 65 years, high-dose NSAID therapy, a history of uncomplicated ulcer, and concurrent use of aspirin, corticosteroids, or anticoagulants. Patients with a history of a complicated ulcer (especially recent) or more than two risk factors are considered at high GI bleeding risk. Patients with one or two risk factors are considered at moderate GI bleeding risk. Patients with no risk factors are considered at low GI bleeding risk. In patients at high cardiovascular risk, naproxen has been advocated as the NSAID of choice in combination with a PPI or misoprostol.39 In patients who are also at high GI risk, avoiding NSAIDs and COX-2 inhibitors is recommended. In patients at low cardiovascular risk, using an NSAID alone is acceptable if the risk of GI bleeding is low. However, a PPI or misoprostol is suggested in patients at moderate GI risk. Finally, in patients at low cardiovascular risk and high risk of GI toxicity, avoiding NSAIDs, if possible, or using a COX-2 inhibitor combined with a PPI or misoprostol is recommended.39

APPROACH TO DIAGNOSIS Data gathered from the history, physical assessment, and laboratory tests dictate the need for resuscitation, describe the severity of bleeding, identify the potential sources of bleeding, and facilitate the triage of further diagnostic or therapeutic interventions.9 The initial assessment begins with an evaluation of hemodynamic stability.

Patients presenting with hypotension, evidence of end-organ ischemia, or large volumes of blood loss need immediate resuscitation. In the clinical setting, most patients who present with upper GI bleeding have hematemesis or melena. Those presenting with melena or hematochezia are typically thought to have lower GI bleeding.

Upper GI Bleeding Presentation with frank hematemesis typically suggests more severe bleeding than presentation with coffee ground emesis. Melena usually indicates upper GI bleeding, but it can also occur with bleeding from the distal small bowel or the proximal colon. Hematochezia usually indicates GI bleeding from the colon, but it can occur with massive upper GI bleeding. The history obtained from the patient or family member can also be valuable. Patients with a history of GI bleeding typically bleed from the same lesion. The approach to diagnosis and management may also be affected by a patient history of liver disease (and knowledge of existing varices or portal hypertension), peptic ulcer disease and its previous investigations, previous H. pylori treatment, malignancy, or alcohol abuse. A medication history specifically looking for use of NSAIDs, aspirin, anticoagulants, antiplatelet agents, and corticosteroids helps identify risk and potential causative factors. Patients taking iron supplements or bismuth-containing products may present with black stools, which can be mistaken for melena. Patients presenting with hemodynamic instability need immediate resuscitation with crystalloid fluids and blood products. Patients may also present with orthostatic hypo-tension, confusion, tachycardia, supraventricular tachyarrhythmias, and cold or mottled extremities. The symptoms reported immediately preceding the acute event can also help predict the source of bleeding. Epigastric or right upper quadrant pain can be indicative of peptic ulcer bleeding, whereas reflux, dysphagia, and odynophagia may predict esophageal ulceration. Intractable vomiting, retching, or even coughing can precede hemorrhage from a Mallory-Weiss tear, and cachexia or significant involuntary weight loss may suggest malignancy.77 Laboratory tests

should include a complete blood cell count, serum electrolytes and chemistries, liver function tests, and coagulation studies. Initial hemoglobin values usually appear normal as patients are losing whole blood. With resuscitation and time, hemoglobin concentrations usually drop within 24 hours.

Lower GI Bleeding Patients with lower GI bleeding typically present with hematochezia or (rarely) melena if they have right-sided colonic bleeding. Patient histories, physical assessments, and laboratory investigations play a similar role in suspected upper GI bleeding. The goals of initial assessment are to assess the severity of bleeding, triage the patient to the appropriate care setting, initiate resuscitation, and consider the potential source of bleeding. After resuscitation, diagnostic and potentially therapeutic interventions such as colonoscopy may be warranted.

INITIAL MANAGEMENT Airway and Vascular Access All patients with GI bleeding and hemodynamic instability should be admitted to the ICU for resuscitation, cardiac monitoring, and pulse oximetry. All patients should receive supplemental oxygen, and patients with decreased levels of consciousness, ongoing hematemesis, or respiratory distress may need endotracheal intubation. Intubation not only helps facilitate endoscopy, but also protects against the risk of aspiration. All patients should receive either a central venous catheter or two large-bore peripheral venous catheters for resuscitation.

Fluid Resuscitation and Blood Transfusion Hemodynamic stabilization before endoscopy improves patient outcomes. Bleeding and/or hypotensive patients should receive

intravenous crystalloid fluids such as normal saline or lactated Ringer solution (i.e., boluses of 500 mL over 30 minutes or less) while being typed and cross-matched for blood transfusions. The frequency and number of fluid boluses should be evaluated in the context of blood pressure response, acknowledging that over-resuscitation may also be harmful. Crystalloid resuscitation causes a dilution of the blood remaining in the vascular space and may result in increased bleeding from clot destabilization and dilution of factors that allow new clot formation.78 Smaller, more frequent, boluses are more likely to result in the smallest effective volume administered to achieve hemodynamic stabilization. Beyond evidence of massive hemorrhage, the decision to transfuse blood should be directed by measured hemoglobin concentrations. A randomized controlled trial of 921 adults with acute upper GI bleeding suggested that a restrictive transfusion practice is associated with improved outcomes compared with a liberal transfusion practice.79 Patients in this trial were randomized to receive blood transfusions when hemoglobin concentrations fell below 7 g/dL (conservative arm) or 9 g/dL (liberal arm). Of note, patients with massive hemorrhage, low risk of further bleeding, acute coronary syndrome, or significant cardiovascular disease were excluded. About one-half of the patients in the study had peptic ulcer disease, whereas one-fourth had variceal bleeding. The conservative transfusion strategy was associated with a lower mortality (hazard ratio 0.55; 95% confidence interval, 0.33– 0.92), less rebleeding, and fewer complications. All patients in this study underwent early endoscopy. In addition to blood, transfusion of fresh frozen plasma (FFP) is indicated for patients with significant coagulopathy (i.e., international normalized ratio [INR] greater than 1.5). Similarly, platelet transfusions are indicated for patients presenting with thrombocytopenia (i.e., platelet count less than 50,000/mm3).80

Reversal of Drug-Associated Bleeding Whenever possible, drugs implicated in causing or facilitating GI

bleeding should be discontinued. In some cases, the effects of these drugs should be reversed (Table 29.1). The original indication for the drug in question, however, must be considered, and the risks and benefits of discontinuation/reversal must be considered. In some cases, consultation with a specialist may be warranted to fully assess the risks versus the benefits (i.e., reversal of a low-molecular-weight heparin [LMWH] for treatment of pulmonary embolism). Antiinflammatory drugs such as NSAIDs and aspirin should be held to prevent further irritation to exposed ulcers and/or blood vessels. If safe to do so, vitamin K antagonists (i.e., warfarin) should be reversed with FFP rather than vitamin K because the onset of activity with vitamin K can be delayed as long as 6–24 hours.81 Prothrombin complex concentrates (PCCs) are also an alternative to FFP and may be considered together with vitamin K as an alternative to FFP. Fourfactor PCCs such as Octaplex or Kcentra contain clotting factors II, VII, IX, and X and are prepared from human plasma. Although vitamin K administered intravenously is rarely associated with anaphylactic reactions, the onset of activity is faster than with other routes of administration and is more desirable in acute or major bleeding.

Table 29.1 Antidotes and Reversal Strategies for DrugAssociated Bleeding Drug Associated with Bleeding

Antidote or Reversal Strategy

Comments

NSAID

Discontinue (or hold) NSAID therapy

Aspirin, clopidogrel, other antiplatelet agents

Platelet transfusion ± DDAVP (0.3 mcg/kg IV over 30 min)

Minimal evidence supporting this practice. Risks and benefits of reversal must be considered

Warfarin

FFP (15–30 mL/kg IV) OR PCCa (i.e., Octaplex: four-factor PCC

If only three-factor PCC is available (containing

containing factors II, VII, IX, and X) AND vitamin K (5–10 mg IV over 20–60 min) Heparin and LMWH (i.e., enoxaparin, dalteparin, tinzaparin)

Heparin infusion: Protamine IV dose is based on the amount of heparin received in the past 2– 2½ hr 1–1.5 mg per 100 units of heparin (< 30 min since heparin)

factors II, IX, X), it should be supplemented with FFP and vitamin K 1 unit of protamine neutralizes ~100 units of heparin. Maximal dose is 50 mg. The effect of LMWH is only 60%–75% reversed with protamine

0.5–0.75 mg per 100 units of heparin (30–120 min since heparin) 0.25–0.375 mg per 100 units of heparin (more than 2 hr since heparin) Enoxaparin: 1 mg of protamine for every 1 mg of enoxaparin Dalteparin and tinzaparin: 1 mg of protamine for every 100 anti-Xa units Direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)

Four-factor PCCa (i.e., Octaplex; 50 units/kg) or activated PCC (i.e., FEIBA; 25–100 units/kg IV). If only three-factor PCC is available, it should be supplemented with FFP

Optimal dose has not been established. Recommended dosing is based on case reports

Direct thrombin inhibitors (i.e., dabigatran)

Activated PCC (i.e., FEIBA; 25–100 units/kg IV)

Optimal dose has not been established. Recommended dosing is based on case reports

aOctaplex

dosing is based on the INR (INR < 4: 25 units/kg to a maximum of 2,500 units; INR = 4–6: 35 units/kg to a maximum of 3,500 units; INR > 6: 50 units/kg to max of 5,000 units). DDAVP = desmopressin; FFP = fresh frozen plasma; IV = intravenous(ly); LMWH = lowmolecular-weight heparin; NSAID = nonsteroidal anti-inflammatory drug; PCC = prothrombin complex concentrate.

Anticoagulation with heparin or LMWH can be reversed with protamine sulfate, which binds to and inactivates heparin molecules that are subsequently cleared by the reticular endothelial system. Anaphylactic reactions, hypotension, and bronchospasm can occur because of histamine release, but these adverse effects are rare and typically transient. Furthermore, in the absence of heparin or at excessive doses, protamine has weak antiplatelet and anticoagulant activity. The clinical importance of these effects in patients who are bleeding is not well established, but they are easily avoided using the maximum dose of 50 mg.82 The time elapsed since the last exposure to heparin should also be considered because less protamine is required if some of the heparin has already been eliminated. Reversal of anticoagulation from unfractionated heparin is more predictable than from LMWH because protamine sulfate only partly reverses the effects of LMWH. Some studies suggest that protamine sulfate reverses only 60% of the antifactor Xa (anti-Xa) activity of LMWH.83 Reversal of anticoagulation from new oral anticoagulants (i.e., dabigatran, rivaroxaban, and apixaban) is a greater challenge as we wait for antidotes that are currently being developed and evaluated in clinical trials. Rivaroxaban and apixaban are inhibitors of factor Xa, and dabigatran is a direct thrombin inhibitor. Dabigatran has the longest half-life at 14–17 hours, whereas the half-lives of rivaroxaban and apixaban are 7–11 hours and 8–14 hours, respectively. Idarucizumab, a monoclonal antibody with a greater affinity for dabigatran than thrombin, may be the first antidote approved for use. Initial evidence suggests that idarucizumab rapidly and completely reverses the effects of dabigatran.84 Andexanet, a recombinant, modified factor Xa molecule, is currently being evaluated for the reversal of anticoagulation from factor Xa inhibitors such as rivaroxaban and apixaban.85 Phase III trials are currently under way. Although these agents represent promising options for patients who are bleeding, rapid reversal strategies are still required until these agents become available. Several prohemostatic agents or coagulation factor concentrates have been suggested, but human evidence is limited for the efficacy of these treatments. The PCCs (e.g., Octaplex and

Kcentra) and the activated PCCs (e.g., FEIBA) can be tried to reverse the effects, with the choice of agent dependent on availability.86 The PCCs appear to be less effective than the activated PCCs in reversing anticoagulation with dabigatran compared with rivaroxaban in healthy volunteers and ex vivo studies.87,88 Evidence for activated factor VIIa is less compelling. Human evidence is limited to describe the efficacy and safety of these products in this setting. Platelet transfusions are commonly administered in the setting of GI bleeding if patients are on antiplatelet agents, but this practice is not evidence based. The role of platelet transfusion is not well defined, but platelets may be indicated in patients on antiplatelet therapy (i.e., aspirin or clopidogrel). The risks of reversal must be considered according to the original indication of the drug (i.e., prevention of acute coronary syndrome or maintenance of stent patency).89 Desmopressin has also been used in this setting because its presumed mechanism of action is the release of von Willebrand factor from endothelial cells, which in turn can stabilize platelets and promote binding to the endothelium. Bleeding times are shortened with desmopressin in healthy volunteers taking aspirin or ticlopidine, but evidence in patients who are bleeding is limited.90,91

Hemostatic Medications Early initiation of acid-suppressive therapy in upper GI bleeding serves two purposes: (1) neutralization of gastric acid can improve the stabilization of blood clots and (2) continued therapy reduces rebleeding rates, hospital lengths of stay, and the need for blood transfusions, particularly in peptic ulcer disease treated endoscopically (Table 29.2).92,93 The role of acid-suppressive therapy before endoscopy in un-differentiated bleeding is a source of controversy because of conflicting findings in clinical trials. A meta-analysis of six randomized controlled trials suggests that although there is no evidence that PPI therapy before endoscopy affects outcomes like mortality, rebleeding, or need for surgery, it reduces the stigmata of recent hemorrhage and subsequently the need for endoscopic therapy during

the index endos-copy.94 Proton pump inhibitors are preferred to H2RAs and traditionally have been initiated as high-dose continuous infusions. Recent evidence suggests that high-dose continuous infusions are associated with no better outcomes than intermittent dosing strategies (i.e., intravenous pantoprazole or esomeprazole 40 mg twice daily).95 However, some still advocate for high-dose therapy in patients with high-risk stigmata (i.e., Rockall scores greater than 6).96 There is no evidence for the use of acid-suppressive therapy in the acute management of lower GI bleeding. Tranexamic acid is an antifibrinolytic agent often used in surgical settings as a hemostatic drug. A recent systematic review suggests that, in the absence of acid-suppressive therapy and endoscopic treatment, a mortality benefit is associated with tranexamic acid. This effect did not occur, however, when only studies with patients who received conventional therapy were retained.97 Given that acidsuppressive therapy plus endoscopic intervention (when indicated) is the standard of care, tranexamic acid currently has no role in the treatment of upper GI bleeding. Prokinetic agents such as erythromycin and metoclopramide have also been studied in upper GI bleeding. Pro-kinetic therapy before endoscopy improves gastric emptying of blood, clots, and food to improve visualization at the time of endoscopy. Results from a metaanalysis of small trials suggest that both erythromycin and metoclopramide reduce the need for repeat endoscopy but that they affect other clinical outcomes.98 There are more trials with erythromycin than with metoclopramide. Meta-analyses of erythromycin studies consistently show a reduced need for second endoscopy, but these meta-analyses also show inconsistent effects on other meaningful clinical outcomes compared with placebo.99,100 Despite these limitations, erythromycin may be considered before endoscopy in patients with upper GI bleeding. Vasopressin, somatostatin, and their synthetic analogs (terlipressin and octreotide, respectively) are vasoactive medications that reduce splanchnic blood flow. They are used to achieve hemostasis in variceal hemorrhage. Theoretically, the same mechanism would be beneficial in

other sources of GI bleeding, but evidence is limited to support their use at this time. However, small, low-quality studies suggest a possible benefit of octreotide in reducing rebleeding rates from lower GI bleeding caused by angiodysplasia. Similar evidence suggests that octreotide leads to a reduction in bleeding time with endoscopically treated peptic ulcers but not for other causes of nonvariceal hemorrhage.101-103

Role of Endoscopy/Colonoscopy and Other Invasive Interventions Early endoscopy (within 24 hours) is advocated for most patients to identify the source of bleeding, to assist in the triage of further interventions and patient management, and for use therapeutically to achieve hemostasis. For diagnosis, endoscopy is the definitive test. Endoscopic findings are typically described using the Forrest classification (class Ia: spurting hemorrhage; class Ib: oozing hemorrhage; class IIa: nonbleeding visible vessel; class IIb: adherent clot; class IIc: flat pigmented spot; class III: clean ulcer base).104 The lesion’s appearance can help determine both the patient’s risk of rebleeding and the need for specific interventions. Although early endoscopy is recommended for most patients with hematemesis, its impact on the outcome is controversial. Studies describing its effect on resource use and patient outcome are conflicting.105-108 Endoscopic treatments aimed at controlling bleeding may include injection of epinephrine, thermal coagulation, use of hemostatic clips or fibrin sealants, argon plasma coagulation, or a combination of these therapies.109 Standard approaches to therapy usually involve a combination of treatments, depending on the location of the lesion and the endoscopist’s preference. Colonoscopy is the definitive test for lower GI bleeding once upper GI bleeding has been ruled out. Colonoscopy is used to visualize and assess the source and severity of bleeding, obtain samples for pathology, and provide therapeutic intervention. Urgent colonoscopy often is done without mechanical bowel preparation, which limits the

ability to visualize the source of bleeding. If a patient is hemodynamically stable after resuscitation, colonoscopy is often delayed to allow time for adequate bowel preparation (i.e., enteral administration of 4 L of polyethylene glycol).110 Similar to early endoscopy for upper GI bleeding, early colonoscopy has been associated with better triage of patients, improved resource use, and a reduction in the risk of rebleeding. However, these findings have not been consistent in clinical trials.111-113 Other diagnostic tests such as radionuclide imaging and angiography can also be used to identify sources of bleeding. These noninvasive or minimally invasive tests require active bleeding at the time of the study to detect the source. These strategies are typically reserved for patients in whom colonoscopy is either not feasible because of severe bleeding or nondiagnostic with persistent or intermittent bleeding.114 In the past, surgery was the mainstay of treatment for both upper and lower GI bleeding. However, early endoscopic intervention has significantly reduced the need for more invasive operations. Now, surgery is usually reserved for failed endoscopic therapies with persistent bleeding, hemodynamic instability caused by persistent or recurrent bleeding despite aggressive resuscitation, or visceral perforation. Interventional angiography with transarterial embolization is another option recommended ahead of surgery for persistent or recurrent bleeding despite endoscopy/colonoscopy.

Table 29.2 Drug Therapy for Hemostasis and Prevention of Rebleeding Indication

Drug Therapy

High-dose IV PPI therapy: Pantoprazole 80 mg IV bolus, followed by 8 mg/hr for 72 hr or Esomeprazole 80 mg IV bolus, followed by 8 mg/hr for 72 hr

Comment

Intermittent dosing is noninferior to high-dose therapy, although some still advocate the highdose regimens for patients presenting with high-risk stigmata

Intermittent-dose IV PPI therapy: Pantoprazole 40 mg IV BID Hemostasis

Esomeprazole 40 mg IV BID Tranexamic acid 10 mg/kg IV QID or 1 g IV QID

Prevention of rebleeding

Tranexamic acid most likely to be of benefit if endoscopy not available or delayed. Many different dosing regimens have been studied for a variety of indications. Others in addition to the recommendation here may also be appropriate

Erythromycin 3 mg/kg IV over 20–30 min given 30–90 min before endoscopy

Erythromycin can enhance gastric emptying to facilitate endoscopy and may reduce the need for repeat endoscopy

Octreotide 50–100 mcg IV bolus, followed by 25 mcg/hr for up to 3 days or until resolution of bleeding

According to small, low-quality studies, octreotide may reduce the risk of rebleeding in angiodysplasia-related GI bleeding. Similar small studies suggest a reduction in the duration of bleeding of endoscopically treated peptic ulcers

Oral PPI Therapy:

Some evidence suggests that once-daily dosing is appropriate for patients at low risk of rebleeding (i.e., Rockall score < 6)

Pantoprazole 40 mg BID Esomeprazole 40 mg QD Lansoprazole 30 mg BID Rabeprazole 20 mg BID Omeprazole 20 mg BID Dexlansoprazole 30 mg BID

BID = twice daily; PPI = proton pump inhibitor; QD = once daily; QID = four times daily.

PREVENTION OF REBLEEDING Risk factors associated with upper GI rebleeding include the presence

of hemodynamic instability, hemoglobin nadirs of less than 10 g/L, active bleeding at the time of endoscopy, larger ulcer sizes, and ulcers in the posterior duodenal bulb or high lesser gastric curvature.115

Risk Stratification Risk assessment using endoscopic, clinical, and laboratory findings can be useful in predicting the risk of rebleeding in patients presenting with acute upper GI bleeding. The two most commonly used scoring tools are the Rockall and Blatchford scores. The Rockall score incorporates risk factors such as age, presence of shock, comorbidities, and endoscopic findings (Table 29.3). A score of 2 or less is associated with a low risk of further bleeding or death.116 The advantages of the Blatchford score are that it does not require endoscopic findings and that it can be used earlier (Table 29.4). This score incorporates laboratory findings, vital signs, comorbidities, melena, and syncope. Scores range from 0 to 23, where a score of zero means that a patient has a low likelihood of requiring urgent endoscopy.117

Acid-Suppressive Therapies A twice-daily intravenous PPI is part of the initial treatment of all patients presenting with upper GI bleeding. This therapy should be continued post-endoscopic treatment. In patients at high risk of rebleeding (i.e., Rockall score 6 or greater), the intravenous PPI may be changed to a twice-daily oral formulation 72 hours postendoscopy.96 Patients at a lower risk of rebleeding may continue acidsuppressive therapy with only once-daily dosing of a PPI.118 Histamine2 receptor blockers have also been studied in this setting, but they are inferior to PPIs.119

Role of H. pylori Screening and Treatment in Peptic Ulcer Disease Antimicrobial treatment of H. pylori–infected individuals with upper GI

bleeding is associated with a significant reduction in ulcer relapse. Relapse rates in untreated infected individuals with duodenal ulcers are 65%–95%, whereas successful eradication with antibiotics reduces the risk of relapse to less than 10%.120 A meta-analysis comparing H. pylori eradication with antisecretory therapy alone suggests that five patients need to be treated to prevent recurrent bleeding episodes.121 All patients presenting with upper GI bleeding should be tested for H. pylori. The American College of Gastroenterology recommends antral biopsy for urease testing as the test of choice in patients undergoing endoscopy.118,122 Other options include histology and culture. The advantage of bacterial culture is that, if isolated, antimicrobial sensitivities can be measured. The challenges are that it is not routinely available and that it is technically difficult. Patients who do not undergo endoscopy should be tested by noninvasive means such as breath testing or fecal antigen testing.118,122 Urea breath testing is an attractive noninvasive option in which patients are given a labeled carbon isotope by mouth; as the H. pylori lyse urea to produce carbon dioxide (CO2) and ammonia, the tagged CO2 can be detected in breath samples. Regardless of the test used, the positive predictive value is high (0.85–0.99), but the negative predictive value is low (0.45–0.75), particularly in the setting of acute upper GI bleeding.118 High false-negative results occur in the context of acute bleeding, PPI use, and preexisting antimicrobial therapy. Guideline recommendations suggest that negative H. pylori diagnostic tests in the acute setting should be repeated.118 The association between H. pylori and duodenal ulcers has traditionally been stronger than that between H. pylori and gastric ulcers, with original reports describing the prevalence of H. pylori infection with duodenal ulcers at 80%–95%. With such a high prevalence, empiric treatment of H. pylori with duodenal ulcers was common without diagnostic testing. Recent reports in the United States and parts of Europe suggest that this association is becoming less common (i.e., 50%–75%).123 Given this observation, it is prudent to confirm the diagnosis before treatment rather than treat empirically.124

Table 29.3 Rockall Score for Stratifying Risk

Scores of 3 or more are associated with mortality.

Many treatment regimens have been investigated for eradicating H. pylori. All of them involve a combination of antimicrobials with an antisecretory agent. Recommended therapies are provided in Table 29.5.122 Clarithromycin-based triple therapy and bismuth-based quadruple therapy have eradication rates of 70%–80%.122 The therapy durations recommended in the United States are usually longer (10–14 days) than those in other parts of the world (7–10 days). Data from meta-analyses suggest that eradication rates are higher with longer durations of therapy.125 This may be because antimicrobial resistance, particularly with clarithromycin and metronidazole, is increasing and is associated with treatment failure.126,127 Thus, it seems prudent to recommend longer durations of therapy. Treatment durations of less than 7 days are clearly inferior and are not recommended. Confirmation of eradication 4 weeks after treatment is strongly recommended, given the emergence of resistance and the availability of inexpensive, noninvasive testing (stool and breath testing).122

Table 29.4 Blatchford Score for Stratifying Riska Risk Factor Systolic blood pressure (mm Hg)

Parameter

Score

100–109

1

90–99

2

< 90

3

> 100

1

Melena

Present

1

Syncope

Present

2

Hepatic disease

2

Heart failure

2

6.5–8.0

2

8.0–10.0

3

10.0–25.0

4

> 25

6

12.0–12.9

1

10.0–11.9

3

< 10.0

6

10.0–11.9

1

< 10

6

Heart rate (beats/min)

Comorbidity

Blood urea nitrogen (mmol/L)

Hemoglobin (g/L) for men

Hemoglobin (g/L) for women

aA score

of 0 means the patient has a low likelihood of needing urgent endoscopy.

REINTRODUCTION OF ANTICOAGULATION, ANTIPLATELET THERAPY, AND NSAIDS Patients presenting with drug-associated GI bleeding may be ineligible for permanent discontinuation of the offending drug. Patients taking NSAIDs for mild pain syndromes may be able to address their pain with non-NSAID alternatives (e.g., acetaminophen and other nonnarcotic analgesics), but patients on antiplatelet or anticoagulant

therapy for cardiovascular or stroke prophylaxis will likely need to reinitiate therapy at some point after the bleeding episode resolves.

Table 29.5 Recommended H. pylori Treatment Regimens Regimen

Any PPIa BID AND

Duration Eradication (days) Rates (%) 10–14

70–85

10–14

70–85

10–14

75–90

10

> 90

Clarithromycin 500 mg BID AND Amoxicillin 1000 mg BID Any PPI BID AND Clarithromycin 500 mg BID AND Metronidazole 500 mg BID Bismuth subsalicylate 525 mg QID AND Tetracycline 500 mg QID AND Metronidazole 250 mg QID AND Ranitidine 150 mg BID OR any PPI QD-BID bAny PPI BID

AND amoxicillin 1000 mg BID for 5 days, followed by any PPI BID AND clarithromycin 500 mg BID AND tinidazole 500 mg BID for another 5 days

aPPI therapy

may include pantoprazole 40 mg BID, lansoprazole 30 mg BID, omeprazole 20 mg BID, rabeprazole 20 mg BID, or esomeprazole 40 mg QD (note: esomeprazole is a delayed-release formulation and is dosed QD). bThe

efficacy of sequential therapy has not been shown in North America. PPI = proton pump inhibitor. Adapted from: Chey WD, Wong BC; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the

management of Helicobacter pylori infection. Am J Gastroenterol 2007;102:1808-25.

In NSAID-induced bleeding where anti-inflammatory therapy needs to be reintroduced, options may include reinitiating the NSAID in combination with a PPI or changing the NSAID to a COX-2 inhibitor either alone or in combination with a PPI. Other combination therapies including misoprostol, sucralfate, and H2RAs have been studied, but they are either poorly tolerated or inferior to PPIs.128,129 Adding a PPI to an NSAID reduces the risk of recurrent bleeding, as does changing from an NSAID to a COX-2 inhibitor. The combination of a COX-2 inhibitor and a PPI is associated with the greatest risk reduction.118 Even in lower GI bleeding, discontinuing NSAID therapy has been associated with reduced re-bleeding rates.42 Discontinuation or prolonged delays in reinitiating low-dose aspirin after a GI bleeding event are associated with significant cardiovascular morbidity. Discontinuation of prophylactic aspirin is associated with a 3fold increase in major cardiac events, most of which occur 7–10 days after discontinuation.130 It is recommended that aspirin therapy be reintroduced as soon as the perceived risks of bleeding no longer outweigh the cardiovascular risks of withholding prophylaxis.129 Analyses of randomized controlled data suggest that immediately reintroducing aspirin post-endoscopy is associated with negligible increases in rebleeding rates, whereas discontinuing aspirin is associated with an increased mortality at 8 weeks.118 In patients who present with dual antiplatelet therapy or with a thienopyridine (e.g., clopidogrel, ticlopidine, or prasugrel), the decision about when to reinitiate is more complicated. Clinical practice guidelines suggest that antiplatelet therapy should be reinitiated as soon as possible post-endoscopy, provided there is no longer a suggestion of ongoing bleeding (usually 3–7 days post-endoscopy). Consultation with a cardiology specialist before endoscopy is recommended to fully assess the risks of withholding antiplatelet therapy.128 The risk of GI bleeding with clopidogrel is greater than with aspirin plus a PPI, and dual antiplatelet therapy has a 2- to 3-fold

increase in the risk of GI bleeding compared with aspirin alone.118,131 Adding a PPI to clopidogrel is associated with up to a 50% reduction in the risk of major bleeding, but this may also increase the risk of adverse cardiovascular events. All PPIs inhibit the cytochrome P450 (CYP) 2C19 necessary to activate clopidogrel to its active form. Pharmacokinetic studies confirm this interaction, but clinical studies fail to consistently show a meaningful clinical impact. Given the inconclusive nature of these data, clinical practice guidelines recommend concomitant PPI use in all patients on antiplatelet therapy for secondary prophylaxis of GI bleeding.131 The concerns of PPI use and clopidogrel do not extend to prasugrel because this drug does not require activation by CYP2C19.132 Data regarding the optimal time and how to resume anticoagulation therapy are scant. Resumption of anticoagulant therapy with warfarin has been studied in patients with atrial fibrillation after a GI bleeding event. A retrospective cohort study of more than 1,300 patients with atrial fibrillation who were recovering from major GI bleeding found that reinitiating warfarin within 7–30 days after the GI bleed was associated with a reduced risk of thromboembolism and mortality compared with delaying reinitiation beyond 30 days.133

CONCLUSION Gastrointestinal bleeding is associated with significant morbidity and mortality, regardless of whether it occurs in the community or in the hospital. Although endoscopy is the cornerstone for diagnostic and therapeutic purposes, drug therapy continues to play an important role in reversal of anticoagulation, achievement of hemostasis, and prevention of rebleeding. This field is actively evolving, with ongoing trials evaluating hemostatic drugs like tranexamic acid and novel antidotes for newer anticoagulants as well as acid-suppressive therapy in the context of early endoscopy. Clinical pharmacists play an important role in assessing patients who are bleeding for providing antidotal therapies, selecting hemostatic agents, and promoting adherence to preventive drug therapy.

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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

LEARNING OBJECTIVES 1. Discuss the epidemiology of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH). 2. Differentiate the different pathophysiologic mechanisms of PAH. 3. Discuss how molecular, cellular, and genetic mechanisms may play a future role in treatment of the critically ill patient. 4. Summarize the diagnosis and classification of PAH. 5. Detail the differing diagnostic scenarios and noninvasive/invasive tools that may be deployed for diagnosing PAH. 6. Review the medications used to treat PAH. 7. Evaluate the treatment options for patients with PAH in the intensive care unit (ICU). 8. Discuss the role of combination therapy in the treatment of PAH and considerations for the critically ill patient. 9. Summarize the adjunctive therapies used in PAH treatment and the level of evidence behind them. 10. Compare the different treatment guidelines published for the practitioner, and assess the evidence-based recommendations that can be used for ICU patients. 11. Explain the management of acutely decompensated patients

with PH/PAH who develop right ventricular failure. 12. Discuss specific clinical pearls for treating patients in the ICU with PH/PAH as it relates to monitoring and adverse effect considerations.

ABBREVIATIONS IN THIS CHAPTER CCB

Calcium channel blocker

CrCl

Creatinine clearance

ETA

Endothelin type A

ETB

Endothelin type B

ICU

Intensive care unit

mPAP

Mean pulmonary artery pressure

NYHA

New York Heart Association

PAH

Pulmonary arterial hypertension

PDE-5

Phosphodiesterase type 5

PGI2

Prostaglandin I2/prostacyclin

PH

Pulmonary hypertension

PVR

Pulmonary vascular resistance

RHC

Right heart catheterization

RV

Right ventricle/ventricular

Study Names ARIES

Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-

Controlled, Multicenter, Efficacy BREATHE CHEST

Protocolised trial of invasive and noninvasive weaning off ventilation Crystalloid versus Hydroxyethyl Starch Trial

FREEDOM-C Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy PATENT

Pulmonary Arterial Hypertension sGCStimulator Trial

SERAPHIN

Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome

TRIUMPH

Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients’ Health Status

INTRODUCTION Pulmonary arterial hypertension (PAH) is a progressive disease caused by a narrowing of the blood vessels in the pulmonary vasculature. Pulmonary arterial hypertension is a rare subset of pulmonary hypertension (PH) that is differentiated from other types of PH as a primary process or in association with another condition.1 Pulmonary arterial hypertension is diagnosed by right heart catheterization (RHC) showing precapillary PH with a mean pulmonary artery pressure (mPAP) of 25 mm Hg or greater and a pulmonary capillary wedge pressure of less than 15 mm Hg.2 According to the patient’s clinical condition, PAH can be divided into various categories on the basis of severity of illness: stable and satisfactory, stable and not satisfactory, and unstable and deteriorating.2

Management of PAH in the intensive care unit (ICU) may consist of diagnostic evaluation for patients with suspected PAH, treatment modifications for patients with PAH on chronic therapies, or a combination of worsening signs and symptoms in patients with PAH complicated with infection/sepsis, medication nonadherence respiratory failure, pulmonary embolism, or arrhythmias. The primary focus of therapy in the ICU setting consists of maintaining or improving pulmonary pressures, optimizing right ventricular (RV) function and hemodynamics, providing enhanced awareness, continuing chronic therapies, and managing the underlying cause of ICU admission. Because of the complexity of PAH treatment and the difficulties with managing this disease in the ICU setting, it is important that clinicians be familiar with its pathophysiology and potential complications and the medications used for treatment. The critical care pharmacist plays a vital role as part of the interdisciplinary team, with an increasing number of patients being admitted to the ICU on chronic PAH treatments. With the recent approval of several pharmacologic modalities for treating PAH, the pharmacist can ascertain patient-specific adverse effects, guide prescribers on the complexity of the pharmacokinetics/pharmacodynamics for each agent, and be a stakeholder for patient education on the intravenous, inhalation, subcutaneous, and oral therapies. The purpose of this chapter is to clarify the classification of PAH versus that of PH, describe tools used for diagnosis and monitoring, and detail pharmaco-therapy options with a focus on treatment in the ICU.

EPIDEMIOLOGY Before the advent of new therapies for PAH treatment, the median survival for this disease entity was very poor. Older data from the Patient Registry for Primary Pulmonary Hypertension also indicated poor survival for patients with the diagnosis of primary PH, with a median survival of 2.8 years (95% confidence interval, 1.9–3.7 years).3 Newer PAH registries indicate better survival rates than previously, but

ultimately, not an overly improved prognosis, despite the newer agents and combination treatment options currently available. The most recent Registry to Evaluate Early- and Long-term Pulmonary Arterial Hypertension Disease Management in the United States (REVEAL registry) showed an improvement in survival after 1 year, an older patient population (mean age of 53 years), a higher proportion of women (1.7:1), and a higher proportion of blacks (4.3:1).4 Pulmonary hypertension is more prevalent than PAH because the most common cause of PH in the United States is left heart failure. Pulmonary arterial hypertension is a rarer entity, but if left untreated, it has a high mortality rate leading to RV failure and death.4 Overall, PAH tends to affect younger women more than males.6 Retrospective studies show that in-hospital mortality is higher in critically ill patients with PAH admitted to the ICU, ranging from 9% overall to 17% in patients with RV failure.7,8

PATHOPHYSIOLOGY The targeted proven therapies for treatment of PAH have centered on three major pathways: the prostacyclin pathway, the endothelial pathway, and the nitric oxide pathway (Figure 30.1). In the prostacyclin pathway, endothelial cells form arachidonic acid that produces endogenous prostacyclin (prostaglandin I2 or PGI2). Prostaglandin I2 has many effects, including antithrombotic, anti-inflammatory, and vasodilatory effects. Epoprostenol, the first prostacyclin analog developed for PAH therapy, is the gold standard for treatment to which other therapies are benchmarked.9 Another pathway contributing to PAH involves the endothelial pathway. Endothelin receptors are located on pulmonary artery smooth muscle cells and are divided into endothelin type A (ETA) and endothelin type B (ETB). Endothelin type A receptors have a higher affinity for endothelin-1, and activation leads to vasoconstriction and proliferation of vascular smooth muscle. Endothelin type B receptors can also produce these effects, but they indirectly produce vasodilation by PGI2 and nitric oxide release from endothelial cells. The

vasoconstrictive and smooth muscle effects of endothelin-1 negatively affect vessel tone and fibroblast activation. Endothelin-1 is the one subtype of naturally occurring peptides that might have the most significant impact on lung vascular remodeling.10,11 The nitric oxide and cyclic guanosine monophosphate (cGMP) pathways are intertwined and center on nitric oxide being produced from l-arginine. Cyclic GMP and soluble guanylate cyclase (sGC) have smooth muscle relaxing effects, thought to be a result of inhibiting phosphodiesterase type 5 (PDE-5) or activating sGC, which keeps smooth muscle relaxed and averts the vasoconstrictor and platelet activation seen in PAH. Nitric oxide may independently have a positive effect on relaxation of smooth muscle.12 Nitric oxide and cGMP are key secondary targets for patient therapy. The dysfunction and pathways described previously combine to result in intimal hyperplasia, medial thickening, and advanced remodeling and fibrosis. This, together with inflammatory and progenitor cells, has been postulated to contribute to the remodeling process of pulmonary vasculature. This progressive increase in pulmonary vascular resistance (PVR) creates an increased RV afterload and right heart failure.9 The platelet dys-function and thrombotic mechanisms are also a hallmark when describing PAH. Many vasoconstrictive substances have been implicated as a cause: von Willebrand factor, plasminogen activator inhibitor type 1, thromboxane A2, platelet-derived growth factor, transforming growth factor β, and endothelial growth factor.9,13,14 Promising advances in the genetic, molecular, and cellular mechanisms of PAH have led to novel targets as potential drug therapies.

Figure 30.1 Established vasomotor pathways targeted by current and emerging therapies in pulmonary arterial hypertension.a aThe three major pathways (ET-1, nitric oxide, and prostacyclin) involved in the regulation of pulmonary vasomotor tone are shown. These pathways represent the targets of all currently approved PAH therapies. Endothelial dysfunction results in decreased production of endogenous vasodilatory mediators (nitric oxide and prostacyclin) and the up-regulation of ET-1, which promotes vasoconstriction and smooth muscle cell proliferation. The ET-1 pathway can be blocked by either selective or nonselective ET-1 receptor antagonists; the nitric oxide pathway can be manipulated by direct administration of exogenous nitric oxide, inhibition of PDE-5, or stimulation of sGC; and the prostacyclin pathway can be enhanced by the administration of prostanoid analogs or non-prostanoid IP receptor agonists. ET = endothelin; ETA = endothelin type A; IP = prostaglandin I2; NO = nitric oxide; PDE −

5 = phosphodiesterase type 5; PGI2 = prostaglandin I2/prostacyclin; sGC = soluble guanylate cyclase. Adapted with permission from: Lippincott Williams & Wilkins/Wolters Kluwer Health: Humbert M, Lau EM, Montani D, et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 2014;130:2189-208.

Data analyses for the past 20 years link familial PAH in 80%–85% of families with a PAH family history to a gene coding bone morphogenetic protein receptor type 2 (BMPR2). The BMPR2 mutations have shown a high risk of PAH development, and the importance of this BMPR2 pathway to vascular remodeling is a focus of current research.9 Additional genetic components related to PAH include mutations to activating A receptor type II–like kinase 1 (ALK1), endoglin (ENG), and SMAD family member 9 (SMAD9) genes.15 Further research in this area may lead to the next generation of targets for PAH pharmacologic therapies.

Table 30.1 Updated Classification of Pulmonary Hypertension 1. Pulmonary arterial hypertension 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2 1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3 1.2.3 Unknown 1.3 Drug and toxin induced 1.4 Associated with: 1.4.1 Connective tissue disease 1.4.2 Human immunodeficiency virus (HIV) infection 1.4.3 Portal hypertension 1.4.4 Congenital heart diseases 1.4.5 Schistosomiasis 1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis

1’’. Persistent pulmonary hypertension of the newborn (PPHN) 2. Pulmonary hypertension due to left heart disease 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies 3. Pulmonary hypertension due to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4. Chronic thromboembolic pulmonary hypertension (CTEPH) 5. Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

Republished with permission from: Journal of the American College of Cardiology, from: Simmoneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62:D34-41. Permission conveyed through Copyright Clearance Center, Inc.

CLASSIFICATION Various iterations in the classification of PH have evolved from 1998 to 2015, with the most recent consensus being reached at the 5th World Symposium in Nice, France.16 This symposium established a

categorical clinical classification of PH according to similar hemodynamic characteristics and similar pathological findings in order to standardize management.16 This resulted in five groups of PH disorders (Table 30.1): group 1 (PAH), group 2 (PH caused by left heart disease), group 3 (PH caused by chronic lung disease, hypoxia, or both), group 4 (chronic thromboembolic PH), and group 5 (PH caused by unclear multifactorial mechanisms).17 Apart from the PH group classifications, patients can be categorized into four World Health Organization (WHO) functional classes according to their functional status and symptoms, adapted from the New York Heart Association (NYHA) classification system (Table 30.2). The advantage for a standardized PH classification schematic is that clinicians and researchers can use similar terminology when making diagnoses and treating patients. In addition, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency can do the same for new product labeling.17 Pharmacists can play an important role in determining the classification of PH by obtaining a thorough medication history (including herbal supplements and over-the-counter products). Identifying definite, likely, or possible risk factors from patients with PAH who have been on medications or other toxins is key to the class 1 diagnosis. Agents linked with a definite cause of PAH include aminorex, fenfluramine, dexfenfluramine, toxic rapeseed oil, benfluorex, and SSRIs (selective serotonin reuptake inhibitors) taken during pregnancy after 20 weeks’ gestation. Agents identified as likely contributing to PAH include amphetamines, l-tryptophan, methamphetamines, and dasatinib. Agents possibly linked to PAH include cocaine, phenylpropanolamine, St. John’s wort, various chemotherapeutic agents, interferon α and β, and amphetamine-like drugs.18

Table 30.2 World Health Organization (WHO) Functional Classification for Patients with Pulmonary Arterial Hypertension

Class

Description

I

Patients with pulmonary hypertension but without resulting limitation of physical activity; ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope

II

Patients with pulmonary hypertension resulting in slight limitation of physical activity; they are comfortable at rest; ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope

III

Patients with pulmonary hypertension resulting in marked limitation of physical activity; they are comfortable at rest; less-than-ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope

IV

Patients with pulmonary hypertension with an inability to carry out any physical activity without symptoms; these patients manifest signs of right heart failure; dyspnea and/or fatigue can even be present at rest; discomfort is increased by any physical activity

Republished with permission from: American Journal of Cardiology, from: Waxman AB, Zamanian RT. Pulmonary arterial hypertension: new insights into the optimal role of current and emerging prostacyclin therapies. Am J Cardiol 2013;111(suppl):1A-16A; permission conveyed through Copyright Clearance Center, Inc.

DIAGNOSIS Medical History Obtaining a personalized medical history from either the patient or the family member is key to eliciting drug or toxin exposure, familial history of PAH, and disease states contributory to PAH, which could entail connective tissue disorders (e.g., scleroderma), HIV, portal hypertension, congenital heart disease, or schistosomiasis.5

Physical Examination Patients in the ICU with PAH may present with signs and symptoms of RV failure, the most common of which are lower extremity edema, dyspnea on exertion, and angina. Patients who are syncopal have a worsening prognosis because this may reflect a low cardiac output state. Clinicians monitor for various cardiac abnormalities such as an

accentuated second heart sound, a tricuspid regurgitation, or a systolic murmur. These symptoms, in whole or in part, occur at rest and may indicate a patient with advanced PAH.5

Blood Tests and Immunology Routine blood tests comprising basic metabolic profiles, hematology, and thyroid function tests should be obtained for patients admitted to the ICU. Workup of thrombotic abnormalities includes obtaining antiphospholipid antibodies, lupus anticoagulant, and anticardiolipin antibodies. If liver involvement is suspected, liver function tests and hepatitis serologies should be obtained, together with HIV testing.2 There is some debate regarding the role of obtaining circulating biomarkers such as brain natriuretic peptide (BNP) concentrations or troponins and what they mean prognostically.2 It has been suggested that with various therapy goals in mind, achieving the lowest possible or personal best BNP or N-terminal pro–B-type natriuretic peptide (NTproBNP) is appropriate.19

Chest Radiographs Chest radiographs are a routine part of the workup for PAH. In most patients presenting with idiopathic PAH, the chest radiograph is abnormal. “Pruning” or loss of the peripheral blood vessels is described. Right ventricular hypertrophy or dilation cannot easily be distinguished on a chest radiograph.5

Electrocardiogram Electrocardiogram (ECG), also part of the diagnostic algorithm for PAH, is used to assess RV hypertrophy and strain, as well as right atrial dilation. The ECG has a sensitivity of 55% and a specificity of 70% as a screening tool for patients with PH. Atrial arrhythmias (e.g., atrial fibrillation or flutter) are common in patients with a diagnosis of advanced PAH.5

Echocardiography The significance of echocardiography is that it can provide the clinician with a rough estimate of right heart size (including the RV and atrium), RV function, and possible PAH. Various equations can measure pulmonary artery systolic pressures. Although not always accurate, pulmonary artery systolic pressure can be elevated in disease states such as cirrhosis, hyperthyroidism, heart failure, kidney disease, and increased blood pressure.20 Transthoracic echocardiography serves as the most important noninvasive tool to assess PH in both ICU and nonICU settings.21

Pulmonary Function Tests Making the diagnosis of PAH in critically ill patients with the aid of pulmonary function tests is often not a practical option, but if feasible, it may help identify interstitial lung disease or chronic obstructive pulmonary disease. The diffusing capacity for carbon monoxide is about 60%–80% of predicted in patients with idiopathic PAH.5 The degree of hypoxemia in patients with PAH centers on ventilationperfusion mismatch, with decreased mixed venous oxygen saturation (Svo2) values stemming from low output cardiac states.

Exercise Testing The 6-minute walk test is a common end point marker in efficacy trials for PAH therapies.5 The 6-minute walk test is a practical simple test that requires a 100-ft hallway but no exercise equipment or advanced training for technicians.22 This test has been correlated with workload, heart rate, oxygen saturation, and dyspnea response. Cardiopulmonary testing (with an upright bicycle or treadmill) is used to grade PH severity in the outpatient setting. Treadmill testing is also an option in the ambulatory workup of PH, but it may not be an appropriate testing determination of PH in the hospital inpatient setting.21 These tests are not only used for diagnosis but also to assess disease progression.

Cardiac Catherization—RHC The gold standard for diagnosing and classifying severity of PAH is an RHC, with or without concomitant vasore-activity testing. Key parameters that are elicited through an RHC include right atrial pressure, pulmonary capillary wedge pressures, and RV pressure. A pulmonary capillary wedge pressure greater than 15 mm Hg excludes the diagnosis of PAH, whereas an mPAP of 25 mm Hg or greater at rest defines PAH. The gold standard for cardiac output measurement is the direct Fick method (which directly measures oxygen uptake); however, the indirect Fick method (which estimates oxygen values from tables) is not reliable. After RHC is performed and a diagnosis of PAH is made, vasoreactivity testing can be done to see whether patients are classified as either responders or nonresponders to determine whether they are candidates for calcium channel blocker (CCB) therapy.5

Vasoreactivity Challenge The three main agents for acute vasodilator challenges are intravenous epoprostenol, intravenous adenosine, and inhaled nitric oxide. A positive acute response is defined as a reduction in mPAP of 10 mm Hg or greater to an absolute value of mPAP of 40 mm Hg or less with an increased or unchanged cardiac output (class I, level of evidence C).2 Patients admitted to the ICU are often in a decompensated state of RV failure whereby pharmacologic treatments must be titrated to improve RV function and ameliorate adverse effects (e.g., dyspnea or exercise intolerance). Patients may also be admitted for the vasodilator challenge, which may elicit better symptomatic and prognostic information. Patients classified as being in an unstable and deteriorating state have worsening WHO functional class, a poor 6minute walk of less than 300 m, a peak VO2 of less than 12 mL/minute/kg, rising BNP/ NT-proBNP plasma concentrations, evidence of pericar-dial effusion, tricuspid annular planar systolic excursion less than 1.5 cm, right atrial pressure greater than 15 mm Hg, or a cardiac

index of 2.0 L/minute/m2 or less.23 The agents and doses used for pulmonary vasoreactivity testing are intravenous epoprostenol (2–12 ng/kg/minute for 10 minutes), intravenous adenosine (50–350 mcg/kg/ minute for 2 minutes), or inhaled nitric oxide (10–20 ppm for 5 minutes).5

TREATMENT Calcium Channel Blockers Calcium channel blockers decrease calcium influx into the smooth muscle cells of the arterial wall and the myocardial cells by inhibiting Ltype voltage-dependent sodium channels. This also represents a possible mechanism of PAH development.24 The concept of CCB responders versus non-responders is relevant when considering CCB as an agent to treat patients with PAH because about 5% of patients will benefit from CCB treatment long term. Two studies have shown that CCB may be useful in patients with PAH. Rich and colleagues studied CCB therapy in 47 patients with PAH. These authors found a 20% reduction in mPAP and PVR (with nifedipine and diltiazem in 72% of patients), with 15 patients (32%) defined as pressure responders (significant improvement in mPAP and PVR index). In another study by the same lead author, 17 of 64 patients (27%) had a 20% reduction in mPAP and PVR when treated with nifedipine 20 mg or diltiazem 60 mg, with a 94% survival at 5 years (compared with 55% in patients who did not respond to therapy.25,26 Advanced therapies with acute vasoactive agents such as adenosine, epoprostenol, and nitric oxide have replaced CCB as the preferred agents in clinical trials. This is primarily due to the significant adverse effects of the CCBs, which include negative inotropy (diltiazem and verapamil), hypotension (seen with all agents with escalating doses from CCB trials), edema, nausea, headache, and acute hospitalization. Overall, CCB efficacy is limited in patients with PAH, and these agents are contraindicated in most patients given the presence of decompensated right/left heart failure or bradycardia.27 Therefore,

CCBs have been relegated to possible last-line therapies, but they are a viable option for patients who may not respond to other therapies.

Implications for the Critical Care Practitioner Although not widely recommended, CCB agents may be used in the early stages of PAH because of their availability and ease of administration. Patients should be closely monitored for changes in blood pressure and heart rate as well as other potential adverse effects. Critical care monitoring flowsheets and medication administration records should be closely monitored to determine the accuracy and efficacy of dosing and the potential need for alterations in therapy.

Epoprostenol Analogues The mainstay of PAH therapy in the critically ill patient has traditionally been epoprostenol. Epoprostenol is a prostacyclin PGI2 analog with unique pharmacologic properties, including direct vasodilation of the pulmonary vasculature and platelet aggregation inhibition. Epoprostenol has shown symptomatic and hemodynamic improvements in patients with severe primary PH, survival benefits longer term in patients with NYHA function class III or IV, and mortality benefits in subsets of patients with PH caused by scleroderma.28,29 In a 12-week, prospective, randomized trial of 81 patients with severe primary PH (NYHA functional class III or IV), 41 patients treated with intravenous epoprostenol at a mean dose of approximately 9 ng/kg/minute showed exercise capacity improvements (6-minute walk test) and hemodynamic improvements (pulmonary artery pressures, PVR) compared with conventional therapies. The most noteworthy finding showed improved survival at 12 weeks in the epoprostenol group, with eight patients dying in the conventional group (p = 0.003) after adjustment of variables.28 Newer trials have shown similar results in both hemodynamic and survival improvement with epoprostenol. Epoprostenol is FDA labeled for the treatment of PAH in WHO group

1 patients to improve exercise capacity.30 The recommended starting dose is 2 ng/kg/minute intravenously, and the dose is slowly titrated in increments of 0.5–2 ng/kg/minute every 15 minutes to a maximum tolerated dose. The most common adverse effects are nausea, vomiting, jaw pain, headache, flushing, erythema, anxiety, musculoskeletal aches/pain, and photosensitivity.30 Epoprostenol can also be administered by the inhalational route; however, this has not been well studied in PAH. A typical dosing strategy is to administer 50– 85 mcg/kg/ minute by nebulizer and then taper to the maximum effect. Another strategy is to nebulize at a fixed concentration of 10–20 mcg/mL at a rate of 0.2–0.3 mL/minute.31

Implications for the Critical Care Practitioner Epoprostenol requires close monitoring because of the effects on decreasing blood pressure, heart rate, increased risk of bleeding, short half-life (4–5 minutes), and unstable nature (specifically the Flolan product).24 Administration of epoprostenol is through a central line with a 0.22-micron filter; however, a peripheral line may be used on a shortterm basis until central access can be established. There are infectious risks from pulmonary artery catheterization, as well as central and peripheral line infections, with the most common pathogens being Staphylococcus aureus and Micrococcus spp.32 The pharmacist should have a good understanding of the different infusion pumps (for home use), priming rates and volumes needed, typical dosage titrations required for acute therapy in the ICU, risks associated with interrupted PGI2 therapy, adverse effects and their potential treatments to optimize titration, compounding, distributing process for timely administration, diluents required for admixture (sterile diluent for Flolan and either 0.9% sodium chloride or sterile water for Veletri), and strategies for transitioning to alternative therapy such as treprostinil.30,33 There are critical elements about epoprostenol management that place the pharmacist at the forefront of care. These center on the use of correct and constant dosing weights, expertise of shelf lives of the various products used, and practical coordination of backup

cartridges/intravenous bags if the patient is in the ICU for greater than 24 hours. Patient dosing weights need to be based on original weights for the patient (and rates that patients have been titrated to in the outpatient setting) and may need to be verified by home infusion nurses/pharmacists or other providers. Errors can occur with nanogram per kilogram per minute conversions to microgram per kilogram per minute conversions by hospital-based pumps, so the patientpharmacist interaction and medication reconciliation on admission is paramount. Backup cartridges (if patients are stable to mix their own infusions) or infusion bags need to be stored appropriately and made available to the nursing units, which requires interdisciplinary collaboration. This change can be seen with the newer Veletri agent and the need for every 24- to 72-hour changes, instead of more frequent 8-hour switches with the older product. Finally, titration of the agent epoprostenol needs to be managed by experienced physicians because hemodynamic instability can occur if lines are primed, agents are abruptly discontinued, or the patient’s baseline condition worsens. Transitioning from intravenous epoprostenol to oral or subcutaneous dosage forms of other classes has been described in case reports in the literature with success, with recommendations not specific regarding whether these can be done in an acute critical care situation.33 Other transitions from subcutaneous to intravenous to inhalational have been described. Conversion from epoprostenol to treprostinil is accomplished by initiating treprostinil while simultaneously decreasing epoprostenol. The treprostinil package insert recommends a seven-step process (Table 30.3).34 Treprostinil Treprostinil is a tricyclic benzidine analog of epoprostenol that has a comparatively longer half-life (4–4.5 hours) and is more stable in solution than epoprostenol.34 Treprostinil is FDA labeled to improve exercise capacity in WHO group 1 patients with PAH. Treprostinil has several routes of administration, including intravenous, subcutaneous, inhalational, and oral.

The efficacy of this agent has been shown in several clinical trials. A double-blind, randomized trial of the subcutaneous infusion was compared with placebo in 470 patients with PAH.35 Treprostinil dosed at 1.25 ng/kg/ minute titrated to effect to a maximum of 22.5 ng/kg/ minute over 12 weeks resulted in improved 6-minute walk distance, Borg dyspnea score, pulmonary hemodynamics, and quality of life.36 The TRIUMPH-1 study was a randomized controlled trial of the addition of inhaled treprostinil or placebo to oral therapy with bosentan or sildenafil in 235 patients with NYHA class III or IV PAH.37 Treprostinil was initiated at a dose of three inhalations four times daily titrated to a maximum of nine inhalations four times daily. Patients in the treprostinil group had a mean increase of 19 m in the 6-minute walk distance and increased quality of life. Two randomized controlled trials (FREEDOM C and FREEDOM C2) investigated the oral dosage form of treprostinil to bosentan or sildenafil in patients with PAH.38,39 The FREEDOM C trial randomized 350 patients to 1 mg of oral treprostinil twice daily to a maximum of 16 mg twice daily or matching placebo. The FREEDOM C2 trial randomized 310 patients to 0.25 mg of oral treprostinil twice daily (mean dose 3.1 mg twice daily) or matching placebo. Neither trial showed a difference in the primary outcome of the 6-minute walk distance. A third trial of monotherapy with oral treprostinil at a starting dose of 0.25–1 mg twice daily to a maximum dose of 12 mg twice daily or placebo showed a difference in 6-minute walk distance and the combined end point of 6-minute walk distance and Borg dyspnea score.40

Table 30.3 Seven-Step Process for Conversion of Epoprostenol to Treprostinil Step

Flolan Dose

Remodulin Dose

1

Unchanged

Initiate at 10% of starting Flolan dose

2

Decrease Flolan to 80% of starting dose

Increase to 30% of starting Flolan dose

3

Decrease Flolan to 60% of

Increase to 50% of starting Flolan dose

starting dose 4

Decrease Flolan to 40% of starting dose

Increase to 70% of starting Flolan dose

5

Decrease Flolan to 20% of starting dose

Increase to 90% of starting Flolan dose

6

Decrease Flolan to 5% of starting dose

Increase to 110% of starting Flolan dose

7

Discontinue Flolan

Continue at 110% and increase in 5%–10% increments as needed

Adapted from: Treprostinil (Orenitram) [package insert]. Research Triangle Park, NC: United Therapeutics, 2014.

Dosing of treprostinil varies by the route of administration. The initial dosing of intravenous treprostinil (Remodulin) is typically 1.25 ng/kg/minute, but this should be reduced to 0.625 ng/kg/minute in severe hepatic insufficiency. The infusion rate should be increased in increments of 1.25 ng/kg/minute per week for the first 4 weeks of treatment and then 2.5 ng/kg/minute per week for the remaining duration of infusion to clinical response.34 In the ICU setting, the dosing titration may be more rapid, with a starting dose of 1–3 mg/kg/minute, gradually increased by 1–2 ng/kg/minute two or three times weekly. The dosing of the inhalational form (Tyvaso) is rarely initiated in the ICU because of the difficulties with the required inhalation system. In these cases, the patient should be transitioned to intravenous therapy. The inhalational form of treprostinil in the outpatient setting is typically initiated as three inhalations four times daily spaced at least 4 hours apart and is increased by three inhalations every 1–2 weeks to a maximum of nine inhalations four times daily.41 Oral treprostinil therapy may also be initiated in the outpatient setting. The dosing of Orenitram is 0.25 mg twice daily or 0.125 mg three times daily administered with food. The dose is increased in increments of 0.25 or 0.5 mg twice daily or 0.125 mg three times daily every 3–4 days to achieve optimal clinical response.42 Oral treprostinil should be avoided in severe hepatic insufficiency and used with caution

because tablets may lodge in diverticuli. The most common adverse effects with treprostinil are hypotension, jaw pain, chest pain, flushing, cough, headache, dizziness, throat irritation, nausea, and diarrhea. If administered in the ICU setting, the extended-release tablets cannot be split, crushed, or chewed.

Implications for the Critical Care Practitioner Diluents required for the intravenous treprostinil admixture include the sterile diluent, 0.9% sodium chloride, or sterile water. Subcutaneous administration may lead to infusion-site reactions, which occur with a prevalence of about 10%. This has prompted some patients to be transitioned to the intravenous or inhalation route. Strategies to reduce these reactions include avoiding sensitive areas, relocating to a new infusion site (abdomen, thighs, posterior upper arms, etc.), and using topical agents (ice, topical agents such as lidocaine, corticosteroids, antihistamines, or calcineurin inhibitors), and oral nonsteroidal agents, anti-histamines, or GABA [γ-aminobutyric acid] analogs.43 The conversion for patients being switched from intravenous treprostinil to intravenous epoprostenol is approximately 1.25:1, respectively.44 Dosing of the subcutaneous formulation requires retitration if the infusion is stopped for more than 4–6 hours, and the oral formulation requires re-titration if more than two consecutive doses are missed. The adverse effect profile of treprostinil is different from that of epoprostenol. With the treprostinil half-life being 4 hours versus 4–6 minutes with epoprostenol, this offers the theoretical advantage of not causing the major rapid pulmonary vasoconstriction and emergency situations that would be seen in sudden discontinuation. Iloprost Iloprost is another example of a prostacyclin analog that is administered as an inhalation, but it can also be given by the intravenous route (although not available in the United States). Iloprost is FDA labeled for the treatment of PAH (WHO group 1) to improve a composite end point consisting of exercise tolerance, symptoms (NYHA

class), and lack of deterioration. Data behind the efficacy of inhaled iloprost centers on the Aerosolized Iloprost Randomized Study (AIR) trial, which randomized patients to receive up to 30 mcg per day (2.5 or 5 mcg inhaled six to nine times per day) or placebo.45 Patients who received iloprost showed improvements in 6-minute walk distance, symptom improvement (NYHA class), decreased PVR, less dyspnea, and improved quality of life. Iloprost is initially dosed at 2.5 mcg administered as six to nine inhalations per day at least 2 hours apart by the I-neb AAD system.46 If the 2.5-mcg dose is well tolerated, the dose can be increased to 5 mcg. Patients with severe hepatic impairment (Child-Pugh class B or C) should have the dosing interval increased to 3–4 hours. Renal dosing adjustments are not required. The adverse effect profile of iloprost is similar to that of epoprostenol and treprostinil, with the most common adverse effects of hypotension, bronchospasm, cough, jaw pain, and headache.46 There are no significant drug interactions; however, concurrent use with antihypertensive agents, anticoagulants, and platelet inhibitors should be closely monitored.

Implications for the Critical Care Practitioner Doses should be reduced (and may need to be avoided) if the systolic blood pressure (SBP) is less than 85 mm Hg or if pulmonary edema develops. There are several limitations to administration of inhaled iloprost, including the feasibility of inhalations administered six to nine times per day, inability to mix with other medications, and inability to administer if a patient requires mechanical ventilation. Patients on mechanical ventilation may receive iloprost by ultrasonic nebulizer; however, this strategy has not been well studied. Therefore, patients admitted to the ICU may need conversion to other agents or discontinuation of therapy if unresponsive to self-inhalation techniques.

Endothelin Receptor Antagonists Endothelin-1 causes vasoconstriction and cell proliferation through

activation of the ETA and ETB receptors on smooth muscle cells.47 Endothelin type A mediates vasoconstriction, whereas ETB mediates vasodilation through release of nitric oxide.10 The mechanism of action for the endothelin receptor antagonists is selective ETA antagonism with minimal effect on ETB. Several clinical trials have shown the efficacy of the endothelin receptor antagonists. The BREATHE-1 trial was a double-blind, placebo-controlled, multicenter study of bosentan in 213 patients with PAH.48 Patients were randomized to one of three groups: bosentan 62.5 mg twice daily increased to 125 mg after 4 weeks of treatment (n = 74), bosentan 62.5 mg twice daily increased to 250 mg after 4 weeks of treatment (n = 70), or placebo (n = 69). The primary outcome of 6-minute walking distance was increased overall by 44 m in bosentan-treated patients (27 m in the bosentan 125-mg group and 46 m in the bosentan 250-mg group), which was a statistically significant difference compared with a decrease of 8 m in the placebo group. Patients treated with bosentan also showed improvements in secondary clinical end points monitored, including Borg dyspnea score, change in WHO functional class, and clinical worsening defined as the sum of death, hospitalization for PAH, discontinuation of therapy for PAH, and need for epoprostenol. The SERAPHIN trial was a phase III, multicenter, double-blind, randomized, placebo-controlled, event-driven study of macitentan in 742 patients with PAH.49 Patients were randomly assigned to one of three treatment groups: macitentan 3 mg daily, macitentan 10 mg daily, or placebo. The primary outcome of the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of PAH was seen in 31.4% of patients in the macitentan 10-mg group, 38% of patients in the macitentan 3-mg group, and 46.4% of patients in the placebo group. The ARIES-1 and ARIES-2 trials were concurrent, double-blind, placebo-controlled trials that randomized patients with PAH to placebo or ambrisentan 5 or 10 mg (ARIES-1) or placebo or ambrisentan 2.5 or

5 mg (ARIES-2).50 All ambrisentan groups showed an increase in the primary outcome of 6-minute walk test distance compared with placebo (ARIES-1: 31 m and 51 m for ambrisentan 5 mg and 10 mg, respectively; ARIES-2: 32 m and 59 m for ambrisentan 2.5 mg and 5 mg, respectively). All three of the currently available endothelin receptor antagonists are FDA labeled for the treatment of PAH in WHO group 1 patients to improve exercise ability and to decrease clinical worsening.51-53 Ambrisentan is initiated at a dose of 5 mg daily, which can be increased to 10 mg daily if tolerated. Bosentan is initiated at 62.5 mg twice daily, which can be increased to 125 mg twice daily. Macitentan is dosed at 10 mg daily (higher doses are not recommended). Renal adjustment is not needed for bosentan or macitentan; however, ambrisentan is not recommended for patients with a creatinine clearance (CrCl) less than 20 mL/minute/1.73 m2. All three agents should be avoided in moderate to severe hepatic impairment. The most common adverse effects with the endothelin receptor antagonists are anemia, nasal congestion, sinusitis, fluid retention, headache, bronchitis, and urinary tract infections. The major drug interactions vary between agents; however, all three agents have increases in serum concentrations when administered with strong cytochrome P450 (CYP) 3A4 (and CYP2C9 with bosentan) inhibitors and decreases in serum concentrations when administered with strong CYP3A4 inducers. All three agents are pregnancy category X and should be avoided in females who are or may become pregnant.

Implications for the Critical Care Practitioner The endothelin receptor antagonists are associated with an increase in peripheral and pulmonary edema, increased bleeding risks, and increases in liver function tests; patients should be closely monitored for signs and symptoms of these potentially serious effects. Decreases in hemoglobin concentrations of more than 0.8 mg/dL are considered significant and warrant further investigation to determine the causality. Medications in this class should not be crushed; however, bosentan

tablets can be split or dissolved in water. If oral or tube administration is not possible, conversion to an intravenous alternative (typically epoprostenol) may be required. With oral agents in this class, it is rare to initiate them in the ICU. Typically, the more critical treatment decision is when to discontinue or hold endothelin receptor antagonists when a patient presents with significant hypotension.31

PDE-5 Inhibitors Nitric oxide induces the formation of intracellular cGMP, which leads to relaxation of the pulmonary vascular smooth muscle and dilation of the pulmonary arterioles.54 The iso-enzyme that is primarily responsible for the breakdown of cGMP is PDE-5. Inhibitors of PDE-5 increase cGMP concentrations and allow for prolonged action of cGMP. Clinical studies with both sildenafil and tadalafil have shown the efficacy of the PDE-5 inhibitors in reducing clinical worsening, improving 6-minute walk test, and improving quality of life, but with no reduction in mortality.55-57 Sildenafil (Revatio) is FDA labeled for the treatment of PAH in WHO group 1 adults to improve exercise ability and delay clinical worsening.58 The oral dose is 5 or 20 mg three times daily, spaced at least 4–6 hours apart. The intravenous dose is 2.5 or 10 mg three times daily administered as a bolus. No dose adjustments are recommended for renal or hepatic impairment. The Viagra formulation of sildenafil is not FDA labeled for use in PAH, but several studies and case series have shown an improvement in pulmonary hemodynamics at doses of 25–100 mg per day.56,59 Tadalafil is FDA labeled for the treatment of PAH in WHO group 1 adults to improve exercise ability.60 The dose is 40 mg once daily, and doses should not be divided. For patients with mild to moderate renal impairment (CrCl 31–80 mL/minute/1.73 m2) or hepatic impairment, the dose should be decreased to 20 mg daily. Use of tadalafil should be avoided for severe renal impairment (CrCl less than 30 mL/minute/1.73 m2) or hepatic cirrhosis. The most common adverse effects associated with the PDE-5 inhibitors are epistaxis, headache, flushing, erythema, dyspepsia,

rhinitis, hypotension, priapism, and visual or hearing loss.58,60 Significant drug interactions include the CYP3A4 inhibitors, amlodipine, α-receptor blocking agents, and organic nitrates. For patients who may require nitrate administration for chest pain, it is recommended to avoid these agents for at least 24–48 hours after the last dose. Blood pressure should be closely monitored in these patients.

Implications for the Critical Care Practitioner Phosphodiesterase type 5 inhibitors may cause hypotension and a resultant increase in heart rate; patients should be closely monitored for signs and symptoms of these potentially serious effects. Sildenafil is available as an oral suspension; however, tablets of all PDE-5 inhibitors can be crushed for feeding tube administration. Others forms of sildenafil (e.g., Viagra) may be used for PAH if needed due to institutional formulary restrictions.

sGC Stimulator Riociguat is a novel agent for the treatment of PAH. The mechanism of action is through stimulation of sGC and increased binding to nitric oxide to sGC, leading to an increase in synthesis of cGMP by the nitric oxide–sGC– cGMP pathway.61 The beneficial effects of cGMP in PAH include vasodilation, inhibition of smooth cell proliferation, prevention of fibrosis, and antithrombotic and anti-inflammatory effects.61 Riociguat has shown efficacy in two major trials: PATENT-1 and CHEST-1. The PATENT-1 trial was a phase III randomized controlled study of 443 patients with PAH.62 Patients with symptomatic PAH who received riociguat 2.5 mg three times daily showed a 30-m increase their 6-minute walk test from baseline compared with a decrease of 6 m in the placebo group. The CHEST-1 trial was a phase III, multicenter, randomized, double-blind, placebo-controlled study of 261 patients with inoperable chronic thromboembolic PH.63 Patients who received riociguat 1 mg three times daily showed a 39-m increase their 6-minute walk test from baseline compared with a decrease of 6 m in

the placebo group. Riociguat is FDA labeled for the treatment of WHO group 1 PAH to improve exercise capacity, improve WHO functional class, and delay clinical worsening.64 It is also FDA labeled for persistent or recurrent chronic thromboembolic PH (WHO group 4) after surgical treatment or inoperable chronic thromboembolic PH to improve exercise capacity and WHO functional class.64 The starting dose is 1 mg three times daily, but this may be reduced to 0.5 mg three times a day for patients with low blood pressure at initiation, or those who develop low blood pressure after initiation. Doses are titrated in increments of 0.5 mg to a maximum of 2.5 mg three times daily. No dosage adjustments are required for renal or hepatic insufficiency, but use is not recommended for a CrCl less than 15 mL/ minute/1.73 m2, hemodialysis, or severe hepatic impairment (Child-Pugh class C). Riociguat is contraindicated in pregnancy (pregnancy category X). The most common adverse effects of riociguat are headache, dyspepsia/gastritis, dizziness, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation.64 Significant drug interactions include azole antifungals, protease inhibitors, nitrates, and PDE-5 inhibitors, all of which may lead to increased hypotensive effects requiring riociguat dose reductions.

Implications for the Critical Care Practitioner Riociguat may increase the risk of bleeding, hypotension, and pulmonary edema; patients should be closely monitored for signs and symptoms of these potentially serious effects. There are few data regarding the ability to split or crush the tablet, but the manufacturer recommends to avoid this because of teratogenic concerns. If doses are held for more than 3 consecutive days, patients will require retitration to their chronic dosage schedule. For patients with a current history of smoking, higher doses may be required in the ICU setting because of an increase in serum concentrations secondary to abrupt discontinuation of smoking (50%–60% serum concentration reduction in smokers).64

Supportive Therapies In addition to the vasodilators, there are several adjunctive therapies that may be beneficial in PAH therapy and are recommended in the most recent guidelines.2 As discussed previously, patients with PAH are at an increased risk of thromboembolism and may benefit from anticoagulation. Use of anticoagulants in this setting is somewhat controversial; however, warfarin is recommended, titrated to an INR (international normalized ratio) of 1.5–2.5 if no bleeding contraindications exist.2 Diuretics are recommended in patients with PAH with signs of RV failure and fluid retention; however, no specific recommendations are made regarding choice of agents.2 Digoxin may improve cardiac index (short-term effect), but it is most commonly used for patients with PAH who develop atrial tachycardia in order to slow the ventricular rate. These strategies may be used in the ICU setting unless contraindicated due to the underlying critical illness.

Treatment of the Critically Ill Patient with PAH Pulmonary arterial hypertension in itself can cause the acute RV decompensation. This is of particularly concern when patients are admitted to the ICU on several pharmacologic therapies. The RV adapts poorly to sudden increases in afterload, and this can result in decreased contractility and hemodynamic collapse.65 Right ventricular dysfunction can result from excess RV afterload, inadequate RV preload, decreased RV contractility, or altered systemic vasodilation.31 In the ICU setting, additional triggers such as sepsis, trauma, anemia, pulmonary embolism, medication nonadherence, interruption of chronic therapy, and arrhythmias can quickly overwhelm the effectiveness of any RV compensatory mechanisms.65 Overall treatment goals are to manage fluids judiciously, reduce venous filling pressures, and normalize cardiac output (Figure 30.2).66 Fluid management should consist of maintaining net negative fluid balance in patients with RV failure and PAH. This may require the use of diuretic therapy or renal replacement therapies as indicated. For maintenance of blood pressure and cardiac output, various agents are

preferred. Dobutamine is a β1-agonist that decreases right and left ventricular afterload and improves cardiac output. This agent has adverse effects related to tachyarrhythmias, which can be problematic in low cardiac output states. Another option is milrinone, a phosphodiesterase type 3 inhibitor. In addition to milrinone’s inotropic properties, it acts as a pulmonary vasodilator and improves RV function and decreases PVR.67 If vasoconstrictors are indicated due to the systemic vasodilation caused by dobutamine, then norepinephrine (predominantly an α1vasoconstrictor at increasing dosages starting at 5–10 mcg/minute) is the vasopressor of choice. Other options for vasopressors include phenylephrine and vasopressin; dopamine and epinephrine are considered last-line options because of the increased potential for adverse effects. Inhalational formulations of phosphodiesterase inhibitors such as milrinone have not been studied in these patients.68 Patients with acutely decompensated PAH require immediate stabilization to improve oxygenation, optimize preload, decrease afterload, and improve RV contractility, all while maintaining therapeutic pulmonary pressures. They also require interventions to their maintenance regimens to dose adjust for end-organ complications such as renal or hepatic dysfunction. Patients with newly diagnosed advanced PAH require centers with expertise in PH management. If further treatments are required after advance treatments and combinations are used, lung or heart-lung transplantation, or the use of bridge therapies with venovenous and venoarterial extracorporeal membrane oxygenation, may be indicated.

Figure 30.2 Treatment algorithm for acute decompensated PAH. Most PH centers have developed treatment algorithms for patients admitted with worsening heart failure. If patients are currently maximized on diuretics, inotropes, intravenous prostacyclins, PDE-5 inhibitors, and endothelin receptor antagonists, inhaled nitric oxide or inhaled prostaglandins (epoprostenol) can be used as last therapeutic options.

MONITORING OF THE CRITICALLY ILL PATIENT WITH PAH Monitoring of the ICU patient with PAH is important for several reasons, including the evaluation of treatment strategies, potential adverse effects of therapy, and clinical worsening. Although the use of pulmonary artery catheters has declined in the ICU, these devices are important for measuring hemo-dynamic parameters in patients with PAH, including RA pressure, left atrial pressure, cardiac output, and Svo2. Echocardiography may be useful in settings where more invasive monitoring is unavailable. Together with cardiac and pulmonary hemodynamic monitoring, patients should have their renal and hepatic function, tissue perfusion/oxygenation, neurohormonal markers, and markers of fluid balance (e.g., daily weight and fluid input and output) monitored very closely (Table 30.4).65 Cardiac biomarkers, such as troponin and natriuretic peptides, may also be useful given that increases in these values are associated with worsening outcomes in PAH.68

PRACTICAL CONSIDERATIONS FOR THE CRITICAL CARE PHARMACIST

The treatment of patients with PAH in the ICU can pose a challenge, and recent data analyses point out that they constitute a complex patient population receiving high-risk medications. A national survey emphasized serious or potentially serious intravenous prostacyclin administration errors.43 There are four major considerations regarding the role of the pharmacist and potential areas of intervention for the critically ill patient with PAH. First, the stability of the patient is of paramount importance. Depending on overall patient status (especially RV failure, septic shock, and cardiogenic shock), intravenous, inhalational, or oral therapies may require adjustment or discontinuation. The RV adapts poorly to sudden increases in afterload, and this can result in decreased contractility and hemodynamic collapse.65 Right ventricular dysfunction can result from excess RV afterload, inadequate RV preload, decreased RV contractility, or altered systemic vasodilaton.31 In the ICU setting, additional triggers such as sepsis, trauma, anemia, pulmonary embolism, medication nonadherence, interruption of chronic therapy, and arrhythmias can quickly overwhelm the effectiveness of any RV compensatory mechanism.65 Because of the short half-life of these agents, most patients should be kept on intravenous prostacyclin without interruption. This includes careful medication reconciliation, often requiring a call to the company providing the parenteral prostacyclin to confirm original dosing weight, rate of administration, and vial concentration. The next decision may involve the provision and decision to use patients’ home infusion pumps or may involve whether to convert the patient to a hospital-based pump where therapies can be prepared and supplied solely from the pharmacy department. Second, there are concerns for the oral or enteral agents with respect to how they can be administered in the mechanically ventilated patient or NPO (nothing by mouth) patient. Among the PDE-5 inhibitors and endothelin antagonists, only sildenafil has a commercially available suspension and is an intravenous alternative, with the five other agents available as tablets or capsules with limited ability to administer enterally or parenterally (Table 30.5).69 Inhalation treatments such as inhaled iloprost may pose a problem in

dosing frequency with a patient on either invasive or noninvasive mechanical ventilation. Of note, when these PAH medication classes were FDA labeled for use in the United States, studies assessing their safety in the critically ill ICU patient were not done. This requires clinical judgment and individualization of therapy when dosing patients with PAH. Third, practitioners need to understand and be well-versed when patients present to the ICU with infected Hickman or PICC (peripherally inserted central catheter) lines and know how to convert to other therapies with the correct priming volumes. Fourth, anticoagulation of the patient with PAH in the ICU, treatment of pregnant patients with PAH, and the decision about mechanical ventilation in the decompensated patient all require the interdisciplinary team to weigh in on these decisions.

Table 30.4 Recommended Monitoring of the Critically Ill Patient with Severe Pulmonary Arterial Hypertension Parameter

Modality

Renal function

Urinary catheter

Hepatic function

Treatment Goal

Serum creatinine; I & O

Maintain kidney function an​d diuresis. In general a net negative fluid balance is required

AST, ALT, bilirubin

Reduce hepatic congestion Maintain hepatic perfusion

Cardiac function

Central venous line (central venous pressure, SCVO2) Pulmonary arterial catheter (RA pressure, cardiac index, PAPm, PVR, SVO2)

Improvement in cardiac function demonstrated by an increase in cardiac output with improvement (reduction) in right atrial pressures SCVO2 > 70%, SVO2 > 65% Improve LV filling

Echocardiography Tissue perfusion/​ oxygenation

Lactate

< 2 mmol/L

Neurohormonal markers

Brain natriuretic peptides (BNP or NT-proBNP)

Reduction in BNP levels

Myocardial perfusion

Systemic blood pressure (noninvasive or invasive)

Ensure adequate systemic diastolic pressure (> 60 mm Hg)

ECG

Avoid/treat tachycardia/​tachyarrhythmia Optimize myocardial perfusion (negative troponin)

Troponin

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BNP = brain natriuretic peptide; ECG = electrocardiogram; LV = left ventricle; NT-proBNP = N-terminal fragment of brain natriuretic peptide; PAPm = mean pulmonary arterial pressure; PVR = pulmonary vascular resistance; RA = right atrial; SCVO2 = central venous oxygen saturation; SVO2 = mixed venous oxygen saturation. Reprinted with permission from: Hoeper MM, Granton J. Intensive care unit management of patients with severe pulmonary hypertension and right heart failure. Am J Respir Crit Care Med 2011;184:1114-24.

Table 30.5 Vasodilator Agents for PAH

BID = twice daily; INH = inhalational; IV = intravenous; LFT = liver function test; PDE − 5 = phosphodiesterase type 5; QID = four times daily; REMS = Risk Evaluation and Mitigation Strategies; SBP = systolic blood pressure; SC = subcutaneous; TID = three times daily. Adapted from: Epoprostenol (Flolan) [package insert]. Research Triangle Park, NC: GlaxoSmithKline, March 2011; Epoprostenol (Veletri) [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, June 2012; Treprostinil (Remodulin) [package insert]. Research Triangle Park, NC: United Therapeutics, 2014; Jing ZC, Keyur P, Pulido T, et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 2013;127:62433; Treprostinil (Tyvaso) [package insert]. Research Triangle Park, NC: United Therapeutics, 2014; Olschewski H, Simmoneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-9; Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy (ARIES) study 1 and 2. Circulation 2008;117:3010-9; Bosentan (Tracleer) [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, October 2012; Macitentan (Opsumit) [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, February 2015; Wang RC, Jiang FM, Zheng QL, et al. Efficacy and safety of sildenafil treatment in pulmonary arterial hypertension: a systematic review. Respir Med 2014;108:531-7; Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomized trial. Lancet 2002;360:895-900; Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369:319-29.

Finally, there should be consideration of administrative oversight from an interdisciplinary perspective on keeping these patients with PAH safe when being admitted to inpatient settings. This could take the form of protocol/ guideline development as it relates to acute vasoactive trials while in the ICU, policies on the criteria of when

patients should be transitioned from home intravenous/sub-cutaneous pumps, electronic medical record assimilation of order sets, and, finally, the integration of home-based infusion services and their roles in educating patients in the institutional setting.

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failure. Am J Respir Crit Care Med 2011;184:1114-24. 66. Zamanian RT, Kudelko KT, Sung YK, et al. Current clinical management of pulmonary arterial hypertension. Circ Res 2014;115:131-47. 67. Poor HD, Venetuolo CE. Pulmonary hypertension in the intensive care unit. Prog Cardiovasc Dis 2012;55:187-98. 68. Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically ill patients. Brit J Pharmacol 2012;165:2015-33. 69. Bauer SR, Tonelli AR. Beyond the evidence: treating pulmonary hypertension in the intensive care unit. Crit Care 2014;18:524.

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

LEARNING OBJECTIVES 1. Summarize the economic impact of acute asthma and COPD on the healthcare system. 2. Evaluate and compare pathophysiologic differences between asthma and COPD. 3. Identify criteria for ICU admission for acute asthma and COPD. 4. Recommend goals/treatment strategies of asthma management in critically ill patients. 5. Recommend goals/treatment strategies of COPD management in critically ill patients. 6. Explain the therapeutic approach to Asthma-COPD overlap syndrome.

ABBREVIATIONS IN THIS CHAPTER

ACOS

Asthma-COPD overlap syndrome

COPD

Chronic obstructive pulmonary disease

ED

Emergency department

FEV1

Forced expiratory volume in 1 second

FVC

Forced vital capacity

GINA

Global Initiative for Asthma

GOLD

Global Initiative for Chronic Obstructive Lung Disease

ICS

Inhaled corticosteroids

ICU

Intensive care unit

LABA

Long-acting β-agonist

MDI

Metered dose inhaler

NIV

Noninvasive ventilation

PEEPi

Intrinsic positive end-expiratory pressure

PEFR

Peak expiratory flow rate

SABA

Short-acting β-agonist

INTRODUCTION Acute respiratory failure secondary to asthma or chronic obstructive pulmonary disease (COPD) commonly requires frequent and prolonged admission to an intensive care unit (ICU). Although mortality has improved over time in patients with asthma, COPD is now the third leading cause of death in the United States. In addition, there has been increased awareness and focus on asthma COPD overlap syndrome (ACOS). Much of the published literature on these topics has targeted epidemiology, pathophysiology, clinical diagnosis, and outpatient and emergency department (ED) therapeutic management, with limited

focus on ICU therapeutic management. Although this chapter will briefly review the epidemiology, pathophysiology, and clinical diagnosis of these diseases, further detailed mechanisms and pathways are beyond the scope of this chapter and may be found in several exceptional texts, guidelines, and reviews. The primary focus of this chapter will be on the evidence-based approach to ICU management of asthma, COPD, and ACOS.

OVERVIEW OF ASTHMA AND COPD Epidemiology Asthma and COPD are significant contributors to morbidity and mortality internationally and have a considerable impact on health care costs. The overall economic impact in the United States is reportedly $56 and $49.9 billion annually for asthma and COPD, respectively.1,2 Asthma, which tends to develop early in life, is genetically and environmentally influenced. The Centers for Disease Control and Prevention (CDC) statistics indicate that 25.7 million people in the United States are given a diagnosis of asthma, increasing steadily from 3.1% in 1980 to 8.4% of the population in 2010.2 This increase in asthma diagnosis in 2010 had a minimal impact on ED visits and hospitalizations, accounting for 1.8 million visits and 439,000 admissions, respectfully. Mortality is usually preventable, as shown by the steady decrease in CDC mortality rates despite similar hospitalizations since 2001. This is secondary to the successful reversibility of airway inflammation with early treatment. Despite decreasing mortality, the health care impact remains substantial. One-fourth of all ED visits are secondary to asthma exacerbations, and 5%–10% reportedly require ICU admission.3,4 Childhood respiratory infections including respiratory syncytial virus and parainfluenza virus may influence the development of asthma.5 Environmental factors that influence the development of asthma include allergens, tobacco smoke, air pollution, and some occupational exposures. Risk of mortality is heightened in pediatric patients,

females, black Americans, and those with lower socioeconomic status.2 Chronic obstructive pulmonary disease has been diagnosed in about 14.2 million people nationally, varies drastically by state, and was associated with 1.5 million ED visits, 715,000 hospitalizations, and 133,965 deaths in 2009.1,6,7 It is reportedly the third leading cause of mortality, with a rate of 40.8 per 100,000 deaths in 2010, preceded by cancer and cardiovascular disease.8 Chronic obstructive pulmonary disease exacerbations resulting in hospitalizations reportedly account for 40%–75% of associated COPD health care costs.9 Up-ward of 20% of COPD hospitalizations may result in ICU admission.10 Smoking and age are the greatest risk factors for developing COPD, and patients with COPD typically present with several comorbidities including, but not limited to, coronary artery disease, congestive heart failure, diabetes with neuropathy, atrial fibrillation/flutter, and lung cancer.9 There is increasingly more literature regarding ACOS.11 The prevalence has been difficult to characterize because often patients with characteristics of a secondary disease were excluded from clinical trials, and in clinical trials that were inclusive, different definitions were used to characterize these patients.11–15 In trials that have investigated overlap syndrome, the prevalence of asthma in COPD cohorts ranged from 15% to 55%.11 Patients with ACOS are reportedly younger and experience a greater frequency and severity of exacerbations.13 A large multicenter population-based survey using standardized definitions to classify asthma, COPD, and overlap syndrome showed that patients with ACOS have worse general health status, increased exacerbation risk, and more hospitalizations than do those with COPD alone.15

Pathophysiology Acute respiratory failure requiring ICU admission is characterized by the inability to maintain homeostasis secondary to hypercapnia and hypoxemia.16 Severe asthma and COPD exacerbations can induce

acute respiratory failure, but through different pathophysiologic pathways. Asthma is defined by the Global Initiative for Asthma (GINA) as “a heterogeneous disease, usually characterized by chronic airway inflammation.”5 It is an immunohistopathologic process mediated by cytokine release and chemokines that trigger and regulate transcription factors that induce inflammatory response.5 The immunologic findings in sudden-onset and fatal asthma differ from those in slow or late-onset asthma, such that neutrophils in bronchial epithelium are more predominant in sudden-onset compared to eosinophils in late-onset. Occupational asthma and smokers also have a predominance of neutrophils. Mast cell activation and epithelial cell injury, together with sub-basement membrane thickening, bronchial smooth muscle hypertrophy and hyperplasia, and increased mucus secretions, contribute to airway structural changes and resultant inflammation.5 These factors influence the severity of asthma according to the degree of obstruction of airflow caused by bronchial smooth muscle contraction, bronchial inflammation-associated mucosal edema, and mucus plugging.17,18 In allergic asthma, the degree of cross-linking of immunoglobulin E (IgE) antibodies by allergen influences the development and severity. This type of bronchoconstriction is induced through mast cell activation and release of histamine, tryptase, cysteinyl-leukotrienes, and prostaglandin D2.5,19–21 Macrophages may further release cytokines and inflammatory mediators after allergen activation.5,22 Airway obstruction results in a decrease in forced expiratory volume in 1 second (FEV1), which in turn leads to air trapping and increasing functional residual capacity and a decreased forced vital capacity (FVC). Thus, a decreased FEV1/FVC ratio, with partial bronchodilator reversibility, is characteristic of asthma. Research is emerging showing inflammatory volatility, in which selective treatment based on phenotype may target improved therapeutic response. Some encouraging research efforts have been focused on leukotriene modifiers and antiIgE, and continued investigations are under way.5,23 Chronic obstructive pulmonary disease has been defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD)

guidelines as “a common preventable and treatable disease, characterized by airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases.”24 Chronic obstructive pulmonary disease typically develops later in life, is characterized by a limitation in expiratory flow and hyperinflation that is not completely reversible, and is usually confounded by several comorbidities. Chronic obstructive pulmonary disease can resemble aspects of both emphysema (alveolar damage) and chronic bronchitis (airway inflammation). The repeated exposure to noxious stimuli activates neutrophils and macrophages, which leads to airway remodeling, mucous hypersecretion, and impaired ciliary function resulting in carbon dioxide (CO2) retention. In smokers, cytotoxic T lymphocytes also contribute to the inflammatory response. The progression of lung damage is affected by the release of various cytokines and oxidative stress. An increase in proteases is evident in patients with COPD. Proteases may induce breakdown in connective tissue, impairing gas exchange through the mediation of elastin damage and resulting in hypoxemia and hypercapnia.24 Patients with severe COPD have weak diaphragm tone and diaphragmatic dys-function, requiring ribcage and abdominal muscles to be recruited during inspiration and end-expiration, respectively. The resultant paradoxical breathing leads to a rise in gastric pressure contributing to intrinsic positive end-expiratory pressure (PEEPi).24,25 Increased airflow limitation can trigger a COPD exacerbation, resulting in an increased work of breathing, air-trapping, a reduction of chest wall and lung compliance, and PEEPi, which over time will result in respiratory muscle fatigue, increased dead space ventilation, and worsening gas exchange.24,26 Increased hypoxemia is also affected by ventilation/perfusion mismatch. Similar to patients with asthma, patients with COPD develop decreased FEV1 and FVC and a resultant decreased FEV1/FVC ratio, mildly to non-reversible with bronchodilators. Patients with COPD also develop increases in residual volume and total lung capacity. Genetic risk factors are thought to contribute to the development and magnitude of inflammatory

response, although there are limited and mixed data regarding the genomes identified.24 α-Antitrypsin deficiency has been the most widely studied genetic disease, with focused efforts to target treatment optimization according to genetic predisposition.24 The pathophysiology of patients with severe asthma exacerbations alone differs from that of patients with severe COPD exacerbations, but several characteristics are shared in ACOS. Patients with ACOS have variable airflow obstruction that is not completely reversible.11,15,27 In addition, these patients experience increased bronchial hyper-responsiveness. Louie et al. proposed two clinical phenotypes: (1) asthma with partly reversible airflow obstruction and (2) COPD with emphysema accompanied by reversible or partly reversible airflow obstruction.28 These phenotypes may then present independently or in a combined fashion represented by eosinophilic bronchiolitis or neutrophilic bronchiolitis.28 Airway inflammation is predominantly a result of neutrophil activation. Cytotoxic T lymphocytes, alveolar macrophages, and proteases have also been implicated in ACOS.23,28 Some genetic similarities have also been described that influence bronchial hyper-responsiveness and FEV1/FVC.29

Triggers of Acute Severe Exacerbations Several triggers are shared in patients with acute severe exacerbations of both asthma and COPD. Among them, medication noncompliance because of educational gap, lack of access to medications, or patient adherence is a leading cause of severe exacerbations. Upper respiratory infections and pneumonia, together with environmental factors such as allergens, are also associated with an increased risk of severe exacerbations.1,2 In addition, exercise can induce bronchospasm and hyperinflation,5,24 and severe stress has been associated with exacerbations, although the exact mechanism is not well understood.5 Patients with additional comorbidities such as cardiovascular disease or other chronic lung disease, those requiring greater than two

canisters of short-acting β-agonist (SABA) per month, and those with two or more hospitalizations or three or more ED visits for asthma in the past year have a higher likelihood of severe asthma exacerbations. Severe COPD exacerbations may be precipitated by pulmonary thromboembolism, ischemic heart disease, acute heart failure, arrhythmias, alcohol consumption, inactivity, history of reflux or heartburn, and COPD exacerbations themselves.30 Severe asthma exacerbations may be drug induced secondary to concomitant diseases requiring the use of medications that can disrupt airway patency and increase airway resistance.16 β-Adrenergic blockers, nonsteroidal anti-inflammatory agents including aspirin, and steroid taper have been associated with bronchospasm.

Clinical Presentation A life-threatening asthma exacerbation is characterized by an inability to speak, a reduced peak expiratory flow rate (PEFR) of less than 25% of a patient’s personal best, and a failed response to frequent bronchodilator administration and intravenous steroids.18,31 Often, PEFR and bedside spirometry cannot be performed in these patients. However, if performed, values generally show an FEV1 or a PEFR less than 25% predicted.31 Vital sign abnormalities include tachycardia (greater than 120 beats/minute), tachypnea (greater than 30 breaths/minute), and hypotension as intravascular volume depletion worsens secondary to insensible fluid loss.31,32 Arterial blood gas may show an acute respiratory alkalosis with normal oxygenation in patients with an asthma exacerbation.33 In more severe cases, patients will develop a mild or acute respiratory acidosis with a widening A-a gradient indicative of respiratory failure.34 It is important that these patients be recognized promptly because they are exhausting their accessory muscles, resulting in excessive CO2 retention. Patients with hypercapnia have wider degrees of pulsus paradoxus, whereas low pulsus paradoxus is indicative of severe hyperinflation, which can result in extracardiac tamponade.31,35,36 Arrhythmias are common in patients with asthma31,37 and may be induced secondary to electrolyte

abnormalities during management of acute exacerbations with highdose β-agonist agents.38 Some patients may develop a pneumothorax or pneumomediastinum, likely because of increases in intrathoracic pressure, and warrant the need for chest tube placement for decompression.5 Severe COPD exacerbation may develop acutely or for a period of days. Patients generally develop worsening dyspnea, increasing cough, or an increase or change in sputum production from baseline as a result of increased inflammation. Physically, patients tend to appear in acute distress. Presentation with fatigue, weight loss, and anorexia is common in patients with severe COPD.24,39 Tachypnea, tachycardia, and decreased blood pressure secondary to PEEPi are common vital sign abnormalities. Respiratory acidosis also develops in acute exacerbations. Use of accessory inspiratory muscles is indicative of increased severity, and paradoxical breathing is associated with a poor prognosis, leading to impending respiratory failure and arrest.24,40 Patients with severe hypoxemia may present cyanotic and/or comatose. Development of hypercapnic respiratory failure with preserved ventilation/perfusion match indicates the need for mechanical ventilation.26

ICU ADMISSION Severity of illness warranting ICU admission for asthma may include presentation of dyspnea refractory to aggressive bronchodilator therapy, pneumonia, pneumothorax, PEFR less than 40% predicted personal best or lack of adequate response despite aggressive treatment, hypercarbia (partial pressure of carbon dioxide in the blood [Paco2] greater than 45 mm Hg), hypoxemia (partial pressure of oxygen in the blood [Pao2] less than 60 mm Hg on room air) requiring oxygen supplementation, or a combination of these factors. A history of several ED visits and tracheal intubation secondary to asthma are additional risk factors for asthma-related mortality. In addition, the absence of wheezing implying minimal air movement, use of accessory muscles, a decrease in systolic blood pressure during inspiration by

greater than 15 mm Hg, bradycardia, diaphoresis, cyanosis, anxiety, and inability to talk imply severe obstruction.31,41–43 The severity of COPD may be assessed using the staging criteria developed by the American Thoracic Society and GOLD, which classifies patients into four categories: stage I (mild), stage II (moderate), stage III (severe), and stage IV (very severe) according to the level of obstruction as defined by FEV1.24 In addition to baseline COPD severity, frequent exacerbations that require hospitalization, several comorbidities, and previous need for mechanical ventilation are risk factors for more severe exacerbations. Early warning scores have also been developed to assist in the triage for ICU admission and taking into consideration parameters associated with poor prognosis.44 Factors influencing ICU admission include severe dyspnea refractory to initial aggressive therapy, mental status changes, persistent or worsening hypoxemia, persistent or worsening respiratory acidosis, hemo-dynamic instability, and the need for mechanical ventilation.24,26 The treatment algorithms for severe asthma and COPD exacerbations are shown in Figure 31.1 and Figure 31.2, respectively. Comparative therapeutic management of severe exacerbations for patients with asthma and COPD admitted to the ICU is outlined in Table 31.1. Supportive respiratory care can be provided in different levels according to patient needs. Critically ill patients may require oxygen therapy, noninvasive ventilation (NIV), or invasive mechanical ventilation. This section will provide a brief overview of these supportive therapy options.

Figure 31.1 Severe asthma exacerbation treatment algorithm.a aSee bNot

Table 31.1 for dosing recommendations.

available in the United States.

IV = intravenous; SABA = short-acting β-agonist.

Figure 31.2 Severe chronic obstructive pulmonary disease exacerbation treatment algorithm.a aSee

Table 31.1 for dosing recommendations.

Oxygen Oxygen therapy is an important component in the management of severe asthma and COPD exacerbations. Patients experiencing severe exacerbations of either etiology often present with hypoxemia and require supplemental oxygen. The current asthma guidelines recommend the administration of oxygen by nasal cannula or mask in order to achieve oxygen saturation (Sao2) values greater than 90%. Other patient populations such as pregnant women and individuals with a cardiac history may have higher oxygen requirements, so an Sao2 of greater than 95% is often desired in these patients.71 In COPD, the target oxygen saturation is 88%–92%, which is partly based on data analyses that show patients who received oxygen therapy titrated to a saturation of 88%–92% had lower mortality than those administered high-flow oxygen therapy.72 Caution is advised with oxygen

supplementation in patients with COPD, however, because many of these patients rely on a slight level of hypoxemia as a trigger for their respiratory drive secondary to chronic hypercapnia.45 In addition, it is important to monitor the degree of oxygen supplementation in these patients, because too much oxygen may also increase ventilation/perfusion mismatch by inducing vasodilation to areas not previously well ventilated, decrease respiratory rate centrally (O2 retainers are very sensitive to O2), and perpetuate the Haldane effect. Inhaled medications are often administered through nebulizers with the use of oxygen to enhance drug delivery to the lower airways, especially in patients with severe airway restriction. It is important to monitor the fractional concentration of oxygen administered to these critically ill patients, given that this may be more harmful than beneficial to these patients. A study by Chien et al. found that patients who received 100% oxygen had elevations in Paco2, and patients with more severe airway obstructions often had more hypercarbia, thereby increasing their risk of respiratory depression secondary to CO2 retention.47,73

Noninvasive Ventilation Noninvasive ventilation may be an option for patients with severe COPD exacerbation, although its potential benefit in asthma exacerbations remains unclear.3,74 In patients with hypercapnia and acute respiratory failure secondary to COPD exacerbation, NIV improves mortality and respiratory acidosis and decreases the need for intubation and treatment failures.75,76 Noninvasive ventilation also decreases complications associated with invasive mechanical ventilation in patients with COPD, such as ventilator-associated pneumonia and hospital length of stay.76 In a recent evaluation of the addition of NIV to standard medical therapy in patients admitted to an ICU for a severe asthma exacerbation, a clear benefit of NIV when added to standard medical therapy was not shown. Overall, the results suggested that adding NIV to standard therapy in patients with asthma reduces inhaled bronchodilator requirements, accelerates improvement

in lung function, and reduces hospital length of stay, but larger studies are needed to further evaluate these findings.74 Although NIV may be appropriate for some patients experiencing a severe asthma exacerbation, data analyses are insufficient for the current guidelines to provide a recommendation regarding its use in severe exacerbations. The GINA guidelines currently recommend proceeding with intubation as soon as it is deemed medically necessary and intubation should not be delayed by the administration of alternative therapies, including NIV.5,71 In patients with COPD, however, NIV should be considered for those with respiratory acidosis and severe dyspnea with increased work of breathing or clinical signs of respiratory muscle fatigue. These may include respiratory accessory muscle use, paradoxical motion of the abdomen, or retraction of the intercostal spaces.40 The use of NIV for severe COPD exacerbation is a level A recommendation from the GOLD guidelines.24

Mechanical Ventilation Patients experiencing worsening respiratory failure during a severe exacerbation despite standard medical therapy often require endotracheal intubation and respiratory support with mechanical ventilation. Currently, there are no parameters to suggest when intubation should occur in severe asthma exacerbation; instead, the decision should be based on clinical judgment.42,71 Indications for intubation in patients with asthma may include worsening hypoxemia and hypercarbia, hemodynamic instability, altered mental status, and increased work of breathing.42,71 Patients with near-fatal asthma can be challenging to intubate and can often have high ventilator requirements because of the high airway resistance and mucus plugging in the distal airways.3 The GINA guidelines recommend a ventilator strategy of permissive hypercapnia or controlled hypoventilation, which provides adequate oxygenation and ventilation but decreases the risk of barotrauma secondary to high airway pressures.5,71 Patients with severe COPD exacerbation who are unable to tolerate

NIV or whose NIV therapy fails may be candidates for invasive mechanical ventilation. Other indications for invasive mechanical ventilation include the inability to clear respiratory secretions, respiratory or cardiac arrest, diminished consciousness, massive aspiration, severe hemodynamic instability without response to fluids and vasoactive medications, and severe ventricular arrhythmias.77 The decision to institute invasive mechanical ventilation in patients with a severe COPD exacerbation should be made depending on the reversibility of the cause of exacerbation, the patient’s wishes, the appropriate resources, the availability of providers with knowledge about ventilator management, and a risk assessment of complications related to invasive ventilation. These complications include ventilatorassociated pneumonia, barotrauma, and inability to wean from mechanical ventilation.24

ASTHMA Treatment Goals The main treatment goals for a severe asthma exacerbation are to correct significant hypoxemia using supplemental oxygen and to rapidly reverse airflow obstruction with the administration of inhaled SABAs and systemic corticosteroids.5,71 Although reducing the risk of future exacerbations is also an important treatment goal, this section will focus on the critical care therapeutic management of life-threatening asthma exacerbations (Figure 31.1).

Pharmacologic Interventions Bronchodilators The current asthma guidelines recommend that all patients experiencing an asthma exacerbation receive a SABA by repeated administration with either a metered dose inhaler (MDI) or nebulization immediately on presentation, which should be continued until resolution

of acute symptoms.18,43,47,71 Short-acting β-agonists stimulate the β2receptors on smooth muscle cells and cause relaxation of respiratory smooth muscle. This relaxation leads to bronchodilation and a decrease in airway obstruction.42,47 Selective SABAs (albuterol, levalbuterol, pirbuterol) are recommended in acute exacerbation to decrease the risk of cardiotoxicity that can be associated with high doses of SABAs.18,71 Albuterol is the most common bronchodilator administered during severe asthma exacerbations. Dosing and monitoring recommendations are provided in Table 31.1. Theoretically, levalbuterol may have fewer cardiovascular adverse effects than albuterol and may be preferable in severe asthma exacerbations when frequent or large doses are required. However, several studies have failed to show a significant difference in heart rate elevation after the administration of albuterol and levalbuterol.18,71,78–81 In addition, the efficacy of levalbuterol when administered as a continuous nebulization has not yet been evaluated.18,71,81 In critically ill patients, it is preferable that SABAs be administered as a nebulizer rather than by an MDI to provide a continuous delivery of medication to the obstructed airways.47 Patients who require ICU admission may have severe airway edema and increased mucus production, which can further worsen airway obstruction.47 Administering β-agonists by nebulizer either intermittently or continuously should improve the likelihood that bronchodilators are delivered to the lower airways during an acute exacerbation.47 Several studies have evaluated the effects of continuous versus intermittent nebulization on pulmonary function in patients presenting to the ED. A meta-analysis of eight studies, most of which enrolled only adults, found that patients who received continuous nebulization of SABAs in the ED had an improvement in their pulmonary function tests (PEFR and FEV1) after 2–3 hours of therapy. Patients with severe acute exacerbations were found to specifically benefit from continuous nebulization of SABAs, but additional studies are needed to confirm these findings.46 Studies have found that systemic β-agonists, such as intravenous or subcutaneous epinephrine or terbutaline, are not more efficacious than

inhaled β-agonists in the management of an acute asthma exacerbation, and it is possible that they are associated with more cardiovascular adverse effects. Critically ill patients may benefit from systemic administration of β-agonists if they lack a good response to inhaled SABA therapy or if they are unable to receive inhaled medications, although data evaluations have not shown improved outcomes with this approach.42 Long-acting β-agonists (LABAs) in combination with inhaled glucocorticoids have been shown to be effective in preventing asthma exacerbations, but their use in the treatment of severe acute exacerbations has not been demonstrated. Inhaled Anticholinergic Agents Inhaled anticholinergic medications such as ipratropium bromide cause bronchodilation by selectively binding to the muscarinic receptors on smooth muscle cells in the airways and reducing bronchoconstriction.47 Administration of ipratropium in addition to a SABA is recommended to promote additional bronchodilation through a different pathway. Studies have not found a significant benefit when ipratropium is continued after the initial doses are given in the ED, but it is often common practice to continue the administration of ipratropium with a SABA in critically ill patients.18 Targeting different sites and mechanisms of airway bronchodilation with different medications may benefit patients who experience severe bronchoconstriction and require ICU admission for an acute asthma exacerbation.47 Corticosteroids Systemic corticosteroids are recommended in patients who have an incomplete response to the initial administration of an inhaled SABA, and they should be continued during hospital admission.18,71 Corticosteroids decrease airway obstruction during an asthma exacerbation by decreasing inflammation, increasing the number of β2receptors and increasing their responsiveness to β-agonists, reducing airway edema, and suppressing certain proinflamma-tory cytokines by interfering with the regulation of their transcription.42,47,82 A meta-

analysis evaluating the use of corticosteroids in patients presenting to the ED found that patients who received corticosteroids had an increase in PEFR at the end of treatment.48 There was often a delay in the improvement of pulmonary function after the administration of corticosteroids in these studies, so it is recommended that corticosteroids be initiated within the first hour of presentation.47,48 An additional meta-analysis evaluated the effects of varying doses of corticosteroids in hospitalized patients and found that there was no added benefit to improvement in pulmonary function when doses of methylprednisolone greater than 60–80 mg per day were used. However, none of the studies that were reviewed included patients who required mechanical ventilation or ICU admission.83 The exact dose of corticosteroids a patient should receive during an acute exacerbation is not known at this time, but studies have indicated that doses of prednisone greater than 100 mg per day do not provide a significant benefit.49 It is recommended that patients receive 60–80 mg per day of prednisone or methylprednisolone during acute exacerbations, followed by a decrease in dose once the patient has signs of improvement in pulmonary function. Corticosteroids should be tapered in patients who require treatment for longer than 1 week unless they only require a 10day course of systemic corticosteroids and are also on an inhaled corticosteroid (ICS).3,5 Studies have indicated that an ICS may prevent hospital admissions for acute asthma exacerbations compared with placebo, but their role in acute exacerbations is less clear. It is possible that adding an ICS to systemic corticosteroids during an acute exacerbation will improve outcomes, but no data suggest that an ICS alone should be used during an acute exacerbation. In addition, the optimal dosing, delivery, and frequency of ICS administration during an exacerbation are currently unknown and require further evaluation.84 Intravenous Magnesium Sulfate In patients with severe and life-threatening asthma exacerbations, intravenous magnesium sulfate may be beneficial.18,71 Magnesium is thought to cause bronchodilation by inhibiting calcium channels on

smooth muscle, which causes relaxation of smooth muscle.3,82 Magnesium may also have anti-inflammatory effects by interfering with the activation and release of neutrophils in patients with asthma.85,86 A meta-analysis of 14 studies found that patients who received magnesium sulfate as a single intravenous dose of 1.2 or 2 g had improved lung function and decreased hospital admissions when inhaled SABAs and systemic corticosteroids did not provide a sufficient response.87 A study by Silverman et al. evaluated the addition of 2 g of intravenous magnesium sulfate to nebulized albuterol and intravenous methylprednisolone therapy in patients who presented to the ED with a severe acute asthma exacerbation defined by an initial FEV1 of 30% or less of predicted. There was no difference in the rate of hospital admissions between the groups, but patients who received magnesium had a significantly higher FEV1 after 240 minutes of the protocol (48.2% of predicted vs. 43.5% of predicted, p0.05). Similar results were seen in the subgroup analysis of patients with COPD exacerbation. Most studies used spacers with MDIs, although they may not be necessary for adequate drug delivery.98 Nebulization may be a more convenient route of delivery for critically ill patients or those who are unable to hold their breath after actuation of an MDI because of severe dyspnea.24

Table 31.1 Comparison of Pharmacologic Management of Asthma and COPD in the ICU Pharmacologic Treatment

Asthma

COPD

Inhaled Short-Acting β-Agonists11,24,42,45,46 Recommendation

Recommended in all patients

SABA preferred agent for bronchodilation; nebulization may be more convenient

Dosing

Nebulization: 0.5–5 mg q20min by nebulizer for three doses, followed by 2.5–10 mg q1–4hr as needed or 10–15 mg administered over 1 hr by continuous nebulization

MDI: 2 puffs q2–4hr Nebulization: 2.5 mg q2–4hr

MDI: 4–8 puffs (18 mcg/puff) q20min for up to 4 hr, followed by 4–8 puffs q1– 4hr as needed Outcome

Monitoring

Improvement in PEFR and FEV1 after 2–3 hr of continuous nebulization

No data in exacerbation

Heart rate, serum potassium

Heart rate, serum potassium

Stable COPD: Improve FEV1, symptoms

Inhaled Short-Acting Anticholinergics11,24,45,47 Recommendation

Recommended in addition to an inhaled SABA

Recommended in addition to SABA for bronchodilation; nebulization may be more convenient

Dosing

Nebulization: 0.5 mg q20min for at least three doses and then 0.5 mg q6hr as needed during ICU admission

MDI: 2 puffs q2–4hr

Studies have not indicated a benefit when it is continued after initial doses in the ED but likely beneficial to target several mechanisms of bronchodilation in ICU patients

No data in exacerbation

Outcome

Nebulizer: 0.5 mg q2–4hr

Stable COPD: Combination βagonist and anticholinergic further improved FEV1 and symptoms

Monitoring

Dry mouth

Dry mouth

Systemic Corticosteroids3,48,49,50–53 Recommendation

Administer to all patients soon after initiation of SABA therapy

Likely beneficial; use lowest effective dose

Dosing

60–80 mg per day of prednisone or methylprednisolone

Lowest effective dose (range prednisone 40 mg daily – methylprednisolone 0.5 mg/kg q6hr); prefer enteral therapy for maximum 10 days

Outcome

Improvement in PEFR

Shorter duration of mechanical ventilation, fewer failures of NIV

Monitoring

Hyperglycemia

Hyperglycemia

Antimicrobial Therapy54–56 Recommendation

Possibly beneficial if cause of exacerbations is expected to be from an infectious source

Likely beneficial; choice based on local susceptibility patterns Common antibiotic classes used may include fluoroquinolones, macrolides, β-lactam/β-lactamase combinations, tetracyclines, and cephalosporins (third or fourth generation)

Dosing

Ceftriaxone 1 g q24 hr and azithromycin 500 mg q24 hr (add oseltamivir if exacerbation occurs during influenza season)

Dose adjust according to renal/hepatic function; 5- to 10-day course

Outcome

May reduce mortality if initiated within 12 hr; data are limited

Lower mortality, shorter duration of MV, shorter hospital LOS, reduced need for additional antibiotics, improved FEV1

Monitoring

Culture results, resistance

Resistance patterns

patterns Intravenous Magnesium Sulfate 57,58 Recommendation

Recommended in patients with severe exacerbations unresponsive to first-line therapies

Not routinely recommended

Dosing

Magnesium sulfate 2 g IV dose in addition to a nebulized SABA and IV corticosteroids

Magnesium sulfate 2 g IV dose

Outcome

Increase in FEV1 after administration, especially in patients with an initial FEV1 < 20% at presentation

Increase in FEV1 after β-agonist administration, improved PEFR

Monitoring

Hypotension, vasodilation, flushing, hypermagnesemia

Hypotension, vasodilation, flushing, hypermagnesemia

Recommendation

Not enough data to support regular use

No recommendation

Dosing

Bolus doses of 0.2–1 mg/kg, followed by infusions of 0.5–1 mg/kg/hr (largest dose was 2.5 mg/kg/hr)

N/A

Potential improvement in FEV1, peak airway pressure, Pao2 and Paco2

N/A

Ketamine 31,59,60

Outcome

Monitoring

Dysphoria, heart rate, blood pressure, oral and respiratory secretions, intracranial pressure

N/A

May benefit patients in severe respiratory distress as a last treatment option before intubation; also beneficial

May be considered as adjunct in select patient populations (high auto-PEEP, try to prevent intubation)

Heliox48,61–65 Recommendation

as the delivery system for inhaled β-agonists Dosing

Heliox as either 70:30 or 80:20 ratios of helium to oxygen

Heliox as either 70:30 or 80:20 ratios of helium to oxygen

Outcome

Increase in mean PEFR compared with oxygen administration of albuterol nebulization. Greatest change in patients with severe asthma exacerbation

Potential for reduced hypercapnia, reduced autoPEEP, reduced systolic pressure variation

Monitoring

Few adverse effects; inconsistent delivery in noncommercially available delivery system

Inconsistent delivery in noncommercially available delivery system

Methylxanthines66–68 Recommendation

Not recommended but may continue in patients who are maintained on them at home

Dosing

Second-line therapy if lack of response to short-acting inhaled bronchodilators

Aminophylline 6 mg/kg IV load; then 0.5–0.9 mg/kg/hr IV infusion

Outcome

Benefits outweighed by risk of adverse effects

Monitoring

Plasma concentration, heart rate, respiratory rate

No benefit in clinical outcomes, FEV1, FVC, or ventilation/perfusion, but increase in AEs Plasma concentrations, heart rate, respiratory rate

Intravenous Leukotriene Receptor Antagonists69,70 Recommendation

May benefit patients with severe asthma but not currently available for use in the United States

No recommendation

Dosing

One dose of IV montelukast 7

N/A

mg in addition to standard treatment (inhaled SABA, IV steroids) Outcome

Improvement in FEV1 compared with patients who only received standard therapy

N/A

Monitoring

Headache and mood changes

N/A

AE = adverse effect; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; ICU = intensive care unit; IV = intravenous; LOS = length of stay; MDI = metered dose inhaler; MV = mechanical ventilation; N/A = not applicable; NIV = noninvasive ventilation; PEEP = peak endexpiratory pressure; PEFR = peak expiratory flow rate; q = every; SABA = short-acting βagonist.

Long-acting β-agonists and anticholinergic agents have been shown to reduce exacerbations,24 but their role in an acute exacerbation remains unclear. An unblinded randomized controlled pilot study compared indacaterol (a LABA) daily with salbutamol (a SABA) three times a day, in addition to standard therapy, in 29 patients admitted to the ED. The authors found that the patients in the indacaterol group had more improvement in pulmonary function (FEV1, PEFR) and Po2/Fio2 (fraction of inspired oxygen) ratio than did the patients in the traditional salbutamol therapy group.99 The results of this study suggest that LABAs have a role in COPD exacerbation. However, this study did not include critically ill patients, and the administration of LABAs to critically ill patients may not always be feasible because LABAs are primarily available as dry powder inhalers that are not compatible with ventilators or may be difficult to use for patients with severe respiratory distress. Corticosteroids The use of corticosteroids in COPD exacerbations is a mainstay of therapy to decrease the systemic and local inflammation. The use of

systemic corticosteroids in COPD exacerbation is recommended by the GOLD guidelines (level of evidence A).24 Corticosteroids have been associated with improved FEV1, decreased treatment failures, and reduced hospital length of stay.100–102 Unfortunately, the optimal dose and duration of corticosteroids remains under debate, especially in the critically ill population. The dose recommended by the GOLD guidelines is 40 mg of prednisone equivalent daily (preferably oral) for 5 days; however, this recommendation is largely based on studies that do not include critically ill patients. A randomized, double-blind trial including 83 patients 18 years and older with COPD exacerbation requiring hospitalization and ventilator support (invasive or NIV) compared methylprednisolone 0.5 mg/kg intravenously every 6 hours for 72 hours, 0.5 mg/kg every 12 hours on days 4–6, and 0.5 mg/kg daily on days 7–10 with placebo. The investigators found that the steroid arm had a shorter duration of mechanical ventilation (p=0.04), shorter length of ICU stay (p=0.09), fewer failures of NIV (p=0.004), and more hyperglycemia (p=0.04). This study was not powered to detect differences in length of stay or mortality.50 Another study of 217 critically ill patients 40 years and older with COPD exacerbation requiring mechanical ventilation compared open-label enteral prednisone 1 mg/kg daily for a maximum of 10 days with a control group. No significant differences in ICU mortality, NIV failure, duration of mechanical ventilation, or ICU length of stay were identified, although the study did not meet power. There was an increase in hyperglycemia in the steroid group (p=0.015).51 A cohort study by Kiser et al. compared high-dose (more than 240 mg/day) and lower-dose (240 mg/day or less) methylprednisolone in 17,239 patients with COPD exacerbation admitted to an ICU. Patients who received higher-dose methylprednisolone had longer ICU and hospital length of stay, higher hospital costs, longer duration of mechanical ventilation, and more hyperglycemia and fungal infections. There was no difference in mortality between the two groups.52 A recent meta-analysis included trials evaluating systemic corticosteroid use in ICU and non-ICU patient populations. The results

showed improvement in treatment success in the overall population in the corticosteroid group. Treatment success was defined to include the following: (1) clinical improvement as assessed by a questionnaire; (2) improvement in FEV1 or blood gases; (3) reduction in length of hospital stay in acute care patients and lack of need for intubation in patients on NIV or reduced mortality for mechanically ventilated, critically ill patients. No difference was seen in mortality, although only 9 of the 12 articles included mortality as an end point. The number of hyperglycemic episodes was higher in the corticosteroid group. Despite the overall benefit in the ICU subgroup, the use of corticosteroids had no effect on treatment success.53 This result should be interpreted with caution, however, because this analysis included only two clinical trials with different study designs, as evidenced by high heterogeneity in this subgroup (I2 = 77.4%). An additional consideration in the critically ill population is whether the possibility of altered bioavailability of corticosteroids secondary to hypoxemia or fluid overload should affect the route of administration of these drugs. Inhaled corticosteroids may provide an additional alternative route because they improve lung function and reduce the frequency of COPD exacerbations,24 but data regarding their utility in the management of COPD exacerbation are currently lacking. According to currently available evidence, corticosteroid therapy seems to be beneficial in patients with COPD exacerbation. The two available studies of ICU patients used different dosing strategies for corticosteroids, and the optimal dose remains unknown. It would be reasonable to use the lowest effective dose of corticosteroid with consideration for a relative maximum dose of methylprednisolone 0.5 mg/kg intravenously every 6 hours (2 mg/kg/day). Oral or enteral therapy is preferred if this route of administration is possible, and the duration of therapy should be limited to a maximum of 10 days to minimize adverse effects.24 Antimicrobial Therapy Chronic obstructive pulmonary disease exacerbation caused by an infection may be of a bacterial or viral etiology.24 Bacteria represent

40%–50% of COPD exacerbations. The most commonly seen bacteria are Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. In a recent study evaluating the etiology of COPD exacerbation in patients with severe COPD, the most common bacterial pathogen isolated was Pseudomonas aeruginosa. There was also a notable percentage of isolates (6%) with Staphylococcus aureus, and patients with more frequent exacerbations had a higher likelihood of having Enterobacteriaceae.103 Atypical bacteria (Chlamydia pneumoniae and Mycoplasma pneumoniae) make up 5%– 10% of COPD exacerbations. Viruses are the causative pathogen in 30%–40% of COPD exacerbations. The most commonly seen virus is rhinovirus, followed by parainfluenza, influenza, respiratory syncytial virus, coronavirus, and adenovirus.104,105 Unfortunately, because of inconsistencies in clinical trial design, including the definition of COPD exacerbation, exclusion of subjects with pneumonia, and lack of placebo-controlled arm, the routine use of antibiotics for COPD exacerbation is controversial. A meta-analysis found that antibiotics in COPD exacerbation were beneficial and decreased the incidence of treatment failure, but they had no effect on mortality or hospital length of stay.104 An ongoing clinical trial is evaluating the need for antibiotic therapy in moderate exacerbation of COPD in an attempt to answer this controversial question.106 Therapy with antibiotics is currently recommended by the GOLD guidelines for patients who have the three cardinal symptoms: increase in dyspnea, sputum production, and sputum purulence (level B recommendation).24 In patients with severe COPD exacerbation, particularly those who require either noninvasive or invasive ventilation, the indication for antibiotic therapy is slightly clearer. A randomized controlled trial was conducted to evaluate the use of ofloxacin in patients with COPD exacerbation requiring mechanical ventilation. The results of this study showed a reduction in mortality in the ofloxacin group compared with placebo of 4% versus 22%, respectively (p=0.01), as well as a significant reduction in the need for additional antibiotics, duration of mechanical ventilation, and length of hospital stay.54 Another study compared amoxicillin/clavulanic acid with placebo in patients with

COPD exacerbation. The results of a subgroup analysis of patients with severe COPD at baseline showed a significant improvement in FEV1 after antibiotic treatment (p 2.2 L/min/m 2

Optimize GDMT and device therapy for chronic heart failure

Subset II: Fluid Overload PCWP > 18 mm Hg, CI > 2.2 L/min/m 2

Intravenous loop diuretic therapy (dose ≥ chronic oral daily dose) If diuresis is inadequate to relieve symptoms: a) increase intravenous loop diuretic dose b) add second diuretic (e.g., thiazide) In the absence of symptomatic hypotension, intravenous vasodilators (nitroglycerin, nesiritide, nitroprusside) for relief

of dyspnea Subset III: Hypoperfusion PCWP 15–18 mm Hga CI < 2.2 L/min/m 2

If PCWP < 15 mm Hg, hold diuretic therapy and liberalize fluid restriction and/or administer intravenous fluids to achieve a PCWP of 15–18 mmHg If end-stage heart failure refractory to GDMT and device therapy, intravenous inotropic therapy (temporary, shortterm): a) to maintain systemic perfusion and preserve end-organ performance b) to “bridge” to MCS or cardiac transplantation If ineligible for MCS or cardiac transplantation, long-term inotropic therapy may be used as palliative therapy

Subset IV:

Intravenous diuretic therapy and intravenous inotropic therapy as described for Subset II and III

Fluid overload and hypoperfusion PCWP > 18 mm Hg, CI < 2.2 L/min/m 2 aIn

the absence of cardiac dysfunction, normal range for PCWP is 5–12 mm Hg; higher filling pressures (i.e., 15–18 mm Hg) are necessary in patients with heart failure to optimize CI. CI = cardiac index; GDMT = guideline-directed medical therapy; MCS = mechanical circulatory support.

Several factors are prognostic for outcomes in patients with ADHF. According to data compiled from the Acute Decompensated Heart Failure National Registry (ADHERE), elevated blood urea nitrogen, low systolic blood pressure, and elevated serum creatinine concentrations were associated with the highest risk of in-hospital mortality; patients with all three features have a 20% risk of in-hospital mortality.10 Hyponatremia, elevations in troponin I, ischemic etiology, and poor functional capacity are also negative prognostic factors.11 In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry, low blood pressure and poor renal function were negative prognostic markers for readmission or death, whereas use of standard heart failure therapies

or placement of an implantable cardioverter-defibrillator at discharge was associated with an improved prognosis.12

VOLUME MANAGEMENT Loop Diuretics Intravenous loop diuretics are recommended for patients with ADHF and evidence of significant volume overload. Furosemide, bumetanide, and torsemide may be used for this purpose, although furosemide is the most widely used agent. After an intravenous bolus, loop diuretics reduce preload within 5–15 minutes through functional venodilation and later (after more than 20 minutes) by sodium and water excretion. In patients receiving chronic loop diuretic therapy before admission, intravenous loop diuretics should be administered at a dose that equals or exceeds the chronic oral daily dose. According to the results of the Diuretic Optimization Strategies Evaluation (DOSE) trial, initial loop diuretic therapy may be administered as either intermittent boluses or continuous infusion7,13 because no differences occurred in the coprimary end points of patient global assessment of symptoms and mean change in serum creatinine when either intermittent bolus versus continuous infusion administration or high versus low dose were compared. However, high doses (2.5 times the oral dose before admission, without accounting for bioavailability) showed greater net fluid loss and change in weight at 72 hours as well as a transient increase in renal dysfunction.13 Among the available loop diuretic agents, bioavailability is the primary difference between oral formulations (Table 32.2), whereas intravenous formulations differ by drug concentration. The latter may be clinically relevant when these agents are administered by continuous infusion, in which case furosemide can be associated with considerable added volume. In light of the DOSE trial, continuous infusions are less often used but may occasionally be necessary to administer very high total daily doses when the dose-response ceiling of bolus administration has been reached.

The rate of diuresis should be closely monitored, with careful measurement of fluid intake and output as well as body weight determined at the same time each day. After a single intravenous bolus of loop diuretic, 250–500 mL of fluid loss should occur within 4 hours. Common 24-hour goals for fluid loss are 1–2 L net negative, although some patients may experience and tolerate greater net fluid loss. Of importance, select patients (e.g., those with poor renal function, low albumin) may only tolerate being net negative less than 1 L/day. Vital signs, daily serum electrolytes, blood urea nitrogen, and serum creatinine should be closely monitored. Dietary sodium and fluid restriction is also warranted. Of importance, the goal PCWP is 15–18 mm Hg in patients with ADHF because of the higher preload necessary to optimize cardiac output (i.e., because of a flatter Frank-Starling curve). Cardiac output may also decline with excess PCWP; thus, improved renal function and enhanced diuresis may occur as elevated filling pressures resolve. This phenomenon may also occur because of reduced renal congestion. An acute reduction in venous return may compromise effective preload in patients with diastolic dysfunction, patients with intravascular depletion, or those in whom the CI is significantly dependent on adequate filling pressure. Of importance, intravascular volume depletion may occur in the setting of rapid diuresis, despite total body volume overload; thus, daily diuresis goals must be highly individualized. Although most patients tolerate a 2 L/day net negative diuresis, some end-stage patients, especially those who are malnourished, may only tolerate ½–1 L/day net negative diuresis. Ototoxicity may be avoided by avoiding rapid infusion rates (greater than 4 mg/minute intravenous bolus) and minimizing other ototoxic agents, such as aminoglycosides. In addition, dose-related adverse effects include hypotension, renal impairment, and electrolyte wasting.

Table 32.2 Loop Diuretics Used in Acute Decompensated Heart Failure

aEquivalent bFor

oral dose: furosemide 40–80 mg = torsemide 20 mg = bumetanide 1 mg.

diuretic-naive patients.

Diuretic Resistance Adjunct Diuretics Occasionally, patients have a suboptimal response to high doses of loop diuretics. In patients with ADHF, both pharmacokinetic and pharmacodynamic mechanisms may lead to diuretic resistance.14 First, delayed absorption may result in concentrations that fail to reach the threshold necessary for producing effective diuresis. In addition, compensatory sodium reabsorption in the distal convoluted tubule may occur as a result of loop diuretic administration; over time, chronic administration of loop diuretics may lead to hypertrophic remodeling of the nephron, which may also increase sodium reabsorption. Finally, reduced cardiac output may limit renal perfusion as well as renal drug delivery.

Table 32.3 Thiazide Diuretics Used in Acute Decompensated Heart Failure

IV = intravenous; N/A = not applicable; PO = oral.

Several strategies have been hypothesized to overcome diuretic resistance. First, higher doses of loop diuretics may be administered to achieve concentrations near the peak of the concentration-response curve. As suggested in Table 32.2, the single dose above which additional response is unlikely to occur (i.e., the ceiling dose) depends on renal function. A second approach for overcoming diuretic resistance is using a continuous intravenous infusion. Although no advantages of initial continuous infusion administration were seen in the DOSE trial, investigators did not enroll patients with diuretic resistance; thus, it is unknown how continuous infusion compares with bolus administration in this population. A third strategy includes adding a second diuretic with a different mechanism of action, such as a thiazide-type diuretic (e.g., oral metolazone, hydrochlorothiazide, or chlorthalidone; or intravenous chlorothiazide; Table 32.3), to produce a synergistic diuretic effect. Sequential nephron blockade with a loop and thiazide diuretic should generally be reserved for hospitalized patients because severe electrolyte and volume depletion may occur. Given the cost associated with intravenous chlorothiazide, oral thiazide diuretics should be considered first line. Intravenous Vasodilators In the absence of symptomatic hypotension, intravenous venodilators such as nitroglycerin and nesiritide may be used in addition to diuretics to aid in acute dyspnea relief.7,15 Intravenous vasodilator therapy will

be discussed in detail later in this chapter. Dopamine Despite mounting evidence that dopamine imparts no benefit in patients with ADHF, its use remains common in select scenarios. As in other critical care settings, lower doses of dopamine (less than 3 mcg/kg/minute) were once theorized to improve renal impairment in the setting of ADHF because of the activation of renal dopaminergic receptors16; however, this has since been discredited in several randomized controlled trials.17,18 When added to low-dose furosemide (5 mg/hour) in the Dopamine in Acute De-compensated Heart Failure (DAD-HF) trial, dopamine at doses of 5 mcg/kg/minute provided the same degree of diuresis as high-dose furosemide (20 mg/hour) with no deleterious impact on renal function.16 However, in the second Dopamine in Acute Decompensated Heart Failure (DADHF II) trial, no differences were demonstrated when the same combination of lowdose furosemide and dopamine was compared with low-dose furosemide alone, suggesting that dopamine had no impact on diuresis or other renal outcomes.17 A similar lack of benefit was shown in the Renal Optimization Strategies Evaluation (ROSE) trial, when patients with ADHF and renal impairment were randomized to low-dose dopamine (2 mcg/kg/minute) or placebo in a randomized controlled fashion.18 Anecdotal reports of improved renal function with dopamine in practice are likely a result of its inotropic effects in ADHF, which have been observed even at low doses.19 However, using dopamine for this purpose is unlikely to provide any additional benefit over traditional inotropes and it may increase tachyarrhythmias by comparison. Although low-dose dopamine is still included as a recommendation for augmenting diuresis in clinical practice guidelines, this recommendation may change when the results of DAD-HF II and ROSE are integrated into future editions.7 Vasopressin Receptor Antagonists Reduced cardiac output may lead to excess stimulation of arterial

baroreceptors, which results in enhanced arginine vasopressin secretion and water retention. Consequently, many patients with heart failure present with some degree of hypervolemic hyponatremia, although its prevalence and severity varies. Hyponatremia is commonly mild, asymptomatic, and self-limited, but patients may present with lethargy, confusion, respiratory arrest, cerebral edema, seizures, coma, or death. Indeed, hyponatremia has been associated with increased mortality in this population.20 The primary strategy for managing hyponatremia in heart failure is to manage volume overload with fluid restriction and diuretic administration. Although a combination of hypertonic saline and loop diuretic therapy has been associated with improved hyponatremia without a deleterious impact on volume status, this strategy is not commonly used.21 Vasopressin antagonists are therefore an alternative for patients with severe hyponatremia who are refractory to initial measures or who develop neurologic symptoms. Of importance, rapid correction of hyponatremia (greater than 12 mmol/L within 24 hours) should be avoided.22 Tolvaptan is an oral inhibitor of vasopressin-2 V2 receptors in renal tubules, where it prevents the formation of aquaporins and thus inhibits free water reabsorption; it is indicated for managing hypervolemic and euvolemic hyponatremia associated with heart failure and other select diseases. Conivaptan, an intravenous inhibitor of V2 and V1a receptors in vascular smooth muscle, is only indicated for euvolemic hyponatremia. Despite being available orally, tolvaptan should be initiated in the hospital to allow for close monitoring and to avoid an overly rapid rise in serum sodium. Of note, hyponatremia recurs after discontinuing therapy with tolvaptan, suggesting it has no impact on underlying pathophysiology.23 In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, patients hospitalized with New York Heart Association class III–IV heart failure were randomized to treatment with tolvaptan or placebo. Tolvaptan was associated with improvement in hyponatremia, diuresis, and some symptoms of congestion; however, global clinical status at discharge, mortality, or heart failure readmissions were unchanged.24,25 Consequently, vasopressin antagonists should be reserved for patients

with ADHF and volume overload who have persistent severe hyponatremia and are at risk of having cognitive symptoms despite water restriction and optimization of GDMT.7 Ultrafiltration Ultrafiltration had previously emerged as an alternative strategy for rapid volume removal, given that salt and water may be eliminated at rates of up to 500 mL/hour. Because of its isotonic method of volume removal, ultrafiltration was surmised to provide a safe and effective approach to improving congestion while avoiding the adverse effects of diuretic therapy, such as hemodynamic perturbations, electrolyte loss, and renal impairment. In patients with ADHF and volume overload, the Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial suggested that ultrafiltration improved weight loss and net fluid loss compared with intravenous diuretics, as well as reduced read-missions and urgent office or emergency department visits.26 However, in the Cardiorenal Rescue Study in Acute De-compensated Heart Failure (CARRESS-HF) trial, a more recent study of patients with ADHF, persistent congestion, and renal impairment; an algorithm of stepped pharmacologic therapy (i.e., loop diuretics, thiazide-type diuretics, vasodilators, and inotropes) was superior to ultrafiltration at preserving renal function with a similar amount of weight loss.27 Ultrafiltration was also associated with a higher rate of adverse events, including infections and bleeding complications. Consequently, ultrafiltration may be considered to alleviate congestive symptoms and fluid weight in patients with obvious volume overload or in those refractory to medical therapy.7

HEMODYNAMIC SUPPORT Vasodilators Vasodilators may exert benefit in patients with ADHF through several mechanisms. First, venous dilatation can improve refractory congestive

symptoms by helping mobilize fluid and enhancing diuresis. In addition, dilating the venous vasculature may improve end-organ function by relieving the deleterious impact of excess venous congestion on the liver, kidneys, and GI tract. For patients whose congestion impairs the Frank-Starling relationship, enhanced volume removal with vasodilators in conjunction with diuretic therapy may restore optimal preload conditions. For vasodilators with effects on the arterial vasculature, reducing the excess systemic vascular resistance imparted by the sympathetic nervous system and renin-angiotensin-aldosterone system can confer improved LV performance as a result of reduced afterload. Although reductions in systemic vascular resistance can significantly reduce blood pressure in patients with normal LV function, improved LV performance as the result of reduced afterload in patients with impaired LV function may lead to minimal changes in mean arterial pressure.

Table 32.4 Intravenous Vasodilators Used in Acute Decompensated Heart Failure

BNP = B-type or brain natriuretic peptide; NO = nitric oxide.

Although oral vasodilators such as long-acting nitrates (e.g.,

isosorbide dinitrate), hydralazine, and angiotensin-converting enzyme (ACE) inhibitors are often used in patients with ADHF, the focus of this chapter will be the continuous infusions unique to this setting. Intravenous vasodilators used in ADHF include nitroglycerin, sodium nitroprusside, and nesiritide, each of which differs slightly in pharmacologic and pharmacokinetic effects (summarized in Table 32.4). Nitroglycerin acts almost exclusively as a venous dilator except at high doses (greater than 100 mcg/minute). Consequently, nitroglycerin is usually reserved for relieving venous congestion and improving refractory congestive symptoms. Sodium nitroprusside and nesiritide act as both venous and arterial vasodilators throughout their respective dosing ranges and may therefore improve LV performance through beneficial reductions in afterload, in addition to improving venous congestion. Although BNP should expectedly produce increased urine output through natriuresis, clinical trials (discussed below) do not suggest that this additional property of nesiritide imparts any clinically meaningful effect. From a pharmacokinetic standpoint, the effects of nitroglycerin and nitroprusside may be seen within minutes, whereas the onset of nesiritide may be delayed by up to 15–20 minutes. Nesiritide also has a longer half-life, which may make it more problematic in patients who develop hypotension. The presence of relative hypotension (i.e., systolic blood pressure less than 90 mm Hg) precludes vasodilator use in many patients with ADHF. As discussed previously, invasive hemodynamic monitoring with a PA catheter can confirm reduced cardiac output in the setting of an elevated systemic vascular resistance, where vasodilator use may still be beneficial despite low systemic pressures. With the exception of nesiritide, prospective studies of vasodilator use in ADHF are limited. In the Acute Decompensated Heart Failure National Registry (ADHERE) assessing the in-hospital mortality of patients with ADHF, nitroglycerin and nesiritide were associated with lower mortality than inotropes but were similar when compared with each other.28 In a single-center retrospective study, patients receiving short-term use of sodium nitroprusside demonstrated improved hemodynamic parameters as well as reduced all-cause mortality compared with patients who did not

receive nitroprusside although the latter was likely a result of increased chronic vasodilator use among patients transitioned from intravenous sodium nitroprusside.29 In contrast to nitroglycerin and sodium nitroprusside, nesiritide has been the subject of several large randomized controlled trials in ADHF. In the Vasodilation in the Management of Acute CHF (VMAC) trial, which compared nitroglycerin and nesiritide in patients with ADHF and congestive symptoms, nesiritide conferred significant improvements in PCWP after several hours, but the differences had mostly dissipated by 48 hours.15 Some, but not all, subjective symptoms of congestion were initially improved with nesiritide compared with nitroglycerin, but were no different at study conclusion. A randomized controlled trial known as the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND) indicated that patients receiving nesiritide did no better or worse when the agent was added to standard therapies.30 Similarly, in the ROSE trial, adding low-dose nesiritide (0.005 mcg/kg/minute) to standard therapy had no impact on urine output or other clinical outcomes in patients with ADHF and renal impairment.18 With respect to disadvantages, all three agents share hypotension as their most common adverse effect. In addition, tachyphylaxis often occurs with prolonged infusions of nitroglycerin (e.g., more than 12–72 hours) and less commonly with sodium nitroprusside. Sodium nitroprusside is associated with the unique risk of cyanide or thiocyanate toxicity in severe hepatic or renal dysfunction, although the risk is low in patients with ADHF given the lower doses and shorter durations commonly used in this setting. Its other disadvantages are of a practical nature; sodium nitroprusside commonly requires admission to an intensive care unit and placement of an arterial line for monitoring. Nesiritide is associated with rates of hypotension comparable to nitroglycerin and nitroprusside, but its long half-life may make it more problematic in patients with ADHF. In addition, given its lack of benefit compared with older agents, the cost of nesiritide precludes its use in most patients. In the absence of symptomatic hypotension, intravenous

nitroglycerin, sodium nitroprusside, or nesiritide may be considered as an adjuvant to diuretic therapy for relief of dyspnea in patients admitted with ADHF, especially in those whose symptoms are potentially life threatening.7 In addition, their use should be preferentially considered over inotropes in patients with low cardiac output and normal or elevated blood pressure because these patients may benefit from improved ventricular performance as a result of reduced afterload. In the latter scenario, assessing invasive hemodynamic parameters with a PA catheter should be strongly considered before initiating vasodilators. Given the tenuous hemodynamic status of most patients with ADHF, nitroglycerin and sodium nitroprusside should be initiated at low doses and titrated no faster than every 5–15 minutes, depending on patient response. For nesiritide, bolus administration can be omitted in patients at risk of hypotension. Among the three agents, nitroglycerin may be more favorable for patients with marginal blood pressure because its mostly venous vasodilatory effects may not impart significant reductions in systemic arterial pressure. Sodium nitroprusside and, to a lesser degree, nesiritide, should be considered for patients with hypertension or those whose hemodynamics suggest systemic perfusion is likely to improve with reduced systemic vascular resistance. Given its minimal benefit over older agents and greater cost, nesiritide offers few practical advantages over nitroglycerin or sodium nitroprusside. As with the nitroprusside study described earlier, the ultimate goal should be to transition from intravenous to oral therapies, specifically a GDMT with similar hemodynamic properties.29

Inotropes Positive inotropic agents enhance tissue perfusion through increased myocardial contractility. Because of their effect on cardiac output, inotropes can also reverse the end- organ abnormalities that often complicate ADHF (e.g., cardiorenal syndrome). However, they do not impart a mortality benefit in ADHF and in fact may increase the risk of death as well as adverse effects. Dobutamine and milrinone are the two most commonly used agents in ADHF and will therefore be the focus of this chapter. Digoxin also has inotropic properties; however,

the role of digoxin is primarily for the management of chronic heart failure in the outpatient setting. Although dobutamine and milrinone increase myocardial contractility, they differ in many aspects (summarized in Table 32.5). Dobutamine exerts its inotropic effects primarily by stimulating myocardial β1 receptors. Some vasodilation may occur at lower doses because of dobutamine’s effects on β2 receptors in vascular smooth muscle, although this may be counteracted by corresponding improvements in cardiac output or its effects on peripheral α1 receptors at higher doses. Milrinone increases intracellular concentrations of cyclic adenosine monophosphate by inhibiting phosphodiesterase type 3, which confers enhanced contractility in myocardial tissue as well as relaxation of vascular smooth muscle in pulmonary and systemic arterial beds. As a result of these combined effects, milrinone is often called an inodilator. Milrinone is often recommended in patients receiving chronic βblockers because it bypasses β receptors, although there is no evidence to suggest it confers a clinically meaningful benefit over dobutamine in this regard. In fact, some small studies suggest that chronic β-blocker use influences adrenergic receptor regulation, thereby preserving the potential for pharmacologic action by dobutamine.31 Studies are underway to address whether the pharmacologic activity of inotrope use in patients receiving β-blockers before admission depends on the inotrope selected and the β-blocker the patient had been receiving. Similarly, whether patients should continue receiving β-blockers in the setting of inotrope therapy also remains an area of controversy. Given the benefits of continuing βblockers during an ADHF episode (as well as the worsened clinical outcomes associated with their discontinuation),32,33 some clinicians may prefer to continue β-blockers when initiating inotrope therapy. Regarding pharmacokinetic properties, dobutamine has a fairly rapid onset of action and a short half-life; thus, it can be titrated rapidly depending on patient response. A notable exception occurs in patients who have been receiving dobutamine for extended periods (greater than 24 hours) because down-regulation of β-adrenergic receptors may

make rapid weaning difficult.34 In this latter scenario, therapy may need to be slowly tapered in a stepwise fashion depending on patient tolerance. Comparatively, milrinone has a slower onset of action and a longer half-life. Milrinone is primarily eliminated by renal clearance, and its half-life can be especially prolonged in patients with significant renal impairment. Consequently, it should be used with caution in patients with renal impairment and, if selected, initiated at lower doses and titrated more slowly. As with vasodilators, few randomized controlled trials have assessed intravenous inotropes in ADHF. As previously discussed, when retrospectively compared with other vasoactive therapies in ADHERE, inotrope use portended an increase in mortality even when adjusted for differences in baseline characteristics.28 The arrhythmogenic potential of inotropic therapy serves as a pharmacologically plausible explanation for an increased risk of mortality, but this impact has not been confirmed in prospective studies. Only milrinone has been the subject of a large, prospective, randomized controlled trial; the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) showed that its routine use did not confer improved clinical outcomes and, instead, increased the risk of hypotension and atrial arrhythmias.35 Of note, patients with an indication for inotropic therapy (e.g., cardiogenic shock) were excluded from the trial; thus, it assessed only the routine use of milrinone in a diverse population with ADHF. The decision to initiate inotrope therapy may be based on clinical features or invasive hemodynamic parameters. Whereas some clinicians prefer to initiate inotropes empirically when patients are refractory to other therapies or when unexpected responses occur (e.g., worsening renal function, ongoing congestion), others prefer invasive hemodynamic monitoring to confirm the presence of low cardiac output. As previously described, routine placement of a PA catheter does not improve outcomes in patients with ADHF, but its use is common when confirming the need for inotrope therapy and guiding dose titration.6

Inotropes may improve cardiac output and therefore end-organ perfusion, but their potential benefit must be weighed against the risk of significant adverse effects. Both dobutamine and milrinone increase the sensitivity of the myocardium to catecholamines and other potentially arrhythmogenic stimuli. The commonly held notion that milrinone increases the risk of atrial arrhythmias whereas dobutamine increases the risk of ventricular arrhythmias has not been conclusively shown in the literature. Both agents likely increase the risk of arrhythmias to a comparable degree. With respect to distinguishing adverse effects, milrinone is associated with higher rates of hypotension as well as rare cases of thrombocytopenia.

Table 32.5 Positive Inotropic Agents Used in Acute Decompensated Heart Failure

cAMP = cyclic adenosine monophosphate; PDE3 = phosphodiesterase type 3. aBolus

dosing listed in labeling but not used in practice

Inotropic agents are warranted as temporary or short-term therapy to maintain systemic perfusion and preserve end-organ function, or as a “bridge” to MCS or cardiac transplantation. For patients who are ineligible for advanced therapies, long-term inotropic therapy may be used as part of a palliative approach.7 As with vasodilators, inotrope administration requires frequent blood pressure monitoring as well as continuous monitoring for arrhythmias. Long-term use of intravenous

inotropes for reasons other than those outlined previously is potentially harmful. Dobutamine can be titrated every 5–15 minutes depending on response, whereas milrinone should be titrated more slowly because of its slower onset of action and longer half-life (e.g., every 6–12 hours, or up to every 12 hours in patients with renal impairment). Tapering should occur gradually with both agents and be guided by patient response. Initiating agents that optimize ventricular loading conditions (e.g., ACE inhibitors or other oral vasodilators) may assist with inotrope weaning. The decision regarding which inotrope to choose is often both clinician- and patient-dependent. An individual patient’s response is often unpredictable, and switching between therapies is common. In the setting of right ventricular (RV) failure, both therapies exert similar inotropic effects, although the vasodilating effects of milrinone may be helpful in patients with elevated pulmonary pressures. The systemic vasodilating effects of milrinone may be problematic in patients with low blood pressure. Therefore, dobutamine is usually preferred in patients with marginal blood pressure, although it, too, can lower blood pressure at low doses. Dobutamine may also be preferred in patients with renal impairment, although milrinone is not absolutely contraindicated. In fact, if renal impairment improves with enhanced tissue perfusion, higher doses may be required.

Dopamine The role of dopamine as an adjunct to diuretics has been discussed previously. Its use may also be considered for patients in whom a decrease in blood pressure with dobutamine or milrinone is problematic because dopamine provides positive inotropic effects without systemic vasodilation; this feature may make it particularly useful in patients with mixed shock syndromes (e.g., combined cardiogenic and septic shock). However, its impact on α and β receptors can be highly variable in individual patients, making dose titration a challenge. Therefore, many clinicians prefer the combined use of dobutamine and a vasopressor with more predictable hemodynamic effects (e.g., norepinephrine) in this setting because titration of one or the other on

the basis of patient response is more straightforward.

MANAGING CHRONIC THERAPIES DURING AN ACUTE DECOMPENSATION In the absence of hemodynamic instability or other contraindications, guidelines recommend that GDMT be continued.7 During hospitalization, every effort should be made to optimize standard heart failure therapy, although the timing of such is critical. β-Blockers should generally be continued during a hospitalization unless recent dose initiation or up-titration is thought to be the etiology of decompensation. In such cases, β-blockers may be dose reduced or temporarily held. Otherwise, discontinuation is discouraged because it has been associated with worse outcomes in both the prospective Beta-Blocker Continuation versus Interruption in Patients with Congestive Heart Failure Hospitalized for a Decompensation Episode (B-CONVINCED) trial and the retrospective OPTIMIZE-HF registry.32,33 For patients not receiving β-blockers, the Initiation Management Predischarge Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial showed that initiating β-blockers before discharge improved use at 90 days without increasing adverse effects.36 Guidelines recommend initiating β-blockers after optimal volume status has been achieved and after intravenous diuretics, vasodilators, and inotropic agents have been discontinued, although caution should be exercised in patients recently requiring inotropic therapy.7 In the setting of renal dysfunction, ACE inhibitors, angiotensin receptor blockers, and aldosterone antagonists may also need to be temporarily held, especially with coexisting oliguria or hyperkalemia. Therapies that can cause worsening renal function (e.g., ACE inhibitors) should be initiated or titrated cautiously during aggressive diuresis. If an aldosterone antagonist is initiated in the setting of aggressive diuresis, serum potassium concentrations should be monitored closely as diuretic therapy is weaned or transitioned to a chronic oral regimen. Elevated serum digoxin concentrations may warrant dose reduction or temporary discontinuation, especially in the

setting of declining renal function. Permanent discontinuation is generally discouraged because an association between digoxin withdrawal and worsening heart failure is well documented.37,38 Digoxin discontinuation may be appropriate if serum concentrations cannot be maintained in a desirable range (0.5–0.9 ng/mL) because of fluctuating renal function.

TEMPORARY MCS Many different temporary MCS modalities are available for patients with rapidly deteriorating ADHF or those refractory to pharmacologic support (Table 32.6). In general, indications for temporary MCS include cardiogenic shock with potentially recoverable cardiac function, hemodynamic support in high-risk patients undergoing cardiovascular procedures, or as a bridge to definitive therapy (e.g., durable MCS, cardiac transplantation).7,39 Three commonly used types of devices include the intra-aortic balloon pump (IABP), temporary ventricular assist device (VAD), and extracorporeal membrane oxygenation (Table 32.6). The role of extracorporeal membrane oxygenation is discussed separately (see page 656). Patients for whom temporary MCS should be avoided include those with advanced peripheral vascular disease (particularly aortic disease for IABP and Impella), irreversible complications (e.g., anoxic brain injury after cardiac arrest), or patients who are otherwise ineligible for definitive therapies. The thrombotic risks of each device warrant systemic anticoagulation, although temporary IABP support without anticoagulation has been reported.40 Consequently, MCS should generally be avoided in patients with bleeding diathesis or other contraindications to anticoagulation. Other complications of temporary MCS include infection and vascular injury.

Intra-aortic Balloon Pump An IABP consists of an elongated balloon affixed to the end of a catheter that is inserted into a large peripheral artery and advanced until the balloon rests in the descending aorta (between the aortic arch

and the splanchnic arteries). An IABP provides hemodynamic support by inflating during diastole, which enhances diastolic pressure and thus coronary perfusion, and by deflating during systole, which exerts a vacuum-like effect to reduce LV afterload, thereby improving cardiac output. According to the results of the second Intraaortic Balloon Pump in Cardiogenic Shock (IABP-SHOCK II) trial, the indiscriminant use of IABP in patients with cardiogenic shock has not been associated with improved outcomes.41 Thrombocytopenia may result from prolonged IABP use, which can be further worsened by concomitant anticoagulation therapy.

Temporary VADs Temporary VADs include the percutaneously placed Impella (Abiomed, Danvers, MA) and TandemHeart (CardiacAssist, Pittsburgh, PA) devices and the surgically implanted CentriMag device (Thoratec Corp., Pleasanton, CA) (Table 32.6). Each provides continuous blood flow, although the Impella device facilitates flow by an axial mechanism, whereas the TandemHeart and the CentriMag both facilitate centrifugal flow. Unique complications of each device relate primarily to the implantation technique or the mechanism for facilitating blood flow. The axial flow mechanism of the Impella device confers an increased risk of hemolysis. Transeptal placement required for the TandemHeart device is associated with complications related to perforation and shunt formation. Finally, the CentriMag device is associated with risks related to the invasive surgical procedure required for its placement (e.g., tissue injury). A more detailed discussion of the hemodynamic complications of VADs, including RV failure, appears in the Durable MCS section.

ADVANCED CARDIOVASCULAR THERAPIES Patients with end-stage heart failure may be eligible for durable MCS or cardiac transplantation. To be considered candidates for these advanced therapies, patients must undergo rigorous evaluation. Although cardiac transplantation remains the most optimal long-term

strategy for end-stage heart failure, limited donor availability as well as advances in durable MCS technology have led to sustained growth of VAD implantation.

Table 32.6 Temporary Mechanical Circulatory Support Devices

CO = cardiac output; LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle.

Durable MCS Indications for durable MCS include patients being evaluated for cardiac transplantation (“bridge to candidacy”), those awaiting a suitable donor (“bridge to transplantation”), or as a permanent strategy (“destination therapy”). Relative contraindications to durable MCS include high perioperative risk, anatomic abnormalities expected to affect device function, irreversible pulmonary hypertension, comorbid conditions expected to limit survival, and inability to manage the device or pharmacologic therapy.7 Durable MCS can be distinguished as providing LV, RV, or biventricular support, although left ventricular assist device (LVAD) implantation is most commonly used in practice and will be the focus of this chapter. The two LVADs currently approved in the United States are the

HeartMate II (Thoratec) and the HeartWare (Heart-Ware, Framingham, MA) ventricular assist systems. The HeartMate II is approved for both bridge to transplantation and destination therapy, whereas the HeartWare is currently approved only for bridge to transplantation. Both devices consist of an inflow cannula inserted into the apex of the left ventricle, a pumping unit, an outflow cannula inserted into the ascending aorta, and a subcutaneously placed driveline that connects the device to an external controller and power supply. The HeartMate II and the HeartWare are capable of producing up to 10 L/minute of continuous blood flow; blood flow is facilitated by axial flow in the HeartMate II and by centrifugal flow in the HeartWare. Although a variety of parameters reported by the LVAD controller can help in troubleshooting complications, only pump speed can be adjusted directly. All LVADs are preload-dependent and afterloadsensitive; thus, the flow reported by the LVAD may indicate changes in hemodynamic status. Low blood flow may indicate hypovolemia or bleeding. High flows may represent systemic vasodilation, which could be an early sign of sepsis. Pulsatility index (PI) is a unique parameter that reflects the alterations in blood flow provided by contraction of the native left ventricle and negatively correlates with the degree of support required of the LVAD. Low PI may therefore represent low preload (e.g., hypovolemia or excess pump speed) or worsening LV function. High PI is uncommon except when LV function has improved. Finally, spikes in the power required by the LVAD to facilitate blood flow can indicate pump thrombosis. A particularly challenging issue in a subset of patients with an LVAD is new-onset RV failure, often because of delayed resolution of pulmonary hypertension secondary to volume overload accompanied by an increase in venous return imparted by the LVAD. In addition, unloading of the left ventricle by the device may cause a leftward shift in the ventricular septum, which may further compromise RV geometry. Inotrope therapy can be used to improve RV contractility. The pulmonary vasodilation exerted by milrinone may be helpful in coexisting pulmonary hypertension, although systemic vasodilation may make dobutamine a better choice in select patients. Selective pulmonary vasodilators, such as phosphodiesterase type 5 inhibitors or

inhaled epoprostenol, may be helpful for reducing RV afterload. Aggressive volume removal and/or temporary reductions in LVAD speed may be required to alleviate excess RV preload. In refractory cases, temporary placement of an RV assist device or extracorporeal membrane oxygenation may be required. The most significant challenge in patients with an LVAD is preventing device thrombosis while mitigating bleeding risk. Antithrombotic regimens often consist of both antiplatelet and anticoagulant therapy (usually aspirin and vitamin K antagonists). Antithrombotic management is complicated by acquired von Willebrand syndrome, which occurs as a result of shear stress imparted by the LVAD.42 In addition, bleeding at specific sites (e.g., intestinal mucosa) is thought to occur as a result of the loss of pulsatile flow with continuous-flow LVADs.42 Nonetheless, hemorrhagic complications may require a temporary decrease in anticoagulation therapy or cessation. Blood transfusion may be required for critical bleeding events, and leukocyte-reduced blood should be selected in patients undergoing bridge to transplantation to reduce the risk of allosensitization. Pump thrombosis is a potentially life-threatening complication requiring urgent evaluation. Consensus on the treatment of thrombosis is lacking; available modalities have included enhanced anti-platelet or anticoagulation therapy, thrombolytics, and, in severe cases, pump exchange or urgent transplantation.43 Other complications of LVADs include infections and arrhythmias. Even mild infections thought to be localized to the driveline site or pump pocket (for HeartMate II) should be treated with aggressive empiric antimicrobial therapy to prevent seeding of the device. Patients with preexisting atrial fibrillation are treated similarly after LVAD implantation. Preexisting ventricular arrhythmias may not resolve after LVAD implantation and may in fact become worse for a time after surgery. If efforts to address hypovolemia (e.g., fluids, lower LVAD speed) are not effective for reducing arrhythmia burden, drug therapy (e.g., amiodarone, β-blockers) should be considered.

Cardiac Transplantation

The immediate postoperative treatment of cardiac transplant recipients is focused on bridging the patient to organ recovery, which can be delayed by prolonged ischemic time as well as reperfusion injury. Because of denervation of the implanted donor heart, inotropic and chronotropic therapy is especially important in the peri-operative period. A variety of inotropic agents (e.g., dobutamine, milrinone, epinephrine, isoproterenol) may be employed in this setting. Delays in myocardial recovery often impair the relationship between preload and stroke volume; thus, the donor heart may be especially reliant on chronotropy to maintain cardiac output. Heart rate targets in excess of 90 beats/minute are often advocated, and additional pharmacologic therapy (e.g., albuterol, theophylline) or temporary pacing may be required in patients whose heart rate remains low despite chronotropic therapy (e.g., isoproterenol).44 Vasopressors may also be required to maintain peripheral perfusion (mean arterial pressure greater than 65 mm Hg). Preventing excess preload (central venous pressure less than 12 mm Hg) with the use of diuretics and venous vasodilators is necessary to prevent right heart overload. As with LVAD implantation, efforts to aggressively manage pulmonary hypertension are necessary to prevent acute right heart failure. Elevated pulmonary pressures that remain refractory to volume removal may require the use of selective pulmonary vasodilators. After the immediate postoperative treatment of cardiac transplant recipients, achieving an appropriate degree of immunosuppression becomes the emphasis of drug therapy management. For patients with inadequate immunosuppression, the most common manifestation of acute graft rejection is ADHF, and patients are initially treated similarly to those with native heart failure. Other manifestations of acute graft rejection include myocardial ischemia, arrhythmias, and cardiac arrest, and each complication is acutely managed similarly in transplant recipients to those with native disease. Until graft dysfunction can be differentiated as being acute cellular rejection or antibody-mediated rejection in nature, aggressive corticosteroid use is often selected as an empiric immunosuppressive approach. Specific strategies for managing acute cellular rejection or antibody-mediated rejection differ

by center.44–46 In addition to corticosteroids, therapeutic approaches for acute cellular rejection often include antithymocyte globulin, whereas consensus on managing antibody-mediated rejection is less clear.45 Therapeutic modalities for antibody-mediated rejection include corticosteroids, plasmapheresis, intravenous immunoglobulin G, and upstream anti-immunoglobulin therapies, such as rituximab and bortezomib.46

PHARMACIST’S ROLE Several studies have shown the positive role that pharmacists can play in managing patients with chronic heart failure. Given the growing emphasis on transitions of care and preventing heart failure readmissions, it is likely that many of these interventions will increasingly affect patients with ADHF. The PHARM (Pharmacist in Heart Failure Assessment Recommendation and Monitoring) study was the first randomized controlled trial to show the role of a clinical pharmacist in managing patients with chronic heart failure (n=192). Patients randomized to pharmacist intervention had a significant reduction in the combined primary end point, all-cause mortality and hospitalization or emergency department visit for heart failure (odds ratio 0.22, p=0.005), primarily because of a reduction in heart failure hospitalization.47 A more recent study showed higher rates of initiation or dose titration of select GDMTs with pharmacist-led 30-minute medication optimization compared with usual care. However, there was no difference in the primary end point, all-cause mortality, or heart failure related hospitalization.48 Multidisciplinary disease management programs, specialized heart failure clinics, and home-based interventions involving pharmacists have been associated with a wide range of benefits, including reduced heart failure readmissions and emergency department visits as well as improved adherence and symptoms.49 Pharmacists can provide a variety of services on the multidisciplinary team, including serving as experts on patient counseling.50 Finally, a recent systematic review of multidisciplinary teams involving a pharmacist showed reductions in all-cause and heart

failure hospitalizations. Lack of impact on mortality may have occurred because of limitations in study design (size, duration of follow-up).51 The American Heart Association recently published a statement describing transitional care interventions and outcomes and discussing implications and recommendations for research and clinical practice to enhance patient-centered outcomes.52 This statement acknowledges that of the transition of care programs for patients with heart failure (n=20), 75% used a collaborative, multidisciplinary team that included pharmacists.

CONCLUSION Optimal management of ADHF requires pharmacists to effectively identify prognostic factors that allow stratification on the basis of potential lack of benefit or propensity for adverse events from ADHF therapies. Initial intravenous diuretic regimens should target prompt dyspnea relief, as should adjunctive strategies for managing refractoriness to diuretics. Select patients warrant intravenous vasodilator and/or inotropic therapy, and appropriate patient selection is critical for safe and effective use of these therapies. In addition to playing a key role in ensuring the optimal use of intravenous therapies, pharmacists should advocate for the appropriate use of GDMTs yet appreciate when referral for cardiac transplantation or MCS is necessary.

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36. Gattis WA, O’Connor CM, Gallup DS, et al.; IMPACT-HF Investigators and Coordinators. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. J Am Coll Cardiol 2004;43:1534-41. 37. Packer M, Gheorghiade M, Young JB, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. N Engl J Med 1993;329:1-7. 38. Uretsky BF, Young JB, Shahidi FE, et al. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol 1993;22:955-62. 39. Rihal CS, Naidu SS, Givertz MM, et al.; Society for Cardiovascular Angiography and Interventions (SCAI); Heart Failure Society of America (HFSA); Society of Thoracic Surgeons (STS); American Heart Association (AHA), and American College of Cardiology (ACC). 2015 SCAI/ACC/HFSA/STS Clinical Expert Consensus Statement on the Use of Percutaneous Mechanical Circulatory Support Devices in Cardiovascular Care: Endorsed by the American Heart Association, the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencion; Affirmation of Value by the Canadian Association of Interventional Cardiology-Association Canadienne de Cardiologie d’intervention. J Am Coll Cardiol 2015; 65:e7-e26. 40. Pucher PH, Cummings IG, Shipolini AR, et al. Is heparin needed for patients with an intra-aortic balloon pump? Interact Cardiovasc Thorac Surg 2012;15:136-9. 41. Thiele H, Zeymer U, Neumann FJ, et al.; IABP-SHOCK II Trial Investigators. Intra-aortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012;367:1287-96.

42. Stewart GC, Givertz MM. Mechanical circulatory support for advanced heart failure: patients and technology in evolution. Circulation 2012;125:1304-15. 43. Goldstein DJ, John R, Salerno C, et al. Algorithm for the diagnosis and management of suspected pump thrombus. J Heart Lung Transplant 2013;32:667-70. 44. Costanzo MR, Dipchand A, Starling R, et al.; International Society of Heart and Lung Transplantation Guidelines. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010;29:914-56. 45. Lindenfeld J, Miller GG, Shakar SF, et al. Drug therapy in the heart transplant recipient: part I: cardiac rejection and immunosuppressive drugs. Circulation 2004;110:3734-40. 46. Chih S, Tinckam KJ, Ross HJ. A survey of current practice for antibody-mediated rejection in heart transplantation. Am J Transplant 2013;13:1069-74. 47. Gattis WA, Hasselblad V, Whellan DC, et al. Reduction in heart failure events by the addition of a clinical pharmacist to the heart failure management team: results of the Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM) Study. Arch Intern Med 1999;159:1939-45. 48. Lowrie R, Mair FS, Greenlaw N, et al. Heart failure optimal outcomes from pharmacy study I. Pharmacist intervention in primary care to improve outcomes in patients with left ventricular systolic dysfunction. Eur Heart J 2012;33:314-24. 49. Milfred-LaForest SK, Chow SL, DiDomenico RJ, et al. Clinical Pharmacy Services in Heart Failure: an opinion paper from the Heart Failure Society of America and American College of Clinical Pharmacy Cardiology Practice and Research Network. Pharmacotherapy 2013;33:529-48. 50. Wiggins BS, Rodgers JE, DiDomenico RJ, et al. Discharge

counseling for patients with heart failure or myocardial infarction: a best practices model developed by members of the American College of Clinical Pharmacy’s Cardiology Practice and Research Network based on the Hospital to Home (H2H) Initiative. Pharmacotherapy 2013;33:558-80. 51. Koshman SL, Charrois TL, Simpson SH, et al. Pharmacist care of patients with heart failure: a systematic review of randomized trials. Arch Intern Med 2008;168:687-94. 52. Albert NM, Barnason S, Deswal A, et al.; American Heart Association Complex Cardiovascular Patient and Family Care Committee of the Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Quality of Care and Outcomes Research. Transitions of care in heart failure: a scientific statement from the American Heart Association. Circ Heart Fail 2015;8:384-409.

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

LEARNING OBJECTIVES 1. Review the pathophysiology and presentation of patients with an acute coronary syndrome (ACS). 2. Describe the role of anti-ischemic therapy in the management of ACS. 3. Compare and contrast the antiplatelets and anticoagulants routinely used in ACS.

ABBREVIATIONS IN THIS CHAPTER ACS

Acute coronary syndrome

ACT

Activated clotting time

AT

Antithrombin

CABG

Coronary artery bypass grafting

CK

Creatine kinase

cTnI

Cardiac troponin I

cTnT

Cardiac troponin T

CV

Cardiovascular

DAPT

Dual antiplatelet therapy

GRACE

Global Registry of Acute Coronary Events

HIT

Heparin-induced thrombocytopenia

ICH

Intracranial hemorrhage

LMWH

Low-molecular-weight heparin

MI

Myocardial infarction

NSTE

Non–ST-segment elevation

PCI

Percutaneous coronary intervention

STEMI

ST-segment elevation myocardial infarction

TIMI

Thrombolysis In Myocardial Infarction

UFH

Unfractionated heparin Groups and Organizations

ACCF/AHA American College of Cardiology Foundation/American Heart Association ESC

European Society of Cardiology

INTRODUCTION Cardiovascular (CV) disease is the leading cause of death in the United States. An acute coronary syndrome (ACS), including unstable angina and myocardial infarction (MI), are the most common cause of CV death.1–3 An estimated 15.5 million Americans older than 20 years have coronary artery disease. The overall prevalence of MI is 2.8% in U.S. adults (4.0% in men vs. 1.8% in women).3 The complexity of the disease combined with the rapidly evolving literature can be overwhelming to practitioners. The primary purpose of this chapter is to discuss important considerations in disease assessment and medication evaluation in ACS management.

PATHOPHYSIOLOGY Mechanism of Plaque Rupture and Thrombus Formation An ACS event begins with the rupture of an unstable coronary atherosclerotic plaque.14 This rupture exposes the plaque contents to the circulating blood. The thrombogenic contents, including collagen and tissue factor, promote platelet adhesion and activation. Plateletderived vaso-active substances such as adenosine diphosphate (ADP) and thromboxane A2 (TXA2) promote additional platelet activation and vasoconstriction. Platelet activation also results in a conformational change to the glycoprotein IIb/IIIa surface receptor. Platelet aggregation involves the crosslinking of activated platelets through the surface glycoprotein IIb/IIIa receptor with fibrinogen. Simultaneously, the extrinsic clotting cascade is activated, leading to the production of thrombin (factor IIa) and ultimately fibrin (factor Ia).

Disease Assessment Patients with suspected ACS should have a comprehensive workup that evaluates chest pain history, cardiac markers, and electrocardiographic (ECG) findings.1,2

Risk Scoring Several risk assessment scores have been developed and validated to encourage the timely diagnosis and treatment of patients presenting with an ACS. A score can easily and objectively risk-stratify patients with non-specific ischemic symptoms. Most clinical prediction algorithms use a combination of clinical history, physical examination, cardiac markers, and ECG. These scoring systems are not designed to assess whether a patient’s signs and symptoms are caused by ACS, but to estimate their in-hospital, 6-month, and 3-year mortality. Three common examples of validated risk assessment scores include the Thrombolysis In Myocardial Infarction (TIMI), Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), and Global Registry of Acute Coronary Events

(GRACE) scores (Table 33.1). The TIMI score uses seven variables, all of which carry the same magnitude of risk, to predict death, MI, or target vessel revascularization at 14 days.4 The PURSUIT score uses five variables to predict short-term outcomes at 30 days, whereas the GRACE score uses eight variables to predict in-hospital mortality and MI.5,6 An updated GRACE score (GRACE 2.0) has been created to simplify and strengthen the predictability of the clinical tool (substitutes Killip class for diuretic use, and serum creatinine with a history of renal dysfunction).7 Patients with an ACS can be assigned a low, moderate, or high-risk score to aid in their prognosis and care. No prediction tool has been proven superior to another, so many clinicians use the TIMI risk score for ease and convenience.

Table 33.1 Predictive Risk Scores4–6

CAD = coronary artery disease; CCS = Canadian Cardiovascular Society; GRACE = Global Registry of Acute Coronary Events; PURSUIT = Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; SBP = systolic blood pressure; TIMI = thrombolysis in myocardial infarction (score).

Table 33.2 PQRST Pain Assessment in Patients Having an ACS Event Precipitative

Nonexertional; may occur at rest

Palliative

No relief with rest or organic nitrates

Quality

Stabbing or crushing

Region

Substernal; anterior midline

Radiation

Either arm or shoulder, back, upper abdomen, and lower jaw

Severity

7–10 on a 10-point scale

Temporal

> 20 min

Chest Pain Story Chest pain is the most common symptom reported in patients experiencing an ACS event.1,2 Because chest pain is subjective, the PQRST [pain characteristics in low back pain syndrome] pain assessment method can be used to accurately and comprehensively acquire the classic characteristics of the event (Table 33.2). The chest pain associated with an ACS event is not typically precipitated by exertion and often occurs at rest. In addition, rest or organic nitrate administration does not typically result in the palliation of ACS chest pain. Patients may qualify the chest pain as a stabbing and/or crushing pain. This pain typically begins at the anterior midline and may radiate to either arm or shoulder, the back, or the lower jaw. Pain reported below the lower jaw and above the umbilicus is possible during or immediately after an ACS event. Patients often report the pain as severe, equivalent to a score of 7/10. Finally, the absence of pain relief from rest and organic nitrates usually results in episodes lasting more than 20 minutes. Although these characteristics describe the classic chest pain symptoms, women, patients with diabetes, and older adult patients may have an atypical presentation. Other associated symptoms that may occur during an ACS event include diaphoresis, shortness of breath, distress, nausea, and vomiting.

Cardiac Markers Patients with severe or prolonged myocardial ischemia will develop

myocardial necrosis. Myocardial infarction is associated with elevations in both specific and non-specific cardiac markers. These biochemical markers are important in the evaluation, diagnosis, and triage of patients with chest pain (Table 33.3). Accurate interpretation of clinically relevant biomarkers requires an understanding of both their biology and their kinetics. Creatine kinase (CK) is composed of three isoenzymes: CK-MB, CK-MM, and CKBB. Although CK is found in many tissues throughout the body, the distribution of the isoenzymes varies significantly. About 20% of total CK in the cardiac muscle is CKMB compared with only 2%–5% of total CK in the skeletal muscle. The total CK is not cardiac-specific, and elevations can been observed in patients with cardiac, skeletal, and cerebral injuries. The CK-MB is the most cardiac-specific isoenzyme because of its relatively low distribution in non-cardiac tissues. Elevations in both total CK and CKMB can be observed after cardiac and non-cardiac injuries. The CKMB/total CK ratio or CK-MB relative index can be used to differentiate cardiac disease from non-cardiac disease.8 A CK-MB greater than 5% of the total CK is suggestive of an ACS event. The CK isoenzymes share a similar kinetic pattern including an initial rise in 4–9 hours, a peak in 24 hours, and normalization in 24–48 hours. Because of advances in troponin assays, CK and CK-MB are no longer recommended in the diagnosis of ACS. If measured in this setting, several CK-MB and total CK measurements should be considered to avoid a false-negative result early (within 0–4 hours) after the onset of chest pain. False-positive results can be observed in patients with muscle disorders, chronic renal failure, hypothyroidism, pulmonary edema, and congestive heart failure.1,2

Table 33.3 Kinetic Profiles of Cardiac Biomarkers8–10

Myoglobin is a small protein found in high concentrations in both cardiac and skeletal muscles. Although non-specific for cardiac disease, the kinetic profile of myoglobin aids in its clinical utility. Myoglobin is released within 1–2 hours after muscle injury. A peak myoglobin concentration is achieved within 4–12 hours and is rapidly cleared from the blood within 24 hours. Myoglobin has a high negative predictive value and poor specificity, making it more clinically useful to rule out ACS, rather than confirming the diagnosis.8 Troponin is a three-protein complex (troponin C [TnC], troponin T [TnT], and troponin I [TnI]) used in the contractile apparatus of muscles. Although cardiac and skeletal muscles both contain TnT and TnI, the amino acid sequence is unique enough to differentiate cardiac troponin (cTnC, cTnT, and cTnI) from skeletal troponin. The troponin subunits share a similar kinetic pattern including an initial rise in 4–9 hours, a peak in 12–24 hours, and normalization within 14 days. Several cTnT or cTnI measurements should be considered to avoid a false-negative result early (within 0–4 hours) after the onset of chest pain. Troponin is routinely measured at baseline, 8 hours, and 16 hours to assist in the diagnosis of ACS. The European Society of Cardiology (ESC) and the American College of Cardiology (ACC) Joint Committee have defined MI as an elevated cardiac troponin above the 99th

percentile of the healthy reference population.9 Troponin has several ideal features, including biologic, kinetic, and prognostic, which makes it a valuable test in the clinical assessment of ACS. First, cTnT and cTnI is found in relatively high concentrations within the myocardium and is absent within non-cardiac tissue and in the blood of healthy individuals. Second, troponin is released rapidly after myocardial injury, aiding in a timely diagnosis. Third, the magnitude of troponin elevation has been correlated with the risk of death after an ACS event. In addition, troponin may be helpful in identifying an optimal management strategy. Finally, the technology to measure cTnT and cTnI has seen several clinically significant advances. The likelihood of a false-positive and negative result with troponin is less than with myoglobin and CK-MB. Most assays are highly sensitive and specific, and point-of-care troponin testing can produce a qualitative and quantitative result in about 15 minutes. False positives can be observed in patients with other cardiac disease states including advanced heart failure, myocarditis, and pericarditis. Some non-cardiac disease states may also result in a false-positive troponin including chronic obstructive pulmonary disease, pulmonary embolism, and chronic renal failure. In renal failure, an elevated cTnT is observed more often than is cTnI because of cTnT’s instability in the serum and higher clearance during dialysis.10

ECG Findings Myocardial ischemia and infarction can be detected using a 12-lead ECG. The ECG can help clinicians understand the presence, extent, and severity of ischemia. Ischemic episodes can be observed on the ECG within minutes of the index event. An ECG should be ordered and interpreted within 10 minutes on arrival to an emergency department.1 Typical ECG findings indicative of ischemia include T-wave inversion, ST-segment depression, and ST-segment elevation. Comparison of a baseline ECG can be helpful in assessing whether ischemic changes are new or old. Changes within specific groupings of ECG leads can suggest the location of the occluded coronary lesion (Table 33.4).11

Table 33.4 ECG Changes During Ischemia and Infarction11

Patients with unstable angina and non–ST-segment elevation (NSTE) may present with T-wave inversion and ST-segment depression, and in some instances, the ECG may remain normal. However, the diagnosis of ST-segment elevation myocardial infarction (STEMI) requires the presence of ST-segment elevation. The ESC and ACC guidelines have defined the amplitude change needed for STsegment elevation as 0.2 mV in men and 0.15 mV in women (leads V2 and V3) or 0.1 mV in any other ECG lead. Pathologic Q waves may also occur several hours to days after an MI. A Q wave appears when electrical activity is absent and rarely disappears despite aggressive pharmacologic and reperfusion strategies.1,2,11 The presence of a left bundle branch block (LBBB), which may occur in 7% of patients, makes interpreting the ECG more difficult during periods of ischemia.12 The baseline ST-segment and T-wave morphology seen with LBBB can mask or mimic the ECG findings during an infarction. A new LBBB is always pathological and may be a sign of MI. The Sgarbossa criteria can be used in patients with a new LBBB and suggestion of an infarct. A Sgarbossa score of 3 or greater

has a specificity of 90% for detecting an infarct.13

ROLE OF GUIDELINES Guidelines Several groups have written guidelines for the management of ACS, including the ACC and the American Heart Association (AHA). The 2013 STEMI and 2014 NSTE ACC/AHA guidelines use both a class and a level system to describe the magnitude and strength of the recommendation. A class I recommendation signifies that the potential benefits outweigh any perceived risks, whereas a class III recommendation implies that the procedure or treatment has no benefit or may be harmful. A level A recommendation is derived from several randomized controlled trials or a meta-analysis, whereas a level C recommendation is based on case studies or expert opinion.1,2 Other expert groups have either written or endorsed guidelines (e.g., Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, ESC). Although other consensus statements and guidelines exist, the ACC/AHA guidelines are considered the gold standard for preventing ACS and treating patients with ACS in the United States.

Core Measures The ACS core measures represent standards of care that have a clear morbidity and mortality benefit. The acute MI set consists of seven measures (Table 33.5) involving care at admission and on discharge. This quality initiative allows patients, accrediting agencies, and reimbursement groups to evaluate institutions on the basis of performance and quality.15

ANTI-ISCHEMIC THERAPY Oxygen

Historically, oxygen has routinely been administered to all patients with suspected ACS on arrival to the hospital. Evidence for this practice is seeded by weak studies performed in non-human models. Oxygen administration has become routine practice because of the hypothesis that supplemental oxygen improves coronary perfusion pressures and reduces myocardial necrosis. However, hyperoxia appears to have some detrimental effects such as reflex vasoconstriction, increased peripheral and systemic vascular resistance, and cardiotoxicity from oxygen free radicals.16 Consequently, guidelines now recommend supplemental oxygen during the first 6 hours after arrival in patients with respiratory distress, hypoxic signs and symptoms, or an oxygen saturation less than 90% (American College of Cardiology Foundation [ACCF]/AHA] NSTE class I, level of evidence [LOE] C and STEMI class I, LOE B).1,2

Table 33.5 Acute MI Core Measures15 Performance Measure No. AMI-1

AMI-3

AMI-5

AMI-7

AMI-7a

AMI-8

Performance Measure Name

Description

Aspirin at arrival

Aspirin administered within 24 hr before or after hospital arrival

ACEI or ARB for LVSD

ACEI or ARB prescribed at hospital discharge in patients with a left ventricular ejection fraction < 40%

β-Blocker prescribed at discharge

β-Blocker prescribed at hospital discharge

Median time to fibrinolysis

Median time from arrival to administration of fibrinolytic therapy in patients with STsegment elevation

Fibrinolytic therapy received within 30 min of hospital arrival

Fibrinolytic therapy administered ≤ 30 min from hospital arrival in patients with STsegment elevation

Median time to primary PCI

Median time from hospital arrival to PCI in patients with ST-segment elevation

AMI-8a

Primary PCI received within 90 min of hospital arrival

PCI performed ≤ 90 min from hospital arrival in patients with ST-segment elevation

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; LVSD = left ventricular systolic dysfunction; MI = myocardial infarction; PCI = percutaneous coronary intervention.

Nitrates The selection and role of nitrate administration in the management of ACS is highly dependent on the formulation’s pharmacokinetic profiles. Nitroglycerin forms free radical nitric oxide, which activates guanylate cyclase, resulting in an increase of guanosine 3’,5’-monophosphate (cyclic GMP) resulting in smooth muscle vasodilation. In general, nitrates should be considered for symptomatic relief because they have no long-term mortality benefit.17,18 Sublingual nitrates are recommended for symptomatic relief in the management of acute chest pain. However, patients experiencing an ACS event may not receive any symptomatic relief from sublingual administration. Most patients with acute chest pain will receive up to 3 sublingual nitroglycerin 0.4-mg tablets administrated 5 minutes apart (ACCF/AHA NSTE and STEMI class I, LOE C).1,2 The sublingual tablets are quickly dissolved and absorbed through buccal absorption with a mean Cmax (maximum concentration) of 6–7 minutes. In the acute setting, nitrates dilate both normal and atherosclerotic coronary arteries to enhance coronary blood flow to the myocardium. In vessels that are almost 100% occluded, additional vasodilation likely has little to no benefit. In the setting of acute chest pain, intravenous nitroglycerin administration may provide additional benefit by decreasing preload and left ventricular end-diastolic volume. Ultimately, these hemodynamic changes provide a reduction in myocardial oxygen demand. Continued use of intravenous nitroglycerin typically occurs in patients who have had an ACS event with ongoing hypertension or symptoms of heart failure (ACCF/AHA NSTE class I, LOE B and STEMI class I, LOE

C).1,2 Extreme caution should be taken in patients who are normotensive, and intravenous nitroglycerin should be avoided in patients with hypotension (systolic blood pressure less than 90 mm Hg). Nitroglycerin should also be avoided in patients with ventricular dysfunction who are preload-dependent. Typically, intravenous nitroglycerin is initiated at 5 mcg/minute with dosage adjustments of 5 to 10 mcg/minute up to a maximum dose of 200 mcg/minute. Tolerance can develop with intravenous nitroglycerin within 12 to 24 hours. Clinicians should reassess the need for and effectiveness of intravenous nitroglycerin every 6–12 hours. β-Blockers β-Blockers are routinely used in both acute and chronic management of ACS. β-Adrenergic inhibitors reduce blood pressure, heart rate, and contractility, which ultimately reduces cardiac demand. Inhibition of norepinephrine on cardiac tissue reduces the need for oxygen-rich blood supply. In general, β-blockers should be selected on the basis of their selectivity and binding properties. Patients experiencing an ACS event should receive a β1-selective agent without intrinsic sympathomimetic activity. β-Blockers have been proven safe and effective in most patients with ACS.19 β-Blockers should be initiated within the first 24 hours in patients without heart failure, low-output state, and cardiogenic shock (ACCF/AHA NSTE class I, LOE A and STEMI class I, LOE B).1,2 The use of β-blockers in patients with other contraindications including a PR interval greater than 0.24 second, second- or third-degree heart block, or severe airway disease should also be avoided. The use of intravenous β-blockers should be avoided in patients in shock or with risk factors for cardiogenic shock, including age older than 70 years, heart rate greater than 110 beats/minute or less than 60 beats/minute, systolic blood pressure less than 120 mm Hg, and late presentation (ACCF/AHA NSTE class III, LOE B and STEMI class IIa, LOE B).1,2 Patients with stable heart failure and an ejection fraction less than 40% should be initiated on metoprolol succinate, bisoprolol, or carvedilol

before discharge. These agents have a proven mortality benefit in patients with systolic heart failure. Several early trials showed benefits with the use of early β-blockers on infarct size, recurrent chest pain, reinfarction, and death.20–23 More recently, the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) study was designed to evaluate the use of β-blockers in the management of acute MI.19 Patients presenting with STEMI were randomized to receive intravenous metoprolol (n=22,929) or placebo (n=22,923). Patients randomized to receive β-blocker therapy were initiated on intravenous metoprolol (up to 15 mg) and then converted to oral metoprolol succinate (up to 200 mg daily). The use of early βblocker therapy resulted in significantly fewer reinfarctions (2.0% vs. 2.5%; p=0.001) and ventricular fibrillation events (2.5% vs. 3.5%; p=0.001) but increased the risk of cardiogenic shock (5.0% vs. 3.9%; p 500 ms in patients with ventricular conduction abnormalities). bAvoid

in patients with heart failure and/or QT interval prolongation.

VT = ventricular tachycardia.

Figure 35.15 Treatment algorithm for termination of VT in critically ill patients.a aAll

drugs administered intravenously.

bClass

IIb, LOE C.8

cClass

IIa, LOE B.8

dClass

IIb, LOE B.8

DCC = direct current cardioversion (synchronized); VT = ventricular tachycardia.

Figure 35.16 Torsades de pointes. Reprinted with permission from: Tisdale JE. Review of cardiac arrhythmias and rhythm interpretation. In: Wiggins BS, Sanoski CA. Emergency Cardiovascular Pharmacotherapy. A Point-of-Care Guide. Bethesda, MD: American Society of Health-System Pharmacists,

2012:38.

Some patients who develop drug-induced TdP may have an underlying genetic predisposition. Polymorphisms of genes associated with the congenital LQTS may be present in 10%–15% of patients with drug-induced TdP.123 Risk factors for QTc interval prolongation in critically ill patients have been identified and incorporated into a QTc interval prolongation risk score, in which 1, 2, or 3 points was assigned to each risk factor.124 Independent risk factors for QTc interval prolongation in critically ill patients were similar to those associated with TdP and included age 68 years or older (1 point), female sex (1 point), taking a loop diuretic (1 point), serum potassium of 3.5 mEq/L or less (2 points), admission QTc interval of 450 milliseconds or greater (2 points), acute MI (2 points), HFrEF (3 points), receiving one QTc interval–prolonging agent (3 points), and receiving two or more QTc interval–prolonging drugs (3 points). In addition, sepsis was an independent risk factor for QTc interval prolongation (3 points).124 A risk score in the intermediate (7– 10) or high (11 or more) range predicted critically ill patients at highest risk of developing QTc interval prolongation.124

Table 35.7 Drugs That May Cause Torsades de Pointes Drug Class

Drug(s)

Anesthetic

Propofol Sevoflurane

Antiarrhythmic

Amiodarone Disopyramide Dofetilide Dronedarone Flecainide Ibutilide

Procainamide Quinidine Sotalol Antibiotic

Azithromycin Ciprofloxacin Clarithromycin Erythromycin Levofloxacin Moxifloxacin

Anticancer

Arsenic trioxide Vandetanib

Antiemetic

Droperidol Ondansetron

Antidepressant

Citalopram Escitalopram

Antifungal

Fluconazole Pentamidine

Antimalarial

Chloroquine Halofantrine

Antipsychotic

Chlorpromazine Haloperidol Pimozide Thioridazine

Cholinesterase inhibitor

Donepezil

Miscellaneous

Cocaine Methadone

Morbidity and Mortality Drug-induced TdP occurring in the ICU may be associated with prolonged duration of hospital stay.114 Torsades de pointes may remain hemodynamically stable, or it may be hemodynamically unstable and rapidly degenerate into ventricular fibrillation and cause cardiac arrest/sudden cardiac death. Prevention and Treatment In critically ill patients receiving drugs that may cause TdP, clinicians must be attentive to methods of reducing the risk of TdP. QTc interval– prolonging drugs should be avoided, whenever possible, in patients with a pretreatment QTc interval greater than 450 milliseconds. If a patient receiving a QTc interval–prolonging drug has a QTc interval increase of 60 milliseconds or greater from pretreatment value, the dose should be reduced or the drug discontinued whenever possible. Drugs with the potential to cause TdP should be discontinued if the QTc interval is prolonged to greater than 500 milliseconds. Serum potassium, magnesium, and calcium concentrations should be maintained within the normal range. When possible, avoid use of drugs with the potential to cause TdP in patients with HFrEF, particularly if the left ventricular ejection fraction is less than 20%. Doses of renally eliminated QTc interval–prolonging drugs should be adjusted in patients with acute kidney injury or chronic kidney disease. When possible, avoid using combinations of drugs that prolong the QTc interval. Avoid concomitant use of cytochrome P450 (CYP) system inhibitors and QTc interval–prolonging drugs that are CYP substrates. Avoid administering drugs with the potential to cause TdP in patients with a history of druginduced TdP and in those with a diagnosis of the congenital LQTS. Critically ill patients receiving therapy with a QTc interval–prolonging drug should be maintained on continuous telemetry monitoring, and the QTc interval should be documented every 8–12 hours.102

Box 35.2. Risk Factors for Drug-Induced TdP

• QTc interval > 500 ms • Increase in QTc interval ≥ 60 ms from pretreatment value • Female sex • Age > 65 yr • HFrEF • Recent myocardial infarction • Hypokalemia • Hypomagnesemia • Hypocalcemia • Treatment with diuretics • Bradycardia • Sequential bilateral bundle branch block • Elevation in serum concentration of QTc interval–prolonging drug because of drug interaction or inadequate dose adjustment for kidney disease • Rapid intravenous injection of QTc interval–prolonging drug • Possible genetic predisposition • History of drug-induced TdP HFrEF = heart failure with reduced ejection fraction; TdP = torsades de pointes.

A treatment algorithm for management of TdP in critically ill patients is presented in Figure 35.17. Patients with TdP that is hemodynamically unstable should undergo asynchronous defibrillation, rather than synchronized cardioversion, because synchronization of shocks in polymorphic arrhythmias is often impossible.8 In patients with TdP that is hemodynamically stable, intravenous magnesium is recommended, primarily on the basis of two observational

studies.125,126 In patients who do not respond to intravenous magnesium, isoproterenol or overdrive pacing may be used if patients have TdP that is associated with bradycardia or that appears to be precipitated by pauses in rhythm. Elective defibrillation may be used in refractory cases that are hemodynamically stable.8 Refractory TdP associated with sotalol has been successfully managed using hemodialysis127 or peritoneal dialysis.128

Figure 35.17 Treatment algorithm for critically ill patients with TdP. a

As polymorphic arrhythmias do not permit synchronization, defibrillation is recommended, rather than synchronized direct current cardioversion.8 Administer sedation when possible. bClass cNo

I, LOE B.8

class of recommendation or level of evidence provided in the guidelines for these therapies.

TdP = torsades de pointes.

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Chapter 36 Pharmacologic

Challenges During Mechanical Circulatory Support in Adults Amy L. Dzierba, Pharm.D., FCCM, BCPS; and Erik Abel, Pharm.D., BCPS

LEARNING OBJECTIVES 1. Describe the different types of mechanical circulatory support (MCS) in an adult patient. 2. Explain altered pharmacokinetics and pharmacodynamics of medications during MCS. 3. State dosing recommendations of common medications used during extracorporeal membrane oxygenation on the basis of current literature.

ABBREVIATIONS IN THIS CHAPTER ECLS

Extracorporeal life support

ECMO

Extracorporeal membrane oxygenation

IABP

Intra-aortic balloon pump

LVAD

Left ventricular assist device

MCS

Mechanical circulatory support

PVC

Polyvinyl chloride

VA-ECMO Venovenous extracorporeal membrane oxygenation VV-ECMO Venoarterial extracorporeal membrane oxygenation VAD

Ventricular assist device

INTRODUCTION Mechanical circulatory support (MCS) is a broad-reaching description of the advanced technology and capability available today to support patients with acute or chronic hemodynamic compromise when conventional therapies have failed or are unsustainable. As MCS has evolved, so has its implementation into clinical practice. As will be discussed later in this chapter, the options for MCS largely depend on the primary organ system needing support— cardiovascular/cardiopulmonary versus pulmonary only. Long-term cardiovascular support with durable implantable ventricular assist devices (VADs) and the total artificial heart provide a management option in end-stage heart failure beyond the traditional construct of palliative care versus transplantation. However, short-term cardiac support allows options to provide acute cardiovascular MCS for temporary support with intra-aortic balloon pumps (IABPs), paracorporeal/extracorporeal VADs, or extracorporeal life support (ECLS)/extracorporeal cardiopulmonary resuscitation (ECPR) by venoarterial (VA) extracorporeal membrane oxygenation (ECMO).1–5 However, ECLS by venovenous (VV) ECMO has grown significantly as a promising modality of therapy for patients with severe acute pulmonary failure.3,6 Early descriptions of MCS were documented in the early 19th century and further described in the 1930s.7 However, these therapies were first applied to human subjects in 1953 by J. Gibbon Jr using a heart-lung machine for atrial septal defect repair and in 1954 by C.

Walton Lillehei, M.D., to successfully perform cardiac surgery using controlled cross-circulation and a bubble oxygenator.8,9 Many notable events have been pioneered to bring us to the advances in MCS we see today (Table 36.1). Although thoracic organ transplantation is commonly considered the gold standard treatment for end-stage heart or lung disease, growing comorbidities, psychosocial concerns, and lack of donor organ availability have driven the advancement of MCS, particularly for cardiovascular support. As MCS has advanced, implantable VADs have evolved from large pulsatile devices to smaller, more durable continuous flow devices. Other advances have allowed exploration into further application of MCS for other populations. In the severely critically ill patient with cardiac or cardiopulmonary compromise, the growing application of ECLS has shown that MCS may have a role in hemodynamic support beyond the operating room or in end-stage heart failure. Extracorporeal membrane oxygenation and ECLS are forms of mechanical respiratory and circulatory support that have considerably evolved during the past decade.10 With new developments in this technology, use in adults has been growing rapidly, a trend that was initially seen after the 2009 influenza A (H1N1) pandemic.11,12 The growing use of MCS and increasing complexity of available devices, in addition to the complicated pathophysiology and pharmacotherapeutic support requirements of these patients, deliver an undeniable need for the critical care clinician to understand the principles and ramifications of MCS.

Table 36.1 Timeline of Landmarks and Advances in Mechanical Circulatory Support 1950s

Membrane oxygenators were first developed

1972

Hill and colleagues used ECMO for respiratory failure for 75 hours

1975

NIH initiates study of ECMO for adult respiratory failure

1975

First NIH-sponsored multicenter trial of temporary LVADs for acute heart failure

1976

Bartlett and colleagues reported the first successful use of ECMO in neonates

1994

HeartMate LVAD (Thermo Cardiosystems, Inc.) FDA approved for BTT

2002

HeartMate XVE for destination therapy approved by FDA

2006

Polymethylpentene oxygenator (Quadrox D, Maquet Cardiovascular) approved by the FDA

2009

Expansion of ECLS for pulmonary failure secondary to the H1N1 influenza epidemic

BTT = bridge to transplantation; DT = destination therapy; ECLS = extra-corporeal life support; ECMO = extracorporeal membrane oxygenation; LVAD = left ventricular assist device; NIH = National Institutes of Health.

INDICATIONS AND TYPES OF MCS The type of MCS, as well as the intent and potential duration, depends on several factors, including patient acuity, comorbidities, and prognosis. The progression and options for support can be dynamic, given a patient’s clinical progress and etiology of hemodynamic compromise. As a general construct, the options for support can be divided according to the primary organ dysfunction (respiratory vs. cardiac) and can further be divided into temporary versus long-term MCS (Table 36.2). For some cardiac indications, a patient may be optimized and go directly to long-term MCS. All forms of MCS are considered a “bridge” or intervention to a progressive improvement in a patient’s clinical status—be it a “bridge” to recovery from the acute pulmonary or cardiac disease; a “bridge” from a temporary to a durable MCS device; or a “bridge” from chronic MCS to transplantation or palliative care. Particularly in relation to long-term MCS, the intent should be declared before the time of implantation with the understanding that during long-term support, clinical factors (new improvement or deterioration) may influence change in the intent of support (Figure 36.1). For long-term MCS, the intent of the “bridge” has been defined by INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) as described in Table 36.3. Resource use and the fundamental oath of primum non nocere (first,

do no harm) are notwithstanding when it comes to patient selection. As such, MCS strategies must consider contraindications that account for complications during MCS and therapies required during support, in addition to the reversibility of the patient’s disease state and likely prognosis when considering comorbidities (Table 36.4 and Table 36.5).

GENERAL DEVICE OVERVIEW AND SETTINGS The MCS devices available for clinical use can vary among institutions; however, for some devices, availability can also differ according to enrollment and participation criteria for clinical trials as well as indication approval/availability by country.19 In general, each device is connected to a controller that mediates the speed or vacuum/rate of the respective pump, and the speed most directly dictates power consumption of the respective pump (other factors may also play a role in power consumption). Aside from IABPs, a list of MCS devices can be found in Table 36.6. Although somewhat proprietary to each device, almost all MCS devices require some level of anticoagulation, which will be discussed later in the chapter.

IABP Counterpulsation 20 An IABP is generally placed by femoral arterial catheter (in some scenarios, it can also be placed by left brachial, axillary, or subclavian arteries) and advanced into the descending thoracic aorta. The IABP is an intervention that can provide selective systolic afterload reduction while enabling diastolic augmentation of blood pressures, all contributing to sustaining an increased mean arterial pressure. Intraaortic balloon pump deflation provides systolic afterload reduction to ease cardiac work (does not directly increase cardiac output). Subsequently, IABP inflation enables diastolic augmentation of systemic mean arterial blood pressures through displacement of blood to increase mean arterial perfusion pressure. The timing of IABP inflation and deflation can be set to trigger from electrocardiogram, pacemaker, or arterial line pressures or can be manually set. Patients with aortic valve regurgitation/insufficiency may not benefit from this means of

afterload reduction because of worsening regurgitation during diastole. Patients with tachyarrhythmias and/or irregular heart rates may have less-than-optimal IABP synchronization. The level of support from an IABP coincides with the timing of inflation/deflation per related heartbeat. For example, 1:1 is one inflation/deflation per every heartbeat (maximal support), and 1:4 is one inflation/deflation for every fourth heartbeat (less support). Blood flow stagnation associated with decreasing of IABP support increases the thrombotic risk and may warrant anticoagulation. Immobility is a predominant limitation to this form of MCS that is particularly seen when the IABP is placed femorally.

Table 36.2 Indications and Associated Types of MCS Primary Indications Dysfunction Respiratory

• Hypoxic and/or hypercapnic respiratory failure owing to any cause (ARDS, BTT, primary graft dysfunction after lung transplantation) • Severe air leak syndromes

Cardiac; temporary MCS

• Cardiogenic shock secondary to one of the below causes and refractory to standard therapies: 1. Post-cardiotomy 2. Myocarditis 3. Nonischemic cardiomyopathy 4. Pulmonary embolism • Extracorporeal cardiopulmonary resuscitation • Bridge to VAD or heart or heart & lung transplantation • Primary graft failure after heart transplantation • Prevention or treatment of right

Potential Means of MCS • VV-ECMO • AV CO2R (hypercapnic respiratory failure only, in limited use) • Intra-aortic balloon pump • VA-ECMO • Extracorporeal VAD • Percutaneous VAD • Paracorporeal VAD

ventricular failure after LVAD implantation • Pulmonary hypertension Cardiac; longterm MCS

• Class IV, ACC/AHA stage D heart failure symptoms, EF < 25% • Refractory cardiogenic shock (INTERMACS category 1) • Dependent on IABP or other form of temporary MCS 7 days

• Durable implantable LVAD or heart assist system • Total artificial heart

• Intermittent/continuous inotropic therapy (INTERMACS category 2–3) for more than 14 days • Evidence of poor cardiac output with low cardiac index (< 2.3 L/min), elevated filling pressures (PCWP > 20 mm Hg) and hypotension with SBP < 90 mm Hg • Cardiopulmonary exercise testing with peak VO2 < 14 mL/kg/min with cardiac limitation and/or poor prognostic indicators with other parameters ACC/AHA = American College of Cardiology/American Heart Association; ARDS = acute respiratory distress syndrome; AV CO2R = arterial venous carbon dioxide removal; ECMO = extracorporeal membrane oxygenation; EF = ejection fraction; IABP = intra-aortic balloon pump; INTERMACS = Interagency Registry for Mechanically Assisted Circulatory Support; MCS = mechanical circulatory support; PCWP = pulmonary capillary wedge pressure; SBP = systolic blood pressure; VAD = ventricular assist device; VA-ECMO = venoarterial extracorporeal membrane oxygenation; VV-ECMO = venovenous extracorporeal membrane oxygenation; VO2 = oxygen consumption.

Percutaneous VADs Currently, a handful of MCS devices can be used for temporary support. In the United States, such devices include the TandemHeart pVAD (Cardiac Assist, Pittsburgh, PA) and the Impella (Abiomed, Danvers, MA). Future developments may include newer or modified percutaneous devices to provide left ventricular support that is more robust, but these are also being developed to provide less invasive right ventricular support.21 These devices are currently used

predominantly in cardiogenic shock or as temporary support during high-risk interventional or electrophysiological cardiac procedures. The TandemHeart pVAD device (Cardiac Assist, Pittsburgh, PA) can be used as an MCS device capable of providing up to 8 L/minute of support by centrifugal pump (continuous non-pulsatile blood flow). Depending on the manner of configuration, it is capable of providing left ventricular support by atrial transseptal puncture cannulation, or using an alternative cannula (Protek Duo), it may also be set up to provide right ventricular support or enable VV-ECLS.22 Another device, the Impella (Abiomed), comes in differing platforms enabling 2.5, 3.5, or 5.0 L/minute of non-pulsatile blood flow support to the left ventricle.23–26 These devices are placed into the aorta across the aortic valve percutaneously for the 2.5- or 3.5-L/minute platforms or by surgical placement if using the 5.0-L/minute platform. As it resides in the left ventricular cavity, blood is suctioned into the inflow port and through the outflow port in the ascending aorta. The anticoagulation regimen for this device is a common topic of debate and medication safety discussion because it requires a heparinized dextrose purge solution (ranging from D5W to D50W) to lubricate and cool the rotary motor and minimize blood-motor interface. Management can be complicated by migration and malposition of the catheter/cannula within the left ventricle, leading to arrhythmias and hemolysis. Specific contraindications to this device include mechanical aortic valve, moderate to severe aortic stenosis, moderate to severe aortic insufficiency, and severe peripheral vascular disease. More recently the Impella RP (Abiomed) was introduced to the market as a temporary MCS device that can provide support to those with acute right ventricular dysfunction/failure. Configured slightly different than the other Impella devices, the Impella RP is placed in the femoral vein and advanced to reside with the inflow area within the inferior vena cava and outflow within the pulmonary artery. A pulmonary artery catheter is commonly used concurrently, however, cardiac outputs are favored to be calculated by Fick method rather than thermodilution because of the heat generated by the pump and subsequent interference. A heparin purge solution is still required with this device.

Figure 36.1 Dynamic progression of heart failure advanced therapies. ACC NYHA = American College of Cardiology, New York Heart Association; IABP = intraaortic balloon pump; VA-ECMO; venoarterial extracorporeal membrane oxygenation.

Table 36.3 Classification of Long-term MCS with Ventricular Assist Devices Destination therapy

Formal designation for patients who meet the criteria for long-term mechanical support but who are not a transplant candidate because of relative or absolute contraindications

BTT

Formal designation for patients eligible to be listed as candidates for heart transplantation

Bridge to candidacy OR bridge to recovery

Designation used to describe the approach to temporary MCS when short-term LVADs are used to support a patient until a long-term prognosis can be determined, which may include explantation with recovery, implantation of long-term durable LVAD support, heart transplantation, or palliative care

BTT = bridge to transplantation; LVAD = left ventricular assist device; MCS = mechanical circulatory support

Extracorporeal or Paracorporeal VADs Various extracorporeal VADs are available, although some common examples include the Thoratec CentriMag Blood Pump (Thoratec Corporation, Pleasanton, CA), BVS 5000 Ventricular Support System (Abiomed), and AB5000 Circulatory Support System (Abiomed). The CentriMag Blood Pump provides up to 9 L/minute of continuous nonpulsatile blood flow by a magnetically levitated impeller. Although commonly used for a longer duration, this device is approved by the U.S. Food and Drug Administration (FDA) for up to 6 hours of MCS as a bridge to decision for other advanced therapies, but it is also approved by the FDA for use as a right VAD for up to 30 days for patients in cardiogenic shock caused by acute right ventricular failure.27,28 The BVS 5000 (Abiomed) can be used for temporary unilateral (left or right) or biventricular support. This device is a more simplistic VAD with two sac-like chambers that fill semi-passively by gravitational force and that are subsequently emptied by an air-driven pump to deliver up to 6 L/minute of pulsatile blood flow by displacement. The filling chamber should be watched closely for signs of thrombus development.29 The AB5000 Circulatory Support System (Abiomed) can also be configured for use as temporary unilateral (left or right) or biventricular support. This device rests in a paracorporeal manner on the chest of the patient and, through vacuum assistance, can provide up to 6 L/minute of pulsatile blood flow.30

Table 36.4 Potential Complications of MCS13–18 • Mechanical (circuit/pump)

• Thrombosis

complications • Bleeding and transfusion ○ Hemorrhagic stroke ○ Gastrointestinal bleeding ○ Pulmonary hemorrhage ○ Acquired von Willebrand factor deficiency • Postoperative right heart failure \TIA =

○ Embolic stroke ○ TIA ○ Systemic embolization ○ Venous thrombosis • Mechanical hemolysis and hemolysisinduced end-organ damage • Arrhythmias • New infections • Cannula/conduit displacement

transient ischemic attack.

Table 36.5 Comorbidities and Prognostic Considerations to Consider Before Initiating MCS Temporary MCS • Active systemic infection, particularly bacteremia • Prolonged ventilation > 10 days or with high airway pressure and/or high FIO2 > 7 days • Established multisystem organ failure • Contraindications to anticoagulation • Refusal to receive blood products

Long-term MCS • Active systemic infection • End-organ or multisystem organ failure including impending renal or hepatic failure • Right ventricular failure • Moderate to severe valvular disease • Neurologic deficits or psychosocial limitations impairing ability to manage device (e.g., daily activities, rehabilitation potential, cognitive function according to neurocognitive evaluation) • Severe pulmonary disease

• Ungrafted severe burns

• Coexisting terminal disease

• Quadriplegia

• Refractory or uncontrolled ventricular tachyarrhythmias

• Bone marrow transplant recipients • Inadequate CPR > 5 minutes or prolonged CPR > 30 minutes • Intracranial hemorrhage

• Known bleeding or clotting disorder • Visual or hearing impairment • Social support network • Insurance/financial means to support

• Evidence of neurologic insult

long-term care needs

• Profound metabolic acidosis with pH < 7.1 • Requirement of prolonged neuromuscular blockade infusion • Requirement of prolonged high-dose vasoactive drugs • Not a transplant candidate and presenting with either primary/idiopathic pulmonary hypertension or end-stage cardiopulmonary disease • Specific to VA-ECMO or IABP: tachyarrhythmias and aortic valve regurgitation CPR = cardiopulmonary resuscitation; FIO2 = fraction of inspired oxygen; IABP = intraaortic balloon pump; VA-ECMO = venoarterial extracorporeal membrane oxygenation.

Durable Implantable VADs and Total Artificial Hearts Ongoing developments have continued to enable prolonged MCS to patients. Early durable VADs, such as the Heart-Mate XVE, were quite large with large-bore drivelines and mediated pulsatile flow by an electrically controlled pusher plate that displaced blood and required minimal anticoagulation. However, the life span of this device was limited by the wear and tear on the metal bearings in the motor as well as the potential acquired dysfunction of the integrated porcine valves within the inflow and outflow cannula/conduits. This device has since been replaced in therapy with newer continuous-flow, non-pulsatile VADs (either axial or centrifugal flow), which has facilitated much longer pump life. Although requiring full anticoagulation, these newer devices such as the HeartMate II (Thoratec, Pleasanton, CA) and HeartWare HVAD (HeartWare, Framingham, MA), have provided acceptable risk profiles for thrombosis and bleeding in clinical trials. Simplistically, these devices are implanted by placing an inflow cannula/conduit into the apex of the left ventricle, which pulls blood through the pump to exit

through the outflow graft that is attached to the ascending aorta. Although these devices provide selective support of the left ventricle, the care management must also facilitate appropriate medical management of right ventricular support to enable successful patient treatment.31 For implantable devices, the connection to the power source and controller is enabled by a driveline that is usually tunneled through the abdomen to an exit site. In select patients, a total artificial heart may be considered, particularly in patients with biventricular heart failure who are listed for heart transplantation. The HeartMate II (Thoratec) can deliver up to 10 L/minute of blood flow by an axial rotor that spins at 8,000–15,000 rpm. The device controller provides alarms regarding flow disturbances, pump failure, low power, power or connection disruptions, and controller malfunction. The HeartWare HVAD (HeartWare) provides up to 10 L/minute by a centrifugal flow impeller spinning at 2,000–3,000 rpm.

Table 36.6 MCS Devices

aCurrently in

clinical trials.

ECLS or ECMO Similar to cardiopulmonary bypass, ECLS/ECMO drains venous blood through large-bore cannulas, pumped through an oxygenator (usually by means of a centrifugal, non-pulsatile pump), where it is oxygenated and cleared of carbon dioxide and then actively pumped back into the

body. The modality of support depends on the means of vascular cannulation. Venovenous cannulation removes deoxygenated venous blood from the vena cava and returns blood near the right atrium after circulating through the oxygenator and circuit; it requires the heart circulate blood to maintain end-organ perfusion. Venoarterial cannulation is more complex. With peripheral cannulation, the venous inflow cannula removes blood from the vena cava by the femoral vein and delivers oxygenated blood by femoral or axillary artery outflow cannula to the descending aorta, resulting in retrograde flow to the ascending aorta. Central cannulation, commonly seen post-cardiotomy, removes blood from the right atrium and delivers oxygenated blood into the ascending aorta immediately distal to the coronary sinus. Femoral cannulation of VA-ECMO can increase the risk of lower limb ischemia obstruction of distal blood flow. This may be avoided by placing a distal perfusion catheter to either the femoral artery or a distal site such as the posterior tibial or dorsalis pedis arteries. Because of the low-flow state within the heart, VA-ECMO can be associated with a risk of intracardiac and/or aortic root thrombus. Considerations of which populations may be considered for VVECMO versus VA-ECMO are outlined in Table 36.2. Beyond anticoagulation considerations, ECMO/ECLS presents considerably more pharmacologic challenges, as will be outlined in the following section. Extracorporeal membrane oxygenation/ECLS has evolved significantly, with almost 250 centers registered with the Extracorporeal Life Support Organization, allowing for variation in circuit setup and management. Although the components required are fundamentally the same (pump, oxygenator, circuit tubing, and cannula), variation in pharmacologic interactions has been described among different proprietary constituents of these ECMO/ECLS circuits.

PHARMACOLOGIC CHALLENGES WITH MCS Drug-Circuit Interactions and Considerations— Overview

When administering a drug, there is a balance between the dose administered and the elicited response, with the goal of providing a therapeutic effect while minimizing toxicity. This relationship between the drug dose and response may be altered in critically ill patients as a result of pharmacokinetic and pharmacodynamic changes.32 The use of ECMO can lead to additional pharmacokinetic alterations.33 Providing optimal dosing regimens for patients receiving ECMO requires a working knowledge of pharmacokinetic and pharmacodynamic alterations propelled by drug, disease, and extracorporeal factors (Figure 36.2). Despite improvements in this technology and resurgence of its application for respiratory failure, there remains a paucity of evidence and understanding of pharmacotherapy in patients receiving MCS. Almost all of the data that have been published on changes in pharmacokinetics during MCS have been with ECMO, with few or no data published regarding pharmacokinetic changes in patients with heart failure having VADs. The elimination of drugs from the body is highly dependent on clearance and volume of distribution.34 The liver and the kidneys serve as the two major organ systems responsible for drug elimination. Additional losses of drugs through the skin and gastrointestinal tract or biliary excretion can serve as minor pathways of drug elimination. Organ impairment or failure, altered plasma protein binding, increases in circulating volume, and perfusion abnormalities are often encountered in critically ill patients, resulting in changes in absorption, distribution, metabolism, and elimination of the drugs, creating challenges in drug dosing. In addition, patients receiving ECMO may have an array of pathophysiological changes, including acute kidney injury and decreased hepatic blood flow, leading to changes in drug clearance; however, these changes from ECMO may be difficult to ascertain in the already critically ill patient.

Figure 36.2 The complex interplay between physiochemical properties of the drug(s), diseasespecific alterations in pharmacokinetics in the critically ill, and extracorporeal factors. Changes in volume of distribution owing to ECMO may be caused by hemodilution, sequestration of drugs as a result of circuit-related factors, decreased circulating albumin, or alterations in protein binding from pH aberrations. Priming solutions (plasma, saline, or albumin) that are used on initiation of ECMO increase the patient’s circulating volume and may lead to pharmacologic alterations with hydrophilic drugs, resulting in potentially decreased plasma concentrations.35,36 In addition, the dilution of plasma proteins, notably albumin, may affect highly protein bound drugs, leading to potential toxicities as a result of an increased proportion of unbound fraction of the drug.37 Data concerning drug sequestration within the ECMO circuit are limited. The membrane oxygenator and polyvinyl chloride (PVC) tubing are two circuit components that provide a large surface area for dug sequestration, leading to potential drug loss over time.38,39 Some studies have shown that both the PVC tubing and the membrane oxygenators absorb drugs to a similar extent, whereas others have shown significant differences.39–45 Results from a simulated circuit showed an average of 80% loss of fentanyl in the circuit without

oxygenators at 120 minutes, with only an additional 5% loss when a Quadrox D oxygenator was added.39 Up to 40% of morphine was lost in all circuits, and no differences were noted in those with and without oxygenators.39 A saturation point may exist, leading to liberation of sequestered drug back into the circulation; however, this concept has not been studied. Understanding the physicochemical properties of drugs can assist in determining the relationship between the dose administered and the anticipated concentration achieved in the blood.41 The octanol-water partition coefficient is a common way to report a drug’s measure of lipophilicity.43 Log P, the logarithm of the ratio of the concentrations of the unionized solute in the solvents, may be used to understand the behavior of drug molecules.43 Therefore, drugs with high log P values (around 2.0) will have a propensity to be very soluble in organic materials such as the plastic tubing used in the ECMO circuit.44 However, to date, there has been no characterization of the drug-circuit interaction beyond 24 hours, and as such, little speculation can be made regarding the adsorptive capacity of the circuit over longer periods of ECMO support. Overall, data are sparse relating to drug dosing in adult patients receiving ECMO. However, extrapolations from ex vivo studies may be useful to anticipate alterations in the pharmacokinetics of a drug that may occur during ECMO. In addition, some generalizations can be made with hydrophilic versus lipophilic drugs. Lipophilic drugs tend to be more affected by the ECMO circuitry and may require higher-thanexpected dosing regimens to achieve the same therapeutic effect without ECMO (Figure 36.3).

Figure 36.3 Proposed pharmacokinetic changes based on physicochemical properties of drugs in critically ill patients receiving mechanical circulatory support. CL = clearance; PK = pharmacokinetics; Vd = volume of distribution.

Drug-Circuit Interactions and Considerations— Analgesia and Sedation The provision of analgesia and sedation is common practice for mechanically ventilated patients in the ICU to provide comfort and maintain patient safety. Medication selection should be based on the patient’s needs, with titration to a predetermined goal in accordance with recently published guidelines.45 The use of analgesia and sedation during ECMO contributes to the reduction in oxygen consumption, facilitates patient-ventilator synchrony, diminishes patient stress and discomfort, and prevents patient-initiated device dislodgement or removal.10 Results from several investigations using ex vivo models have shown a loss of analgesics and sedatives within the ECMO circuit.42,46,47 These studies using neonatal ECMO circuits composed of PVC tubing and silicone rubber membrane oxygenators established an early loss of

commonly used sedatives.42,46,47 One investigation observed up to a 68% loss of midazolam and a 98% loss of propofol within 40–120 minutes.42 Steady morphine concentrations have been observed over time, with only about 20% drug loss over 6–24 hours.46,47 However, in contrast, significant reductions in fentanyl concentrations have been observed within 3 hours.46 Reductions of up to 30% from the original concentration of lorazepam have also been detected.47 An adult ECMO in vitro circuit using PVC tubing with a hollow polymethylpentene fiber membrane oxygenator showed up to a 93% decrease in dexmedetomidine concentrations at 24 hours.48 A more recent study used ex vivo ECMO circuits to measure concentrations of morphine, fentanyl, and midazolam throughout a 24-hour period.44 At 24 hours, average drug recovery relative to baseline from both the circuits and the controls was lower with the lipophilic drugs, including fentanyl 3%, midazolam 13%, and morphine 103%.44 Of interest, in the first hour of the ECMO run, up to 70% and 50% of fentanyl and midazolam, respectively, were lost in the circuit, and fentanyl was undetectable at 24 hours.44 Because of the lack of sequestration of morphine in the ECMO circuit, it would seem to be a preferred agent for prolonged periods of ECMO; however, the risks of accumulation, especially in patients with renal injury; the profound hypotensive effects; and the deliriogenic effects make morphine an unattractive agent for prolonged sedation.45 Adult patients receiving ECMO for respiratory failure appear to have increased requirements of analgesia and sedation over time.49,50 A small, single-center, retrospective study showed an increase in the daily dose of midazolam on average by 18 mg (p=0.001) and morphine on average by 29 mg (p=0.02).50 Patients receiving VV-ECMO had a significantly higher daily midazolam dose requirement than did patients receiving VA-ECMO (p=0.005).50 Despite these studies showing an increased need for analgesics and sedatives during ECMO, it remains unknown whether the increased requirements clinically observed are a result of circuit-related factors alone or whether other factors such as tolerance, age, or organ function are contributors.47 To date, data are sparse to guide the

appropriate dosing of analgesics and sedatives in adult patients receiving ECMO with newer technology. Furthermore, there is a lack of outcomes data associated with these observational experiences. One approach to achieving adequate deep sedation in patients receiving ECMO would be to start with continuous infusions of both an analgesic and a sedative, anticipating requirements that exceed standard doses. In addition, establishing daily sedative goals with the potential for sedative interruption, anticipating significant dose reductions at ECMO discontinuation, and monitoring for signs of withdrawal and delirium should be considered.

Drug-Circuit Interactions and Considerations—Antiinfective Agents Infections are commonly encountered in critically ill patients. Source control in addition to timely and appropriate antimicrobials remains the cornerstone to the success of the treatment for a critically ill patient.51 Most antimicrobial dosing regimens are established in healthy adults with normal physiology; however, significant changes in rate of clearance and volume of distribution may have profound effects on drug concentrations in the critically ill patient on ECMO.52 The changes in clearance and volume of distribution could result in substantial drug losses, leading to therapeutic failures, development of resistance, and worse outcomes. Monitoring of drug concentrations is not possible with many anti-infective agents; therefore, clinicians must rely on knowledge of a drug’s physiochemical properties, pharmacokinetic characteristics, and published experience to guide appropriate dosing. Until recently, there has been very little in the literature on the effects of antimicrobial dosing in the critically ill adult patient receiving ECMO. Vancomycin Vancomycin pharmacokinetics has been described in adult patients receiving ECMO.53,54 Using a population pharmacokinetic model for vancomycin, a significant decrease in clearance and increases in volume of distribution were observed in a mixed population receiving

ECMO.53 A more recent study compared the pharmacokinetics of vancomycin in adult patients receiving continuous infusion vancomycin with and without the use of ECMO.54 All patients received a 35-mg/kg loading dose over 4 hours, followed by a continuous infusion aimed to target a serum concentration of 20–30 mg/L.54 Throughout the first 24 hours of the study, there were no differences in clearance or volume of distribution between the two groups. In addition, an ex vivo study showed very little loss of vancomycin using modern adult ECMO circuitry.44 Current dosing of vancomycin in critically ill adult patients receiving ECMO appears to be no different than critically ill patients not receiving ECMO; however, because therapeutic drug monitoring is widely available, concentrations should be routinely monitored to ensure adequate therapy. Aminoglycosides Aminoglycosides have concentration-dependent killing, often used in conjunction with other gram-negative antimicrobial agents to treat lifethreatening infections in adult patients. As a class, these agents are hydrophilic, with a low molecular weight, low protein binding, and a small volume of distribution. The study of aminoglycoside pharmacokinetic alterations with ECMO is largely limited to the neonatal population. These studies have consistently observed a significant increase in volume of distribution and a decrease in clearance leading to an extension of the dosing interval in this population, despite the variability in trial design and methodology.55–58 No studies currently address the pharmacokinetic changes of aminoglycosides in the adult patient receiving ECMO; however, because of the highly hydrophilic nature of this class, no changes in clearance as a result of sequestration would be expected. Therapeutic drug monitoring is readily available for this class of anti-infectives, thereby ensuring effective concentrations to treat the infection while limiting nephrotoxicity. Penicillins/Extended-Spectrum Penicillins/Cephalosporins/Carbapenems

There is no adult literature on changes in pharmacokinetic parameters in adult patients receiving ECMO with the penicillin, extended-spectrum penicillin, or cephalosporin antimicrobial classes. These classes of antiinfectives are commonly used in the treatment of gram-negative infections in the critically ill patient population. They have timedependent bactericidal effects and are therefore most effective when concentrations are maintained above the minimum inhibitory concentration for at least 40% of the dosing interval. Substantial increases in meropenem clearance were observed in two patients receiving ECMO for treatment of severe respiratory failure secondary to pneumonia.59 Only when the dose of meropenem was administered as a high-dose infusion (6.5 g every 24 hours) were optimal concentrations attained.59 Supporting this concept, a recent ex vivo ECMO study observed a 24-hour average drug recovery relative to baseline from the circuits and controls for meropenem to be 20% and 42%, respectively.44 Increases in volume of distribution and clearance of meropenem have been observed in the critically ill patient with sepsis not receiving ECMO, leading to suboptimal drug concentrations.36,60 Mechanical circulatory support can induce a systemic inflammatory-like response, independently from sepsis, augmenting clearance and volume of distribution. In addition, significant meropenem degradation has been observed at ambient temperatures (37°C); this may therefore lead to inaccurate conclusions of the effects of ECMO circuitry on increased clearance. Dosing regimens in the adult patients receiving one of these anti-infective classes should account for these significant changes in pharmacokinetics while the patients are receiving ECMO, resulting in higher doses with more frequent dosing intervals, extended infusions, or continuous infusions. Antifungals Few studies have been published on the pharmacokinetic changes of antifungal agents in adult patients receiving ECMO. Significant drug sequestration of voriconazole has been observed in an ex vivo model.46 The authors observed a 71% loss of voriconazole at 24 hours.46 One case report observed undetectable voriconazole serum concentrations

despite dose increases (8 mg/kg) in an adult patient receiving ECMO.61 However, in another case report, voriconazole concentrations were sustained with an increased dose.62 Given the relatively high lyophilic nature of voriconazole, it would not be surprising to have decreased plasma concentrations with recommended doses; however, there are no current recommendations on dosing regimens in critically ill patients receiving ECMO. Conflicting case reports have been published on caspofungin, observing either no effect on pharmacokinetic parameters or an increase in clearance. Others The results of a case series in adult patients receiving linezolid and ECMO showed alterations in linezolid pharmacokinetics.63 Two of the three patients had no changes in volume of distribution, with one patient with cystic fibrosis having a substantial decrease in volume of distribution, and all three patients had an increased clearance.63 The hydrophilic nature of this drug and the documented variability of linezolid serum concentrations in critically ill patients potentially caused by augmented renal clearance may influence these pharmacokinetic alterations to a greater extent than sequestration from the ECMO circuit.64 One case reports no pharmacokinetic changes in a patient receiving ECMO.65 Many tigecycline classes of anti-infectives are used in the critically ill patient receiving ECMO; however, no data have been published in adult patients thus far.

COMPLICATIONS OF MCS Complications of MCS can be multifactorial, which, in some cases, may partly be a result of the comorbidities of the patient population. Nonetheless, there are commonalities largely related to neurologic events, bleeding, thrombosis, hemolysis, device malfunction, or infection (see Table 36.6).

BLEEDING, THROMBOSIS, AND ANTICOAGULATION

Fundamentally, successful MCS depends on the function of the MCS device and its impact on the intrinsic rheologic properties of blood and particularly its influence on key interactions in thrombosis and hemostasis. Many proprietary MCS devices (predominantly VADs) provide device-specific anticoagulation recommendations, although the translation of these recommendations into practice is sometimes limited by clinical processes, variance in coagulation assays, coagulation assay availability, and interpretation. Nonetheless, anticoagulation strategies for MCS are without robust data, but often, they are standardized within a given institution. For temporary MCS, the most widely used form of systemic anticoagulation is heparin, and in some centers, aspirin and other antiplatelet agents are also integrated (see Table 36.7 for examples). In addition, some centers have used alternative parenteral anticoagulation with direct thrombin inhibitors (e.g., bivalirudin or argatroban), even in the absence of active concerns for heparin-induced thrombocytopenia.66–68 For long-term MCS, recommendations are largely proprietary and device-specific, with the commonalities in the anti-thrombotic regimens being aspirin, warfarin with variable patient/institutional targets, and variable use of parenteral anticoagulation among institutions for perioperative anticoagulation bridging (see Table 36.7 for examples). Nonetheless, the safety and efficacy of apixaban, dabigatran, rivaroxaban, enoxaparin, or other anticoagulants in patients with MCS devices has not been established. Coagulopathies that may occur because of MCS include fibrinolysis and acquired von Willebrand syndrome, thereby increasing bleeding risk. The development of acquired von Willebrand syndrome has been described in both ECLS and VAD populations.69–72 Procedural- and surgical-related bleeding commonly are sources of major bleeding; however, some of the most common other sources include significant epistaxis or gastrointestinal bleeding. In some scenarios, this may be isolated to the identified arteriovenous malformations or angiodysplasias that are thought to be related to decreases in pulse pressure concomitantly with increased continuous flow pressures within the capillary bed, leading to the exposure of existing arteriovenous malformations or the development of new ones.72,73

In contrast, there remains potential increased thrombotic risk secondary to infection as well as hemolysis. Infection, particularly bacteremias, is sometimes a forgotten thrombotic risk factor not well characterized in MCS. The complex interaction of the inflammatory and coagulation cascades existing in sepsis can be further complicated in patients undergoing MCS.74 Because the circulatory dynamics are somewhat compensated for in MCS patients with sepsis, the first presenting symptom of sepsis is sometimes hemoglobinuria or hemolysis. Hemolysis or pump thrombosis can have varying presentations including pump-related alarms (often indicating low flow and/or power elevations), which may also coincide with hyperkalemia, new non-hemorrhagic anemia, or urine color changes (may appear as hematuria, but in severe cases, can be tea-colored, brown, or black). It is also important to recognize that hemolysis may occur because of several other factors within the MCS circuit (Figure 36.4). At a minimum, at least low levels of mechanical hemolysis can be expected with most forms of MCS. However, worsening hemolysis may potentiate further ramifications that commonly appreciated.77 Through hemolysis, hemoglobin is liberated from the red blood cells into circulation, together with other intracellular enzymes and electrolytes. Circulating plasma-free hemoglobin is usually scavenged by haptoglobin, thus limiting downstream effects. However, in severe hemolysis when haptoglobin cannot maintain this balance, plasma-free hemoglobin may facilitate a prothrombotic state. This state may be enabled through direct platelet activation by plasma-free hemoglobin as well as scavenging of endothelial derived nitric oxide that, under normal circumstances, minimizes thrombotic interactions of the endothelium and platelets.78 Further end-organ damage may be mediated by hemolysis such as acute kidney injury.79,80 Although more investigation is still needed on the optimal detection and management, current recommendations indicate further workup for hemolysis and device thrombosis if lactate dehydrogenase (LDH) is 2.5– 3 times the upper limit of normal (normal range 140–280 IU/L) or if the plasma-free hemoglobin is greater than 40 mg/dL (normal 0–10 mg/dL).81,82

Coagulation and Testing During MCS Expected changes in the coagulation are expected during MCS, including activation and amplification of the coagulation cascade and activation of platelets—all largely because of continual interaction with an artificial surface. Differing attempts for advancement have been made to lessen this effect such as altering the surface of the device (as seen in the Heartmate XVE) or enhancing the bio-compatibility of the tubing by adding bonded surfaces to the inner lining. Currently, the only available guidelines for MCS anticoagulation are the 2014 ELSO Anticoagulation Guidelines and the 2013 International Society of Heart and Lung Transplantation (ISHLT) Guidelines for Mechanical Circulatory Support, both of which provide general recommendations on the management according to the available evidence.2,83 In both acute and chronic management, monitoring coagulation parameters is imperative to navigating the delicate balance between bleeding and thrombotic complications. Nonetheless, the science surrounding the optimal management and monitoring of antithrombotics and hemostatics remains quite uncertain—as evidenced by considerable variability in practice and gaps in supporting evidence. Heparin therapy has been the mainstay for anticoagulation in the acute setting for many disease states, including those in the MCS population. One of the most common areas of clinical debate and uncertainty revolves around heparin therapy in MCS. The debate is at least 3-fold surrounding the monitoring assays (ACT [activated clotting time], activated partial thromboplastin time [aPTT], and anti-factor Xa [anti-Xa]); the definition of “therapeutic range,” particularly with aPTT and anti-Xa; and the role of antithrombin. Debate exists largely because of the lack of consistent evidence to guide therapy and the inability to directly translate the evidence into practice among institutions. The best example of this is the definition of a heparin therapeutic range. Years ago, Chiu and colleagues established heparin therapeutic ranges for aPTT monitoring in an animal model deriving a ratio-based goal of aPTT of 1.5–2.5 times the baseline aPTT.84 Some guidelines and institutions still apply this in practice, which results in common aPTT goals of 40–60 seconds or 60–80 seconds. However,

concerns about data with this ratio-based heparin therapeutic goal approach were published by Brill-Edwards and colleagues, where protamine titrations of heparinized samples had considerable sensitivity variation among aPTT reagents, thus refuting ratio-based aPTT goals for heparin monitoring.85 Today, many laboratories use a modified BrillEdwards method with an anti-Xa correlation curve to derive an institution-specific aPTT therapeutic range for heparin monitoring. Fundamentally, this presents inherent limitations in translating heparin anticoagulation goals between institutions.

Table 36.7 Example of Initial Post-MCS Insertion Antithrombotic Regimena

aSee

also https://evidencebasedpractice.osumc.edu/Documents/Guidelines/VAD.pdf.

bMonitoring

and adjustments should be made at routine feasible time windows that adhere to both blood conservation considerations and safe, assertive antithrombotic management.

Recent interest in anti-Xa monitoring of heparin also stimulated similar interest within the MCS population, and so far, anti-Xa and aPTT monitoring have shown discordance.86 Anti-Xa activity may be a potential option, but they are not well validated in all populations, particularly the MCS population. As previously mentioned, all MCS

types induce at least minimal levels of mechanical hemolysis. Of note, the presence of hyperbilirubinemia or hemolysis has been shown to influence the chromogenic anti-Xa assay, potentially representing the activity as falsely low.87 Overall, anticoagulation management and monitoring during MCS remains a conundrum. The roles of common laboratory tests used in monitoring and decision-making regarding anticoagulation, thrombosis, and hemostasis can be found in Table 36.8.

Management of Device-Related Severe Hemolysis and Thrombosis Severe hemolysis and pump thrombosis are of serious concern with MCS devices and require thorough troubleshooting to further complications, although in some scenarios, operative intervention or device change-out is required. In MCS, hemolysis and device thrombosis are commonly discussed in similar contexts, largely because of the associated clinical progression that is commonly seen as the pathogenesis continues from thrombus initiation to complete thrombosis (see Figure 36.5). The workup for confirmation of device thrombosis commonly entails evaluating the device and cardiac function for contributing factors including documentation and alarm history for suction events, power spikes, speed changes, volume status, and arrhythmias. Additional considerations include urinalysis and blood cultures; imaging to evaluate cannula(e) position and obstruction/thrombus by echocardiography or computed tomography (CT); and imaging to evaluate right ventricular function, gas exchange evaluation of the oxygenator for ECLS, or the echocardiographic ramp study in the scenario of left ventricular assist devices (LVADs).88 The ramp study can provide an indirect evaluation of a potential intra-device thrombus because the VAD itself cannot be viewed internally by imaging. The ramp study evaluates for decreases in left ventricular end-diastolic dimension by echocardiogram during simultaneous increases in LVAD speeds and correlating power consumption. If thrombus were likely, potential obstruction within the VAD would be evidenced by lacking augmentation of VAD flows as well as minimal

decreases in left ventricular end-diastolic dimension despite increasing VAD speeds. Additional investigation into compliance with anticoagulation regimen and goals should be assessed, together with quantifiable hemolysis laboratory values to evaluate the degree of elevation (e.g., LDH and plasma-free hemoglobin). Although manipulation of the cannulae or changing of the oxygenator can be accomplished with a somewhat lower risk in temporary MCS or ECLS, the management decision for implanted durable MCS devices (LVADs) is more complex. The most definitive option for device thrombosis is surgical change-out of the device. However, surgical intervention comes with many other risks, most notably the risk of bleeding because of reoperation (particularly with a redo sternotomy). Some centers have tried to standardize the thought process for evaluation and treatment of suspected LVAD thrombosis.81 There-fore, in some scenarios, medical treatment of hemolysis and/or partial pump thrombosis may be pursued to avoid unnecessary surgery or extreme surgical risk. Although this strategy may be successful if the process is identified early, published data of the attempts with alteplase, glycoprotein IIb/IIIa inhibitors, or direct thrombin inhibitors have not shown it to be largely successful.89

Figure 36.4 Factors contributing to mechanical circulatory support device–related hemolysis or thrombosis.75,76

Table 36.8 Antithrombotic and Hemostasis Monitoring: Roles and Limitations in MCS

DTI = direct thrombin inhibitor.

Figure 36.5 Progression of device-related hemolysis and thrombosis in MCS.75

INFECTION TREATMENT AND PREVENTION IN PATIENTS WITH MCS The consequence and management of infections in patients with MCS create many clinical challenges beyond the pharmacologic challenges

described earlier in this chapter. The presence of indwelling or implanted prosthetic material lends itself to greater infectious complexities, and in the case of long-term devices, the driveline care must be consistent and meticulous to avoid seeding infectious risk at this abdominal wound. Infections in these long-term MCS devices have been characterized by ISHLT (Table 36.9). Furthermore, before placement of the device or for surgical procedures occurring after device placement, antibiotic coverage for surgical prophylaxis for MCS-related or non–MCS-related surgical procedures should account for the site of procedure, previous infections (if VAD), proximity to driveline site or VAD pocket, and any other potential exposure or bacteremia secondary to the procedure. In some circumstances, this requires broader prophylactic antibiotic coverage.91 Beyond the immediate perioperative/periprocedural period of up to 48 hours after device placement, evidence neither supports nor refutes the use of ongoing prophylactic antibiotics owing to indwelling cannulae for MCS, and practice patterns have considerable variability.92,93 Nonetheless, consideration for appropriate antimicrobial stewardship practices should be advocated. However, if an infection is identified or suspected, antibiotic coverage should account for the site of suspected infection, previous pathogens and susceptibilities, proximity to driveline site or VAD pocket, and any other potential exposure or bacteremia. Once the source is identified and controlled, treatment duration largely depends on the nature of the infection. However, if the infection is VADrelated or VAD-specific, prolonged (greater than 4 weeks) antimicrobial therapy is commonly used. In addition, because LVAD change-out is not without considerable risk, long-term oral antibiotic suppression therapy may be considered for some infections.

FUTURE DIRECTIONS Mechanical circulatory support has shown considerable advances through the years; however, the pharmacotherapeutic challenges remain complex and require familiarity among the clinical care team to

provide optimal outcomes. Advances in the future, including transcutaneous power supplies and smaller devices, may help eliminate some of these obstacles. However, ongoing research is needed to help refine recommendations for anticoagulation in MCS, particularly for the ideal management of sedation, analgesia, and antibiotic dosing in ECLS. Although some data can assist in our management today, every opportunity should be taken to provide a more individualized approach through guided therapy with therapeutic drug monitoring and with dosing tailored to known pharmacokinetic alterations. Various organizations are have been involved in the regulation, registry development, and advancement of MCS therapy. For further information, please see the following:

Table 36.9 ISHLT Definitions of Infections in Patients with VADs90 Infection Type VAD-specific infections

Defined Areas Affected • Pump and/or cannula infections • Pocket infections • Percutaneous driveline infections ○ Superficial infection ○ Deep infection

VAD-related infections

• Infective endocarditis • Bloodstream infections that may be VAD related or non-VAD related • Mediastinitis ○ Sternal wound infection SSI-organ space ○ VAD pocket infection (continuous with mediastinum or already situated in the mediastinum depending on the device used) ○ Non-VAD: Other causes of mediastinitis, perforation of the esophagus

Non-VAD infections

• Lower respiratory tract infection • Cholecystitis

• Clostridium difficile infection • Urinary tract infection SSI = surgical site infection.

■ ELSO: Extracorporeal Life Support Organization ■ INTERMACS: Interagency Registry for Mechanically Assisted Circulatory Support ■ ISHLT: International Society of Heart and Lung Transplantation

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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

LEARNING OBJECTIVES 1. Understand the basic underlying pathophysiology of hypertensive crisis within the context of underlying disease states and etiologies. 2. List the possible organ system dysfunctions that are possible with hypertensive crisis. 3. Describe management options that are preferred and those that should be used with caution. 4. Understand disease- and etiology-specific treatment options.

ABBREVIATIONS IN THIS CHAPTER ACEI

Angiotensin-converting enzyme inhibitor

APH

Acute postoperative hypertension

aSAH

Aneurysmal subarachnoid hemorrhage

DBP

Diastolic blood pressure

ICH

Intracerebral hemorrhage

ICU

Intensive care unit

MAP

Mean arterial pressure

RAAS

Renin-angiotensin-aldosterone system

SBP

Systolic blood pressure

INTRODUCTION Epidemiology Hypertension is extremely common with a prevalence of about 25%– 30% and affects an estimated 80 million adults in the United States and more than 970 million adults worldwide. Compared with other dietary, lifestyle, and metabolic risk factors, hypertension is the leading cause of death in women and the second leading cause of death in men, behind smoking. In the United States, there is a higher prevalence of hypertension in black populations than in white, Hispanic, and Asian populations. In addition, the prevalence of hypertension in all population groups increases with age.1 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure ( JNC-7) classified patients according to systolic blood pressure (SBP) and diastolic blood pressure (DBP) values ([prehypertension (SBP 120–139 mm Hg or DBP 80–89 mm Hg], stage 1 hypertension [SBP 140–159 mm Hg or DBP 90–99 mm Hg], and stage 2 hypertension [SBP of 160 mm Hg or greater or DBP of 100 mm Hg or greater]) and recommended that patients with a diagnosis of stage 1 or 2 hypertension receive pharmacologic management if lifestyle modifications have failed to achieve blood pressure goals.2 The 2014 report relaxes treatment initiation for the general population 60 years and older to a threshold of SBP of 140 mm Hg or greater or DBP of 90 mm Hg or greater in the absence of other risk factors such as chronic kidney disease, diabetes mellitus, and cerebrovascular disease.3 Although much of the morbidity and mortality associated with hypertension is attributed to processes developing over time, patients may also present with in hypertensive crisis, placing them at risk of impending or progressive organ damage. Hypertensive crisis has been estimated to occur in 1% of adults with a history of hypertension

annually; however, the true incidence may be higher, especially given that one investigation showed that 23% of hypertensive crisis cases requiring emergency department management occurred in patients with no history of hypertension.4

Pathophysiology Acute blood pressure elevation in hypertensive crisis may be caused by a variety of underlying etiologies, and it may occur in patients with a history of hypertension or in those without. Several different causes of hypertensive crisis exist including, but not limited to, history of essential hypertension, renal disease, pregnancy, endocrine disorders, druginduced hypertension, autonomic dysfunction, and disorders of the central nervous system.5 With respect to patients with essential hypertension, situations such as inadequately controlled hypertension, medication nonadherence, and lack of consistent medical follow-up are common patient-specific scenarios that lead from essential hypertension to hypertensive crises. Although the overall precipitating causes may differ, the underlying pathology of hypertensive crisis can be defined by how it affects the regulation of hemodynamic parameters. Systolic blood pressure is determined by cardiac output, a product of strove volume and heart rate, and systemic vascular resistance, a function of peripheral vascular resistance and renal vascular resistance.6 Marked hypertension is often associated with increased levels of vasoactive substances, such as norepinephrine, antidiuretic hormone, and the renin-angiotensin-aldosterone system (RAAS), or by direct pressure-related effects on the vasculature. Increased blood pressure caused by an increased systemic vascular resistance can be mediated by an increase in circulating endogenous catecholamines. Vasoconstriction and increased heart rate mediated by increased norepinephrine and epinephrine, whether as a primary disease process or as a secondary response, can contribute to hypertensive crisis.7 Renin is typically released from the kidneys as a response to a perceived decreased arterial blood volume, and once in circulation, it catalyzes the conversion of angiotensinogen, a liverderived zymogen, to angiotensin I. Circulating angiotensin I is converted

by angiotensin-converting enzyme to active angiotensin II, which has several mechanisms by which it affects blood pressure by augmenting circulating blood volume and inducing vasoconstriction. Angiotensin II acts directly on vascular smooth muscle to induce vasoconstriction, thus increasing systemic vascular resistance. Increased circulating blood volume is influenced by angiotensin II because it enhances the release of aldosterone, increasing sodium reabsorption as well as increasing secretion of antidiuretic hormone. Angiotensin II also plays a role in smooth muscle cell growth and migration, but the role of this effect in acute hypertensive crisis remains unclear.8 In sustained or severe hypertension, stressed vascular endothelium may be overwhelmed and unable to balance vasoconstrictive processes with compensatory nitric oxide and prostacyclin, continuing the cycle of ongoing hypertension. This loss of endothelial function is not well understood; however, proinflammatory processes and pressure-related endothelial damage are likely involved in furthering vasoconstriction.9

CLINICAL PRESENTATION Hypertensive crises can be subdivided into hypertensive urgency and emergency. Presence of end-organ damage is the distinction between the two, with end-organ damage being present with hypertensive emergency. Clinical presentation varies from patient to patient. Organ dys-function is uncommon with DBPs less than 130 mm Hg (except in children and in pregnancy). One recent study by Zampaglione and colleagues found single-organ involvement in 83%, two-organ involvement in 14%, and three- or more organ involvement in only 3% of hypertensive emergencies (Table 37.1).4 In another study examining the prevalence of various end-organ complications in patients with hypertensive crisis, neurologic complications—specifically cerebral infarctions—were the most prevalent, followed by acute heart failure and acute myocardial infarction.10 Standard treatment of a hypertensive crisis in the intensive care unit (ICU) involves continuous blood pressure monitoring and parenteral administration of an antihypertensive agent.2,11,12

Blood Pressure Hypertensive emergencies are characterized by severe elevations in blood pressure (greater than 180/120 mm Hg) complicated by evidence of impending or progressive target organ dysfunction. Examples include hypertensive encephalopathy, intracerebral hemorrhage, acute myocardial infarction, acute left ventricular failure with pulmonary edema, unstable angina pectoris, dissecting aortic aneurysm, and eclampsia. Hypertensive urgencies are situations associated with severe elevations in blood pressure without progressive target organ dysfunction. Examples include upper levels of hypertension associated with severe headache, shortness of breath, epistaxis, or severe anxiety. Most of these patients present as nonadherent or inadequately treated patients with hypertensive emergencies, often with little or no evidence of target organ damage.4,11

Table 37.1 End-Organ Damage Associated with Hypertensive Emergency End-Organ Damage Type

Cases (%)

Cerebral infarction

24.5

Intracerebral or subarachnoid bleed

4.5

Hypertensive encephalopathy

16.3

Acute pulmonary edema

22.5

Acute congestive heart failure

14.3

Acute myocardial infarction or unstable angina

12.0

Aortic dissection

2.0

Eclampsia

2.0

Data from: Zampaglione B, Pascale C, Marchisio M, et al. Hypertensive urgencies and emergencies. Prevalence and clinical presentation. Hyper-tension 1996;27:144-7.

Optic Fundi Retinopathy is a hallmark symptom of hypertensive crisis and is present in many patients on presentation. Typical findings on optic examination include hard exudates, hemorrhages, and papilledema. Retinal hemorrhages are a result of necrosis of the capillary and precapillary arteriolar walls. This endothelial necrosis leads to leakage and deposition of plasma proteins in the posterior retina, which manifests as hard exudates. Papilledema is defined as a swelling of the optic disc and, in the past, was associated with a poor prognosis; however, this finding is no longer a prognostic indicator. With blood pressure management, retinal lesions may be reversed.4,11-13

Cardiovascular Hypertensive crisis can result in acute heart failure and lead to pulmonary edema. This can be attributed to increases in preload and afterload. Acute heart failure is the presenting symptom in 11%–15% of patients. Common cardiovascular findings in these patients may include underlying ischemic heart disease, acute myocardial infarction, angina symptoms, and left ventricular hypertrophy. Aortic dissection is less common, but when it does occur, it is life threatening.2,11,13

Neurologic Neurologic symptoms are often the presenting complaint in hypertensive crisis. More than 60% of patients present with headaches, and up to 28% experience dizziness.4 Cerebrovascular events occur in 7% of patients with hypertensive crisis and include transient or focal cerebral ischemia as well as cerebral and subarachnoid hemorrhage. Hypertensive encephalopathy is characterized by headache, nausea, vomiting, and blurred vision. Other symptoms may include impaired cognition, generalized seizures, and

cortical blindness. Hypertensive encephalopathy is likely to arise from loss of autoregulation in cerebral vessels as the result of severe increases in SBP. Normally, cerebral blood flow is maintained constant despite fluctuations in a range of perfusion pressures. With chronic hypertension, adaptive processes allow cerebral blood flow to be maintained at a higher perfusion pressures and thereby prohibit or attenuate the severity of hypertensive encephalopathy during sudden increases in blood pressure. At very high pressures, this autoregulatory process breaks down. This may occur when the blood pressure is greater than 160/100 mm Hg in previously normotensive patients. In patients with chronic hypertension, it rarely develops until the blood pressure is greater than 200/120 mm Hg. Pathologic findings include cerebral microinfarctions, petechial hemorrhages, and cerebral edema. As the blood pressure is reduced, fluid extravasation decreases, and cerebral autoregulation gradually normalizes. In patients with chronic hypertension, autoregulation may take time to reestablish. Therefore, depending on the clinical scenario, blood pressure should be lowered slowly in severely hypertensive subjects with chronic hypertension to avoid precipitating cerebral ischemia.4,11-14

Renal Renal involvement is also a common complication. Non-nephrotic–range proteinuria is commonly associated with elevated serum creatinine concentrations. Increased serum creatinine (greater than 2.3 mg/dL) occurs in 31% of patients at presentation. Overt nephrotic syndrome is uncommon. Urinalysis may be useful in differentiating if kidney injury is acute versus chronic in nature. Hypokalemic metabolic alkalosis may develop as a result of volume depletion and secondary hyperaldosteronism. Plasma renin activity and aldosterone are increased in most cases.4,13,15

Hematologic Microangiopathic hemolytic anemia, thrombocytopenia, increased fibrin degradation, and increased fibrinogen are commonly seen. Erythrocyte

sedimentation rate is often elevated because of renal failure and anemia.16

DIAGNOSTIC CONSIDERATIONS AND CLINICAL EVALUATION Early triage to emergency departments to initiate appropriate therapeutic interventions for these patients is critical to affecting morbidity and mortality. Patients presenting with hypertensive crisis may represent up to 25% of all patient visits to busy urban emergency departments.2 Evaluation of patients with hypertension involves assessment of lifestyle, identification of risk factors and comorbidities that may affect prognosis and guide treatment, identification of potential causes of high blood pressure, and assessment for the presence of target organ damage and cerebrovascular disease. Patient evaluation is made through ascertaining medical history, physical examination, routine laboratory tests, and other diagnostic procedures. The physical examination should include an appropriate measurement of blood pressure with verification in the contralateral arm; examination of the optic fundi; calculation of BMI (body mass index); auscultation for carotid, abdominal, and femoral bruits; palpation of the thyroid gland; thorough examination of the heart and lungs; examination of the abdomen for enlarged kidneys, masses, distended urinary bladder, and abnormal aortic pulsation; palpation of the lower extremities for edema and pulses; and neurologic assessment.12,14,16 Patients with hypertensive crisis should be admitted to an ICU for continuous hemodynamic monitoring and administration of intravenous antihypertensive agents. According to the JNC-7 guidelines, the initial goal of therapy in hypertensive emergencies is to reduce the mean arterial blood pressure by no more than 20%–25% (within minutes to 1 hour) and then, if stable, to an SBP of 160 mm Hg and/or a DBP of 100–110 mm Hg during the next 2–6 hours. More aggressive blood pressure reductions may precipitate and perpetuate renal, cerebral, or coronary ischemia. This recommendation is based on the body’s ability

to autoregulate tissue perfusion in the brain, heart, and kidneys. If this level of blood pressure reduction is well tolerated, further gradual reductions toward a goal blood pressure can be executed in the next 24–48 hours. There are exceptions to this treatment strategy. There is no clear evidence from clinical trials that patients with an acute ischemic stroke benefit from the use of immediate intravenous antihypertensive treatment unless it is lowered to enable the use of thrombolytic agents. In addition, patients with aortic dissection should have their SBP lowered to less than 120 mm Hg as quickly as possible, if tolerated. It is imperative to ensure appropriate monitoring for signs or symptoms of ischemia-related end-organ system deterioration that may accompany changes in SBP, DBP, or mean arterial pressure (MAP).12,14,16 The JNC-7 criteria for accurate blood pressure measurements require that two readings be taken 5 minutes apart with the patient at rest in a seated and standing position.2 Recall that there is a statistical tendency for repeat measurements to regress toward the mean of measurements. A study of 195 consecutive patients with hyper-tension in an emergency department validated this mathematical principle and documented a mean decline of 11.6 mm Hg in repeated DBP readings. Unexpectedly high blood pressure readings should be repeated because a measurement error can occur from the misapplication of the sphygmomanometer cuff, use of an inappropriately sized cuff, or operator error. In addition, consider whether the hypertension is reactive in nature. If the hypertension is caused by anxiety, pain, or use of sympathomimetics (such as decongestants or cocaine) or by withdrawal states (e.g., withdrawal from alcohol or antihypertensive medication), addressing the underlying condition is an imperative part of management. Urine toxicology for cocaine can be helpful in select, high-risk patient populations. A thorough patient history is needed to determine concomitant disease states and home blood pressure readings, if possible. Furthermore, elucidating the patient’s home medications and medication adherence is essential. This history should include prescription medications, over-the-counter medications, and

recreational drugs as well as any supplements because any of these may contribute to the patient’s clinical picture.11 Neurologically, patients should be evaluated for any symptoms associated with ischemic or hemorrhagic stroke or hypertensive encephalopathy. A funduscopic optical examination to assess for papilledema, hemorrhage, or exudates within the eye may be indicated. A thorough cardiovascular assessment is also necessary. Crucial components include auscultation for new murmurs associated with aortic insufficiency or dissection as well as checking for mitral regurgitation, which could be associated with ischemia. A gallop could indicate acute heart failure. The lung fields should be auscultated to check for crackles suggestive of pulmonary edema. Laboratory tests should be assessed to validate physical examination findings. These should include serum electrolytes, serum creatinine, and a complete blood cell count with peripheral smear. A 12-lead electrocardiogram should be ascertained to determine myocardial ischemia or left ventricular hypertrophy. A chest radiograph could help determine the presence of pulmonary edema, widened mediastinum, or cardiac enlargement. A urine analysis may be helpful in assessing for casts and proteinuria. More extensive testing for identifiable causes of hypertensive crisis are not usually indicated unless blood pressure control is not achieved or unless the clinical and routine laboratory evaluation strongly suggests an identifiable secondary cause (i.e., vascular bruits, symptoms of catecholamine excess, unprovoked hypokalemia). In addition, two emerging risk factors may be evaluated, particularly in those with cerebrovascular disease but without other risk factor abnormalities: (1) high-sensitivity C-reactive protein, a marker of inflammation; and (2) homocysteine. Current data do not highlight the role of these factors in the management of hypertensive crisis, but they may come to play a role in chronic management and risk assessment.

General Therapeutic Approach In patients with hypertensive urgencies, blood pressure is lowered over 24–48 hours, usually with oral medication. Some patients with

hypertensive urgencies may respond to treatment with an oral, shortacting agent such as captopril, labetalol, or clonidine together with a period of observation. However, there is no evidence to suggest that failure to aggressively lower blood pressure in these patients while admitted to the emergency department is associated with any increased short-term risk to these patients. Furthermore, they may benefit from adjustment in their current antihypertensive therapy or reinstitution of medications if nonadherence is a problem. Patients should be discharged from the emergency department with a confirmed follow-up visit within 24–48 hours postdischarge. The term urgency may lead to overly aggressive antihypertensive treatment with intravenous drugs or even oral agents to rapidly lower blood pressure. However, this practice is not without risk. Oral loading doses of antihypertensive agents may lead to accumulation of drug, which may result in hypotension after discharge from the emergency department. Patients who continue to be nonadherent often return to the emergency department within weeks.13,14,16 Patients with hypertensive emergency require immediate control of the blood pressure to attenuate end-organ damage. Blood pressure in patients with hypertensive emergencies should be treated in a controlled fashion in an ICU. Continuous blood pressure monitoring should be considered in these patients to assist in appropriate titration of therapeutic agents. Type of monitoring may vary from blood pressure cuff to more invasive intra-arterial blood pressure monitoring. Choice of monitoring mechanism is complex and may depend on the type of patient, cause of hypertensive crisis, and agents used to control hemodynamics. Once therapeutic end points have been achieved, the patient can be initiated on a regimen of oral maintenance antihypertensive therapy.

Medical Therapies Calcium Channel Antagonists Calcium channel antagonist agents or calcium channel blockers have clinical application in a variety of cardiovascular disease states.

Although there are six known types of calcium channels, only the L- and T-type channels are thought to have effects relevant to cardiovascular disease.17 The clinical role of T-type calcium channel antagonism remains undefined and is an area for further research.18 L-type calcium channel antagonists can be subdivided into three major subclasses: dihydropyridines (nicardipine and clevidipine), phenylalkylamines (verapamil), and benzothiazepines (diltiazem). L-type calcium channels are widespread in a variety of tissues including the cardiovascular system, neuronal, and secretory tissue. Calcium channel antagonists inhibit calcium influx during depolarization and result in end effects such as decreased vascular constriction, decreased atrioventricular nodal conduction, and negative inotropy— though these are strongly influenced by calcium channel antagonist structure and subclass. The classical targets for calcium channel antagonists are the Cav1 L-type receptors found on myocardial and vascular smooth muscle, which can reach the receptor either by the open channel or though the lipid membrane of a closed channel. Verapamil and diltiazem are charged at physiologic pH, enter calcium channels in the open state, and have increased activity on cardiac Ltype channels. This results in the decreased atrioventricular node transduction and negative inotropy associated with these agents. In contrast, dihydropyridine agents are more lipophilic, exerting their action on closed or inactive calcium channels with a higher affinity for vascular calcium channels.19 For this reason, we will now focus on dihydropyridine calcium channel antagonists, of which two are currently available in intravenous formulations: nicardipine and clevidipine. Nicardipine Nicardipine is a dihydropyridine calcium channel antagonist, indicated for short-term management of hypertension. Nicardipine exerts its antihypertensive action by selective dilation of arterial and coronary vascular smooth muscle with no significant venodilatory effects. A fairly quick onset of action of 5–15 minutes is observed with a duration of antihypertensive effects of 4–6 hours and a terminal half-life of 14 hours, prolonged in patients with hepatic impairment (Table 37.2).

Nicardipine has linear kinetics, is highly (greater than 95%) protein bound, and is metabolized by the liver by the cytochrome P450 (CYP) enzymes, primarily by CPY2C8, CYP2D6, and CYP3A4. No pharmacokinetic differences have been seen between younger individuals and those older than 65 years. Nicardipine is contraindicated in patients with advanced aortic stenosis.11,20 Nicardipine should be initiated at 5 mg/hour and increased by 2.5 mg/hour every 15 minutes until goal blood pressure is attained, with a maximum of 15 mg/hour. Once goal blood pressure is achieved, a taper of 3–5 mg/hour every 15 minutes should be tried, as tolerated. Nicardipine is available as a premixed infusion of either 0.1 or 0.2 mg/mL (in either dextrose or saline solutions) or as a concentrated solution (2.5 mg/mL), which is recommended to be diluted to a concentration of 0.1 mg/mL in buffered solutions for a pH of 3.7–4.7 and 3.5, respectively.21,22 Although typically well tolerated, adverse events associated with nicardipine are typically those associated with vaso-dilation such as headache, hypotension, and tachycardia. To avoid potential peripheral vein irritation, manufacturers recommend changing infusion sites every 12 hours. Clevidipine Clevidipine is a third-generation dihydropyridine calcium channel antagonist, also indicated for short-term management of hypertension. Clevidipine exerts its antihypertensive action by a selective effect of arterioles, with minimal effects on venous capacitance vessels and cardiac preload. Clevidipine has a rapid onset of action, about 2–4 minutes, with a terminal half-life of about 15 minutes because it is metabolized by esterases predominantly in the blood and extravascular tissues (Table 37.2). Clevidipine is highly protein bound (greater than 99%), and although data are limited, no drug-drug interactions are likely because it is hydrolyzed by esterases, and neither clevidipine nor its metabolites are expected to interfere with CYP enzymes at therapeutic concentrations. No dose adjustments are recommended in the setting of hepatic or renal impairment, though it may be prudent to initiate dosing at the lower end of the recommended range in the older adult population. Clevidipine is generally well tolerated, showing

minimal to modest reflex tachycardia and an increase in serum triglyceride concentrations in some study populations (decreased with the discontinuation of clevidipine).23

Table 37.2 Medications Used for the Management of Hypertensive Crisis

aSAH = aneurysmal subarachnoid hemorrhage; BP = blood pressure; ICH = intracerebral hemorrhage; IM = intramuscularly; IV = intravenously; q = every.

It is recommended to initiate clevidipine at a dose of 1–2 mg/hour, with a doubling of the dose at short (90 seconds) intervals initially, lengthening to every 5–10 minutes as goal blood pressure is attained. Clinical experience is limited with doses above 32 mg/hour. Clevidipine is available for intravenous use in a 20% lipid emulsion (2 kcal/mL) and, like similar formulations, contraindicated in patients with allergies to soybeans/soy products or eggs/egg products. Because of the lipid vehicle, doses greater than 1,000 mL/day (an average of 21 mg/hour/day) are not recommended. In addition, there is limited experience with treatment courses exceeding 72 hours in duration.

Caloric intake and triglyceride concentrations should be assessed for patients receiving clevidipine. Clevidipine may be infused by central or peripheral venous access, and because of the risk of bacterial growth in the lipid medium, the vial must be changed every 12 hours.23,24 Angiotensin-Converting Enzyme Inhibitors Enalaprilat Enalaprilat is the active form of the prodrug enalapril and is the only angiotensin-converting enzyme inhibitor (ACEI) available in an intravenous formulation. Like all ACEIs, enalaprilat prevents the conversion of angiotensin I to angiotensin II as part of the RAAS. This system is vital in maintaining blood pressure, electrolyte balance, and volume status. Renin, released by juxtaglomerular cells in the afferent arterioles in response to decreased renal per-fusion and/or sodium load, cleaves angiotensinogen to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme, the target for ACEI agents. Angiotensin II stimulates G-protein angiotensin II type 1 receptors, resulting in arteriolar constriction, including marked efferent arteriole constriction, release of aldosterone and antidiuretic hormone, and increased sympathetic nervous system activity, and it has a role in cardiac mitogenesis and remodeling. Angiotensin-converting enzyme inhibitors also prevent the breakdown of substance P and bradykinin, a vasodilator.25,26 Enalaprilat may be given in hypertensive crisis with an initial dose of 1.25 mg intravenously every 6 hours, given as a slow intravenous push over 5 minutes, with antihypertensive effects seen as quickly as 10–15 minutes after infusion, a maximal onset in 0.5–1 hour, and duration of action of 12–24 hours (Table 37.2).27,28 Although this is advantageous in maintenance therapy, allowing for daily dosing of oral enalapril, this long duration of action may be detrimental in patients experiencing hypotension after drug administration. Also of note is that the baseline degree of RAAS activity may affect patient response to enalaprilat. The degree of blood pressure lowering in patients with hypertensive crisis has been correlated with plasma renin concentration, with a

higher degree of response in patients having a high degree of RAAS activity.29 Enalaprilat is primarily excreted unchanged in the urine (61%) and feces (33%), with a recommended lower initial dose of 0.625 mg in patients with a CrCl of less than 30 mL/minute/1.73 m2 and care taken in patients on hemodialysis. Renal impairment is associated with enalaprilat use, mediated by its overall hypotensive effects and specifically alteration of angiotensin II–mediated efferent arteriolar vasoconstriction, more often observed in patients with baseline renal compromise. In addition, enalaprilat should be used with caution in patients with aortic stenosis or hyperkalemia, and it is contraindicated in pregnant patients and patients with a history of hereditary or idiopathic angioedema.26,28,30 Reported adverse effects with enalaprilat include cough, angioedema, and hypotension. The inhibition of bradykinin and substance P is thought to relate to the incidence of ACEI-associated cough. Angioedema is a relatively rare (0.1%–0.3% incidence) but potentially life-threatening adverse effect of ACEI therapy, typically manifesting with edema of the face, tongue, and throat with reports of death from laryngeal edema reported. Elevated bradykinin is also thought to be associated with angioedema, more commonly seen in women and black patients than in non-black patients.26,31,32 Vasodilators Sodium Nitroprusside Functionally, sodium nitroprusside is a nitric oxide donor that is converted to a free radical that activates endovascular guanyl cyclase. This results in myosin dephosphorylation and subsequent vascular smooth muscle relaxation. Sodium nitroprusside acts on arteriolar and venous smooth muscle, thereby reducing both preload and after-load. Unpredictable decreases in blood pressure are often seen in patients with hypovolemia or diastolic dysfunction because of sodium nitroprusside effects on preload. In patients with left ventricular failure, decreases in preload may result in a decreased cardiac index,

whereas reductions in afterload prohibit the reflexive tachycardia that would normally occur with a drop in cardiac output.11 Sodium nitroprusside infusion is typically initiated as a continuous intravenous infusion with a starting infusion rate of 0.3–0.5 mcg/kg/minute, with increases in increments of 0.5 mcg/kg/minute to achieve hemodynamic targets (Table 37.2).11 The treatment duration should be as short as possible, and to avoid doses exceeding 2 mcg/kg/minute. The dosage requirement in older adult patients is typically lower than in younger patients. The exact mechanism of this increased sensitivity is unknown but is thought to be related to diminished baroreceptor reflex activity, resistance of cardiac adrenergic receptors to catecholamine stimulation, or variations in the direct vasodilating effects of sodium nitroprusside.33 It has an immediate onset and duration of effect of 2–3 minutes. Tachyphylaxis may develop while using this agent. More severe toxicity associated with sodium nitroprusside is a result of the release of cyanide with interference with cellular respiration. Sodium nitroprusside is metabolized into cyanogen, which is converted to thiocyanate by the enzyme thiosulfate sulfurtransferase. It contains 44% cyanide by weight.11 Cyanide is released non-enzymatically from sodium nitroprusside, the amount generated being dependent on the dose of sodium nitroprusside administered. Cyanide toxicity may manifest as an unexplained cardiac arrest, coma, encephalopathy, convulsions, hyperreflexia, blurred vision, tinnitus, and irreversible focal neurologic changes. Because free cyanide radicals may bind and inactivate tissue cytochrome oxidase, thereby preventing oxidative phosphorylation, increased cyanide concentrations may also cause tissue anoxia, anaerobic metabolism, and lactic acidosis. Patients receiving sodium nitroprusside with symptoms of central nervous system dysfunction, cardiovascular instability, and increasing metabolic acidosis should be assessed for cyanide toxicity.34 The current laboratory monitoring methods for cyanide toxicity may be insensitive, given that the accuracy of laboratory results relies on proper storage conditions of blood samples. However, if clinical suspicion of toxicity is high, initiating treatment can be considered before receiving laboratory results. In addition, a rise in serum

thiocyanate concentrations is a late-occurring event and is not directly related to cyanide toxicity. Red blood cell cyanide concentrations may be a more reliable method of monitoring for cyanide toxicity, but this is not currently widely available. A red blood cell cyanide concentration above 40 nmol/mL correlates with detectable metabolic changes. Cyanide toxicity is unusual until the total dose exceeds 300 mg or the infusion rate is above 20 mcg/kg/minute, although toxic cyanide concentrations have been seen at various infusion rates. In general, the risk of toxicity increases incrementally with increasing doses.34 Concentrations greater than 200 nmol/mL are associated with severe clinical symptoms, and concentrations greater than 400 nmol/mL are considered lethal. To avoid potential toxicity, the treatment duration with sodium nitroprusside should be as short as possible, and the infusion rate should be no greater than 2 mcg/kg/minute. The concentrations should be maintained below 10 mg/dL to avoid thiocyanate toxicity. When toxicity is confirmed or suspected, sodium nitroprusside administration should be discontinued. An infusion of thiosulfate may be used in patients receiving higher dosages (4–10 mcg/kg/minute) of sodium nitroprusside.35 For sodium nitroprusside infusions of 4–10 mcg/kg/minute or greater or infusions longer than 30 minutes, thiosulfate can be coadministered at a 10:1 sodium nitroprusside/thiosulfate ratio to avoid cyanide toxicity. Furthermore, sodium nitroprusside comprises a ferrous ion center complexed with five cyanide moieties, which may react with methemoglobin and produce cyanomet-hemoglobin. Normal methemoglobin concentrations can bind the cyanide released from 18 mg of sodium nitroprusside. The total dose of sodium nitroprusside required to cause 10% methemoglobinemia is greater than 10 mg/kg (greater than 10 mcg/kg/minute for more than 16 hours).11 Other methods of cytotoxicity may arise through the release of nitric oxide, with hydroxyl radical and peroxynitrite generation leading to lipid peroxidation. Sodium nitroprusside activates guanylate cyclase, which stimulates the formation of cyclic guanosine monophosphate that relaxes smooth muscle.35 Thiocyanate is also toxic; however, it is 100-fold less toxic than

cyanide. It is eliminated by renal excretion, with a half-life of 3–7 days.11 Sodium nitroprusside infusions of 2–5 mcg/kg/minute for 7–14 days may be needed to generate thiocyanate toxicity. Nonspecific symptoms of thiocyanate toxicity include fatigue, tinnitus, nausea, and vomiting; clinical signs include hyperreflexia, confusion, psychosis, and miosis.35 Normally, adults can detoxify 50 mg of sodium nitroprusside using existing stores of sulfur, but malnutrition, surgery, diuretic use, or other factors can reduce this capacity. Cyanide is metabolized in the liver to thiocyanate and requires thiosulfate to occur. Thiocyanate is 100 times less toxic than cyanide. Thiocyanate is excreted through the kidneys. Cyanide removal therefore requires adequate liver function, adequate renal function, and adequate bioavailability of thiosulfate. Cyanide is known to interfere with cellular respiration. Friederich and colleagues showed that lipid peroxidation in the substantia nigra of rats occurs after the administration of sodium nitroprusside. Lipid peroxidation has also been shown in hepatocytes. In addition, sodium nitroprusside causes concentration- and time-dependent ototoxicity.34 As an alternative to thiosulfate, hydroxycobalamin (vita-min B12a) received marketing approval in 2006 from the U.S. Food and Drug Administration (FDA) for the treatment of known or suspected cyanide poisoning at a starting dose of 5 g administered by intravenous infusion over 15 minutes.11,16 Nitroglycerin Nitroglycerin is primarily a venodilator; however, arteriodilation of vascular smooth muscle can occur at high doses. Regarding mechanism of action, nitroglycerin is converted to nitric oxide, which activates guanylate cyclase and stimulates the production of cyclic GMP. This produces venous smooth muscle relaxation and reduction in preload.36 In volume-depleted patients, a reduction in preload reduces cardiac output, which may be undesirable in patients with compromised myocardial, cerebral, or renal perfusion. Severe hypotension and reflex tachycardia have been reported in these patients quickly after initiating a nitroglycerin infusion. For the treatment of hypertensive crisis,

nitroglycerin is initiated at a rate of 5 mcg/minute by continuous intravenous infusion. The dose may be titrated in increments of 5 mcg/minute every 3–5 minutes to an infusion rate of 20 mcg/minute. If blood pressure response is inadequate to this infusion rate, the dose may be increased by 10 mcg/minute every 3–5 minutes, up to a maximum rate of 200 mcg/minute (Table 37.2). If a weight-based dosing algorithm is used, the usual starting dose is 0.2 mcg/kg/minute. The dose may be increased in increments of 0.2–0.5 mcg/kg/minute every 3–5 minutes to a maximum dose of 2 mcg/kg/minute. Onset of action of nitroglycerin is within 2–5 minutes, and the duration of action is 5–10 minutes, with a half-life of 1–3 minutes.11 Tolerance of the hemodynamic effects of nitroglycerin limits its clinical utility.37 Headache is the most common adverse effect, and methemoglobinemia is a rare complication of prolonged infusions.2 It can also cause hypotension and reflex tachycardia. Administration of low-dose nitroglycerin (approximately equal to 60 mcg/minute) as an adjunct to other intravenous antihypertensive agents may be useful for patients with hypertensive emergencies associated with acute coronary syndromes or acute pulmonary embolism.38 Hydralazine Hydralazine is a peripheral, direct-acting vasodilator that relaxes arteriolar smooth muscle by inhibiting calcium ion release from the sarcoplasmic reticulum. The specific mechanism of action is not well understood, but proposed mechanisms include inhibition of calcium release caused by inositol trisphosphate and reducing calcium turnover.39 There is also a potential for direct myocardial effect from increased influx of calcium into the sarcolemma that may be a result of the stimulation of β-adrenergic receptors.40 Other proposed mechanisms of action include membrane hyperpolarization and inhibition of oxidase formation.41 The arteriodilation reduces cardiac afterload and may improve cardiac function in patients with heart failure. The initial dose of hydralazine is a 10-mg bolus by slow intravenous administration every 4–6 hours as needed to attain target blood

pressure (Table 37.2). Repeated bolus doses generally should not exceed 20 mg, although they may be increased to 40 mg. Blood pressure begins to decrease within 10–30 minutes, and the fall can last from 2–4 hours.11 Hydralazine may also be given intramuscularly, which may be advantageous in patients with poor vasculature making it difficult to obtain intravenous access. The onset of action postintravenous administration is 10–20 minutes, and its duration of action of 1–4 hours. After intramuscular or intravenous administration, a latency period of 5–15 minutes is followed by a progressive and often precipitous fall in blood pressure that can last up to 12 hours postadministration. Although the circulating half-life of the drug is only about 3 hours, the context-sensitive half-life of activity on blood pressure is about 100 hours.42 Although the mechanism behind this finding is unclear, it may be a result of active metabolites, arteriolar endothelial tissue binding, or a prolonged effect on endothelium-derived relaxing factor. Because of its prolonged and unpredictable antihypertensive effects and its inability to be titrated efficiently, hydralazine is best avoided in the management of hypertensive crises and is not usually considered a first-line agent for the management of hypertensive crisis. Adrenergic-Receptor Antagonists Esmolol Esmolol is a cardioselective β1-adrenergic antagonist with a rapid onset of action and a short duration of action. It is a negative inotrope and chronotrope. Because it is a β1-cardioselective drug, it pairs well with a direct-acting α-adrenergic vasodilator such as phentolamine because esmolol possesses no direct vasodilatory actions. A loading dose of esmolol can be given as a 0.5- to 1-mg/kg loading dose over 1 minute, followed by initiation of an infusion at 50 mcg/kg/minute (Table 37.2). The bolus dose can be repeated. The infusion can be titrated in 25-to 50-mcg/kg/minute increments as needed to a maximum of 300 mcg/kg/minute.43 The onset of action is about 1 minute with a terminal half-life of 9 minutes and a duration of action of 10–20 minutes. The drug is rapidly metabolized by erythrocyte esterases; thus, concomitant

anemia may prolong the duration of effect.16,43,44 One significant indication for esmolol is to attenuate the sympathetic discharge seen with severe postoperative hypertension, given that cardiac output, heart rate, and blood pressure are increased.45 Esmolol is also safe in the setting of myocardial ischemia.46 Patients should be closely monitored for bradycardia, which may occur more often in older adults. If bradycardia occurs, the infusion should be discontinued, and the effects of esmolol on heart rate are eliminated within 20 minutes. Esmolol reduces cardiac index and may worsen or exacerbate the symptoms of patients with acute heart failure. Patients with reactive airway disease should be monitored for exacerbation, though several studies have shown that esmolol, being a cardioselective drug, is well tolerated in patients with pulmonary disease.47 Contraindications to esmolol use include concurrent βblocker therapy, bradycardia, and acute decompensated heart failure. Accidental overdoses of esmolol caused by dilution errors have been reported, which have resulted in fatalities attributed to bolus doses of 625–2500 mg (12.5–50 mg/kg). Premixed injection solutions are available and may help mitigate such dosage errors. Labetalol Labetalol is a combined α1- and nonselective β-adrenergic receptor antagonist. Pharmacodynamically, its action is primarily mediated by βblockade, with an α- to β-receptor activity ratio of 1:7 when given intravenously.15 Unlike cardioselective β-blockers, which decrease cardiac output, labetalol maintains cardiac output because α1-blockade minimizes the reductions in cardiac output seen with β-blockade alone. It also reduces peripheral vascular resistance without diminishing peripheral blood flow, thereby maintaining cerebral, renal, and coronary blood flow. Given that labetalol has little effect on cerebral circulation, it is not associated with increased ICP. Because it is a nonselective βblocker, labetalol should be used with caution in patients with reactive airway disease or chronic obstructive pulmonary disease. It may exacerbate or precipitate acute decompensated heart failure and should not be used in patients with second- or third-degree

atrioventricular block or bradycardia.48 Labetalol can be given as an intravenous bolus, with incrementally larger doses should repeat dosing be required, until the desired hemodynamic state is achieved. The patient is less likely to respond if no response is observed after a cumulative dose of 300 mg is given (Table 37.2). An intravenous loading dose of labetalol 10–20 mg typically precedes either an infusion or ongoing bolus doses of labetalol. As a single bolus dose, labetalol has an onset of action of 2– 5 minutes, with a duration of action of 2–4 minutes.16 Incremental bolus doses of 20–80 mg every 10 minutes can be continued until the target blood pressure is attained. Labetalol may also be administered as a continuous intravenous infusion initiated at 0.5–1 mg/minute, adjusted by 0.5–1 mg/minute every 30 minutes until the target blood pressure is attained. Intravenous bolus doses of 1–2 mg/kg have resulted in clinically significant decreases in blood pressure; these should therefore be avoided, if possible. The duration of effect with repeated sequential bolus doses or infusions is 2–4 hours, with an elimination half-life of 5.5 hours. Phentolamine Phentolamine is a competitive antagonist of peripheral α1- and α2receptors and antagonizes the effects of epinephrine and norepinephrine at these receptors, resulting in vasodilation. Furthermore, it has positive inotropic and chronotropic effects on the heart as a result of its α2-blockade. It is generally used to treat hypertensive emergencies induced by catecholamine excess. Examples of such disorders include pheochromocytoma, interactions between monoamine oxidase inhibitors and other drugs or food, cocaine toxicity, amphetamine overdose, and cloni-dine withdrawal.11,49 Phentolamine is initiated as an intravenous bolus dose of 5–15 mg (Table 37.2). Its onset of action is 1–2 minutes, with a duration or action of 10–30 minutes. It should be used with caution in those with coronary artery disease because it can potentiate angina symptoms or myocardial infarction. Tachycardia, flushing, and headache are also commonly occurring adverse effects. The compensatory tachycardia can be

ameliorated by administering an intravenous β-blocker.2 Fenoldopam Fenoldopam is a dopamine type 1 receptor agonist in the periphery with no activity on dopamine type 2 receptors.50 It is 10 times more potent at renal dopamine type 1 receptors than dopamine. Agonism of postsynaptic dopamine type 1 receptors results in vasodilation of peripheral arteries as well as the renal and mesenteric vasculature. Fenoldopam is typically initiated as a continuous intravenous infusion with a starting rate of 0.1–0.3 mcg/kg/minute. The infusion rate may be titrated in increments of 0.05–0.1 mcg/kg/minute every 15 minutes until the target hemodynamics are achieved, to a maximal infusion rate of 1.6 mcg/kg/minute (Table 37.2).11 Data are limited regarding the use of fenoldopam in patients older than 65 years. Fenoldopam should be initiated cautiously in the older adult, usually starting at the low end of the dosing range. The onset of action is less than 5 minutes with a halflife of 9.8 minutes.2,15,50 Adverse effects associated with fenoldopam include headache, flushing, tachycardia, and dizziness. A dose-related increase in intraocular pressure is also possible; thus, fenoldopam should be administered with caution in patients with narrow-angle glaucoma. The drug formulation contains sodium metabisulfate, which should be avoided in patients with an allergy to sulfites.50 The overall effect of this vasodilation is a lowering of blood pressure and total peripheral resistance while preserving renal blood flow. Fenoldopam has been shown to improve creatinine clearance, urine flow rates, and sodium excretion in patients with severe hypertension with both normal and impaired renal function. The effects of fenoldopam on renal function were assessed in a meta-analysis involving patients from 16 randomized controlled trials. Authors evaluated the renal-protective properties of fenoldopam in a variety of settings. Fenoldopam was associated with a lower risk of the need for renal replacement and in-hospital death.51

SPECIAL CONSIDERATIONS

Hypertension in Pregnancy Hypertension, although common in the general population, is also a complication in 10% of pregnancies worldwide. Although the etiologies of hypertension are multifactorial, the American College of Obstetricians and Gynecologists has streamlined hypertension during pregnancy to four categories: (1) preeclampsia-eclampsia, (2) chronic hypertension, (3) chronic hypertension with superimposed preeclampsia, and (4) gestational hyper-tension.52 Of these, preeclampsia is the most commonly seen etiology of hypertension in pregnancy and is most often associated with hypertensive emergency. Preeclampsia typically develops after 20 weeks of gestation and may manifest through the postpartum period. Diagnostic criteria for preeclampsia include elevated blood pressure of 140/90 mm Hg or greater (on two separate occasions) or confirmed persistent blood pressure of 160/110 mm Hg or greater, and concomitant proteinuria or any of thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral/visual symptoms (Table 37.3). Hypertensive urgency in the pregnant patient is defined as an SBP of 180 mm Hg or greater and/or a DBP of 120 mm Hg or greater without progressive end-organ damage. Hypertensive emergency in the pregnant patient is defined as persistent (15 minutes or more) hypertension (SBP of 160 mm Hg or greater and/or DBP of 110 mm Hg or greater) in a pregnant or postpartum patient with preeclampsia or eclampsia. Blood pressure criteria for hypertensive emergency are set at lower levels because peripartum patients may develop complications of hypertensive crisis, such as myocardial infarction, stroke, hypertensive encephalopathy, and pulmonary edema, at lower levels of hypertension compared with the general population.53,54 For pregnant patients presenting with hypertensive crisis, initial clinical goals of patient stabilization and prevention of end-organ damage remain at the forefront, but in addition, preservation of adequate uteroplacental perfusion must be considered. For patients with hypertensive urgency, blood pressure should be lowered slowly over 24–48 hours, and oral antihypertensive agents are typically used. For patients with hypertensive emergency, immediate blood pressure

intervention should be made, with goals of reducing MAP by 15%–25% and/or a goal SBP range of 140–150 mm Hg and a DBP range of 90– 100 mm Hg. In addition to antihypertensive medications, other interventions may be considered such as administration of magnesium for associated eclampsia, support of end-organ dysfunction, and consideration of fetal delivery. A recent Cochrane review showed no preferred agent for the treatment of hypertensive emergency in pregnancy, though—as with all hypertensive crisis treatment options— intravenous agents that are short acting and titratable are preferred.55

Table 37.3 Special Considerations for Hypertensive Crisis Management

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

Figure 37.1 Management of hypertensive crisis in pregnancy. BP = blood pressure; HTN = hypertension.

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.

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

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 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 5 ft Females: 45.5 kg + 2.3 kg/in. for height > 5 ft

Lean body weight (kg)17

Males: (9270 × TBW)/(6680 + 216 × BMI) Females: (9270 × TBW)/(8780 + 244 × BMI)

Adjusted body weight (kg)

CF (TBW – IBW) + IBW

CF = correction factor (usually = 0.4); IBW = ideal body weight (kg); TBW = total body weight (kg).

Although there may be a preferred weight measure for a particular drug, each of the aforementioned size descriptors is limited by its inability to assess the ratio of fat mass to fat-free mass. This permits assumptions about body composition that may not be entirely accurate. The importance of this is shown in the following example. Suppose a loading dose is needed for a medication in three male patients, all 40 years of age, all 70 inches tall, and all weighing 100 kg. The first patient is very muscular with very little fat mass, the second has obesity, and the third has substantial fluid retention. All would receive the same dose based on all weight descriptors (i.e., TBW, IBW, LBW, etc.), but there are clearly differences in body composition that could influence volume of distribution and/or clearance and the resultant drug concentrations.

Pharmacokinetic Considerations

The two independent pharmacokinetic parameters commonly used to describe drug disposition in the body are volume of distribution and clearance. Volume of distribution is a theoretical parameter used to describe the size of the compartment into which a drug will distribute. This is the most influential parameter when a single dose of medication is administered such as a loading dose. In general, drugs with a smaller volume of distribution tend to be hydrophilic drugs and remain in the extracellular space with little distribution into adipose tissue. Drugs with larger volumes of distribution are often more lipophilic and distribute into adipose tissue and other areas of the body. The second pharmacokinetic factor used to describe drug disposition is clearance. Studies evaluating the impact of obesity on clearance have produced mixed results. Some studies have shown an increase in clearance, largely because of increased kidney size and blood flow, whereas others have shown no difference. One challenge related to clearance in the patient with obesity is which weight to use in formulas for estimating creatinine clearance. One study compared measured creatinine clearance with calculated estimates using the Cockcroft-Gault formula and different measures for weight (TBW, IBW, AdjBW with correction factors of 0.3 and 0.4, LBW).22 Total body weight overestimated true clearance by almost 2-fold, whereas IBW underestimated clearance by around 23%. Lean body weight using the formula from Janmahasatian et al.17 provided the most accurate estimations of measured creatinine clearance. Strengths of this study are that it included hospitalized patients as opposed to healthy volunteers, though patients admitted to an ICU were excluded. When considering the pharmacokinetic differences that exist in patients with obesity versus nonobese patients, the concept of dose proportionality must be examined. Dose proportionality suggests that as weight increases (from standard size to a nonstandard size), pharmacokinetic parameters such as volume of distribution and clearance increase by the same ratio. For example, assume that a drug is given as a 1-mg/kg dose with a volume of distribution of 50 L and a clearance of 100 mL/minute according to studies of middle-aged adults with normal size, shape, and weight. Next, assume that the

same drug is given to a group of patients with morbid obesity who have the same age and height but who weigh twice as much. If the resultant volume of distribution and clearance are 100 L and 200 mL/minute, the concept of dose proportionality will apply because a doubling in weight is associated with a doubling in volume of distribution and clearance and no change in volume of distribution or clearance relative to weight (i.e., liters per kilogram or liters per hour per kilogram). In that setting, TBW would be the most appropriate measure to use for weight-based dosing. In contrast, if the volume of distribution and clearance do not change in proportion to the observed differences in TBW, another weight measure such as LBW or AdjBW using some correction factor may better reflect the changes that occur. In general, few drugs that are renally eliminated have characteristics of dose proportionality.

Calculating a Dose in the Patient with Morbid Obesity Although several factors must be considered when calculating a dosing regimen for the critically ill patient with morbid obesity, a few overarching principles exist (Box 41.1). These factors should be assessed in conjunction with the stepwise approach presented in the paragraphs that follow. With that in mind, the first step is to assess the degree of obesity in the individual patient. When dealing with mild to moderate forms of obesity (i.e., BMI 25–35 kg/m2), published dosing recommendations are usually appropriate because these patients were likely included in the trials that led to the dosing in the product label. As BMI approaches and exceeds 40 kg/m2 (i.e., morbid obesity), drug dosing is more complicated because these patients were often excluded from dosing studies or represented in such small numbers that a meaningful conclusion cannot be drawn. In these instances, the clinician should evaluate clinical trials with that medication conducted in patients with morbid obesity. It is important to assess whether the degree of obesity presented in the trials is similar to that of the individual patient at hand, especially if dealing with more extreme forms of obesity (i.e., BMI greater than 50 kg/m2). If clinical trials do not exist or if the patient does not fit the profile of the patients in the clinical investigations, the clinician should search for

pharmacokinetic trials of patients with obesity and assess whether dose proportionality exists. For medications that are weight based (i.e., milligrams per kilogram of body weight), the clinician must weigh the benefits and risks of using TBW versus LBW or some correction factor AdjBW. For medications that are non–weight based (i.e., milligrams per dose), the clinician may choose to administer a dose on the higher end of the recommended dosing range. If pharmacokinetic trials specific to patients with obesity do not exist, some generalizations can be made regarding pharmacokinetic parameters. Drugs that have a small volume of distribution typically do not distribute extensively into adipose tissue. Weight-based dosing, particularly for loading doses, can be performed using LBW. Drugs with a large volume of distribution would be anticipated to require loading doses based on TBW or AdjBW, but there are exceptions to this generalization. For example, digoxin has an average volume of distribution of around 500 L but is proportional to IBW (according to the Devine equations) and not TBW.23 This is because digoxin has a high affinity for cardiac and skeletal muscle, and adipose tissue is not an active reservoir. Clinicians must therefore use caution when making assumptions based on volume of distribution, especially when it is high. In some situations, when clinical and pharmacokinetic trials do not exist, it may be necessary to extrapolate dosing information from similar drugs (i.e., drugs in the same structural class) or consider an alternative agent. Other important factors to consider are the adverse effect profile of the medication and the method for administering and titrating to effect. For some medications (especially those with dosedependent adverse effects), it may be preferable to use a series of smaller doses that can be rapidly titrated to effect versus a single, large loading dose or maintenance doses that may be based on TBW (even when TBW may be the preferred weight measure for dosing). This method is commonly used for sedatives and analgesics in the postoperative setting. Finally, the ability to do therapeutic drug monitoring may be considered when selecting an agent and used whenever available. This allows the clinician to rapidly assess whether pharmacokinetic and pharmacodynamic goals are being met and to

adjust the dosing regimen as necessary.

Medication-Specific Recommendations Analgesics Even though opioid medications are highly lipophilic compounds, LBW is the most appropriate weight measurement for dosing them. One study evaluated analgesic response with a fixed 4-mg dose of morphine and reported no significant differences between individuals who were nonobese, individuals with obesity, and individuals with morbid obesity.24 Similarly, studies with fentanyl have shown a nonlinear relationship between dosing requirements and TBW. Dosing regimens based on TBW could therefore lead to excessive dosing in patients with morbid obesity.25,26 Remifentanil pharmacokinetics were evaluated in one study where the volume of distribution and the clearance were more closely related to lean body mass than to TBW.27 A second study evaluated sufentanil and showed a linear correlation between the volume of distribution and the degree of obesity, with a prolonged half-life in patients with obesity.28 This suggests that TBW should be used for loading doses, but LBW or IBW for maintenance dosing. In summary, available data analyses suggest that dosing adjustments with opioids are unnecessary in patients with obesity and that the same strategy as used in nonobese patients can be sought. Because opioid doses in adult patients are typically non–weight based, incremental doses that can be rapidly titrated to effect (similar to what is used in a recovery room setting) are recommended. In all cases, the degree of underlying pain, age of the patient, presence of ventilatory support, and likelihood that tolerance is occurring should be used to guide therapy.

Box 41.1. Practical Considerations When Calculating Drug Regimens in Critically Ill Patients with Morbid Obesity

Seek consistency with the weight measure that is used for weightbased dosing and for all dosing-related calculations (e.g., creatinine clearance calculations). Use dosing calculators or computer programs to assist with calculations from complex formulas. When evaluating the literature for data to assist with dosing, verify the weight of the actual patient in question is within the range of weights included in the clinical trial. The degree of variability in pharmacokinetic parameters (such as volume of distribution and clearance) is much greater in critically ill patients than in the non–critically ill population. When no outcomes data are available, clinicians should evaluate pharmacokinetic studies to assess for dose proportionality. When there are no comparative pharmacokinetic data, the clinician must balance the risk of adverse effects using a higher dose (or dosing based on TBW) with the risk of treatment failure using lower doses (or dosing based on LBW). In some cases, even when TBW may be the most appropriate measure for weight-based dosing, the adverse effect profile may preclude its use in favor of smaller doses that can be rapidly titrated to effect. LBW = lean body weight; TBW = total body weight.

Sedatives Sedation strategies that use non-benzodiazepine medications are preferred in mechanically ventilated, critically ill patients because of

their association with reduced durations of mechanical ventilation and shorter ICU lengths of stay.29 Propofol is the most widely used sedative because of its favorable pharmacokinetic profile, including a rapid onset and short duration of effect.30 Several pharmacokinetic models have been developed to evaluate propofol pharmacokinetics and pharmacodynamics in patients with morbid obesity. Servin et al. reported that both clearance and volume of distribution were correlated with TBW (r=0.76 and 0.61 for clearance and volume of distribution, respectively).31 Others have developed allometric models using TBW or some form of AdjBW to better characterize propofol dosing.32–34 Nevertheless, despite these data implying that TBW is the preferred weight measure for weight-based dosing, several studies have shown obesity to be an independent predictor of propofol-related adverse effects.35,36 Therefore, because of the hemodynamic concerns with large doses of propofol and the fact that propofol can rapidly be titrated to effect, either LBW or some correction factor AdjBW should be used for initial dosing calculations. There are no data evaluating the impact of obesity on dexmedetomidine pharmacokinetics in the ICU. Pharmacokinetic studies with dexmedetomidine have shown a large volume of distribution (greater than 100 L), and one study noted clearance to be correlated with weight.37 Nevertheless, because of concerns with adverse effects such as bradycardia and hypotension, either LBW or AdjBW should be used for weight-based calculations, with titration to the desired level of sedation. Benzodiazepines are highly lipophilic compounds, and marked differences in pharmacokinetic variables have been detected in individuals with obesity compared with nonobese individuals. In one study with midazolam, both volume of distribution and elimination halflife were significantly greater in the obese cohort (volume of distribution 2.66 vs. 1.74 L/kg; half-life 5.94 vs. 2.27 hours).38 The observed increase in half-life was presumed to be caused by the large volume of distribution because no difference was noted in total clearance (472 vs. 530 mL/minute). Therefore, LBW should be used to calculate doses for continuous infusions, but TBW can be considered for single doses

(because of increased volume of distribution). A safer approach, though, would be to use LBW or a series of smaller intravenous doses until the desired effect is achieved. Neuromuscular Blocking Agents Most neuromuscular blocking agents are polar, hydrophilic compounds, which suggests that distribution into adipose tissue is limited and that LBW is the preferred weight measure for both loading and maintenance doses. This was confirmed in several pharmacokinetic studies evaluating the neuromuscular blocking agents vecuronium, rocuronium, atracurium, and cisatracurium, where a longer duration of action was seen when doses were calculated according to TBW.39–42 Succinylcholine, however, should be dosed according to TBW because of the strong correlation between pseudocholinesterase activity and BMI.43 Furthermore, research has shown a substantial number of patients with poorer intubating conditions when either IBW or LBW was used rather than TBW.44 Anticoagulants Anticoagulant dosing can be particularly challenging because of the deleterious effects associated with doses that are too low and the increased risk of bleeding when doses are too high. Several studies have evaluated the pharmacokinetics of anticoagulants in obesity when used for both venous thromboembolism (VTE) prophylaxis and treatment. Prophylaxis In most hospitalized patients, the choice of an anticoagulant for VTE prophylaxis is between a low-molecular-weight heparin (LMWH) and low-dose unfractionated heparin. There is no class I evidence to provide guidance on the preferred agent, but one study of more than 24,000 bariatric surgery patients showed the adjusted rates of VTE to be lower in patients who received LMWH (0.25%) compared with those who received unfractionated heparin (0.68%).45 No significant difference in hemorrhage rates occurred. Other studies have evaluated

prophylactic dosing of LMWH in obesity, most of which are specific to the bariatric surgery population and not the critically ill. Overall, it appears that higher doses are necessary to achieve antifactor Xa (antiXa) concentrations in the recommended range, but the exact dose is less clear. Scholten et al., who conducted a pre-post study using enoxaparin 40 mg every 12 hours (compared with 30 mg every 12 hours) in bariatric surgery patients, reported significantly fewer VTE events (0.6% vs. 5.4%, p MIC

> 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 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

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.

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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

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 3 mo

H. influenzae S. pneumoniae

Cefotaxime or ceftriaxone ± vancomycina

N. meningitidis Immunocompromised

Pseudomonas aeruginosa S. aureus

Ceftazidime or cefepime or piperacillin/tazobactam + vancomycin

S. epidermidis Ventriculoperitoneal (VP) shunt

S. aureus S. epidermidis

Cefotaxime or ceftriaxone ± vancomycina

Gram-negative enterics Associated with head trauma or chronic otitis media

aVancomycin

S. pneumoniae

trough level 15–20 mcg/mL.

Cefotaxime or ceftriaxone ± vancomycina

In an effort to develop a consensus definition of the pediatric sepsis continuum including systemic inflammatory response syndrome (SIRS), infection, sepsis, severe sepsis, septic shock, and multisystem organ dysfunction syndrome, a group of international experts in the fields of adult and pediatric sepsis and clinical research gathered in 2002. A panel was chosen that consisted of published pediatric critical care physicians and scientists with clinical research experience in pediatric sepsis.16 Because the clinical variables used to define SIRS and organ dysfunction are greatly affected by the normal physiologic changes that occur as children age, the group first defined six age-specific clinical and physiologic categories for vital sign and laboratory variables to meet SIRS criteria (Table 44.3): newborn, neonate, infant, toddler and preschool, school-aged child, and adolescent and young adult. Premature infants were not included because their care occurs primarily in NICUs (neonatal intensive care units), not PICUs.

Table 44.3 Pediatric Age Groups for Severe Sepsis Definitionsa Age Category

Definition

Newborn

0 days to 1 wk

Neonate

1 wk to 1 mo

Infant

1 mo to 1 yr

Toddler and preschool

2–5 yr

School-aged child

6–12 yr

Adolescent and young adult

13 to < 18 yr

aGoldstein

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.

Table 44.4 Definitions of SIRS, Infection, Sepsis, Severe Sepsis, and Septic Shocka SIRS

The presence of at least two of the following four criteria, one of which must be abnormal temperature or leukocyte count: - Core temperature of > 38°C or < 36°C (must be measured by rectal, bladder, oral, or central catheter probe) - Tachycardia defined as at least 2 SD above normal for age in the absence of external stimulus, chronic drugs, or painful stimuli; or otherwise persistent elevation over 0.5–4 hr OR for children < 1 yr old: bradycardia, defined as a mean HR < 10% percentile for age in the absence of external vagal stimulus, β-blocker drugs, or congenital heart disease; or otherwise unexplained depression over a 0.5-hr period - Mean respiratory rate > 2 SD above normal for age or mechanical ventilation for an acute process not related to underlying neuromuscular disease or receipt of general anesthesia - Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced neutropenia) or > 10% immature neutrophils

Infection

A suspected or proven (by positive culture, tissue stain, or polymerase chain reaction test) infection caused by any pathogen OR a clinical syndrome associated with a high probability of infection. Evidence of infection includes positive findings on clinical examination, imaging or laboratory tests (e.g., white blood cells in a normally sterile body fluid, perforated viscus, chest radiograph consistent with pneumonia, petechial or purpuric rash, or purpurea fulminans)

Sepsis

SIRS in the presence of or as a result of suspected or proven infection

Severe sepsis

Sepsis plus one of the following: cardiovascular organ dysfunction OR acute respiratory distress syndrome OR two or more other organ dysfunctions. Organ dysfunctions are defined in Table 44.5

Septic shock

Sepsis and cardiovascular organ dysfunction as defined in Table 44.5

aGoldstein

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. SIRS = systemic inflammatory response syndrome.

Table 44.5 Age-Specific Vital Signs and Laboratory Variablesa,b

aGoldstein

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. bLower

values for HR, leukocyte count, and systolic BP are for the 5th percentile, and upper values for HR, respiratory rate, or leukocyte count are for the 95th percentile. N/A = not applicable.

Before discussing treatment, practitioners should understand the terms used to define sepsis. In 1992, SIRS was proposed by the American College of Chest Physicians and the Society of Critical Care Medicine to describe the nonspecific inflammatory process occurring in adults after trauma, infection, burns, pancreatitis, and other diseases.16,17 Sepsis was defined as SIRS associated with infection.17,18 The SIRS criteria were developed for use in adults. Not until 2005 was a consensus definition published for SIRS in children; this definition is listed in Table 44.4. A separate pediatric definition for SIRS was essential. Tachycardia and tachypnea, pivotal to the adult definition of SIRS, are common presenting symptoms of many pediatric disease processes. Therefore, the pediatric definition also includes that temperature and leukocyte abnormalities be present. Finally, numeric values for each criterion were established to account for the different physiology in children. Table 44.5 gives the age-specific cutoffs for each criterion. These values were established according to the expert

opinion of the international panel on sepsis that was convened in 2002. Temperature is one of the features of the pediatric SIRS definition. A core temperature of greater than 38.5°C or less than 36°C may indicate serious infection. A core temperature is one measured by rectal, bladder, oral, or central catheter probe. Hypothermia is more likely to occur in infants.19,20 Temperatures measured by the tym-panic, toe, or auxiliary route are not sufficiently accurate. Temperature may also be documented by a reliable source at home within 4 hours of presentation to the hospital or physician’s office. If environmental overheating, such as that produced by over-bundling, is suspected, the child should be returned to a neutral temperature environment, unbundled, and the temperature measurement repeated in 15–30 minutes.16 In children, SIRS requires the presence of an abnormal temperature (hypothermia or hyperthermia) or an abnormal leukocyte count (low or high) in the presence of tachypnea and tachycardia. Sepsis is defined as the proven or suspected infection in the setting of SIRS.16-18 Severe sepsis is defined as sepsis in the setting of acute respiratory distress syndrome, cardiovascular organ dysfunction, or two or more acute organ dysfunctions (respiratory, renal, hematologic, neurologic, or hepatic). Organ dysfunctions are modified for children and summarized in Table 44.6. Carcillo et al. defined septic shock in pediatric patients as the presence of tachycardia and poor perfusion, including decreased peripheral pulses compared with central pulses, altered alertness, capillary refill greater than 2 seconds, mottled or cool extremities, and decreased urine output.10 The definition of septic shock in children does not include hypotension, as required in adults. This is because children often maintain their blood pressure until they are severely ill. Shock may occur long before hypotension occurs in children with septic shock (failure to improve with adequate fluid resuscitation), catecholamine-resistant septic shock (failure to improve with fluids and catecholamines), and refractory septic shock (failure to improve with fluids, catecholamines, and vasodilators). In addition, there are developmental differences in the hemodynamic response to sepsis between neonates, children, and adults. Practitioners in the

PICU may encounter all age ranges and must thus be familiar with the clinical differences between age groups because this may affect therapy. Adult and pediatric patients have different adaptive responses that must be considered when selecting therapeutic management. This is important for pediatric practitioners to understand because many adolescent patients may respond as an adult. Among adult patients, the most common hemodynamic alterations include diminished systemic vascular resistance (SVR) and elevated CO. Systemic vascular resistance is diminished because of decreased vascular responsiveness to catecholamines, alterations in α-adrenergic receptor signal transduction, and the elaboration of inducible nitric oxide synthase. Adults have myocardial dysfunction with a decreased ejection fraction; however, CO is maintained or increased by tachycardia and reduced SVR. Pediatric septic shock is associated with severe hypovolemia, and children often respond well to aggressive fluid resuscitation. Pediatric patients have diverse hemodynamic profiles during fluid-refractory septic shock: 58% have low cardiac indexes responsive to inotropic medications with or without vasodilators, 20% have high cardiac indexes and low SVR responsive to vasopressor therapy, and 22% present with both vascular and cardiac dysfunctions, necessitating the use of vasopressors and inotropic support.21 The pediatric patient is different from the adult patient with septic shock because low CO, not low SVR, is associated with mortality in pediatric septic shock. In fact, 78% of children show some degree of cardiac dysfunction on presentation after fluid resuscitation. Furthermore, about 50% of patients require a change in their vasopressor or inotropic management, or the addition of another agent, emphasizing that the hemodynamic status in children can change rapidly. Finally, a reduction in oxygen delivery rather than a defect in oxygen extraction can be the major determinant of oxygen consumption in children.22

Table 44.6 Organ Dysfunction Criteria

Cardiovascular Dysfunction Despite administration of isotonic IV fluid bolus ≥ 40 mL/kg in 1 hr • Decrease in BP (hypotension) < 5th percentile for age or systolic BP < 2 SD below normal for agea OR • Need for vasoactive drug to maintain BP in normal range (dopamine > 5 mcg/kg/min or dobutamine, epinephrine, or norepinephrine at any dose) OR • Two of the following: • Unexplained metabolic acidosis: Base deficit > 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

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

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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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.

Figure 45.2 Drugs actively on shortage by quarter, January 2010 – June 2015. Reprinted with permission from: University of Utah Drug Information Service.

Since drug shortages started increasing in 2004, the FDA has improved its ability to prevent and respond to drug shortages. The FDA reported that in 2013, it helped prevent almost 80% of impending shortages.1 Some of the success at prevention is the result of new powers granted by the FDA Safety and Innovation Act of 2012, which, among other things, require manufacturers to report discontinuations of their products 6 months in advance and allow the FDA to expedite its review of new or abbreviated drug applications that would help mitigate a shortage.4

IMPACT ON PATIENT SAFETY AND QUALITY OF CARE Drug shortages have a negative impact at all levels of the health care system, including at the patient, health care professional, and institution or system level. Drug shortages may lead to patients receiving suboptimal care, patients being at an increased risk for adverse events or medication errors, treatment delays, cancellation of procedures, and patient harm. Two surveys of several groups of health care professionals done in 2010 and 2012 showed that drug shortages have a significant impact on patient care.5,6 From 20% to 40% of respondents to each survey noted that at least one patient had experienced an adverse event at a health system because of a drug shortage. In addition, more than 50% of respondents reported that medication errors had occurred in their facilities in the past year that were directly related to shortages. Other reports have noted the more serious harms that have occurred related to drug shortages such as a greater relapse rate of patients with certain types of cancer. In 2011, 15 deaths were potentially caused by the use of substitute drugs because of a drug shortage.7,8 Specific examples of medication errors and adverse events reported in surveys that were caused by drug shortages include the following5: Because of conservation efforts, a patient received inadequate sedation with propofol during a procedure and woke up Patients could not be extubated or weaned off the ventilator because of excess sedation from use of less familiar drugs A patient received rocuronium at the infusion rate intended for cisatracurium A patient received a 10-fold overdose of epinephrine during a code when there was confusion from having to stock an unfamiliar concentration of the drug A patient died when the patient could not receive amikacin (which was the only medication the patient’s infection was sensitive to)

Two patients died after receiving intravenous hydromorphone that was prescribed and administered at the dose intended for intravenous morphine In addition to direct harm to the patient, health care professionals are significantly affected by drug shortages. According to the same 2010 survey cited previously, the most common issue noted by health care professionals was the lack of timely information about a given shortage.5 Drug shortages can lead to conflict and a tense work environment, which may be related to the lack of available information, the need to use nonoptimal therapies that providers are not used to using, and the need to make tough ethical decisions in order to conserve the dwindling supply of a drug.9 There is speculation that shortages lead to changes in the training of prescribers and in prescribing patterns as prescribers become used to using a second- or third-line therapy when the first-line agent is on a long-term shortage.10 The additional time required to manage shortages may add to the fatigue of a health care worker with an already full load of responsibilities, which could lead to errors and patient adverse effects. Drug shortages also force providers to take time away from other “high-impact, high-value” tasks such as patient care, education, and research.9,11 Finally, drug shortages have a significant financial impact. For example, the Premier Health Alliance estimated that an average of $230 million was spent annually from 2011 to 2013 across the country to purchase supplies of drugs on shortage from alternative suppliers.7 In addition to the higher purchase price, the financial burden on institutions comes from ordering an increased quantity of a drug before or during an ongoing shortage. Also contributing to the financial burden are the additional personnel costs that may be required to manage shortages and potential lost revenue because of the delay or cancellation of procedures. A 2011 survey of pharmacy directors tried to quantify the impact of drug shortages on personnel time and costs.11 The survey showed that an average of 17 hours was spent weekly on managing drug shortages. The survey also estimated that the personnel costs for managing shortages was $216 million annually in

the United States, with the cost ranging from $25,000 to $48,000 per hospital, depending on the size of the hospital. However, this figure is likely an underestimate because some health systems have hired personnel solely to manage shortages, and at the time the survey was administered, the number of drug shortages was lower than it is now.

MANAGEMENT STRATEGIES FOR DEALING WITH DRUG SHORTAGES It is vital for a hospital or health system to have a clearly defined plan and process for managing drug shortages to help mitigate the related risks and costs mentioned earlier (Figure 45.4). The strategic planning to manage drug shortages has been compared with the strategic planning for an emergency weather event or mass-casualty incident.12 This planning and management is particularly vital for critically ill patients because generic injectables continue to be a significant portion of the drugs on shortage.

Figure 45.3 Top 5 drug classes on shortage.

Reprinted with permission from: University of Utah Drug Information Service.

Table 45.1 Reasons for Shortages as Determined by UUDIS During Investigation, 2014 Unknown 47% Manufacturing 25% Supply / Demand 17% Raw Materials 2% Business decision 9%

The first step in effectively managing drug shortages is to identify which medications are (or are likely to be) on shortage and gather information on the cause and expected duration of the shortage.12,13 Having someone in charge of purchasing help to identify shortages by monitoring the issues with a product in the supply chain is one place for identification to occur. In addition, there are two main websites to find details about current drug shortages.14,15 Both the American Society of Health-System Pharmacists (ASHP) and the FDA maintain online databases of current shortages together with pertinent information specific to each shortage (e.g., cause of shortage, alternative manufacturers). When researching a potential or actual shortage, it is helpful to visit both websites for details because the content may be different depending on the different ways each group defines a shortage and gathers its information. In general, the ASHP website will list more shortages and will include content directed more toward the health care professional.1,16 After the identification of an actual or potential shortage issue, the identified individual or group in charge of managing shortages should begin assessing the potential impact. The first task of assessment is to

verify the current stock of the drug on hand and compare that with historic purchasing and drug use data to assess when the impact of the shortage may be felt. In addition, it is important to investigate and factor in the availability of the drug from any preapproved alternative sources, the availability and use of therapeutic alternatives, and the financial impact of ordering alternative agents. Ideally, at this point, the group in charge of managing shortages can analyze the threat to patients from a given shortage.12,13

Figure 45.4 Algorithm for the management of drug shortages. A plan for best mitigating the impact of the shortage should be created according to the information initially gathered. There are several different means of mitigating risks of a drug shortage, and the mitigation plan for each shortage is unique. Often, alternative sizes or concentrations are available for a drug on shortage. In some instances, it may be possible to make background operational changes within the

pharmacy such that providers prescribing or administering these agents are completely unaffected. If this is not possible, it may be necessary to decrease use of the drug by prioritizing patients, restricting the drug’s use, and ordering and using alternative drugs. In these cases, it is important to engage the pharmacy and therapeutics committee or the ethics committee of an institution to help establish and communicate clear guidelines for the drug’s use. One large academic medical center developed a policy around an ethically justifiable rationing approach for shortages.17 Regardless of the plan, communication to any potential end users is vital to help ensure that a plan remains effective for as long as necessary. Regular communication through several different venues (electronic health and prescriber order entry systems, e-mail, postings on bulletin boards in applicable places, staff meetings, and any other means that your organization uses well) will help ensure that regular communication occurs.12,13 Depending on the severity and potential ramifications of the shortage, senior medical and administrative leadership may need to be notified and engaged in supporting and disseminating any action plans. Strong relationships and communication are vital to make the response to a drug shortage as safe and effective as possible. Although a pharmacy department may often take the lead, it is important to have relevant stakeholders, leaders, and committees from many different disciplines involved with planning and regularly providing feedback throughout the process. It may also be important to engage risk management and legal departments within an institution for a given shortage in order to help assess the impact of shortages that pose a larger threat to patient care so that they can plan accordingly. Finally, it may be helpful to build relationships with other hospitals to share information and emergency supplies.12,13

CONCLUSION Although the number of new drug shortages per year has been declining since 2012, the ongoing drug shortage problem continues to place patients, health care teams, and health care institutions at risk of

adverse outcomes. Drug shortages have several complex causes that are not quickly or easily fixed. Because of this, ongoing management with a team-based approach is necessary at the hospital level to mitigate these risks and prevent patient harm.

REFERENCES 1. Wosinka M, Fox E, Jensen V. Are shortages going down or not? Interpreting data from the FDA and the University of Utah drug information service. Health Affairs Blog. April 8, 2015. Available at http://healthaffairs.org/blog/2015/04/08/are-shortages-goingdown-or-not-interpreting-data-from-the-fda-and-the-university-ofutah-drug-information-service/. Accessed May 15, 2015. 2. Loftus P. US drug shortages frustrate doctors, patients. Wall Street Journal. May 31, 2015. Available at www.wsj.com/articles/u-s-drug-shortages-frustrate-doctorspatients-1433125793. Accessed June 5, 2015. 3. U.S. Government Accountability Office. Drug Shortages: Public Health Threat Continues, Despite Efforts to Help Ensure Product Availability. GAO-14.-194. February 2014. Available at www.gao.gov/assets/670/660785.pdf. Accessed May 15, 2015. 4. American Hospital Association (AHA), American Society of Anesthesiologists (ASA), American Society of Clinical Oncology (ASCO), American Society of Health-System Pharmacists (ASHP), Institute for Safe Medication Practices (ISMP), and the Pew Charitable Trusts. 2014 Drug Shortages Summit Summary Report. August 1, 2014. Available at www.ismp.org/pressroom/2014-Drug-Shortages-Summit.pdf. Accessed May 15, 2015. 5. Institute for Safe Medication Practices. Drug shortages: national survey reveals high level of frustration, low level of safety. ISMP Med Saf Alert 2010;15:1-6. Available at www.ismp.org/newsletters/acutecare/articles/20100923.asp. Accessed May 15, 2015.

6. McLaughlin M, Kotis D, Thomson K, et al. Effects on patient care caused by drug shortages: a survey. J Manag Care Pharm 2013;19:783-8. 7. Johnson LJ. Hospitals coping better as drug shortages persist. Associated Press. February 28, 2014. Available at www.bostonglobe.com/business/2014/02/28/hospitals-copingbetter-drug-shortagespersist/ri3StaN3qSfC2itCxVnHeN/story.html. Accessed June 5, 2015. 8. Koba M. The US has a drug shortage – and people are dying. Fortune Online. January 6, 2015. Available at http://fortune.com/2015/01/06/the-u-s-has-a-drug-shortage-andpeople-are-dying/. Accessed June 5, 2015. 9. The Joint Commission. Health care worker fatigue and patient safety. Sentinel Event Alert. 2011;48:1-4. Available at www.jointcommission.org/assets/1/18/sea_48.pdf. Accessed June 5, 2015. 10. George A. A potential unexpected consequence of drug shortages on long-term prescribing patterns. Am J Health Syst Pharm 2015;72:916. 11. Kaakeh R, Sweet BV, Reilly C, et al. Impact of drug shortages on US health systems. Am J Health Syst Pharm 2011;68:1811-9. 12. Fox ER, Birt A, James KB, et al. ASHP guidelines on managing drug product shortages in hospitals and health systems. Am J Health Syst Pharm 2009;66:1399-406. 13. Institute for Safe Medication Practices. Weathering the storm: managing the drug shortage crisis. ISMP Med Saf Alert 2010;15:1-4. Available at www.ismp.org/newsletters/acutecare/arve meticles/20101007.asp. Accessed June 15, 2015. 14. U.S. Food and Drug Administration. Current Drug Shortages. Available at www.fda.gov/Drugs/DrugSafety/DrugShortages/.

Accessed June 15, 2015. 15. American Society of Health-System Pharmacists. Drug Shortages: Current Drugs. Available at www.ashp.org/drugshortages/current/. Accessed June 15, 2015. 16. U.S. Food and Drug Administration Drug Shortage Staff, American Society of Health-System Pharmacists, and the University of Utah Drug Information Service. Contrasting the FDA (CDER) and ASHP Drug Shortage Websites: What’s the Difference? August 2014. Available at www.ashp.org/DocLibrary/Policy/DrugShortages/FDA-versusASHP.pdf. Accessed August 5, 2015. 17. Rosoff PM, Patel, KR, Scates A, et al. Coping with critical drug shortages: an ethical approach for allocating scarce resources in hospitals. Arch Intern Med 2012;172:1494-9.

Chapter 46 Drug Interactions in the

Intensive Care Unit Cristian Merchan, Pharm.D.; and John Papadopoulos, Pharm.D., B.S., FCCM, BCNSP

LEARNING OBJECTIVES 1. Discuss the importance of recognizing drug interactions. 2. Differentiate between a pharmacokinetic and a pharmacodynamic drug-drug interaction (DDI). 3. Analyze specific examples of clinically significant DDIs relevant in the intensive care unit setting. 4. Explain the importance of drug-nutrient interactions. 5. Summarize an approach to evaluate the evidence of DDIs.

ABBREVIATIONS IN THIS CHAPTER AUC

Area under the curve

DDI

Drug-drug interaction

DIPS

Drug Interaction Probability Scale

H2RA

Histamine-2 receptor antagonist

ICU

Intensive care unit

MAO

Monoamine oxidase

P-gp

P-glycoprotein

TdP

Torsades de pointes

TOAC

Target-specific oral anticoagulant

INTRODUCTION The care of the critically ill patient is a complex process that requires clinicians to draw on their knowledge of pathophysiology, pharmacology, pharmacokinetics, clinical trials, and differential diagnoses. Patients cared for in an intensive care unit (ICU) environment receive several medications to treat a variety of acute and chronic ailments, as well as prophylactic medications to prevent complications such as stress-related mucosal damage and deep vein thrombosis. Each ICU clinician needs to understand the importance of drug interactions, given the complexity of pharmacologic interplay in the ICU environment, the common presence of organ dysfunction, and our heightened awareness for the need to provide optimal and safe care for our patients. Published data quantifying the magnitude of drug interactions and their effects on clinical outcomes in the ICU are limited. A single-center, prospective, observational study of 281 patients admitted to a medical ICU reported that drug interactions accounted for 4% of ICU admissions.1 Additional data analyses report that the percentage of patients in the ICU with at least one drug interaction is 40%–73%.2-6 Several observational studies have been conducted to identify significant potential drug-drug interactions (DDIs) in a variety of ICU settings. Smithburger and colleagues conducted a prospective, observational study to identify DDIs in the cardiovascular and cardiothoracic ICUs.2 Micromedex and Lexi-Interact interaction databases were used to screen each patient’s medication profile and determine the severity of identified DDIs. Of the 400 patient medication profiles evaluated, 56% had one or more potential DDIs. The most significant DDIs were determined by assignment to the major

interaction category by just one of the interaction databases. These included drugs that can prolong the corrected QT (QTc) interval, enhance antiplatelet or anticoagulant effects, and inhibit the cytochrome P450 (CYP) 3A4 enzyme. The most common drugs cited as involved in major interactions included amiodarone, aspirin, clopidogrel, heparin, warfarin, clonidine, and β-blockers. Smithburger and colleagues also conducted a similar evaluation in the medical ICU.3 From the 240 patient medication profiles evaluated, 46% had one or more potential DDIs. The most significant DDIs involved medications that can enhance antiplatelet or anticoagulant effects, prolong the QTc interval, or inhibit CYP3A4 or that can be classified as an antiepileptic. The most common drugs cited as involved in major interactions included aspirin, clopidogrel, selective serotonin reuptake inhibitors (SSRIs), β-blockers, valproic acid, and posaconazole. In addition, these studies highlight the importance of considering the differences between ICU populations when developing clinical decision support systems in order to reduce alert fatigue, and the studies provide enough information to determine an appropriate risk-benefit ratio for the patient receiving the interacting drugs. Nonetheless, further data are needed to adequately determine the impact of drug interactions in the ICU environment. Drug interactions are generally classified as pharmaco-kinetic or pharmacodynamic, depending on the underlying mechanism. A pharmacokinetic interaction occurs when one drug alters the absorption, distribution, metabolism, or elimination of another agent. These interactions can be quantified by changes in area under the curve (AUC), half-life, or peak serum concentration. A pharmacodynamic interaction changes the pharmacologic response to a drug in an additive, synergistic, or antagonistic way. This review will focus on DDIs and drug-nutrient interactions that have high clinical relevance in the ICU setting.

PHARMACOKINETIC DDIS

Absorption The small intestine is the primary site for enteral drug absorption, except for a few drugs that are absorbed in the stomach (e.g., aspirin). Patient and drug-specific factors influence enteral drug absorption and net bioavailability in the critically ill.7,8 The clinical status of the patient is an important consideration when determining the intestine’s ability to absorb enterally administered medications. Many factors contribute to intestinal ischemic damage in the critically ill, including acute hemorrhage, cardiac and abdominal surgery, inotropic and vasopressor therapy, various forms of shock, and abdominal compartment syndrome.7,8 These factors redistribute blood flow away from the gastrointestinal (GI) tract and may prolong the time to reach peak concentrations and AUC of enterally administered medications. In addition, critically ill patients commonly receive stress ulcer prophylaxis with intravenous histamine-2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs). Because many drugs are weak acids, the associated increase in gastric pH induced by the administration of gastric acid inhibitors can potentially alter the bioavailability of drugs normally absorbed through the GI tract that require an acidic medium for absorption (e.g., ketoconazole, itraconazole, dipyridamole).7,8 Furthermore, delayed gastric emptying is commonly observed in patients who have postoperative ileus, mechanical ventilation, electrolyte abnormalities, splanchnic hypoperfusion, increased intracranial pressure, or opioid and sedative medication needs. Because these parameters delay the rate of gastric emptying, they may lead to a delay in the rate of drug absorption, time to peak concentration, and onset of drug action for enterally administered medications.9 Another factor to consider in the critically ill is the effect of systemic inflammation on P-glycoprotein (P-gp) function. Pglycoprotein acts as an efflux pump that transports drugs back into the intestinal lumen after absorption. This efflux pump, in combination with any intestinal CYP3A4 inhibition, may substantially limit the bioavailability of drugs given enterally that are substrates for these systems. Systemic inflammation decreases the intestinal P-gp activity, which may lead to a consequential increase in the net oral

bioavailability of enterally administered medications that are substrates for these systems.10,11 Finally, the administration of enteral feeds, binders, or chelators can lead to a decrease in the AUC of select drugs. Table 46.1 provides specific examples of DDIs that affect the absorption of various medications prescribed in the ICU.

TARGETED TREATMENT STRATEGIES FOR DDIS INVOLVING ABSORPTION Drug-drug interactions involving absorption can be handled in various ways. Therapeutic substitution (i.e., sucralfate or an H2RA instead of a PPI) for drugs that require gastric acidity or appropriate administration spacing in the presence of a binder or chelator may mitigate an absorption-related interaction. Use of the intravenous route of medication administration should be considered in a critically ill patient when a medication need is critical.

P-glycoprotein (B) P-glycoprotein acts as a drug efflux pump that is responsible for transporting drugs from the circulation into the lumen of the small intestine, bile duct, and proximal convoluted tubule (Table 46.2).36-38 These pumps are located on the luminal membrane of the small intestine and blood-brain barrier and in the apical membranes of excretory cells such as hepatocytes and renal proximal tubule cells. The role of P-gp on the intestinal epithelial cells is to limit the cellular uptake and absorption into enterocytes, compared with its location in hepatocytes and renal tubular cells, where it enhances the elimination of drugs into the bile and urine, respectively.36-38 In addition, P-gp provides enhanced opportunities for medications to be metabolized by intestinal CYP3A4. Subsequently, there is increased contact of medications to the CYP3A4 enzymes that contribute toward biotransformation and decreased overall systemic exposure.36-38

Targeted Treatment Strategies for DDI Involving P-gp

The role of P-gp in the realm of drug interactions may be limited (except for digoxin) unless there is concomitant CYP enzyme inhibition or induction (Table 46.3). If a concomitant P-gp/CYP enzyme interaction is identified, vigilance in therapeutic drug monitoring, indices of clinical end points, and signs and symptoms of toxicity needs to be used to determine the best clinical treatment course. Medication substitution, as described in the section on DDIs involving metabolism, may need to be used.

Table 46.1 Clinically Relevant Drug Interactions of Absorption

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

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

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

ASA = aspirin; CVD = cardiovascular disease; ICH = intracranial hemorrhage; MI = myocardial infarction; TIMI = thrombolysis in myocardial infarction.

Table 46.13 Clinically Relevant Drug-Nutrient Interactions in the ICU95-99 Medication

Mechanism

Action

Carbamazepine

Adheres to polyvinyl chloride walls of feeding tubes

Dilute the suspension with equal amounts of sterile water or 0.9% sodium chloride injection

Fluoroquinolones

Chelation of fluoroquinolones with the calcium, aluminum, magnesium, and zinc found in enteral nutrition results in decreased absorption. Absorption may also be decreased if administered by a jejunostomy tube

For severe infections, administer the fluoroquinolone intravenously

Cyclosporine, tacrolimus

Grapefruit juice inhibits intestinal CYP3A4 and P-gp

Avoid grapefruit juice

Diazepam solution

Adheres to polyvinyl chloride walls of feeding tubes

Avoid solution

Digoxin99

Poorly absorbed in presence of enteral feeding formulas that contain fiber

May not be clinically significant

(ciprofloxacin and levofloxacin)

For mild to moderate infections or for prophylaxis: Hold enteral nutrition for 1 hr before and 2 hr after medication administration Flush enteral feeding tube with 20 mL of water before and after medication administration If the jejunostomy tube is the only enteral route available, consider administering the fluoroquinolone intravenously

Monitor concentrations of each respective medication

Crush tablets or administer intravenously

Monitor concentrations, if warranted

The largest reported change in plasma digoxin caused by the addition of 10– 22 g of dietary fiber is < 15% Levodopa

Amino acids may compete with levodopa for absorption in the small intestine. Effects observed

Enteral nutrition should be held for 2 hr before and after levodopa administration Flush enteral feeding tube with 20 mL of water before and after medication

with protein intake > 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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51. Kondo Y, Abe T, Kohshi K, et al. Revised trauma scoring system to predict in-hospital mortality in the emergency department: Glasgow Coma Scale, Age, and Systolic Blood Pressure score. Crit Care 2011;15:R191. 52. Osler T, Baker SP, Long W. A modification of the injury severity score that both improves accuracy and simplifies scoring. J Trauma 1997;43:922-5; discussion 925-6. 53. Lavoie A, Moore L, LeSage N, et al. The New Injury Severity Score: a more accurate predictor of in-hospital mortality than the Injury Severity Score. J Trauma 2004;56:1312-20. 54. Bellomo R, Ronco C, Kellum JA, et al.; workgroup ADQI. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204-212. 55. Bagshaw SM, George C, Bellomo R, et al. A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008;23:1569-74. 56. Bagshaw SM, George C, Dinu I, et al. A multi-centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008;23:1203-10. 57. Lopes JA, Fernandes P, Jorge S, et al. Acute kidney injury in intensive care unit patients: a comparison between the RIFLE and the Acute Kidney Injury Network classifications. Crit Care 2008;12:R110. 58. Joannidis M, Metnitz B, Bauer P, et al. Acute kidney injury in critically ill patients classified by AKIN versus RIFLE using the SAPS 3 database. Intensive Care Med 2009;35:1692-702. 59. Haase M, Bellomo R, Matalanis G, et al. A comparison of the RIFLE and Acute Kidney Injury Network classifications for cardiac surgery-associated acute kidney injury: a prospective cohort study. J Thorac Cardiovasc Surg 2009;138:1370-6.

60. Englberger L, Suri RM, Li Z, et al. Clinical accuracy of RIFLE and Acute Kidney Injury Network (AKIN) criteria for acute kidney injury in patients undergoing cardiac surgery. Crit Care 2011;15:R16. 61. Colpaert K, Hoste EA, Steurbaut K, et al. Impact of real-time electronic alerting of acute kidney injury on therapeutic intervention and progression of RIFLE class. Crit Care Med 2012;40:1164-70. 62. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. 63. Chang CH, Lin CY, Tian YC, et al. Acute kidney injury classification: comparison of AKIN and RIFLE criteria. Shock 2010;33:247-52. 64. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41. 65. Ranson JH, Rifkind KM, Roses DF, et al. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet 1974;139:69-81. 66. Ranson JH, Rifkind KM, Roses DF, et al. Objective early identification of severe acute pancreatitis. Am J Gastroenterol 1974;61:443-51. 67. Papachristou GI, Muddana V, Yadav D, et al. Comparison of BISAP, Ranson’s, APACHE-II, and CTSI scores in predicting organ failure, complications, and mortality in acute pancreatitis. Am J Gastroenterol 2010;105:435-41; quiz 442. 68. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut 2013;62:102-11. 69. Bollen TL, Singh VK, Maurer R, et al. A comparative evaluation of radiologic and clinical scoring systems in the early prediction of severity in acute pancreatitis. Am J Gastroenterol 2012;107:6129.

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.

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

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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)