Reasoning in Medicine Reasoning in Medicine Thomas Brown, MD Hospitalist Charlotte Hungerford Hospital Torrington, Connecticut Sonali Shah MD, PhD Candidate University of Connecticut School of Medicine Farmington, Connecticut 2013 People’s Medical Publishing House–USA Shelton, Connecticut People’s Medical Publishing House-USA 2 Enterprise Drive, Suite 509 Shelton, CT 06484 Tel: 203-402-0646 Fax: 203-402-0854 E-mail: info@pmph-usa.com © 2013 PMPH-USA, Ltd. All rights reserved. Without limiting the rights under copyright reserved above, no part of this publication may be reproduced, stored in or introduced into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise), without the prior written permission of the publisher.

13 14 15 16/Sheridan/9 8 7 6 5 4 3 2 1 ISBN-13 978-1-60795-160-5 ISBN-10 1-60795-160-6 eISBN-13 978-1-60795-252-7 Printed in the United States of America by Sheridan Books, Inc. Editor: Jason Malley; Copyeditor/Typesetter: diacriTech; Cover designer: Mary McKeon Library of Congress Cataloging-in-Publication Data Evidence-based clinical reasoning in medicine / [edited by] Thomas Brown, Sonali Shah. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-60795-160-5 ISBN-10: 1-60795-160-6 ISBN-13: 978-1-60795-252-7 (e-ISBN) I. Brown, Thomas A. (Thomas Andrew), 1972- II. Shah, Sonali J. [DNLM: 1. Clinical Medicine—Case Reports. 2. Diagnosis, Differential—Case Reports. 3. Evidence-Based Medicine—Case Reports. 4. Risk Factors—Case Reports. WB 293] 616.07’5—dc23 2012033757 Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs. Any treatment regimen, particularly one involving medication, involves inherent risk that must be weighed on a case-bycase basis against the benefits anticipated. The reader is cautioned that the purpose of this book is to inform and enlighten; the information contained herein is not intended as, and should not be employed as, a substitute for individual diagnosis and treatment. Sales and Distribution Canada McGraw-Hill Ryerson Education Customer Care 300 Water St Whitby, Ontario L1N 9B6 Canada Tel: 1-800-565-5758 Fax: 1-800-463-5885 www.mcgrawhill.ca Australia, New Zealand Elsevier Australia Locked Bag 7500 Chatswood DC NSW 2067 Australia Tel: 161 (2) 9422-8500 Fax: 161 (2) 9422-8562 www.elsevier.com.au Foreign Rights John Scott & Company International Publisher’s Agency P.O. Box 878 Kimberton, PA 19442 USA Tel: 610-827-1640 Fax: 610-827-1671 Japan United Publishers Services Limited 1-32-5 Higashi-Shinagawa Shinagawa-ku, Tokyo 140-0002 Japan Tel: 03-5479-7251 Fax: 03-5479-7307 Email: kakimoto@ups.co.jp United Kingdom, Europe, Middle East, Africa McGraw Hill Education Shoppenhangers Road Maidenhead Berkshire, SL6 2QL England Tel: 44-0-1628-502500 Fax: 44-0-1628-635895 www.mcgraw-hill.co.uk Singapore, Thailand, Philippines, Indonesia, Vietnam, Pacifi c Rim, Korea McGraw-Hill Education 60 Tuas Basin Link Singapore 638775 Tel: 65-6863-1580 Fax: 65-6862-3354 www.mcgraw-hill.com.sg Brazil SuperPedido Tecmedd Beatriz Alves, Foreign Trade Department R. Sansao Alves dos Santos, 102| 7th floor Brooklin Novo Sao Paolo 04571-090 Brazil Tel: 55-16-3512-5539 www.superpedidotecmedd.com.br India, Bangladesh, Pakistan, Sri Lanka, Malaysia CBS Publishers 4819/X1 Prahlad Street 24 Ansari Road, Darya Ganj, New Delhi-110002 India Tel: 91-11-23266861/67 Fax: 91-11-23266818 Email:cbspubs@vsnl.com People’s Republic of China People’s Medical Publishing House International Trade Department No. 19, Pan Jia Yuan Nan Li Chaoyang District Beijing 100021 P.R. China Tel: 8610-67653342 Fax: 8610-67691034 www.pmph.com/en/ Dedication To my family, for their unconditional support in seeing me through a difficult time. And of course to my precious girls, Maya and Anjali. —TAB To my loving family—Kalpana, Jagdish, Hemal, and Travis—my eternal gratitude for your unconditional support.

—SJS Contents Contributors xiii Preface xvii Acknowledgments xix CHAPTER 7 Spontaneous Bacterial Peritonitis 63 Allyson Reid CHAPTER 1 Lower Gastrointestinal Bleed 1 Teresa Doucet, MD CHAPTER 8 Transient Ischemic Attack 71 Jordan Sherwood CHAPTER 2 Peptic Ulcer Disease 9 Neena T. Qasaba, MD CHAPTER 3 Acute Viral Hepatitis 23 Joseph Palter, MD CHAPTER 4 Ruptured Esophageal Varices 33 Nathan Selsky, MD CHAPTER 5 Ischemic Colitis 43 Nathan Selsky, MD CHAPTER 6 Upper Gastrointestinal Bleeding 51 Pauley Chea CHAPTER 9 Ischemic Stroke 87 N. Abimbola Sunmonu, MD, PhD CHAPTER 10 Acute Spinal Cord Compression 101 Olga P. Fermo, MD CHAPTER 11 Perioperative Beta-Blockers 115 Paul J. D. Roszko, MD CHAPTER 12 Epidemiology and Perioperative Management of Hip Fracture 135 Paul J. D. Roszko, MD ix x Contents CHAPTER 13 Asthma Exacerbation Arija I. Weddle CHAPTER 15 Community-Acquired Pneumonia 189 Claire Li, MD 159 CHAPTER 22 Aortic Dissection 279 Heeseop Shin, MD CHAPTER 14 COPD Exacerbation Christian Acharte 177 CHAPTER 24 Indications for Pacemaker Placement 307 Song Li, MD CHAPTER 16 Complicated Pleural Effusion 199 Stephen Andrew Gannon, MD CHAPTER 17 Nosocomial Pneumonia 213 Aaron Robert Soufer, MD CHAPTER 18 Cocaine-Induced Chest Pain 229 Priscilla Owusu Ansah, MD CHAPTER 19 Acute Decompensated Congestive Heart Failure 241 Martine Saint-Cyr, MD CHAPTER 25 Aortic Stenosis 317 Samantha S. Huq CHAPTER 26 Temporal Arteritis 331 Adeel Shahid, MD CHAPTER 27 Venous Thromboembolism 341 Patrick Koo, MD CHAPTER 28

Syncope 355 Faith J. Ross, MD CHAPTER 29 Hypertensive Emergency 363 Erealda Prendaj, MD CHAPTER 20 Non-ST Segment Elevated Myocardial Infarction 253 Noel M. Baker, MD CHAPTER 30 Rhabdomyolysis 373 Jessica Intravia, MHA CHAPTER 21 ST Segment Elevation Myocardial Infarction 263 Muneer A. Hameer CHAPTER 23 Atrial Fibrillation 289 Lisa Josephine Gupta, MD CHAPTER 31 Endocarditis 381 Vishal Joshi, MD, Anuradha Subramanian, MD Contents xi CHAPTER 32 Bacterial Meningitis 395 Tamer Fakhouri, MD CHAPTER 40 Heparin-Induced Thrombocytopenia 471 Lisa Josephine Gupta, MD CHAPTER 33 Cellulitis 403 Brandon Olivieri, MD CHAPTER 41 Thrombocytopenia 479 Krishna Patel CHAPTER 34 Clostridium difficile Infection 413 Jesús Gutierrez, MD, MPH CHAPTER 42 Acute Renal Failure 489 Eric Addo CHAPTER 35 Latent Tuberculosis Infection 423 Jesús Gutierrez, MD, MPH CHAPTER 36 Delirium 435 Hailun Wang, MD CHAPTER 37 Myxedema Coma Rajasree Ramachandra Pai, MD CHAPTER 38 Diabetic Ketoacidosis Vatsal Patel 443 CHAPTER 45 Hyponatremia from Syndrome of Inappropriate Antidiuretic Hormone Secretion 519 Jonathan Shupe, MD 449 CHAPTER 46 Hypernatremia 531 Alexandria Thornton, MD Index 541 CHAPTER 39 Adrenal Insufficiency Rickinder Grewal 461 CHAPTER 43 Acute Interstitial Nephritis 501 Aimee S. Ang, MD CHAPTER 44 Minimal Change Disease 509 Chika Anekwe, MD

Contributors Christian Acharte [14] MD Candidate, Class of 2013 University of Connecticut School of Medicine Farmington, Connecticut Noel M. Baker, MD [20] Psychiatry resident Medical School of New Jersey UMDNJ Newark, New Jersey Eric Addo [42] MD Candidate, Class of 2013 University of Connecticut School of Medicine Farmington, Connecticut Pauley Chea [6] MD Candidate, Class of 2013 University of Connecticut School of Medicine Farmington, Connecticut Chika Anekwe, MD [44] Resident Department of Pediatrics NYU School of Medicine New York, New York Teresa Doucet, MD [1] Internal Medicine, 2nd year resident University Hospitals at Case Medical Center Cleveland, Ohio Aimee S. Ang, MD [43] Resident Primary Care Internal Medicine University of Connecticut School of Medicine Farmington, Connecticut Priscilla Owusu Ansah, MD [18] University of Connecticut School of Medicine Farmington, Connecticut Tamer Fakhouri, MD [32] Internal Medicine Resident Yale–New Haven Hospital New Haven, Connecticut Olga P. Fermo, MD [10] Neurology Resident, PGY2 The Johns Hopkins Hospital Baltimore, Maryland xiii Stephen Andrew Gannon, MD [16] MD Candidate, Class of 2012 University of Connecticut School of Medicine Farmington, Connecticut Vishal Joshi, MD [31] Consultant, Department of Internal Medicine Division of Infectious Disease Rouge Valley Health System—Ajax Ajax, Ontario, Canada Rickinder Grewal [39] MD Candidate, Class of 2013 University of Connecticut School of Medicine Farmington, Connecticut Patrick Koo, MD [27] Chief Medicine Resident University of Connecticut School of Medicine Farmington, Connecticut Lisa Josephine Gupta, MD [23, 40] University of Connecticut School of Medicine Farmington, Connecticut Claire Li, MD [15] Department of Internal Medicine, PGY-1 Saint Mary’s Hospital Waterbury, Connecticut Jesús Gutierrez, MD, MPH [34, 35] Resident Physician, Internal Medicine and Pediatrics Indiana University School of Medicine Indianapolis, Indiana Muneer A. Hameer [21] 4th year Medical Student Geisel School of Medicine Dartmouth University Hanover, New Hampshire Song Li, MD [24] Internal Medicine Resident Emory University School of Medicine Atlanta, Georgia Brandon Olivieri, MD [33] Yale–New Haven Hospital New Haven, Connecticut Joseph Palter, MD [3] University of Connecticut School of Medicine Farmington, Connecticut Samantha S. Huq [25] MD/PhD Candidate, Class of 2014 University of Connecticut School of Medicine Farmington, Connecticut Krishna Patel [41]
MD Candidate, Class of 2013 University of Connecticut School of Medicine Farmington, Connecticut Jessica Intravia, MHA [30] MD Candidate, Class of 2013 University of Connecticut School of Medicine Farmington, Connecticut Contributors xv Vatsal Patel [38] MD/MBA Candidate University of Connecticut School of Medicine Farmington, Connecticut Martine Saint-Cyr, MD [19] University of Connecticut School of Medicine Farmington, Connecticut Erealda Prendaj, MD [29] Pediatrics, 2nd year resident Hasbro Children’s Hospital Brown University Providence, Rhode Island Nathan Selsky, MD [4, 5] Chief Medical Resident Department of Internal Medicine University of Connecticut School of Medicine Farmington, Connecticut Neena T. Qasaba, MD [2] Obstetrics and Gynecology, PGY-2 Indiana University Bloomington, Indiana Rajasree Ramachandra Pai, MD [37] Resident Department of Internal Medicine University of Connecticut School of Medicine Farmington, Connecticut Adeel Shahid, MD [26] Resident, PGY-2 Department of Internal Medicine University of Connecticut School of Medicine Farmington, Connecticut Jordon Sherwood [8] MD Candidate, Class of 2013 University of Connecticut School of Medicine Farmington, Connecticut Allyson Reid [7] MD Candidate, Class of 2013 University of Connecticut School of Medicine Farmington, Connecticut Heeseop Shin, MD [22] University of Connecticut School of Medicine Farmington, Connecticut Faith J. Ross, MD [28] Resident Department of Anesthesiology University of Pittsburg Medical Center Pittsburg, Pennsylvania Jonathan Shupe, MD [45] Resident Department of Family Medicine University of California—Los Angeles Los Angelos, California Paul J. D. Roszko, MD [11, 12] Resident, PGY-3 Department of Emergency Medicine Warren Alpert School of Medicine Brown University Providence, Rhode Island Aaron Robert Soufer, MD [17] University of Connecticut School of Medicine Farmington, Connecticut Anuradha Subramanian, MD [31] Clinical Assistant Professor of Medicine, Infectious Diseases University of Maryland School of Medicine Baltimore, Maryland N. Abimbola Sunmonu, MD, PhD [9] University of Connecticut School of Medicine Farmington, Connecticut Alexandria Thornton, MD [46] University of Connecticut School of Medicine Farmington, Connecticut Hailun Wang, MD [36] Resident Department of Otolaryngology The Mount Sinai Hospital New York, New York Arija I. Weddle [13] MD Candidate, Class of 2013 University of Connecticut School of Medicine Farmington, Connecticut Preface

Medicine has largely been taught as an apprenticeship. The methods to diagnose and treat various conditions, the so-called “standards of care,” are passed down to clinicians-in-training, but less commonly are these young clinicians provided the tools to assess the appropriateness of these standards. How often do clinicians and medical students stop to critically examine the evidence behind many of our medical decisions? Most would argue not enough. Although we may not routinely stop to consider it, the standard of care is nonetheless constantly evolving, as important findings emerge from quality trials. Routine medical practices that have been based on conclusions drawn from cohort, case-control, and observational studies or “expert consensus” recommendations are continuously susceptible to change, as new data emerge from large, well-designed, and randomized clinical trials. Postmenopausal women are no longer routinely given hormone replacement therapy, following the Women’s Health Initiative Study. Patients with atrial fibrillation are more likely to be treated with rate-controlling rather than rhythm-controlling agents since the release of the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial findings. At the time of this writing, the widespread practice of perioperative β-blockade is being questioned as a result of findings from the POISE (PeriOperative ISchemic Evaluation Study) trial. Given the frequency with which clinicians and trainees encounter scenarios in which a working knowledge of the evidence base might well affect management decisions, the need to stay current on the literature is of paramount importance. However, it is extremely challenging for the busy medical student and practicing clinician to do so. Indeed, particularly frank clinicians might concede that making such an attempt is a financial conflict of interest. So how are these clinicians to know whether the patient with alcoholic hepatitis or streptococcal meningitis xvii xviii Preface should receive corticosteroids, whether the patient with a nonthrombotic “demand-ischemic” troponin elevation should be treated identically to the patient with a “real” heart attack, whether the patient with a large ischemic infarct from atrial fibrillation should immediately be given anticoagulants, or whether the risks of hemorrhagic conversion outweigh the benefits? This book dissects many of the most controversial medical issues and landmark clinical trials that have and will continue to influence the practice of medicine.

Acknowledgments Many physicians inspired this text, but two deserve special recognition. The first, Dr. Jonathan M. Ross, Professor of Medicine at Dartmouth Hitchcock Medical Center, showed me and countless other young physicians the importance of staying current with the literature and challenging the status quo. The second, Dr. Michael R. Grey, Professor and Chair of Medicine at The Hospital of Central Connecticut, lent his enthusiasm and support to this project in its earliest, and most vulnerable, stages. To both I am greatly indebted. —TAB xix Lower CHAPTERGastrointestinal Bleed 1 TERESA DOUCET, MD CASE A 71-year-old man with no significant medical history presents to the hospital with painless but profuse bleeding per rectum that started 3 hours ago. He feels weak and light headed. Vital signs are stable with a blood pressure of 109/62 mm Hg, heart rate of 90 bpm, respiratory rate of 18/min, and an oxygen saturation of 97%. A stat hematocrit is 27% (NL 40–52%). Physical examination

reveals gross bright red blood per rectum (hematochezia) but is otherwise entirely unrevealing. Laboratory workup is pending. 1. What are the most common causes of acute gastrointestinal bleeding and what is the most likely cause of bleeding in this patient? This is a classic presentation for a lower gastrointestinal bleed (LGIB), although a brisk upper gastrointestinal bleed (UGIB) remains a possibility. A review of acute LGIB sources and frequencies as they are reported in the literature was recently published by the American College of Gastroenterology (Table 1.1): Due to the benign examination findings, the history of painless hematochezia, and the epidemiology discussed above, this patient likely has a diverticular bleed. Angiodysplasia, although less common, has a similar clinical presentation and should be considered. Neoplasm, hemorrhoids, and anal fissures usually present with intermittent bleeding and are rarely hemodynamically significant. Massive bleeding is also rarely seen in colitis, which would be accompanied by severe pain and leukocytosis. Although diverticulosis and angiodysplasia have long been considered as leading causes of hematochezia, especially in the elderly population, recent trends suggest an increased incidence of diverticulosis (33.5%) and decreased incidence of angiodysplasia (3.4%) preceding acute 1 TABLE 1.1 LGIB Sources and Frequencies Source Finding frequency (%) Diverticulum 17–40 Angiodysplasia 9–21 Colitis (ischemic, infectious, radiation2–30 induced, chronic irritable bowel disease (IBD)) Neoplasia, postpolypectomy 11–14 Anorectal disease (hemorrhoids and rectal 4–10 varices) Upper gastrointestinal bleeding 0–11 Small bowel bleeding 2–9 TABLE 1.2 Common Etiologies of LGIB by Age Age group Etiology of LGIB Adolescent/young Meckel’s diverticulum, irritable bowel adult disease (IBD) Adult, <60 yr Diverticular, irritable bowel disease (IBD), neoplasm Adult, >60 yr Diverticular, angiodysplasia, neoplasm LGIB.2 This trend is likely reflective of true changes in the epidemiology of LGIB as well as the advent and increasingly widespread use of colonoscopy as a diagnostic tool.3 Small bowel bleeding and UGIB continue to be reported as uncommon causes of hematochezia. Of note, the most common causes of gastrointestinal (GI) hemorrhage vary by age group (Table 1.2).4 Although acute bleeding in the lower GI tract stops spontaneously in the majority (80–85%) of patients, the etiology of the bleed should still be sought for the purposes of prognosis and therapeutic intervention. Bottom line: Diverticulosis is the most common cause of acute, painless hematochezia, especially in the elderly population. 2. How is the severity of intestinal bleeding assessed? Blood loss from the GI tract that is of recent onset ( <3 days duration) and that results in unstable vital signs, anemia, and/or need for blood transfusion is considered to be an acute bleed. The severity of the bleed can be further assessed by physical examination (Table 1.3).5,6 TABLE 1.3 Relationship of Exam Findings with Blood Loss Volume Physical examination findings Blood loss volume (mL) Normal heart rate and blood pressure <200 Orthostatic decrease in systolic blood >800 pressure of 10 mm Hg or increase in heart rate of 10 bpm Shock (with signs of fatigue, pallor, >1500 palpitations, chest pain, dyspnea, tachypnea, and postural changes) Those patients with clinical evidence of ongoing or aggressive bleeding as determined by postural changes in vital signs, low hematocrit and presence of bright red blood on rectal examination, altered mental status, elevated PTT, presence of unstable comorbid disease, and those with a transfusion requirement of greater than 2 units of packed red blood cells are at a high risk of rebleeding and hemodynamic decompensation and should be monitored in an intensive care unit (ICU) setting.7 A number of studies have determined that acutely ill ward patients with dysfunctional airways, breathing and circulation issues, and problems relating to system failures receive suboptimal care compared with those who are managed in the ICU.8 Bottom line: The severity of intestinal bleeding can be assessed by patient history, physical examination, and assessment of vital signs. High-risk patients should be monitored in the ICU. 3. What is the first step in the management of a patient with acute LGIB? The first step in management is volume resuscitation, including fluid administration via large bore intravenous catheter and blood transfusion as needed. Hemoglobin levels are an unreliable marker of tissue oxygenation in a patient with acute bleeding because of the substantial lag period between fluid resuscitation and hemodilution. Therefore, the clinical condition of the patient (e.g., vital signs, evidence or possibility of active bleeding, presence of comorbidities) should drive the decision to transfuse. There exists only limited data in defining subgroups of patients for whom the benefits of transfusion outweigh the risks, and thus, the decision is largely a clinical one, dependent on the individual characteristics of the patient. In an otherwise young, healthy patient, up to 40% blood loss (e.g., 2 L for an average adult male) can be replaced with crystalloid alone. In these patients, adequate oxygen delivery is present at hemoglobin levels as low as 6–7 g/dL, and crystalloid therapy has been shown to result in a lower 30-day mortality compared with transfusion.9 For the elderly and those with comorbid conditions, no clear evidence exists, and the decision to transfuse is weighed heavily by the patient’s clinical condition.10 Bottom line: The first step in management of any patient with acute LGIB is assessment of hemodynamic status and fluid resuscitation by fluid or blood transfusion. The decision to transfuse is highly dependent on the characteristics and clinical condition of the patient. 4. Does evidence suggest that hematochezia is a reliable indicator of a LGIB? Although hematochezia is a reasonably good indicator of a LGIB, the passage of red blood per rectum can originate from any level in the GI tract, including massive UGIB in up to 11% of cases.11 Bottom line: Although hematochezia usually suggests a LGIB, a brisk UGIB needs to be considered in the differential. 5. What intervention is reasonably effective in “ruling out” an UGIB? Placement of a nasogastric tube with evaluation of the aspirate for blood. An aspirate that is positive for bile but negative for blood makes an upper source of bleeding unlikely. Upper GI endoscopy can also be used for this purpose and is useful in localizing an upper GI lesion when the bleeding has ceased. Although this approach has not been studied prospectively, it should be strongly considered,12 especially in the setting of hemodynamic instability, because a brisk UGIB more commonly leads to shock than LGIB (35% vs. 19%, respectively) and more frequently leads to decreased hemoglobin levels.13 Bottom line: Nasogastric (NG) tube placement is indicated early in the evaluation of hematochezia to rule out UGIB. An aspirate that is positive for bile and negative for blood makes an upper source unlikely. 6. Is colonoscopy indicated in this patient? Yes.14 Once UGIB has been ruled out, colonoscopy is the first diagnostic option in the evaluation of LGIB. Colonoscopy offers a high diagnostic yield, identifying the causative lesion in 85% of cases14 and up to 97% of cases in older studies. Colonoscopy also allows for endoscopic treatment when a bleeding stigmata is identified, including thermal coagulation and injection of vasoconstrictors and/or sclerosants. It presents a relatively low risk of complications (1 in 1000) when compared with other diagnostic methods.1 Colonoscopy is safe and effective for patients with acute LGIB when preceded by adequate fluid resuscitation. It should be performed within 12–48 hours following rapid purge with a polyethylene glycol-based solution over 3–4 hours (at a rate of 1 L every 30–45 minutes) to improve visualization and safety of the procedure.12,15 When colonoscopy is unrevealing, EGD should be used to revisit the upper GI tract as a source of bleeding that has perhaps ceased, and other endoscopic methods can be used to search for small bowel lesions (Barnert 2009). Bottom line: Colonoscopy is safe, effective, and indicated as the firstline diagnostic procedure for acute LGIB in patients who have received sufficient fluid resuscitation and a colonic purge. 7. When is visceral angiography indicated? Angiography, while highly specific, has lower sensitivity (41%–78%) and higher rate of complications (9.3%) compared with colonoscopy. In addition, angiography will not detect small bleeds (<0.5–1.0 mL/min). Unlike colonoscopy, however, angiography does not require time to prepare the colon and does not require the patient to be hemodynamically stable. Thus, angiography should be reserved for those patients for whom ongoing massive GI bleed precludes colonoscopy. Angiography can also be used for patients with recurrent/persistent hematochezia when colonoscopy cannot identify a source. Like colonoscopy, angiography is used for therapy (transcatheter embolization and vasopressin injections) once a bleeding site is identified.6,15,16 Computed tomography angiography is currently being studied as a diagnostic tool and appears to compare the efficacy with visceral angiography. Bottom line: Angiography is not indicated for small GI bleeds but has the advantage of not requiring bowel preparation. Thus, angiography can be performed on those patients with ongoing massive GI bleeds for whom colonoscopy is contraindicated. 8. Is barium enema indicated? No. Barium enema is in fact contraindicated in patients with acute LGIB because it lacks the ability to identify the bleeding site and interferes with the efficacy of other diagnostic tools.16 Bottom line: Barium enema is contraindicated in patients with acute LGIB. TAKE-HOME POINTS: LOWER GASTROINTESTINAL BLEED 1. Severity of blood loss in a patient with acute LGIB is determined by combining patient history with physical examination findings and assessment of vital signs. 2. Hematochezia can result from a lesion anywhere along the GI tract although it most commonly indicates a LGIB. 3. The most common etiology of acute LGIB is diverticular disease, especially in the elderly. Angiodysplasia and colitis are also common causes of LGIB, whereas neoplasm, postpolypectomy bleeding, anorectal disease, and upper GI/small bowel sources are less common causes. 4. The first step in management is adequate resuscitation with fluids or blood transfusion, depending on the specificity of the clinical scenario. 5. After fluid resuscitation, an NG tube should be placed to rule out upper GI bleed as a source, especially if a major bleed is suspected. 6. Colonoscopy is the first-line diagnostic tool for acute LGIB. 7. Angiography can be used for patients who cannot receive colonoscopy due to persistent hemodynamic instability. 8. Barium enema is contraindicated in patients with acute LGIB. REFERENCES 1. Barnert, J., and H. Messman. 2009. “Diagnosis and Management of Lower Gastrointestinal Bleeding.” Nature Reviews Gastroenterology and Hepatology 6: 637–46. 2. Gayer, C., et al. 2009. “Acute Lower Gastrointestinal Bleeding in 1,112 Patients Admitted to an Urban Emergency Medical Center.” Surgery 146: 600– 7. 3. Strate, L. 2005. “Lower GI Bleeding: Epidemiology and Diagnosis.” Gastroenterology Clinics of North America 34: 643–64. 4. Hoedema, R., and M. Luchtefeld. 2005. “The Management of Lower Gastrointestinal Hemorrhage.” Diseases of the Colon and Rectum 48: 2010–24. 5. Ebert, R. V., E. A. Stead, and J. G. Gibson. 1941. “Response of Normal Subjects to Acute Blood Loss.” Archives of Internal Medicine 68: 578. 6. Zuccaro, G. 1998. “ACG Practice Guidelines. Management of the Adult Patient With Acute Lower Gastrointestinal Bleeding.” American Journal of Gastroenterology 93: 1202–8. 7. Strate, L., J. Saltzman, R. Ookubo, M. Mutinga, and S. Syngal. 2005. Validation of a Clinical Prediction Rule for Severe Acute Lower Intestinal Bleeding. American Journal of Gastroenterology 100: 1821–27. 8. Massey, D., L. Aitken, and W. Chaboyer. 2009. “What Factors Influence Suboptimal Ward Care in the Acutely Ill Ward Patient?” Intensive and Critical Care Nursing 25: 169–80. 9. Hebert, P. C., G. Wells, M. A. Blajchman, et al. 1999. “A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care.” The New England Journal of Medicine 340: 409–17. 10. Miller, Y., et al. 2007. Practice Guidelines for Blood Transfusion: A Compilation From Recent Peer-Reviewed Literature. 2nd ed., 10–12. American Red Cross. Available at http://www.redcross.org/www-files/Documents/ WorkingWiththeRedCross/practiceguidelinesforbloodtrans.pdf. 11. Jensen, D. M., and G. A. Machicado. 1997. “Colonoscopy for Diagnosis and Treatment of Severe Lower Gastrointestinal Bleeding.” Gastrointestinal Endoscopy Clinics of North America 7: 477–98. 12. Davila et al. 2005. “ASGE Guideline: The Role of Endoscopy in the Patient With Lower-GI Bleeding.” Gastrointestinal Endoscopy 62: 656–60. 13. Peura, D. A., F. L. Lanza, C. G. Gostout, and P. G. Foutch. 1997. “The American College of Gatroenterology Bleeding Registry: Preliminary Findings.” American Journal of Gastroenterology 92: 924–28. 14. Zia, N., et al. 2008. “Diagnostic Evaluation of Patients Presenting With Bleeding per Rectum by Colonoscopy.” Journal of Ayub Medical College, Abbottabad 20: 73–76. 15. Elta, G. 2004. “Urgent Colonoscopy for Acute Lower-GI Bleeding.” Gastrointestinal Endoscopy 59: 402–8. 16. Padia, S., B. Bybel, and J. Newman. 2007. “Radiologic Diagnosis and Management of Acute Lower Gastrointestinal Bleeding.” Cleveland Clinic Journal of Medicine 74: 417–20. Peptic Ulcer Chap T er Disease 2 NeeNa T. Qasba, MD CASE A 56-year-old man originally from Peru presented to the emergency department for evaluation of a 2-week history of abdominal pain, weakness, and lightheadedness and several bouts of hematemesis earlier in the day. His pain has not been relieved with over-the-counter antacids. He consumes 3–4 beers per week and smokes cigars on weekends. For the past several months, he has been

taking ibuprofen daily for a sports-related muscle strain. On examination, he appears pale, has positive orthostatic vitals, epigastric tenderness, and heme- positive stool. A nasogastric tube (NGT) is placed and drains 500 mL of hemepositive, coffee-ground material. Hematocrit on admission is 31%. 1. What is the most likely diagnosis and why? Upper gastrointestinal bleed (UGIB) secondary to peptic ulcer disease(PUD). Based on the systematic reviews of over 18 studies, risk factors for PUD include advanced age (>75 years), history of PUD, Helicobacter pylori infection, male gender, and nonsteroidal anti-inflammatory drug (NSAID) use.1 Men have a twofold greater risk of developing UGIB than women.1 This patient possesses some of these risk factors including NSAID use and male gender. Developing countries have higher rates of H. pylori infection. The incidence of H. pylori infection in the United States was 6 and 3 times higher among Hispanic immigrants and their first-degree relatives, respectively, when compared with second-degree relatives.2 In other words, the closer one is to being raised in a developing country, the higher their risk for infection. This patient has obvious bleeding demonstrated by hematemesis, heme-positive nasogastric aspirate (NGA), and heme-positive stool. These constitute alarm signs when UGIB is suspected; these include 9 bleeding, bowel obstruction, malignancy, penetration, and perforation (Table 2.1). Bottom line: Risk factors for PUD include NSAID use, advanced age, prior history, H. pylori infection, and male gender. Alarm signs and symptoms should be aggressively evaluated. 2. Is the risk for developing PUD the same for all types of NSAIDs? No. Ketorolac is said to have the highest risk of all NSAIDs for UGIB.3 Information given in Table 2.2 is based on more than 9000 treatment courses in almost 4000 patients with rheumatoid arthritis.4 The risk is likely dose dependent for all NSAIDs. Bottom line: Various NSAIDs result in different risks for upper intestinal bleeding, and the risk is likely dose dependent. TAblE 2.1 Alarm signs Bleeding Obstruction Malignancy Penetration Perforation Alarm Features for UGIB Clinical presentation Anemia, hematemesis, melena, or heme-positive stool Vomiting Anorexia or unintentional weight loss Persistent upper abdominal pain radiating to the back Severe, expanding upper abdominal pain Abbreviations: UGIB, upper gastrointestinal bleed. TAblE 2.2 Risk of Stomach Bleeding with Different NSAIDs Low risk Nabumetone (Relafen) Etodolac (Lodine) Salsalate (Disalcid, Trilisate) Sulindac (Clinoril) Medium risk Diclofenac (Voltaren) High risk Flurbiprofen (Ansaid) Ibuprofen, ketoprofen Aspirin Piroxicam (Feldene) Fenoprofen Naproxen Tolmetin (Tolectin) Indomethacin Meclofenamate (Meclomen) Oxaprozin (Daypro) Abbreviations: NSAID, nonsteroidal anti-inflammatory drug. 3. Is there a relationship between NSAID use and H. pylori infection in the etiology of PUD? A relationship is likely. One study has found synergism of NSAID use and H. pylori infection.4 PUD was significantly more common in H. pylori–infected NSAID users than in uninfected NSAID users, suggesting a possible interaction between NSAID use and H. pylori infection for the development of peptic ulcer.5 Furthermore, studies have shown that H. pylori infection may increase the risk of bleeding among NSAID users.6 Genetic factors may play an important role in determining individual predisposition to developing PUD with exposure to NSAIDs and/or H. pylori infection.7 Bottom line: H. pylori infection may be a contributing factor even if NSAID- related disease is suspected. 4. Do steroids or other medications contribute to the risk of developing PUD? Although the data are controversial, one study has shown that the use of oral steroids alone is associated with a twofold risk of having a new episode of a bleeding or perforated peptic ulcer.8 Patients using systemic steroids concomitantly with high-dose NSAIDs have the highest risk of upper gastrointestinal complications.8 Spironolactone is also associated with an increased risk of upper gastrointestinal events, and this risk seems to be dose dependent.9 Aldosterone promotes the formation of fibrous tissue and tissue repair. Inhibition of aldosterone through spironolactone could therefore impair the healing process and result in the formation of gastroduodenal ulcers with or without bleeding.9 Bottom line: Steroids, NSAIDs, and spironolactone may all predispose to PUD. 5. What does evidence suggest is the usefulness of diagnostic testing for H. pylori in patients presenting with an UGIb? Testing for H. pylori is recommended for all patients presenting with a bleeding peptic ulcer, and if positive, triple-therapy treatment is warranted.10 Based on a systematic review that assessed six different diagnostic tests for H. pylori infection in patients with UGIB, the C-13 urea breath test may be the most accurate (Table 2.3). Stool antigen testing has less diagnostic accuracy in active intestinal bleeding. Although serology does not seem to be influenced by upper intestinal bleeding, it is not recommended as the initial testing tool for H. pylori infection in a setting of an active intestinal bleed.11 TAblE 2.3 Types of test Noninvasive Reference lab serology ELISA antiH. pylori IgG Office-based whole blood ELISA antiH. pylori IgG Urea Breath Test Urine ELISA for H. pylori IgG Saliva ELISA for H. pylori IgG Stool for H. pylori antigen (HpSAg) Invasive Gastric biopsy with Steiner’s stain Gastric biopsy with Campylobacter-like organism test Gastric biopsy with H. pylori culture Performance Characteristics of Diagnostic Tests for H. pylori12–15 Sensitivity (%) Specificity (%) 90–93 95–96 50–85 75–100 95–100 95 70–96 77–85 82–91 71–85 95–98 92–95 95 99–100 93–97 >95 70–80 100 Bottom line: H. pylori testing with the C-13 urea breath test is highly recommended in all patients with suspected PUD. However, in practice, patients with an active upper intestinal bleed will almost certainly undergo esophagogastroduodenoscopy (EGD) with biopsy. 6. How important is H. pylori treatment in patients with PUD? The Health Assessment Program in the United Kingdom determined that treatment of H. pylori infection is more effective than proton pump inhibitor (PPI) therapy (with or without long-term maintenance therapy) in preventing recurrent bleeding from PUD. Rebleeding was less frequent after H. pylori eradication therapy than after short- or long-term PPI maintenance therapy. The number needed to treat to prevent 1 episode of rebleeding with H. pylori eradication therapy is 7 (95% confidence interval [CI] 5–11) compared with short-term PPI treatment alone and 20 (95% CI 12–100) when compared with longterm maintenance PPI therapy. H. pylori eradication therapy was also shown to be equally effective in prevention of new ulcer formation and rebleeding in NSAID-induced PUD.16 TAblE 2.4 Predictors for an UGIB in the Absence of Hematemesis Patients with upper No. of risk factors present gastrointestinal source (%) 05 1 55 2 or 3 93 Abbreviations: UGIB, upper gastrointestinal bleed. Bottom line: H. pylori eradication therapy is clinically indicated and cost effective in the treatment and prevention of PUD. 7. How might one predict active upper intestinal bleeding in a patient presenting without hematemesis? The 3 strongest independent predictors of upper intestinal bleeding without hematemesis are black stool, age more than 50 years, and serum Blood urea nitrogen (BUN):creatinine ratio ≥30.17 Bottom line: Although hematemesis is a common symptom of UGIB, black stool, age more than 50 years, and BUN:creatinine ratio ≥30 also suggest an upper intestinal source. 8. Does the evidence indicate that an EGD should be performed in this patient? Yes. EGD is indicated in patients with “alarm symptoms,” those whose symptoms do not respond to medications, and those older than 55 years. EGD is the diagnostic tool of choice for evaluation of lesions above the ligament of Treitz. EGD is more than 90% sensitive and specific in diagnosing gastric and duodenal ulcers and cancers. EGD is more sensitive and specific for PUD than upper gastrointestinal barium studies and allows for biopsy of gastric lesions.18,19 Barium contrast radiography is indicated when endoscopy is unsuitable or not feasible or if complications such as gastric outlet obstruction are suspected. This type of study can determine the size, location, and degree of the obstruction. Diagnostic sensitivity is 80%–90% in detecting duodenal ulcers, and accuracy increases with disease severity.19 Bottom line: EGD is a diagnostic tool of choice for patients with “alarm symptoms,” those who do not respond to medical therapy, and those of 55 years and older. CASE CONTINUED An EGD performed the next morning reveals extensive gastritis, large gastric ulcer, small proximal duodenal ulcer, and diffuse mucosal inflammation of the duodenal bulb. Pharmacological treatment is initiated. 9. What is the role of H2 blockers in treating PUD? H2-receptor blockers reduce gastric acidity and allow acid-sensitive drugs (e.g., amoxicillin and clarithromycin) to work more effectively. A randomized, double-blinded controlled study showed that high-dose H2-receptor blocker (famotidine) therapy was inferior to PPI therapy (pantoprazole) in preventing recurrence of aspirin-related peptic ulcers and erosions.20 However, both Villanueva et al. and Prassler et al. reported no significant difference in rebleeding rate between groups receiving intermittent boluses of intravenous (IV) omeprazole (80 mg bolus plus 40 mg every 8 or 12 hours) versus IV ranitidine, regardless of whether infusion was intermittent (50 mg every 4 or 6 hours) or continuous (0.125 mg/kg/h). Ranitidine, H2-receptor blocker, has also been combined with bismuth to form ranitidine bismuth citrate (RBC), which produces a more soluble and possibly more effective form of bismuth. Comparative studies showed that the efficacy of RBC–triple therapy may be superior to PPI triple therapy especially in case of H. pylori antimicrobial resistance.21 Unfortunately, RBC is not commercially available in many areas, including the United States. Bottom line: H2 blockers have a role in treating gastric acidity and H. pylori infection. The role of H2 blockers in preventing reoccurrence of NSAID-related ulcers is still controversial. 10. Is there a difference in efficacy between PPIs administered in a continuous intravenous drip, intravenous PPIs given twice daily, or PPIs administered orally? PPI therapy for PUD seems superior to both placebo and H2 blockers for prevention of rebleeding and need for surgery but does not seem to reduce mortality.22 Oral (PO) and IV pantoprazole are equipotent in raising gastric pH and duration of action. A pilot study conducted by Bajaj et al. compares the efficacy of PO versus IV pantoprazole for reducing rebleeding after non–variceal UGIB (NV-UGIB) by randomizing patients to receive pantoprazole PO (80 mg BID for 3 days) or IV (80 mg bolus and 8 mg/h infusion for 3 days) followed by pantoprazole 40 mg PO BID for 30 days. The study concludes that the effect of PO pantoprazole on 30-day rebleeding rate in patients with NV-GIB is similar to that of IV pantoprazole.23 Another study by Julapalli and Graham states that the only reliable way for continuous acid suppression is by continuous infusion of a PPI. A comparison of continuous IV omeprazole (80 mg loading dose then 8 mg/h), intermittent bolus IV omeprazole (80 mg bolus, then 40 mg every 6 hours), continuous IV ranitidine (50 mg loading dose, then 0.25 mg/kg per hour), and intermittent bolus IV ranitidine (100 mg every 6 hours) in healthy volunteers shows that all regimens increase intragastric pH above 6 within an average of 60 minutes of initiation. The study demonstrates that continuous infusion of omeprazole is more effective in acid suppression, although no clinical outcomes were studied.24 In terms of dosage, the study by Andriulli et al. demonstrates that low-dose PPI therapy (omeprazole or pantoprazole 40 mg infusion daily for 72 hours) after endoscopic hemostasis is associated with a shorter length of hospital stay and a similar rate of recurrent bleeding compared with high-dose PPI therapy (omeprazole or pantoprazole 80 mg infusion then 8 mg hourly for 72 hours). After 72 hours, all patients were treated with omeprazole or pantoprazole 20 mg PO BID twice daily until discharge. When comparing low-dose versus highdose therapy, the hospital stay was less than 5 days in 47% versus 37%, respectively (P = .03, Number Needed to Treat (NNT) 10). The difference in bleeding recurrence and units of blood transfused were not statistically significant between the low- and high-dose groups.25 Randomized trials directly comparing different doses of PPIs and administration of PPIs PO and IV in patients with PUD as well as headto-head comparisons of different PPIs are lacking. Bottom line: Further studies are warranted to safely conclude the effectiveness of different types, doses, and administration of PPI in treating PUD. 11. What are the criteria for red blood cell transfusion? When should crystalloids be administered in active UGIb? Maintaining the systolic blood pressure above 100 mm Hg and a heart rate below 100 bpm reduces the risk of end-organ damage from ischemia. There are several guidelines for fluid resuscitation in UGIB. The British Society of Gastroenterology recommends red blood cell transfusion when bleeding is extreme (i.e., active hematemesis, hematemesis with shock, or both), and/or when the hemoglobin is less than 10 g/dL in patients with no previous history of anemia. The evidence for this transfusion threshold is relatively poor, but it is known that a hemoglobin concentration of less than 7 g/dL has significant adverse cardiac effects in the intensive care setting. Thus, it seems reasonable to perform transfusion when hemoglobin level drops below 10 g/dL in actively bleeding patients.26 A systemic review by Hearnshaw et al. looked at 3 randomized controlled trials that suggested that blood transfusion may not actually improve clinical outcomes and may even worsen outcomes. Although there were more deaths recorded in the transfusion arm of the combined studies compared with the control arm, the deaths were too few and trials too different in design to make any firm conclusions.27 More studies are needed to make a conclusion regarding the effectiveness and safety of transfusion. Crystalloids, particularly normal saline, are used most commonly as the first step in fluid resuscitation. Colloids such as Gelofusine, which contains modified fluid gelatin that mimics natural albumin, are often used in the presence of major hypotension; however, there is no evidence that they have advantages over crystalloids.26 Bottom line: Current guidelines recommend transfusion depending on clinical or laboratory findings. However, it is far from clear that red blood cell transfusion results in improved outcomes; so, further studies need to be done. Crystalloids are generally used as the first step in fluid resuscitation. 12. What are the criteria for immediate intervention in patients with active UGIb? There are several scoring methods to triage patients with UGIB. The clinical Rockall score (Table 2.5) consists of clinical variables, whereas the Complete Rockall score (Table 2.6) consists of clinical and endoscopic variables. Both are used to identify patients with acute TAblE 2.5 Clinical Rockall Score Score Variable 0 1 Age (y) <60 60–79 Hemodynamic Pulse ≥100 bpm stability (not hypotensive) Comorbidities 2 >80 Systolic blood pressure <100 mm Hg Heart failure Coronary artery disease Renal failure Liver failure Metastatic disease Adapted from Chen et al. 2007.28 3 TAblE 2.6 Complete Rockall Score: Clinical Rockall Score Plus Endoscopic Variables Variable Endoscopic diagnosis Stigmata of recent hemorrhage 0 Mallory-Weiss tear or no lesion No stigmata of recent hemorrhage Score 1 PUD or erosive esophagitis 2 Malignancy of upper GI tract Blood in upper GI tract, clot, visible vessel, bleeding Abbreviations: PUD, peptic ulcer disease; GI, gastrointestinal tract. Patients with clinical Rockall scores (before endoscopy) of greater than 0 and patients with complete Rockall scores (after endoscopy) of greater than 2 are considered to be at a high risk for developing adverse outcomes (recurrent bleeding and death). Adapted from Chen et al. 2007.28 TAblE 2.7 Estimated Mortality Risk Based on the Rockall Score Score Mortality risk (%) 0–2 0.2 3–4 6.8 ≥5 20 ≥8 43 Adapted from Ebell.29 UGIB who have an increased risk of mortality (Table 2.7) or risk for recurrent bleeding. The Blatchford score (Table 2.8) consists of only clinical and laboratory data and is used to identify patients with acute UGIB who need clinical intervention before endoscopy. In the study conducted by Chen et al., the Blatchford score predicts need for treatment (blood transfusion or intervention to stop bleeding) in patients with NV-UGIB with a sensitivity of 99.6%. Scores of 6 or more in the validation group are associated with a greater than 50% risk of needing an intervention before endoscopy. Blatchford score of 0 is associated with “low risk” for UGIB. This was confirmed TAblE 2.8 Blatchford Score Risk factors Blood urea nitrogen (mg/dL) Hemoglobin (g/dL) Systolic blood pressure (mm Hg) Pulse rate Melena Syncope Heart Failure Finding Points 18.2–22.4 2 22.4–28 4 28–70 5 ≥70 6 12–13 in males 1 10–12 in males 3 10–12 in females 1 <10 in males or females 6 100–109 1 90–99 2 <90 3 ≥100/min 1 Present 1 Present 2 Present 2 Adapted from Chen et al.28 Scores of ≥6 were associated with a greater than 50% risk of needing an intervention. Score is equal to “0” if the following are all present: 1. Hemoglobin level >12.9 g/dL (men) or >11.9 g/dL (women) 2. Systolic blood pressure >109 mm Hg 3. Pulse <100/min 4. Blood urea nitrogen level <18.2 mg/dL 5. No melena or syncope 6. No past or present liver disease or heart failure in the study by Stanley et al.30 where patients with a score of 0 were actually discharged and had no GI bleeding mortality at 6-month follow-up. Bottom line: Blatchford score has been shown to be more effective in triaging UGIB patients who require immediate intervention versus outpatient management. 13. Does the data suggest that placing a NGT in patients presenting with an UGIb is the correct thing to do? Some studies have argued that NGA has some prognostic value as an independent predictor of active bleeding or visible nonbleeding vessel. A retrospective study found red blood cell in the NGA to be one of several independent predictors of an adverse outcome.31 However, approximately 50% of patients with recent bleeding from duodenal lesions have a nonbloody NGA. Aljebreen et al. found that compared with clear or bile-stained NGA, a bloody NGA was significantly associated with the presence of a high-risk lesion on endoscopy (i.e., spurting bleeding, oozing of blood, or a visible vessel). However, further analysis of the study found that regardless of whether an NGA was obtained, diagnosis and treatment did not change given the results of the NGA.32 Applied alone, the NGA cannot be expected to alter outcomes in patients with UGIB. The role of the NGA in monitoring patients after initial endoscopic treatment and before the recurrence of bleeding and retreatment has not been fully evaluated. However, it is well established that the longterm use of a NGT is associated with adverse effects, including the development of stenotic stricture of the distal esophagus. There are data to suggest that NGT-related complications can arise within a few days of placement.33 Based on the assessment of available data, further prospective and randomized controlled trials are needed to determine the true utility of NGT placement and NGA in the management of patients with UGIB.34 Bottom line: Placement of a NGT is clinically acceptable in the management of an acute UGIB; however, diagnosis and treatment should not be solely based on its contents and attention should be given to the well-documented consequences of its long-term use. TAKE-HOME POINTS: PEPTIC UlCER DISEASE 1. Consider discontinuing aspirin, clopidogrel, and NSAIDs when possible. This decision will depend on discussion between gastroenterologists and other specialists. For patients who need to continue these drugs because of vascular disease or severe arthritis, a PPI should typically be given. 2. Current standards of care call for the administration of a highdose IV PPI immediately after endoscopic therapy for patients at high risk of rebleeding. PPIs are not required for other patients and are not indicated before endoscopy. 3. Treat uncontrolled, NV-UGIBs with repeat endoscopic therapy, selective arterial embolization, or surgery. 4. Test for H. pylori infection in all patients presenting with PUD and NV- UGIB; treat if results are positive. Highly consider testing to confirm posttreatment eradication. REFERENCES 1. Hernández-Díaz, S., and L. A. Rodríguez. 2000. “Association Between Nonsteroidal Anti-Inflammatory Drugs and Upper Gastrointestinal Tract Bleeding/Perforation: An Overview of Epidemiologic Studies Published in the 1990s.” Archives of Internal Medicine 160 (14): 2093–99. 2. Tsai C. J., S. Perry, L. Sanchez, and J. Parson. 2005 “ Helicobacter pylori Infection in Different Generations of Hispanics in the San Francisco Bay Area”. American Journal of Epidemiology 162:351–357. 3. García Rodríguez, L. A., C. Cattaruzzi, M. G. Troncon, and L. Agostinis. 1998. “Risk of Hospitalization for Upper Gastrointestinal Tract Bleeding Associated with Ketorolac, other Nonsteroidal Anti-Inflammatory Drugs, Calcium Antagonists, and other Antihypertensive Drugs.”Archives of Internal Medicine 158: 33–39. 4. Singh, G., D. R. Ramey, D. Morfeld, H. Shi, H. T. Hatoum, and J. F. Fries. 1996. “Gastrointestinal Tract Complications of Nonsteroidal AntiInflammatory Drug Treatment in Rheumatoid Arthritis. A Prospective Observational Cohort Study.”Archives of Internal Medicine 41 (1996): 1530–36. 5. Huang, J. Q., S. Sridhar, and R. H. Hunt. 2002. “Role of Helicobacter pylori Infection and Nonsteroidal Anti-Inflammatory Drugs in Peptic-Ulcer Disease: A Meta-Analysis.” Lancet 359: 14–22. 6. Aalykke, C., J. M. Lauritsen, J. Hallas, S. Reinholdt, K. Krogfelt, and K. Lauritsen.1999. “Helicobacter pylori and Risk of Ulcer Bleeding Among Users of Nonsteroidal Anti-Inflammatory Drugs: A Case-Control Study.” Gastroenterology 116 (6): 1305. 7. Musumba, C., D. M. Pritchard, and M. Pirmohamed. 2009. “Review article: cellular and molecular mechanisms of NSAID-induced peptic ulcers.” Alimentary Pharmacology & Therapeutics 30, 517–531. 8. Hernández-Díaz, S., and L. A. Rodríguez. 2001. “Steroids and Risk of Upper Gastrointestinal Complications.” American Journal of Epidemiology 153 (11): 1089–93. 9. Verhamme, K., G. Mosis, J. Dieleman, B. Stricker, and M. Sturkenboom. 2006.“Spironolactone and Risk of Upper Gastrointestinal Events: Population Based Case-Control Study.” British Medical Journal 12 (333): 330. 10. Vilaichone, R. K., V. Mahachai, and D. Y. Graham. 2006. “ Helicobacter pylori Diagnosis and Management.” Gastroenterology Clinic of North America 35: 229–47. 11. Gisbert, J. P., and V. Abraira. 2006. “Accuracy of Helicobacter pylori Diagnostic Tests in Patients With Bleeding Peptic Ulcer: A Systematic Review and Meta-Analysis.” American Journal of Gastroenterology 101 (4): 848–63. 12. Hahn, M., M. B. Fennerty, C. L. Corless, N. Magaret, D. A. Lieberman, and D. O. Faigel. 2000. “Noninvasive Tests as a Substitute for Histology in the Diagnosis of Helicobacter pylori Infection.” Gastrointestinal Endoscopy 52 (1): 20–26. 13. Ho, B., and B. J. Marshall. 2000. “Accurate Diagnosis of Helicobacter pylori. Serologic Testing.”Gastroenterology Clinics of North America 29 (4): 853–62. 14. Cutler, A. F., S. Havstad, C. K. Ma, M. J. Blaser, G. I. Perez-Perez, and T. T. Schubert. 1995. “Accuracy of Invasive and Noninvasive Tests to Diagnose Helicobacter pylori Infection.”Gastroenterology 109 (1): 136–41. 15. Alemohammad, M. M., T. J. Foley, and H. Cohen. 1993. “Detection of immunoglobulin G antibodies to Helicobacter pylori in urine by an enzyme immunoassay method.” Journal of Clinical Microbiology 31(8):2174–7. 16. Leontiadis, G. I., A. Sreedharan, S. Dorward, P. Barton, B. Delaney, C. W. Howden, et al. 2007. “Systematic Reviews of the Clinical Effectiveness and Cost-Effectiveness of Proton Pump Inhibitors in Acute Upper Gastrointestinal Bleeding.” Health Technology Assessment 11 (51):iii–iv, 1–164. 17. Witting, M. D., L. Magder, A. E. Heins, A. Mattu, C. A. Granja, and M. Baumgarten. 2006. “ED Predictors of Upper Gastrointestinal Tract Bleeding in Patients Without Hematemesis.” American Journal of Emergency Medicine 24 (3): 280–85. 18. Talley, N. J., N. B. Vakil, and P. Moayyedi. 2005. “American gastro enterological association technical review on the evaluation of dyspepsia.” Gastroenterology 129(5):1756–80. 19. Ramakrishnan K., and R. C. Salinas. 2007. “Peptic Ulcer Disease.” American Family Physician 76(7): 1005–12. 20. Ng, F. H., S. Y. Wong, K. F. Lam, W. M. Chu, P. Chan, Y. H. Ling, C. Kng, et al. 2010. “Famotidine is Inferior to Pantoprazole in Preventing Recurrence of Aspirin-Related Peptic Ulcers or Erosions.” Gastroenterology 138(1):82–8. 21. Bardhan, K. D., D. Morton, M. J. Perry, D. S. Sanders, P. Morris, A. Rowland, M. Thompson, T. R. Mitchell, and P. M. Roberts. 2001. “Ranitidine Bismuth Citrate With Clarithromycin Alone or With Metronidazole for the Eradication of Helicobacter pylori.” Alimentary Pharmacology Therapy 15: 1199–204. 22. Leontiadis, G.I., V. K. Sharma, C. W. Howden. 2007. “Proton pump inhibitor therapy for peptic ulcer bleeding: Cochrane collaboration meta-analysis of randomized controlled trials.” Mayo Clinic Proceedings. 82.3: 286–96. 23. Bajaj, J. S., K. S. Dua, K. Hanson, and K. Presberg. 2007. “Prospective, Randomized Trial Comparing Effect of Oral Versus Intravenous Pantoprazole on Rebleeding After Nonvariceal Upper Gastrointestinal Bleeding: A Pilot Study.” Digestive Diseases and Sciences 52: 2190–94. 24. Julapalli, V., and D. Graham. 2005. “Appropriate Use of Intravenous Proton Pump Inhibitors in the Management of Bleeding Peptic Ulcer.” Digestive Diseases and Sciences 50 (7): 1185–93. 25. Andriulli, A., S. Loperfido, R. Focareta, P. Leo, F. Fornari, A. Garripoli, P. Tonti, et al. 2008. “High- Versus Low-Dose Proton Pump Inhibitors After Endoscopic Hemostasis in Patients With Peptic Ulcer Bleeding: A Multicentre, Randomized Study.” American Journal of Gastroenterology 103: 3011–18. 26. Palmer, K. 2007. “Acute Upper Gastrointestinal Haemorrhage.” British Medical Bulletin 83 (1): 307–24. 27. Hearnshaw, S., S. Brunskill, C. Doree, C. Hyde, S. Travis, and M. F. Murphy. 2009. “Red Cell Transfusion for the Management of Upper Gastrointestinal Haemorrhage.” Cochrane Database of Systematic (2): CD006613. 28. Chen, I.-C., M.-S. Hung, T.-F. Chiu, J.-C. Chen, and C.-T. Hsiao. 2007. “Risk scoring systems to predict need for clinical intervention for patients with nonvariceal upper gastrointestinal tract bleeding.”American Journal of Emergency Medicine 7: 774–79. 29. Ebell, M. H. Prognosis in Patients With Upper GI Bleeding. 2004. American Academy of Family Physicians 70: 2348. 30. Stanley, A. J., D. Ashley, H. R. Dalton, C. Mowat, D. R. Gaya, E. Thompson, U. Warshow, et al. 2009.“Outpatient Management of Patients With LowRisk Upper-Gastrointestinal Haemorrhage: Multicentre Validation and Prospective Evaluation.” Lancet 373: 42–47. 31. Perng, C. L., H. J. Lin, C. J. Chen, F. Y. Lee, S. D. Lee, and C. H. Lee. 1994. “Characteristics of Patients With Bleeding Peptic Ulcer Requiring Emergency Endoscopy and Aggressive Treatment.” American Journal of Gastroenterology 89: 811–14. 32. Aljebreen, A. M., C. A. Fallone, and A. N. Barkun. 2004. “Nasogastric Aspirate Predicts High-Risk Endoscopic Lesions in Patients With Acute Upper Gastrointestinal Bleeding.” Gastrointestinal Endoscopy 59: 172–28. 33. Spiliopoulos, A., and R. Megevand. 1980. “Stenotic Peptic Esophagitis Following Gastric Intubation.” Helvetica ChirurgicaActa 47: 527–32. 34. Leung, F. 2004. “The Venerable Nasogastric Tube.”Gastrointestinal Endoscopy 59 (2): 255–60.

Chapter Acute Viral Hepatitis 3 Joseph palter, MD CASE A 27-year-old nurse presents to the occupational health office 10 weeks after an unreported needle stick injury for evaluation of several weeks of fatigue. When pressed, she states that the reason she finally came in was because her husband noticed her eyes were “looking yellow.” On review of systems, she denies nausea or vomiting, but complains of a continuous ache in her right upper abdomen. Examination is significant for low-grade fever (temperature, 100.9°F), obvious jaundice, and tender hepatomegaly. 1. What is the most likely diagnosis and why? When approaching a patient with abdominal pain, the initial differential diagnosis may be overwhelming. As always, a detailed history is critical. The patient’s symptoms of jaundice, right upper abdominal pain, and low-grade fever suggest liver disease. Although the initial differential diagnosis should be wide and includes disorders such as obstructive jaundice, autoimmune hepatitis, alcoholic hepatitis, and Fitz-Hugh Curtis Syndrome, in this case, it is the history of a recent needle stick that is the smoking gun. Most patients with acute viral hepatitis will have a clear exposure in their history, and discovering that exposure plays a vital role in making the diagnosis. Whenever there is a history of blood-to-blood exposure, one’s index of suspicion for an infectious etiology should increase substantially. When considering this patient’s specific history within her constellation of symptoms, acute viral hepatitis becomes the most likely diagnosis. 23 2. What are the classic presenting symptoms for acute viral hepatitis? Acute hepatitis B virus (HBV) or hepatitis C virus (HCV) is associated with a variety of symptoms, ranging from an asymptomatic presentation to nausea/vomiting associated with abdominal pain to fulminant hepatic failure. The majority of patients will present with subclinical hepatitis (i.e., no signs or symptoms of illness). Only 30% of individuals with acute viral hepatitis will present with icteric hepatitis. The most common complaint is prolonged fatigue, but other possible symptoms and signs include anorexia, nausea, vomiting, low- grade fever, jaundice, myalgias, right upper quadrant pain, and epigastric pain.1,2 Patients with acute HBV are twice as likely to develop presenting symptoms compared to those with acute HCV.3 Fulminant hepatic failure is a presenting symptom in only 0.1%–0.5% of acute HBV or HCV. Bottom line: Although prolonged fatigue, right upper quadrant abdominal pain, low-grade fever, and/or jaundice are classic symptoms for viral hepatitis, most patients with viral hepatitis are actually asymptomatic. 3. How are HBV and HCV most commonly transmitted? The three routes of HBV infection are parenteral (either via intravenous drug use or occupational exposure with needle stick), sexual (through tears in the mucous membranes), or perinatal (from mother to child during birth). HCV can also be transmitted parenterally, sexually, or perinatally, although the rate of transmission of HCV is significantly lower compared with HBV.3 In most developed nations, screening blood donors has greatly reduced the chance of contracting an infection from the use of blood products. In the United States, the risk of transfusion-associated HCV infection is less than 1 in 103,000 transfused patients.2 The majority of newly documented HCV infections come from intravenous drug users. Bottom line: The three routes of transmission for HBV and HCV are parenteral, sexual, and perinatal. 4. How should a serologic diagnosis of acute HBV infection be made? The serologic diagnosis of acute HBV infection is made by analysis of HBV antigens and antibodies. Because HBV infections can have either an acute or a chronic profile, the appropriate interpretation of these examinations is critical. If a patient is positive for either hepatitis B surface antigen (HBsAg) or hepatitis B core IgM antibody (HBcAb IgM), then they are serologically positive for acute HBV.3 In addition, if a patient is also hepatitis B e-antigen (HBeAg) positive, they are more likely to have active hepatitis, and the infectiousness of the patient is increased3,4 (Table 3.1). Bottom line: Patients positive for HBsAg and HBcAb IgM have acute hepatitis B. In addition, patients who are positive for HBeAg have higher rates of viral transmission. 5. How do you make a serologic diagnosis of acute hepatitis C infection? A patient must be positive in only 1 of the following 3 tests to be diagnosed with acute HCV: antibodies to hepatitis C virus (anti-HCV), HCV recombinant immunoblot assay (RIBA), or nucleic acid test for HCV RNA.6 TABlE 3.1 Serologic Markers for HBV Antigen and antibodies HBsAg HBsAb HBcAb IgM HBeAg Significance Active infection, does not discriminate between acute and chronic Successful elimination of hepatitis B infection or immunized status First antibody produced in acute hepatitis B infection Increased likelihood of active hepatitis and infectiousness of patient Abbreviations: HBsAg, hepatitis B surface antigen; HBsAb, hepatitis B surface antibody; HBcAb IgM, hepatitis B core antibody IgM; HBeAg, hepatitis B e antigen. Adapted from USMLE Secrets.5 TABlE 3.2 Serologic Markers for HCV Antigen and antibodies HCV RNA Anti-HCV HCV RIBA Significance Viral genetic material that indicates infection, does not discriminate between acute and chronic. Antibody that indicates exposure to prior or current hepatitis C, but does not indicate immunity. Confirmatory test used for weakly positive anti-HCV results. Can determine whether result is true positive or false positive. Abbreviations: HCV RNA, hepatitis C virus ribonucleic acid; HCV RIBA, hepatitis C virus recombinant immunoblot assay. Adapted from Ref. 6. Bottom Line: Patients positive for anti-HCV, HCV RNA, or HCV RIBA have acute hepatitis C infection. 6. Which liver laboratory abnormalities might you expect in acute HBV and HCV infection and why? While working up a patient who presents with nonspecific symptoms such as fever, fatigue, or jaundice, evaluating the status of the liver becomes important. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), commonly referred to as “liver function tests” (LFTs), are a good starting place, along with viral serologies. However, it is important to remember that ALT and AST do not represent true liver function, but rather hepatocellular injury. The LFT label is, therefore, somewhat of a misnomer. Depending on the severity of insult to the liver, AST and ALT can range from mildly elevated to values in the several thousands for fulminant hepatic failure (normal range varies from lab to lab, but typically span from 5 to 60 U/L). Serum albumin concentration and prothrombin time (PT) can be used to assess synthetic function of the liver and are much more reflective of true liver function than LFTs. As the liver becomes increasingly damaged, hepatocytes begin to decrease the production of albumin and of the vitamin K-dependent clotting factors II, V, VII, IX, and X, resulting in hypoalbuminemia and increased bleeding time. Bottom line: AST and ALT are used to evaluate hepatocellular damage, whereas albumin concentration and PT are used to evaluate synthetic function. 7. Does the evidence support performing diagnostic imaging studies for acute HBV or HCV infections? Ultrasonography of the liver can serve to rule out alternative causes of abnormal LFTs (e.g., pancreatitis, cholelithiasis) but provides no definitive evidence to confirm the diagnosis of acute HBV or HCV infection.1,2 One prospective study did find that a collapsed gallbladder with increased wall thickening and pericholecystic edema was present in 50% of patients, which were later serologically confirmed to have acute HBV.7 Although this does show some correlation between ultrasound findings and acute HBV, the association is not strong enough to promote ultrasound as a diagnostic tool. The study suggests that ultrasound findings may be helpful in increasing the index of suspicion if serologic results are not yet available.7 Computed tomography is not specifically indicated to diagnose acute HBV or HCV but may be done incidentally as part of a workup for an undiagnosed patient with symptoms and will likely show hepatic inflammation. Bottom line: Ultrasound has little diagnostic utility for acute viral hepatitis when serologic analysis is available. 8. Are there any modifications that need to be made to a patient’s current medical management if they are diagnosed with acute HBV or HCV? Because patients with acute HBV and HCV can lose liver function, all their medications should be carefully evaluated. Medications that are metabolized by the liver are especially at risk to cause toxicity and should therefore be carefully evaluated in any patient with newly diagnosed hepatitis of any variety.1,2 Patients who are on blood “thinners” should also be carefully monitored because they may become overly anticoagulated due to decreased coagulation factor production.3 No specific recommendations exist for use of acetaminophen in the setting of acute viral hepatitis, although patients with chronic liver disease are instructed to use less than 2 g/d. Even at these doses of acetaminophen, some patients will experience an increase in their LFTs and an exacerbation of their symptoms.8 In the outpatient setting, patients can be managed with regular laboratory work to monitor LFTs and for subsequent adjustments of relevant medications.1–3 It is also important to restrict the use of alcohol during this period until resolution of the acute viral hepatitis occurs. Bottom line: Acute hepatitis affects metabolism of liver products. Patients often require adjustment of medications that are metabolized by the liver to avoid toxicity. 9. What does the data suggest first-line therapy should be for acute HCV infection? A short course of low-dose interferon appears to improve LFTs and viral clearance for patients with acute HCV infection compared with no treatment, but data are lacking for clinical outcomes.9 Antiviral therapy can also be considered for patients with acute HCV infection after a period of time allows for spontaneous self-clearance of virus.10 Although the use of antiviral therapy may make sense intuitively, combination therapy of interferon and ribavirin has not been shown to improve outcome compared with interferon treatment alone10; hence, further studies remain necessary and combination therapy remains a viable option for care. Additionally, at this time, there is a question as to the optimal method, dosage, and duration of therapy with interferon and/or an antiviral medication. Most experts suggest that treatment be initiated no later than 2–3 months after initial symptoms and that therapy lasts between 12 and 24 weeks.10 There is no evidence that the use of glucocorticoids impedes the progression of liver inflammation and necrosis; thus, they are not recommended for therapy of viral hepatitis at this time.11 Note that this is in stark contrast to alcoholic hepatitis, in which glucocorticoids are recommended. No vaccine exists for hepatitis C at this time. Bottom line: Treatment with interferon or interferon plus ribavirin has been shown to improve outcomes of acute HCV infection compared with no treatment. 10. What does the data suggest first-line therapy should be for acute HBV infection? The best treatment for acute HBV infection is the prevention of the disease with the hepatitis B vaccine, and there have been several studies showing its effectiveness in reducing the prevalence of both acute and chronic HBV infections.12 This notion has been supported by the sharp decline in cases of acute HBV infection, especially in those born after 1991, when universal vaccination was initiated.13 Those who are vaccinated are essentially protected from HBV, and if an exposure to HBV occurs, there is a prescribed protocol in place for potential treatment. In an unvaccinated individual presenting with acute hepatitis, treatment is often supportive and includes plenty of rest and fluids.13 If the infection progress to a chronic stage, treatment includes interferon injections with antiviral medication.13 Bottom line: The most effective treatment for HBV is prevention with vaccination. In an unvaccinated person, supportive care and antiviral treatment are recommended. 11. What does the data suggest is the therapy of choice for acute viral hepatitis infection that progresses to fulminant liver failure? Although progression is rare, fulminant liver failure remains a potential outcome of acute viral hepatitis. Acute liver failure is a devastating clinical syndrome, which the majority of patients will not survive without rapid aggressive intervention. Typically, treatment has been limited to admittance to the intensive care unit for supportive care pending an emergency liver transplant.14 Advances in antiviral medications have made it possible to offer a potential alternative for those with HBV-induced acute hepatic failure. Previously, studies have been inconclusive about the effectiveness of lamivudine, a nucleoside reverse transcriptase inhibitor (NRTI), in treatment of fulminant liver failure resulting from viral hepatitis. A recent study, however, has conducted a preliminary series examining the use of the NRTI entecavir in acute hepatic failure.14 All patients enrolled in the study met criteria for liver transplants and had a prognosis of 3 months without transplant.14 After entecavir treatment, all patients displayed dramatic improvements in LFTs, significantly reduced HBV viral load and HBsAg levels to a point that none of these patients required future liver transplants.14 Bottom line: There is no conclusive evidence in favor of a specific treatment course in situations where acute HBV patients experience fulminant liver failure. Antiviral medication is the medical treatment of choice at this time. Liver transplant, if feasible, remains the best option overall. 12. What is the postexposure paradigm for individuals with exposure to HBV? If potential exposure to HBV occurs, such as in the case example provided above, it is important to determine the vaccination status of the exposed person and the disease status of the fomite responsible for exposure. Assuming that the exposed material is positive for HBV, the exposed person’s vaccination status determines his or her treatment course.15 The risk of acquiring HBV from an exposure ranges from 5% to 25%, which highlights the importance of preventative vaccination.15 TABlE 3.3 Post-Exposure Treatment Alogrithm Exposed person’s HBV vaccination status Nonvaccinated Vaccinated, sufficient antibodies Vaccinated, failure to develop antibodies Vaccinated, unverified presence of antibodies Treatment Anti-HBV immunoglobulin and start HBV vaccination series No treatment necessary Anti-HBV immunoglobulin and a HBV vaccination booster or 2 doses of anti-HBV immunoglobulin Check exposed person’s antibody level (Anti-HBs IgG). If sufficient, no treatment. If insufficient, anti- HBV immunoglobulin and a booster Adapted from Ref. 15. 13. What would serology results demonstrate following acute infection? Patients who have recovered from acute HCV infection would have formed anti- HCV antibodies, but these antibodies are nonprotective against future infections.2 In addition, the patients will no longer have evidence of HCV RNA. Patients who have recovered from acute HBV infections will have both anti- HBsAg antibodies and anti-HBcAg antibodies, indicating that viral production took place at some point in time.1 The patient will no longer test positive for HBV DNA or any of the HBV antigens. The presence of the anti-HBsAg antibody is protective against future HBV infections. Bottom line: Patients exposed to and recovered from acute HBV infections will have lifelong protection from this virus. Patients who experience acute illness secondary to HCV are still susceptible to future infections. 14. What is the chance that acute HBV infection will progress to chronic HBV infection? The risk of progression from acute HBV to chronic HBV increases inversely with age. Patients at greatest risk are those in whom virus is vertically transmitted, with approximately 90% progressing from acute to chronic HBV.13 Children aged 1–5 have a roughly 25%–50% chance of progressing to chronic HBV. On reaching late adolescence, the risk of progressing to chronic HBV falls to roughly 5% with more than 95% of adults capable of clearing the infection entirely.13 Bottom line: Risk of progression from acute to chronic HBV infection decreases with advancing age. 15. What are the chances of acute HCV infection progressing to chronic HCV infection? There is a 75%–80% chance of progression from acute HCV to chronic HCV infection. There are no clear indications for why some people are able to clear the infection while others are not.16 Bottom line: The risk for progression from acute HCV to chronic HCV is very substantial. 16. Is follow-up of patients infected with acute HBV or HCV encouraged? Yes. Most adults will be able to clear an acute hepatitis infection caused by HBV, although there is a small risk that they may progress to the carrier or chronically infected state. Patients who are able to clear the virus and who have LFTs that have returned to normal with no additional clinical syndromes are considered to be in a resolved state and immune to future HBV infection. For patients who progress to carrier or chronic status, closer follow-up is encouraged. Follow-up is vital for patients known to have HCV caused acute hepatitis because of the high likelihood of progression to chronic hepatitis C, and the subsequent risk of developing hepatocellular carcinoma. Follow-up with analysis of HCV viral load and LFTs should be done periodically (every 6 months or so) if asymptomatic.2,16 Bottom line: Follow-up is important with acute HBV and HCV patients to track potential progression to chronic illness. TAKE-HOME POINTS: ACUTE VIRAl HEPATITIS B AND C 1. Presentation of acute HBV and HCV infection can range from asymptomatic to fulminant liver failure. Obtaining a history of exposure is vital in making the diagnosis. 2. HBV and HCV are transmitted parenterally, sexually, or perinatally. 3. Blood tests showing the presence of HBsAg and HBcAb IgM indicate acute HBV infection. 4. Blood tests showing the presence of anti-HCV, HCV RNA or a positive HCV recombinant immunoblot assay indicate acute HCV infection. 5. LFTs are used to quantify the extent of hepatocellular damage, whereas albumin levels and prothrombin time are used to quantify hepatic synthetic function. 6. Ultrasound has minimal utility in the diagnostic workup of acute viral hepatitis. 7. Treatment with interferon with or without ribavirin has been shown to minimize hepatocellular damage and increase viral clearance of acute HCV. 8. Widespread vaccination is the most effective way to reduce HBV infections. 9. Treatment for acute HBV includes supportive care and follow-up to track if the patient progresses to a carrier or chronic state. 10. Liver transplant remains the mainstay of treatment for fulminant liver failure caused by acute HBV. 11. Patients exposed to and recovered from acute HBV typically have lifelong immunity. Patients exposed to and recovered from acute HCV typically remain susceptible to recurrent infections. REFERENCES 1. Pyrsopoulos, N. T., and K. R. Reddy. 2009. “Hepatitis B.” eMedine Clinical Knowledge Base, Instituional Edition, 1996–2009. WebMD. http:// www.imedicine.com/DisplayTopic.asp?bookid=6&topic=992. 2. Mukherjee, S., and V. K. Dhawan. 2009. “Hepatitis C.” eMedine Clinical Knowledge Base, Instituional Edition, 1996–2009. WebMD. http://www. imedicine.com/DisplayTopic.asp?bookid=6&topic=993. 3. Finnish Medical Society Duodecim. 2008. “Viral Hepatitis.” In EBM Guidelines: Evidence-Based Medicine. Helsinki, Finland: Wiley Interscience, John Wiley & Sons; http://www.guidelines.gov/summary/summary. aspx? view_id=1&doc_id=12806#s24 4. Center of Disease Control. 2008. “Hepatitis B, Acute 2000 Case Definition.” http://www.cdc.gov/ncphi/disss/nndss/casedef/hepatitisb2000.htm 5. Brown, T. 2008. USMLE Step I Secrets, 2nd edition. Mosby-Saunders. 6. Division of Viral Hepatitis. 2005. Guidelines for Viral Hepatitis Surveillance and Case Management. Atlanta, Georgia: Centers for Disease Control and Prevention. http://www.cdc.gov/ncphi/disss/nndss/casedef/hepatitiscacutecurrent.htm 7. Sudhamshu, K. C. 2006. “Ultrasound Findings in Acute Viral Hepatitis.” Kathmandu University Medical Journal (KUMJ) 4 (4): 415–18. 8. Moling, O., E. Cairon, G. Rimenti, F. Rizza, R. Pristerá, and P. Mian. 2006. “Severe Hepatotoxicity After Therapeutic Doses of Acetaminophen.” Clinical Therapeutics 28 (5): 755–60. 9. Myers, R. P., C. Regimbeau, T. Thevenot, V. Leroy, P. Mathurin, P. Opolon, J. P. Zarski, and T. Poynard. 2001. “Interferon for Acute Hepatitis C.” Cochrane Database Systematic Reviews (4): CD000369. 10. Dienstag, J. L., and J. G. McHutchison. 2006. “American Gastroenterological Association Medical Position Statement on the Management of Hepatitis C.” Gastroenterology 130 (1): 225–30. 11. Brok, J., M. T. Mellerup, K. Krogsgaard, C. Gluud, and J. Brok. 2009. “Glucocorticosteroids for Viral Hepatitis C (Cochrane Review).” In The Cochrane Library, Issue 2. Chichester: John Wiley and Sons Ltd. 12. Chen, D. S. 2009. “Hepatitis B Vaccination: The Key Towards Elimination and Eradication of Hepatitis B.” Journal of Hepatology 50 (4): 805–16. 13. Hepatitis, B. 2008. “CDC Division of Viral Hepatitis.” http://www.cdc. gov/hepatitis/HBV/HBVfaq.htm 14. Jochum, C., R. K. Gieseler, I. Gawlista, A. Fiedler, P. Manka, F. H. Saner, M. Roggendorf, G. Gerken, and A. Canbay. 2009. “Hepatitis B-Associated Acute Liver Failure: Immediate Treatment With Entecavir Inhibits Hepatitis B Virus Replication and Potentially Its Sequelae.” Digestion 80: 235–40. 15. Panlilio, A. L., D. M. Cardo, L. A. Grohskopf, W. Heneine, and Ross, C. S. 2001. “Updated U.S. Public Health Service Guidelines for the Management of Occupation Exposures to HBV, HCV, and HIV Reccommendations forPostexposure Prophylaxis.” MMWR 50 (RR11): 1–42. 16. Hepatitis, C. 2009. “CDC Division of Viral Hepatitis.” http://www.cdc. gov/hepatitis/HCV/HCVfaq.htm#section3 Ruptured

Chapter Esophageal Varices 4 NathaN SelSky, MD CASE A 56-year-old man with a 30-year history of alcohol abuse presents with bloody vomitus for 2 hours. He had been having dark stools for the past several days. He admits to progressive dizziness associated with significant thirst during the last 2 hours and increased shortness of breath. 1. What is the likely diagnosis and why? He is demonstrating clinical signs of significant blood loss and the bloody vomit suggests an upper gastrointestinal (GI) source. Given the history of alcohol abuse, the differential, although broad, must include ruptured esophageal varices. 2. What are the common causes of esophageal varices? The most common cause of esophageal varices is cirrhosis, which is itself most commonly due to alcohol or hepatitis B/C infection, and is less commonly due to primary biliary cirrhosis. Other less common causes of cirrhosis, and by extension esophageal varices, include severe congestive heart failure, portal or splenic vein thrombosis, sarcoidosis, schistosomiasis, and Budd–Chiari syndrome. Bottom line: The most common cause of esophageal varices is cirrhosis. 3. What is the pathogenesis of varix formation? The majority of blood from the esophagus, other than that from the mucosa, is drained by the esophageal vein. This blood is then shunted via the azygous vein to the superior vena cava. The venous drainage of the esophageal mucosa is instead drained by the superficial esophageal veins that run along the mucosa into the left gastric vein, which drains into the portal vein. With the development of portal hypertension, 33 these veins dilate from approximately 1 mm to 1–2 cm. These are thin-walled vessels and are not designed to tolerate high pressures and are prone to rupture. Bottom line: Esophageal varices are caused by pathologic dilatation of superficial esophageal veins, which can easily rupture. 4. What increases bleeding risk for esophageal varices? (1) High portal vein pressure resulting in large varices; large varices are more likely to bleed due to the increased wall tension associated with increased intraluminal radius, as described by the Law of Laplace. Continued alcohol use has shown a progression from the smallest grade of varices to the largest over an average of 50 months and of those patients followed, ongoing drinking led to ruptured varices in 37%.1 (2) Red marks on the varices, including streaks known as “wale spots,” have been associated with recent as well as looming bleeding.2 (3) Severe cirrhosis or liver failure. (4) Esophageal reflux disease, which will allow for gastric acids to operate in proximity to the varices, can damage the esophageal wall contributing to mucosal breakdown of the varices. Bottom line: Increased portal vein pressure is the primary mechanism of variceal bleeding. 5. What are the signs and symptoms of rupture? Signs include substantial bloody vomitus, melanotic stools, decreased urination, and shock, as well as any other signs of hemodynamic compromise. Symptoms include excessive thirst, lightheadedness, weakness, and fatigue. Note that signs of instability may appear suddenly and progress swiftly as ruptured varices can be rapidly fatal. Although it is difficult to estimate mortality with first rupture because of prehospital death and ethical issues with a control arm, it is known that with current treatments, mortality remains between 20% and 30% at 6 weeks.3 Bottom line: Although there are no specific signs to indicate variceal rupture, it manifests as large volume blood loss and must be considered in any unstable cirrhotic. 6. What are the other causes of upper GI bleed? The causes for upper GI bleed may be divided based on its location in esophageal, gastric, and duodenal. The esophageal causes include varices, esophagitis, cancer, and ulcers. The gastric causes include gastritis, ulcers, cancer, varices, vascular ectasia (tortuous and dilated vessels), and Dieulafoy’s lesions (tortuous arterioles in the mucosa that may erode and bleed). The duodenal causes include ulcers, vascular malformations, bleeding from the biliary tract, or bleeding from the pancreatic duct. Bottom line: Upper GI bleeds can have esophageal, gastric, or duodenal etiologies. 7. How the diagnoses of both ruptured and nonruptured varices are made? The gold standard for both is direct visualization via esophagogastroduodenoscopy (within 12 hours in the case of suspected rupture). There are alternative methods of diagnosis for the presence of varices including platelet count, Fibrotest (a series of serum studies to measure liver damage), spleen size by computed tomography or physical examination, portal vein diameter by ultrasound, and transient elastography (a noninvasive method in which stiffness of tissue is measured). Despite the multitude of options, the accuracy of these indicators has not been appropriately evaluated and EGD (esophagogastroduodenoscopy) remains the method of choice. The diagnosis of rupture may be made when the EGD shows one or more of the following: an actively bleeding varix, a clot overlying a varix, a white nipple (unknown etiology, but possibly a fibrin plug) overlying a varix, or varices with no other potential sources of bleeding. Bottom line: Variceal bleeding is best diagnosed by direct endoscopic visualization. 8. What are the general principles of management of an actively bleeding varix? The 3 general principles of management are as follows: (1) achieving hemodynamic stability, (2) prevention of nonhepatic complications like aspiration pneumonia/pneumonitis and renal failure, and (3) treatment of the underlying cause.4 All 3 must be done concurrently and, ideally, within the confines of the ICU (given the mortality rate of >20% at 6 weeks). 1. Hemodynamic stability is achieved by large volume intravascular resuscitation via either twin peripheral lines or a central line. Blood should be replaced with packed red cells to maintain Hb around 8 g/dL (higher levels increasing the portal pressure and chances of rebleeding),4 with clotting factors replaced as needed, and platelets replaced when below 50,000 with bleeding or below 10,000 without bleeding. Beware that complete correction of coagulopathy may not be possible with FFP due to volume overload leading, again, to portal hypertension and rebleeding. Further, large volume transfusions require monitoring of serum ionized-calcium due to citrate binding, with correction as needed. 2. Prevention of complications involves reducing the risk for aspiration, hepatic encephalopathy, renal failure, and the use of prophylactic antibiotics (discussed later). Endotracheal intubation can serve to both protect the airway and prevent aspiration pneumonia/pneumonitis. Encephalopathy may be treated with lactulose, but this should not preclude the further search for other reversible factors. The risk of renal failure, in the form of acute tubular necrosis or hepatorenal syndrome, may be reduced with appropriate hydration and avoidance of nephrotoxic medications. 3. Treatment of the varices includes balloon tamponade, surgery with either shunt or nonshunt operations (esophageal transection or devascularization of the GE [gastroesophageal] junction), a transjugular intrahepatic portosystemic shunt (TIPS) procedure that shunts portal blood into the inferior vena cava and thereby reduces pressure in the portal vein and its tributaries (Figure 4.1) or via endoscopy, either sclerotherapy or band ligation. Balloon tamponade achieves early resolution of bleeding in up to 90% of patients.5 Significant complications include postdeflation rebleeding and esophageal rupture. A TIPS procedure involves creating an anastomosis between the portal and hepatic veins (Figure 4.1). This procedure is generally reserved for those patients with recurrent

Portal vein Superior mesenteric vein

Inferior mesenteric vein

Esophagus Coronary v. Liver Splenic vein Kidney Left renal vein Inferior vena cava Shunt Esophagus Coronary v. Stomac Spleen

Portal vein Superior mesenteric vein

Inferior mesenteric vein Liver

Stomac Spleen Splenic vein Kidney Left renal vein Inferior vena cava FIGurE 4.1 Schematic of TIPS Procedure. (A) Portal hypertension before the TIPS procedure is performed. (B) After the TIPS procedure is performed. Permission granted by Pradeep Muley, M.D., Department of Body and Neuro Interventional Radiology, Fortis Hospital, Vasant Kunj, New Delhi. variceal bleeding in the setting of both endoscopic and pharmacologic therapy. Endoscopy is the treatment of choice and allows for simultaneous diagnosis and treatment.6 By endoscopy, one can either inject a sclerosing agent into the varix or the varix may be ligated with a rubber band. Bottom line: Triple goals include achieving hemodynamic stability, preventing nonhepatic complications, and identifying and correcting the cause of bleeding. 9. When blood transfusions should be given? Repletion with packed red cells should be considered immediately at the time of initial assessment. The goal of therapy should be to maintain hemodynamic stability but not to replace all lost volume. As mentioned above, the practitioner

should take care to avoid overtransfusion, which leads to volume overload and increases the risk of rebound portal hypertension. Further, those receiving large volumes of blood products should be monitored for hypocalcemia secondary to citrate binding. Significant bleeding is defined by a transfusion requirement of 2 units of blood within 24 hours of admission to the first hospital in conjunction with a systolic BP less than 100 mm Hg, or orthostatic change of more than 20 mm Hg, or a pulse above 100 bpm.7 As in any clinical situation, medical judgment should be used to dictate the need for RBC transfusion. It should be noted that the definition of therapy failure is based on the volume of blood products required to maintain a hemoglobin concentration above 8 g/dL. Bottom line: A [Hb] ≥8 g/dL or hematocrit ≥24% is a reasonable goal for oxygen carrying capacity repletion in these patients. 10. If detected, how is a coagulopathy corrected? The clotting factors should be replaced as needed. Platelets should be replaced if the platelet count falls below 50,000/mm3 with active bleeding. Fresh frozen plasma can be used but may not be able to reverse coagulopathy adequately. In the patients with coagulopathy, small studies have shown that recombinant factor VIIa is associated with normalization of serum prothrombin time. However, there were 2 trials, which failed to show a benefit during active variceal hemorrhage. In light of these studies, there are currently no recommendations for use of this factor in routine practice. Bottom line: Consider transfusion of platelets when the platelet countfalls below 50,000/mm in the setting of an active bleed. 11. What are the available pharmacologic treatments to treat active bleeding and prevent early recurrence? Vasopressin and its analogs decrease portal vein pressures by constricting mesenteric arterioles. This treatment may achieve hemostasis in 60%–80% of patients but with little effect on early rebleeding and no improvement in survival.8 Side effects are caused by extrasplanchnic vasoconstriction and the consequential vitalorgan ischemia. Somatostatin inhibits the release of various hormones, among which is glucagon. It promotes splanchnic vasoconstriction when one might normally have an increase in mesenteric blood flow postprandially or in the case of variceal hemorrhage, an increase in mesenteric blood flow in response to the high-protein content of the blood within the gut. This leads to a decreased portal vein pressure. Octreotide, the longer-acting analog of somatostatin, can continue to do so for up to 48 hours.9 Bottom line: Both vasopressin and somatostatin can decrease splanchnic blood flow, but somatostatin will achieve chemical hemostasis in 60%–80% of patients with fewer adverse effects. 12. Which is the best combination therapy to treat active bleeding? The combination of somatostatin (or an analog) and sclerotherapy has shown significant decreases in the rate of early rebleeding in several studies when compared with the same procedure paired with a placebo, but has failed to consistently show a decrease in mortality across the same trials.10–13 The combination of somatostatin (or an analog) with variceal banding was similar in that trials were able to consistently show a decrease in early rebleeding compared with placebo/procedure combination, but there was no clear benefit in overall mortality.14,15 Bottom line: Pharmacotherapy will improve early bleeding control but does not decrease mortality risk. 13. What defines the failure of medical treatment to control active bleeding? Failure of primary control of the bleeding episode was defined at the 2005 consensus meeting in Baveno, Italy, as a need to change therapy due to one of the following criteria: hematemesis ≥2 hour after the start of a pharmacologic or endoscopic therapy, a 3 g drop in hemoglobin if red blood cells are not given, an adjusted blood transfusion index* ≥0.75 at any time, or death.16 Bottom line: Patients must be monitored for failure of treatment and a repeat or alternate therapy must be considered. 14. What is the management of a patient who has failed initial medical therapy? According to the recommendation made at Baveno, intravenous (IV) failed combination (pharmacologic and endoscopic) therapy should be followed by either repeat endoscopic therapy or a TIPS procedure.16 Bottom line: Therapy may require several attempts, after which salvage treatment is recommended. 15. Should antibiotics be given prophylactically? Antibiotics show significant benefits in reducing the incidence of bacterial infections (RR, 0.40) and in reducing mortality (RR, 0.73), presumably from decreased bacteremia and sepsis.17 Despite the multitude of trials regarding the use of antibiotics, there are no antibiotic regimens that show a clearly superior benefit over others. The American Association for the Study of Liver Diseases has made the following recommendation: oral norfloxacin or IV ciprofloxacin should be used in any patient with cirrhosis and GI hemorrhage for a maximum of 7 days. If the patient has advanced cirrhosis (Child-Pugh class B/C) or if there is known local quinolone resistance, the recommendation is to use IV ceftriaxone.18 Bottom line: Every cirrhotic patient with variceal bleeding should receive prophylactic antibiotics. 16. What are the risks for early rebleeding? After the initial hemorrhage is terminated, there is a 6-week period in which there is an increased risk of a recurrent bleed. Risk is highest within the first 48 hours with 50% of episodes occurring in the first 10 days. Following the completion of 6 weeks, patients return to a baseline risk similar to others that have not bled. Risk factors for rebleeding include hyperbilirubinemia, increased prothrombin time, hypoalbuminemia, encephalopathy, age greater than 60 years, and initial bleed severity. Endoscopic signs including visible bleeding, signs of a recent bleed, and large varices all indicate increased risk for rebleeding.19 Bottom line: Risk for esophageal variceal rebleeding remains elevated for approximately 6 weeks following termination of the initial bleed. * ABRI = Units transfused/[(final Hct − initial Hct) + 0.01]. 17. What follow-up is necessary for the patient with a recent esophageal variceal bleed? Following an acute variceal hemorrhage, the American Association for the Study of Liver Disease recommends that patients who underwent endoscopic variceal ligation should have the procedure repeated every 1–2 weeks until all varices have been banded. Afterward, surveillance should be at 1–3 months and then may be repeated at 6–12 month intervals. Patients who received sclerotherapy during the initial hemorrhagic episode should not have secondary prophylactic procedures of the same type, but rather nonselective β-blockers combined with variceal banding.18 Bottom line: Serial examination with repeat variceal ligation is recommended until all varices have been banded. TAKE-HOME POINTS: ruPTurED ESOPHAGEAL VArICES 1. The most common cause of esophageal varices is cirrhosis. 2. Diagnosis of varices and their status is made by endoscopy. 3. Nonselective β-blockers are the best therapy to prevent initial variceal rupture. 4. Treatment of active bleeding includes hemodynamic stabilization, variceal treatment to achieve hemostasis, and the prevention of complications. 5. Optimal treatment of active bleeding is with the combination of vasoconstrictive medications and either endoscopic variceal ligation or endoscopic sclerotherapy. 6. Blood products should be considered immediately as should the possibility of exacerbating portal hypertension. 7. Antibiotics should be given to all cirrhotics with an active variceal bleed. 8. Risk for rebleeding is highest in the first 48 hours. rEFErENCES 1. Dagradi, A. E. 1972. “The Natural History of Esophageal Varices in Patients with Alcoholic Liver Cirrhosis–An Endoscopic and Clinical Study.” GUT 57: 520. 2. Merli M, G. Nicolini, S. Angeloni, V. Rinaldi, A. De Santis, C. Merkel, A. F Attili, O. Riggio. 2003. “Incidence and Natural History of Small Esophageal Varices in Cirrhotic Patients.” Journal of Hepatology 38: 266. 3. de Frachis, R. 2005. “Evolving Consensus in Portal Hypertension: Report of the Baveno IV Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension.” Journal of Hepatology 43: 167. 4. Garcia-Tsao, G., A. J. Sanyal, N. D. Grace, W. Carey. 2007. “AASLD Guidelines for Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis.” Hepatology 46: 922. 5. Hunt, P. S., M. G. Korman, J. Hansky, and W. G. Parkin. 1982. “An 8-year Prospective Experience with Balloon Tamponade in Emergency Control of Bleeding Esophageal Varices.” Digestive Disease and Sciences 27: 413. 6. Grace, N. D. 1997. “Diagnosis and Treatment of Gastrointestinal Bleeding Secondary to Portal Hypertension. American College of Gastrenterology Practice Parameters Committee.” American Journal of Gastroenterology 92: 1081. 7. de Franchis, R. 1996. “Developing Consensus in Portal Hypertension.” Journal of Hepatology 25: 390–94. 8. Ioannou, G., J. Doust, and D. C. Rockey. 2003. “Terlipressin for Acute Esophageal Variceal Hemorrhage.” Cochrane Database of Systematic Reviews CD002147. 9. Ludwig, D., S. Schädel, A. Brüning, B. Schiefer, E. F. Stange. 2000. “48-hour Hemodynamic Effects of Octreotide on Post-prandial Splanchnic Hyperemia in Patients with Liver Cirrhosis and Portal Hypertension: Double-blind, Placebocontrolled Study.” Digestive Disease and Science 45: 1019. 10. Besson, I., P. Ingrand, B. Person, D. Boutroux, D. Heresbach, P. Bernard, P. Hochain, J. Larricq, A. Gourlaouen, D. Ribard. 1995. “Sclerotherapy with and without Octreotide for Acute Variceal Bleeding.” New England Journal of Medicine 333: 555. 11. Avgerinos, A., F. Nevens, S. Raptis, J. Fevery, and The ABOVE study group. 1997. “Early Administration of Somatostatin and Efficacy of Sclerotherapy in Acute Esophageal Variceal Bleeds: The European Acute Bleeding Oesophageal Variceal Episodes (ABOVE) Randomized Trial.” Lancet 350: 1495. 12. Primignani, M., B. Andreoni, L. Carpinelli, A. Capria, G. Rocchi, I. Lorenzini, C. Staudacher, L. Beretta, R. Motta, R. de Franchis. 1995. “Sclerotherapy Plus Octreotide versus Sclerotherapy alone in the Prevention of Early Rebleeding from Esophageal Varices: A Randomized, Double-blind, Placebo-controlled, Multicenter Trial. New Italian Endoscopic Club.” Hepatology 21: 1322. 13. Villanueva, C., J. Ortiz, M. Sabat, et al. 1999. “Somatostatin Alone or Combined with Emergency Sclerotherapy in the Treatment of Acute Esophageal Variceal Bleeding: A Prospective Randomized Trial.” Hepatology 30: 384.
14. Calès, P., C. Masliah, B. Bernard, P. P Garnier, C. Silvain, N. Szostak- Talbodec, J. P. Bronowicki, D. Ribard, D. Botta-Fridlund, P. Hillon, K. Besseghir, D. Lebrec. 2001. “Early Administration of Vapreotide for Variceal Bleeding in Patients with Cirrhosis. French Club for the Study of Portal Hypertension.” New England Journal of Medicine 344: 23. 15. Sung, J. J., S. C. Chung, M. Y. Yung, C. W. Lai, J. Y. Lau, Y. T. Lee, V. K. Leung, M. K. Li, A. K. Li. 1995. “Prospective Randomized Study of Effect of Octreotide on Rebleeding from Esophageal Varices after Endoscopic Ligation.” Lancet 346: 1666. 16. de Frachis, R. 2005. “Evolving Consensus in Portal Hypertension: Report of the Baveno IV Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension.” Journal of Hepatology 43: 167. 17. Soares-Weiser, K., M. Brezis, R. Tur-Kaspa, and L. Leibovici. 2002. “Antibiotic Prophylaxis for Cirrhotic Patients with Gastrointestinal Bleeding.” Cochrane Database Systematic Review CD002907. 18. Garcia-Tsao, G., A. J. Sanyal, N. D. Grace, W. Carey 2007. “AASLD Guidelines for Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis.” Hepatology 46: 922. 19. De Franchis, R., and M. Primignani. 1992. “Why do Varices Bleed?” Gastroenterology Clinics of North America 21: 85.

Chapter Ischemic Colitis 5 NathaN SelSky, MD CASE A 78-year-old diabetic woman presents with abdominal pain for 3 days. On the last two of these days, she experienced several bloody bowel movements. 1. What is the most likely diagnosis and why? Although the differential diagnosis of gastrointestinal bleeds can be fairly broad, age, medical history, and presentation serve to stratify enumeration of the various disease processes. Given her age, hemorrhoids, bleeding diverticulosis, and arteriovenous malformation are all possible. However, none of these should present with diarrhea. Neoplasms must also be considered based on her age, but this presentation would be atypical (i.e., shortened time course, no weight loss, and abdominal pain without signs of obstruction). Inflammatory bowel disease does have a bimodal distribution but the second peak is more likely found in males in the fifth decade. Mesenteric ischemia is often an acute presentation with severe and sudden pain in a clearly defined moment in time that is likely to correspond with the moment of infarction. The most likely cause of this woman’s pain and subsequent gastrointestinal (GI) distress would be ischemic colitis. Given her history of diabetes, she is likely to be a vasculopath secondary to the small vessel damage caused by persistent hyperglycemia. In this case, the pathology is likely due to a low-flow state rather than an occlusive event. Consideration of her vasculopathy, gradual onset of pain, and the start of bleeding relatively early in her course makes for a likely diagnosis of ischemic colitis. Bottom line: Abdominal pain with bloody diarrhea in an elderly vasculopathic patient is ischemic colitis until proven otherwise. 43 2. What else should be included in the differential diagnosis? The differential for patients with the above presentation should include Crohn’s Disease, ulcerative colitis, pseudomembranous colitis, diverticulitis, proctitis, and appendicitis. Alternative diagnoses can often be excluded via a careful history with an assessment of risk factors for vascular disease and a physical examination that includes a digital rectal examination. Bottom line: GI bleeding has a broad differential that must be narrowed via adequate history, thorough physical examination, and epidemiology-based stratification. 3. What are the causes of ischemic colitis? Broadly, ischemic colitis is caused by any form of vascular occlusion including venous thrombotic state, small vessel disease, low-flow-shock states, mechanical obstructions to arterial flow, blood dyscrasias, and iatrogenic causes of both the surgical and drug types. Rare causes of ischemic colitis include high elevation, prolonged vigorous exercise, dialysis, infection, and neurogenic causes. Bottom line: Ischemic colitis can be caused by any pathology that significantly reduces perfusion of the colon. 4. What is the epidemiology surrounding ischemic colitis? There is no well-established data to quantify the incidence of this particular disease. There is likely significant under-reporting due to both lack of presentation in those with mild disease and misdiagnosis in the form of inflammatory bowel disease and infectious colitis.1 Although normally considered to be a disease of the elderly, there has been an increase in the number of ischemic colitis cases in younger people, which is associated with long-distance running, medications, cocaine abuse, and various coagulopathies.2 There are no controlled studies showing an increased prevalence of ischemic colitis in any racial group or one gender versus the other. Bottom line: There is little epidemiologic data regarding this disease, as its manifestations are not specific and easily confused with other maladies. 5. How does the anatomy of the colonic blood supply influence the onset of ischemic colitis? The duty of supplying the colon is shared by two vessels: the superior mesenteric artery and the inferior mesenteric artery. The superior mesenteric artery gives off 4 vessels, which supply the terminal ileum, the cecum, appendix, ascending colon, and proximal transverse colon. At that point in the colon, the inferior mesenteric artery takes over supply and gives branches to the distal transverse colon, the descending colon, the sigmoid colon, and the proximal rectum. It should be noted that the rectum is rarely ischemic because of the secondary blood supply from the internal iliac arteries. Blood from both the superior and inferior mesenteric arteries are connected at the border of the mesentery via the marginal artery of Drummond. There are two spots most subject to ischemia because of the narrow bore of the vessels that supply them: the splenic flexure (Griffith’s point) and the rectosigmoid junction. These are referred to as the watershed regions of the colon. Bottom line: Ischemia is most likely to occur at the splenic flexure and the rectosigmoid junction. 6. What anatomical variations predispose to ischemic colitis? The marginal artery of Drummond, which is an anastomosis between the superior mesenteric artery (SMA) and inferior mesenteric artery (IMA), is the most important collateral to the left colon. It serves to connect the left branch of the middle colic artery with the ascending branch of the left colic artery. It is this anastomosis that directly serves Griffith’s point. In up to 5% of individuals, the artery of Drummond is either inadequate or absent, rendering that portion of the population is exceptionally vulnerable to ischemic colitis. In up to 50% of individuals, the marginal artery is poorly developed along the right side of the colon, which explains the susceptibility to right-sided ischemic colitis events in this population.3 Bottom line: The various common malformations of the marginal artery of Drummond are most common setup for ischemia of the colon. 7. What is the difference between occlusive and nonocclusive ischemia? Occlusive ischemia is caused by those pathologies that obstruct either the arterial or venous portions of the blood supply. Large bore occlusion is generally intraluminal and is either due to primary wall abnormalities such as thrombi, atheromatous plaques, dissection, and arteritis. It can also result from embolization. Small arteries can be blocked due to the sequelae of diabetes, radiation, or arteritis. Venous causes include pancreatitis, portal hypertension, and a hypercoagulable state. Occlusion may also be caused by extrinsic compression of the vessels by adhesions, volvulus, or distention.4 Nonocclusive ischemia is due to hemodynamically compromised conditions that ultimately result in intense vasoconstriction. This is thought to have the most pronounced effect on the right side of the colon. Although the exact mechanism remains unknown, the sparse natural collateralization, the intense vasospasm (which may continue well beyond resolution of the hypoperfusion state), and the hypothesized mesenteric steal perpetrated by proximal arteries of the SMA all lead to a necrotic state.5 The compromise can be due to any of those causes mentioned in Section 1 including systemic shock and drug side effects. Bottom line: Decreased colonic perfusion can be caused by various pathologies from inflammation or atherosclerosis to thrombi and circulatory state compromise. 8. Based on the evidence, what are the most common clinical symptoms of ischemic colitis? Although largely variant based on severity of ischemia and timing of presentation, the suggestive symptoms are readily identifiable. These include a nontoxic appearing patient with mild tenderness, which is often localized to the left side of the abdomen. Rectal bleeding is commonly present and will develop after the onset of abdominal pain. Often times, the patient will be unable to specifically identify a moment at which the pain started but able to give a history of gradual onset with progression. This is in stark contrast to mesenteric ischemia, which is usually associated with sudden onset acute abdominal pain in a toxic appearing patient. Of note, bleeding presents fairly early in the course of ischemic colitis but is usually a late finding in mesenteric ischemia. Bottom line: Gradual onset of pain, early bleeding, and a nontoxic appearance are the hallmarks of ischemic colitis. 9. How is the diagnosis predicted? One study has suggested that patients with lower quadrant abdominal pain and bloody bowel movements with 4 of the following 6 risk factors have ischemic colitis with 100% positive predictive value: age > 60 years, hemodialysis, hypertension, hypoalbuminemia, diabetes mellitus, and constipation inducing medications.6 Bottom line: Clinical factors can be used to categorize risk and likelihood ratios. 10. Based on the evidence, what diagnostic tests should be ordered in this patient? Although not always useful, initial workup will usually include an abdominal radiograph. In one study, only 30% of the patients with autopsy or surgically confirmed mesenteric ischemia had abnormalities on plain film imaging specific for this disease. The computed tomography (CT) findings from the same study were that 39% of patients had findings specific for ischemia.7 Of note, angiography is generally not informative in that large artery occlusions that are rarely the cause of the disease, and impediment to flow is usually at the arteriolar level. Furthermore, perfusion is often restored prior to presentation. In terms of serum markers, none have proven sensitive or specific enough to rule in or out a case of ischemia.2 Bottom line: An abdominal plain film or CT scan may be ordered but will likely show only nonspecific changes and may well be normal initially. Current serum markers are of no clinical value. 11. Does the evidence provide any recommendations for how the diagnosis of ischemic colitis should be made? Diagnosis may generally be confirmed by direct visualization during colonoscopy or with sigmoidoscopy. This examination should be done without the standard bowel preparation, which would dehydrate the bowel and increase the risk for exacerbating the condition. Mesenteric angiograms are generally not indicated but should be done if there is concern for associated mesenteric ischemia. This may manifest as isolated right-sided colitis or physical findings are more severe than usual with colitis.7 Bottom line: Diagnosis is confirmed with visual inspection of the colon. 12. What are the pathological findings associated with ischemic colitis? Although there are no pathognomonic colonoscopic findings, many can be suggestive of ischemia. These include ulceration, friability, erythema, and loss of vascularity. It has also been noted that a single linear colonic ulcer is associated with ischemic colitis. The study did not evaluate the sensitivity or specificity of the sign but noted that its presence was generally associated with a better outcome and may be the hallmark of a milder form of ischemia.8 Bottom line: Colonoscopic findings can be suggestive of ischemia, but not diagnostic. 13. Based on the evidence, what treatment is indicated in this patient? Most patients, including the patient in this vignette, will not require any specific treatment. Those who present with severe or unremitting pain should be treated supportively and their underlying risk factors should be mitigated as possible. This should include bowel rest, fluids to optimize colonic perfusion, and careful monitoring for disease complications. Bottom line: Supportive care is generally all the treatment that is necessary. 14. What is the role of antibiotics in treatment? Antibiotics are recommended for all patients with moderate or severe presentations. It should be noted that there is no clinical evidence for these recommendations and they are based on the studies done between 1945 and 1962. These studies showed decreased severity and extent of bowel damage when antibiotics were given.9–11 Another recent study showed that with the loss of the structural elements of the colonic wall in rats, there is movement of bacteria, against which antibiotics create a theoretical protection.12 Bottom line: With minimal available evidence, antibiotics are only recommended for moderate to severe disease. 15. When is surgery indicated? There are 3 acute indications for surgery, which include peritoneal signs, massive bleeding, and patients with fulminant ischemic colitis in the presence or absence of toxic megacolon. The subacute and chronic indications include colitis that does not respond to standard medical therapy with ongoing symptoms for 2– 3 weeks, apparent healing with recurrent sepsis, symptomatic colon stricture, and symptomatic segmental colitis.2 Bottom line: Surgery is indicated for peritoneal signs and massive bleeding. 16. What are the long-term complications of ischemic colitis? Complications of ischemia include transition of acute ischemia to a chronic ischemic state. The symptoms of this condition can include chronic abdominal pain, diarrhea, weight loss, anemia, and possibly infection. Treatment is often beyond the point of revascularization and necessitates resection of the poorly perfused segment of colon. Another complication of ischemic colitis is associated with healing at the site of ischemia. The fibrotic tissue comprising the scar can cause a stricture at the site of ischemia. Pathologic narrowing of the lumen may resolve spontaneously or may ultimately cause an obstruction. Depending on the site of obstruction, either the stricture may be expanded using endoscopic techniques or the site may be resected. Bottom line: Beware of chronic ischemia and stricture formation due to scarring. TAKE-HOME POINTS: ISCHEMIC COLITIS 1. Ischemic colitis is caused by a lack of aerobic respiration with multiple possible etiologies. 2. Gradual onset of pain, early bleeding, and a nontoxic appearance are the hallmarks of ischemic colitis. 3. Diagnosis is made by clues on direct visualization. 4. Treatment is supportive with reversal of the underlying cause. 5. Antibiotics are rarely indicated and should be reserved for moderate to severe disease. 6. Scar formation increases the risk of development of late colonic strictures. REFERENCES 1. Stamatakos, M., E. Douzinas, C. Stefanki, C. Petropoulou, H. Arampatzi, C. Safioleas, G. Giannopoulos, C. Chatziconstantinou, C. Xiromeritis, and M. Safioleas. 2009. “Ischemic Colitis: Surging Waves of Update.” Tohoki Journal of Experimental Medicine 218: 83–92. 2. Brandt, L. J., and S. J. Boley. 2000. “AGA Technical Review on Intestinal Ischemia. American Gastrointestinal Association.” Gastroenterology 118: 954. 3. Sonneland, J., L. J. Anson, and L. E. Beaton. 1958. “Surgical Anatomy of the Arterial Supply to the Colon from the Superior Mesenteric Artery Based Upon a Study of 60 Specimens.” Surgical Gynecology & Obstetrics 106: 385–97. 4. Toursarkissuan, B., and R. W. Thompson. 1997. “Ischemic Colitis.” Surgical Clinics of North America 77: 461–70. 5. Landreneau, R. J., and W. J. Fry. 1990. “The Right Colon as a Target Organ of Non-Occlusive Mesenteric Ischemia.” Archives of Surgery 125: 591–94. 6. Park, C. J., M. K. Jang, W. G. Shin, H. S. Kim, H. S. Kim, K. S. Lee, J. Y. Lee, K. H. Kim, J. Y. Park, J. H. Lee, H. Y. Kim, E. S. Nam, and Y. Yoo. 2007. “Can We Predict the Development of Ischemic Colitis among Patients with Lower Abdominal Pain?” Diseases of the Colon and Rectum 50: 232. 7. Smerud, M. J., C. D. Johnson, and D. H. Stephens. 1990. “Diagnosis of Bowel Infarction: A Comparison of Plain Films and CT Scans in 23 Cases.” American Journal of Roentgenology 154: 99. 8. Zuckerman, G. R., C. Prakash, R. B. Merriman, M. S. Sawhney, K. DeSchryver-Kecskemeti, and R. E. Clouse. 2003. “The Colon SingleStripe Sign and its Relationship to Ischemic Colitis.” American Journal of Gastroenterology 98: 2018. 9. Sarnoff, S. J., and J. Fine. 1945. “Effect of Chemotherapy on Ileum Subjected to Vascular Injury.” Annals of Surgery 121: 74–82. 10. Poth, E. J., and J. N. McClure. 1950. “Intestinal Obstruction: Protective Action of Sulfasuxidine and Sulfathalidine to Ileum Following Vascular Damage.” Annals of Surgery 131: 159–70. 11. Cohn, I., C. E. Floyd, C. F. Dresden, and G. H. Bornside. 1962. “Strangulation Obstruction in Germ-Free Animals.” Annals of Surgery 156: 692–702. 12. Redan, J. A., B. F. Rush, T. W. Lysz, and G. W. Machiedo. 1990. “Organ Distribution of Gut-Derived Bacteria Caused by Bowel Manipulation or Ischemia.” American Journal of Surgery 159: 85–90. Upper

Gastrointestinal CHAPTER Bleeding 6 PAULEY CHEA CASE A 66-year-old man with a history of alcoholism, coronary artery disease, and deep vein thrombosis (pulmonary embolism) presents to the emergency department for evaluation of a 3-week history of worsening abdominal pain and vomiting. He reports that the pain peaks in intensity approximately 2 hours after meals. He describes his vomitus as “bloody” and also notices that his stools are “much darker than usual.” He also complains of fatigue and lack of appetite, which he attributes to his nausea. He has chronic back pain for which he takes ibuprofen on a regular basis. Conjunctival pallor is noted on physical examination. Vitals are as follows: blood pressure (BP): 104/74 mm Hg, heart rate (HR): 105 bpm, temperature (T) 98°F, RR (respiratory rate) : 19. Bowel sounds are reduced and there is mild epigastric tenderness. Current medications include warfarin and ibuprofen. 1. What is the most likely diagnosis and why? This patient is mostly likely experiencing an upper gastrointestinal (GI) bleed. Upper GI bleeding is defined as bleeding that originates from a location above the ligament of Treitz. Signs of an upper GI bleed (UGIB) include hematemesis and melena, which is described as tarry, foul smelling stool. Melena is distinguished from lower GI bleeding, which may present as hematochezia (bright red blood in the stool). The most common causes of UGIBs appear to be gastric ulcers (32%), duodenal ulcers (28%), esophageal varices (9%), and Mallory– Weiss tears (6%).1 This patient presents with signs of upper GI bleeding most likely originating from the duodenum since the pain occurs hours after a meal rather than with meals. Duodenal ulcers typically elicit pain hours after eating because food contents enter the duodenum only after gastric processing. Pain occurring immediately with meals is suggestive of a gastric ulcer.51 Upper GI bleeding is a common indication for hospital admission with an incidence of approximately 100 cases per 100,000 people per year. Mortality is relatively high and is estimated to be in the range of 6%–10%.2 Like our patient, individuals suffering from GI bleeding are generally older, more likely to be male, and more likely to use alcohol, tobacco, and prescription or over-the- counter aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs).3 Gastrointestinal disease has been strongly linked to NSAID use. Thus, a thorough medication history should be obtained from patients presenting with signs of GI bleed.4,5 Bottom line: When attempting to differentiate between the 2 most common causes of UGIB, gastric and duodenal ulcers, duodenal ulcers typically present with pain that is relieved with meals whereas gastric ulcers are typically worsened with meals. 2. What does the evidence suggest should be the initial step in management for our patient with a suspected UGIB? There are currently no direct, evidence-based recommendations for the initial management of suspected UGIB. However, current standard of care necessitates a focused medical history, physical examination, and initial laboratory values such as complete blood count (CBC), serum chemistry, liver “function” tests (LFTs), and coagulation profile. When managing any acutely ill patient, standard practice includes evaluating the airway, breathing, and circulation (ABCs) of the patient. It is also important to assess for signs of hemodynamic instability such as hypotension and tachycardia that may indicate a severe or chronic bleed, and if necessary, start fluid resuscitation.6 Patients with evidence of hypotension secondary to hemorrhage have an approximate 3-fold increase in mortality if not immediately managed.7–10 Our patient presents with resting tachycardia (HR: 105 bpm) and probable hypotension (BP: 104/74 mm Hg), suggesting mild to moderate hypovolemia. Bottom line: Assessing a patient’s hemodynamic status is perhaps the most critical initial step in managing patients with suspected UGIB. Routine blood work should include CBC, electrolytes, kidney function, LFTs, and coagulation profile. 3. Does evidence support aggressive fluid resuscitation in our patient? No. Despite aggressive fluid resuscitation being the standard of care, there are no current, high-quality studies that clearly demonstrate improved outcomes with fluid resuscitation. Although several studies show that initial hypotension is associated with increased rates of morbidity in patients with UGIB, there is a lack of data to determine the exact resuscitation parameters that produce the best survival rates.7–11 Nevertheless, current recommendations for fluid resuscitation have originated from an international consensus report on UGIB management.12 The report recommends that if a patient is suspected to be hypovolemic, fluids should be delivered via venous access using 2 large bore intravenous cannulae to initiate a fluid challenge. Evidence suggests that colloid fluids do not reduce the risk of death in critically ill patients compared with more cost-effective crystalloids such as normal saline.13 Bottom line: Standard practice dictates that patients who demonstrate obvious hemodynamic instability may be resuscitated with normal saline and admitted to the intensive care unit despite a lack of data to clearly demonstrate improved outcomes in these patients. 4. How are patients with acute UGIB risk stratified and has such stratification been shown to improve outcomes? Patients can be stratified into low- and high-risk groups based on history, clinical examination, and laboratory data. The 2 most popularly accepted and externally validated scoring systems for upper GI bleeding are the Rockall Score and the Glasgow–Blatchford bleeding score (GBS).14–16 Both approaches are used to estimate chance of rebleeding based on specific risk factors. Unlike the GBS, the complete Rockall method requires endoscopy because it correlates the descriptive appearance of the ulcer to future mortality.15 Although both methods are validated, prognostication should be based on a variety of clinical factors rather than a single score exclusively. 4.1 Rockall scoring The Rockall approach uses factors such as age, presence of shock, comorbidities, and evidence of bleeding to predict mortality in patients with UGIB.15 The scale runs from 0 to 11, with 11 representing the highest risk. A score of less than or equal to 2 represents rather low risk. Patients with a score of 0 can be managed as outpatients.15 Although the Rockall scoring system was specifically derived to predict mortality, it is also used to predict rebleeding. Without endoscopy, the complete Rockall score cannot be calculated; however, we can calculate a partial Rockall score. In our patient, 1 point is earned for age between 60 and 79 years, 1 point is earned for a resting tachycardia, and 2 points are earned for a history of ischemic heart disease giving a total of 4 points, which puts him in the high- risk category (Tables 6.1 and 6.2). TABLE 6.1 Rockall Scoring 0 Points Age <60 y Shock No shock 1 Point 60–79 y Pulse > 100 BP > 100 2 Points >80 SBP <100 3 Points Comorbidity None CHF, IHD, major morbidity Renal failure, liver failure, metastatic cancer Diagnosis Mallory– following Weiss; endoscopy No lesion found Evidence of None bleeding All other diagnoses GI malignancy Blood, adherent clot, spurting vessel Abbreviations: GI, gastrointestinal; SBP, Systolic Blood Pressure; CHF, Congestive Heart Failure; IHD, Ischemic Heart Disease. TABLE 6.2 Risk of Rebleeding and Mortality for Rockall Scoring Rockall score Risk for rebleeding (%) Mortality (%) 000 1 3.4 0 2 5.3 0.2 3 11.2 2.9 4 14.1 5.3 5 24.1 10.8 6 32.9 17.3 7 43.8 27 ≥8 41.8 41.1 4.2 Glasgow–Blatchford scoring Glasgow–Blatchford is another validated method of risk stratification but does not depend on endoscopy to calculate the score (Table 6.3). Initial laboratory values are used to determine risk. Factors such as elevated blood urea nitrogen, low initial hemoglobin, hypotension, and TABLE 6.3 Glasgow–Blatchford Scoring Risk factor Score Blood urea ≥6.5 < 8.0 2 ≥8.0 < 10.0 3 ≥10.0 < 25.0 4 ≥25 6 Hemoglobin (g/L) for men ≥12.0 <13.0 1 ≥10.0 <12.0 3 <10.0 6 Hemoglobin (g/L) for women ≥10.0 < 12.0 1 <10.0 6 Systolic blood pressure (mm Hg) 100–109 1 90–99 2 <90 3 Other markers Pulse 100 (per min) 1 Presentation with melena 1 Presentation with syncope 2 Hepatic disease 2 Cardiac failure 2 other comorbidities such as liver and heart disease put patients at greater risk.17 Scores greater than or equal to 6 are associated with at least a 50% risk for needing an intervention such as transfusion and endoscopy.14 Bottom line: Rockall and Glasgow–Blatchford are validated, predictive scoring systems used for risk stratification and predication of mortality and rebleeding risk. The complete Rockall score depends on the results of endoscopy. 5. Does evidence suggest that a blood transfusion would confer a mortality benefit to our patient? No. Although administering blood transfusions to patients suspected of active UGIB is largely the standard of care, evidence does not support this practice. Rather, evidence actually suggests that transfusing patients with UGIB results in worse outcomes. A recent Cochrane Review found no conclusive evidence demonstrating survival advantage for patients presenting with acute UGIB who received blood transfusions18; however, it is generally accepted that acute UGIB is an indication for blood transfusion, which serves to improve global oxygenation of organs and hemostasis.17,18 In the Cochrane Review of 3 studies containing 126 patients with UGIB and subsequent mortality data, there was a higher rate of complications and death in the group receiving transfusion. However, since the study did not have significant power due to its small sample size, no conclusive facts can be established. One explanation for this peculiar result may be rationalized by the suggestion that the sickest patients are most likely to be transfused. Their initial status typically puts them at higher risk of death and complications, and thus it merely appears that transfusion is associated with increased mortality.18 International consensus suggests that transfusion may be initiated when a patient's hemoglobin level is less than or equal to 7.0 g/dL in the absence of tissue hypoperfusion, hemorrhage or coronary artery disease.1,8 Although the complications associated with anemia are to be avoided, blood transfusions are associated with increased risk of other complications such as infection and Acute Respiratory Distress Syndrome (ARDS).9 The Cochrane Review cited earlier suggests that large, wellconcealed RCTs (randomized controlled trials) are needed to conclusively determine benefit of this common practice.18 Bottom line: Large scale, high-powered studies have not been completed to determine if transfusion of packed RBCs reduces mortality, although it is a commonly practiced procedure in patients with UGIB. 6. Does the evidence support endoscopy for our patient at this time? Risk stratification using validated systems is one approach to judge if endoscopy is indicated. Our patient would score at least 4 points based on the Rockall criteria for age, evidence of resting tachycardia, and history of ischemic heart disease. Patients with a Rockall score >0 should receive endoscopy for assessment of bleeding risk.12 For this patient, endoscopy within 24 hours of presentation of acute UGIB is recommended by international consensus.19,20 Endoscopy will provide a view to identify, classify, and treat actively bleeding ulcers. Our patient is taking warfarin, a factor that may complicate endoscopy. Although correction of coagulopathy in patients receiving anticoagulant therapy is recommended, endoscopy in actively bleeding patients should not be delayed. A retrospective cohort study showed that there was no greater risk for rebleeding in patients with UGIB whose INR (International Normalized Ratio) was above 1.3 versus patients whose INR was below 1.3.21 Before initiating endoscopy, evidence suggests that use of prokinetic agents improves the outcome of endoscopy by promoting gastric emptying and reducing the need for repeat studies due to obscuration of lesions.11,22,23 Although nasogastric tube insertion is used to confirm presence and quality of blood before endoscopy, evidence is mixed regarding the benefit of NG lavage, as complications and patient discomfort are frequently noted with this procedure.23,24 Bottom line: Use the predictive systems to determine need for endoscopy and do not delay the procedure even if the patient has been on anticoagulant therapy. 7. How are endoscopic findings classified? The Forrest classification has been shown to accurately prognosticate morbidity based on endoscopic findings.25,26 It is also used to help guide intervention strategies and provides a complete picture for the Rockall Scoring system. In a prospective study of 239 patients, the Forrest classification system was ultimately shown to be superior to the Rockall and Glasgow–Blatchford systems using each respective system to predict rebleeding and death in high-risk patients.27 The descriptive categories of the Forrest classification and associated risk of rebleeding is given in Table 6.4. Bottom line: The Forrest system determines risk of rebleeding and mortality based on direct visualization from endoscopy and is superior in predicting rebleeding compared with the Rockall and Glasgow– Blatchford scores. 8. What treatment does evidence suggest provides the best outcome for acute upper GI bleeding? Endoscopy can be used for both diagnostic and therapeutic purposes. Under endoscopic guidance, ulcers may be injected with epinephrine, which reduces bleeding by causing vasoconstriction. A bipolar probe can also be used to cauterize and coagulate the lesion. In a metaanalysis of 27 studies containing 2472 patients, it was demonstrated that combined used of epinephrine injection and coagulation reduced TABLE 6.4 Forrest Classification Type Risk of rebleeding (%) Ia: Spurting bleed 100 Ib: Oozing bleed 55 IIa: Visible vessel 43 IIb: Sentinel clot 22 IIc: Flat spot 10 III: Clean base 5 the risk of rebleeding over epinephrine injection alone28 (odds ratio [OR], 0.59 [0.44–0.80], P = .0001). Risk for emergent surgery was also reduced with dual therapy (OR, 0.66 [0.49–0.89], P = .03). Bottom line: Endoscopic therapy using combined epinephrine and coagulation provides the best outcomes. 9. What does evidence suggest should be the pharmacologic treatment for our patient? For an active UGIB? For prevention of recurrence? A meta-analysis based on randomized controlled trials of 5792 subjects showed that patients treated with PPI therapy had a decreased incidence of rebleeding (OR: 0.4 with 95% CI: 0.36–0.57) and reduced need for surgery22 (OR: 0.56 with 95% CI: 0.45–0.70). Lau et al. showed that high-dose intravenous proton pump inhibitor treatment substantially reduced the risk of rebleeding in patients with actively bleeding or nonbleeding, visible, vessel ulcers after endoscopic therapy with epinepherine and coagulation.29 Theoretically, PPIs raise gastric pH levels, which may serve to enhance platelet aggregation and thus improve coagulation.12 Intravenous PPIs are recommended for postendoscopy, starting with a 80 mg bolus followed by 8 mg/h for 72 hours.30 Intravenous PPI administration is generally not recommended for preendoscopic use unless there is evidence of active bleeding.30 Bottom line: The most effective pharmacological treatment for patients with PUD is a proton pump inhibitor. 10. Based on the evidence, how are patients with UGIB best managed at discharge? Patients should be prescribed daily proton pump inhibitor with a duration specifically tailored for the type of bleed.12 Peptic ulcer disease is strongly associated with Helicobacter pylori infection, and it is recommended that patients should be tested for this organism to reduce the chance of rebleeding.12 If positive for H. pylori, patients should receive eradication therapy since a body of evidence shows that rebleeding risk is reduced.12,16, 31–33 A meta-analysis of 7 studies with a total of 578 patients without long-term maintenance PPI therapy showed that the mean percentage of rebleeding in the H. pylori eradication therapy group was 2.9% versus 20% in the noneradication group.31 A second meta-analysis of 3 studies with a total of 470 patients who were receiving long- term maintenance therapy demonstrated a mean percentage of rebleeding of 1.6% in the eradication group versus 5.6% in the noneradication group.31 Bottom line: At discharge, patients should be started on a PPI and be referred for H. pylori testing. TAKE-HOME POINTS: UPPER GASTROINTESTINAL BLEEDING 1. Upper GI bleeding is most commonly caused by gastric and duodenal ulcers and can be distinguished from history. 2. Patients should be initially assessed for hemodynamic instability and aggressively hydrated if deemed appropriate. 3. Predictive scoring systems like the Rockall System and Glasgow– Blatchford are validated for risk stratification. 4. There is no conclusive evidence to show that transfusion of RBCs in patients with UGIB reduces mortality, but it is nevertheless a commonly practiced procedure. 5. Combined endoscopic epinephrine injection and coagulation reduces the risk of rebleeding. 6. The most effective treatment for PUD is a proton pump inhibitor. 7. H. pylori is strongly associated with PUD and patients should be sent for testing at discharge. REFERENCES 1. Wilcox, C. M., and W. S. Clark. 1999. “Causes and Outcome of Upper and Lower Gastrointestinal Bleeding: The Grady Hospital Experience.” Southern Medical Journal 92 (1): 44–50. 2. Fallah, M. A., C. Prakash, and S. Edmundowicz. 2000. “Acute Gastrointestinal Bleeding.” The Medical Clinics of North America 84 (5): 1183– 208. 3. Peura, D. A., F. L. Lanza, C. J. Gostout, and P. G. Foutch. 1997. “The American College of Gastroenterology Bleeding Registry: Preliminary findings.” American Journal of Gastroenterology 92 (6): 924–28. 4. Smalley, W. E., and M. R. Griffin. 1996. “The Risks and Costs of Upper Gastrointestinal Disease Attributable to NSAIDS.” Gastroenterology Clinics of North America 25 (2): 373–96. 5. Griffin, M. R., J. M. Piper, J. R. Daugherty, M. Snowden, and W. A. Ray. 1991. “Nonsteroidal Anti-Inflammatory Drug use and Increased Risk for Peptic Ulcer Disease in Elderly Persons.” Annals of Internal Medicine 114 (4) 257–63. 6. Barkun, A., J. K. Nonvariceal, and Upper GI Bleeding Consensus Conference Group. 2003. “Consensus Recommendations for Managing Patients with Nonvariceal Upper Gastrointestinal Bleeding.” Annals of Internal Medicine 139: 843–57. 7. Rockall, T. A., R. F. Logan, H. B. Devlin, and T. C. Northfield. 1995. “Incidence of and Mortality from Acute Upper Gastrointestinal Haemorrhage in the United Kingdom. Steering Committee and Members of the National Audit of Acute Upper Gastrointestinal Haemorrhage.” British Medical Journal 311 (6999): 222–26. 8. Blatchford, O., L. A. Davidson, W. R. Murray, M. Blatchford, and J. Pell. 1997. “Acute Upper Gastrointestinal Haemorrhage in West of Scotland: Case Ascertainment Study.” British Medical Journal 315 (7107): 510–14. 9. Barkun, A., S. Sabbah, R. Enns, D. Armstrong, J. Gregor, R. N. Fedorak, E. Rahme, Y. Toubouti, M. Martel, N. Chiba, and C. A. Fallone. 2004. “The Canadian Registry on Nonvariceal Upper Gastrointestinal Bleeding and Endoscopy (RUGBE): Endoscopic Hemostasis and Proton Pump Inhibition are Associated with Improved Outcomes in a Real-Life Setting.” The American Journal of Gastroenterology 99 (7): 1238–46. 10. Cameron, E. A., J. N. Pratap, T. J. Sims, S. Inman, D. Boyd, M. Ward, and S. J. Middleton. 2002. “Three-Year Prospective Validation of a Pre-Endoscopic Risk Stratification in Patients with Acute UpperGastrointestinal Haemorrhage.” European Journal of Gastroenterology & Hepatology 14 (5): 497–50. 11. Blatchford, O., L. A. Davidson, W. R. Murray, M. Blatchford, and J. Pell. 1997. “Acute Upper Gastrointestinal Haemorrhage in West of Scotland: Case Ascertainment Study.” British Medical Journal 315 (7107): 510–14. 12. Jairath, V. 2011. “The Overall Approach of Management in Upper Gastrointestinal Bleeding.” Gastrointestinal Endoscopy Clinics of North America 21 (4): 657–70. 13. Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD000567. DOI: 10.1002/14651858.CD000567.pub4. 14. Stanley, A. J., D. Ashley, H. R. Dalton, C. Mowat, D. R. Gaya, E. Thompson, U. Warshow, M. Groome, A. Cahill, G. Benson, O. Blatchford, and W. Murray. 2009. “Outpatient Management of Patients with Low-Risk Upper-Gastrointestinal Haemorrhage: Multicentre Validation and Prospective Evaluation.” Lancet 373 (9657): 42–47. 15. Rockall, T. A., R. F. Logan, H. B. Devlin, and T. C. Northfield. 1996. “Risk Assessment After Acute Upper Gastrointestinal Haemorrhage.” GUT 38 (3): 316–21. 16. Graham, D. Y., K. S. Hepps, F. C. Ramirez, G. M. Lew, and Z. A. Saeed. 1993. “Treatment of Helicobacter Pylori Reduces the Rate of Rebleeding in Peptic Ulcer Disease.” Scandinavian Journal of Gastroenterology 28 (11): 939– 42. 17. Blatchford, O., W. R. Murray, and M. Blatchford. 2000. “A Risk Score to Predict Need for Treatment for Upper-Gastrointestinal Haemorrage.” Lancet 356 (9238): 1318–21. 18. Jairath, V., S. Hearnshaw, S. J. Brunskill, C. Doree, S. Hopewell, C. Hyde, S. Travis, and M. F. Murphy. “Red Cell Transfusion for the Management of Upper-Gastrointestinal Haemorrhage.” Cochrane Database of Systematic Reviews 2010 Issue 9. Art. No.: CD006613. DOI: 10.1002/14651858. CD006613.pub3 19. Barkun, A. N., M. Bardou, E. J. Kuipers, J. Sung, R. H. Hunt, M. Martel, and P. Sinclair 2010. “International Consensus Recommendations on the Management of Patients with Nonvariceal Upper Gastrointestinal Bleeding.” Annals of Internal Medicine 152 (2): 101–13. 20. Sung, J. J., F. K. Chan, M. Chen, J. Y. Ching, K. Y. Ho, U. Kachintorn, N. Kim, et al 2011. “Asia-Pacific Working Group Consensus on Non-Variceal Upper Gastrointestinal Bleeding.” Gut. 2011 Sep;60(9):1170–7. 21. Wolf, A. T., S. K. Wasan, and J. R. Saltzman. 2007. “Impact of Anticoagulation on Rebleeding Following Endoscopic Therapy for Nonvariceal Upper Gastrointestinal Hemorrhage.” American Journal of Gastroenterology 102: 290– 96. 22. Barkun, A. N., M. Bardou, M. Martel, I. M. Gralnek, and J. J. Sung. 2010. “Prokinetics in Acute Upper GI Bleeding: A Meta-Ana3lysis.” Gastrointestinal Endoscopy 72 (6): 1138–45. 23. Pateron, D., E. Vicaut, E. Debuc, K. Sahraoui, N. Carbonell, X. Bobbia, D. Thabut, F. Adnet, P. Nahon, R. Amathieu, M. Aout, N. Javaud, P. Ray, and J. C. Trinchet. “Erythromycin Infusion or Gastric Lavage for Upper Gastrointestinal Bleeding: A Multicenter Randomized Controlled Trial.” Annals of Emergency Medicine 57 (6): 582–89. 24. Cappell, M. S. 2005. “Safety and Efficacy of Nasogastric Intubation for Gastrointestinal Bleeding after Myocardial Infarction: An Analysis of 125 Patients at Two Tertiary Cardiac Referral Hospitals.” Digestive Diseases and Sciences 50 (11): 2063–70. 25. Forrest, J. A., N. D. Finlayson, and D. J. Shearman. 1974. “Endoscopy in Gastrointestinal Bleeding.” Lancet 17: 394–97. 26. Heldwein, W., J. Schreiner, J. Pedrazzoli, and P. Lehnert. 1989. “Is the Forrest Classification a Useful Tool for Planning Endoscopic Therapy of Bleeding Peptic Ulcers?” Endoscopy 21 (6): 258–62. 27. Kim, B. J., M. K. Park, S. J. Kim, E. R. Kim, B. H. Min, H. J. Son, P. L. Rhee, J. J. Kim, J. C. Rhee, and J. H. Lee. 2009. “Comparison of Scoring Systems for the Prediction of Outcomes in Patients with Nonvariceal Upper Gastrointestinal Bleeding: A Prospective Study.” Digestive Diseases and Sciences 54 (11): 2523–29. 28. Marmo, R., G. Rotondano, R. Piscopo, M. A. Bianco, R. D’Angella, and L. Cipolletta 2007. “Dual Therapy Versus Monotherapy in the Endoscopic Treatment of High-Risk Bleeding Ulcers: A Meta-Analysis of Controlled Trials.” American Journal of Gastroenterology 102: 279–289. 29. James Y. W. Lau, Joseph J.Y. Sung, K. K. C. Lee, M.- Y. Yung, and S. K. H. Wong. 2000. “Effect of Intravenous Omeprazole on Recurrent Bleeding oafter Endoscopic Treatment of Bleeding Peptic Ulcers.” New England Journal of Medicine 343: 310–16. 30. Afif, W., R. Alsulaiman, M. Martel, and A. N. Barkun. 2007. “Predictors of Inappropriate Utilization of Intra-Venous Proton Pump Inhibitors.” Alimentary Pharmacology & Therapeutics 25 (5): 609–15. 31. Gisbert, J. P., S. Khorrami, F. Carballo, X. Calvet, E. Gené, and J. E. Dominguez-Muñoz. 2004. “Meta-analysis: Helicobacter Pylori Eradication Therapy vs. Antisecretory Non-Eradication Therapy for the Prevention of Recurrent Bleeding from Peptic Ulcer.” Alimentary Pharmacology & Therapeutics 19 (6): 617–29. 32. Rokkas, T., A. Karameris, A. Mavrogeorgis, E. Rallis, and N. Giannikos. 1995. “Eradication of Helicobacter Pylori Reduces the Possibility of Rebleeding in Peptic Ulcer Disease.” Gastrointestinal Endoscopy 41 (1): 1–4. 33. Jaspersen, D., T. Koerner, W. Schorr, M. Brennenstuhl, C. Raschka, and C. Hammar. 1995. “Helicobacter Pylori Eradication Reduces the Rate of Rebleeding in Ulcer Hemorrhage.” Gastrointestinal Endoscopy 41 (1): 5–7.

Spontaneous CHAPTER Bacterial Peritonitis 7 ALLYSON REID CASE A 53-year-old man with a history of cirrhosis from untreated hepatitis C was admitted to the hospital for evaluation of altered mental status thought to be due to liver failure. His ammonia level is found to be elevated, and lactulose therapy has begun. The patient’s mental status improves as the serum ammonia levels slowly decrease. On day 4 of the hospital stay, the patient became febrile to 101.4°F, dyspneic, and tachycardic. He is visibly uncomfortable and complains of diffuse abdominal pain and nausea. He has gained 5 kg over the past 7 days. His abdomen is firm, distended, and exquisitely tender to palpation in the right and left lower quadrants. A large fluid wave can be appreciated. Bowel sounds are normoactive. A urinalysis is unrevealing. 1. What is the likely diagnosis and why? Given his abdominal pain with rigidity and distension, and fever in a setting of known cirrhosis, bacterial peritonitis (BP) is the likely diagnosis. 2. What does the evidence suggest should be the initial step in the diagnosis and management of this patient? In any patient with ascites, especially in the setting of fever without an obvious source, a diagnostic paracentesis should be considered.1,2 There are 2 possible locations for paracentesis that minimize potential damage to vascular structures: midline 2 cm inferior to the umbilicus and left lower quadrant lateral to the rectus abdominis muscle. For diagnostic paracentesis, fluid must be collected for analysis and culture. It is imperative that at least 10 mL of ascitic fluid be directly inoculated into 1 aerobic and 1 anaerobic blood culture vials. This improves bacterial detection significantly over delayed inoculation in 63 the laboratory. The ascitic fluid should be sent for cell count, gram stain, culture, and albumin concentration.1 Elevated white blood cell count, specifically neutrophil count, suggests an acute bacterial etiology. Gram stain and culture should be obtained to determine the exact bacterial cause for the illness. Albumin concentration of the ascitic fluid is needed for comparison with serum albumin concentration to help to determine whether the fluid is an exudate or transudate, which will help to narrow the differential diagnosis.3 Simultaneous blood cultures augment bacterial detection sensitivity, because as many as 50% of BP cases are associated with bacteremia (note that this is the case only for spontaneous bacterial peritonitis [SBP] but not secondary).4 Arterial samples sent for arterial pH and serum albumin must be drawn within 30 minutes of the paracentesis to be considered valid. These samples are necessary to calculate the serum-ascites albumin gradient (SAAG).1 The risks of paracentesis include bleeding complications (3%) and bowel perforation (1.2%).1 These risks can be minimized by avoiding superficial veins and surgical scars, which may contain adhesed bowel or aberrant vasculature.1 Bottom line: In any patient with ascites and unexplained fever (or leukocytosis), it is critical to obtain a diagnostic paracentesis with direct inoculation into blood culture vials as opposed to a therapeutic paracentesis (i.e., symptomatic relief of ascites without analysis of ascitic fluid), so that a proper diagnosis can be made. Blood samples must be obtained within 30 minutes of the paracentesis. In addition, it is important to send the ascitic fluid for cell count, gram stain, culture, and albumin, while blood should be sent for culture, pH, and serum albumin. CASE CONTINUED A left lower quadrant diagnostic paracentesis is performed, and 4.5 L of fluid is removed. The fluid is turbid. Preliminary results of the Gram stain demonstrate the presence of neutrophils and gram-negative rods. Cell counts, albumin, SAAG, and cultures are still pending. 3. What are the two major diagnostic possibilities to explain the presence of neutrophils and gram-negative bacteria in the ascitic fluid? By definition, the presence of elevated numbers of inflammatory cells and bacteria in the ascitic fluid indicates the occurrence of an infectious process within the peritoneal space. Based on the etiology of the infected ascitic fluid, BP is classified into two major types, secondary and spontaneous. Secondary BP results from direct inoculation of gastrointestinal (GI) bacterium into the ascitic fluid via a physical breach in the peritoneal membrane.2,5 This can occur in the setting of any perforated viscus, particularly ruptured appendix, perforated diverticulum, bleeding duodenal ulcer, or Crohn’s disease with fistula formation. As the integrity of the intestinal epithelial barrier is obliterated, bacteria gain access to the previously accumulated ascitic fluid, resulting in an acute immune response. This leads to the findings of bacteria and elevated neutrophil count in the ascitic fluid.2 Therefore, the inflammation of the peritoneum is secondary to another intra-abdominal process. This form of peritonitis is exceedingly rare, reportedly less than 1% of all cases of peritonitis.2 Presumably, this is due to the requirement for an acute abdominal pathology superimposed on chronic liver disease with ascites. SBP results from infection of a previously sterile ascitic fluid without an easily identifiable intra-abdominal source of infection.2 Thus, SBP is a diagnosis of exclusion when criteria for secondary BP are not met. It is important to note that SBP results in the absence of obvious infection, inflammation, and perforation (hence the name “spontaneous”). The pathophysiology of SBP includes alterations in intestinal epithelial barrier function that allow normal GI bacteria to gain access to the ascitic fluid without a direct connection from the GI lumen to the peritoneal cavity.2 In other words, the intestinal barrier is intact but chronically “leaky” in patients with SBP. Factors that contribute to this “leakiness” are discussed in depth in Section 5. Note that at this stage, it is impossible to determine the etiology of the infection in this patient without further studies. Bottom line: Secondary BP indicates complete perforation of GI epithelium in the setting of major inflammation or infection within the GI tract. On the other hand, SBP is associated with a “leaky” epithelium that allows normal flora to enter the peritoneal space. 4. Does the evidence suggest that there is any benefit to performing imaging studies in this patient? Before the diagnosis of SBP can be made, a clinician must rule out a perforated visceral peritoneum. This may be done either clinically, if a low degree of suspicion exists for perforated viscus, or with the use of imaging if the clinician cannot comfortably rule out perforation based on the patient’s clinical presentation.6 Although not terribly sensitive, the most specific test for perforation is the simple x-ray. Abdominal x-rays must be obtained in two views, upright and left lateral decubitus positions, to allow for visualization of free air in the abdomen. Dark pockets under the diaphragm in the upright view that shift to the right side of the abdomen when in the left lateral decubitus position suggests the presence of free air. This is diagnostic for perforation of the GI tract, a surgical emergency.5 If free air is seen on x-ray, the patient should be rushed to the operating room. A computed tomography (CT) scan or magnetic resonance imaging (MRI) without contrast are more sensitive tests than the abdominal x-ray and avoid the potential for contrast-induced renal injury.6 An abdominal CT or MRI with contrast would better visualize soft tissue inflammation, but it is dangerous considering the suspicion of perforation. Contrast itself can induce peritonitis if a perforation is present.2 Bottom line: If an abdominal CT without contrast can be quickly obtained, this test should be considered first due to its high sensitivity. If unavailable, abdominal x-rays with the patient upright and in left lateral decubitus can quickly rule in or out a more significant perforation. CASE CONTINUED The laboratory calls up to the floor while the patient is in radiology. Peritoneal aspirate is found to contain 432 neutrophils/dL, albumin concentration is found to be 0.8 g/dL, and a serum ascites albumin gradient is 1.4 g/dL. Ascitic fluid and blood culture results are still pending. 5. How do the characteristics of the ascitic fluid aid in diagnosis of bacterial peritonitis? A neutrophil count more than 250/dL is a diagnostic of SBP.1,2 The overwhelming majority of patients with SBP also have ascitic fluid albumin concentrations less than 1.0 g/dL as well as SAAG greater than 1.1 g/dL.1 On the other hand, the paracentesis of secondary BP classically demonstrates the following characteristics: neutrophils more than 50/dL, ascitic albumin more than 1.0 g/dL often more than 3.0 g/dL, glucose less than 50 mg/dL, and ascitic fluid lactate dehydrogenase 3 times more than serum lactate dehydrogenase.1 This patient gained 5 kg within 7 days before becoming febrile. This makes it likely that the ascitic fluid began to accumulate before admission. The characteristics of his peritoneal fluid satisfy the diagnostic criterion of more than 250 neutrophils/dL as well as the supporting criteria of ascitic fluid albumin less than 1.0 g/dL and SAAG more than 1.1 g/dL. Bottom line: Neutrophil count more than 250/dL is diagnostic of SBP in a patient with fever in the setting of chronic ascites without an identifiable source of intra-abdominal infection.1 CASE CONTINUED After 30 minutes, the abdominal CT scan has been read as negative by the on- call radiologist. You check the images yourself and agree that there is no evidence for perforation. Considering the results of the ascitic fluid analysis and the negative abdominal CT, you feel comfortable in diagnosing the patient with SBP. 6. What is the likely etiology of SBP in this patient? The major factor in the development of SBP is translocation of endogenous intestinal flora across an increasingly permeable intestinal wall to the mesenteric lymph nodes and blood stream.2,4,7 Portal hypertension, a common consequence of cirrhosis and vascular fibrosis, leads to edema, vascular congestion, widened intracellular spaces, and inflammation, all of which serve to collectively increase intestinal membrane permeability. With increased permeability, bacterial can traffic across from the intestinal lumen to the lymphatics more easily.2 In this patient, two additional sources of infection are possible: the urinary catheter and intravenous (IV) line. In any hospitalized patient who develops a fever, the possibility of nosocomial infection must be considered. This is important because nosocomial infections in cirrhotic patients typically result from gram-positive organisms (especially Staphylococcus aureus) and carry a significantly worse prognosis than in noncirrhotic patients.7 Between 5% and 7% of noncirrhotic patients will develop a nosocomial infection during a hospital stay, with a mortality of approximately 7%.2,7 In contrast, 33% of cirrhotic patients will develop a nosocomial infection while in the hospital, with a mortality rate of 15% and a sepsis rate of 70%.2,7 Bottom line: Cirrhotic patients are at a high risk for gram-positive nosocomial infections, which may result in the development of SBP. CASE CONTINUED The next morning, the culture results are back from the laboratory. The ascitic fluid grew Escherichia coli. Blood cultures demonstrated no growth. 7. What are the typical causative organisms of SBP? Gram-negative organisms, mainly E. coli and Klebsiella spp, are the typical causative organisms for SBP in 60% of cases.2 SBP caused by Streptococcus and Staphlycoccus occurs approximately 25% of the time and can include methicillin-resistant S. aureus.2,7 These gram-positive species are often implicated in cases of acquired bacteremia from infected catheters or IV lines. Bottom line: The most likely causative agents in patients with SBP are aerobic, gram-negative, endogenous, GI flora. 8. What antibiotic regimen does the evidence suggest for treatment of SBP? Current treatment guidelines for SBP call for the use of a thirdgeneration cephalosporin, particularly cefotaxime or ceftazidime, at a dose of 2.0 g every 8 hours (q8h) for 5 days.6,8 This regimen has been shown to be equally or more effective than combination ampicillin and aminoglycoside therapy, and it is often cheaper with fewer side effects.6 Duration of treatment is typically 5 days, after which the cephalosporin may be stopped completely.8 9. How does the evidence suggest intravenous albumin be administered to patients with SBP? Although it was initially believed that IV albumin should be reserved for patients undergoing large volume (>5 L) paracentesis or at high risk of death, beneficial effects of IV albumin have been shown in all patients with SBP. The administration of IV albumin is supported to reduce the incidence of renal impairment and has been shown to improve hospital survival compared with antibiotic treatment alone.9 The current treatment guideline suggested by the American Association of the Study of Liver Disease calls for administration of 1.5 g/kg albumin IV on day 1 within 6 hours of diagnosis and 1.0 g/kg on day 3 for all patients with SBP, regardless of the amount of fluid removed by paracentesis.6 Bottom line: A third-generation cephalosporin and IV albumin should be administered to patients with SBP. CASE CONTINUED You select cefotaxime because it is on the hospital formulary and begin IV albumin according to the current treatment guidelines. Thankfully, after 5 days, the patient significantly improved. 10. According to the evidence, how might this patient’s prognosis be determined? The important predictors of resolution of SBP and survival include young age, absence of acidemia and renal impairment during the course of the illness, peak serum bilirubin levels of 5 mg or less, and community rather than hospital- acquired infection.10 On average, the 1-year survival rate post-SBP is only 40%.10 The presence or absence of renal failure independently predicts mortality in these patients, with those patients in renal failure at twice the risk of death in the acute period than those without renal failure.9,10 11. Is primary prophylaxis available for high-risk patients? High-risk patients can be identified by the presence of ascitic fluid protein concentration less than 10 g/L and bilirubin levels more than 3 mg/dL.10 Although no specific recommendations for primary prophylaxis exist for these patients,6 1 study examined the effect of norfloxacin 400 mg daily for 12 months in patients with either less than 15 g/L ascites protein concentration and advanced liver failure (Child Pugh >9 and serum bilirubin >3 mg/dL) or renal dysfunction (serum creatinine >1.2 mg/dL and blood urea nitrogen >25 mg/dL or serum sodium <130 mmol/L).11 Results demonstrated that primary prophylaxis with norfloxacin 400 mg daily reduced the 1-year probability of SBP from 61% to 7%. The incidence of hepatorenal syndrome was also reduced from 41% to 28%. Three-month survival was improved from 62% to 94%. Unfortunately, 1- year survival rates were not significantly changed.11 Bottom line: Norfloxacin 400 mg daily as primary prophylaxis seems to reduce the rates of initial SBP infection and hepatorenal syndrome, and it significantly improves 3-month survival rates in high-risk patients. TAKE-HOME POINTS: SPONTANEOUS BACTERIAL PERITONITIS 1. With rare exceptions, patients with fever and ascites should undergo a diagnostic paracentesis. 2. Ascitic fluid demonstrating more than 250 neutrophils/dL is a diagnostic of SBP. Albumin less than 1.0 g/dL and SAAG more than 1.1 g/dL also suggest SBP. 3. The most likely causative organisms in SBP are E. coli and Klebsiella. Gram- positive etiology occurs 25% of the time and is typically due to nosocomial infection. 4. If GI perforation is suspected, CT of the abdomen is the most sensitive imaging modality. Abdominal plain films are specific but not as sensitive. 5. SBP should be treated with a third-generation cephalosporin. In addition, IV albumin should be administered to prevent renal morbidity and overall mortality. REFERENCES 1. Wong, C., J. Holroyd, K. Thorpe, S. Straus. 2008. “Does This Patient Have Bacterial Peritonitis or Portal Hypertension? How Do I Perform a Paracentesis and Analyze the Results?” JAMA 299: 1166–78. 2. Bernardi, M. 2010. “SBP: From Pathophysiology to Prevention.” Internal and Emergency Medicine 5 (Suppl 1): S37–S44. 3. Chinnock, B., and G. W. Hendey. 2007. “Can Clear Ascitic Fluid Appearance Rule Out SBP?” The American Journal of Emergency Medicine 25: 934–37. 4. Ho, H., M. J. Zuckerman, T. K. Ho, L. G. Guerra, A. Verghese, P. R. Casner. 1996. “Prevalence of Associated Infections in CommunityAcquired SBP.” American Journal of Gastroenterology 91(4): 735. 5. O’Mara, S. R., K. Gebreyes. 2011. “Hepatic Disorders, Jaundice, and Hepatic Failure.” In Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, edited by Tintinalli, J. E., J. S. Stapczynski, D. M. Cline, O. J. Ma, R. K. Cydulka, G. D. Meckler. Chapter 83, 7th ed. New York: McGrawHill. http://www.accessmedicine.com/content.aspx?aID=6361074. 6. Runyon, B. A.; Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD). 2004. “Management of Adult Patients With Ascites Due To Cirrhosis.” Hepatology 39: 841–56. 7. Campillo, B., J. Richardet, T. Kheo, C. Dupeyron. 2002. “Nosocomial SBP and Bacteremia in Cirrhotic Patients: Impact of Isolate Type on Prognosis and Characteristics of Infection.” Clinical Infectious Disease 35: 1–10. 8. Soares-Weiser, K., M. Brezis, L. Leibovici. 2007. “Antibiotics for SBP in Cirrhotics (Cochrane Review).” In The Cochrane Library. Issue 1. Chichester, UK: John Wiley and Sons Ltd. 9. Sort, P., M. Navasa, V. Arroyo, X. Aldeguer, R. Planas, L. Ruiz-del-arbol, L. Castells, et al. 1999. “Effect of Intravenous Albumin on Renal Impairment and Mortality in Patients With Cirrhosis and SBP.” New England Journal of Medicine 341: 403–9. 10. Thuluvath, P. J., S. Morss, R. Thompson. 2001. “SBP—In-Hospital Mortality, Predictors of Survival, and Health Care Costs From 1988 to 1998.” American Journal of Gastroenterology 96: 1232–36. 11. Fernández, J., M. Navasa, R. Planas, S. Montoliu, D. Monfort, G. Soriano, C. Vila, et al. 2007. “Primary Prophylaxis of SBP Delays Hepatorenal Syndrome and Improves Survival in Cirrhosis.” Gastroenterology 133: 818–24.

Transient Ischemic CHAPTER Attack 8 JORDAN SHERWOOD CASE A 65-year-old female smoker with a history of type 2 diabetes mellitus and poorly controlled hypertension is brought to the emergency department (ED) by her daughter for evaluation of a 1-hour history of slurred speech. The patient denies a history of falls, head trauma, seizures, or headache. Review of system is positive for an episode of painless vision loss in her right eye several weeks ago, which resolved on its own within an hour. On arrival to the emergency room, her vital signs are as follows: temperature (T): 98.1°F, blood pressure (BP): 138/88 mm Hg, heart rate (HR): 78, and respiratory rate (RR): 18. She is alert and oriented to person, place, and time. She has a right-sided carotid bruit. Her speech is slurred but her fluency, comprehension, and naming abilities are intact. Cranial nerves II–XII are grossly intact. Strength is 4/5 in her left upper extremity but 5/5 in all other muscle groups. Deep tendon reflexes are +1 in the left arm and +2 elsewhere. The remainder of the neurological examination, noncontrast computer tomography (CT) of the head, laboratory workup, and electrocardiogram (ECG) are unrevealing. When you return to the room to discuss your treatment plan with the family, 40 minutes after the patient presented to the ED, the patient is no longer slurring her words and her neurological examination has normalized. 1. What is the likely diagnosis in this patient and why? This patient is a 65-year-old female smoker with diabetes and hypertension with an acute onset of dysarthria, left upper extremity weakness on exam, and a recent episode of monocular vision loss that resolved on its own. The differential diagnosis for acute transient focal neurological deficit includes transient ischemic attack (TIA), cerebrovascular accident (CVA, “stroke”), seizure, migraine, cerebral 71 hemorrhage, and brain mass. However, given her cardiovascular risk factors (diabetes, smoking, and hypertension) and evidence of atherosclerotic macrovascular disease (carotid bruit on examination), this patient has likely experienced a TIA. Often referred to as a “ministroke,” a TIA is defined as a transient episode of neurologic deficit caused by focal brain, spinal cord, or retinal ischemia without acute infarction.1 In the past, TIAs were solely defined as neurological deficits lasting less than 24 hours. However, diffusion-weighted magnetic resonance imaging (MRI) studies have demonstrated that many ischemic episodes with symptoms lasting less than 24 hours are associated with tissue infarction,1 and so the definition of TIA now excludes acute infarct. While TIAs and strokes have similar symptoms, TIA symptoms typically resolve within the first few hours of onset, whereas symptoms from stroke often persist for much longer. A large majority of studies have demonstrated that classically defined TIAs last less than 1 hour in duration. A pooled analysis of MRI-based studies demonstrated that 60% of TIAs lasted less than 1 hour, 71% lasted less than 2 hours, and 14% lasted more than 6 hours.2 Symptoms of TIA are numerous and are related to the vascular territory of the brain that is affected. Symptoms may include amaurosis fugax (temporary, partial, or complete monocular loss of sight caused by retinal artery ischemia), aphasia, dysarthria, hemianesthesia (loss of sensation on one side of body), hemiparesis (loss of strength on one side of body), and vertigo. Of note, neither TIAs nor CVAs generally cause altered mental status or headache. Bottom line: TIAs are brief episodes of neurological deficits typically lasting less than 2 hours that resolve without radiographic evidence of cerebral infarction. Symptoms of TIA can include amaurosis fugax, dysarthria, aphasia, hemiparesis, hemianesthesia, and vertigo but will not normally cause confusion or headache. 2. What is the likely etiology of this patient’s TIA and what other etiologies need to be considered in all patients? There are many possible etiologies of TIA. The most common cause is a thromboembolic source from either cardiac origin (e.g., atrial fibrillation), extracranial neurovascular origin (e.g., carotid artery stenosis), or intracranial origin (small vessel atherosclerosis). Approximately 20%– 30% of cerebral infarctions (not TIAs) result from cardiac emboli.3 Possible cardiac embolic sources include myocardial infarction (left ventricular wall hypokinesis), cardiomyopathy, and arrhythmias such as atrial fibrillation (stasis of blood in left atrium). Valvular sources include rheumatic heart disease of the mitral valve, bacterial endocarditis, or severe mitral valve prolapse. Carotid atherosclerosis is responsible for an estimated 10% of ischemic stroke cases.3 This patient likely has carotid artery stenosis as evidenced by her carotid bruit and history of amaurosis fugax. Note that patients may present with carotid disease without evidence of carotid bruit, as the presence of a carotid bruit has only a 20%–30% sensitivity for diagnosing carotid artery stenosis. Less common causes of TIA include hypercoagulable states such as protein C or S deficiency, homocysteinemia, systemic lupus erythematosus (antiphospholipid antibody), or malignancy. Vasculitides such as temporal arteritis, cerebral vasculitis, and polyarteritis nodosa are rare causes of TIA. In addition, specific drugs (e.g., amphetamines, cocaine, and sympathomimetic agents) may also cause TIA secondary to vasospasm.3 Bottom line: The most common etiologies of TIA include thromboemboli, carotid artery stenosis, and intracranial small vessel atherosclerosis. Much less common causes of TIA include hypercoagulable states, vasculitides (rare), and drugs of abuse such as cocaine. 3. Does the evidence suggest that brain imaging studies should be ordered for this patient? Yes. The 2009 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend patients with suspected TIA undergo imaging within 24 hours of symptom onset.1 The goals of neuroimaging in the evaluation of TIA are to obtain evidence of a vascular origin (acute infarct/hypoperfusion), to exclude a nonischemic origin, and to help determine underlying mechanism of the event (e.g., large-vessel atherothrombotic, small- vessel/lacunar, and cardioembolic), which helps guide therapy. MRI with diffusion-weighted imaging (DWI) is the preferred imaging modality.1 If MRI is unavailable, computer tomography (CT) with contrast is a reasonable alternative.1 MRI is superior to CT in the very early stages of acute infarction.1 Approximately 90% of patients with ischemic stroke will show MRI changes within 24 hours.4 Pooled data from 19 studies show that DWI provides a more precise evaluation of ischemic insult in TIA patients compared with standard CT and MRI.1 Unfortunately, the use of MRI is associated with several drawbacks including high cost and limited availability. As a result, contrast head CT is considered to be a good alternative to MRI. For diagnosis of acute intracranial hemorrhage, MRI had a sensitivity of 81% and a specificity of 100% (98%–100%), whereas noncontrast CT has a sensitivity and specificity of 89% and 100%, respectively.5 Bottom line: All patients suspected of having a TIA should undergo imaging of the brain. Although diffusion weighted MRI is ideal, a noncontrast CT performed early can effectively rule out an intracranial bleed whereas a contrast CT performed the next day can effectively detect an acute infarct. 4. What extracranial neurovascular imaging does the evidence suggest should be performed in this patient? Evaluation of large vessel disease obstruction is indicated in the event of a TIA to determine cause and management. For example, if thromboembolism from critical carotid artery stenosis is felt to be the cause, carotid endarterctomy or percutaneous intervention may be indicated.6 The 2009 ASA guidelines recommend noninvasive imaging of cervicocephalic vessels in patients with TIA.1 Noninvasive neurovascular imaging of the carotid arteries including carotid doppler (ultrasound), magnetic resonance angiography (MRA), and CT angiography (CTA) is recommended to determine whether there is carotid obstruction. CTA and MRAs of the head are also reliable in showing intracranial stenosis. Ultrasonography, CTA, and MRA each have their own benefits. Carotid ultrasonography is inexpensive and fairly sensitive and specific (88% and 76%, respectively), although its results are highly operator dependent.7 CTA is a noninvasive procedure to evaluate either extracranial or intracranial cerebral circulation. The sensitivity and specificity ranges for the detection of critical internal carotid artery stenosis (>70%) by CTA are 74%–100% and 83%–100%, respectively, with the comparative gold standard being MRA. Sensitivity for detecting complete carotid artery occlusion is 100%.8 However, conditions that would not allow the use of contrast dye, such as renal failure and allergy to contrast dye, may limit this technique. MRA has a sensitivity of 83%–95% and a specificity of 89%–94% for detection of extracranial ICA stenosis greater than 70%. The sensitivities and specificities are similar for detection of stenosis greater than 50%. For complete occlusion, the sensitivity and specificity are 98% and 100%, respectively. Limitations of MRA are its cost and availability. The procedure is contraindicated in patients with certain implantable metal devices such as pacemakers and implantable cardiac defibrillators. Bottom line: Extracranial neurovascular imaging studies such as carotid artery ultrasound are indicated in the workup in patients with TIA as the results may alter acute management. 5. Does the evidence suggest that cardiac evaluation should be performed in the diagnostic workup of suspected TIA? Yes. The 2009 AHA stroke guidelines state that cardiac evaluation should include at minimum an electrocardiogram (ECG) to evaluate for atrial fibrillation, as atrial fibrillation is one of the most common embolic sources of TIA.1 Telemetry and/or Holter monitoring may also be used to evaluate for the possibility of paroxysmal atrial fibrillation, if this is suspected. For example, in one study, 7-day ambulatory Holter monitoring was able to detect 22% of atrial fibrillation cases that were not found on initial ECG on patients who were admitted with TIA or stroke. Echocardiogram is recommended in cases where a cardiac thromboembolic source is suspected.1 Transesophageal echocardiogram (TEE) has advantages over transthoracic echocardiogram that it is the best way to detect interatrial septum defects that are associated with thromboembolism such as atrial septal defect (ASD), patent foramen ovale (PFO), and interatrial septal aneurysm. TEE is also better in detecting left ventricular thrombi and in visualizing the left atrium, which is the main site of thrombus formation.10 However, in practice, for various reasons transthoracic rather than transesophageal echocardiograms are typically performed. The 2009 AHA/ASA guidelines state that an echocardiogram should be performed if no other embolic source is identified by other aspects of the work up.1 Bottom line: ECG is indicated in all patients with TIA. Echocardiogram is recommended in cases where a cardiac thromboembolic source is suspected. 6. How does one risk stratify TIA patients with respect to their likelihood of stroke in the near future? By calculating the ABCD2 score, a risk assessment tool is designed to calculate the short-term stroke risk following TIA. The ABCD2 score is calculated by summing up points for the following 5 independent factors: age >60 years, presence of hypertension, clinical symptomatology, duration of symptoms, and presence of diabetes (Table 8.1). The score estimates the risk of stroke within 2 days, 7 days, and 90 days of a TIA (Table 8.2). This patient has an ABCD2 score of 6. She scores 1 point for her age of more than 60, 2 points for unilateral weakness, 2 points for symptoms lasting more than 60 minutes, and 1 point for diabetes. Thus, this patient is at high risk for stroke in the near future. TABLE 8.1 Components of the ABCD2 Score Risk factor Points Age ≥60 (yr) 1 Blood pressure systolic ≥140 mm Hg or diastolic ≥90 1 Clinical features Unilateral weakness with or without speech impairment 2 Speech impairment without unilateral weakness 1 Duration TIA 60 min 2 TIA 10–59 min 1 Diabetes 1 Total ABCD2 score 0–7 Abbreviations: TIA, transient ischemic attack. TABLE 8.2 ABCD2 Score for Risk Stratification for Stroke ABCD2 score Risk of stroke (%) 2 d 7 d 90 d 0–3 (Low risk) 1.0 1.2 3.1 4–5 (Intermediate 4.1 5.9 9.8 risk) 6–7 (High risk) 8.1 11.7 17.8 Bottom line: ABCD2 can be used to risk stratify patient’s risk of stroke following TIA. 7. Does the evidence support hospitalizing this patient? Yes, because her 2-day risk for stroke is unacceptably high at approximately 8%. The 2009 AHA and ASA guidelines state that it is reasonable to hospitalize any patient presenting within 72 hours of symptom onset and who meets one of following criteria: ABCD2 score ≥3, ABCD2 score 0–2 and uncertainty workup can be completed within 2 days, and ABCD2 score 0–2 and other evidence that the event was caused by ischemia. Additionally, the National Stroke Association recommends hospitalization for patients presenting within the first 48 hours of symptoms with the following conditions: crescendo TIAs (defined as either 2 TIAs within 24 hours, 3 TIAs within 3 days, or 4 TIAs within 2 weeks), duration of symptoms greater than 1 hour, symptomatic carotid stenosis (patients with carotid stenosis who experience TIA or transient retinal ischemia), known cardiac source of emboli, or hypercoagulable state. Patients who are not hospitalized should have access to complete studies as an outpatient within 48 hours.11 Bottom line: TIA patients with high risk for stroke in the near future as based on prediction models such as the ABCD2 score should be admitted to the hospital and undergo an appropriate inpatient diagnostic evaluation. 8. Based on the evidence, what medication(s) would be indicated in this patient? How effective are they? According to the ASA guidelines, antiplatelet therapy is recommended for prevention of recurrent TIA or stroke in this patient.11 There have been many studies regarding the ideal antiplatelet therapy for stroke prevention (e.g., aspirin, clopidogrel, dipyridamole, or combination of these). The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial found that clopidogrel was marginally more effective than aspirin in reducing the risk of stroke.12 The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial examined the use of aspirin versus combination aspirin and clopidogrel. This study found no benefit of clopidogrel combined with aspirin compared with aspirin alone.13 The Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH) study compared combined clopidogrel and aspirin use to clopidogrel use alone in the secondary prevention of TIA or stroke. The MATCH trial found no difference in TIA or stroke prevention with this combination, but did show a small but significant increase in major bleeding complications with combination therapy.14 Due to the risk of bleeding, use of clopidogrel in combination with aspirin is not recommended for stroke prevention. Aspirin therapy is recommended for patients with previous TIA. Clopidogrel monotherapy may also be used for secondary prevention of stroke. It is important to note that the studies did not look at the benefits of the combination of clopidogrel and aspirin in the acute setting after a TIA. Further research is being conducted to determine whether combination therapy is beneficial for the acute period following a TIA. Additional studies have examined the use of combination aspirin and dipyridamole. The European Stroke Prevention Study (ESPS-2) and Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) were the 2 major studies that examined dipyridamole against aspirin against dipyridamole with aspirin showed an efficacy of both aspirin and extended-release dipyridamole in preventing stroke. When the 2 were combined, there was a significantly better risk reduction compared when used individually. Efficacy measurements in ESPS-2 found that stroke relative risk reductions were 18% for Aspirin monotherapy, 16% for dipyridamole monotherapy, and 37% for combination ASA plus dipyridamole, respectively. In ESPRIT, patients who received ASA + dipyridamole had a 20% relative risk reduction versus ASA monotherapy. ESPRIT found that combination treatment was not associated with a higher complication rate than ASA monotherapy, but that the rate of withdrawal due to adverse events (headache as side effect from dipyridamole) was higher in the group that received the combination.15 Combination of aspirin and dipyridamole is more effective than aspirin alone at reducing vascular events (Table 8.3). Bottom line: This patient will require antiplatelet therapy that may include aspirin, clopidogrel, or a combination of aspirin and dipyridamole (Aggrenox). Due to the findings from the MATCH trial, the combination of clopidogrel and aspirin is not recommended. 9. What risk factor modifications does the evidence suggest should be undertaken to minimize the risk for future TIA or stroke? Patients with a history of TIA should be treated for comorbid conditions to prevent recurrent ischemic cerebrovascular events. Treatment for hyperlidemia, hypertension, control of diabetes, smoking cessation, and diet and lifestyle modification is indicated in this patient as discussed below. Hyperlidemia : The AHA recommends a Step II diet (30% of calories derived from fat, 7% from saturated fat, and 200 mg/d cholesterol consumed) along with maintenance of ideal body weight and engagement in regular physical activity. The goal of the therapy should be an LDL level less than 100 mg/dL.11 Treatment with a statin is recommended for patients after atherothromboembolic TIA. Several studies have shown that statins reduce the risk of stroke even in patients without increased LDL or low HDL.3 The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial was a randomized control of high-dose atorvastatin (80 mg) versus placebo in patients with normal low-density lipoprotein (LDL) levels 100–190 mg/dL in patients with recent TIA or stroke.16 The trial showed an 18% relative risk reduction for secondary stroke in patients treated with atorvastatin.16 In the primary prevention JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial, it was found that patients with low LDL (<130 mg/dL) caused by increased C-reactive protein benefitted by the daily use of this statin. Primary stroke occurrence was reduced by 51%.3 Statin is recommended for patients who have had a TIA even if the patient had normal cholesterol or no known coronary artery disease (Table 8.4). Hypertension : People presenting after a TIA should start blood pressure lowering medication unless the person has symptomatic hypotension. Treatment should start concurrently with intensive lifestyle changes. It is usually advisable to wait 7–14 days before starting blood pressure lowering medication.3 Lowering blood pressure can lead to a reduction in stroke risk. In a pooled analysis that compared 17 trials, the effects of β-blocker and diuretic with a placebo or no treatment were determined; in 6 trials, the comparison drug was angiotensin- converting enzyme (ACE) inhibitors, and in 2 trials, it was calcium antagonists. In total, there were over 73,500 patients. There was clear evidence of a reduction in stroke risk with BP lowering with each drug versus placebo comparison, with pooled relative risk reductions for β-blocker and diuretic, ACE inhibitors, and calcium antagonists of 35%, 28%, and 39%, respectively.17 An absolute target BP level and reduction are uncertain, but benefit has been associated with an average reduction of approximately 10/5 mm Hg.3 Diabetes : Oral hypoglycemics or insulin should be prescribed as needed to control diabetes for long-term secondary prevention of stroke.11 Diabetes is a well-defined risk factor for stroke; however, no trial sufficiently powered to detect a significant reduction in stroke after has yet been performed.3 Bottom line: Smoking cessation, hyperlidemia, hypertension, and diabetes should be aggressively controlled following TIA or stroke. A statin should be initiated for secondary prevention of stroke or TIA regardless of whether the patient has increased LDL levels. Antihypertensive medication is also indicated for patients with hypertension post TIA. 10. Does evidence suggest that this patient will benefit from surgery or carotid artery revascularization? Yes. As mentioned above, this patient presents with symptomatic carotid artery stenosis. Carotid endarterectomy has been found to be beneficial in prevention of future stroke in patients with symptomatic carotid stenosis.6 Symptomatic carotid artery stenosis was studied in the North American Symptomatic Carotid Endarterectomy Trial (NASCET).6 This study showed reduction in stroke incidence for surgery in patients who had 70%–99% carotid artery stenosis. In NASCET, the average stroke risk at 2 years was 26% for patients who were medically managed (statin, antiplatelet, and antihypertensive) compared with 9% for those receiving the same medical treatment plus a carotid endarterectomy.6 Carotid surgery may be indicated for certain patients with a history of carotid territory TIA and stenosis of 50%–69%. This is valid only for centers with a perioperative complication rate (all strokes and death) of less than 6%. Carotid endarterectomy is not recommended for patients with carotid stenosis less than 50% (Table 8.5).11 Bottom line: CEE is indicated within 2–4 weeks of TIA or retinal ischemia due to high-grade internal carotid artery stenosis of 70%–99%. CEE is recommended for patients with 50%–69% stenosis at centers with perioperative complication rate less than 6%. No surgery is indicated for stenosis less than 50%. TAKE-HOME POINTS: TRANSIENT ISCHEMIC ATTACK 1. TIAs are brief episodes of neurological dysfunction typically lasting less than 2 hours that resolve without radiographic evidence of infarction. 2. Symptoms of TIA may include dysarthria, aphasia, hemiparesis, and hemianesthesia and may rarely include amaurosis fugax and vertigo. Headache and confusion are not typically seen with TIA. 3. Patients with suspected TIA should receive early imaging with a noncontrast CT of the head to rule out an intracranial bleed or mass. While DWI MRI is the preferred modality for detecting acute cerebral ischemia, a contrast CT performed 24 hours after symptom onset is a reasonable alternative. 4. Neurovascular studies such as CTA, MRA, or carotid ultrasound should be considered in the diagnostic workup of TIA. 5. All patients with suspected TIA should undergo an ECG ± cardiac monitoring (inpatient) or Holter monitoring (outpatient) to evaluate for the possibility of atrial fibrillation as an underlying etiology, as studies suggest this is the cause in approximately 15% of patients. 6. A transthoracic or transesophageal echocardiogram should be considered if an intracardiac thromboembolic source is suspected. 7. The ABCD2 score can be calculated to determine near-term risk of stroke. Patients with ABCD2 scores ≥3 should be hospitalized. 8. Treatment options for patients who have suffered a TIA include aspirin (50– 325 mg) or aspirin plus dipyridamole (200 mg BID). Clopidogrel (75 mg) can be given instead of aspirin. A statin should be started for secondary prevention of TIA/ stroke in all patients who have had a TIA. 9. CEE is indicated for patients with symptomatic carotid stenosis of 70% or more. REFERENCES 1. Easton J. D, Saver J. L, Albers G. W, Alberts M. J, Chaturvedi S, Feldmann E, Hatsukami T. S et al. 2009. “Definition and Evaluation of Transient Ischemic Attack: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease.” Stroke 40: 2276–93. 2. Shah S. H, Saver J. L, Kidwell C. S, Albers G. W, Rothwell P. M, Ay H, Koroshetz W. J et al. 2007. “A Multicenter Pooled, Patient-Level Data Analysis of Diffusion-Weighted MRI in TIA Patients.” Stroke 38: 463. 3. Smith, W. S., J. D. English, and S. C. Johnston. 2012. “Cerebrovascular Diseases.” In Harrison’s Principles of Internal Medicine, 18th ed., edited by D. L. Longo, A. S. Fauci, D. L. Kasper, S. L. Hauser, J. L. Jameson, J. Loscalzo, Chapter 370. New York: McGraw-Hill. http://www.accessmedicine.com/content.aspx?aID=9145753. 4. Culebras A, Kase C. S, Masdeu J. C, Fox A.J, Bryan R. N, Grossman C. B, Lee D. H, Adams H. P, Thies W. 1997. “Practice Guidelines for the Use of Imaging in Transient Ischemic Attacks and Acute Stroke. A Report of the Stroke Council, American Heart Association.” Stroke 28: 1480–97. 5. Chalela J.A, Kidwell C.S, Nentwich L.M, Luby M, Butman J.A, Demchuk A.M, Hill M.D et al. 2007. “Magnetic Resonance Imaging And Computed Tomography in Emergency Assessment of Patients with Suspected Acute Stroke: A Prospective Comparison.” Lancet 369 (9558): 293–8. 6. North American Symptomatic Carotid Endarterectomy Trial Collaborators. 1991. Beneficial Effect of Carotid Endarterectomy in Symptomatic Patients With High-Grade Stenosis. New England Journal of Medicine 325: 445–53. 7. Buskens E, Nederkoorn P. J, Buijs-Van Der Woude T, Mali W. P, Kappelle L. J, Eikelboom B. C, Van Der Graaf Y, Hunink M. G. 2004. “Imaging of Carotid Arteries in Symptomatic Patients: Cost-Effectiveness of Diagnostic Strategies.” Radiology 233: 101–12, 136. 8. Flemming K. D, Brown R. D Jr, Petty G. W, Huston J 3rd, Kallmes D. F, Piepgras D. G. 2004. “Evaluation and Management of Transient Ischemic Attack and Minor Cerebral Infarction.” Mayo Clinic Proceedings 79: 1071. 9. Jabaudon D, Sztajzel J, Sievert K, Landis T, Sztajzel R. 2004. “Usefulness of Ambulatory 7-Day ECG Monitoring for the Detection of Atrial Fibrillation and Flutter After Acute Stroke and Transient Ischemic Attack.” Stroke 35 (7): 1647– 51. 10. Peterson, G. E., M. E. Brickner, and S. C. Reimold. 2003. “Transesophageal Echocardiography: Clinical Indications and Applications.” Circulation 107: 2398–402. 11. Johnston S. C, Nguyen-Huynh M. N, Schwarz M. E, Fuller K, Williams C. E, Josephson S. A, Hankey G. J et al. 2006. “National Stroke Association Guidelines for the Management of Transient Ischemic Attacks.” Annals of Neurology 60: 301. 12. Ferguson J. J 3rd, Gonzalez E. R, Kannel W. B, Olin J. W, Raps E. C. 1998. “Clinical Safety and Efficacy of Clopidogrel—Implications of the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Study for Future Management of Atherosclerotic Disease.” Clinical Therapeutics 20 (Suppl B): B42–53. 13. Hankey G. J, Hacke W, Easton J. D, Johnston S. C, Mas J. L, Brennan D. M, Bhatt D. L et al. 2010. “Effect of Clopidogrel on the Rate and Functional Severity of Stroke among High Vascular Risk Patients: A Prespecified Substudy of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Trial.” Stroke 41 (8): 1679–83. 14. Diener H. C, Bogousslavsky J, Brass L. M, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht H. J. 2004. Management of Atherothrombosis With Clopidogrel in High-Risk Patients With Recent Transient Ischaemic Attack or Ischaemic Stroke (MATCH): Study Design and Baseline Data. Cerebrovascular Diseases 17 (2–3): 253–61. 15. Chaturvedi, S. 2008. “Acetylsalicylic Acid + Extended-Release Dipyridamole Combination Therapy for Secondary Stroke Prevention.” Clinical Therapeutics 30 (7): 1196–205. 16. Poisson, S., and S. C. Johnston. 2011. “Prevention of Stroke Following Transient Ischemic Attack.” Current Atherosclerosis Reports 13 (4): 330–37. 17. Lawes, C. M., D. A. Bennett, V. L. Feigin, and A. Rodgers. 2004. “Blood Pressure and Stroke: An Overview of Published Reviews.” Stroke 35 (4): 1024.

CHAPTER Ischemic Stroke 9 N. ABIMBOLA SUNMONU, MD, PHD CASE A 68-year-old man is evaluated in the emergency department (ED) after he suddenly slumped from his seat while having lunch with his daughter. Emergency medical responders reported that he was unable to move the right side of his body and had trouble speaking, and his daughter stated that he did not lose consciousness. Medical history is significant for hypertension treated with hydrochlorothiazide, a recent diagnosis of mild hyperlipidemia controlled by diet and exercise, and atrial fibrillation for which he has been taking warfarin. His daughter reported that he had been particularly health-conscious for the past few weeks, eating more vegetables and fruits. A few days ago, he complained of being clumsier than usual, even accidentally dropping his coffee mug. Physical examination is significant for an expressive aphasia and right-sided hemiparesis and hemianesthesia. 1. What is the likely diagnosis and why? Given this man’s age, risk factors, and sudden focal neurologic symptoms he most likely had a cerebrovascular accident (CVA, “stroke”). Note that he has recently increased vitamin K consumption, which decreases warfarin efficacy (recall that warfarin is a vitamin K antagonist) and, therefore, increases the risk of a thromboembolic event from his atrial fibrillation. The differential diagnosis of sudden onset neurologic dysfunction includes ischemic stroke or transient ischemic attack (TIA), hemorrhagic stroke, and space-occupying lesions such as tumors, cerebral abscesses, and subdural hematomas.1 The acuity of neurologic deficits and associated symptoms may suggest other etiologies. For instance, additional symptoms like altered mental status (e.g., loss of consciousness or delirium) in this man would indicate either a more 87 global cerebral process like encephalitis or a metabolic derangement like hypoglycemia. Trauma can also cause stroke-like symptoms. Headaches and vomiting may be caused either by a migraine or by an increased intracranial pressure (ICP), such as with a mass lesion or hemorrhagic event. Papilledema can help to distinguish between a migraine headache and an increased ICP. However, even people without a history of migraines may develop a migraine that appears similar to a stroke. In fact, a type of migraine called acephalic migraine can develop in migraine-naïve individuals and it may present with prominent sensory and motor deficits. Diagnosis of this unusual migraine may rest on less rapid onset of sensory impairment, involvement of multiple vascular territories, presence of characteristic visual symptoms, and normal head imaging. Fever, neck stiffness, and leukocytosis with left shift suggest an infectious etiology. Pain is rarely a prominent feature of acute stroke. Despite the clues to other potential causes of neurologic dysfunction that any associated symptoms may provide, diagnosis of an acute CVA may still be difficult due to considerable overlap in symptoms with other neurologic conditions. For instance, cerebellar strokes can present with vertigo and vomiting, which may be confused with labyrinthitis. Tumors causing hemorrhage, seizure, or increased ICP can also mimic stroke. Therefore, a clinical evaluation based on a thorough history (and physical examination) should be complemented by imaging studies. Furthermore, the patient’s medical history and presence of risk factors for stroke (e.g., hypertension and dyslipidemia) must also be considered. In this case, the patient’s symptoms developed suddenly, and because there were witnesses, we know that he had neither altered mental status nor seizures. He also had a history notable for atrial fibrillation and a recent TIA. Together, these clues significantly narrow the differential. A useful mnemonic for the differential diagnosis of acute ischemic stroke is MEDICS2: Migraine Epilepsy (postictal) Dissection (aortic) Intoxication (drugs, alcohol); infection Contusion; trauma Sodium; electrolytes; glucose Bottom line: Sudden onset of focal neurologic deficits without associated symptoms such as confusion is highly suspicious for ischemic stroke, especially in an individual with risk factors for stroke. 2. How do you explain this man’s specific neurologic symptoms? The acuity of his symptoms suggested a CVA. His daughter, who witnessed the incident, verified that he had neither convulsions nor lost consciousness. Therefore, an epileptic seizure, drug-induced delirium, and encephalopathy are unlikely events, but mass lesions and cerebral hemorrhage should remain on the differential. Aphasia is a cortical deficit, most likely representing a left middle cerebral artery (MCA) infarct because language is usually lateralized to the left hemisphere in both right- and left-handed individuals. Language output is controlled by the posterior-inferior frontal gyrus (Broca’s area), which is supplied by the superior division of the MCA. Broca’s aphasia disrupts language expression, whereas comprehension remains relatively intact. Confinement of this particular patient’s paralysis to the right side of his body suggested that his lesion is in the left MCA. A stroke presents as a sudden onset of neurological dysfunction of vascular etiology. Often, the location of the infarct can be determined by relating the clinical deficits to the distribution of an artery. Furthermore, the patient appeared to have had a TIA the week before his stroke, which explains his clumsiness. A TIA is a focal neurologic deficit caused by brain, spinal cord, or retinal ischemia. Previously, the distinction between TIAs and CVAs was based on duration: sudden neurological symptoms lasting for less than 24 hours were considered as a TIA, whereas those lasting for more than 24 hours were defined as a CVA. Increasingly, current convention distinguishes between a TIA and stroke by radiological and not by clinical criteria. Thus, a neurologic event is defined as a stroke if there is any evidence of acute ischemia on brain imaging even if the symptoms gets resolved in a few hours. Conversely, the event is termed as a TIA if there is no evidence of a lesion on brain imaging. A TIA is an important predictor of ischemic stroke, and the preventive strategies aimed at reducing the risk of stroke are also effective for preventing TIAs.3 Bottom line: An acute ischemic stroke typically presents as a sudden onset of neurologic impairment and may be preceded by a TIA. 3. How does an ischemic stroke occur? An ischemic stroke, or cerebral infarction, results via thrombolic or embolic disease. Atherosclerotic disease can result in the formation of arterial thrombi in arteries supplying the brain, typically the extracerebral carotid artery or basilar artery, causing ischemia in the tissues supplied by these arteries distally. Emboli are pieces of atherosclerotic material that dislodge from a thrombus and are carried to the other sites. They typically lodge in the intracerebral arteries (particularly the MCA and its branches) from cardiac thrombi secondary to atrial fibrillation, myocardial infarcts, and valvular disease. Other emboli may come from carotid artery thrombi or paradoxical emboli, as can occur with a patent foramen ovale. When thromboembolic disease results in an acute occlusion of an intracranial vessel, the ischemia results in neuronal death. Immediately adjacent to the initial infarcted core of cell death is a region called the penumbra. The penumbra is composed of ischemic cells, whose function may be restored if reperfusion is achieved in a timely manner. Thus, these neurons may be salvaged. Bottom line: Ischemic stroke is the result of arterial occlusion, thereby leading to ischemia and cellular necrosis in a specific vascular distribution. The resulting neurologic impairments reflect the distribution of the affected artery. 4. What are the risk factors for stroke? Hypertension, diabetes, dyslipidemia, smoking, advanced age, atrial fibrillation, physical inactivity, and metabolic syndrome increase the risk of stroke. Other etiologies include patent foramen ovale that allows an embolus of venous origin to gain access to the systemic arterial circulation, hypercoagulable states such as hyperhomocysteinemia, sickle cell disease, antiphospholipid syndrome, pregnancy,4–6 and usage of exogenous hormones such as oral contraceptives and hormone replacement therapy.7,8 Additionally, the history of a previous stroke is a strong risk factor for future recurrence.3 In fact, about a quarter of the nearly 800,000 strokes occur in the United States each year in the people who have suffered a previous stroke.3 In the assessment of a patient with ischemic stroke, it is important to differentiate between hemorrhagic and ischemic events. In addition, it is important to identify the risk factors and precipitants such as carotid artery stenosis and atrial fibrillation, which can be treated to prevent future strokes (secondary prevention). Bottom line: Risk factors for ischemic stroke include medical conditions (e.g., hypertension, dyslipidemia, atrial fibrillation) and lifestyle factors (e.g., smoking) that predispose to atherosclerotic disease, vasculopathy, and thromboembolism. 5. What does the evidence suggest should be the diagnostic workup for suspected ischemic stroke? On arrival in the hospital, the patient should be medically stabilized and then evaluated with a noncontrast computed tomography (CT) scan of the head as soon as possible. Noncontrast CT helps to distinguish between an acute ischemic stroke and hemorrhagic stroke and largely rules out structural causes. As the management of these entities is completely different, it is important that the study should be performed without delay, as successful salvage of brain tissue and function by thrombolysis and reperfusion of an infarcted region is time sensitive: “time is brain.” If the patient is within the 4.5-hour time window and the ischemic stroke is severe, then thrombolytic therapy should be strongly considered, although one should realize that the risk of hemorrhagic conversion increases with increasing size of the ischemic lesion. Any evidence of acute intracranial hemorrhage is an absolute contraindication to thrombolytic therapy. There is much controversy about noncontrast CT versus magnetic resonance imaging (MRI) for the initial assessment of patients with suspected ischemic stroke. Some studies suggest that CT is more sensitive than MRI for detecting acute intracranial hemorrhage, whereas others suggest that MRI may be equally sensitive.9,10 However, MRI is considered superior to CT for detecting chronic hemorrhage and detailed pathologic information.9,10 In practice, CT has become the standard of care in the initial triage of suspected stroke patients because it is readily available in most emergency rooms and is inexpensive. Bottom line: In practice, noncontrast CT is performed almost solely for the purpose of ruling out a bleed, as its sensitivity for detecting ischemic CVA, particularly in the first 24 hours, is poor. 6. What does the evidence suggest should be the initial management of this patient? Addressing Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) is the first priority. Thereafter, a secondary survey of neurologic deficits is performed. In addition to obtaining a thorough history from the patient, observers in the event and the medical response team should also be interviewed. The history helps to narrow the diagnoses and exclude the medical mimics. A noncontrast CT scan should also be performed to rule out hemorrhagic stroke and other diagnoses. Aspirin should be given immediately unless thrombolytic therapy will be administered or the patient is allergic. In the case of allergy, clopidogrel can be given instead. Other tests to be performed are blood glucose, electrocardiogram, cardiac enzymes, complete blood count with differential, international normalized ratio (INR), coagulation studies (PT and PTT), and arterial blood gases. In certain cases, it may be useful to obtain liver function tests, blood alcohol level, electroencephalogram (to r/o seizures), chest x-ray (to r/o lung disease or malignancy), toxicology screen, and lumbar puncture (to r/o suspected subarachnoid hemorrhage not detected on CT scan).11 Note that a lumbar puncture should be performed only after a CT scan is negative for hemorrhage. To objectively quantify and characterize the degree of neurologic impairment, the National Institutes of Health Stroke Score (NIHSS) is administered. The NIHSS is an objective clinical evaluation tool designed to be used quickly at the bedside by trained examiners and can be administered concurrently with the medical treatment. Specific functional areas of deficit based on 25 items are graded from 0 to 30, with more than 25 indicating a more severe stroke and less than 4 indicating a smaller stroke. Parameters measured include the level of consciousness, language, motor strength and sensory loss, among others. Once an ischemic stroke is diagnosed, the primary goal of medical treatment is 2-fold: (1) to minimize brain injury and (2) to minimize functional deficits. Brain injury can be prevented or reversed by (1) supportive treatments, (2) revascularization, and (3) antithrombotic treatment. The main target of reperfusion efforts is the zone immediately surrounding the infarct, called the penumbra. Neurons in the penumbra are ischemic but may recover if reperfusion occurs in a timely manner. Medical issues that impair blood flow to the brain worsen ischemia, or otherwise contribute to neuronal damage must be addressed, especially blood pressure, glucose concentration, and cerebral edema. High arterial pressure may increase the risk of cerebral edema and hemorrhagic transformation. In addition, both high and low arterial pressures are associated with poor outcomes.11 Blood pressure >185/110 mm Hg should be treated. Currently, there are no conclusive data supporting the use of specific agents in the setting of acute ischemic stroke, so the choice of antihypertensive should be based on the patient’s clinical circumstances (e.g., no β-blocker if the patient is asthmatic). Concomitant myocardial ischemia should also be addressed, for example, by the usage of β- blockers to reduce myocardial oxygen demand. Both high and low glucose levels appear to cause neuronal damage in patients with acute ischemic stroke via multiple pathways. Hypoglycemia in and of itself causes neuronal damage and may cause focal symptoms and signs that mimic stroke.11 Hyperglycemia has been reported in about one-third of patients with stroke on admission. Both hyperglycemia and history of diabetes are associated with the unfavorable outcomes in acute ischemic stroke.11 Fever may indicate a cause of ischemic stroke, such as infective endocarditis, or a complication, such as pneumonia, and its presence portends a worse prognosis.11 Despite the promise of medically induced hypothermia as a neuroprotective mechanism during the periods of hypoxia or ischemia, there are no data to suggest that it may be beneficial for patients with ischemic stroke. Cerebral edema is unusual in the acute phase but an increased ICP can be treated by free-water restriction, elevation of the head of the bed, hyperventilation, osmotic diuretics, decompressive craniotomy, and avoidance of antihypertensives, which may promote cerebral vasodilation.11 7. What are our options for addressing this patient’s thrombosed vessel? Intravenous thrombolytics and endovascular approaches can be used to restore perfusion to the infracted region. Thrombolysis is achieved by recombinant tissue plasminogen activator (rtPA). Criteria for its use are very strict, and contraindications are numerous, as outlined in Table 9.1. Recently, the time frame for receiving rtPA was extended from 3 to 4.5 hours in selected patients.12,13 The rtPA thrombolytic therapy in the 3–4.5 hour range is contraindicated if the patient is older than 80 years, on oral anticoagulants, has a baseline NIH stroke scale score >25 or has a medical history of both stroke and diabetes.14 The earlier treatment is initiated, the better the outcome, so it is recommended to begin the treatment as soon as possible. Serious risks of rtPA include symptomatic intracranial hemorrhage. Intra-arterial thrombolysis is another technique, which has been attempted in acute ischemic stroke. Large-volume clots may fail to lyse with intravenous rtPA alone because of the greater thrombus burden and poor delivery of thrombolytic agents. Although an early study showed that intra-arterial thrombolysis with recombinant prourokinase in acute MCA stroke improved recanalization when given up to 6 hours after a stroke,15 intra-arterial thrombolysis for treatment of acute ischemic stroke is currently not FDA approved. Nevertheless, many centers now perform intra-arterial thrombolytics administration because it potentially maximizes thrombolytic action while minimizing the hemorrhagic effects. Mechanical endovascular thrombectomy is another promising field of stroke treatment. Currently, 2 devices are FDA approved for endovascular removal of clots in acute stroke: the Merci Retriever and the Penumbra System. The Merci Retriever has a flexible wire with coil loops that removes clots, whereas the Penumbra System uses suction to break up and aspirate clots. These systems improve recanalization of occluded arteries and clinical outcomes (see Ref. [16]) and may be used with more traditional thrombolytic methods as adjuncts. They are particularly attractive because they can be used for the patients who are not eligible for rtPA treatment or have failed rtPA treatment. TABLE 9.1 Guidelines for the Use of rtPA in Acute Ischemic Stroke. Indications for rtPA • Clinical diagnosis of stroke • Onset of symptoms to time of drug administration ≤3 h (or ≤4.5 h in selected patients) • CT scan showing no hemorrhage or edema of >1/3 of the MCA territory • Age ≥18 y • Consent by patient or surrogate Contraindications for rtPA • BP >185/110 despite treatment • Platelets <100,000; Hct <25%; glucose <50 or >400 mg/dL • Use of heparin within 48 h and prolonged PTT or elevated INR • Rapidly improving symptoms • Prior stroke or head injury within 3 mo; prior intracranial hemorrhage • Minor stroke symptoms • GI bleeding in preceding 21 d • Recent MI • Coma or stupor Abbreviations: rtPA, recombinant tissue plasminogen activator; BP, blood pressure; CT, computed tomography; MCA, middle cerebral artery; PTT, partial thromboplastin time; INR, international normalized ratio; GI, gastrointestinal; MI, myocardial infarction. Adapted from Kasper DL, et al. (2008). Harrison’s principles of internal medicine (17th ed.). New York: McGraw-Hill Medical Publishing Division. Antithrombotic treatment : Aspirin is a safe treatment that reduces mortality and risk of stroke recurrence 19, and is recommended for the treatment of acute stroke when used within 48 hours.2,17 Other antiplatelet agents are used only for the secondary prevention of stroke and include clopidogrel, aspirin, warfarin (only w a-fib), and Aggrenox. 8. In light of the patient’s symptoms, what are his chances of making a full recovery? This patient presented with severe symptoms, suggesting a large area of infarct. Fortunately, treatment was begun shortly after stroke onset, improving his chances of making a good recovery. Rehabilitation is the cornerstone of functional recovery. Physical, occupational, and speech therapies are combined with the patient and family education to enhance recovery and provide support. To assess global disability after a stroke, the modified Rankin Scale (mRS) is widely used. The mRS is a 6-item scale that judges the ability to walk and perform activities of daily living. Unlike the NIHSS, it does not provide detailed information on specific areas of impairment, but it can be a useful guide to predict the disability and associated needs, as well as the long-term survival. Bottom line: The NIHSS provides a useful tool to quantify the neurological impairment. Intravenous and intra-arterial thrombolysis, mechanical thrombectomy, and antiplatelet treatment with aspirin are all evidence-based treatments for acute stroke. Rehabilitation is critical for long-term functional recovery. 9. In addition to the long-term functional sequelae, what are the significant short- term complications of stroke? Are there any adverse effects of medical interventions? Complications in the immediate poststroke period that have been associated with poorer outcomes and higher mortality include cerebral edema that leads to an increased ICP, hyperthermia, hyperglycemia, and elevated blood pressure.20 Current guidelines advise withholding antihypertensive medicines in the immediate poststroke period — with some exceptions — unless systolic and diastolic blood pressures exceed 220 and 120 mmHg, respectively. Reduction of ICP by surgical and nonsurgical means is also recommended. The major adverse effect of thrombolytic therapy is hemorrhage. 10. What evidence-based pharmacologic interventions reduce the risk of a recurrent stroke in patients with a previous stroke or TIA? Medical management following a stroke is often guided by the patient’s underlying risk factors, but in general should include aspirin and other antiplatelet agents, statins, and lifestyle modifications. In patients with atrial fibrillation, an oral anticoagulant like warfarin is required, and INR should be in the therapeutic range of 2–3 when taking this medicine. Both antiplatelet therapy and warfarin are reasonable choices for patients with cardiac valvular disease, although when combined the risk of bleeding increases. FDA-approved antiplatelet agents for treatment in noncardioembolic stroke or TIA are aspirin, the phosphodiesterase inhibitor dipyridamole plus aspirin combination, and the ADP receptor antagonists, clopidogrel, and ticlopidine (ticlopidine is currently disfavored due to adverse effects). Recommendations for secondary prevention of an ischemic stroke vary according to the patient’s risk factor(s). The American Heart Association and American Stroke Association have specific guidelines for patients with specific risk factors.3 In patients with hypertension, antihypertensive medications have been shown to reduce the risk of cardiovascular disease in general and stroke in particular. Diuretic monotherapy or the combination of diuretics and ACE (angiotensin-converting enzyme) inhibitors appear to be most beneficial. In fact, even blood pressure reductions of 10/5 mmHg are beneficial, and lifestyle modifications such as weight loss, regular exercise, limited alcohol intake, salt restriction, and a fruit- and vegetable-rich diet are also recommended. In the setting of atrial fibrillation, native valvular heart disease, prosthetic heart valve, or acute myocardial infarction complicated by left ventricle mural thrombus, anticoagulation with warfarin with a target INR of 2–3 has been shown to be beneficial. Tight glycemic and blood pressure control in diabetic patients with a previous stroke or TIA is beneficial in preventing a stroke in the future.2 Other strategies for reducing the risk of stroke in the future include targeting abnormal lipid profiles with statins, niacin, or fibrates and lifestyle modification, as appropriate; smoking cessation; reduction of alcohol consumption or cessation in heavy drinkers; and at least 30 minutes of moderate-to-intense physical activity most days of the week or tolerable exercise regimen in individuals with a disability.2 Bottom line: Optimal medical therapy following a stroke includes antiplatelet agents, statins, and risk factor modification (e.g., smoking cessation, increased physical activity, and healthy diet). Guidelines for the secondary prevention of stroke echo those for primary stroke prevention and include maintaining a healthy lifestyle and treating risk factors like diabetes, hypertension, and hyperlipidemia. CASE CONTINUED After arriving in the emergency department, the patient was immediately assessed and medically stabilized. A brain CT scan of the patient performed revealed a large hypodense lesion on the left side of his brain corresponding to the MCA territory. There was no evidence of a hemorrhagic event. His NIHSS stroke score was 21. With no absolute contraindications to thrombolytic therapy, rtPA was administered and revascularization of the MCA was achieved. 11. How should this patient’s prognosis be evaluated? Several factors influence the long-term outcome of a stroke, including the exact location and size of the lesion, time to appropriate medical treatment, medical comorbidities, patient compliance with medication, and lifestyle choices. In addition, prognostication is further complicated by the fact that deficits typically evolve over a period of time, and there may be some degree of slow improvement in the months following the stroke. If perfusion is not restored in a timely manner, the ischemic penumbra may infarct as well. Therefore, achieving rapid revascularization is critical to prevent permanant damage to the penumbral area. In general, the larger the distribution of the blood vessel affected and the longer the interval between symptom onset and treatment, the greater the degree of neurologic impairment. The mRS can be used as an objective tool to assess residual neurologic deficits and is a helpful adjunct in prognostication. Bottom line: As a general rule of thumb, larger lesions are associated with more functional deficits and poorer prognosis for functional recovery than smaller lesions. The mRS can aid with prognosis and assessment of residual deficits. TAKE-HOME POINTS: ISCHEMIC STROKE 1. Sudden onset of focal neurologic symptoms, especially in an individual with risk factors, is highly suggestive of a stroke (CVA). 2. A transient neurologic deficit (TIA) may precede a CVA. 3. Ischemic stroke is caused by vascular occlusion and results in cell death within a specific vascular distribution. 4. Risk factors for ischemic stroke include hypertension, dyslipidemia, atrial fibrillation, smoking, and obesity. History may often reveal a recent TIA. 5. A noncontrast head CT should be performed immediately to evaluate for an intracranial bleed or mass as a cause of the symptoms. An MRI or contrast CT can then be performed at a later time to evaluate for acute cerebral ischemic or infarction. 6. The NIHSS is a useful tool to quantify the extent of neurologic impairment and guide therapeutic management decisions. 7. Acute treatment for an ischemic stroke consists of thrombolysis, mechanical thrombectomy, and aspirin. Long-term management includes antiplatelet agents, statins, and risk factor modification. Rehabilitation is important for long-term functional recovery. REFERENCES 1. Allen, C. M. 1984. “Differential Diagnosis of Acute Stroke: A Review.” Journal of the Royal Society of Medicine 77 (10): 878–81. 2. Fulgham, J. R., Ingall T. J, Stead L. G, Cloft H. J, Wijdicks E. F, Flemming K. D. 2004. “Management of Acute Ischemic Stroke.” Mayo Clinic Proceedings 79 (11): 1459–69. 3. Karen L. Furie, Scott E. Kasner, Robert J. Adams, Gregory W. Albers, Ruth L. Bush, Susan C. Fagan, Jonathan L. Halperin, et al. 2010. “Guidelines for the Prevention of Stroke in Patients with Stroke or Transient Ischemic Attack: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association.” Stroke 42 (1): 227–76. 4. Salisbury, M., G. Pfeffer, and S. Yip. (2011). “Stroke in Young Women.” The Canadian Journal of Neurological Sciences 38 (3): 404–10. 5. Tate, J., and C. Bushnell. (2011). “Pregnancy and Stroke Risk in Women.” Womens Health (London England) 7 (3): 363–74. 6. Acciarresi M, De Rango P, Pezzella F. R, Santalucia P, Amici S, Paciaroni M, Mommi V, Agnelli G, Caso V. (2011). “Secondary Stroke Prevention in Women.” Womens Health (London England) 7 (3): 391–7. 7. Manwani, B., and L. D. McCullough. (2011). “Sexual Dimorphism in Ischemic Stroke: Lessons from the Laboratory.” Womens Health (London England) 7 (3): 319–39. 8. Renoux, C., and S. Suissa. (2011). “Hormone Therapy Administration in Postmenopausal Women and Risk of Stroke.” Womens Health (London England) 7 (3): 355–61. 9. Lövblad K. O, Altrichter S, Viallon M, Sztajzel R, Delavelle J, Vargas M. I, El-Koussy M, Federspiel A, Sekoranja L, et al. 2008. “Neuro-imaging of Cerebral Ischemic Stroke.” The Neuroradiology Journal 35 (4): 197–209. 10. Kidwell C. S, Chalela J. A, Saver J. L, Starkman S, Hill M. D, Demchuk A. M, Butman J. A, et al. 2004. “Comparison of MRI and CT for Detection of Acute Intracerebral Hemorrhage.” Journal of the American Medical Association 292 (15): 1823–30. 11. Adams HP Jr, del Zoppo G, Alberts M. J, Bhatt D. L, Brass L, Furlan A, Grubb R. L, et al. 2007. “Guidelines for the Early Management of Adults with Ischemic Stroke: A Guideline from the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology Affirms the Value of this Guideline as an Educational Tool for Neurologists.” Stroke 38 (5): 1655–711. 12. Lansberg, M. G., E. Bluhmki, and V. N. Thijs. 2009. “Efficacy and Safety of Tissue Plasminogen Activator 3 to 4.5 Hours after Acute Ischemic Stroke: A Metaanalysis. Stroke 40: 2438–41. 13. Werner Hacke, Markku Kaste, Erich Bluhmki, Miroslav Brozman, Antoni Dávalos, Donata Guidetti, Vincent Larrue, et al. for the ECASS Investigators. 2008. “Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke.” The New England Journal of Medicine 359: 1317–29. 14. del Zoppo, G. J., Gregory J. del Zoppo, Jeffrey L. Saver, Edward C. Jauch, Harold P. Adams Jr, 2009. “Expansion of the Time Window for Treatment of Acute Ischemic Stroke with Intravenous Tissue Plasminogen Activator: A Science Advisory from the American Heart Association/American Stroke Association.” Stroke 40 (8): 2945–8. 15. del Zoppo, G. J., Higashida R. T, Furlan A. J, Pessin M. S, Rowley H. A, Gent M. 1998. “PROACT: A Phase II Randomized Trial of Recombinant Pro- urokinase by Direct Arterial Delivery in Acute Middle Cerebral Artery Stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism.” Stroke 29 (1): 4–11. 16. Millan, M., L. Dorado, and A. Davalos. 2010. “Fibrinolytic Therapy in Acute Stroke.” Current Cardiology Reviews 6 (3): 218–26. 17. Alberts, M. J. 2003. “Medical Management of Patients with an Acute Stroke: Treatment and Prevention.” Topics in Stroke Rehabilitation 10 (3): 34–45. 18. van Kooten, F., Giovanni Ciabattoni, Carlo Patrono, Diederik W. J. Dippel, Peter J. Koudstaal. 1997. “Platelet Activation and Lipid Peroxidation in Patients with Acute Ischemic Stroke.” Stroke 28 (8): 1557–63. 19. Chen, Z. M., Sandercock P, Pan H. C, Counsell C, Collins R, Liu L. S, Xie J. X, Warlow C, Peto R. 2000. “Indications for Early Aspirin use in Acute Ischemic Stroke: A Combined Analysis of 40,000 Randomized Patients from the Chinese Acute Stroke Trial and the International Stroke Trial. On behalf of the CAST and IST collaborative groups.” Stroke 31 (6): 1240–49. 20. Lukovits, T. G., and R. P. Goddeau, Jr. 2011. “Critical Care of Patients with Acute Ischemic and Hemorrhagic Stroke: Update on Recent Evidence and International Guidelines.” Chest 139 (3): 694–700.

Acute Spinal Cord CHAPTER Compression 10 OLGA P. FERMO, MD CASE A 65-year-old man with a history of hypertension presents to the emergency department (ED) for evaluation of a 4-month history of lower back pain and stiffness. The pain was initially dull, 3/10 in intensity; but now it is 6/10, radiating around the costal margins, and is exacerbated by coughing, straining, and lying flat. For the last day he has not been able to urinate but he became incontinent in the ambulance. He has not seen his primary care doctor in over 3 years. Review of systems is otherwise remarkable only for unintentional weight loss of 10 lbs in recent months. He denies fever, chills, chest pain, dyspnea, and gastrointestinal complaints. On physical examination, the patient appears to be in pain but vital signs are within normal limits. Palpation over the thoracic spine produces pain. There is 5/5 strength in the upper extremities and 3/5 strength in the lower extremities bilaterally. The examination is difficult to perform secondary to pain but the lower extremity flexors appear slightly weaker than the extensors. Reflexes are slightly more brisk (3+) in the lower extremities than the upper extremities (2+). Babinski sign is present bilaterally. Sensation to pinprick and light touch is diminished from the umbilicus down. Vibratory sense is diminished in the lower extremities. Rectal examination reveals normal sphincter tone. Gait is wide- based. 1. What is the differential diagnosis and what is the likely diagnosis? On the basis of the history and neurological examination, the patient’s lesion is most likely at the level of T8. The first hint is the band-like characteristic of his pain which points toward a thoracic as opposed to lumbosacral lesion. The patient also has a sensory level at the umbilicus, 101 102 Evidence-Based Clinical Reasoning in Medicine or T10, suggesting that his spinal cord is compressed 2 segments above this (T8). Spinal cord compression is generally defined as compression of the dural sac and its contents, which include the spinal cord and cauda equina, by a tumor or mass with radiological evidence of at least indentation of the theca at the level corresponding to the clinical features.1 In a 1992 review, Schmidt and Markovchick described the 4 most common causes of nontraumatic spinal cord compression along with their most common etiologies and presentations. These include spinal canal hemorrhage, spinal abscess, malignancy, and skeletal disease.2 Findings of the review are summarized in Table 10.1. In 1988, based on a study of 75 patients with metastatic spinal cord compression, Li and Poon found breast and prostate to be the most common primary neoplasms. Others include lymphoma, multiple myeloma, renal cell carcinoma, bronchogenic, melanoma, thyroid, parathyroid, laryngeal, colon, chondrosarcoma, and cardinoma of the vulva.3 Schiff et al. conducted a review of 337 patients with epidural spinal cord compression seen in the Mayo Clinic between 1985 and 1993. The primary tumor type was prostate in 24% of patients, breast in 19%, and lung in 17%. Other neoplasms include lymphoma, myeloma, renal cell, sarcoma, colorectal, unknown, thyroid, melanoma, head and neck, hepatocellular, pancreatic, esophageal, gastric, chronic myelogenous leukemia (CML), carcinoid, ovarian, and malignant schwannoma.4 In 2001, Husband et al. studied 280 patients with malignant spinal cord compression. The primary tumor site was lung (bronchus) in 26% of patients, breast in 23%, and prostate in 20%. Others include hematological, urinary tract, and gastrointestinal tract.5 In a 2005 review, Prasad and Schiff reported that 8–34% of cases with epidural spinal cord compression represent the initial presentation of malignancy. Cancers for which such a presentation is unlikely are breast and prostate. On the other hand, spinal cord compression is a common initial manifestation of malignancy of unknown primary origin, non-Hodgkin lymphoma, myeloma, and lung cancer.6 Bottom line: Suspect malignancy as the cause of spinal cord compression, particularly in patients with known lung, breast, or prostate cancer. Be aware that in a number of malignancies, spinal cord compression may be the initial manifestation. Other causes of spinal cord compression that should be considered are spinal hemorrhage, abscess, and skeletal disease. 2. Given the suspected diagnosis, what does the evidence suggest needs to be performed on examination? There is no evidence regarding the predictive value of physical examination in working up malignant spinal cord compression. Although equivocal, there is evidence for the predictive value of history and physical examination in cauda equina syndrome (CES). CES is a surgical emergency, classically described as a combination of low back pain, unilateral or bilateral sciatica, weakness in the lower extremities, saddle sensory loss, and/or urinary retention with overflow incontinence.7 Although the spinal cord ends at L1-2 in most adults, compression of the cauda equina is often grouped with spinal cord compression because some etiologies are similar which include abscess, epidural hematoma, and malignancy.8 Others are lumbar disc herniation, spinal anesthesia, ankylosing spondylosis, inferior vena cava thrombosis, and sarcoidosis.8,9 Balasubramanian et al. studied the reliability of clinical assessment in diagnosing CES in 80 patients. Fifteen of these patients had confirmed CES. Only saddle sensory deficit significantly associated with magnetic resonance imaging (MRI) confirmed CES. Association of other symptoms and signs, namely back pain, unilateral and bilateral leg pain, bladder retention, bladder incontinence, previous lumbar surgery, and decreased sphincter tone was not statistically significant.7 In 2009, Domen et al. published the results of a retrospective review investigating the predictive value of clinical examination in patients suspected to have CES. Out of 58 patients, 8 patients had cauda equina compression confirmed on MRI. Six of these patients underwent a bladder scan and all were found to have urinary retention. The clinical picture of urinary retention is greater than 500 ml and at least 2 of the following—bilateral sciatica, patient perception of urinary retention, or bowel incontinence—was associated with MRI-positive CES with an odds ratio of 48, 95% CI (3.30–697.21), (P = .04).10 Jalloh and Minhas identified 32 patients with CES who were transferred to a London neurosurgical center. Only 19% presented with the cluster of symptoms representing the characteristic of CES, namely lower back pain, bilateral sciatica, motor loss, sacral sensory loss, and sphincter disturbance. The strongest predictive features were lower back pain, sacral sensory loss, and urinary symptoms.11 Bottom line: Given the importance of prompt diagnosis and management, CES should immediately be suspected in a patient with back pain and urinary retention or saddle sensory loss. 3. What are the initial signs and symptoms of malignant spinal cord compression? The classical signs and symptoms are back pain, lower extremity muscle weakness, sensory deficits, and autonomic dysfunction such as changes in bowel and bladder continence. Thoracic metastases are the most common and cause bilateral band-like pain. Lumbar metastases are the next most common and cause radicular pain. Cervical lesions are the least common, with cervical pain being the most common initial symptom. Neurological deficits with upper cervical lesions are delayed due to the wider spinal canal. Lower cervical lesions are more likely to cause radicular motor weakness and parasthesias.12 It is clear that the initial symptoms are nonspecific and there is often a delay from onset of symptoms to diagnosis. The most important predictor of outcome after treatment for spinal cord compression is pre-treatment neurological function.13 As the patient outcome is highly dependent on the ability to recognize signs and symptoms of compression, it is important to be aware of the most common early findings. In a 2005 review, Prasad and Schiff named the most common progression of neurological symptoms in patients with malignant spinal cord compression. Patients initially present with localized pain becomes more intense over time. The discomfort is exacerbated by recumbency and Valsalva maneuver. Metastasis to lumbosacral regions causes pain to take on a radicular quality over time, whereas the involvement of thoracic spine causes patients to experience a bilateral, band-like pain. Patients experience pain for a median of 8 weeks before the recognition of etiology. The next most common presenting symptom is motor weakness. Lesions here also produce hyperreflexia and the Babinski sign. This is in contrast to lesions affecting the cauda equina, which result in hyporeflexia. Patients with lesions affecting the thoracic cord experience the most weakness. Presentation with sensory deficits was found to be less common than the presentation with weakness. Different patterns of sensory deficit may point to lesion location: sensory deficit in a radicular distribution is typical of lumbosacral compression, saddle sensory loss is seen in CES, and Lhermitte’s phenomenon is associated with cervical and thoracic compression. Bowel and bladder function is affected later, with the most common presentation being urinary retention. Gait ataxia may be associated with spinal cord compression in the presence of other characteristic symptoms (Table 10.2).6,14 Bottom Line: Most patients with malignant spinal cord compression experience pain for several weeks before experiencing graver TABLE 10.2 Clinical Presentation of Malignant Spinal-Cord Compression in 5 Studies. Patients Pain (%) Weakness 398 83 67 153 88 61 130 96 76 79 70 91 77 94 85 Sensory Autonomic Deficit (%) Dysfunction (%) 90 48 78 40 51 57 46 44 57 52 Reproduced from Ref. [6]. neurological symptoms. There should be a high index of suspicion for involvement of the spinal cord in patients with back pain and known or possible malignancy. 4. Given our concern for malignant spinal cord compression, does the evidence support empiric therapy with glucocorticoids before diagnostic imaging is undertaken? Since time is an extremely important factor in the management and prognosis of spinal cord compression, it is reasonable to administer dexamethasone to patients who are likely to have cord compression based on clinical presentation. However, the evidence is far from clear that steroids are of benefit. In 1994, Sorensen et al. published the results of their randomized single blind study in which 57 patients with symptomatic metastatic spinal cord compression confirmed on myelography and MRI received either high-dose dexamethasone or no dexamethasone before undergoing radiotherapy. After treatment with dexamethasone, 81% of patients retained gait function compared with 63% who were not treated with steroids. Six months after initial treatment, 59% of patients treated with dexamethasone retained gait function compared with 33% in the untreated group. Three patients in the dexamethasone group experienced significant side effects (hypomania, psychosis, and perforated gastric ulcer).15 Vecht et al. administered a bolus of either conventional dose dexamethasone (10 mg IV followed by 16 mg p.o. daily) or high dose dexamethasone (100 mg IV followed by 16 mg p.o. daily) to 37 patients with confirmed malignant spinal cord compression prior to radiotherapy. There were no significant differences in pain, ambulation, and bladder function between the 2 groups.16 Graham et al. randomized 20 patients with metastatic cord compression to receive 96 mg or 16 mg dexamethasone daily for 2 days followed by rapid taper. All participants received prophylactic omeprazole and nystatin drops, and those with indwelling catheters were given trimethoprim daily. Serious side effects occurred in 5 out of 9 patients receiving high-dose steroids when compared with 4 out of 11 receiving low-dose steroids. The authors reported that the death of 1 patient in the high-dose group, which was caused by Staphylococcus aureus sepsis, was probably related to steroid usage. In another patient, cholangitis sepsis secondary to obstruction was deemed as possibly associated with high- dose steroid usage. Two other patients in the high-dose group also died from sepsis; the association with steroids was thought to be unlikely. The fifth death was unrelated to the treatment. All 4 adverse outcomes in the low-dose group were unrelated to the study. The authors designed this pilot study with the knowledge that it did not have enough power to statistically analyze ambulation outcome, so the statistical analysis of ambulation was descriptive. When adjusted for baseline, high-dose dexamethasone did not improve ambulation in 1 month.17 A 2008 Cochrane meta-analysis concluded that these 3 trials provided “insufficient evidence about the role of corticosteroids” in the management of malignant epidural spinal cord compression. However, the meta-analysis confirmed that the occurrence of serious adverse effects were significantly higher in patients treated with high-dose corticosteroids.18 Bottom line: There is limited evidence to support the usage of dexamethasone in malignant spinal cord compression even after the diagnosis is confirmed. Although there are no studies to support such practice, it is generally acceptable to administer high-dose dexamethasone to patients with progressive motor symptoms during diagnosis and moderate-dose dexamethasone to patients with mild or nonprogressive motor symptoms.19 No evidence exists regarding the usage of empirical dexamethasone in suspected malignant spinal cord compression. 5. In terms of the evidence base, which imaging test(s) should be ordered in this patient? At the time of this writing, it is generally accepted that whole-spine MRI should be the initial imaging modality. Before the availability of MRI, introduction of contrast into the subarachnoid space (myelography) was the gold standard for the diagnosis of metastatic epidural spinal cord compression. Other useful imaging modalities include computed tomography (CT), positron emission tomography (PET), and radionuclide bone scans. Changes on plain radiographs of the spine consistent with neurological findings can sometimes predict spinal cord compression, thereby raising the question of whether they should be performed as the initial imaging study.6 In 2000, Kienstra et al. conducted a prospective study to determine whether there was a subgroup of patients with cancer and back pain in whom the neurological examination and plain films were enough to exclude metastatic disease to the spine, thereby avoiding the need for MRI. The finding of a metastatic abnormality on plain film was a strong predictor of vertebral metastasis, as were night pain, progressive pain, and Karnofsky score, whereas advanced age and osteoporotic fracture were associated with a lower risk for vertebral metastasis. Despite these findings, the authors concluded that the discriminatory value of a standard neurological evaluation with plain films of the spine was too low to substantially reduce the number of MRIs performed. They therefore recommended forgoing plain films in patients with cancer and back pain and choosing MRI as initial imaging study.20 Husband et al. compared the results of neurological examination and plain films with MRI in a prospective study of 280 patients with suspected malignant spinal cord compression. All patients received plain radiographs of the spine and neurological examination, and based on the results they were separated into a “MRI mandatory” and “MRI nonmandatory” groups for the purpose of further diagnosis and treatment. All patients then received MRI to determine the concordance of diagnostic and treatment decisions. Out of 280 patients, 201 were found to have cord compression by MRI. Plain films and neurological examination detected consistent changes in 104/280 patients, and 91/104 patients were placed in the “MRI nonmandatory” group for diagnosis and radiotherapy. However, it was found that MRI would have led to a change in the radiotherapy plan in 48 out of 91 patients if it was performed, and in 19 out of 48 the change would have been viewed as major. The authors concluded that most patients with suspected cord compression will need whole-spine MRI following plain films and neurological examination because of the additional information it provides.5 Schiff et al. reviewed 337 cases of epidural spinal cord compression, and found that the incidence of metastasis at multiple locations was 30%. When patients had symptomatic thoracic or lumbar lesions, omitting the imaging of cervical spine would have missed 1% of metastases. However, the omission of thoracic or lumbar imaging in patients with symptomatic lesions elsewhere would have missed 21% of metastases. This is significant because the presence of multiple epidural metastases was independently associated with poor survival (19 versus 33 weeks).4 Li and Poon compared the results from MRI, myelography, surgery, clinical follow-up, and surgery in 75 patients with cancer and suspicion for spinal cord compression/CES. The sensitivity of MRI in detecting metastatic compression was 93%, the specificity was 97%, and overall accuracy was 95%.3 Bottom line: The evidence supports the whole-spine MRI as the initial diagnostic imaging modality for patients with suspected metastatic spinal cord compression and without contraindications. Information gained from the plain films of the spine does not eliminate the need for subsequent MRI. As the presence of multiple sites of epidural metastases changes prognosis and management even if asymptomatic, the entire spine should be included in imaging. TAKE-HOME POINTS: ACUTE SPINAL CORD COMPRESSION 1. The four most common causes of nontraumatic spinal cord compression are spinal canal hemorrhage, spinal abscess, malignancy, and skeletal disease. 2. Urinary retention and/or saddle sensory loss in a patient with back pain reliably predict cauda equina compression. 3. Patients with malignant spinal cord compression first present with pain, followed by motor weakness, sensory deficit, and then bowel and bladder symptoms (i.e., urinary retention). 4. The available literature addresses the treatment of established malignant cord compression with dexamethasone. There is no literature regarding empirical treatment when cord compression is suspected. However, given the ability of dexamethasone to reduce white matter vasogenic edema and potentially avert serious neurological consequences, it is acceptable to administer moderate- to high-dose dexamethasone based on the severity of symptoms. 5. Whole-spine MRI should be the initial imaging modality in suspected malignant spinal cord compression. REFERENCES 1. Loblaw, D. A., J. Perry, A. Chambers, and N. J. Laperriere. 2005. “Systematic Review of the Diagnosis and Management of Malignant Extradural Spinal Cord Compression: The Cancer Care Ontario Practice Guidelines Initiative’s Neuro- Oncology Disease Site Group.” Journal of Clinical Oncology 23 (9):2028–37. 2. Schmidt, R. D., and V. Markovchick. 1992. “Nontraumatic Spinal Cord Compression.” The Journal of Emergency Medicine 10: 189–99. 3. Li, K. C., and P. Y. Poon. 1988. “Sensitivity and Specificity of MRI in Detecting Malignant Spinal Cord Compression and in Distinguishing Malignant from Benign Compression Fractures of Vertebrae.” Magnetic Resonance Imaging 6: 547–56. 4. Schiff, D., B. P. O’Neil, C. H. Wang, and J. R. O’Fallon. 1998. “Neuroimaging and Treatment Implications of Patients with Multiple Epidural Spinal Metastases.” Cancer 83: 1593–601. 5. Husband, D. J., K. A. Grant, and C. S. Romaniuk. 2001. “MRI in the Diagnosis and Treatment of Suspected Malignant Spinal Cord Compression.” The British Journal of Radiology 74: 15–23. 6. Prasad, D., and D. Schiff. 2005. “Malignant Spinal-Cord Compression.” Lancet Oncology 6: 15–24. 7. Balasubramanian, K., P. Kalsi, C. G. Greenough, and M. P. K. Seetharam. 2010. “Reliability of Clinical Assessment in Diagnosing Cauda Equina Syndrome.” British Journal of Neurosurgery 24 (4): 383–86. 8. Todd, N. V. 2009. “An Algorithm for Suspected Cauda Equina Syndrome.” Annals of the Royal College of Surgeons of England 91 (4): 358–59. 9. Olivero, W. C., H. Wang, W. C. Hanigan, J. P. Henderson, P. T. Tracy, P. W. Elwood, J. R. Lister, and L. Lyle. 2009. “Cauda Equina Syndrome (CES) from Lumbar Disc Herniations.” Journal of Spinal Disorders and Techniques 22 (3): 202–6. 10. Domen, P. M., P. A. Hofman, H. van Santbrink, and W. E. J. Weber. 2009. “Predictive Value of Clinical Characteristics in Patients with Suspected Cauda Equina Syndrome.” European Journal of Neurology 16: 416–19. 11. Jalloh, I., and P. Minhas. 2007. “Delays in the Treatment of Cauda Equina Syndrome due to its Variable Clinical Features in Patients Presenting to the Emergency Department.” Emergency Medicine Journal 24: 33–34. 12. Papagelopoulos, P. J., A. F. Mavrogenis, B. L. Currier, P. Katonis, E. C. Galanis, G. S. Sapkas, and D. S. Korres. 2004. “Primary Malignant Tumors of the Cervical Spine.” Orthopedics 27 (10): 1066. 13. Sun, H., and A. Nemecek. 2009. “Optimal Management of Malignant Epidural Spinal Cord Compression.” Emergency Medicine Clinics of North America 27 (2): 195–208. 14. Helweg-Larsen, S., and P. S. Sorensen. 1994. “Symptoms and Signs in Metastatic Spinal Cord Compression: A Study of Progression from First Symptom until Diagnosis in 153 Patients.” European Journal of Cancer 30A: 396–98. 15. Sorensen, P. S., S. Helweg-Larsen, H. Mouridsen, and H. H. Hansen. 1994. “Effect of High-Dose Dexamethasone in Carcinomatous Metastatic Spinal Cord Compression Treated with Radiotherapy: A Randomised Trial.” European Journal of Cancer 30A: 22–27. 16. Vecht, C. J., H. Haaxma-Reiche, W. L. J. van Putten, M. de Visser, E. P. Vries, and A. Twijnstra. 1989. “Initial Bolus of Conventional Versus HighDose Dexamethasone in Metastatic Spinal Cord Compression.” Neurology 39: 1255– 57. 17. Graham, P. H., A. Capp, G. Delaney, G. Goozee, B. Hickey, S. Turner, L. Browne, C. Milross, and A. Wirth. 2006. “A Pilot Randomized Comparison of Dexamethasone 96 mg vs 16 mg per Day for Malignant Spinal-Cord Compression Treated by Radiotherapy: TROG 01.05 Superdex Study.” Clinical Oncology 18 (1): 70–76. 18. George, R., J. Jeba, G. Ramkumar, A. G. Chacko, M. Leng, and P. Tharyan. 2008. “Interventions for the Treatment of Metastatic Extradural Spinal Cord Compression in Adults.” Cochrane Database of Systematic Reviews 4: CD006716. 19. Cole, J. S., and R. A. Patchell. 2008. “Metastatic Epidural Spinal Cord Compression.” Lancet Neurology 7: 459–66. 20. Kienstra, G. E. M., C. B. Terwee, F. W. Dekker, L. R. Canta, A. C. W. Borstlap, C. C. Tijssen, D. A. B. Bosch, J. G. P. Tijssen. 2000. “Prediction of Spinal Epidural Metastases.” Archives of Neurology 57: 690–94.

Perioperative Cha P te R Beta-Blockers 11 Paul J. D. Roszko, MD CASE You are the admitting senior resident on-call when you receive a page from the emergency department (ED). They are treating a stable 81-yearold woman involved in a motor vehicle accident. She is nonambulatory and complaining of some mild pain in her left hip. She has already been evaluated by orthopedics and has been found to have an intertrochanteric fracture of the left femur. Orthopedics would like to book her for the operating room, but require you to medically “clear” the patient before they proceed. Medical history is significant for hyperlipidemia and hypertension. Prior to today, she had been in her usual state of good health. 1. What are the theoretical benefits of β-blockers in patients undergoing orthopedic surgery? In patients undergoing noncardiac surgery, a surge in catecholamines causes an increase in various cardiovascular parameters (e.g., heart rate and blood pressure). This increases myocardial oxygen demand, which may result in myocardial ischemia in patients with limited physiologic reserve (e.g., coronary artery disease).80 β-blockers are thought to counteract this potentially harmful chain of events by reducing the effect of catecholamines on the cardiovascular system.80 This produces a decrease in heart rate, limits the time spent in systole, and improves coronary perfusion, thereby increasing coronary perfusion while simultaneously decreasing myocardial oxygen demand.81 This ultimately may reduce the incidence of cardiac complications in noncardiac surgery.80 β-Blockers in the perioperative period have been shown to be effective at: • Modulating blood pressure fluctuations.68,83,84 • Reducing the number of perioperative ischemic episodes.68,81,85–88 115 • Reducing the incidence of postoperative atrial fibrillation.68,89 • Reducing the incidence of congestive heart failure.90 • Reducing the incidence of myocardial infarction (MI).68,88,90–92 • Reducing the need for emergent revascularization.90 • Reducing the incidence of nonfatal cardiac arrest.68,90–92 • Reducing the relative risk of cardiac death by ~30% for every 10 bpm reduction in heart rate in patients with a history of MI.93 The potential importance of β-blockers is highlighted in the studies by Mangano, Rao, and Yeager, which report that perioperative MI is associated with a 30%– 50% risk of perioperative mortality and a reduction in the long-term survival.68,94–97 Another study by McFalls et al. demonstrates that MI is the most common postoperative complication in patients undergoing noncardiac surgery, resulting in 10%–40% of postoperative fatalities.88,98 Furthermore, cardiovascular complications remain to be the most common and most treatable adverse event associated with noncardiac surgery.68,88 β-Blockers have been viewed over the years as a potential treatment to address this issue. Bottom line: Orthopedic surgery induces a stress response that can contribute to adverse cardiac events. Perioperative β-blockers have been shown to be effective at reducing their incidence and are thus proposed to be a potential intervention that can improve perioperative and postoperative outcomes. 2. Are there significant concerns about the current of periopaerative β-blockers? What are the current American College of Cardiology and American Heart Association (ACC/AHA) recommendations for the perioperative use of β- blockers? Current concerns over the use of perioperative β-blockade include68: • Actual efficacy in reducing perioperative cardiac events. • Limited evidence that is based on only a few randomized trials which used different β-blockers, sometimes with doses substantially different from those used in clinical practice. • Lack of trials demonstrating ideal preoperative titration, duration of therapy, route of administration, and so forth. • Lack of studies demonstrating a role for β-blockers in intermediate- and low- risk patients. • Concern over harm in β-blocker therapy for low-risk patients. These concerns were further heightened by following the publishing of the PeriOperative ISchemic Evaluation (POISE) trial, the largest multicenter randomized clinical trial to date evaluating the efficacy and Chapter 11: Perioperative Beta-Blockers 117 safety of β-blockers in noncardiac surgery (see Question 3). Following this study, the clinical guidelines by the ACC/AHA over the perioperative management of patients undergoing noncardiac surgery were updated. Specifically in regards to the use of perioperative β-blockade, the following are the most current recommendations as of 200968: Class I recommendations: • Continue β-blockers in patients undergoing surgery who are receiving β- blockers for the treatment of conditions with ACCF/AHA class I indications for the drugs (level C evidence). Class IIa recommendations: • β-Blockers titrated to heart rate and blood pressure are reasonable for patients in whom preoperative assessment identifies coronary artery disease or high cardiac risk (i.e., >1 clinical risk factor) in patients undergoing intermediate- risk surgery (level B evidence) Class IIb recommendations: • The usefulness of β-blockers is uncertain in patients who are undergoing either intermediate-risk procedures or vascular surgery in whom preoperative assessment identifies a single clinical risk factor in the absence of coronary artery disease (level C evidence). Class III recommendations: • The routine administration of high-dose β-blockers in the absence of dose titration is not useful and may be harmful to patients not currently taking β- blockers who are undergoing noncardiac surgery (level B evidence). These current recommendations are the cumulative result of decades worth of data from studies that vary according to methodology, patient population, type of β-blocker used, study size, type of surgery, and so forth. Thus, many of the classes IIa and IIb recommendations continue to be vague. 3. How are the findings of the landmark POISE trial relevant to this discussion? The POISE trial was a large, randomized, controlled trial involving 8351 patients undergoing noncardiac surgery that examined the effect of moderately high-dose metoprolol succinate (extended release formulation) started on the day of surgery and continued for 30 days postsurgery on cardiovascular death, nonfatal MI, and nonfatal cardiac arrest. Those patients who received a β- blocker perioperatively had a reduction in the primary end points (5.8% vs. 6.9%, P = .0399) as well as a reduction in the incidence of MI (4.2% vs. 5.7%, P = .0017). However, the metoprolol group also had an overall greater rate of allcause mortality (3.1% vs. 2.3%) and a higher rate of stroke (1% vs. 0.5%). The authors concluded that the routine administration of highdose β-blockers in the absence of dose titration is not useful and may be harmful to β-blocker naive patients undergoing surgery. In the POISE trial, β-blockers were initiated acutely and continued for 30 days postoperatively. Although β-blockers were not titrated to goal heart rate and blood pressure in this trial, their initiation near the time of surgery closely mimics how β-blockers would be administered to patients with an acute hip fracture. The results from this trial demonstrated an increased rate of all-cause mortality and stroke, as well as increased rates of significant perioperative hypotension and bradycardia, in patients randomized to metoprolol.68,80 More specifically, results from the POISE trial suggest that for every 1000 patients with a similar risk profile undergoing noncardiac surgery, metoprolol usage will prevent the onset of MI in 15 patients, need for coronary revascularization in 3 patients, and development of atrial fibrillation in 7 patients. However, the POISE trial also demonstrates that metoprolol usage is associated with mortality in an excess of 8 patients and onset of stroke in 5 patients. As mentioned earlier, the results of this study influenced the ACC/AHA to update their 2009 guidelines on perioperative management of patients undergoing noncardiac surgery to include the following warning, “Routine administration of high-dose β-blockers in the absence of dose titration for patients undergoing noncardiac surgery is not useful, may be harmful, and cannot be advocated.”68 The POISE trial findings alone should prompt the physician to exercise extreme caution when promoting the acute usage of β-blockers in an extremely frail patient population, such as the aged people who sustain hip fractures. Keeping it in mind that this is a group of people who have been shown to have high rates of cardiovascular complications and may be extremely sensitive to the effects of β- blockers, as cardiovascular changes (e.g., conduction abnormalities, decreased chronotropic response, and reduced response to catecholamines) may predispose them to symptomatic bradycardia and hypotension in the perioperative period.128 Thus, the elevated rates of perioperative hypotension and bradycardia reported in the literature may be even more pronounced in this group of people, who are less physiologically adept at responding to an episode of hypotension or bradycardia (Table 11.1). Bottom line: In the POISE trial, the intermediate risk patients undergoing noncardiac surgery were started on relatively high dose β-blockers immediately before surgery. Perioperative β-blockers, administered in this fashion, were associated with significant cardiac benefits (reduced rate of MI and incidence of A-fib) but at the expense of increased total mortality, stroke, and clinically significant hypotension and bradycardia. 4. How are the findings of the DECREASE-IV trial relevant to this discussion? The DECREASE-IV (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) trial, a randomized controlled trial of 1066 patients published in 2009, studied the effectiveness of bisoprolol titrated to a goal heart rate of 50–70 bpm and daily fluvastatin XL on composite cardiac death and nonfatal MI up to 30 days postoperatively. Although this study was, in reality, a 2 × 2 factorial design, we have avoided addressing the fluvastatin arm in Table 11.2 for the purpose of discussing the utility of perioperative β- blockade. Patients included in the study scheduled for noncardiac surgery, were at least 40 years of age, had an intermediate-risk of perioperative MI and death, and on an average were started on the study medications 34 days in advance of the procedure and continued till 30 days postoperatively. Of the patients who received bisoprolol, there was a reduction in the incidence of perioperative cardiac death and nonfatal MI (2.1% vs. 6.0%, P = .002) without any increase in the incidence of perioperative stroke or mortality. It is noteworthy that DECREASE-IV differs greatly in design from POISE in which the patients were generally started on TAblE 11.2 Findings of the DECREASE-IV Trial Study design Randomized prospective multicenter clinical trial Inclusion criteria Intervention IntermediateBisoprolol risk patients undergoing noncardiac surgery started approximately 1 mo before the surgery and titrated to reach heart rate Control arm No β-blocker Primary endpoints Composite of 30-d cardiac death and MI 30 d results Reduced rate of MI and cardiac death, 2.0% vs 6.7% (67% relative risk reduction) low-dose β-blockers well before surgery and the dose was titrated over time to goal heart rate.68,99,102 If you wish to learn more about the differences between the POISE and DECREASE_IV trials, visit the following website to read an extensive debate between the respective investigators of both trials: http://www.ccjm.org/content/76/Suppl_4/S84.full Bottom line: In the DECREASE-IV trial, intermediate-risk patients undergoing noncardiac surgery were started on low-dose β-blockers titrated to heart rate and started several weeks before surgery. This trial, in stark contrast to the findings of the POISE trial, found significant benefit to start perioperative β-blockers. 5. Does current evidence make clear recommendations for the perioperative usage of β-blockers? Not at all. The perioperative usage of β-blockers remains a controversial and highly debated topic in the medical literature. For instance, Poldermans et al. performed a multicenter study of 112 patients undergoing vascular surgery that were randomized to receive either perioperative bisoprolol or placebo. The authors noted a significant reduction in composite cardiac death and nonfatal MI (3.4% vs. 34%, P < .001), as well as individual reductions in cardiac death (3.4% vs. 17%, P = .02) and nonfatal MI (0% vs. 17%, P < .001).68,92 On the other hand, Yang et al. performed a randomized controlled trial of 496 patients undergoing abdominal aortic surgery and infrainguinal or axillofemoral revascularization. Patients were randomized to either dose-adjusted metoprolol or placebo and were studied for the composite primary outcome of 30-d nonfatal MI, unstable angina, new CHF, new atrial or ventricular dysrhythmias, or cardiac death. No significant difference in primary outcomes between study groups was observed.68,101 Lindenauer et al. performed a retrospective cohort study using administrative records of more than 600 000 patients undergoing noncardiac surgery in the United States. They concluded that patients who are at highest cardiac risk (≥3) according to the Revised Cardiac Risk Index (RCRI) were less likely to die in- hospital if they received a perioperative β-blocker, whereas those with a RCRI of 1 or 2 received no mortality benefit and those with a RCRI of 0 were actually more likely to die in-hospital (Table 11.3).68,107 In 2008, Bangalore et al. performed a meta-analysis after the publication of the POISE trial results. The analysis included 33 trials and 12,306 patients. Overall, β-blockers were not associated with a reduction in all-cause mortality, cardiovascular mortality, or CHF. TAblE 11.3 Direct Relationship between Perioperative β-Blockade and Risk of Death Risk of death (odds RCRI Score ratio) 0–1 No benefit, trend toward harm 2 0.88 3 0.71 4 0.58 95% Confidence interval 0.80–0.98 0.63–0.80 0.50–0.67 β -Blockers were, however, associated with a reduction in nonfatal MI (NNT = 63) and myocardial ischemia (NNT = 16). In regards to side effects, β-blockers were associated with an increased risk of nonfatal stroke (NNH = 293), perioperative bradycardia (NNH = 8), perioperative bradycardia requiring treatment (NNH = 22), perioperative hypotension (NNH = 11), and perioperative hypotension requiring treatment (NNH = 17). This analysis also reported that most positive effects of β-blockers came from the studies at a high risk of bias. Interestingly, of the trials studied, 5 were on the use of β-blockers in high-risk (vascular or emergent) surgical patients. A strong benefit was shown in this subgroup, with β-blockers being associated with a 63% reduction in all-cause mortality and 44% decrease in nonfatal MI.88 Notably in 2002, Auerbach and Goldman performed a meta-analysis of 5 trials that showed β-blockers would need to be given to 3–7 patients (NNT of 2.5–6.7) to achieve a reduction in the incidence of myocardial ischemia, as well as a to 3– 8 patients (NNT of 3.2–8.3) to achieve a reduction in cardiac or all-cause mortality.68,103 It is important to mention that there have been many additional studies conducted on this subject that have been eliminated from this discussion for sake of brevity. However, the above studies show that the data on the usage of β- blockade in noncardiac surgery are extremely variable and dependent on several different factors. Thus, it is hard to draw any hard conclusions about their effectiveness in the perioperative medical management of noncardiac surgery patients. However, this should not diminish the importance of results from the recent POISE and DECREASE-IV trials, which were large trials that provided some solid conclusions on proper ways to administer β-blockers.99 For instance, there is now some data regarding methods to properly titrate β-blockers in the perioperative period. All available evidence suggests that fixed-dose medication is ineffective and that dose titration to 50 or 60 bpm is associated with cardioprotective effects in patients undergoing noncardiac surgery.68,80,88,93,109 Problems with fixed-dose therapy are thought to be due to the fact that it is more difficult to account for individual variability in response to medication doses as well as difficult to respond to the effects of long-acting medications.68 Bottom line: Although still very controversial, the weight of evidence suggests that perioperative β-blockade results in patients undergoing major noncardiac surgery which results in reduced in-hospital mortality among high-risk patients, but not low-risk patients. 6. It is well established that hip fracture patients have an elevated 1-year postfracture mortality rate when compared to age-matched controls. To what is this increased mortality rate related? Being able to identify the causes of excess mortality after hip fracture may help physicians to use perioperative and postoperative treatments aimed at reducing the incidence of the excess mortality. Identifying postoperative cardiac complications (e.g., MI, CHF, and arrhythmias) as a main component of excess mortality could provide a rationale for the utilization of β-blockers to reduce their incidence in patients who sustain a hip fracture. Although the reported causes of elevated mortality within 1-year after a hip fracture vary, infection and cardiac complications seem to play a major role in describing the excess mortality rates.4,11–13,38 Part of the difficulty in describing the causes of excess mortality in hip fracture patients is that these patients are already extremely frail. It has also been noted that risk factors for frailty have also been recognized as risk factors for mortality (e.g., limited mobility, reduced muscle strength, impaired cognition, poor nutritional status, increased risk of falls, etc.).36,110–114 Furthermore, 2 of the above studies proposed a linkage between excess mortality after hip fracture and high levels of medical comorbidity at the time of fracture.7,37 Thus, it is quite possible that these patients are inherently sicker than their age- and gender-matched counterparts and not only more likely to sustain a hip fracture but also more likely to die. Therefore, it must be asked if the hip fracture is a cofounder rather than a direct cause of excess mortality.13,38 As Tosteson et al. concluded, “Fracture prevention may be of limited benefit in extending overall life expectancy due to the multiple competing mortality risks faced by the frail elderly.”14 Bottom line: There is an elevated rate of mortality within the year following a hip fracture. Much of this seem to be attributed to an increased rate of infection and cardiac disease, although it is difficult to say if the hip fracture is merely a cofounder and not a direct cause for the lowered survival rates seen in this patient population. 7. based on the above information, is there any evidence that β-blockers help to reduce the 1-year post-fracture mortality rate? At the time of this writing, there is no evidence in the literature that addresses the effectiveness of perioperative β-blockers in reducing the excess postoperative mortality observed in hip fracture patients. 8. What other interventions might be considered in hip fracture patients to improve overall outcomes? Given the frequency of hip fractures in the United States and worldwide2,23, and their expected increased incidence over the next several decades16, finding interventions to improve the outcomes in this specific population is a worthwhile task. There is evidence that certain interventions in hip-fracture patients— specifically prophylactic anticoagulants58, prophylactic antibiotics61, and postoperative administration of bisphosphonates62—can improve outcomes. Postoperative use of zoledronic acid was even associated with improved 1-year all-cause mortality outcomes.62 9. Can β-blockers be administered prior to emergency surgery? Although a specific trial has not been conducted looking at their benefit in emergency noncardiac surgery, one has to conclude that with all available evidence, starting β-blockers just prior to emergent surgery would not be beneficial and may in fact be harmful. From this standpoint alone, it is therefore currently very difficult to advocate for the use of β-blockers in patients who are undergoing emergency surgery for correction of a hip fracture. Keeping in mind that if β-blockers are to be used at all, they should be started well in advance of surgery, titrated over time to goal heart rate and blood pressure and should not be given in fixed-dose intervals.68,90,99 Bottom line: During emergent surgery, the initiation of β-blockade in patients who are β-blocker naïve may cause more harm than good. TAKE-HOME POINTS: PERIOPERATIVE β-blOCKADE IN PATIENTS UNDERGOING NONCARDIAC SURGERY 1. There is no clear and compelling evidence to support the routine usage of acute perioperative β-blockade in patients who are undergoing surgical repair of hip fractures. 2. On the basis of the POISE trial, the practice of initiating β-blockers immediately before noncardiac surgery in clinically stable β-blocker naive patients should be abandoned. However, there is reasonable evidence to continue the use of chronic β-blockers in patients who sustain an acute hip fracture. 3. Further trials are needed that specifically look at interventions aimed at reducing early postoperative mortality in patients who suffer a hip fracture, as well as trials that examine the effectiveness of β-blockade in patients undergoing emergent noncardiac surgery. REFERENCES 1. Fisher, E. S., J. A. Baron, D. J. Malenka, J. A. Barrett, W. D. Kniffin, F. S. Whaley, and T. A. Bubolz. 1991. “Hip Fracture Incidence and Mortality in New England.” Epidemiology 2: 116–22. 2. Cummings, S. R., S. M. Rubin, and D. Black. 1990. “The Future of Hip Fractures in the United States: Numbers, Costs, and Potential Effects of Postmenopausal Estrogen.” Clinical Orthopaedics 252: 163–66. 3. Wan, H. 2005. U.S. Census Bureau, Current Population Reports, 65+ in the United States. Washington, DC: U.S. Government Printing Office. 4. Roche, J. J. W., R. T. Wenn, O. Sahota, and C. G. Moran. 2005. “Effect of Comorbidities and Postoperative Complications on Mortality After Hip Fracture in Elderly People: Prospective Observational Cohort Study.” British Medical Journal: 1–5. doi:10.1136/bmj.38643.663843.55 (published 18 November 2005) 5. Brauer, C. A., M. Coca-Perraillon, D. M. Cutler, and A. B. Rosen. 2009. “Incidence and Mortality of Hip Fractures in the United States.” The Journal of the American Medical Association 302 (14): 1573–79. 6. Tsuboi, M., Y. Hasegawa, S. Suzuki, H. Wingstrand, and K. G. Thorngren. 2007. “Mortality and Mobility After Hip Fracture in Japan—A Ten-Year Follow-Up.” The Journal of Bone and Joint Surgery. British Volume 89-B: 461– 66. 7. Moran, C. G., R. T. Wenn, M. Sikand, and A. M. Taylor. 2005. “Early Mortality After Hip Fracture: Is Delay Before Surgery Important?” The Journal of Bone and Joint Surgery. American Volume 87: 483–89. 8. Fisher, A. A., E. N. Southcott, S. L. Goh, W. Srikusalanukul, P. E. Hickman, M. W. Davis, J. M. 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Kasperk. 2003. “Osteoporosis and Cardiovascular Disease—Two Sides of the Same Coin?” Medizinische Klinik (Munich) 98 (8): 437–46. 117. Sennerby, U., H. Melhus, R. Gedeborg, L. Byberg, H. Garmo, A. Ahlbom, N. L. Pedersen, and K. Michaelsson. 2009. “Cardiovascular Diseases and Risk of Hip Fracture.” The Journal of the American Medical Association 302 (15): 1666–73. 118. McFarlane, S. I., R. Muniyappa, J. J. Shin, G. Bahtiyar, and J. R. Sowers. 2004. “Osteoporosis and Cardiovascular Disease: Brittle Bones and Boned Arteries, Is There A Link?” Endocrine 23 (1): 1–10. 119. Tankó, L. B., C. Christiansen, D. A. Cox, M. J. Geiger, M. A. McNabb, and S. R. Cummings. 2005. “Relationship Between Osteoporosis and Cardiovascular Disease in Postmenopausal Women.” Journal of Bone and Mineral Research 20 (11): 1912–20. 120. Bauer, D. C., G. R. Mundy, S. A. Jamal, D. M. Black, J. A. Cauley, K. E. Ensrud, M. van der Klift, and H. A. Pols. 2004. “Use of Statins and Fracture: Results of 4 Prospective Studies and Cumulative Meta-Analysis of Observational Studies and Controlled Trials.” Archives of Internal Medicine 164 (2): 146–52. 121. Rejnmark, L., M. L. Olsen, S. P. Johnsen, P. Vestergaard, H. T. Sørensen, and L. Mosekilde. 2004. “Hip Fracture Risk in Statin Users—a Population- Based Danish Case-Control Study.” Osteoporosis International 15 (6): 452–58. 122. Godet, G., M. Dumerat, C. Baillard, S. Ben Ayed, M. A. Bernard, M. Bertrand, K. Kieffer, and P. Coriat. 2000. “Cardiac Troponin I is Reliable with Immediate but not Medium-Term Cardiac Complications After Abdominal Aortic Repair.” Acta Anaesthesiologica Scandinavica 44 (5): 592–97. 123. Bursi, F., L. Babuin, A. Barbieri, L. Politi, M. Zennaro, T. Grimaldi, A. Rumolo, et al. 2005. “Vascular Surgery Patients: Perioperative and LongTerm Risk According to the ACC/AHA Guidelines, the Additive Role of Post-Operative Troponin Elevation.” European Heart Journal 26 (22): 2448–56. 124. Kim, L. J., E. A. Martinez, N. Faraday, T. Dorman, L. A. Fleisher, B. A. Perler, G. M. Williams, D. Chan, and P. J. Pronovost. 2002. Cardiac Troponin I Predicts Short-Term Mortality in Vascular Surgery Patients. Circulation 106 (18): 2366–71. 125. Filipovic, M., R. Jeger, C. Probst, T. Girard, M. Pfisterer, L. Gürke, K. Skarvan, and M. D. Seeberger. 2003. “Heart Rate Variability and Cardiac Troponin I are Incremental and Independent Predictors of One-Year All-Cause Mortality After Major Noncardiac Surgery in Patients at Risk of Coronary Artery Disease.” Journal of the American College of Cardiology 42 (10): 1767– 76. 126. Kertai, M. D., E. Boersma, J. Klein, H. Van Urk, J. J. Bax, and D. Poldermans. 2004. “Long-Term Prognostic Value of Asymptomatic Cardiac Troponin T Elevations in Patients After Major Vascular Surgery.” European Journal of Vascular and Endovascular Surgery 28 (1): 59–66. 127. Dawson- Bowling, S., K. Chettiar, H. Cottam, R. Worth, J. Forder, I. Fitzgerald- O’Connor, D. Walker, and H. Apthorp. 2008. “Troponin T as a Predictive Marker of Morbidity in Patients with Fractured Neck of Femur.” Injury, International Journal of the Care of the Injured 39: 775–80. 128. Auron-Gomez, M., and F. Michota. 2008. “Medical Management of Hip Fracture.” Clinics in Geriatric Medicine 24: 701–19. Epidemiology and Perioperative Management of Hip Cha P te R Fracture

12 Paul J. D. Roszko, MD CASE A 76-year-old widowed female being treated for osteoporosis with alendronate (Fosamax®) presented to the emergency department (ED) after experiencing a traumatic fall while shoveling snow in her driveway. EMS was contacted by her neighbor who witnessed the fall. On arrival to the ED, the paramedic reports that the patient was found on the ground, nonambulatory, and complaining of severe pain in her left thigh. She was stabilized, boarded, had a C-collar placed, and brought directly to the ED. Initial assessment reveals a patent airway, equal but rapid breath sounds, and 2+ central pulses with 1+ distal pulses. Vital signs are stable, although she is slightly tachycardic at 105 bpm. Upon taking an appropriate history, revealing no medical problems other than the aforementioned treated osteoporosis, a secondary survey is performed revealing pain on palpation of the patient’s left pelvis and proximal femur. Plain films reveal that the patient has a displaced fracture of the left femoral neck. Orthopedics is consulted and the patient is scheduled for surgery to replace her femoral head. 1. What is the epidemiology of hip fractures in the United States? Hip fracture is one of the most feared medical complications of the aging process and is a major cause of morbidity and mortality.1 As of 1990, it was estimated that ~250,000 hip fractures occurred every year in the United States, the majority of which were in patients aged 50 years or more.2 The incidence rate in patients aged 65 years or more is reported as 818 of 100,000 persons,3 whereas the median age range of patients who sustain hip fracture is 75–84 years.4–14 By 135 2050, the hip fracture rate in the United States is expected to double to ~500,000 per year,15 and by 2040, the cost of treating hip fractures in the United States is projected to be $240 billion per year.16 Hip fracture is well recognized as a problem of the elderly female population, with 71.8%–82% of cases occurring in this population.4–14,17 Much of the difference in rate of hip fracture between men and women is thought to be due to the following reasons: men having a higher peak bone density, men developing osteoporosis at lower rates (3%–6% in men vs. 13%–18% in women), women going through menopause, and men having a shorter life expectancy;18 however, men have been reported to be ~2 years younger than women at the time of fracture, have higher rates of medical comorbidities, have longer lengths of hospitalization, and be more likely to experience postoperative complications.12 The risk for one experiencing a hip fracture depends on a person’s ability to ambulate as well as the strength of their bone.6 Hip fractures of about 90%–95% are due to falls19,20 and 1 in 3 persons aged 65 years or more will experience a fall each year.21 Persons who have had previous falls are estimated to have their risk of experiencing another fall increased by 3-fold.22 Following are the risk factors for hip fracture23: • Maternal history of hip fracture24 • Excessive EtOH or caffeine consumption25 • Physical inactivity26 • Low body weight27 • Tall stature28 • Previous hip fracture29 • Use of psychotropic medications30 • Institutionalization31 • Visual impairment32 • Dementia33 • Osteoporosis32 • Diabetes32 • There is an increased risk of death in men and women after hip fracture, and the extent of this risk varies in several published studies.4,7,11–14,17,34,36–38 Tsuboi et al.6 performed a 10-year follow-up study and reported survival rates at 1, 2, 5, and 10 years after fracture to be 81%, 67%, 49%, and 26%, respectively. A separate study by Wehren et al.12 demonstrated a 1-year mortality rate in men of 31.4% and a 2-year mortality rate of 42%. In women, the mortality rates were 23.3% and 23%, respectively. Interestingly, a study by Brauer et al.5 showed that from 1985 to 2005, mortality rates at 30, 180, and 360 days after hip fracture have decreased, the cause of which is thought to be multifactorial (e.g., arrival of bisphosphonates, increasing calcium and vitamin D supplementation, emphasis on regular weight-bearing exercise, smoking cessation). Mortality rates have also decreased since 1985.5 The reasons for this are thought to be due to timely surgical interventions, improved surgery and replacement arthroplasty, early weight-bearing exercise, prophylactic antibiotics, and use of bisphosphonates.5 Several different types of risk factors have been associated with mortality after hip fracture, but they vary from study to study (most notably, medical comorbidity and age). Some of these include: • Advanced age13,17,34,39,40 • Younger age11,41 • High American Society of Anesthesiologists (ASA) scores34 • Male gender4,11–13,34,36,39,41 • Female gender17 • Prefracture residence34 • Prefracture mobility34 • Extracapsular fracture34 • Pathologic fractures (related to tumors)34 • Postoperative heart failure4,13,36 • Perioperative cardiac arrest13 • Postoperative chest infection4,36 • High medical comorbidity4,17,36,37,39 • Active medical complications on admission7 • Sedentary lifestyle17 • Current smoker17 • Postoperative dementia13 Outcomes for those who survive a hip fracture are usually poor. Hip fracture is a main cause of institutionalization in the elderly.42 From 2003 to 2005 in the United States, 52.8% of patients with hip fracture were discharged to a skilled nursing facility (SNF).5 In the Scottish Hip Fracture Audit, only 51% of the extremely elderly patients (aged 95 years or more) who lived in their homes prefracture were able to return home by 120 days after the fracture, compared to 77% who were aged 75–89 years.40 Approximately, only one-third of patients with postoperative dementia (a common postoperative complication) are able to return to independent living 4 months after the event.43 Patients younger than 65 years who sustain a hip fracture are more likely to return home and recover the ability to walk, unaided and unaccompanied, by 120 days and have shorter length of hospitalization and rehabilitation.35 Only 50%–65% of patients who sustain a hip fracture will return to their previous level of ambulation, 10%–15% will be household ambulatory only, and up to 20% will become nonambulatory.44 Bottom line: Hip fracture is a major cause of morbidity and mortality in the elderly. Interventions are needed that can improve postevent outcomes in this vulnerable patient population. 2. What is the current treatment for hip fractures? The majority of hip fractures due to falls are either intracapsular (femoral neck) or intertrochanteric fractures (90%) with the remaining 10% or so being subtrochanteric fractures.45,46 In the majority of cases of femoral neck fractures, the preferred treatment option is surgical fixation, which can be open reduction with internal fixation (ORIF), femoral head replacement via hemiarthroplasty, or total hip arthroplasty (THA).47 Patients are mobilized as early as possible after surgery, preferably within 24 hours.23,48 This reduces venous stasis in the lower extremities and may therefore reduce the incidence of venous thromboembolism (VTE) or pulmonary embolism (PE)49,50 as well as the incidence of pressure ulcers.50 In a 2007 review by Leighton et al.,47 evidence was presented to advocate for femoral head replacement over ORIF as the standard of treatment for displaced fractures in most cases, as multiple studies demonstrated a reduction in reoperation rates in hemiarthroplasty versus ORIF.47 Furthermore, a study by Haidukewych et al. demonstrated that at 11.7-year follow-up, the majority (96.2%) of patients who underwent hemiarthroplasty had no or slight pain in the replacement joint, as well as an excellent 10-year event-free survival (94%).47 From these results, current proposed indications for femoral head replacement are: • Garden III or IV (i.e., displaced) fracture in patients who are aged more than 60 years • Symptomatic osteoarthritis • Inflammatory disease of the hip • A reduced predicted lifespan • Poor bone quality not suitable for ORIF47 Leighton et al.47 has advocated that use of ORIF be limited to patients with nondisplaced, stable fractures. In the same review, data from Gebhardt were presented that advocated for the use of THA over hemiarthroplasty, as patients were reported to achieve better functional outcomes, albeit with the tradeoff of slightly higher dislocation rates.47 Thus, proposed indications for performing THA include: • Femoral neck fracture with concomitant disease of the hip • Symptomatic contralateral hip disease • Femoral neck fracture in bone of poor quality where ORIF is very likely to fail • Fractures secondary to metastatic disease • Highly active patients • Patients with an excellent mental status and long life expectancy (more than 10 years)47 There have been repeated studies that have shown that relative to those patients who receive surgery for fixation of a hip fracture, those who do not undergo surgical fixation have worse outcomes, including increased mortality rates.23,51– 53 The current standard of treatment, therefore, in patients with hip fracture, is to proceed to emergent surgery with a stabilized and medically optimized patient in the shortest possible time period from the time of admission.48 The goals of surgery should be to correct the hip fracture, alleviate pain,48 and return the patient to their prefracture levels of mobility, residency, and daily functioning.49 Bottom line: The current gold standard of treatment for hip fractures is surgery. 3. Is there a difference in mortality if hip fracture repair is delayed? This is an important question to address as it defines the ideal window whereby a patient should be stabilized, optimized, and taken to the OR. Delayed surgery may allow for a detailed perioperative workup of the patient, identification of medical comorbidities that if missed could increase a patient’s risk of perioperative death, and possible titration of perioperative β-blockers. On the other hand, proceeding to surgery as quickly as possible is not only an ethical necessity but also thought that rapid surgical fixation of hip fracture can lead to improved outcomes, including improved mortality. A number of studies have attempted to address the question of whether delayed surgery in hip fracture patients increases the risk of mortality, and it seems that the literature remains controversial in its opinion. A systematic review by Shiga et al. looked at 5 prospective and 11 retrospective studies that evaluated mortality at 30 days and 1 year postoperative in patients who underwent surgery for hip fracture. In the trials that evaluated 30-day mortality, surgery delayed past 48 hours resulted in an increased mortality (OR 1.44, P < .001, number needed to harm, NNH = 40). In the trials that evaluated 1-year mortality, surgery delayed past 48 hours resulted in an increased mortality (OR 1.33, P < .001, NNH = 20). The authors concluded that surgery delayed past 48 hours results in a 41% increase in 30-day all-cause mortality and a 32% increase in an 1-year allcause mortality.10 On the other hand, the Scottish Hip Fracture Audit did not find any association between the time of admission to time of surgery and mortality at 30- or 120-day postoperative.34 Similarly, a retrospective cohort study of 8383 patients by Grimes et al.9 found no relationship between time to surgery (up to 72 hours) and overall mortality. This study did not evaluate the effects of delayed surgery past 72 hours. It is important to note that delayed surgery has been reported to negatively impact several different postoperative outcomes, which include total length of hospital stay,39,43 risk of developing pressure sores,9,39 and risk of major medical complications in the hospital setting [e.g., PE, cardiac arrest, critical care unit (CCU) transfer, major infections, renal failure requiring dialysis, and respiratory failure requiring ventilation].39 In addition, persons with surgery delayed for more than 36 hours from admission were less likely to return to independent living.43 In the study, the authors proposed that delayed surgery may lead to worse outcomes because of the reduced fluid and caloric intake patients undergo while waiting for their surgery, which when combined with the body’s stress response to the fracture may lead in an accelerated muscle wasting and weakness.43 In contradiction to the above findings, 1 study failed to find a significant difference in the rate or type of complications between patients who undergo surgery within 24 hours of admission and those who have surgery 1–4 days after admission.7 Some studies have tried to evaluate the reason for delay in surgery. Of those that have studied this phenomenon, 54%7 and 69%43 of the time surgery was delayed past 24 hours due to system-related factors, whereas 15%7, 29%9, and 31%43 of the time, it was delayed past 24 hours due to medical reasons. Unfortunately, many of the studies that look at the relationship between surgical delay and increased mortality in hip fracture patients suffer from the main limitation that it is not ethical to perform a randomized controlled trial to address this clinical question. Thus, it remains in doubt whether the increased mortality rates reported when surgery is delayed is in fact caused by the delay to surgery. Nonetheless, it is probably reasonable to adopt the policy laid out by the NHS Quality Improvement, Scotland: (1) For patient comfort, perform surgery as soon as possible, and (2) Bring as many patients as possible (goal in Scotland is 98%) to surgery within 24 hours of safe operating time (8:00 am–8:00 pm).34 Bottom line: Although the data are conflicting, there is evidence to show an improvement in clinical outcomes and mortality if patients are brought to the operating room in a timely fashion after admission to the hospital. Outcomes aside, the author would argue for ethical reasons that persons with hip fracture not have their surgery delayed, as it increases patient discomfort, increases immobility, and decreases a patient’s nutritional status. 4. What are the major complications associated with hip fractures? It is clear that hip fracture is not only an orthopedic problem. Those who experience a hip fracture often have active medical comorbidities at the time of fracture or develop medical complications following correction of the fracture. There are also several long-term consequences of hip fractures, in addition to the aforementioned increased mortality risk. The major complications of hip fracture are shown in Table 12.1. To note, the study by Roche et al. reported that in the 9% of patients who developed a postoperative chest infection, there was a 43% 30-day mortality rate [HR 3.0, confidence interval (CI) 2.1–4.2] and a 71% 1-year mortality rate (HR 2.4, CI 1.9–3.0). Furthermore, in the 5% of patients who developed postoperative heart failure, there was a 65% 30-day mortality rate (HR 8.0, CI 5.5–11.6) and a 92% 1-year mortality rate (HR 5.0, CI 3.9–6.5).4 Bottom line: Interventions targeted at reducing the incidence of postoperative complications could help improve outcomes in patients who suffer from a hip fracture. TAblE 12.1 Preoperative comorbidities on admission Major Complications of Hip Fracture (Actual Percentages Unknown) Type of complication Elevated INR7 Active chest infection7 Anemia7 Dysrhythmia7 Electrolyte imbalance7 Heart failure7 Malnutrition54 Postoperative complications Delirium39,55,56 Muscle breakdown43 Chest infection7, 13, 55, 57, 74 Heart failure4,7,57 MI4 Cardiac arrest13, 39 Arrhythmia13 UTI4,7,13,55 CVA4 Pressure sores13,39,55 PE13,39 Renal failure and dialysis39 DVT39,58–60 Wound infection7,13,61 Long-term consequences Institutionalization35,42 Loss of mobility17,35,44,64 New fractures62,63 Increased fall risk22 Loss of functional independence12,23,65–67 Loss of quality of life17 Overall Incidence Incidence incidence in men13 in women13 —————————————————— 20% on — —admission 61%56 10.6% 9.2% — — — 9%4, 7 18.1% 7% 5%4,7 9.3% 8.5% 1%4 — — — 2.3% 0.8% — 5.6% 2.6% 4%4,7 13% 21% 1.4%4 ———6%3.1%——— ——— Without prophylaxis, rate of 50% total DVT and 27% proximal DVT58–60 1.1%7 1.9% 0.4% — — 10.4%/year 3 × increased risk 14%–21% regain ability to perform IADLs 33%–40% regain ability to perform ADLs — Abbreviations: INR, international normalized ratio; MI, myocardial infarction UTI, urinary tract infection; CVA, cerebrovascular accident; PE, pulmonary embolism; DVT, deep vein thrombosis; IADL, instrumental activities of daily living; ADL, activities of daily living. 5. How should this patient be assessed prior to surgery? The goal of the preoperative assessment by the medical specialist is to identify risks that would potentially alter (either delay or cancel) the operative management of patients scheduled for surgery. Specifically in regards to cardiac risks, the medical specialist must exclude the presence of serious coronary artery disease that would warrant direct intervention even if no operation was to be performed.68 The following are the current American College of Cardiology (ACC) or American Heart Association (AHA) recommendations for the perioperative cardiac assessment of patients scheduled for noncardiac surgery68: Class I • Emergent surgery should proceed to the operating room (level C evidence). • Patients with active cardiac conditions should be treated per the ACC/AHA guidelines (level B evidence). • Patients undergoing low-risk surgery may proceed to planned surgery (level B evidence). • Patients with less than 4 metabolic equivalents (METs) (poor functional capacity) or unknown functional capacity should proceed with planned surgery (level B evidence). Class IIa • Patients with a functional capacity of 4 METs or greater without symptoms should proceed to surgery (level B evidence). • Patients with less than 4 METs and 3 or more risk factors that are scheduled for vascular surgery should have additional cardiac testing if that would change patient management (level B evidence). • Patients with less than 4 METs and 3 or more risk factors that are scheduled for intermediate-risk surgery should proceed with planned surgery with heart rate control (level B evidence). • Patients with less than 4 METs and 1 or 2 risk factors that are scheduled for vascular or intermediate-risk surgery should proceed with planned surgery with heart rate control (level B evidence). Class IIb • Noninvasive testing should be considered if it would change the management of patients with less than 4 METs and 3 or more risk factors if they are scheduled for intermediate-risk surgery (level B evidence). • Noninvasive testing should be considered if it would change the management of patients with less than 4 METs and 1 or 2 risk factors if they are scheduled for vascular or intermediaterisk surgery (level B evidence). Any preoperative history should include assessment for the following conditions (Class I, level B evidence).68 • Unstable coronary syndromes (e.g., acute MI occurring 7 days or less before examination, recent myocardial infarction (MI) occurring between 7 and 30 days before examination) • Decompensated heart failure [Class IV, worsening, or new-onset congestive heart failure (CHF)] • Significant arrhythmias (e.g., high-grade AV block, Mobitz type II, third grade AV block, symptomatic ventricular arrhythmias, new-onset ventricular tachycardia) • Severe valvular disease (e.g., aortic stenosis with mean pressure gradient >40 mm Hg or aortic valve area <1.0 cm2, mitral stenosis with progressive dyspnea on exertion or heart failure) Any of the above conditions is considered to be major clinical risk factor. Their presence in the perioperative assessment may prompt either delay to surgery or cancelation of surgery unless the surgery is emergent. There have also been identified intermediate clinical risk factors and minor predictors of cardiac events that should be elicited in the perioperative history (Table 12.2). TAblE 12.2 Predictors of Cardiac Events in the Perioperative Period Intermediate clinical
risk factorsa68,69 History of ischemic heart disease History of compensated heart failure History of cerebrovascular disease Diagnosis of diabetes mellitus Minor predictors of cardiac riskb68 Age more than 70 years Abnormal electrocardiogram (e.g., LVH, LBBB, ST-T abnormalities) Nonsinus rhythm Uncontrolled systematic hypertension Renal insufficiency (serum creatinine >2 mg/dL) aSame risk factors as in the Revised Cardiac Risk Index. bNot been shown to increase cardiac risk independently. Evaluation of a patient’s functional status (number of METs) has also been shown to be beneficial as a reliable predictor of perioperative and long-term cardiac events. Its assessment is most important in those patients with low functional capacity, as management will rarely change on the basis of cardiovascular testing in high-functioning individuals.68,70–76 Some examples of this scale include: • 1 MET = taking care of oneself • 2 MET = walking indoor around the house • 4 MET = doing light work around the house (e.g., washing dishes), walking 4 blocks, or climbing 2 flights of stairs • 5 MET = running a short distance • 9 MET = moderate recreational activities (e.g., golf, bowling, throwing a baseball) • >10 MET = participation in strenuous sports (e.g., swimming, singles tennis) Of most importance to the medical specialist is the recognition of 4 METs as a general cutoff point in evaluating a patient’s cardiac risk before surgery. Under current recommendations, if the patient can function at 4 METs or greater, they generally can proceed safely to the OR without further interventions or cardiac testing.68 Thus, the medical specialist should follow these steps in their evaluation of any patient who presents for noncardiac surgery68: 1. Does the patient need emergent surgery? If yes, then the patient should proceed to the OR. 2. Does the patient have any active cardiac conditions? If yes, those conditions should be evaluated and treated per ACC/AHA guidelines. Surgery may need to be either delayed or canceled. 3. Is the patient scheduled for low-risk surgery? If yes, the patient can proceed to the OR. 4. Does the patient have a functional capacity greater than or equal to 4 METs without symptoms? If yes, the patient can proceed to the OR. 5. If the patient’s functional capacity is less than 4 METs or unknown, the patient’s clinical risk factors should be evaluated: a. If the patient has no clinical risk factors, they may proceed to the OR. b. If the patient has 1 or 2 clinical risk factors and undergoing vascular or intermediate-risk surgery, they may proceed Same risk factors as in the Revised Cardiac Risk Index. to the OR with either perioperative heart rate control or may undergo noninvasive testing if it will change management. c. If the patient has 3 or more clinical risk factors and is undergoing vascular surgery, the patient should undergo cardiac testing if it will change their management. d. If the patient has 3 or more clinical risk factors and is under going intermediate-risk surgery, the patient may proceed to the OR with either perioperative heart rate control or may undergo noninvasive testing if it will change management. Using the above information, our patient in the clinical vignette has only 1 minor predictor of cardiac risk: age greater than 70 years. Therefore, her risk of cardiac complications is low. In addition, this patient presents with the diagnosis of a hip fracture, an emergent surgical procedure. Therefore, regardless of if she had any intermediate clinical risk factors, she should still proceed with surgery after an appropriate medical workup and surgical optimization. It is important to mention that results from a retrospective cohort study by Ricci et al. who evaluated the utility of preoperative cardiac testing in patients with hip fracture demonstrated that preoperative cardiac testing did not lead to changes in medical or orthopedic management and that such testing introduced, on an average, a delay of 3 days to surgery. Preoperative cardiac testing was also estimated to cost approximately $1250 per patient, a figure which did include the costs of extended hospitalization.77 Bottom line: Currently, there is little evidence to support the routine use of preoperative cardiac testing in patients with a hip fracture. This information, when combined with the ACC/AHA recommendations, should prompt physicians to proceed with hip fracture fixation surgery without delay once a patient is adequately stabilized and optimized for surgery. 6. What is the risk of cardiac death and nonfatal MI associated with hip fracture fixation? The risk of adverse cardiac events in orthopedic surgery is relatively low, estimated to be only 1%–5%. However, given that hip fracture fixation is considered an emergent procedure, the predicted risk of cardiac events is greater than 5% and is most likely higher in the elderly.68,78 Note that emergent surgical procedures carry a high cardiac risk due to the inability to perform a normal preoperative cardiac assessment that is possible in patients undergoing elective surgery.68,79 It is therefore reasonable to see whether interventions that reduce adverse cardiac outcomes can help reduce morbidity and mortality in patients who suffer a hip fracture. Bottom line: Hip fracture fixation is associated with high risk (greater than 5%) of cardiac death and nonfatal MI. TAKE-HOME POINTS: EPIDEMIOlOGY AND PERIOPERATIVE MANAGEMENT OF HIP FRACTURE 1. Hip fracture is a common disease of the elderly, occurring most frequently in people aged 75–84 years, typically resulting from a fall. 2. Major postoperative complications following repair of hip fractures include pneumonia, delirium, urinary tract infection (UTI), heart failure, and loss of functional independence. 3. Most epidemiologic studies demonstrate lower survival rates in persons who sustain a hip fracture several years after the time of injury when compared to controls. 4. All patients who sustain a hip fracture should be managed with surgical fixation, an emergent operation. Emergent operations carry a higher risk of cardiac events (cardiac death and nonfatal MI) than those performed on an elective basis. 5. 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Mosekilde. 2004. “Hip Fracture Risk in Statin Users—A Population- Based Danish Case-Control Study.” Osteoporosis International 15 (6): 452–58. 122. Godet, G., M. Dumerat, C. Baillard, S. Ben Ayed, M. A. Bernard, M. Bertrand, K. Kieffer, and P. Coriat. 2000. “Cardiac Troponin I Is Reliable With Immediate but not Medium-Term Cardiac Complications After Abdominal Aortic Repair.” Acta Anaesthesiologica Scandinavica 44 (5): 592–97. 123. Bursi, F., L. Babuin, A. Barbieri, L. Politi, M. Zennaro, T. Grimaldi, A. Rumolo, et al. 2005. “Vascular Surgery Patients: Perioperative and Long-Term Risk According to the ACC/AHA Guidelines, the Additive Role of Post- Operative Troponin Elevation.” European Heart Journal 26 (22): 2448–56. 124. Kim, L. J., E. A. Martinez, N. Faraday, T. Dorman, L. A. Fleisher, B. A. Perler, G. M. Williams, D. Chan, and P. J. Pronovost. 2002. “Cardiac Troponin I Predicts Short-term Mortality in Vascular Surgery Patients.” Circulation 106 (18): 2366–71. 125. Filipovic, M., R. Jeger, C. Probst, T. Girard, M. Pfisterer, L. Gürke, K. Skarvan, and M. D. Seeberger. 2003. “Heart Rate Variability and Cardiac Troponin I Are Incremental and Independent Predictors of OneYear All-Cause Mortality After Major Noncardiac Surgery in Patients at Risk of Coronary Artery Disease.” Journal of the American College of Cardiology 42 (10): 1767– 76. 126. Kertai, M. D., E. Boersma, J. Klein, H. Van Urk, J. J. Bax, and D. Poldermans. 2004. “Long-Term Prognostic Value of Asymptomatic Cardiac Troponin T Elevations in Patients After Major Vascular Surgery.” European Journal of Vascular and Endovascular Surgery 28 (1): 59–66. 127. Dawson-Bowling, S., K. Chettiar, H. Cottam, R. Worth, J. Forder, I. Fitzgerald-O’Connor, D. Walker, and H. Apthorp. 2008. “Troponin T as a Predictive Marker of Morbidity in Patients With Fractured Neck of Femur.” Injury, International Journal of the Care of the Injured 39: 775–80. 128. Auron-Gomez, M., and F. Michota. 2008. “Medical Management of Hip Fracture.” Clinics in Geriatric Medicine 24: 701–19. Asthma

Ch A pter Exacerbation 13 ArijA i. Weddle CASE A 25-year-old man with a history of asthma since childhood is evaluated in the emergency department (ED) for a 2-day history of progressively worsening shortness of breath, cough, wheezing, and fever. He is accompanied by his wife, who gives the history, as the patient is in moderately severe respiratory distress. The patient’s asthma has been well controlled over the years and he has had few exacerbations. His occasional symptoms typically respond promptly to inhaled albuterol. However, despite using his albuterol inhaler frequently over the past 2 days, his symptoms have continued to worsen. On examination he has diffuse expiratory wheezes across all lung fields. His blood pressure is 130/80 mm Hg, heart rate is 125 bpm, and respiratory rate is 32 breaths/min. Peak flow is 226 L/min, approximately 37% of his predicted 610 L/min. Pulse oximetry reveals an oxygen saturation of 88% on room air. 1. What is the differential diagnosis for severe dyspnea with concomitant hypoxemia? There is a broad differential for respiratory distress with hypoxemia but in a patient with known asthma an asthmatic exacerbation is most likely. Other causes of dyspnea with hypoxemia include chronic obstructive pulmonary disease (COPD) exacerbation, congestive heart failure (CHF), pulmonary embolism, malignancy (e.g., primary lung cancer), and vasculitides such as Wegener’s granulomatosis and Churg–Strauss syndrome. Bottom line: There is a broad differential for respiratory distress with hypoxemia but in a patient with known asthma an asthmatic exacerbation is most likely. 159 2. What is the likely diagnosis in this patient? Based on the history (e.g., existing asthma diagnosis), examination (e.g., diffuse wheezes, decreased oxygen saturation), and reduced peak flow values, the most likely cause of this patient’s distress is an acute asthmatic exacerbation. The best way to confirm suspected asthma is by measuring of the FEV1 (forced expiratory volume in 1 second) and PEF (peak expiratory flow) rate.1–3 FEV1 values measure the degree of airflow obstruction in small- to medium-caliber whereas PEF values measure abnormalities of the more effort dependent large-caliber airways. Peak expiratory flow rates are less preferable than spirometry but are easier to obtain in the clinical/emergency setting. FEV1 values <80% of predicted (as determined by height, weight, age, gender, etc) are 29% sensitive and 99% specific for diagnosing asthma in the acutely symptomatic patient and are therefore helpful in confirming an asthma diagnosis.4 Reductions in PEF have 86% sensitivity and 89% specificity for diagnosing asthma; one study shows that the sensitivity increases to 100% when PEF values are paired with positive clinical history or physical findings.5 Physical examination findings in the patient with asthma are variable, and the evidence shows that the signs on physical examination and symptom severity do not necessarily correlate well with severity of airflow obstruction.6,7 Still, there are several findings that can further strengthen the clinical suspicion of asthma. End-expiratory wheezing associated with prolongation of the expiratory phase has a sensitivity of 47% and a specificity of 90% for diagnosing asthma in acute exacerbations.8 A meta-analysis of 17 studies in patients with histories of asthma symptoms rated the sensitivity of wheeze as a predictor of asthma between 16% and 95%, with a mean of 57%.9 The specificity of wheeze in the same studies ranged from 62% to 96%, with a mean of 80%. In acutely symptomatic patients, wheezing had a sensitivity of 45% and a specificity of 93%, and wheeze with cough had a sensitivity of 76% and a specificity of 72%.10 Other signs have not been evaluated for sensitivity and specificity in adults but are nevertheless reported in the literature as being seen in asthma attacks. The patient with asthma may be found sitting in a hunched position with his arms supporting the torso (also known as the tripod position) with a limited ability to speak. The use of accessory muscles for breathing indicates respiratory distress and can be seen in severe asthma exacerbations (as well as in COPD and CHF). Pulsus paradoxus >25 mm Hg can also be seen in severe exacerbations. A very concerning finding is “silent chest,” which represents such severe airflow obstruction that air movement is not sufficient to even produce wheezing or that the patient is so fatigued from the prolonged respiratory distress that he does not have the energy for forceful breathing. Paradoxical thoracoabdominal movement, a phenomenon whereby the chest deflates and the abdomen protrudes during inspiration (the opposite of what normally occurs), is another sign of impending respiratory collapse. Other causes of dyspnea to consider in this patient are upper airway obstruction, COPD, cardiogenic pulmonary edema, and pulmonary embolism. Upper airway obstruction, such as vocal cord dysfunction, foreign body aspiration, or epiglottitis, would typically present with inspiratory wheezes and stridor not seen in asthma exacerbations. Symptoms are less acute and less responsive to treatment with bronchodilators than those of asthma. Many COPD signs and symptoms mirror those of acute asthma, such as prolongation of the expiratory phase of the respiratory cycle accompanied by wheezing, hyperinflation on chest x-ray, and increased lung volumes on pulmonary function testing.11 However, COPD most commonly presents in the elderly patient with smoking history of 20+ pack years and is usually accompanied by fine crackles rather than wheezes.8 Cardiogenic pulmonary edema (sometimes called “cardiac asthma”) results from severe CHF and, as with COPD, typically presents in the elderly patient with a long history of worsening disease. Finally, while pulmonary emboli are relatively common, the large size or number of emboli required to produce symptoms resembling an asthma exacerbation render this diagnosis a rarity. The presence or absence of hypercoagulability risk factors also help to distinguish PE from asthma.12 Bottom line: Based on the history of the patient and presenting signs and symptoms, the most likely diagnosis is acute asthma exacerbation. A cursory physical examination revealing end-expiratory wheezes and FEV1 or PEF values <80% of predicted will further support this initial diagnosis. 3. What is the epidemiology of asthma in the United States? According to 2009 Centers for Disease Control (CDC) data,13 approximately 7.7% of Americans have asthma. Prevalence is higher in women than men, and children up to age 18 are more commonly affected than are adults 18 and over. Asthma also disproportionately affects minority groups: 16.6% of Puerto Ricans and 11.1% of blacks suffer from asthma, compared with 7.8% of whites. In 2007, there were 1.11 million emergency department (ED) visits and 299,000 hospitalizations for asthma exacerbations in adults. Bottom line: Asthma is more prevalent among minorities and is a significant cause of ED visits each year. 4. What is the pathophysiology of allergic asthma and what can precipitate an acute attack? Allergic asthma is an episodic obstructive lung disease characterized by reversible airway narrowing with subsequent airflow limitation. Several mechanisms contribute to the flow limitation found in asthma are as follows: Inflammation : Allergic asthma is characterized by chronic inflammation of the lower airway mucosa. The pattern of inflammation in asthma is complex, involving a multitude of inflammatory cells, structural cells (epithelium), and inflammatory mediators. The inflammatory pattern of allergic asthma resembles that of allergic or atopic diseases, that is, an IgE-mediated response induced by a Th2 phenotype. Evidence suggests that asthma severity directly correlates with the degree of airway eosinophilia. Bronchoconstriction : IgE-mediated constriction of the airways results from the release of inflammatory mediators, especially histamine, tryptase, leukotrienes, and prostaglandins, which induce airway smooth muscle contraction. Asthmatics have particularly robust bronchoconstriction reactions, a phenomenon known as airway hyper-responsiveness (AHR). The mechanisms involved in AHR include inflammation, dysfunctional neuroregulation, and structural changes to the airways. Airway remodeling: Over time, if the inflammation is poorly controlled, severe, and persistent, structural changes occur in the airways. Airway edema and mucus hypersecretion with formation of mucus plugs is an important change seen in all asthmatics. Subepithelial fibrosis leading to thickening of the airway basement membrane, airway smooth muscle hypertrophy, and blood vessel proliferation also occur, and all of these effects can be refractory to treatment and make pharmacologic management of asthma difficult, especially during exacerbations.14 Common causes of asthma exacerbations include allergens (pollen, dust mites, pets, and foods), respiratory viruses, drugs (aspirin and beta-blockers), environmental exposures (tobacco smoke, air pollution, and cockroaches), and exercise. Bottom line: Allergic asthma is a complex disease involving reversible airway inflammation mediated by a Th2-type inflammatory response leading to AHR and remodeling over time. Environmental factors are common triggers of exacerbations. 5. How would you assess the severity of the asthma exacerbation in this patient? Severity of asthma can be difficult to definitively determine, as patient reports of symptoms and objective signs often differ widely among cases and can correlate poorly within individual patients. Therefore, the classification of asthma attack severity can be a somewhat arbitrary clinical diagnosis.15 Serial measurements of lung function are the most efficient tools to measure asthma severity. The presence of signs and symptoms in addition to functional assessment can improve the accuracy of diagnosis by 5%–10%.16 Laboratory studies are typically not needed except in very severe cases. The 2007 Expert Panel Report from the National Asthma Education and Prevention Program (NAEPP) provides the PEF values (Table 13.1) as evidence used to determine severity of the exacerbation. This patient’s symptoms and signs include breathlessness, difficulty speaking, agitation, increased pulse and respiratory rates, and wheeze. Breathlessness at rest indicates a moderate-to-severe exacerbation, and greater difficulty in speaking correlates with increasing severity of the exacerbation. Agitation is seen in moderate-tosevere exacerbations, whereas drowsiness is an excellent predictor of acute respiratory acidosis and ventilatory failure (odds ratio [OR] 8.00, sensitivity 30%, and specificity 95%).18 Respiratory rate >30 breaths/min and heart rate >120 bpm are indicators of severe exacerbation (while bradycardia can be a sign of imminent respiratory failure). Pulse oximetry evaluation is indicated for this patient, as he is in severe distress (evidenced by PEF < 40% predicted combined with symptoms). SaO2 less than 90% can serve to confirm the presence of a severe exacerbation. On its own, oxygen saturation via pulse oximetry has not been shown to be a good predictor of asthma severity.19 TAblE 13-1 Relationship of PEF to Severity of Asthma Exacerbation Mild Moderate Severe Life threatening PEF (% of Predicted ≥70 40–69 <40 <25 or Personal Best) Abbreviations: PEF, peak expiratory flow. The predicted percentages for each severity category are similar for measurements of FEV1.17 This patient’s initial PEF rate was 37% of predicted, indicating that a classification of severe exacerbation should be strongly considered. Arterial blood gas (ABG) measurements are only indicated for patients with life- threatening exacerbations and are used mainly to assess for hypoventilation with hypercarbia and respiratory acidosis, which would indicate imminent respiratory collapse. Evidence suggests that measurement of PEF rates instead of ABG values is adequate to determine impending respiratory failure.20 Bottom line: Asthma severity is best determined by pulmonary function studies. Patient-reported symptoms and pulse oximetry values can aid in confirming a diagnosis of severe asthma exacerbation. 6. What does the evidence suggest should be the pharmacologic treatment of an acute asthma exacerbation? The evidence clearly shows that patients presenting to the ED with a suspected asthmatic exacerbation benefit from systemic corticosteroids (either orally or intravenously [IV]), a short-acting β-agonist (SABA) like albuterol (given either via metered dose inhaler or nebulizer), and possibly from inhaled ipratropium. Short-acting β-agonists: Albuterol has been the mainstay of treatment of asthma exacerbations for many years. Recent studies have shown that levalbuterol is at least as effective as albuterol in improving symptoms of airway obstruction and FEV1/PEF values, with some studies suggesting fewer β-mediated side effects (such as tachycardia) with levalbuterol therapy.21–24 NAEPP guidelines specify that either intermittent or continuous dosage of inhaled albuterol via nebulizer is the most effective treatment of airflow obstruction in severe asthma exacerbations. In mild-to-moderate exacerbations, administration of SABA via metered-dose inhaler (MDI) with spacer is just as effective as nebulized therapy (relative ratio [RR] 0.97; 95% confidence interval [CI]: 0.63–1.49), provided the patient has received proper instruction and coaching by a trained professional.25 The efficacy of levalbuterol delivered through continuous nebulization has not been evaluated in adults. Continuous administration of β-agonists in the ED in patients presenting with asthma exacerbation was associated with reduced hospital admissions (RR: 0.68; 95% CI: 0.5–0.9) compared with patients receiving intermittent β-agonist treatment. This effect was even more pronounced for patients with severe airway obstruction (RR: 0.64; 95% CI: 0.5–0.9). Continuous administration was also associated with statistically significant improvements in FEV1 and PEF values (0.3 and 0.33, respectively) as compared with intermittent administration.26 At high doses, only β2-selective SABAs (albuterol and levalbuterol) should be used to prevent the cardiotoxic effects of β1 agonists. Oxygen : Oxygen via nasal cannula or mask should be started in the ED (or in EMS transport, if applicable) for patients demonstrating signs and symptoms of hypoxemia. Oxygen should be administered until SaO2 > 90% (95% in pregnant women or patients with coexistent heart disease), or until FEV1 or PEF ≥40% of predicted if SaO2 monitoring is not available. Inhaled ipratropium bromide : Adding ipratropium bromide to SABA inhalation produces additional bronchodilatory effects and has been shown to reduce hospital admission in adults with moderate-to-severe exacerbations (RR = 0.68; 95% CI 0.53– 0.86, P = .002).27 No data exist for use of inhaled ipratropium bromide in hospitalized adults. The addition of ipratropium to levalbuterol has not been shown to produce improvements in FEV1 or decrease need for hospitalization when compared with use of levalbuterol alone.28 Systemic corticosteroids : Steroids should be administered to all patients presenting to the ED with moderate-to-severe asthma exacerbation, as well as to any patient who does not respond well (as demonstrated by improvement in FEV1/PEF) to initial SABA treatment. Administration of systemic corticosteroids has been shown to reduce hospitalization rates and improve symptoms in adults.29,30 Use of oral versus IV steroids is controversial and has not been well studied in adults. Some evidence has shown that oral corticosteroids are equally effective as IV corticosteroids in improving symptoms of acute asthma and preventing hospitalization when administered in the ED.31–33 As such, the NAEPP panel of experts has issued the recommendation to use oral systemic corticosteroids whenever possible, due to ease of administration.17 However, IV steroid use in the ED is common, and patients who are unable to be dosed orally should be dosed IV.34 Guidelines for patients admitted to the hospital are similar, with IV steroids being recommended for very severe exacerbations, or if the patient is unable to be dosed orally. The recommended oral dosage is 40–80 mg/d in 1 or 2 divided doses until PEF ≥ 70% predicted; no benefit has been shown for higher doses of steroids.35 Inhaled corticosteroids : The evidence on use of inhaled corticosteroids (ICS) for asthma exacerbation in an emergency or inpatient setting is inconclusive; as such, systemic corticosteroids are the preferred treatment. Antibiotics : Evidence for or against antibiotic use in asthma exacerbations is largely inconclusive;36 however, patients who present with signs and symptoms suggesting co-occurring respiratory infection may benefit from broad-spectrum antibiotic therapy if blood count analysis demonstrates increased neutrophilia indicating a bacterial infection. Treatment with broad-spectrum antibiotics should include coverage for atypical agents and should be held off until response to first-line treatments is able to be assessed.33 Other treatments : Inhaled magnesium sulfate and heliox may be considered in certain severe exacerbations, but the evidence is not sufficient to determine their utility as mainstays of treatment. Bottom line: The goals of treatment for acute asthma in the hospital are to rapidly correct hypoxemia and reverse airflow obstruction. Treatment with a SABA and oxygen should be immediately initiated in the ED. Systemic corticosteroids should also be administered to patients who do not rapidly respond to initial therapies. Additionally, inhaled ipratropium may be appropriate for ED management of severe asthma exacerbations. 7. What does the evidence suggest should be the criteria used in determining whether this patient should be admitted? Evidence suggests that the patient’s response to treatment is an important predictor of need for hospitalization, and the assessment of asthma severity after 1 hour of ED treatment is better than initial severity assessment for determining the need for hospital admission for those patients with moderate- or- severe asthma exacerbations.16 7.1 Response to initial treatment in the ED Based on initial severity assessment as determined principally by peak flow rates, the following treatments should be initiated: • Mild-to-moderate (PEF ≥ 40%): oxygen to achieve SaO2 of 90% or greater; SABA via nebulizer or MDI with spacer for every 20 minutes; systemic corticosteroids if no immediate response to bronchodilator therapy. • Severe (PEF < 40%): oxygen to achieve SaO2 of 90% or greater; SABA plus ipratropium via nebulizer or MDI with spacer every 20 minutes or continuously; systemic corticosteroids The NAEPP guidelines recommend reassessment of PEF values at 30–60 minutes after initial treatment. Evidence shows that change in PEF values measured at 30 minutes was the most important predictor of a good or poor response and subsequent need for hospitalization.37 Other evidence suggests that reassessment of PEF rates after 15 minutes is highly specific for predicting the need for hospitalization.38 7.2 Severity of exacerbation after 1 hour of treatment After no more than an hour of treatment, the patient’s asthma severity should be reassessed using the guidelines for initial classification. A good response is defined as PEF ≥ 70% of predicted and sustained response to treatment 60 minutes after last dosage of inhaled medication, per NAEPP guidelines. These patients do not need to be admitted for further observation or care. Patients with severe exacerbation may have findings consistent with severe asthma on physical examination and often show no improvement after the initial hour of treatment. Treatment should be continued as follows: • Moderate (PEF 40%–69%): inhaled SABA every 60 minutes; systemic corticosteroids. Continue treatment for 1–3 hours if improvement is seen. • Severe (PEF ≤ 40%): oxygen; nebulized SABA + ipratropium every 60 minutes or continuously; systemic corticosteroids; consider adjunct therapies such as magnesium sulfate or heliox. Hospitalization should be considered for an incomplete response (PEF 40%– 69% after a maximum of 4 hours of treatment) and is warranted for a poor response (PEF ≤ 40%, physical examination findings). A caveat to this algorithm is for the patient who presents with signs and symptoms of a life-threatening exacerbation. In these cases, PEF assessment is not indicated and the patient should be admitted immediately to the intensive care unit. Bottom line: Treatment should be initiated as soon as severity of the exacerbation is assessed. Immediate response to treatment and reassessment of severity after 1 hour are the best predictors of need for hospitalization. 8. What other methods can be used to monitor the progression of an acute asthmatic exacerbation in this patient? Although changes in PEF values are the most important indicators of the progression and outcome of acute asthma, other tests can add useful supplemental information. Patient’s report of symptoms : Evidence has shown that patient’s reports of improvements in sensations of dyspnea can correlate with improvements in asthma exacerbation severity.39 Other subjective symptom reports do not correlate well with asthma exacerbation progression.40,41 Pulse oximetry : Pulse oximetry is warranted for this patient, as his exacerbation is severe.42,43 Complete Blood Count (CBC): CBC should be ordered only in patients with signs of suspected infection, such as purulent sputum or fever. CBC values obtained after treatment may not accurately reflect cell counts, as corticosteroid treatment causes leukocytosis 1–2 hours after administration.17 Serum electrolytes: Frequent SABA administration can cause transient decreases in magnesium, potassium, and phosphate, and therefore, it is often prudent to monitor electrolytes, especially in patients who receive extended courses of treatment.17 ABG: As above, these tests are reserved for patients in severe distress and typically provide useful information only in patients with hypoventilation, FEV1 ≤ 25% predicted, and physical examination findings consistent with respiratory failure. Electrocardiogram (EKG): EKGs are not required routinely, but a baseline reading and subsequent continual cardiac monitoring are indicated for patients who are older than 50 and those who have coexistent heart disease or COPD.17 Chest x-ray: CXRs are not generally recommended for asthmatic patients except for in situations of suspected CHF or complicating pulmonary comorbidity such as pneumothorax.44 Bottom line: Serial measurements of lung function (PEF or FEV1) are the best way to monitor progression of the exacerbation. Serial measurements of pulse oximetry are also useful in patients experiencing severe exacerbations. 9. What nonpharmacological interventions does the evidence suggest should be considered for an asthma attack? On the basis of initial presentation, the patient in this example would not be a candidate for mechanical ventilation, as he is not apneic or in coma, and he had an initial PEF > 25%. However, during the course of his ED visit, if the patient shows signs of impending respiratory failure (as discussed earlier), ventilation and transfer to the intensive care unit (ICU) should be considered. Endotracheal intubation (ETI): The decision to intubate in the patient who is not apneic or in coma is a clinical one and is based on many factors. These include, but are not limited to respiratory acidosis and hypercapnia, signs such as silent chest or pulsus paradoxus and depressed mental status. Observational studies45,46 suggest that the ETI technique associated with the best outcomes in asthma exacerbation is “permissive hypercapnia” or “controlled hypoventilation,” a technique focusing on increasing arterial oxygenation by accepting the presence of hypercapnia and treating respiratory acidosis with IV sodium bicarbonate. The recommendation for initial ventilator settings, based on a meta-analysis of intubated asthmatics, include ventilation rate of 10 breaths/min, tidal volume of 7–8 mL/kg, peak inspiratory flow of 60 L/min, and fraction of inspired oxygen of 1.0.47 Noninvasive positive pressure ventilation (NPPV): Preliminary evidence48 is limited but suggests that improvements in respiratory rate, FEV1, and PEF values, as well as decreased length of hospital stay, are associated with the use of NPPV. Bottom line: Intubation and mechanical ventilation should be considered only for the most severe and life-threatening cases of asthma exacerbation, and evidence surrounding technique and outcomes is limited. 10. What patient care measures does the evidence suggest should be established before discharge? This patient may be discharged from the ED (or the hospital if the decision was made to admit) when he is no longer displaying signs and symptoms of respiratory distress, when his oxygen saturation has stabilized > 90%, and when his PEF ≥ 70% and remains stable for 30–60 minutes after the last bronchodilator treatment.17 Other findings suggest that a PEF ≥ 70% is a very conservative assessment, and patients can safely be discharged home with a PEF < 50% predicted, provided they have no symptoms and few or no risk factors for asthmarelated death, such as smoking or non-white race.49 Before discharge, however, it is important to implement a medication regimen and, if possible, arrange for patient follow-up with a primary care provider. Corticosteroids : Evidence strongly shows that a short course of systemic corticosteroids for patients being discharged from the ED following an asthma exacerbation is beneficial in preventing relapse of symptoms and rehospitalization.50,51 A fixed dose of no more than 50–100 mg/kg of oral corticosteroids is sufficient and no taper is needed.31 A new study (2011) suggests that 2 days of dexamethasone may be at least as effective as the traditional 5 days of prednisone in returning asthma patients to baseline after an ED visit.52 Additionally, patients should be started on a daily inhaled corticosteroid, as evidence showed that ICS users had 45% fewer relapse ED visits than ICS nonusers.53 Bronchodilators : Patients should continue with SABA treatment postdischarge, dosing at regular intervals (usually every 4–6 hours) rather than on an as-needed basis. This therapy (“sick plan”) should be continued until the patient’s follow- up appointment (ideally 1–4 weeks postdischarge).17 Action plan : Written action plans have been shown to be beneficial in managing future asthma exacerbations and preventing subsequent ED visits.54 Action plans should detail when to increase treatment (i.e., an “action point”), how to increase treatment and for how long, and when to seek medical attention. The evidence suggests that written plans based on personal best PEF, 2–4 “action points,” and use of both oral and inhaled corticosteroids for exacerbations were the most effective in improving asthma health outcomes.55 Additionally, use of written action plans has been associated with a statistically significant reduction in death from asthma (OR 0.29; 95% CI 0.09–0.93).56 Follow-up with primary care provider : Although evidence is inconclusive about optimal referral procedure (e.g., primary care provider or asthma specialist, timing of the visit) as it relates to long-term asthma health outcomes, when feasible, the ED physician should attempt to schedule a follow-up appointment with the patient’s primary provider, as this assistance significantly increases the likelihood that the patient obtains and attends that appointment.57 Bottom line: Patients may be discharged when they appear clinically well, and PEF is ≥ 70% of predicted or personal best and remains there for 30–60 minutes following last bronchodilator treatment. Patients should be discharged with a written action plan detailing instructions regarding steroid and SABA use. TAKE-HOME POINTS: ASTHMA EXACERbATION 1. In a patient with an established history of asthma who presents with severe dyspnea and hypoxemia, acute asthma exacerbation is the most likely diagnosis. Wheeze, dyspnea, and cough are characteristic of an acute asthma exacerbation, while FEV1 and PEF values are the most important criteria in making the diagnosis of asthma exacerbation. 2. PEF is easier and more convenient to assess than FEV1 and is therefore generally preferred in an emergency setting. 3. Asthma severity is primarily assessed by comparing initial PEF values to the patient’s predicted or personal best; values less than 40% indicate a severe exacerbation. 4. All patients presenting to the ED with an asthma exacerbation should receive a SABA via nebulizer or metered dose inhaler and systemic corticosteroids. 5. Oral systemic corticosteroids may as effective as IV steroids and can be used in the ED unless the patient is unable to be dosed orally. 6. Oxygen therapy should be initiated for patients with oxygen saturation values below 90%. 7. Inhaled ipratropium bromide is recommended for patients experiencing severe exacerbations. 8. The decision to admit should be based on response to initial therapies and reassessment of exacerbation severity after 1 hour of treatment. 9. Serial measurements of PEF are the most reliable indicators of severity progression, and serial pulse oximetry measurements can also be useful. 10. ETI or noninvasive positive pressure ventilation should be considered for patients with PEF < 25% of predicted or who show signs of impending respiratory failure and very poor response to treatment. REFERENCES 1. Rodrigo, G., and C. Rodrigo. 1993. “Assessment of the Patient with Acute Asthma in the Emergency Department: A Factor Analytic Study.” Chest 104: 1325–28. 2. Jain, P., M. S. Kavuru, C. L. Emerman, and M. Ahmad. 1998. “Utility of Peak Expiratory Flow Monitoring.” Chest 114: 861–76. 3. Leroyer, C., L. Perfetti, C. Trudeau, J. L’Archeveque, M. Chan-Yeung, and J. Malo. 1998. “Comparison of Serial Monitoring of Peak Expiratory Flow Rate and FEV1 in the Diagnosis of Occupational Asthma.” American Journal of Respiratory Critical Care Medicine 158: 827–32. 4. Dupont, L. J., M. G. Demedts, and G. M. Verleden. 2003. “Prospective Evaluation of the Validity of Exhaled Nitric Oxide for the Diagnosis of Asthma.” Chest 123 (3): 751–56. 5. Cote, J., S. Kennedy, and M. Chan-Yeung. 1990. “Sensitivity and Specificity of PC20 and Peak Expiratory Flow Rate in Cedar Asthma.” Journal of Clinical Immunology 85: 592–98. 6. Teeter, J. G., and E. R. Bleecker. 1998. “Relationship between Airway Obstruction and Respiratory Symptoms in Adult Asthmatics.” Chest 113: 272– 77. 7. Pratter, M. R., D. M. Hingston, and R. S. Irwin. 1983. “Diagnosis of Bronchial Asthma by Clinical Evaluation: An Unreliable Method.” Chest 84 (1): 42–47. 8. van Schayck, C. P., C. van Weel, H. J. Harbers, and C. L. van Herwaarden. 1991. “Do Physical Signs Reflect the Degree of Airflow Obstruction in Patients with Asthma or Chronic Obstructive Pulmonary Disease?” Scandinavian Journal of Primary Health Care 9: 232–38. 9. Toren, K., J. Brisman, and B. Jarvholm. 1993. “Asthma and Asthma-like Symptoms in Adults Assessed by Questionnaires: A Literature Review.” Chest 104: 600–8. 10. Kilpeläinen, M., E. O. Terho, H. Helenius, and M. Koskenvuo 2001. “Validation of a New Questionnaire on Asthma, Allergic Rhinitis, and Conjunctivitis in Young Adults.” Allergy 56: 377–84. 11. Tilles, S. A. 2006. “Differential Diagnosis of Adult Asthma.” The Medical Clinics of North America 90: 61–76. 12. Cydulka, R. K. 2011. “Acute Asthma in Adults.” In Tintinalli's Emergency Medicine: A Comprehensive Study Guide. 7th ed., edited by J. E. Tintinalli, J. S. Stapczynski, D. M. Cline, O. J. Ma, R. K. Cydulka, and G. D. Meckler, Chapter 72. New York: McGraw-Hill. Accessed November 13. http:// www.accessmedicine.com/content.aspx?aID=6352648 13. Akinbami, L. J., J. E. Moorman, and X. Liu. 2011. “Asthma Prevalence, Health Care Use, and Mortality: United States, 2005–2009.” National Center for Health Statistics. National Health Statistics Reports 32. http:// www.cdc.gov/nchs/data/nhsr/nhsr032.pdf 14. Barnes, P. J. 2011. “Asthma.” In Harrison’s Principles of Internal Medicine. 18th ed., edited by D. L. Longo, A. S. Fauci, D. L. Kasper, S. L. Hauser, J. L. Jameson, and J. Loscalzo, Chapter 254. New York: McGraw-Hill. http://www.accessmedicine.com/content.aspx?aID=9127709 15. McFadden, E. R. 2003. “Acute Severe Asthma.” American Journal of Respiratory Critical Care Medicine 168: 740–59. 16. Kelly, A., D. Kerr, and C. Powell. 2004. “Is Severity Assessment After One Hour of Treatment Better for Predicting the Need for Admission in Acute Asthma?” Respiratory Medicine 98: 777–81. 17. National Asthma Education and Prevention Program. 2007. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. NIH Pub No 07–4051. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health. Available from http://www.nhlbi.nih.gov/guidelines/asthma/ 18. Cham, G. W. M., W. P. Tan, A. Earnest, and C. H. Soh. 2002. Clinical Predictors of Acute Respiratory Acidosis during Exacerbation of Asthma and Chronic Obstructive Pulmonary Disease. European Journal of Emergency Medicine 9: 225–32. 19. Hardern, R. 1996. “Oxygen Saturation in Adults with Acute Asthma.” Journal of Accident and Emergency Medicine 13: 28–30. 20. Martin, T. G., R. M. Elenbaas, and S. H. Pingleton. 1982. “Use of Peak Expiratory Flow Rates to Eliminate Unnecessary Arterial Blood Gases in Acute Asthma.” Annals of Emergency Medicine 11: 70–73. 21. Lötvall, J., M. Palmqvist, P. Arvidsson, A. Maloney, G. P. Ventresca, and J. Ward 2001. “The Therapeutic Ratio of R-Albuterol is Comparable with that of RS-albuterol in Asthmatic Patients.” The Journal of Allergy and Clinical Immunology 108 (5): 726–31. 22. Handley D. A, D. Tinkelman, M. Noonan, T. E. Rollins, M. E. Snider, and J. Caron 2000. “Dose-Response Evaluation of Levalbuterol versus Racemic Albuterol in Patients with Asthma.” Journal of Asthma 37 (4): 319–327. 23. Schreck, D. M., and S. Babin. 2005. “Comparison of Racemic Albuterol and Levalbuterol in the Treatment of Acute Asthma in the ED.” American Journal of Emergency Medicine. 23: 842–47. 24. Donohue, J. F., N. A. Hanania, R. L. Ciubotaru, L. Noe, D. J. Pasta, K. Schaefer, R. Claus, W. T. Andrews, and J. Roach. 2008. “Comparison of Levalbuterol and Racemic Albuterol in Hospitalized Patients with Acute Asthma or COPD: A 2-week, Multicenter, Randomized, Open-label study.” Clinical Therapeutics 30: 989–1002. 25. Cates, C. J., J. A. Crilly, and B. H. Rowe. 2006. “Holding Chambers (Spacers) versus Nebulisers for Beta-Agonist Treatment of Acute Asthma.” The Cochrane Database of Systematic Reviews (2): CD000052. 26. Camargo, C. A., Jr., C. Spooner, and B. H. Rowe. 2003. Continuous versus Intermittent Beta- Agonists for Acute Asthma.” The Cochrane Database of Systematic Reviews (4): CD001115. 27. Rodrigo, G. J., and J. A. Castro-Rodriguez. 2005. “Anticholinergics in the Treatment of Children and Adults with Acute Asthma: A Systematic Review with Meta-Analysis.” Thorax 60: 740–46. 28. Cydulka, R. K., C. L. Emerman, and A. Muni. 2010. “Levalbuterol versus Levalbuterol Plus Ipratropium in the Treatment of Severe Acute Asthma.” Journal of Asthma 47 (10): 1094–100. 29. Edmonds, M., C. A. Camargo, C. V. Pollack, and B. H. Rowe. 2003. “Early Use of Inhaled Corticosteroids in the Emergency Department Treatment of Acute Asthma.” The Cochrane Database of Systematic Reviews (3): CD002308. 30. Rowe, B. H., C. Spooner, F. M. Ducharme, J. A. Bretzlaff, G. W. Bota. 2001. “Early Emergency Department Treatment of Acute Asthma with Systemic Corticosteroids.” The Cochrane Database of Systematic Reviews (1): CD002178. 31. Krishnan, J. A., S. Q. Davis, E. T. Naureckas, P. Gibson, and B. H. Rowe. 2009. “An Umbrella Review: Corticosteroid Therapy for Adults with Acute Asthma.” The American Journal of Medicine 122 (11): 977–91. 32. Ratto, D., C. Alfaro, J. Sipsey, M. M. Glovsky, and O. P. Sharma. 1988. “Are Intravenous Corticosteroids Required in Status Asthmaticus?” Journal of American Medical Association 260 (4): 527–29. 33. Rowe, B. H., J. L. Keller, and A. D. Oxman. 1992. “Effectiveness of Steroid Therapy in Acute Exacerbations of Asthma: A Meta-Analysis.” American Journal of Emergency Medicine 10 (4): 301–10. 34. Winters, A. C. 2004. “Management of Acute Severe Asthma.” Critical Care Nursing Clinics of North America 16: 285–91. 35. Manser, R., D. Reid, and M. J. Abramson. 2001. “Corticosteroids for Acute Severe Asthma in Hospitalised Patients.” The Cochrane Database of Systematic Reviews (1): CD001740. 36. Graham, V., T. J. Lasserson, and B. H. Rowe. 2001. “Antibiotics for Acute Asthma.” The Cochrane Database of Systematic Reviews (2): CD002741. 37. Rodrigo, G., and C. Rodrigo. 1998. “Early Prediction of Poor response in Acute Asthma Patients in the Emergency Department.” Chest 114: 1016–21. 38. Piovesan, D. M., D. M. Menegotto, S. Kang, E. Franciscatto, T. Millan, C. Hoffmann, L. R. Pasin, J. Fischer, S. S. Barreto, and T. Dalcin Pde. 2006. “Early Prognosis of Acute Asthma in the Emergency Room.” Brazilian Journal of Pulmonology 32 (1): 1–9. 39. Karras, D. J., M. E. Sammon, C. A. Terregino, B. L. Lopez, S. K. Griswold, and G. K. Arnold. 2000. “Clinically Meaningful Changes in Quantitative Measures of Asthma Severity.” Academic Emergency Medicine 7 (4): 327–34. 40. Rodrigo, G. J. 2009. “Predicting Response to Therapy in Acute Asthma.” Current Opinion in Pulmonary Medicine 15: 35–38. 41. Corre, K. A., and R. J. Rothstein. 1985. “Assessing Severity of Adult Asthma and Need for Hospitalization.” Annals of Emergency Medicine 14: 45– 52. 42. Boychuk, R. B., L. G. Yamamoto, C. J. DeMesa, and K. M. Kiyabu. 2006. “Correlation of Initial Emergency Department Pulse Oximetry Values in Asthma Severity Classes (Steps) with the Risk of Hospitalization.” American Journal of Emergency Medicine 24 (1): 48–52. 43. Ribeiro de Andrade, C., M. C. Duarte, and P. Camargos. 2007. “Correlations between Pulse Oximetry and Peak Expiratory Flow in Acute Asthma.” Brazilian Journal of Medical and Biological Research 40 (4): 485–90. 44. Tsai, T. W., E. J. Gallagher, G. Lombardi, P. Gennis, and W. Carter. 1993. “Guidelines for the Selective Ordering of Admission Chest Radiography in Adult Obstructive Airway Disease.” Annals of Emergency Medicine 22 (12): 1854–58. 45. Tuxen, D. V. 1994. “Permissive Hypercapnic Ventilation.” American Journal of Respiratory and Critical Care Medicine 150: 870–74. 46. Darioli, R., and C. Perret. 1984. “Mechanical Controlled Hypoventilation in Status Asthmaticus.” The American Review of Respiratory Disease 129 (3): 385–87. 47. Brenner, B., T. Corbridge, and A. Kazzi. 2009. “Intubation and Mechanical Ventilation of the Asthmatic Patient in Respiratory Failure.” Proceedings of the American Thoracic Society 6: 371–79. 48. Ram, F. S. F., S. R. Wellington, B. H. Rowe, and J. A. Wedzicha. 2005. “Non-invasive Positive Pressure Ventilation for Treatment of Respiratory Failure due to Severe Acute Exacerbations of Asthma.” The Cochrane Database of Systematic Reviews (3): CD004360. 49. Weber, E. J., R. A. Silverman, M. L. Callaham, C. V. Pollack, P. G. Woodruff, S. Clark, and C. A. Camargo Jr. 2002. “A Prospective Multicenter Study of Factors Associated with Hospital Admission Among Adults with Acute Asthma.” American Journal of Medicine 113: 371–78. 50. Rowe, B. H., C. Spooner, F. Ducharme, J. Bretzlaff, and G. Bota. 2007. “Corticosteroids for Preventing Relapse Following Acute Exacerbations of Asthma.” The Cochrane Database of Systematic Reviews (3): CD000195. 51. Krishnan, J. A., R. Nowak, S. Q. Davis, and M. Schatz. 2009. “Anti- inflammatory Treatment after Discharge Home from the Emergency Department in Adults with Acute Asthma. Journal of Emergency Medicine 37 (2S): S35–41. 52. Kravitz, J., P. Dominici, J. Ufberg, J. Fisher, and P. Giraldo. 2011. “Two Days of Dexamethasone versus 5 Days of Prednisone in the Treatment of Acute Asthma: A Randomized Controlled Trial.” Annals of Emergency Medicine 58 (2): 200–5. 53. Sin, D. D., and S. F. P. Man. 2002. “Low-dose Inhaled Corticosteroid Therapy and Risk of Emergency Department Visits for Asthma.” Archives of Internal Medicine 162: 1591–95. 54. Hodder, R., M. D. Lougheed, B. H. Rowe, J. M. FitzGerald, A. G. Kaplan, and R. A. McIvor. 2009. “Management of Acute Asthma in Adults in the Emergency Department: Nonventilatory Management.” Canadian Medical Association Journal 182 (2): E55–67. 55. Gibson, P. G., and H. Powel. 2004. “Written Action Plans for Asthma: An Evidence-based Review of the Key Components.” Thorax 59: 94–99. 56. Abramson, M. J., M. J. Bailey, F. J. Couper, J. S. Driver, O. H. Drummer, A. B. Forbes, J. J. McNeil, E. H. Walters, and the Victorian Asthma Mortality Study Group. 2001. “Are Asthma Medications and Management Related to Deaths from Asthma?” American Journal of Respiratory and Critical Care Medicine 163: 12–18. 57. Baren, J. M., E. D. Boudreaux, B. E. Brenner, R. K. Cydulka, B. H. Rowe, S. Clark, and C. A. Camargo Jr. 2006. “Randomized Controlled Trial of Emergency Department Interventions to Improve Primary Care Follow-up for Patients with Acute Asthma.” Chest 129: 257–65.

Chapter COPD Exacerbation 14 Christian aCharte CASE A 57-year-old man with a 40-pack-year history of smoking presents to the emergency department for evaluation of a 2-day history of progressively worsening dyspnea, productive cough, and subjective fever. Seven years ago, he began to feel short of breath while climbing stairs and during extended walks. The breathing difficulties gradually worsened and were soon accompanied by a chronic, productive cough. Recent pulmonary function testing revealed an FEV1/FVC ratio of 45% and an FEV1 of 65% of predicted. Examination is significant for mild respiratory distress and fever of 101.5°F. He has diffuse expiratory wheezes and coarse crackles in the right lung base. A chest x-ray (CXR) suggests consolidation of the right lung base with a small pleural effusion. An arterial blood gas reveals an O2 saturation of 80% and a PaCO2 of 58 mm Hg. White blood cell count is 13,000/μL. 1. What is the likely diagnosis in this patient and what other conditions should be included in the differential? The patient’s significant smoking history and previous symptoms of gradually worsening dyspnea and productive cough along with mild leukocytosis and hypoxemia suggest that acute exacerbation of chronic obstructuve pulmonary disease (COPD) is a likely diagnosis. Progression of COPD is characterized by a constant decline of pulmonary function with sudden worsening of symptoms that ultimately leads to ventilation–perfusion (V/Q) mismatch and potential respiratory failure.1 The differential for sudden dyspnea with productive cough is broad and should include respiratory, cardiac, and infectious etiologies. This patient has no history of asthma, but a quick way to differentiate asthma 177 exacerbation from COPD exacerbation is by the patient’s response to bronchodilator treatment. Asthmatic airflow obstruction, by definition, is largely reversible with bronchodilators, whereas COPD exacerbations have limited reversibility (although some COPD patients will nonetheless respond to bronchodilators). Note that the symptoms described above could potentially indicate a respiratory infection like pneumonia, but low fever and mild leukocytosis make this less likely. Finally, lack of edema, jugular venous distention, and cardiac murmurs suggest that a cardiac etiology is unlikely.2,3 Bottom line: Consider acute COPD exacerbation in any patient who presents with appropriate risk factors (i.e., extensive smoking history) and symptoms of a respiratory disorder (e.g., productive cough, dyspnea, and hypoxemia). 2. What could have served as potential triggers for this patient’s exacerbation? History of smoking is a common trigger for acute COPD exacerbation, however, the patient’s low-grade fever and radiographic opacity on CXR point toward a respiratory tract infection as the likely trigger. Unfortunately, approximately 30% of the time the etiology of exacerbation is unclear.4 Infections account for up to 75% of COPD exacerbations. Respiratory infections can be classified into bacterial (40%–60%) and viral (15%–30%) origins. Common viral causes of respiratory illness include rhinovirus, influenza, parainfluenza, coronavirus, adenovirus, and respiratory syncytial virus. COPD patients have a subtle vulnerability to gram-negative bacterial infections as shown by increased rates of Haemophilus influenza and Pseudomonas aeruginosa infections among COPD patients with FEV1 < 50%.5 The usual culprits infecting these patients are H. influenza (30%–59%), Moraxella catarrhalis (3%–22%), and Streptococcus pneumoniae (15%–25%). A special subgroup of bacterial infections involving P. aeruginosa, Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae have been noted to cause severe exacerbations.6–8 Acute COPD exacerbation can also be triggered by industrial pollutants, allergens, and sedatives. In addition, pulmonary embolism (PE) and congestive heart failure (CHF) can act as COPD triggers, although making this connection can be tricky as both may present independently with similar findings of dyspnea and cough. The presence of all these triggers can set the stage for an exacerbation with a multifactorial etiology. Bottom line: Although one-third of exacerbations are of unknown etiology, many cases of COPD exacerbation are triggered by respiratory infections, which are often bacterial in origin. 3. Based on the evidence, what is considered to be an appropriate diagnostic workup for this patient? Although a broad workup, including physical examination, electrocardiogram (ECG), and sputum culture, could be used to help elucidate the diagnosis, no clear evidence has shown that such testing results in better outcomes in suspected COPD exacerbations.1 However, CXRs were shown to be useful in adequately evaluating and ultimately changing the treatment of individuals in need of emergency care for COPD exacerbations.9 This comes from an analysis comparing rates of treatment by altering CXR abnormalities found in patients deemed “complicated” obstructive airway disease cases of which COPD exacerbations were the primary contributor.9 Complicated cases were defined as individuals presented with obstructive airway disease with a history of COPD, fever greater than 100.0°F, heart disease, intravenous drug use, seizures, or immunosuppression. This study showed that CXR resulted in a therapeutic change in 21% of these patients with “complicated” obstructive airway disease. Ultimately, according to the study, it would be unsafe to forgo CXR of patients with COPD exacerbations given the likelihood of finding further thoracic complications.9 Bottom line: Although examination findings and sputum cultures almost certainly remain the standard of care for the diagnostic workup of suspected acute COPD exacerbation, no clear evidence supports their use. CXR findings have been shown to significantly alter management. 4. How would you classify the severity of this patient’s COPD exacerbation? Will such classification help guide clinical management? As per Anthontsen and colleagues’ scale, this patient’s severity would be classified as Type II as a result of worsening dyspnea and increased sputum production although this classification should not be used to guide clinical management.2 Anthontsen’s scale uses a symptomatic basis to assess acute exacerbation severity and is the favored criteria in research.2 This model looks for the presence of three symptoms to assess disease severity: worsening dyspnea, increase in sputum purulence, and increased sputum volume. Various COPD exacerbation classification models focus on different aspects of the disease (Table 14.1). Unfortunately, there are no data that suggest a correlation between the use of any of these classification systems and prognosis. They cannot be relied upon as guiding tools for determining admission or treatment. Such decisions depend on clinical judgment. Other models suggested by the American Thoracic Society TABlE 14.1 Relationship of COPD Severity and FEV1 COPD Severity: ATS/ERS criteria stage FEV1 I, Mild >80 II, Moderate >50, <80 III, Severe >30, <50 IV, Very severe <30 Abbreviations: FEV1, forced expiratory volume in 1 second. (ATS) and European Respiratory Society (ERS) are retrospective and defined by the level of treatment used to stabilize the patient during a COPD exacerbation.10 Bottom line: Although there are various classification systems for acute COPD exacerbations, they seem to be of little use in determining therapy or prognosis. 5. Does evidence indicate whether performing spirometry in the acute setting has diagnostic value? No, the diagnostic value of spirometry performed in acute COPD exacerbations has been shown in multiple studies to have minimal diagnostic or prognostic value.1,11 There is a poor correlation between a patient’s clinical status, which is typically related to oxygen saturation, and spirometric changes during an exacerbation.1 Despite these findings, patients with severe chronic COPD, as determined by Global initiative for chronic Obstructive Lung Disease (GOLD) criteria, which grades exacerbation severity on spirometric results,3 have more frequent exacerbations and have an increased risk of mortality. This patient’s FEV1 of 75% indicates that he has Stage II COPD according to ATS/ERS criteria. Thus, one may predict that he is at a greater risk for mortality than an individual with mild COPD but has a reduced risk when compared to an individual with severe COPD. Fortunately, 54% of COPD exacerbations are found in individuals with mild to moderate disease and are usually easier to treat.12 Bottom line: Spirometry has little diagnostic utility during COPD exacerbations because there is a poor correlation between clinical status and spirometric readings. 6. Based on the evidence, what is this patient’s likely prognosis during his hospitalization? The patient’s recent history of COPD exacerbations is concerning on many levels. Given that this is his third exacerbation this year, the patient is at a high risk for an in-hospital mortality.13 Admitted patients with a history of 3 or more COPD exacerbations within a year have a 4.3 times increased risk of death when compared to COPD patients without exacerbations.13 Other independent variables that have been identified as negative prognostic indicators during COPD exacerbations include body mass index, current smoking, advanced age, poor functional status, a low PaO2:FiO2 ratio, CHF, and corpulmonale.13 Bottom line: COPD patients who experience acute exacerbations are at a greater risk of mortality compared to patients who do not experience exacerbations. 7. What is the prognostic significance of this patient’s elevated pCO2? The evidence suggests that this patient’s elevated pCO2 of 58 mm Hg increases his risk for early mortality.10 One study of hospitalized patients with COPD exacerbations demonstrates an inverse correlation between mortality and rates of hypercarbia (pCO2 > 50 mm Hg).2 Although most patients with hypercarbia that were enrolled in this study survived their initial hospital stay (11% inpatient mortality rate), there was a dramatic increase in the mortality rate of surviving individuals to 33% at 6 months, 42% at 1 year, and 49% at 2 years.14 Bottom line: Patients presenting with COPD exacerbation with a pCO2 greater than 50 mm Hg have a poor prognosis, as roughly 50% of these patients die within two years of their hospitalization. 8. Does evidence suggest that bronchodilators should be used to treat this patient? Yes, the evidence supports the use of bronchodilators in this patient. The patient is showing signs of respiratory distress, as supported by the presence of dyspnea and decreased oxygen saturation. These symptoms in a patient with COPD exacerbation are largely due to bronchoconstriction, thus warranting the use of fast-acting bronchodilator therapy to reverse respiratory obstruction.3 Depending on the severity of the exacerbation, this form of treatment has been shown to alleviate symptoms of dyspnea and decreased exercise tolerance in addition to improving gas exchange. The 2 main types of bronchodilators used are short- acting β-agonists and anticholinergic agents. Treatment for this patient should begin with dual administration of inhaled ipratropium and albuterol, as this combination is well studied and commonly used. Various studies have shown these 2 bronchodilators to be equally efficacious and to have an additive effect on relief of respiratory function when administered together. There was no significant difference between the two drugs when their individual effects on hospital stay and pulmonary function were compared.15 One study reported a 28% versus 26% improvement in FEV1 when comparing ipratropium and albuterol, respectively. The same study also reported a 9% increase in FEV1 with combined bronchodilator therapy when compared to monotherapy.16 Although, two medications are equally efficacious, albuterol and other β- agonists should not be given to patients with COPD exacerbations without coadministration of ipratropium. Due to the widespread use of β-agonists for management of chronic respiratory diseases (COPD and asthma), the use of albuterol as sole therapy has been shown on occasion to have little to no effect on some patients with COPD exacerbations. According to 1 study, a 2.5-fold increase in respiratory death was noted in patients with COPD exacerbation treated with albuterol when compared to the placebo group. This was later explained by the development of tolerance and resurfacing of hypersensitivity with chronic β-agonist use.17 The coadministration of ipratropium has been shown to offset this occasional decline in respiratory response.18,19 Patients taking albuterol for COPD exacerbation showed no statistical improvement in pulmonary function beyond 2.5 mg, although a more rapid onset of peak flow recovery was noted with higher doses.20 Ipratropium use in these patients showed no improvement beyond 125 μg. Both medications were found to provide adequate protection when given in 4- to 6-hour intervals and were found to be most efficacious when administered as inhalants.21 Bottom line: Ipratropium and albuterol have equal efficacy and have additive properties in improving symptoms of respiratory failure. Thus, they should be used in unison as first-line treatment in any COPD exacerbation. 9. Does the evidence suggest that theophylline be used for treatment in this patient? No, this patient should not be started on theophylline. He should only be considered for theophylline treatment if ipratropium and albuterol prove to be ineffective. Although improvement in as many as 21% of unresponsive patients has been noted with theophylline use, the narrow therapeutic index of this drug limits its widespread use. A dosing study implementing the same amount of theophylline across a population resulted in 47% of patients at subtherapeutic levels, 46% at therapeutic levels, and 7% at toxic levels.22,23 Bottom line: Methylxanthines such as theophylline should be considered as second-line treatment in COPD patients if anticholinergics and β-agonists treatment fails. 10. Does the evidence suggest that this patient should receive corticosteroids? Yes, this patient should be given corticosteroids to help reduce hospital stay and improve pulmonary function.24 The use of corticosteroids in COPD exacerbations has been shown to reduce relapse rates as well as treatment failure by as much as 10%. Furthermore, use of corticosteroid has been shown to improve FEV1 spirometric findings by as much as 10%. The change remained statistically significant through the first 3 days of treatment but not beyond 2 weeks.25 Studies have shown little difference in efficacy between intravenous and oral corticosteroid administration. Inhaled corticosteroids have proven to be unfavorable due to significant association with the development of pneumonia.23 The most annoying side effect of corticosteroid use is the potential for hyperglycemic episodes. Two-thirds of these episodes occurred in individuals with a history of diabetes mellitus within the first 30 days of treatment.21 Bottom line: Corticosteroids have been shown to reduce treatment failure and relapse rates and improve the pulmonary function. Hyperglycemia is the most significant side effect of corticosteroid use. 11. Does the evidence suggest that this patient receive oxygen treatment? Yes.26 Given this patient’s hypoxic state (less than 90% O2 saturation), he should be started on oxygen treatment. Studies have demonstrated that oxygen, in the setting of an acute COPD exacerbation, can decrease respiratory failure and mortality.26 Oxygen has also been shown to help decrease pulmonary vasoconstriction and right heart strain. In an acute COPD exacerbation, the most concerning complication of O2 use is the development of hypercarbia. The prevalence of hypercarbia was reported to be as high as 94% in certain studies.27 The patients with the most drastic elevation in pCO2, upon oxygen administration, were those with the lowest- presenting PaO2.28 A predictive model was developed that describes the correlation between presenting arterial pH and PaO2 in individuals who were likely to progress to respiratory failure later in treatment. The model was found to be 77% sensitive.29 This phenomenon can be explained by the Haldane effect and depression of respiratory drive by decomposition of oxygen-dependent respiration in extremely hypoxic individuals. Bottom line: Oxygen is a very important form of therapy for patients in respiratory distress. The most important side effect is the risk of hypercarbia and potential progression to respiratory failure. 12. Does the evidence suggest that this patient should receive antibiotic treatment? No, this patient should not receive antibiotics. Given this patient’s moderate severity, as shown by low-grade fever, mild oxygen saturation depression, and mildly elevated WBC count, the use of antibiotics is not likely to afford any real benefit because there is poor evidence for bacterial infection.17 A study comparing the efficacy of antibiotic use among patients with severe COPD exacerbations reported symptomatic improvement among 63% of those treated with antibiotics versus 43% in the placebo group.30 The study went on to show drastically reduced improvement rates for those with moderate and mild COPD exacerbations. Thus, the use of antibiotics should only be administered during severe exacerbations. Although expert advice points toward the use of a 3- to 14-day antibiotic regimen, there are few data to support this duration. In one retrospective study, amoxicillin and ciprofloxacin were administered to 2 similar groups with COPD exacerbation.31 Both treatment options showed improvement in ∼70% of patient groups. Amoxicillin showed notable improvement between 6 and 10 days of treatment, whereas ciprofloxacin showed similar therapeutic effects with 10–15 days of treatment. To date, no data have shown that any particular antibiotic is more efficacious than another.31 Bottom line: Antibiotics are unlikely to have a significant benefit in mild or moderately severe COPD exacerbations and should typically be reserved for severe exacerbations. 13. What should be considered before starting this patient on noninvasive positive pressure ventilation? Studies have shown that use of noninvasive positive pressure ventilation (NPPV) decreases the need for intubation. One prospective randomized study reported a 3-fold decrease in intubation rates among those treated with NPPV versus those who were not.33 A meta-analysis, similarly, concluded that patients receiving NPPV were less likely to need mechanical ventilation therapy and had a reduced mortality compared to similarly ill patients who did not receive NPPV.34 However, NPPV should not be considered in a patient such as this one who presents with a moderate COPD exacerbation unless he or she fails to respond to first-line therapy. This is due to potentially serious complications of NPPV administration, which include aspiration, mucus plug formation, and hypotension.32 Bottom line: NPPV has been shown to decrease rate of intubation and risk of death in patients admitted for COPD exacerbation, but should not be administered as first-line therapy due to potentially serious adverse effects associated with its use. TAKE-HOME POINTS: ACUTE COPD EXACERBATION 1. COPD exacerbations present as sudden episodes of worsening productive cough, dyspnea, and hypoxia and are often accompanied or triggered by a respiratory infection. 2. The evidence does not support the routine use of spirometry, sputum culture, and the electrocardiogram in the diagnostic workup of suspected COPD exacerbation. 3. There are various classification systems for COPD exacerbation severity, none of which substantially alter clinical decision making in the emergency department. 4. The frequency of exacerbations and presenting hypercarbia are the most harrowing signs of increased mortality in COPD patients. 5. Inhaled ipratropium and albuterol should be used as first-line treatments in patients with COPD exacerbation. 6. Corticosteroid use beyond two weeks has not been shown to have any added benefits when compared with short-term administration. 7. Antibiotic use has been associated with improved outcomes in patients with severe exacerbations, but not in patients who experience mild to moderate exacerbations. 8. NPPV use decreases the likelihood that intubation will be necessary. REFERENCES 1. Bach, P. B., C. Brown, S. E. Gelfand, and D. C. McCrory. 2001. American College of Physicians—American Society of Internal Medicine, and American College of Chest Physicians. “Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Summary and Appraisal of Published Evidence.” Annals of Internal Medicine 134 (7): 600–20. 2. Snow, V., S. Lascher, and C. Mottur-Pilson. 2001. “Evidence Base for Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease.” Annals of Internal Medicine 134: 595–99. 3. Rabe, K. F., S. Hurd, A. Anzueto, P. J. Barnes, S. A. Buist, P. Calverley, and Y. Fukuchi. 2007. Global Initiative for Chronic Obstructive Lung Disease. “Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: GOLD Executive Summary.” American Journal of Respiratory and Critical Care Medicine 176: 532–55. 4. Anzueto, A. 2010. “Impact of Exacerbation on COPD.” European Respiratory Review 19 (116): 113–18. 5. Miravitlles, M., C. Espinosa, E. Fernández-Laso, J. A. Martos, J. A. Maldonado, and M. Gallego. 1999. “Relationship between Bacterial Flora in Sputum and Functional Impairment in Patients with Acute Exacerbations of COPD.” Chest 116 (1): 40–46. 6. Wilkinson, T. M. A., J. R. Hurst, W. R. Perera, G. C. Donaldson, and J. A. Wedzicha. 2006. “Effect of Interactions between Lower Airway Bacterial and Rhinoviral Infection in Exacerbations of COPD.” Chest 129 (2): 317–24. 7. Hirschman, J. V., T. F. Murphy, S. Sethi, and M. S. Neiderman. 2001. “Bacteria and COPD Exacerbations Redux.” Chest 119 (2): 663–67. 8. Guthrie, R. 2001. “Community-Acquired Lower Respiratory Tract Infections: Etiology and Treatment.” Chest 120: 2021–34. 9. Bach, P. B., C. Brown, S. E. Gelfand, and D. C. McCrory. 2001. American College of Physicians—American Society of Internal Medicine, and American College of Chest Physicians. “Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Summary and Appraisal of Published Evidence.” Annals of Internal Medicine 134 (7): 600–20. 10. Tsai T. W., E. J. Gallagher, G. Lombardi, P. Gennis, and W. Carter. 1993. “Guidelines for the Selective Ordering of Admission Chest Radiography in Adult Obstructive Airway Disease.” Annals of Emergency Medicine 22: 1854–58. 11. Rabe, K. F., S. Hurd, A. Anzueto, P. J. Barnes, S. A. Buist, P. Calverley, Y. Fukuchi. 2009. “Characteristics of Patients Admitted for the First Time for COPD exacerbation.”Respiratory Medicine 103: 1293–302. 12. Emerman, C. L., A. F. Connors, T. W. Lukens, D. Effron, and M. E. May. 1989. “Relationship between Arterial Blood Gases and Spirometry in Acute Exacerbations of Chronic Obstructive Pulmonary Disease.” Annals of Emergency Medicine 18 (5): 523–27. 13. Soler-Cataluna, J. J., M. A. MartinezGarcia, P. Romn Sanchez, E. Salcedo, M. Navrro, and R. Orchando. 2005. “Severe Acute Exacerbations and Mortality in Patients with Chronic Obstructive Pulmonary Disease.”Thorax 60: 925–31. 14. Connors, A. F., Jr., N. V. Dawson, C. Thomas, F. E. Harrell, Jr., N. Desbiens, W. J. Fulkerson, P. Kussin, P. Bellamy, L. Goldman, and W. A. Knaus. 1996. “Outcomes Following Acute Exacerbation of Severe Chronic Obstructive Lung Disease.”American Journal of Respiratory and Critical Care Medicine 54 (4 Pt 1): 959–67. 15. Moayyedi, P., J. Congleton, R. L. Page, S. B. Pearson, and M. F Muers. 1995. “Comparison of Nebulised Salbutamol and Ipratropium Bromide with Salbutamol Alone in the Treatment of Chronic Obstructive Pulmonary Disease.” Thorax 50 (8): 834–37. 16. Combiventtrialists. 1994. “In Chronic Obstructive Pulmonary Disease, a Combination of Ipratropium and Albuterol is More Effective than Either Agent Alone. An 85-day Multicenter Trial. COMBIVENT Inhalation Aerosol Study Group.” Chest 105: 1411–19. 17. Salpeter, S. R., and N. S. Buckley. 2006. “Systematic Review of Clinical Outcomes in Chronic Obstructive Pulmonary Disease: β-Agonist use Compared with Anticholinergics and Inhaled Corticosteroids.” Clinical Reviews in Allergy and Immunology 31 (2–3): 219–30. 18. Anthonisen, N. R., J. E. Connett, J. P. Kiley, M. D. Altose, W. C. Bailey, A. S. Buist, W. A. Conway. 1994. “The Effects of Smoking Intervention and the Use of an Inhaled Anticholinergic Bronchodilator in the Rate of Decline of FEV1: The Lung Health Study.” Journal of the American Medical Association 272: 1497–505. 19. Brown, C. D., D. McCrory, and J. White. 2001. Inhaled Short-Acting β2- Agonists Versus Ipratropium for Acute Exacerbations of Chronic Obstructive Pulmonary Disease (Cochrane Review). In The Cochrane Library, Issue 4, Oxford: Update Software. 20. Nair, S. 2005. “A Randomised Controlled Trial to Assess the Optimal Dose and Effect of Nebulised Albuterol in Acute Exacerbations of COPD.”Chest 128: 48–54. 21. Patel, K. R., and W. M. Tullet. 1983. “Bronchoconstriction in Response to Ipratropium Bromide.” British Medical Journal 286: 1318. 22. Mahon, J. L., A. Laupacis, R. V. Hodder, D. A. McKim, N. A. Paterson, T. E. Wood, and A. Donner. 1999. “Theophylline for Irreversible Chronic Airflow Limitation: A Randomized Study Comparing n of 1 Trials to Standard Practice.” Chest 115: 38–48. 23. Emerman, C. L., A. F. Connors, T. W. Lukens, M. E. May, and D. Effron. 1990. “Theophylline Concentrations in Patients with Acute Exacerbation of COPD. The American Journal of Emergency Medicine 8: 289–92. 24. de Jong, Y. P., S. M. Uil, H. P. Grotjohan, D. S. Postma, H. A. Kerstjens, and J. W. van den Berg. 2007. “Oral or IV Prednisolone in the Treatment of COPD Exacerbations: A Randomized, Controlled, Double-Blind Study.” Chest 132: 1741. 25. Niewoehner, D. E., M. L. Erbland, R. H. Deupree, D. Collins, N. J. Gross, R. W. Light, P. Anderson, and N. A. Morgan. 1999. “Effect of Systemic Glucocorticoids on Exacerbations of Chronic Obstructive Pulmonary Disease. Department of Veterans Affairs Cooperative Study Group.”The New England Journal of Medicine 340: 1941–47. 26. Austin, M. A., L. E. Wills, L. Blizzard, E. H. Walters, and R. Wood-Baker. 2010. “Effect of High Flow Oxygen on Mortality in Chronic Obstructive Pulmonary Disease Patients in Prehospital Setting: Randomised Controlled Trial.” British Medical Journal 7779: 927. 27. Bedon, G. A., A. J. Block, W. C. Ball, Jr. 1970. “The ‘28 Percent’ Venturi Mask in Obstructive Airway Disease.”Archives of Internal Medicine 125: 106– 13. 28. Eldridge, F., and C. Gherman. 1968. “Studies of Oxygen Administration in Respiratory Failure.” Annals of Internal Medicine 68: 569–78. 29. Bone, R. C., A. K. Pierce, and R. L. Johnson, Jr. 1978. “Controlled Oxygen Administration in Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease: A Reappraisal.” The American Journal of Medicine 65: 896–902. 30. Anthonisen, N. R., J. Manfreda, C. P. Warren, E. S. Hershfield, G. K. Harding, and N. A. Nelson. 1987. “Antibiotic Therapy in Exacerbations of Chronic Obstructive Pulmonary Disease.” Annals of Internal Medicine 106: 196–204. 31. Boyter, A. C., P. G. Davey, S. A. Hudson, R. A. Clark, and B. J. Lipworth. 1995. “Evaluation of an Antibiotic Prescribing Protocol for Treatment of Acute Exacerbations of Chronic Obstructive Airways Disease in a Hospital Respiratory Unit.” The Journal of Antimicrobial Chemotherapy 36: 403–9. 32. Gay, P. C. Feb 2009. “Complications of Noninvasive Ventilation in Acute Care.”Respiratory Care 54 (2): 246–57. 33. Brochard, L., H. Mancebo, M. Wysocki, F. Lofaso, G. Conti, A. Rauss, and G. Simonneau. 1995. “Noninvasive Ventilation for Acute Exacerbations of Chronic Obstructive Pulmonary Disease.”The New England Journal of Medicine 333: 817–22. 34. Keenan, S. P., P. D. Kernerman, D. J. Cook, C. M. Martin, D. McCormack, and W. J. Sibbald. 1997. “Effect of Noninvasive Positive Pressure Ventilation on Mortality in Patients Admitted with Acute Respiratory Failure: A Meta- Analysis.” Critical Care Medicine 25: 1685–92.

Community-Acquired Chapter Pneumonia 15 Claire li, MD CASE A 45-year-old man with a history of chronic obstructive pulmonary disease (COPD) and a 50-pack-year smoking history presents to the emergency department (ED) for evaluation of a 12-hour history of worsening shortness of breath and a 2-week history of productive cough. He has had subjective fevers over the past 2 days. He denies recent sick contacts or travel. Vitals on triage are as follows: temperature (T), 101.8°F; blood pressure (BP), 130/96 mm Hg; heart rate, 78; respiratory rate, 24; and O2 saturation of 94% on room air. Further workup reveals right basilar crackles on examination, a right lower lobe infiltrate on chest x-ray (CXR), and a WBC count of 19,000 with 23% bands. 1. What is the most likely diagnosis and why? The most likely diagnosis is community-acquired pneumonia (CAP), although the differential is broad and includes bronchitis, COPD exacerbation, pulmonary embolism, tuberculosis, and even congestive heart failure. Typical symptoms of CAP include fever, productive cough, and dyspnea.1 Hemoptysis and pleuritic chest pain may also be present.1 Extrapulmonary symptoms such as nausea, vomiting, diarrhea, headache, myalgia, and confusion may also be seen.2 Tachypnea is frequently observed in CAP patients. A respiratory rate of more than 30 breath/ min is associated with poor prognosis.3 Pulmonary auscultation may reveal rales, crackles, or decreased breath sounds due to consolidation. Bottom line: Typical symptoms of CAP include fever, productive cough, and dyspnea, with workup likely revealing respiratory distress, pulmonary consolidation, and leukocytosis with a left shift. 189 2. What are the most common pathogens causing this man’s condition? “Typical” pathogens include Streptococcus pneumoniae (most common)4, Hemophilus influenzae, Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitides, Moraxella catarrhalis, Klebsiella pneumoniae, other gram negative rods, and influenza virus.5 “Atypical” pathogens include Mycoplasma pneumoniae (most common), Chlamydia pneumoniae, and Legionella species.2 Chlamydia psittaci and the rarely encountered zoonotic pathogens Francisella tularensis and Coxiella burnetii may also cause CAP.2 Bottom line: The most common typical pathogens causing CAP are S. pneumoniae and H. influenza, whereas the most common atypical pathogens are M. pneumonia, C. pneumoniae, and Legionella species. 3. What test does the evidence suggest should be included in the diagnostic workup of CAP? The presence of an infiltrate on CXR or other imaging is typically required for the diagnosis of pneumonia.1,6 Although computed tomography (CT) is more sensitive than CXR in detecting pulmonary infiltrates, it is not routinely performed.2 While sputum culture and Gram stain are helpful in determining the causative pathogen, in approximately 50% of cases a pathogen cannot be identified.7 There may be some benefit to obtaining blood cultures in all patients suspected of having CAP. One study showed that obtaining blood cultures within 24 hours of hospitalization lowered 30-day mortality by 10%.8 According to the National CAP Guidelines, two sets of blood cultures should ideally be drawn before initiation of antibiotics.8,9 The thought is that early blood culture results will allow for better targeting of antibiotic therapy, resulting in better outcomes. Bottom line: In the appropriate clinical setting, the presence of an infiltrate on CXR is highly sensitive for diagnosing CAP. Although sputum cultures and Gram stain may help guide therapy, they are of limited diagnostic utility. Blood cultures obtained within the first 24 hours may reduce in-hospital mortality by improving antibiotic selection. 4. Do scoring systems for prognosticating outcomes in CAP exist and are they of any clinical significance? Yes, several exist. The CURB-65 score, pneumonia severity index (PSI)/patient outcomes research team (PORT) score, and severe community-acquired pneumonia (SCAP) score are used in predicting mortality and need for hospitalization in patients with CAP. CURB-65 is used to assess disease severity by taking into account the following risk factors: Confusion of new onset, Urea > 7 mmol/L, Respiratory rate > 30 breaths/min, Blood pressure < 90 mm Hg or diastolic pressure < 60 mm Hg, and Age > 65 years. Each factor scores 1 point. Patients with a score of 0–1 are typically treated as outpatients.11 Patients with a score of 2 can be admitted to the hospital or treated as outpatients, while patients with scores of 3 or higher are typically admitted to the hospital (Table 15.1).11 The PSI or Pneumonia PORT score is used to classify and determine the severity of CAP. The score is based on the patient’s demographics, comorbid conditions, physical findings, and diagnostic studies (Table 15.2).11 Patients in classes I and II are typically treated as outpatients, whereas patients in class III can be treated either as outpatients or inpatients.11 However, patients in classes IV and V should be hospitalized.11 SCAP scores are useful in predicting hospital mortality risk, need for mechanical ventilation, and risk of septic shock. The scores are based on major criteria: arterial pH and systolic pressure, and minor criteria: confusion, BUN, respiratory rate, CXR findings, and PaO2 < 54 mm Hg or PaO2 < 250 mm Hg, and age ≥ 80 years10 (Figure 15.110). One or more major criteria or 2 or more minor criteria warrants the diagnosis of severe CAP and indicated need for hospitalization with possible triage to the intensive care unit (ICU). The SCAP score also has predictive value for 30-day mortality in low risk patients.10 Some evidence suggests that the SCAP score is superior to PSI and CURB65 in predicting adverse outcomes in patients hospitalized with CAP.10 TAblE 15.1 The CURB-65 Score for CAP Risk Stratification Total score Mortality (%) Risk level 0 0.6 Low 1 2.7 Low 2 6.8 Moderate 3 14.0 Moderate to high 4 or 5 27.8 High Abbreviations: ICU, intensive care unit. Adapted from OSU College of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine. http://internalmedicine.osu.edu/pulmonary/cap/10674.cfm Suggested site-of-care Outpatient Outpatient Short inpatient/ supervised outpatient Inpatient Inpatient/ICU TAblE 15.2 PSI/PORT Score for Risk Stratification Patient characteristics Points Demographics Male Age (y) Female Age (y)-10 Nursing home resident +10 Comorbid illness Neoplastic disease +30 Liver disease +20 Congestive heart failure +10 Cerebrovascular disease +10 Renal disease +10 Physical examination findings Altered mental status +20 Respiratory rate > 30 breaths/min +20 Systolic blood pressure < 90 mm Hg +20 Temperature 35°C (95°F) or > 40°C (104°F) +15 Pulse rate > 125 bpm +10 Laboratory and radiographic findings Arterial pH < 7.35 +30 Blood urea nitrogen > 64 mg per dL +20 (22.85 mmol/L) Sodium 130 mEq/L (130 mmol per L) +20 Glucose > 250 mg/dL (13.87 mmol/L) +10 Hematocrit 30% +10 Partial pressure of arterial oxygen < 60 mm Hg or +10 oxygen percent saturation < 90% Pleural effusion Total points: +10

---

Point total Risk No Low predictors ≤ 70 Low 71–90 Low 91–130 Moderate > 130 High Mortality % (no. of Risk class patients) I 0.1 (3034) Recommended site of care Outpatient II 0.6 (5778) III 2.8 (6790) IV 8.2 (13,104) V 29.2 (9333) Outpatient Inpatient (briefly) Inpatient Inpatient Bottom line: Several scoring systems exist, which provide prognostic information for CAP outcomes and help the clinician decide whether the patient can be treated as an outpatient, on the medicine ward, or in the ICU. Of these, the SCAP scoring system may be superior in predicting adverse outcomes in patients hospitalized with CAP. Patient P Ph<7.30 C Confusion S Systolic pressure<90 mm Hg U Urea>30 mg /dl R Respiratory rate>30/min X X-Ray multilobar bilteral O PaO2<54 or PaO2/FiO2<250 mHg 80 Age≥80 Yes Yes Present≥1Present≥2 Management in hospital as severe CAP Intermedia care ICU FigurE 15.1 SCAP score classification algorithm10. CASE CONTiNuED The patient is admitted to the hospital. Gram stain and sputum culture reveals S. Pneumoniae. 5. Does the evidence suggest that CAP should be treated differently based on the clinical setting (outpatient, medicine ward, iCu)? In a patient who was previously well with no antibiotic use in the last 3 months, monotherapy with a macrolide (e.g., azithromycin) or doxycycline can be used in an outpatient setting.12 However, for inpatient therapy, the data suggest that a combination of a β-lactam plus a macrolide, or monotherapy with a fluoroquinolone is recommended for patients with comorbidities.5 Acceptable choices for β-lactam antibiotics include ceftriaxone, cefotaxime, or ampicillin- sulbactam. Some studies show that the combination therapy for CAP is superior to fluoroquinolone monotherapy,13,14 although this is very controversial.15 In general, combination therapy is thought to cover a broader range of polymicrobial infections, as these drugs have synergistic effects.16 CAP patients in the ICU should be treated with a β-lactam plus a macrolide or a β-lactam plus a fluoroquinolone.5 Both combinations should cover S. pneumoniae and Legionella spp. The β-lactam selected should be effective against P. aeruginosa; piperacillin–tazobactam, cefepime, ceftazidime, or imipenem all qualify. Vancomycin or linezolid may be included to cover methicillin-resistant S. aureus (MRSA). In addition, a macrolide plus a second- generation cephalosporin or a nonpseudomonal third-generation cephalosporin lowers the mortality rate.14 Fluoroquinolone alone is just as effective in lowering the mortality rate. Administering antibiotics within 8 hours on arrival to the ED is also found to lower the mortality rate.14 Bottom line: Administer broad-spectrum antibiotics for empirical treatment of CAP. Monotherapy with a macrolide or fluroquinolone is appropriate in the outpatient management of CAP. Combination therapy with a β-lactam plus a macrolide or monotherapy with fluoroquinolone is appropriate in the hospitalized patient. Antipseudomonal coverage is necessary when managing ICU patients with CAP. 6. What does the evidence suggest should be done to minimize the incidence of CAP? Smoking cessation and appropriate vaccination: Influenza vaccination reduces incidence of pneumonia in patients with multiple comorbidities, because these patients are at high risk for mortality from bacteria pneumonia associated with influenza virus.17 However, there is insufficient evidence regarding reduction in hospital stay and mortality.17 Pneumococcal vaccination is also recommended for this patient population based on the results of observational studies.18 However, a 2009 meta-analysis of 22 high-quality clinical trials evaluating pneumococcal vaccine suggests that pneumococcal vaccination may not be effective in preventing pneumonia, even within populations for whom the vaccine is currently recommended.19 Trials included in this metaanalysis compared the benefits of pneumococcal polysaccharide vaccine in prevention of 8 outcomes with the effects of no intervention, placebo, or other vaccines. These outcomes included: 1. Definitive pneumococcal pneumonia (typical clinical/radiologic findings and S. pneumoniae isolated from normally sterile body fluids) 2. Presumptive pneumococcal pneumonia (typical clinical/radiologic findings, and S. pneumoniae isolated from the respiratory tract or seroconversion against S. pneumoniae). 3. Pneumonia from all causes. 4. Bronchitis from all causes. 5. Death from all causes. 6. Death from pneumonia. 7. Death from pneumococcal infection. 8. S. pneumoniae bacteremia (isolation of S. pneumoniae from a normally sterile body fluid). TAblE 15.3 Relative Risks of Outcomes of Pneumococcal Vaccine Trials

Trials Combined RR Outcome (#Participants) # Cases (95% CI)

Definitive pneumonia 2 (794) 7 0.62 (0.05–8.61) (S. pneumoniae) Presumptive Pneumonia 11 (56,564) 589 0.64 (0.43–0.96) (S. pneumoniae) Pneumonia (all causes) 19 (82,665) 2722 0.73 (0.56–0.94) Bacteremia 6 (32,770) 44 0.90 (0.46–1.77) (S. pneumoniae) Bronchitis 4 (20,589) 1698 0.92 (0.76–1.12) Death (S. pneumoniae) 3 (15,942) 18 0.93 (0.29–3.05) Death (all pneumonias) 8 (33,384) 214 0.88 (0.62–1.25) Death (all causes) 12 (45,365) 2246 0.97 (0.87–1.09) Adopted from Ref. 19. A high degree of variation was noted between trials when examining the effectiveness of pneumococcal vaccine in prevention of the above clinical outcomes, much of which could be explained by vast differences among methodologies used to conduct the studies. Relative risk of individual outcomes as determined by results of the meta-analysis is listed in Table 15.3. It is important to note that results from this meta-analysis on effects of pneumococcal vaccine in prevention of S. pneumoniae bacteremia (RR, 0.90) contrast with results from a 2008 Cochrane review, which supports use of the vaccine against invasive pneumococcal disease (RR, 0.26; 95% CI, 0.15–0.46).20 This may be explained by the inclusion of a 1977 Papua New Guinea study in the Cochrane review that was excluded in the Huss et al. meta-analysis due to limited access to care and diagnostic testing.19 Bottom line: Smoking cessation is important in preventing CAP. Although still controversial, pneumococcal vaccination may not have a significant morbidity or mortality benefit, even within populations for whom the vaccine is currently recommended. 7. What are some feared complications of CAP and what steps can be taken to minimize their risk of occurrence? Complicated pleural effusion, empyema, and lung abscess are the most common complications of CAP. Other complications include respiratory failure, shock, and multiorgan failure leading to acute kidney injury, gastrointestinal dysfunction, bleeding diatheses, and metastatic infections such as meningitis, pericarditis, and septic arthritis.17 To reduce the risk of CAP complications, a number of steps can be taken. These include early initiation of antibiotics, streamlining the choice of antibiotics if the causative agent is identified through blood culture, sputum culture, or Gram stain, and performing follow up CXR or CT scan. For patients with pleural effusions > 10 mm on chest films (in the lateral decubitus position), diagnostic thoracentesis should be performed to evaluate for the possibility of complicated parapneumonic effusions, which may require chest tube placement and drainage.12 Bottom line: Appropriate antibiotic treatment and follow-up imaging reduce the risk of developing complications of CAP. TAKE-HOME POiNTS: COMMuNiTY-ACQuirED PNEuMONiA 1. Infection with S. pneumoniae is the most common cause of CAP. 2. CXR is usually a sufficient imaging modality for diagnosis of CAP. 3. Several CAP scoring systems exist: CURB-65, PSI, and SCAP. Scores are used to evaluate the severity of CAP and to assist with triaging of patients to outpatient, medicine ward, or ICU care. While SCAP scores appear superior to the other scoring systems, no scoring system replaces a thorough clinical evaluation. 4. Macrolides or fluoroquinolones are preferred for outpatient treatment of CAP. β-Lactams with a macrolide or monotherapy with a fluoroquinolone can be used for the hospitalized patient. A β-lactam with P. aeruginosa coverage should be included for ICU patients. 5. Potential complications of CAP, aside from death, include complicated pleural effusion, empyema, and lung abscess. rEFErENCES 1. Brandenburg, J. A., T. J. Marrie, C. M. Coley, D. E. Singer, D. S. Obrosky, W. N. Kapoor, and M. J. Fine. 2000. “Clinical Presentations, Processes and Outcomes of Care for Patients with Pneumococcal Pneumonia.” Journal of General Internal Medicine 15 (9): 638–46. 2. Cunha, B. A. 2006. “The Atypical Pneumonias: Clinical Diagnosis and Importance.” Clinical Microbiology and Infection 12 (Suppl 3): 12–24. 3. Lim, W. S., S. Lewis, and J. T. Macfarlane. 2000. “Severity Prediction Rules in Community Acquired Pneumonia: A Validation Study.” Thorax 55: 219–23. 4. Fine, M. J., M. A. Smith, C. A. Carson, S. S. Mutha, S. S. Sankey, L. A. Weissfeld, and W. N. Kapoor. 1996. “Prognosis and Outcomes of Patients with Community-Acquired Pneumonia.” JAMA 275 (2): 134–41. 5. Bartlett, J. G., S. F. Dowell, L. A. Mandell, T. M. File, Jr, D. M. Musher, and M. J. Fine. 2000. “Practice Guidelines for the Management of CommunityAcquired Pneumonia in Adults. Infectious Diseases Society of America.” Clinical Infectious Diseases 31 (2): 347–82. 6. Mandell, L. A., R. G. Wunderink, A. Anzueto, J. G. Bartlett, G. D. Campbell, N. C. Dean, and S. F. Dowell. 2007. “Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults.” Clinical Infectious Diseases 44 (Suppl 2): S27. 7. Houck, P. M., D. W. Bratzler, W. Nsa, A. Ma, and J. G. Bartlett. 2004. “Timing of Antibiotic Administration and Outcomes for Medicare Patients Hospitalized with Pneumonia.” Archives of Internal Medicine 164: 637–44. 8. Meehan, T. P., M. J. Fine, H. M. Krumholz, J. D. Scinto, D. H. Galusha, J. T. Mockalis, and G. F. Weber. 1997. “Quality of Care, Process, and Outcomes in Elderly Patients with Pneumonia.” JAMA 278 (23): 2080–84. 9. Arbo, M. D. J., and D. R. Snydman. 1994. “Influence of Blood Culture Results on Antibiotic Choice in Treatment of Bacteremia.” Archives of Internal Medicine 154: 2641. 10. Yandiola, P. P. E., A. Capelastegui, J. Quintana, R. Diez, I. Gorordo, A. Bilbao, and R. Zalacain. 2009. “Prospective Comparison of Severity Scores for Predicting Clinically Relevant Outcomes for Patients Hospitalized with Community-Acquired Pneumonia.” Chest 135: 1572–79. 11. Ebell, M. H. 2006. “Outpatient vs. Inpatient Treatment of CommunityAcquired Pneumonia.” Family Practice Management 13 (4): 41–44. 12. Niederman, M. S., L. A. Mandell, A. Anzueto, J. B. Bass, W. A. Broughton, G. D. Campbell, and N. Dean. 2001. American Thoracic Society. “Guidelines for Management of Adults with Community-Acquired Pneumonia: Diagnosis, Assessment of Severity, Antimicrobial Therapy, and Prevention.” American Journal of Respiratory and Critical Care Medicine 163: 1730–54. 13. Waterer, G. W., G. W. Somes, and T. G. Wunderink. 2001. “Monotherapy May Be Sub- Optimal for Severe Bacteremic Pneumococcal Pneumoniae.” Archives of Internal Medicine 161: 1837–42. 14. Martinez, J. A., J. P. Horcajada, M. Almela, G. Marco, A. Soriano, E. Garcia, and M. A. Marco. 2003. “Addition of a Macrolide to a Beta-Lactam- Based Empirical Antibiotic Regimen is Associated with Lower In-Hospital Mortality for Patients with Bacteremic Pneumococcal Pneumonia.” Clinical Infectious Diseases 36 (4): 380–95. 15. Chokshi, R., M. I. Restrepo, N. Weeratunge, C. R. Frei, A. Anzueto, and E. M. Mortensen. 2007. “Monotherapy versus Combination Antibiotic Therapy for Patients with Bacteremic Streptococcus Pneumonia Community-Acquired Pneumonia.” European Journal of Clinical Microbiology & Infectious Diseases 26: 447–51. 16. Feldman, C., and R. Anderson. 2009. “Therapy for Pneumococcal Bacteremia: Monotherapy or Combination Therapy?” Current Opinion in Infectious Diseases 22 (2): 137–42. 17. Jefferson, T. O., D. Rivetti, C. Di Pietrantonj, A. Rivetti, and V. Demicheli. 2007. “Vaccines for Preventing Influenza in Healthy Adults.” The Cochrane Database of Systematic Reviews 18: CD001269. 18. Centers for Disease Control and Prevention. Recommended Adult Immunization Schedule—United States, October 2006–September 2007. Morbidity and Mortality Weekly Report. 2006; 55:Q1-Q4. 19. Huss, A., P. Scott, A. E. Stuck, C. Trotter, and M. Egger. 2009. “Efficacy of Pneumococcal Vaccination in Adults: A Meta-Analysis.” Canadian Medical Association Journal 180: 48–58. 20. Moberley, S. A., J. Holden, D. P. Tatham, and R. M. Andrews. 2008. “Vaccines for Preventing Pneumococcal Infection in Adults.” The Cochrane Database of Systematic Reviews (1): CD000422.

Complicated Pleural CHAPTER Effusion 16 STEPHEN ANDREW GANNON, MD CASE A 46-year-old man with a history of hypertension and coronary artery disease presents for evaluation of a 9-day history of chest pain and worsening shortness of breath. The pain localizes to the left lateral chest wall and is described as sharp in quality, moderate in intensity, worse with inspiration, and without radiation. The patient presented to the emergency department of an outside hospital 7 days prior and was diagnosed with pneumonia. He was prescribed antibiotics and given PRN narcotics for pain. The patient reports compliance with the prescribed medications, and his pain has been fairly well controlled. Additional history reveals low-grade fevers, intermittent sweats, and a mild nonproductive cough. The patient denies recent sick contacts. He is a lifetime nonsmoker. Physical examination in the emergency department reveals a temperature of 100.8°F, heart rate 85 bpm, blood pressure 142/90 mm Hg, respiratory rate 24, and an oxygen saturation of 94% on room air. The patient appears mildly dyspneic and diaphoretic. Chest examination is remarkable for dullness to percussion one-half up the left hemithorax, diminished breath sounds in the left lower lung fields, bilateral inspiratory and expiratory wheezes, and decreased tactile and vocal fremitus at the left lung base. Examination is otherwise normal. Chest radiograph demonstrates a left-sided pleural effusion with possible loculation. Initial chemistries and counts: Na 133 mEq/L, K 3.9 mEq/L, Cl 95 mEq/L, HCO3 27 mEq/L, BUN 31 mg/dl, Cr 1.0 mg/dl; white blood cell (WBC) 23.6 K/ul, Hb 15.8 g/d, platelets 646 K/μL. 1. What is the most likely diagnosis in this patient? Due to the history of recent pneumonia, pleuritic chest pain, examination findings, and radiographic findings, this patient most 199 likely has a parapneumonic pleural effusion. Parapneumonic pleural processes can be classified into 3 categories. 1. Uncomplicated parapneumonic effusions: Exudative, neutrophilic effusions resulting from the passage of interstitial fluid into the pleural space secondary to inflammation. The fluid may be slightly cloudy or even clear. Organisms may or may not be noted on Gram stain or culture. 2. Complicated parapneumonic effusions: Result from bacterial invasion into the pleural space. Pleural fluid analysis shows neutrophils, decreased glucose levels, pleural fluid acidosis, and an elevated lactate dehydrogenase (LDH) concentration. These effusions can be sterile because bacteria are cleared rapidly from the pleural space through lymphatics. The pleural fluid is typically cloudy. 3. Empyema: Development of frank pus in the pleural space; believed to be the result of inadequately treated parapneumonic effusions. The pus is classically thick, viscous, and opaque. Bottom line: The classification of parapneumonic pleural processes can be thought of as a continuum from an uncomplicated parapneumonic effusion with transudative qualities to an empyema, which consists of frank pus between the parietal and visceral pleura. 2. What does the evidence suggest regarding the accuracy of the physical examination in detecting and identifying a pleural effusion? A careful physical examination should be performed in all those suspected of having a pleural effusion. In addition to the pulmonary examination, cardiac and abdominal examinations may be helpful in determining the etiology of the effusion. The presence of physical examination signs classic for pleural effusion often depends on the size and composition of the effusion, with increased sensitivities at volumes greater than 300–500 mL.1 Common findings include asymmetry of chest expansion (sensitivity 0.74 and specificity 0.91), asymmetry of tactile fremitus (sensitivity 0.82 and specificity 0.86), dullness to percussion (sensitivity 0.53–0.89 and specificity 0.71), absent breath sounds (sensitivity 0.42–0.82 and specificity 0.83–0.90), and a pleural rub (sensitivity 0.05 and specificity 0.99).1 Compared with chest ultrasonography, Diacon et al.2 determined the sensitivity and specificity of clinical examination to be 0.76 and 0.60, respectively. In critically ill patients, Lichtenstein et al.3 described auscultatory findings as having a similar sensitivity and superior specificity for detecting pleural effusion compared with chest radiograph. Auscultatory percussion is not a frequently taught technique but may possess some value in the evaluation of a suspected pleural effusion. To perform this test, clinicians tap the patient’s manubrium while auscultating the posterior chest. Guarino and Guarino4 found auscultatory percussion to be 95% sensitive and 100% specific for the detection of a pleural effusion in a prospective blinded study. Bottom line: Physical examination is an inexpensive, noninvasive means of evaluating patients for a pleural effusion. Examination sensitivities often vary based on effusion size but may rival that of chest radiograph in certain patient populations. Auscultatory percussion is a less well-known physical examination technique that seems to have value in the diagnosis of a pleural effusion. 3. What are the important aspects of pleural anatomy and physiology to remember when discussing this case? The pleura are composed of two distinct membranes. The thin visceral pleura are tightly adherent to the lung parenchyma and consist of an elastic and collagenous connective tissue layer and a mesothelium. The parietal pleura overlie the ribs and intercostal muscles and are composed with a loose, irregular connective tissue layer, and a mesothelium. The mesothelia of the two membranes are juxtaposed creating a potential space. The intrapleural space is important for the development of negative pleural pressures that are essential for normal lung function. Normally, a small amount of fluid exists in the pleural space, approximately 8.4 ± 4.3 mL. Pleural fluid is produced by the visceral pleura at a rate of approximately 15 mL/d in a 50-kg individual. Pleural fluid is reabsorbed through lymphatics in the parietal pleura.5 Bottom line: The pleural space is a potential space that normally contains minimal, sterile serous fluid. 4. What additional imaging studies would be most appropriate in the workup of this patient? In addition to the chest radiograph already obtained, computed tomography (CT) of the chest is indicated to further define the pleural anatomy. Conventional chest radiography is the first step in assessing a patient with physical examination findings and history consistent with a pleural effusion. Fluid from a pleural effusion initially builds up between the inferior surface of the lung and the diaphragm.6 Findings consistent with a subpulmonic effusion include elevation of the lung base and lateral shift of the apex of the diaphragm. On the left, a separation of the lung from the stomach bubble of greater than 2 cm suggests a subpulmonic effusion. Spillover and subsequent visualization of the effusion in the costophrenic recesses on lateral chest radiography does not occur until the volume approaches 75 mL. The lateral costophrenic recesses do not blunt until approximately 175 mL of fluid has accumulated. Loculation is suspected with the following radiographic findings: obtuse angle between the pleural opacity and chest wall, homogenous content, smooth surface when viewed in tangent, and droopy appearance on upright images (Figure 16.1).7 CT is best for visualizing small effusions (<10 mL) and accurately characterizing the complexity and structure of the pleural process (Figure 16.2). CT imaging can be further evaluated for pleural thickening, which may be present if the process is more exudative in nature. Thoracentesis and tube thoracostomy can be more accurately executed with the knowledge of the pleural anatomy.8,9 Occasionally, CT will help to determine the etiology of the effusion through detection of a parenchymal or pleural mass or an intra-abdominal process. Chest ultrasonography can help to distinguish a free from a loculated pleural effusion and a loculated pleural effusion from a mass lesion.10 Thoracentesis can be facilitated by ultrasonography. Magnetic resonance imaging of a pleural process is generally reserved for situations when chest wall invasion by a malignancy is suspected.

FIGURE 16.1 Chest radiography revealing loculated pleural effusions. Source: From radiology.vlahos.org CT image with loculated pleural effusion on the left

Fluid is here, but if not loculated would be here FIGURE 16.2 Computed tomography scan revealing a left loculated pleural effusion. Source: From onctalk.com Bottom line: Most pleural disease is best evaluated with conventional chest radiographs and CT. Ultrasonography and magnetic resonance imaging have roles in certain pleural diseases. 5. Is diagnostic thoracentesis indicated in this patient? What laboratory tests should be ordered on the pleural fluid obtained? Diagnostic thoracentesis is absolutely indicated in this patient based on the size of the effusion alone. Diagnostic thoracentesis should be performed for all clinically significant pleural effusions of unknown origin greater than 1 cm in height on lateral decubitus chest radiograph, ultrasound, or CT. Thoracentesis is unnecessary for patients in obvious heart failure except when the patient is febrile, has pleuritic chest pain, or the effusion fails to respond to heart failure management strategies.11 Pleural effusions in heart failure are typically bilateral, but when they occur unilaterally, they are typically found on the right. Approximately 75% of effusions due to congestive heart failure resolve within 48 hours after appropriate therapy is initiated.12 Analysis of pleural fluid should include cell count, cytology, Gram stain and culture (aerobic and anaerobic), pH, lactate dehydrogenase (LDH), total protein, and glucose. A stain for acid-fast bacilli and measurement of adenosine deaminase should be performed if tuberculosis is a consideration. Effusions related to pancreatitis or esophageal rupture typically TABLE 16.1 Test Results Commonly Used to Classify Pleural Effusion Test Result Positive cytology WBC >10,000 cell/ul Neutrophils >50% Lymphocytes >50% RBC >100,000 cells/ul Fluid protein: serum protein ratio >0.5 Fluid LDH: serum LDH ratio >0.6 LDH >2/3 upper limit of normal for serum Adenosine deaminase >40 units/L Glucose <60 mg/dL Suggested Etiology Primary or metastatic disease Empyema or other exudate Parapneumonic effusion, pulmonary embolism Malignancy, tuberculosis, pulmonary embolism Trauma, malignancy, parapneumonic effusion, pulmonary embolism Exudative process Exudative process Exudative process Tuberculosis, empyema, complicated pleural effusion Complicated pleural effusion, empyema, rheumatoid arthritis, malignancy, tuberculosis Abbreviations: WBC, white blood cell; RBC, red blood cell; LDH, lactate dehydrogenase. have an elevated amylase level. In general, a pleural effusion can be characterized as transudative or exudative. Exudative effusions meet at least one of the following criteria, whereas transudative processes meet none: pleural fluid protein/serum protein ratio greater than 0.5, pleural fluid LDH/serum LDH ratio greater than 0.6, and/or pleural fluid LDH more than two-thirds of normal upper limit for serum. Using these criteria, 25% of transudative processes are misidentified as exudative.13 Table 16.1 outlines test results that may help classify a pleural effusion. Pleural fluid laboratories pH 6.16 WBC 131,000 cells/ul (>90% neutrophils) Red blood cell (RBC) 0–20,000 cells/ul LDH 3230 units/L, serum LDH 201 units/L Total protein 3.4 g/dL, serum total protein 7.3 g/dL Glucose < 2 mg/dL Pleural fluid microscopy/cytology Negative for acid-fast bacilli Negative for malignant cells Bottom line: Tap all pleural effusions greater than 1 cm in height, which are unrelated to congestive heart failure. Test pleural fluid for the following: cell count, cytology, Gram stain and culture (aerobic and anaerobic), pH, lactate dehydrogenase, total protein, and glucose. 6. On the basis of the pleural fluid analysis, was our suspicion for a parapneumonic effusion correct? What additional etiologies of a pleural effusion must be considered? The patient’s previous diagnosis of pneumonia as well as the high pleural fluid/serum LDH ratio, low pleural fluid glucose, and predominantly neutrophilic characteristics of the pleural infiltrate are diagnostic for a parapneumonic effusion. Despite our certainty, it is important to remember that pleural effusions can be caused by a variety of pulmonary and extrapulmonary conditions. The 7 most common TABLE 16.2 Common Causes of Pleural Effusion11,13 Pulmonary, Nonmalignant Pneumonia Pulmonary embolism Tuberculous empyema Asbestos pleural disease Viral pleuritis Cardiac Congestive heart failure Secondary to bypass surgery Dressler’s syndrome Traumatic Hemothorax Chylothorax Esophageal perforation Duropleural fistula Drug induced Amiodarone Methotrexate Nitrofurantoin Pulmonary, Malignant Non–small cell lung cancer Small cell lung cancer Mesothelioma Primary effusion lymphoma Metastatic disease Kaposi’s sarcoma Intra-abdominal Pancreatitis Cirrhosis Subphrenic abscess Rheumatologic Rheumatoid arthritis Systemic lupus erythematosus Miscellaneous Post–partum pleural effusion Uremic pleuritis Trapped lung causes include congestive heart failure, pneumonia, cancer, pulmonary embolism, viral disease, coronary artery bypass surgery, and cirrhosis with ascites (see Table 16.2 for a more complete list).13 Congestive heart failure is suggested by an appropriate history of dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea and the physical signs of jugular venous distention, an S3 gallop, and peripheral edema. Cancer may be suspected in the setting of weight loss, lymphadenopathy, and carcinogenic exposure. Pulmonary embolism should always be on the differential and suspected in individuals with derangements of Virchow’s triad and signs or symptoms of deep vein thrombosis. Cirrhotic patients with pleural effusions typically have the stigmata of chronic liver disease and physical findings of shifting dullness and fluid wave on abdominal examination. Bottom line: The three most common causes of pleural effusion are congestive heart failure, pneumonia, and cancer. Pulmonary embolism and viral disease follow close behind. 7. What is the likely bacteriology of this patient’s parapneumonic effusion/empyema? Which antibiotics should be initiated? Culture results from community- and hospital-acquired infections tend to vary. Maskell et al. conducted a large, multicentered trial in the United Kingdom, which included 430 subjects with pleural infections. Cultures were positive in 54% of cases. Streptococcus milleri was the most common pathogen (29%), followed by staphylococci species (21%) and Streptococcus pneumoniae (16%). Anaerobic organisms were isolated in 15% of cases. Other organisms cultured included various streptococci species, Haemophilus influenzae, enterobacteria, Mycobacterium tuberculosis, and Nocardia.14 The same group reported most nosocomial infections to be caused by methicillin-resistant Staphylococcus aureus (MRSA) (27%), other staphylococci (22%), and enterobacteria (20%).15 Antibiotic choice is typically guided by treatment guidelines for pneumonia. Changes can be made to accommodate fluid cultures and sensitivities. For community-acquired infections such as with this patient, intravenous ampicillin/sulbactam or a combination of a second-generation cephalosporin with metronidazole would be appropriate regimens. For patients with a β-lactam allergy, monotherapy with clindamycin is acceptable. Patients with nosocomial- acquired infections need gram-negative coverage with a carbapenem, antipseudomonal penicillin, or a third- or fourth-generation cephalosporin plus metronidazole. If MRSA is suspected, vancomycin or linezolid should be added to the regimen.16 Pleural fluid cultures (from Case patient) Negative for fungus Positive for Prevotella species Streptococcus viridians Mixed anaerobes Bottom line: For community-acquired infections, cover gram positives (not MRSA) and anaerobes. For nosocomial infections, cover gram positives (including MRSA), gram negatives, and anaerobes. 8. Is drainage of this patient’s effusion indicated? Patients with parapneumonic effusions can be risk stratified for poor outcome into four categories (Table 16.3).17 Category 1 and 2 effusions may not require drainage, whereas categories 3 and 4 are best treated with drainage. Indications for tube thoracostomy include empyema, pH < 7.2, positive bacteriological studies, loculations, and effusions larger than half of a hemithorax. Clearly, our patient meets criteria for drainage and chest tube insertion. A onetime ultrasound-guided, therapeutic thoracentesis is a reasonable option for most moderately sized pleural effusions involving less than 1 hemithorax in the absence of empyema or pH < 7.2. In addition to the diagnostic value of pleural fluid analysis, the procedure may result in definitive treatment.16 Ultrasound- guided procedures minimize the risk of iatrogenic pneumothorax, especially in the setting of small or loculated effusions.18 Chest tubes are generally inserted in the dependent part of the lung, typically the posterior costophrenic recess. Some debate remains over whether larger bore (24–28 French) chest drains are superior to 8- to 12-French pigtail catheters or 10- to 12-French catheters inserted with the Seldinger technique.16 Bottom line: Insert a temporary chest drain for the following: large effusions, empyema, loculations, pH < 7.2, or positive bacteriologic studies. 9. What role does intrapleural tissue plasminogen activator (tPA) and DNase play in the management of pleural infections? The procoagulant state in complicated pleural effusions and empyemas results in dense fibrin deposits and loculations.16 Therefore, many clinicians consider it appropriate to use intrapleural fibrinolytics to expedite the healing process and potentially avoid surgical intervention. Initial case series and controlled trials showed an increase in pleural drainage and improved radiographic appearance of effusions with the use of intrapleural fibrinolytics.19 The largest trial conducted to date, the first Multicenter Intrapleural Sepsis Trial (MIST 1), was published in 2005. Unfortunately, this trial showed no difference in mortality, need for surgery, radiographic outcome, or length of hospitalization.14 A subsequent meta-analysis demonstrated similar findings. DNase has also been suggested as a potential therapeutic intrapleural agent. Rahman et al. published the MIST 2 trial in 2011, which included 210 patients and evaluated the efficacy of intrapleural tPA and DNase. Study results showed an increase in pleural fluid drainage, decrease in surgical referrals, and decreased hospital stay in patients treated with intrapleural tPA and DNase. Treatment with DNase alone or tPA alone was ineffective.20 Multiple studies have confirmed the limited systemic side effects of intrapleural fibrinolytics.19 Streptokinase and urokinase seem to be equally efficacious.21 Bottom line: Intrapleural tPA and/or DNase seem to be safe and may provide therapeutic benefit to patients with complicated pleural effusions or empyemas. 10. If our patient fails to recover despite appropriate drainage and maximal medical therapy, what surgical interventions are available? Thoracoscopy is a treatment option for incompletely drained, loculated, and parapneumonic effusions. Visualized adhesions and loculations can be broken down, and a chest tube can be optimally placed during the procedure.22 Several small, retrospective studies have shown thoracoscopy to be superior to fibrinolytics in reducing the need for thoracotomy or tube thoracostomy.23–26 There are essentially two indications for open thoracotomy: (1) failure of medical management to control pleural sepsis and (2) failure of thoracoscopy or tube thoracostomy to result in lung reexpansion.22,27 Thoracotomy with drainage of pleural debris and subsequent closure of the chest with one or more drains left in place is the standard procedure. Decortication involves excision of all pleural fibrous tissue with or without drainage of the pleural space. The aim is to aid in chest reexpansion.28 Decortication has significant associated morbidity and approximately 10% mortality.29 Many clinicians will wait up to 6 months to see whether pleural thickening resolves on its own before recommending this procedure.30 Bottom line: The goal of medical management is to avoid surgical intervention. If there is failure to control sepsis or poor lung reexpansion, surgical options may be necessary. TAKE-HOME POINTS: COMPLICATED PLEURAL EFFUSION 1. Pleural effusions often can be diagnosed by physical examination and further defined by chest radiograph and chest CT. 2. The majority of pleural effusions are the result of congestive heart failure, pneumonia, cancer, or pulmonary embolism. 3. Perform a diagnostic thoracentesis on all pleural effusions greater than 1 cm in height, which are thought to be unrelated to congestive heart failure. 4. A temporary chest drain should be inserted in the following scenarios: large effusions, empyemas, loculations, pH < 7.2, or positive bacteriologic studies. 5. Appropriate antibiotic therapy for parapneumoic processes depends on whether the pneumonia is community acquired or nosocomial, but in general gram positives and anaerobes should be covered. 6. Intrapleural tPA and/or DNase as well as surgical options can be considered if drainage and maximal medical therapy fail. REFERENCES 1. Diaz-Guzman, E., and M. M. Budev. 2008. “Accuracy of the Physical Examination in Evaluating Pleural Effusion.” Cleveland Clinic Journal of Medicine 75 (4): 297–303. 2. Diacon, A. H., M. H. Brutsche, and M. Soler. 2003. “Accuracy of Pleural Puncture Sites: A Prospective Comparison of Clinical Examination With Ultrasound.” Chest 123: 436–41. 3. Lichtenstein, D., I. Goldstein, E. Mourgeon, P. Cluzel, P. Grenier, and J. J. Rouby. 2004. “Comparative Diagnostic Performances of Auscultation, Chest Radiography, and Lung Ultrasonography in Acute Respiratory Distress Syndrome.” Anesthesiology 100: 9–15. 4. Guarino, J. R., and J. C. Guarino. 1994. “Auscultatory Percussion: A Simple Method to Detect Pleural Effusion.” Journal of General Internal Medicine 9: 71–74. 5. Light, R. W. 2007. Pleural Diseases, 5th ed. Philadelphia: Lippincott Williams & Wilkins. 6. Raasch, B. N., E. W. Carsky, E. J. Lane, J. P. O'Callaghan, and E. R. Heitzman. 1982. “Pleural Effusion: Explanation of Some Typical Appearances.” AJR American Journal of Roentgenology 139 (5): 899. 7. Stark, P. 2000. “The Pleura.” In Radiology: Diagnosis Imaging, Intervention, edited by J. M. Taveras, and J. T. Ferrucci, 1–29. Philadelphia: Lippincott. 8. Evans, A. L., and F. V. Gleeson. 2004. “Radiology in Pleural Disease: State of the Art.” Respirology 9 (3): 300. 9. Stark, D. D., M. P. Federle, P. C. Goodman, A. E. Podrasky, and W. R. Webb. 1983. “Differentiating Lung Abscess and Empyema: Radiography and Computed Tomography.” American Journal of Roentgenology 141 (1): 163. 10. Moore, C. L., and J. A. Copel. 2011. “Point-of-Care Ultrasonography.” New England Journal of Medicine 364 (8): 749. 11. Light, R. W., and J. M. Porcel. 2006. “Diagnostic Approach to Pleural Effusions in Adults.” American Family Physician 73: 1211–20. 12. Shinto, R. A., and R. W. Light. 1990. “Effects of Diuresis on the Characteristics of Pleural Fluid in Patients With Congestive Heart Failure.” American Journal of Medicine 88: 230–34. 13. Light, R. W. 2002. “Clinical Practice: Pleural Effusion.” New England Journal of Medicine 346: 1971–77. 14. Maskell, N. A., C. W. Davies, A. J. Nunn, E. L. Hedley, F. V. Gleeson, R. Miller, R. Gabe, et al. 2005. “U.K. Controlled Trial of Intrapleural Streptokinasefor Pleural Infection.” New England Journal of Medicine 352: 865–74. 15. Maskell, N. A., C. W. Davies, E. Jones, and R. J. O Davies. 2002. “The Characteristics of 300 Patients Participating in the MRC/BTS Multicenter Intra- pleural Streptokinase vs. Placebo Trial.” In Proceedings of the American Thoracic Society Meeting, Atlanta. 16. Koegelenberg, C. F. N., A. H. Diacon, and C. T. Bolliger. 2008. “Parapneumonic Pleural Effusion and Empyema.” Respiration 75: 241–50. 17. Gene, L., G. L. Colice, A. Curtis, J. Deslauriers, J. Heffner, R. Light, B. Littenberg, S. Sahn, R. A. Weinstein, and R. D. Yusen. 2000. “Medical and Surgical Treatments of Parapneumonic Effusions.” Chest 118: 1158–71. 18. Jones, P. W., J. P. Moyers, J. T. Rogers, R. M. Rodriguez, Y. C. Lee, and R. W. Light. 2003. “Ultrasound-Guided Thoracentesis: Is It a Safer Method?” Chest 123: 418–23. 19. Davies, R. J., Z. C. Traill, and F. V. Gleeson. 1997. “Randomised Controlled Trial of Intrapleural Streptokinase in Community Acquired Pleural Infections.” Thorax 52: 416–21. 20. Rahman, N. M., N. A. Maskell, A. West, R. Teoh, A. Arnold, C. Mackinlay, D. Peckham, et al. 2011. “Intrapleural Use of Tissue Plasminogen Activator and DNase in Pleural Infection.” New England Journal of Medicine 365: 518–26. 21. Bouros, D., S. Schiza, G. Patsourakis, G. Chalkiadakis, P. Panagou, and N. M. Siafakas. 1997. “Intrapleural Streptokinase versus Urokinase in the Treatment of Complicated Parapneumonic Effusions: A Prospective, Double- blind Study.” American Journal of Respiratory and Critical Care Medicine 155: 291–95. 22. Light, R. W. 2006. “Parapneumonic Effusions and Empyema.” Proceedings of the American Thoracic Society 3: 75–80. 23. Cassina, P. C., M. Hauser, L. Hillejan, D. Greschuchna, and G. Stamatis. 1999. “Video-assisted Thoracoscopy in the Treatment of Pleural Empyema: Stage-based Management and Outcome.” The Journal of Thoracic Cardiovascular Surgery 117: 234–38. 24. Silen, M. L., and K. S. Naunheim. 1996. “Thoracoscopic Approach to the Management of Empyema Thoracis: Indications and Results.” Chest Surgery Clinic of North America 6: 491–99. 25. Wait, M. A., S. Sharma, J. Hohn, and A. Dal Nogare. 1997. “A Randomized Trial of Empyema Therapy.” Chest 111: 1548–51. 26. Pothula, V., and D. J. Krellenstein. 1994. “Early Aggressive Surgical Management of Parapneumonic Empyemas.” Chest 105: 832–36. 27. Mandal, A. K., H. Thadepalli, A. K. Mandal, and U. Chettipally. “Outcome of Primary Empyema Thoracis: Therapeutic and Microbiological Aspects.” The Annals of Thoracic Surgery 66: 1782–86. 28. Thurer, R. J. 1996. “Decortication in Thoracic Empyema: Indications and Surgical Technique.” Chest Surgery Clinic of North America 6: 461–90. 29. Pothula, V., and D. J. Krellenstein. 1994. “Early Aggressive Surgical Management of Parapneumonic Empyemas.” Chest 105: 832–36. 30. Neff, C. C., E. van Sonnenberg, D. W. Lawson, and A. S. Patton. “CT Follow-up of Empyemas: Pleural Peels Resolve After Percutaneous Catheter Drainage.” Radiology 176: 195–97.

Nosocomial CHAPTER Pneumonia 17 AARON ROBERT SOUFER, MD CASE A 68-year-old man with a history of coronary artery disease, hypertension, and type 2 diabetes mellitus presents for evaluation of a several day history of worsening dyspnea, orthopnea, and lower extremity edema. Workup in the emergency department suggests a diagnosis of congestive heart failure (CHF) and he is admitted and responds well to intravenous (IV) furosemide. On day 3, the team is prerounding on the patient with a tentative plan to discharge him in the afternoon. The night-float resident tells you that the patient spiked a fever and developed low oxygen saturations overnight. The patient is currently complaining of mild shortness of breath and productive cough. On physical examination, he is febrile with crackles and egophony at the right lung base. Laboratory evaluation reveals a mild leukocytosis (white blood cell 14,000, up from 7000 the previous day) with 90% polymorphonuclear cells and no bands. CXR reveals a new infiltrate in the right lower lobe with recession of pulmonary edema when compared to the previous chest radiograph. 1. What is the likely diagnosis? The likely diagnosis is hospital-acquired pneumonia (HAP). This patient is presenting with pneumonia on the third day of his hospitalization for a CHF exacerbation. These patients typically present with productive cough, dyspnea, and frequently fever, tachycardia, and respiratory distress. Egophony, crackles, and dullness to percussion are often appreciated on lung examination, in addition to bronchial breath sounds over the posterior lung fields. Mental status changes may be present in some patients.1 Leukocytosis is commonly apparent with neutrophilic predominance or leftward shift, while a new alveolar infiltrate may be found on CXR. 213 It is important to consider the clinical entities of HAP, ventilatorassociated pneumonia (VAP), and healthcare-associated pneumonia (HCAP) when making the diagnosis of pneumonia in hospitalized patients. Identification of these nosocomial subsets of pneumonia will help to narrow down the pathogenic microbe involved in the infection and will ultimately guide empiric antibiotic treatment. HAP is defined as pneumonia that occurs 48 hours or more after admission. It is assumed that the pneumonia was not incubating at the time of admission. VAP is a pneumonia that occurs more than 48–72 hours after endotracheal intubation. HCAP occurs in nonhospitalized patients with extensive healthcare contact. HCAP is included in the spectrum of HAP and VAP, and similar infectious organisms must be considered in these patients. It is defined by the diagnosis of pneumonia with 1 or more of the following risk factors: • Hospitalization in an acute care hospital for more than 2 days within the past 90 days of symptoms • IV therapy, chemotherapy, or wound care within 30 days of infection • Residence in nursing home or long-term care facility • Attendance to hospital or hemodialysis center within 30 days of infection2 The patient in the above scenario should be diagnosed with HAP, because he had been hospitalized for more than 48 hours before developing a new pulmonary infiltrate on chest radiograph. He also shows clinical signs of pneumonia including leukocytosis, fever, and cough with purulent sputum production. HAP explains the patient’s newonset dyspnea and oxygen desaturation in the face of adequate treatment for his CHF exacerbation. Bottom line: The differential diagnosis for pneumonia in hospitalized patients includes HAP, VAP, and HCAP. HAP is defined as pneumonia that occurs more than or equal to 48 hours after hospital admission. 2. What are the most common etiologies of pneumonia in hospitalized patients? Bacterial etiology is far more common than viral or fungal pathogens in immunocompetent patients. In general, the bacteriology of nonventilated patients with HAP and HCAP has been shown to be similar to ventilated patients.2 Core pathogens in bacterial nosocomial pneumonia include Streptococcus pneumoniae, Haemophilus influenzae, methicillinsensitive Staphylococcus aureus, and antibiotic-sensitive gram-negative enteric species including Enterobacter spp., Escherichia coli, Klebsiella spp., Proteus spp., and Serratia marcescens. Patients with risk factors for resistant organisms (discussed below) may be infected with Pseudomonas aeruginosa, Acinetobacter spp., or methicillin-resistant S. aureus (MRSA).2,3 Certain circumstances may lead to alternative etiologic pathogens. Anaerobes may cause HAP secondary to aspiration, but this is not a source of infection in VAP. Patients with acute respiratory distress syndrome more often demonstrate polymicrobial infections. Immunocompromised hosts may undergo infection due to the overgrowth of oropharyngeal commensal bacteria, Legionella pneumophila, Candida, Aspergillus fumigates, or viral etiologies.2 Many of the pathogens involved in HAP, HCAP, and VAP are multidrug- resistant (MDR) bacteria. While vancomycin-resistant enterococcus and MRSA are defined by resistance to a single antibiotic, MDR in gram-negative organisms is more difficult to define. In gram-negative organisms, MDR generally refers to resistance to more than 1 of the following drug classes: antipseudomonal cephalosporins, antipseudomonal carbapenems, β-lactamβ-lactamase inhibitor combinations, antipseudomonal fluoroquinolones, and aminoglycosides.4 Propensity for MDR has been found in all common species of HAP, VAP, and HCAP, including P. aeruginosa, Klebsiella pneumoniae, Acinetobacter species, and MRSA, in addition to S. pneumoniae and L. pneumophila.2 Specific risk factors for infection with an MDR organism include: • Antimicrobial therapy in the past 90 days • Current hospitalization greater than 5 days • Elevated prevalence of antibiotic resistance in the hospital or community • Immunosuppressive disease and/or therapy • HCAP risk factors (as discussed above).2 Sources of inoculation include healthcare equipment, air, water, fomites, and transfer of pathogens between staff and patients.5 Although controversial, it is thought that the oral flora, stomach, and sinuses are potential reservoirs of nosocomial pathogens(ATS, 2005).6 The primary route of bacterial entry into the lower respiratory tract is microaspiration of oropharyngeal contents previously colonized with pathogenic bacteria. Microaspirations or infected pooling secretions may leak around the endotracheal tube cuff and enter the lower respiratory tract.7 Gross aspiration of gastric contents is a less common cause of HAP but may occur in patients with altered level of consciousness and impaired gag reflex. Hematogenous spread of infectious agents from distant sites is rare but may occur in patients with recent surgery, IV, or genitourinary catheters. Once bacteria have entered the lower respiratory tract, they have the opportunity to colonize and will cause infection if they overwhelm the host’s defense.2,3 Bottom line: Immunocompetent patients who are diagnosed with pneumonia in the hospital setting are most commonly infected by S. pneumoniae, H. influenzae, methicillin-sensitive S. aureus, or gramnegative enteric species. MDR has been noted in most common pathogens that result in HAP, VAP, or HCAP. 3. How common are the diagnoses of HAP and VAP? What is the associated mortality rate of these conditions? HAP is the second most common nosocomial infection. It constitutes up to 27% of nosocomial intensive care unit (ICU) infections, 86% of which are associated with mechanical ventilation.8 Indeed, VAP occurs in 8%–28% of intubated patients.9 The associated mortality ranges from 33% to 50% for patients with HAP and VAP, but this is affected by the severity of underlying illness, presence of bacteremia, type of infectious bacterial species, and proper use of antibiotics. The crude mortality rates of HAP and VAP are considerably higher compared to other nosocomial infections and are increased with MDR organisms. Onset of HAP and VAP less than 5 days from admission is associated with better morbidity and mortality with respect to later onset of disease, as the latter group of patients is at increased risk for multidrug resistance.2 Bottom line: Onset of HAP and VAP less than 5 days after hospital admission is associated with better prognosis due to decreased risk of acquiring multidrug resistance. 4. How is the diagnosis of nosocomial pneumonia made? Establishing the clinical diagnosis of nosocomial pneumonia is the first step in the management of HAP, VAP, or HCAP. This requires a comprehensive history and physical examination in addition to selected laboratory and imaging studies. Pneumonia may be diagnosed based on a new radiographic infiltrate plus 2 of the 3 clinical findings suggestive of infection including fever, leukocytosis or leukopenia, and purulent sputum.2,3 In addition to the diagnosis of pneumonia, the required criteria for HAP, VAP, or HCAP must be met (e.g., hospitalization >48 hours for HAP). Note that the clinical diagnosis of this condition is sensitive and timely. Early diagnosis is important to initiate empiric antibiotic therapy, as delayed initiation of appropriate antibiotics in these patients is associated with increased mortality (ATS, 2005).10,11 It is recognized that false positives may be encountered with clinical diagnosis, leading to unnecessary or inappropriate antibiotic treatment. To determine the accuracy of clinical diagnosis, one study compared the results of clinical diagnosis to immediate postmortem lung biopsies in 25 deceased VAP patients. Different combinations of clinical variables (e.g., fever, leukocytosis, or purulent sputum production) were used in the presence of new CXR infiltrate to make the initial diagnosis of VAP, which was then compared to postmortem lung pathology and quantitative cultures to confirm the diagnosis. Using 1 clinical variable in addition to new radiographic infiltrate was highly sensitive but not specific (sensitivity 85% and specificity 33%). Alternatively, requiring 3 clinical variables in addition to radiographic infiltrate lacked sensitivity (sensitivity 23% and specificity 92%). Using 2 clinical variables in addition to new radiographic infiltrate demonstrated a reasonable balance between sensitivity and specificity (sensitivity 69% and specificity 75%). Based on this study and others, the American Thoracic Society and Infectious Disease Society of America offer a level II recommendation that clinical diagnosis be made based on 2 clinical variables in addition to new infiltrate on CXR.2,12 Bottom line: Clinical diagnosis is sensitive for HAP, VAP, and HCAP and is necessary to initiate empiric antibiotic treatment, which has been associated with decreased mortality risk compared to patients in whom empiric therapy is delayed. 5. What laboratory tests and imaging results should be required for patients with a diagnosis of nosocomial pneumonia? The following are the recommendations based on the 2005 American Thoracic Society and Infectious Disease Society of America consensus statement on HAP, VAP, and HCAP, for which level II evidence is described. All patients should have a chest radiograph, preferably in the posterior-anterior (PA) and lateral views if possible. A complete blood count should be obtained for diagnosis. Serum electrolytes, renal, and liver function tests may be obtained to rule out multiorgan dysfunction and can be used to define the severity of illness. Arterial oxygen saturation should be obtained to determine the need for supplemental oxygen. Arterial blood gas should only be obtained if there is concern for metabolic or respiratory acidosis, and/or in mechanically ventilated patients. Blood cultures should be obtained in VAP patients, although the sensitivity of blood cultures is less than 25% in VAP. Positive blood cultures may also reflect an extrapulmonary site of infection.2 Bottom line: CXR, complete blood count, serum electrolyte levels, and renal/liver function tests should be obtained in all patients with nosocomial pneumonia. Blood cultures are recommended in patients with VAP. 6. Is there evidence that Gram stain of endotracheal aspirates is useful in making a clinical diagnosis in VAP patients? Yes. Gram stain of endotracheal aspirates may provide visualization of bacteria and inflammatory cells, which is helpful in clinical diagnosis. In patients with VAP without recent antibiotic changes, the tracheal aspirate has a high negative predictive value (94%).13 Therefore, negative Gram stain for bacteria and inflammatory cells in these patients is highly suggestive of extrapulmonary source of infection. However, semiquantitative cultures may reflect colonization and can result in a false-positive diagnosis of pneumonia.2 Bottom line: Negative Gram stain of tracheal aspirates in patients with VAP is highly suggestive of an extrapulmonary source of infection. 7. Is there evidence suggesting utility of lower respiratory tract cultures obtained by broncheoalveolar lavage, protected specimen brush, or endotracheal aspirates? Yes. Invasive sampling methods can be used to gather lower respiratory tract specimens for quantitative culture. Quantitative cultures serve to distinguish bacterial infection versus colonization, in addition to specifying the infectious organism, which aids in narrowing the spectrum of antibiotic therapy. Growth above a threshold level is diagnostic of nosocomial pneumonia, whereas growth under this threshold indicates colonization or contamination. Thresholds depend on the technique used and may also be adjusted based on the clinical likelihood of infection and the recent administration of antibiotics. For instance, the threshold may be lowered if the clinical likelihood of infection is high and/or if antibiotics were recently administered.14 It is generally recommended that lower respiratory tract cultures be obtained before the administration of antibiotics if possible.2 The bacteriologic approach is specific and results in fewer recipients of antibiotics of a narrower spectrum. When compared to clinical diagnosis, invasive diagnosis has been shown to produce improved 14-day mortality, decreased septic-related multiorgan failure, and decreased overall antibiotic use in 1 multicenter, randomized, uncontrolled trial in 413 patients with suspected VAP.15 However, there is a risk of false-negative results, especially in the face of recent antibiotic initiation or change within 24–72 hours of obtaining cultures. It must also be kept in mind that these results do not return immediately, so any patients who have signs of infection or who are clinically unstable should receive early empiric therapy before culture results return, as this reduces morbidity and mortality.2 One must also consider the risk of causing harm to patients when performing invasive lower respiratory tract sampling, although complications are rare with these procedures.16 Bottom line: Lower respiratory tract cultures are specific for the diagnosis of HAP, VAP, and HCAP and can characterize the infectious organism to direct more targeted antibiotic therapy. 8. Are there evidence-based recommendations describing how both clinical and bacteriologic strategies can be used together? Yes. The American Thoracic Society and Infectious Disease Society of America created an algorithm utilizing both the clinical and the bacteriologic approaches to diagnosis, considering that the advantages and disadvantages of these 2 strategies are somewhat complimentary (Figure 17.1). The algorithm begins with clinical diagnosis to guide empiric administration of antibiotics. This is followed by re-evaluation of treatment at 48–72 hours by observing clinical progression and results from lower respiratory tract cultures that were obtained before the administration of antibiotics. 9. Does early initiation of antibiotic therapy and proper antibiotic choice affect mortality in hospitalized patients? Yes. Both early initiation of antibiotic therapy and correct antibiotic choice have been shown to improve survival for patients with HAP, VAP, and HCAP.2,10,11,17 One study of 107 VAP patients showed that the likelihood ratio of hospital mortality was 7.68 in patients who received proper antibiotics more than or equal to 24 hours after diag HAP, VAP or HCAP Suspected Obtain lower respiratory tract (LRT) sample for culture (quantitative or semi- quantitative) & microscopy) Unless there is both a low clinical suspicion for pneumonia & negative microscopy of LRT= Lower Respiratory Tract sample, begin empiric antimicrobial therapy Days 2 & 3: check cultures & assess clinical response: (temperature, WBC, chest X-ray, oxygenation, purulent sputum, hemodynamic changes & organ function) Clinical improvement at 48-72 hours NO YES Cultures− Cultures+ Cultures− Cultures+ Search for other pathogens, complications, other Adjust antibiotic therapy, search for other pathogens, diagnoses or other complications, other sites of infection diagnoses or other sites of infection De-escalate Consider stopping antibiotics antibiotics, if possible. Treat selected patients for 7-8 days & reassess FIGURE 17.1 Management algorithm for hospital acquired pneumonia (HAP), ventilator associated pneumonia (VAP), and health care associated pneumonia. This approach utilizes both clinical and bacteriologic diagnostic strategies (see text). nostic criteria of VAP were met, when compared to patients receiving proper antibiotics within 24 hours.10 A retrospective cohort analysis of 431 culture positive HCAP patients showed that inappropriate initial antibiotic selection—as determined by inactivity of antibiotic upon in vitro testing—was associated with significantly higher hospital mortality. This effect was more pronounced in nonbacteremic patients when compared to bacteremic patients and was not attenuated by the escalation of antibiotic therapy after the initial administration of inappropriate antibiotics.17 Bottom line: Prompt initiation of appropriate empiric antibiotic therapy in patients with nosocomial pneumonia is associated with reduced mortality. 10. What is the proper approach to choose empiric antibiotic therapy? It is important to consider the risk factors for MDR in each patient and to take local drug resistance patterns into account when choosing empiric antibiotic therapy.18 As with many other infections, therapy is guided by initial empiric therapy followed by de-escalation of therapy specific to the cultured organism. Antibiotics may be narrowed based on the organism’s unique resistance pattern as determined by microbiologic identification and sensitivities of lower respiratory tract cultures (ATS, 2005).21
The most important determinant of empiric antibiotic therapy is whether the patient has risk factors for MDR organisms. Careful attention must be paid to whether the pneumonia is late onset (>5 hospital days). If MDR is suspected, then broad spectrum antibiotics should be initiated as empiric therapy, as opposed to limited spectrum therapy in the alternative situation. Broad-spectrum empiric therapy for suspected MDR should cover MDR P. aeruginosa, MDR K. pneumoniae, and MDR Acinetobacter species in addition to MRSA when suspected. This therapy should also cover core pathogens including S. pneumoniae, H. influenzae, methicillin-sensitive S. aureus, and antibiotic- sensitive gramnegative enteric species (including Enterobacter spp., Escherichia coli, Klebsiella spp., Proteus spp., and Serratia marcescens). MDR antibiotic coverage should include the following: Antipseudomonal cephalosporin (cefepime or ceftazidime), Or Antipseudomonal carbapenem (imipenem or meropenem) Or β-Lactam/β-lactamase inhibitor (piperacillin/tazobactam) And Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) Or Aminoglycoside (gentamicin, amikacin, or tobramycin) If MRSA is suspected, then one should add Vancomycin Or Linezolid This regimen will also cover core pathogens noted above. As stated, local resistance patterns and organism prevalence must be taken into account when choosing empiric antibiotics. More limited therapy may be used if MDR organisms are not suspected. These include the core pathogens as mentioned, namely S. pneumoniae, H. influenzae, methicillin-sensitive S. aureus, and antibiotic-sensitive gram-negative enteric species.2,3 Potential antibiotic therapy includes the following: Nonpseudomonal third- generation cephalosporin (e.g., ceftriaxone) Or Respiratory fluoroquinolone (levofloxacin, moxifloxacin, and ciprofloxacin) Or Ampicillin/sulbactam Or Ertapenem Patients may present with risk factors for alternative organisms, which should influence antibiotic choice. Witnessed aspiration or recent abdominal surgery raise risk for anaerobic infection, which may be treated with clindamycin or β- lactam/β-lactamase inhibitor. Coma, head trauma, diabetes mellitus, and renal failure are risk factors for S. aureus, which may warrant treatment with vancomycin until MRSA is ruled out. High-dose steroids may predispose patients to Legionella species, which may be treated with a macrolide (e.g., azithromycin) or a fluoroquinolone(e.g., levofloxacin). Rifampin may be added to macrolide treatment of Legionella. Pseudomonas may be suspected in the setting of prolonged ICU stay, steroids, antibiotics, and structural lung disease. This may be treated with broad-spectrum empiric therapy as described above.2,3 Empiric therapy should ideally avoid classes of antibiotics used for a recent infection, as antimicrobial resistance can be higher to such agents. Adequate dosage must be implemented to penetrate the site of infection. Agents should be started IV and can be switched to oral route if the patient demonstrates an adequate response and has a functioning gastrointestinal tract.2 Medication allergies of every patient should be reviewed when selecting antibiotics, as medications known to induce life-threatening reactions in a patient should be avoided. The risks of antibiotic toxicities must also be weighed with respect to the benefits of treatment in every patient. Bottom line: Antibiotic treatment is initiated after clinical diagnosis. Use broad- spectrum antibiotics as empiric therapy if MDR is suspected and/or if pneumonia is late onset. Use narrow-spectrum empiric therapy if this is not the case. 11. Is there evidence suggesting that de-escalation of antibiotic therapy improves mortality in HAP, VAP, and HCAP patients? Yes. When culture results return, therapy can be narrowed based on organism identification, sensitivities, and local drug resistance patterns. This is termed “de-escalation” of therapy. In 1 prospective observational cohort study including 398 patients with suspected VAP, mortality was significantly lower in patients whose therapy was de-escalated compared to patients whose antibiotic regimen was escalated or unchanged.20 Bottom line: After 48–72 hours, results of cultures and sensitivities should be used in conjunction with clinical status to reassess diagnosis and de-escalate antibiotics as appropriate. 12. When should antibiotics be discontinued? If initial antibiotic regimen was appropriate, effort should be made to reduce the effective antibiotic course to periods as short as 8 days, unless the organism identified is P. aeruginosa.21 Although traditional antibiotic durations have lasted for 14–21 days, these extended treatment durations of nonpseudomonal infections have been shown to cause colonization by antibiotic-resistant organisms.2 Patients should be monitored for improvement of clinical parameters to infer the success of treatment. Clinical response is usually evident between 48 and 72 hours. The responding patient should undergo deescalation of therapy as discussed. The nonresponding patient should be evaluated for unsuspected drug- resistant organisms, extrapulmonary site of infection, noninfectious pulmonary process, or complications of pneumonia and its therapy.2 Bottom line: Antibiotic course is ideally restricted to 8 days in nonpseudomonal infections to limit the risk of developing MDR. 13. How can bacterial nosocomial pneumonia be prevented in patients at risk for the condition? There are several ways to prevent bacterial nosocomial pneumonia. Education of healthcare staff on the epidemiology of these infections is a key step in prevention, in addition to proper hand and equipment hygiene. Endotracheal, tracheostomy, and/or enteral tubes should be removed from patients as soon as clinically indicated, and noninvasive positive pressure ventilation should be used as an alternative to intubation when possible and not medically contraindicated. Placement of feeding tubes should be routinely verified to prevent aspiration, and the head of the bed may be elevated to 30°–45° when not medically contraindicated. Hospitals should collect and monitor data regarding in-house nosocomial infection patterns, with recorded microbiology and antimicrobial susceptibility patterns. Oral hygiene programs with antiseptic agents may also prevent oropharyngeal colonization for patients in acute-care settings or residents in long-term care facilities who are at high risk for HCAP. It is also important to encourage spirometry, deep breathing, and early ambulation in postoperative patients, when not medically contraindicated.5 In addition, there are many modifiable risk factors that have been targeted as a source of prevention of bacterial nosocomial pneumonia, which are as follows • Mechanical ventilation—the most significant risk factor, increases risk 6- to 21-fold2 • Enteral feeding—mainly due to microaspiration of gastric contents. There is a higher incidence of aspiration in the supine position • Poor hand hygiene • Poor equipment cleaning and sterilization • Oropharyngeal colonization with gram-negative enteric organisms and P. aeruginosa • Stress bleeding prophylaxis—altered gastric acidity with H2 receptor antagonists and antacids have been shown as independent risk factors for HAP- acquired in the ICU • Age more than 70 years • Chronic lung disease • Aspiration • Previous antibiotic exposure19,2,5 More information on the prevention of bacterial nosocomial pneumonia can be found at the Center for Disease Control Website: http:// www.cdc.gov/mmwr/preview/mmwrhtml/rr5303a1.htm Bottom line: Nosocomial pneumonia is strongly associated with mechanical ventilation. Efforts should be made to reduce time of mechanical ventilation and to maintain proper hand and equipment hygiene. TAKE-HOME POINTS: NOSOCOMIAL PNEUMONIA 1. HAP and VAP must be considered in hospitalized and/or ventilated patients with new infiltrate on chest radiograph accompanied by new-onset fever, leukocytosis, and/or purulent sputum production. HCAP must be considered in patients with the same clinical presentation, who have had extensive contact with the healthcare system (as detailed in Section 1). 2. HAP and VAP are common nosocomial infections and are highly associated with mechanical ventilation. 3. Bacterial nosocomial pneumonias may be prevented by reducing the duration of mechanical ventilation to the minimum period that is clinically necessary, in addition to proper equipment sterilization and hand hygiene. 4. Common pathogens in HAP, VAP, and HCAP include core pneumonia pathogens (S. pneumoniae, H. influenzae, methicillinsensitive S. aureus) plus antibiotic-sensitive gramnegative enteric species. 5. When specific risk factors for MDR apply (see Section 2), infection may be caused by MDR P. aeruginosa, MDR K. pneumoniae, MDR Acinetobacter species, or MRSA. 6. Clinical diagnosis is determined by new infiltrate on chest radiograph plus 2 or more associated signs including fever, leukocytosis, or purulent sputum production. Clinical diagnosis is sensitive and facilitates early initiation of antibiotics to reduce mortality risk. 7. If MDR is suspected, then broad-spectrum antibiotics should be initiated as empiric therapy, as opposed to limited spectrum therapy in the alternative situation (antibiotic choices are outlined in Section 10). 8. If possible, lower respiratory tract specimens should be obtained before the initiation of antibiotics, for quantitative or semiquantitative cultures and microscopy. However, collection of cultures should not delay antibiotic administration in critically ill patients. 9. After 48–72 hours, results of cultures and sensitivities should be used in conjunction with clinical status to reassess diagnosis and de-escalate antibiotics as appropriate. 10. Early initiation of antibiotics and proper antibiotic choice are associated with improved mortality outcomes. REFERENCES 1. Mcgee, S. 2007. Evidence Based Physical Diagnosis, 2nd ed. 351–57. St. Louis: Saunders Elsevier. 2. American Thoracic Society, and Infectious Disease Society of America. 2005. “Guidelines for the Management of Adults With Hospital-Acquired, Ventilator- Associated, and Health Care-Associated Pneumonia.” American Journal of Respiratory and Critical Care Medicine 171: 388–416. 3. American Thoracic Society. 1996. “Hospital-Acquired Pneumonia in Adults: Diagnosis, Assessment of Severity, Initial Antimicrobial Therapy, and Preventive Strategies [Consensus Statement].” American Journal of Respiratory and Critical Care Medicine 153: 1711–25. 4. Paterson, D. L. 2006. “The Epidemiological Profile of Infections With Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter Species.” Clinical Infectious Diseases 43 (Suppl 2): S43. 5. Tablan, O. C., L. J. Anderson, R. Besser, C. Bridges, and R. Hajjeh, Healthcare Infection Control Practices Advisory Committee. 2004. “Guidelines for Preventing Health-Care–Associated Pneumonia, 2003: Recommendations of the CDC and the Healthcare Infection Control Practices Advisory Committee.” Centers for Disease Control and Prevention. MMWR Recommendations and Reports 53 (RR-3): 1–36. 6. Rouby, J. J., P. Laurent, M. Gosnach, E. Cambau, G. Lamas, A. Zouaoui, J. L. Leguillou, L. Bodin, T. D. Khac, and C. Marsault. 1994. “Risk Factors and Clinical Relevance of Nosocomial Maxillary Sinusitis in the Critically Ill.” American Journal of Respiratory and Critical Care Medicine 150: 776–83. 7. Valles, J., A. Artigas, J. Rello, N. Bonsoms, D. Fontanals, L. Blanch, R. Fernandez, F. Baigorri, and J. Mestre. 1995. “Continuous Aspiration of Subglottic Secretions in Preventing Ventilator-Associated Pneumonia.” Annals of Internal Medicine 122: 179–86. 8. Richards, M. J., J. R. Edwards, D. H. Culver, and R. P. Gaynes. 1999. “Nosocomial Infections in Medical ICUs in the United States: National Nosocomial Infections Surveillance System.” Critical Care Medicine 27: 887– 92. 9. Chastre, J., and J. Y. Fagon. 2002. “Ventilator-Associated Pneumonia.” American Journal of Respiratory and Critical Care Medicine 165: 867–903. 10. Iregui, M., S. Ward, G. Sherman, V. J. Fraser, and M. H. Kollef. 2002. “Clinical Importance of Delays in the Initiation of Appropriate Antibiotic Treatment for Ventilator-Associated Pneumonia.” Chest 122: 262–68. 11. Alvarez-Lerma, F. 1996. “ICU-Acquired Pneumonia Study Group. Modification of Empiric Antibiotic Treatment in Patients With Pneumonia Acquired in the Intensive Care Unit.” Intensive Care Medicine 22: 387–94. 12. Fabregas, N., S. Ewig, A. Torres, M. El-Ebiary, J. Ramirez, J. P. de la Bellacasa, T. Bauer, and H. Cabello. 1999. “Clinical Diagnosis of Ventilator Associated Pneumonia Revisited: Comparative Validation Using Immediate Postmortem Lung Biopsies.” Thorax 54: 867–73. 13. Blot, F., B. Raynard, E. Chachaty, C. Tancrede, S. Antoun, and G. Nitenberg. 2000. “Value of Gram Stain Examination of Lower Respiratory Tract Secretions for Early Diagnosis of Nosocomial Pneumonia.” American Journal of Respiratory and Critical Care Medicine 162: 1731–37. 14. Cook, D., and L. Mandell. 2000. “Endotracheal Aspiration in the Diagnosis of Ventilator-Associated Pneumonia.” Chest 117: 195S–7S. 15. Fagon, J. Y., J. Chastre, M. Wolff, C. Gervais, S. Parer-Aubas, F. Stephan, T. Similowski, et al. 2000. “Invasive and Noninvasive Strategies for Management of Suspected Ventilator-Associated Pneumonia: A Randomized Trial.” Annals of Internal Medicine 132:621–30. 16. Islam, S. 2011. “Flexible Bronchoscopy: Equipment, Procedure, and Complications.” UpToDate. 17. Zilberberg, M. D., A. F. Shorr, S. T. Micek, S. H. Mody, and M. H. Kollef. 2008. “Antimicrobial Therapy Escalation and Hospital Mortality Among Patients With Healthcare-Associated Pneumonia: A Single-Center Experience.” Chest 134: 963–68. 18. Beardsley, J. R., J. C. Williamson, J. W. Johnson, C. A. Ohl, T. B. Karchmer, and D. L. Bowton. 2006. “Using Local Microbiologic Data to Develop Institution-Specific Guidelines for the Treatment of Hospital-Acquired Pneumonia.” Chest 130: 787–93. 19. File, T. M. 2011. “Risk Factors and Prevention of Hospital-Acquired, Ventilator-Associated, and Healthcare-Associated Pneumonia in Adults.” UpToDate. 20. Kollef, M. H., L. E. Morrow, M. S. Niederman, K. V. Leeper, A. Anzueto, L. Benz-Scott, and F. J. Rodino. 2006. “Clinical Characteristics and Treatment Patterns among Patients with Ventilator-Associated Pneumonia.” Chest 129: 1210–18. 21. Chastre, J., M. Wolff, J. Y. Fagon, S. Chevret, F. Thomas, D. Wermert, E. Clementi, et al. 2003. “Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator-Associated Pneumonia in Adults: A Randomized Trial.” JAMA 290: 2588–98. 22. File, T. M. 2011. “Treatment of Hospital-Acquired, Ventilator-Associated, and Healthcare-Associated Pneumonia in Adults.” UpToDate.

Cocaine-Induced cH a P ter Chest Pain 18 Priscilla Owusu aNsaH, MD CASE A 30-year-old man is brought to the emergency department (ED) by his friends after acting strangely at a party. Approximately 1 hour earlier, he suddenly became erratic and violent. In the ED, he complains of dyspnea and substernal chest pressure with radiation to the left shoulder. On examination, he is diaphoretic with dilated pupils. Vital signs are as follows: temperature 101°F, HR 120 and irregular, blood pressure 150/100 mm Hg, and RR 18 breaths/min. The remainder of the examination is unrevealing. 1. What is the differential diagnosis for general chest pain? The differential diagnosis is quite broad and includes musculoskeletal causes, cardiac causes, pulmonary causes, gastrointestinal causes, psychosomatic causes, and dermatologic conditions such as herpes zoster. Table 18.1 presents a detailed listing of the differential diagnosis for chest pain. Bottom line: The differential diagnosis for chest pain is broad. The cause of most chest pain is noncardiac. 2. What other information would be important to obtain from this patient’s history? Has there been any recent use of sympathomimetics such as cocaine or methamphetamines, history of illicit drug use, smoking history, prior cardiac disease, diabetes, family history of premature heart disease in first-degree relatives (less than 55 in men, less than 65 in women), or sudden cardiac death? Although in young adults, chest pain is unlikely to be secondary to atherosclerotic coronary artery disease (CAD), the presence of familial dyslipidemia, smoking, and diabetes significantly 229 TAblE 18.1 Causes of Chest Pain Etiology Musculoskeletal Cardiac Pulmonary Syndrome Costochondritis Cervical spine disease Osteoarthritis Unstable angina Myocardial infarction Aortic dissection Pericarditis Atrial fibrillation Pulmonary embolism Gastrointestinal Miscellaneous Tension pneumothorax Lung cancer Pneumonia Peptic ulcer disease Esophageal spasm Ruptured esophagus/ Boerhaave’s syndrome Pancreatitis Biliary disease Druginduced (e.g., cocaine, amphetamine) Herpes zoster Anxiety Frequency for cause of chest pain Common Rare Rare Common Common Rare Rare Common Moderately common Rare Common Common Common Uncommon Rare Rare Uncommon Common Common increases the risk for CAD. Of these, smoking is the most potent modifiable risk factor for CAD. In young adults, acute coronary syndrome (ACS) is more likely due to nonartherosclerotic causes such as coronary artery spasm, aortic or coronary dissection, coronary artery embolism, and mycocarditis, all of which may be exacerbated by existing valvular disease, vasculitides, and connective tissue diseases such as Marfan syndrome. Bottom line: It is important to take an extensive history, particularly in young adults presenting with chest pain. CASE CONTINUED His friends inform the staff that there was cocaine at the party, and they suspect he used some. 3. What are the characteristics of the typical patient with cocaine-induced chest pain? Does this patient have these characteristics? Findings from The Cocaine-Associated Myocardial Infarction study1 and a study by Mittleman et al.2 show the following: Age less than 50 years: 84% Males: 57%–84% Non-white: 63%–72% Smokers: 84%–91% Cocaine use within the previous 24 hours: 88% Bottom line: Young non-Caucasian adult male smokers with a history of cocaine use in the last 24 hours are typical characteristics in patients with cocaine-related chest pain. 4. What percentage of patients with cocaine-related chest pain experience an acute myocardial infarction? The incidence of acute myocardial infarction (AMI) in patients presenting with cocaine-induced chest pain is reported by various studies as ranging from 0.7% to 6%.3–6 In these studies, AMI was determined using the WHO criteria: Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis with at least one of the following:
(1) ischemic symptoms such as chest pain; (2) development of pathologic Q waves on electrocardiogram (EKG); (3) EKG changes indicative of ischemia (ST segment elevation or depression); or (4) need for cardiac catheterization. The variability in incidence was postulated to likely reflect the differences in sample characteristics and AMI diagnostic criteria among the various studies.5 AMI in these patients is thought to occur as a result of coronary artery vasospasm-induced myocardial ischemia in a setting of increased myocardial oxygen demand, a so-called nonthrombotic “demand-ischemic elevation” in cardiac enzymes rather than a “true” thrombotic myocardial infarction. However, the pathophysiology of AMI in these patients may also involve disruption of atheromatous plaque as a result of the hypertension-mediated increase in shear forces.5,7 Furthermore, cocaine has been reported to increase platelet aggregation and may lead to in situ thrombus formation.5,8–10 Bottom Line: AMI is relatively infrequent in patients presenting with cocaine- associated chest pain. AMI is felt to be precipitated by severe coronary artery vasospasm and/or disruption of atherosclerotic plaques from increased shear forces. 5. How long after cocaine use are patients susceptible to cocaine-induced chest pain from myocardial ischemia? In a case-crossover studyof 3946 patients with recent MI, 38 patients admitted to cocaine use in the preceding year and 9 patients reported cocaine use within an hour before the onset of MI symptoms. This survey reported a 24-fold higher risk of MI in the first hour after cocaine use with a rapid decline in risk thereafter.11,2 In another study, two-thirds of MIs occurred within 3 hours of cocaine use.7 However, it has been noted that onset of ischemic symptoms can still occur several hours after cocaine ingestion, at a time when the blood concentration is low or undetectable. One study reports the median duration of 18 hours between cocaine use and onset of MI12, whereas some studies report onset up to 4 days later.7 The occurrence of MI in these delayed cases is attributed to cocaine metabolites, which rise several hours after cocaine ingestion, persist in the circulation for up to 24 hours, and may cause recurrent or delayed coronary vasoconstriction.8 Bottom line: Cocaine-induced myocardial ischemia typically occurs within a few hours after use, but may still occur up to 4 days postexposure. 6. Does the evidence suggest that this patient should be admitted to the hospital? No. The data suggest that the patient can be “admitted” under observation status and observed and discharged without a formal admission if ruled out for AMI. Patients with normal levels of troponin I, without new ischemic changes on EKG, and who have no cardiovascular complications (dysrrhythmias, AMI, or recurrent symptoms) during a 6- to 12-hour period in a chest-pain observation unit have a very low risk of death or MI during 30 days after discharge.5,13,14 In a retrospective study of 136 patients at 29 institutions, all patients with cardiovascular complications were identified by observation over a 12-hour Matched case-control study that compares, within the same subject, exposure during an interval when the event does not occur (control period) with exposure during the interval when the event occurs (hazard period). period by the findings of ischemia or infarction on an initial EKG or an elevated level of CK-MB within 12 hours after presentation. The conclusion from the study was that less than 1.6 per 1000 patients with cocaine-associated chest pain would be expected to have shortterm cardiovascular complications that were not identified during a 12-hour observation period.1,14 Several other studies corroborate these findings.13,15 Overall, these studies suggest that given the low incidence of MI in these patients, risk stratification based on the established criteria in an observation unit should significantly decrease unnecessary admissions.5 Bottom line: Patients with cocaine-associated chest pain should typically be monitored in an observation unit and not formally admitted to the hospital. 7. What does the evidence suggest the workup should be for this patient? The appropriate diagnostic evaluation for patients presenting with chest pain after cocaine use is unclear. Therefore, it is recommended that practitioners follow general principles for risk stratification of patients with possible ACS.5 Ascertaining cocaine use in a patient presenting with chest pain should rest primarily on self-reporting. Patients, particularly young ones, should be questioned about cocaine use as this may influence treatment strategies. However, there is not enough evidence to dictate routine screening. As such, the qualitative measurement of cocaine metabolites in the urine should be done only in specific cases. These include times when the patient is unable to provide a history and there is no other reliable historian, or when the level of suspicion is high even though the patient does not admit to cocaine use. Screening should also be considered for a patient with minimal risk factors for CAD that presents with MI, especially, if the patient is young and/or has a history of illicit drug use.5 Otherwise, the evaluation of cocaine-associated chest pain in the ED is similar to that of patients for non-cocainerelated possible ACS.5 Cardiac enzymes: Cocaine can induce rhabdomyolysis with consequent increase in myoglobin and total creatine kinase levels, which may confound the diagnosis of cocaine-associated MI. A study showed an increase in total creatinekinase in 75% of patients, including 65% without MI.12 Rather, the most sensitive and specific markers for the diagnosis of cocaine-induced MI are cardiac troponins, specifically troponin I.16 EKG: Abnormal EKGs have been reported in as many as 56%–84% of patients presenting with chest pain after cocaine use.17 Many of these are young patients who have early repolarization patterns with ST elevations in anterior leads, a normal variant that can mimic an acute infarct.18 Therefore, it is recommended that patients be kept for a minimum of 12 hours to monitor cardiac enzymes, regardless of EKG findings.19 Stress testing: In a study evaluating resting myocardial perfusion imaging in 216 patients with low to moderate risk for CAD who presented to the ED with chest pain after cocaine use, 5 had positive results. Of these 5 subjects, 2 had an MI documented by appropriate cardiac marker elevations. Only 2 of those with negative results were found to have significant CAD. It was postulated that the high rate of negative results was at least in part because only half of the patients were injected at the time of the chest pain. The sensitivity for MI was therefore 100% (95% confidence interval 50%–100%), with a specificity of 99% (95% confidence interval, 96%–100%). Of 67 patients who had follow-up stress perfusion studies, 4 (6%) had a reversible defect during stress. Three of the 4 patients underwent angiography with significant CAD found in 2. At 30-day follow-up, there were no cardiac events in patients with negative results after rest perfusion imaging.5,15 Echocardiogram: One study demonstrated that cavity size was normal in chronic cocaine users presenting with chest pain even though there was left ventricular (LV) hypertrophy, leading to the postulation that long-term cocaine use is associated with concentric LV hypertrophy.20 These findings may decrease the utility of echocardiography to look for ischemia in the evaluation of chest pain, as LV hypertrophy may mask regional wall motion abnormalities.5,21,22 Other testing: Individuals who use cocaine are at risk for endocarditis. As such, blood cultures should be considered.23 The decision is based on the risk factors, history, and physical examination indications, and is made at the discretion of the physician. Bottom line: Elevated cardiac troponin concentration is diagnostically sensitive and specific for AMI. Stress testing is useful to rule out MI in this population and also to prognosticate for cardiac events following the acute episode of chest pain. 8. Can the EKG rule in or out an acute infarction? Not entirely. In the Cocaine Associate Chest Pain study,4 the sensitivity of an EKG in detecting myocardial infarction was only 36% with a specificity of 89.9%.5 The positive and negative predictive values of the EKG are 17.9% and 95.8%, respectively.5 Bottom line: The EKG should not be used as the sole measure of the presence or absence of acute infarction. 9. What does the evidence suggest should be the treatment for this patient? As of the time of this writing, there have been no randomized controlled trials comparing different treatment regimens for cocaine-associated myocardial ischemia. Treatment strategies for cocaine-induced myocardial ischemia are based on the known cardiac and nervous system toxicity effects of cocaine.24 Treatment is the same as for spontaneous ACS with a few exceptions as outlined below. Nitroglycerin (level I/B recommendation): Nitroglycerin is a potent vasodilator and relieves chest pain by reversing cocaineinduced coronary vasoconstriction. It is recommended as the primary therapy.5,24,25 Benzodiazepines (level I/B recommendation): Benzodiazepines should be used as first-line therapy in cocaine-associated chest pain as they relieve chest pain and have beneficial hemodynamic effects. Management of supraventricular or ventricular tachyarrhythmias, which may be precipitated by cocaine, is also facilitated by administration of benzodiazepines.16,24,25 In addition, management of the neuropsychiatric symptoms favorably impacts the cardiovascular complications of cocaine toxicity as these two are interrelated.5 Bottom line: Benzodiazepines and nitroglycerin are the recommended first-line treatments for cocaine-induced chest pain. Antiplatelet therapy: Cocaine use is associated with an increase in platelet count26 as well as increased platelet activation and platelet hyperaggregation.2,5,9,10 Treatment with aspirin, glycoprotein IIb/IIIa antagonists, clopidogrel, unfractionated heparin, lowmolecular-weight heparin, or direct thrombin inhibitors has not been well studied in this population. However, these therapies are theoretically beneficial and have been used in some cases. Bottom line: Antiplatelet therapy may be beneficial in reducing thrombosis associated with cocaine use. Calcium channel blockers (Level IIB/C): Treatment with calcium channel blockers (CCB) in animal studies has shown variable results in terms of survival, seizures, and cardiac dysrrhythmias.27 In cardiac catheterization studies, verapamil has been shown to reverse cocaine-associated vasoconstriction.28 Clinical trials in patients with ACS unrelated to cocaine use have not shown any beneficial effects of CCB, and in certain subgroups, CCB may worsen mortality rates. Short-acting nifedipine should never be used, and verapamil or diltiazem should be avoided in patients with evidence of heart failure or LV dysfunction.29,30 In light of all these findings, CCB should not be used as a first- line treatment but can be considered if ischemic discomfort persists after administration of benzodiazepine and nitroglycerin. Bottom line: CCB should not be used as a first-line treatment. 10. What does the evidence suggest in regard to the use of β-blockers in this patient? β -Blockers should be avoided in the acute setting because there is a potential for increased coronary vasoconstriction as well as uninhibited α-mediated hypertensive crisis.24,5 For patients with noncocainerelated MI, β-blocker administration is recommended because it can lower mortality rates. However, this does not hold for cocaineassociated MI, as deaths from this are so low that the risk-benefit ratio is altered.1 However, some studies are re-evaluating this, as β-blockers are effective in blocking the hyperadrenergic effects of cocaine that cause thrombosis and vasospasm.31 Chronic β-blocker use can be considered for long-term therapy. This long-term therapy is recommended only for patients at low risk for recurrent cocaine use and who have documented MI, LV systolic dysfunction, or ventricular arrhythmia.5,24 Bottom line: β-Blocker use in the acute setting may be detrimental. However, it may be appropriate for long-term therapy. TAKE-HOME POINTS: COCAINE-INDUCED CHEST PAIN 1. The differential diagnosis for chest pain is broad. The cause of most chest pain is noncardiac. 2. Young age, male gender, smoking history, and non-Caucasian ethnicity are the most common characteristics in patients presenting with cocaine-associated chest pain. 3. Cocaine can cause an MI but more commonly causes chest pain without infarction. Cocaine can also lead to rhabdomyolysis. 4. β-Blockers should be avoided in cocaine-induced myocardial ischemia to prevent α-mediated vasoconstriction that could exacerbate myocardial ischemia. Rather, benzodiazepines, nitroglycerin, and antiplatelet therapy should be used. 5. Cocaine-induced chest pain typically occurs within several hours of ingestion but can occur up to 3-4 days post-exposure. 6. Most patients with cocaine-induced chest pain will not require formal admission to the hospital. 7. EKG changes may not reliably predict the presence or absence of acute infarction and thus should not be singly used to rule an infarction in or out. REFERENCES 1. Hollander, J. E., R. S. Hoffman, J. Burstein, R. D. Shih, and H. C. Thode Jr. 1995. “Cocaine-Associated Myocardial Infarction: Mortality and Complications. Cocaine Associated Myocardial Infarction Study Group.” Archives of Internal Medicine 155: 1081–86. 2. Mittleman, M. A., D. Mintzer, M. Maclure, G. H. Tofler, J. B. Sherwood, and J. E. Muller. 1999. “Triggering of Myocardial Infarction by Cocaine.” Circulation 99: 2737–41. 3. Feldman, J. A., S. S. Fish, J. R. Beshansky, J. L. Griffith, R. H. Woolard, and H. P. Selker. 2000. “Acute Cardiac Ischemia in Patients With Cocaine- Associated Complaints: Results of a Multicenter Trial.” Annals of Emergency Medicine 36: 469–76. 4. Hollander, J. E., R. S. Hoffman, P. Gennis, P. Fairweather, M. J. DiSano, D. A. Schumb, J. A. Feldman, et al. 1994. “Prospective Multicenter Evaluation of Cocaine-Associated Chest Pain. Cocaine Associate Chest Pain (COCHPA) Study Group.” Academic Emergency Medicine 330: 454–59. 5. McCord, J., H. Jneid, J. E. Hollander, J. A. de Lemos, B. Cercek, P. Hsue, W. B. Gibler, et al. 2008. “Management of Cocaine-Associated Chest Pain and MI: A Scientific Statement From the American Heart Association Acute Care Committee of the Council on Clinical Cardiology.” Circulation 117: 1897–907. 6. Weber, J. E., C. R. Chudnofsky, M. Boczar, E. W. Boyer, M. D. Wilkerson, and J. E. Hollander. 2000. “Cocaine-Associated Chest Pain: How Common Is Myocardial Infarction?” Academic Emergency Medicine 7: 873–77. 7. Hollander, J. E., and R. S. Hoffman. 1992. “Cocaine-Induced Myocardial Infarction: Analysis and Review of the Literature.” The Journal of Emergency Medicine 10: 169–77. 8. Brogan, W. C. III, R. A. Lange, A. S. Kim, D. J. Moliterno, and L. D. Hillis. 1991. “Alleviation of Cocaine-Induced Coronary Vasoconstriction by Nitroglycerin.” Journal of the American College of Cardiology 18: 581–86. 9. Kugelmass, A. D., A. Oda, K. Monahan, C. Cabral, and J. A. Ware. 1993. “Activation of Human Platelets by Cocaine.” Circulation 88: 876–83. 10. Rezkalla S. H., and R. A. Kloner.“Cocaine-Induced Acute Myocardial Infarction.” Clinical Medicine & Research 5 (3): 172–76. 11. Hsue, P. Y., D. McManus, V. Selby, X. Ren, P. Pillutla, N. Younes, N. Goldschlager, and D. D. Waters. 2007. “Cardiac Arrest in Patients Who Smoke Crack Cocaine.” The American Journal of Cardiology 99: 822–24. 12. Amin, M., G. Gabelman, J. Karpel, and P. Buttrick. 1990. “Acute Myocardial Infarction and Chest Pain Syndromes After Cocaine Use.” The American Journal of Cardiology 66: 1434–37. 13. Kushman, S. O., A. B. Storrow, T. Liu, and W. B. Gibler. 2000. “CocaineAssociated Chest Pain in a Chest Pain Center.” The American Journal of Cardiology 85: 394–96, A10. 14. Weber, J. E., F. S. Shofer, G. L. Larkin, et al. 2003. “Validation of a Brief Observation Period for Patients With Cocaine-Associated Chest Pain.” The New England Journal of Medicine 348: 510–17. 15. Kontos, M. C., K. L. Schmidt, C. S. Nicholson, J. P. Ornato, R. L. Jesse, and J. L. Tatum. 1999. “Myocardial Perfusion Imaging With Technetium99m Sestamibi in Patients With Cocaine-Associated Chest Pain.” Annals of Emergency Medicine 33: 639–45. 16. Hollander, J. E., M. A. Levitt, G. P. Young, E. Briglia, C. V. Wetli, and Y. Gawad. 1998. “Effect of Recent Cocaine Use on the Specificity of Cardiac Markers for Diagnosis of Acute Myocardial Infarction.” American Heart Journal 135 (pt1): 245–52. 17. Forrester, J. M., A. W. Steele, J. A. Waldron, and P. E. Parsons. 1990. “Crack Lung: An Acutepulmonary Syndrome With a Spectrum of Clinical and Histopathologic Findings.” The American Review of Respiratory Disease 142: 462–67. 18. Gitter, M. J., S. R. Goldsmith, D. N. Dunbar, and S. W. Sharkey. 1991. “Cocaine and Chest Pain: Clinical Features and Outcome of Patients Hospitalized to Rule Out Myocardial Infarction.” Annals of Internal Medicine 115: 277–82. 19. Weber J. E., F. S. Shofer, L. G. Larkin, A. S. Kalaria, and J. E. Hollander. 2003. “Validation of a Brief Observation Period for Patients With Cocaine- Associated Chest Pain.” The New England Journal of Medicine 348: 510–17. 20. Brickner, M. E., J. E. Willard, E. J. Eichhorn, J. Black, and P. A. Grayburn. 1991. “Left Ventricular Hypertrophy Associated With Chronic Cocaine Abuse.” Circulation 84: 1130–35. 21. Nueman, Y., B. Cercek, J. Aragon, S. Lee, S. Kobal, T. Miyamoto, H. Luo, et al. 2004. “Comparison of Frequency of Left Ventricular Wall Motion Abnormalities in Patients With a First Acute Myocardial Infarction With Versus Without Left Ventricular Hypertrophy.” The American Journal of Cardiology 94: 763–66. 22. Om, A., S. Ellahham, and G. Disciascio. 1993. “Management of CocaineInduced Cardiovascular Complications.” American Heart Journal 125: 469–75. 23. Kazimir, M., and J. A. Paul. 2008. “Cardiomyopathy, Cocaine.” E-medicine. http://emedicine.medscape.com/article/152535-overview 24. Hollander, J. E. 1995. “The Management of Cocaine-Associated Myocardial Ischemia.” The New England Journal of Medicine 333: 1267–72. 25. Baumann, B. M., J. Perrone, S. E. Hornig, F. S. Shofer, and J. E. Hollander. 2000. “Randomized, Double-Blind, Placebo-Controlled Trial of Diazepam, Nitroglycerin, or Both for Treatment of Patients With Potential CocaineAssociated Acute Coronary Syndromes.” Academic Emergency Medicine 7 (8): 878–85. 26. Rinder, H. M., K. A. Ault, P. I. Jatlow, T. R. Kosten, and B. R. Smith. 1994. “Platelet Alpha Granule Release in Cocaine Users.” Circulation 90: 1162–67. 27. Sharma, A. K., S. M. Hamwi, N. Garg, M. T. Castagna, W. Suddath, S. Ellahham, and J. Lindsay. 2002. “Percutaneous Interventions in Patients With Cocaine Associated Myocardial Infarction: A Case Series and Review.” Catheterization and Cardiovascular Interventions 56: 346–52. 28. Negus, B. H., J. E. Willard, L. D. Hillis, D. B. Glamann, C. Landau, R. W. Snyder, and R. A. Lange. 1994. “Alleviation of Cocaine-Induced Coronary Vasoconstriction With Intravenous Verapamil.” The American Journal of Cardiology 73: 510–13. 29. Furberg, C. D., B. M. Psaty, and J. V. Meyer. 1995. “Nifedipine. DoseRelated Increase in Mortality in Patients With Coronary Heart Disease.” Circulation 92: 1326–31. 30. Psaty, B. M., S. R. Heckbert, T. D. Koepsell, D. S. Siscovick, T. E. Raghunathan, N. S. Weiss, F. R. Rosendaal, et al. 1995. “The Risk of Myocardial Infarction Associated With Antihypertensive Drug Therapies.” Journal of the American Medical Association 274: 620–25. 31. Smith, A. L, and W. M. Book.“Effect of Noncardiac Drugs, Electricity, Poisons, and Radiation on the Heart (Chapter).” In Hurst's The Heart, 12 ed., edited by V. Fuster, R. A. O’Rourke, R. A. Walsh, P. Poole-Wilson, Assoc. editors: S. B. King, R. Roberts, I. S. Nash, and E. N. Prystowsky, Chapter 93. http://www.accessmedicine.com/content.aspx?aID=3066701. Bottom of Form. 32. El Menyar, A. A. 2006. “Drug-Induced Myocardial Infarction Secondary to Coronary Artery Spasm in Teenagers and Young Adults.” Journal of Postgraduate Medicine 52(1): 51–56. Acute Decompensated Congestive Heart Chapter Failure

19 Martine Saint-Cyr, MD CASE A 65-year-old woman with a history of poorly controlled hypertension (HTN) is evaluated for a 2-month history of worsening dyspnea with mild exertion. For several weeks, she has also experienced pillow orthopnea. In the last month, she has gained approximately 10 lbs. She also reports having to urinate frequently at night for the past few months. She was unable to fill any of her medications because she has been unemployed for a year and is without health insurance. 1. What is the most likely diagnosis and why? Congestive heart failure (CHF) exacerbation is the most likely diagnosis. Patients with CHF exacerbation classically present with worsening dyspnea associated with orthopnea, paroxysmal nocturnal dyspnea (PND), and weight gain due to increased sodium and water retention. Common precipitants of CHF exacerbations include medication and/or dietary nonadherence as well as uncontrolled HTN. Shortness of breath (dyspnea) is the most prominent symptom of CHF due to the pulmonary congestion. Orthopnea results from volume pooling in the central vasculature during recumbency, which leads to increased intravascular volume and, in turn, to increased left ventricular filling pressures, pulmonary congestion, and dyspnea. At night when the patient is recumbent, nocturnal diuresis may occur due to increased renal perfusion as a result of the augmented cardiac output that results from the return of interstitial fluid to the vascular compartment (recall the Frank-Starling relationship). Bottom line: CHF exacerbations are typically characterized by dyspnea, orthopnea, PND, edema and weight gain. 241 CASE CONTINUED Examination in the emergency department (ED) is significant for moderate respiratory distress. Vitals are as follows: blood pressure (BP)182/100 mm Hg, heart rate 110 bpm, and respiratory rate 20 breaths/min. Pulsations of the external jugular vein can be appreciated approximately 10 cm above the angle of Louis. Cardiopulmonary examination reveals an S4 in the left lateral decubitus position and bibasilar crackles. Examination is otherwise significant only for 2+ pitting edema of the shins to the level of the knees. Chest x-ray is suggestive of pulmonary edema. 2. On the basis of this patient’s symptoms, to which New York Heart Association class of heart failure does she belong? The New York Heart Association (NYHA) functional classification is a comprehensive and simple way of classifying heart failure based on symptomatic severity. It is proven to be a strong predictor of overall mortality and is an established instrument for risk stratification in patients with heart disease. Higher NYHA classes correlate with poorer prognoses (see Table 19.1). The NYHA classification system places patients in 1 of 4 categories based on their physical activity limitations. Class I patients are asymptomatic with no limitations with ordinary physical activity. Class II patients have mild symptoms (mild shortness of breath and/or angina) and slight limitation with ordinary activity. Class III patients have marked limitations with less-than-ordinary activity (i.e. walking short distances of 20–100 m) and are generally comfortable only at rest. Class IV patients have severe activity limitations and experience symptoms at rest. These patients are often bedbound as a result. Given this patient’s symptoms, her CHF would be classified as NYHA class III. Bottom line: The NYHA classification system classifies patients in terms of symptom severity. A higher classification portends increased morbidity and mortality. 3. Should such classification alter management? Yes, studies such as the Randomized Aldactone Evaluation Study (RALES) have clearly demonstrated that patients with class III–IV heart failure have a mortality and morbidity benefit if treated with an aldosterone antagonist such as spironolactone. This study further emphasized the point that standard doses of an angiotensin-converting-enzyme TAblE 19.1 New York Heart Association Classification of Heart Failure Class Class I (mild) Class II (mild) Class III (moderate) Class IV (severe) Patient Symptoms No limitation of physical activity. Ordinary physical activity does not causes undue fatigue, rapid/irregular heartbeat (palpitation), or shortness of breath (dyspnea) Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, rapid/irregular heartbeat (palpitation), or shortness of breath (dyspnea) Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, rapid/irregular heartbeat (palpitation), or shortness of breath (dyspnea) Unable to carry out any physical activity without discomfort. Symptoms of fatigue, rapid/irregular heartbeat (palpitation), or shortness of breath (dyspnea) are present at rest. If any physical activity is undertaken, discomfort increases. Adapted from Ref 1. (ACE) inhibitor do not effectively suppress the production of aldosterone. The marked beneficial effects of b blockade has been well demonstrated in large-scale clinical trials of symptomatic patients such as this with NYHA classes II–IV heart failure and reduced left ventricular ejection fraction (LVEF) (HFSA, 2010). 4. How does the physical examination and chest x-ray support the diagnosis of acute decompensated CHF? The patient’s examination is an example of the complex interplay of hemodynamic and neurohormonal mechanisms of the body as it attempts to compensate in acute decompensated heart failure (ADHF). Abnormally high blood pressure as seen in this patient increases the amount of work the left ventricle has to do to eject blood into the systemic circulation. Over time, this greater workload can damage and weaken the heart, ultimately leading to heart failure if left unchecked. An increased heart rate occurs in heart failure due to increased catecholamines as a compensatory mechanism for maintaining cardiac output. Catecholamines increase both the force and rate of cardiac contraction. Pulmonary crackles are caused by pulmonary edema resulting from increased left atrial filling pressures, which cause increased hydrostatic pressures in the pulmonary veins and transudation of fluid into the alveolar space. As air circulates through the alveoli, crackling sounds (“rales”) are produced and pulmonary edema is seen on chest x-ray. As the heart is failing, it becomes more dependent on the Frank–Starling mechanism. The distended neck vein reflects elevated right-sided filling pressures and venous congestion. The patient’s lower extremity edema is also an indicator of increased venous pressure that results in transudation of fluid into the interstitium, particularly in dependent areas like the legs. Bottom line: Classic findings in decompensated CHF include jugular venous distention, an S3, bibasilar crackles, and lower extremity edema. While insensitive, these signs are relatively specific for CHF. 5. Given your diagnosis, does the evidence suggest further workup should be performed? The diagnosis of acute decompensated CHF should be based primarily on signs and symptoms, that is, it is a clinical diagnosis (HFSA 2010). However, evidence shows that if the diagnosis is uncertain, measurement of B-type natriuretic peptide (BNP) or N-terminal proBtype natriuretic peptide concentration can provide valuable diagnostic information.17 Echocardiography is an excellent tool in further assessing the severity and type of heart failure. Bottom line: BNP concentration can provide valuable diagnostic information in suspected CHF. CASE CONTINUED BNP concentration is 3325 mg/mL (normal, less than 50 pg/mL) and an echocardiogram reveals left ventricular hypertrophy with an ejection fraction of 60%. 6. Does the elevated bNP level have any diagnostic or prognostic value? Will it alter the patient management? The patient’s elevated BNP, along with the clinical assessment, further supports the diagnosis of acute decompensated CHF. BNP levels are higher in hospitalized CHF patients and tend to decrease with aggressive diuresis.2 A high predischarge BNP level is a strong, independent marker of death or readmission following hospitalization for CHF.2 In fact, an elevated predischarge BNP level has more prognostic value than commonly employed clinical parameters such as physical examination and chest x-ray or echocardiographic findings.17 The STARS-BNP Multicenter study provided evidence that a BNP-guided strategy reduces the incidence of a combined endpoint (death and hospital stay related to heart failure) compared with a standard strategy.17 Further studies are required to determine whether serial BNP monitoring can improve patient management, for example, by determining the optimal timing of discharge and subsequent care requirements.3 Bottom line: The BNP assay is an effective and inexpensive test that enhances current diagnostic assessment tools. It also appears to provide valuable prognostic information. 7. Do specific criteria exist to help physicians decide which patients with CHF exacerbation should be admitted to the hospital? No admission criteria such as the PORT score for pneumonia or Ottawa rules for ankle injury currently exist. However, evidence-based guidelines from the Agency for Healthcare Research and Quality (AHRQ) and The Heart Failure Society of America (HFSA) suggest admitting a CHF patient if any of the following criteria are present: 1. Respiratory distress (respiratory rate more than 40 breath/min) or pulmonary edema (determined by radiography) 2. Hypoxia (oxygen saturation less than 90%) 3. Anasarca or significant edema 4. Syncope or hypotension (systolic blood pressure ≤ to 80 mm Hg) 5. Recent diagnosis of CHF 6. Evidence of myocardial ischemia 7. Inadequate social support for outpatient management 8. Failed of outpatient management 9. Concomitant acute medical illness Based on these recommendations, given that our patient has new onset CHF, significant edema, and is noncompliant with outpatient therapy, he would likely be admitted. Bottom line: Although there are no formal admission criteria for ADHF, evidence-based guidelines as discussed above have been proposed. 8. What does the evidence suggest the treatment should be for this patient? It is recommended that patients admitted with ADHF and evidence of fluid overload be initially treated with loop diuretics (HFSA, 2010). Intravenous furosemide (Lasix) or bumetanide (Bumex) are the preferred diuretics, particularly in the setting of acute pulmonary edema. Diuretics may also have an early action as weak venodilators that further reduce left ventricular preload and pulmonary capillary pressure. Morphine is also used as a venodilator to facilitate pooling of blood peripherally. Successful reduction of BP and cardiac filling pressures is reflected by a marked improvement in respiratory status well before any significant diuresis. The patient should be positioned upright to permit pooling of blood within the systemic veins of the lower body, thereby reducing venous return to the heart. Supplemental oxygen should be provided. Bottom line: Patients admitted with ADHF and evidence of fluid overload should be treated with intravenous loop diuretics. 9. Is there any good evidence for treating this patient with “ultrafiltration”? In the UNLOAD trial, it was conclusively shown that early ultrafiltration versus aggressive diuresis with IV loop diuretics safely produces greater weight and fluid loss in ADHF. Ultrafiltration significantly decreases rehospitalizations for heart failure and unscheduled medical visits. The cost-effectiveness of ultrafiltration is not established; however, this treatment may have favorable economic implications for patients and payers owing to reduced resource utilization after the index hospitalization.4–7 Intravenous loop diuretics induce a rapid diuresis that reduces lung congestion and dyspnea.8 However, loop diuretics’ effectiveness declines with repeated exposure.4–7 Unresolved congestion may contribute to high rehospitalization rates.9 Furthermore, loop diuretics may be associated with increased morbidity and mortality attributable to deleterious effects on neurohormonal activation, electrolyte balance, and cardiac and renal functions.4–8,10,11 Bottom line: Although not the current standard of care, ultrafiltration may be considered in lieu of diuretics and there is some evidence to suggest that it is more effective in treating ADHF. 10. What parameters does the evidence indicate should be monitored during admission of a patient having ADHF with fluid overload? Careful monitoring of changes in body weight is recommended, because clinical experience suggests that it is difficult to determine that congestion has been adequately treated in most patients.11 Monitoring of daily weights and fluid intake and output is recommended to assess clinical efficacy of diuretic therapy.13 Due to risk for infection, routine use of a Foley catheter is not recommended for monitoring volume status. However, placement of a catheter is recommended when close monitoring of urine output is needed or if a bladder outlet obstruction is suspected of contributing to worsening renal function.13 Careful observation for development of a variety of side effects including renal dysfunction, electrolyte abnormalities, symptomatic hypotension, and gout is recommended in patients treated with diuretics, especially when used at high doses and in combination.11,13,14–16 Patients should undergo routine laboratory studies and clinical examination as dictated by their clinical response. It is recommended that serum potassium and magnesium levels be monitored at least daily and maintained in the normal range. More frequent monitoring may be necessary when diuresis is rapid, such as in the use of ultrafiltration.14 Overly rapid diuresis may be associated with severe muscle cramps. If indicated, treatment with potassium replacement is recommended.11,13–16 Bottom line: Patients who are admitted with the diagnosis of ADHF with fluid overload should be carefully monitored to ensure that their fluid overload status is approving; such parameters can be followed through observation of weight changes, monitoring input and output, and routine laboratory studies. 11. What does the evidence suggest should be the discharge plan? Long-term goals are to control congestion and to eliminate or reduce the factors, including HTN that predisposes the patient to readmission for ADHF.13,15 Patient needs to be put on diuretics (with a subsequent dosage adjustment, depending on the clinical response), and an ACE inhibitor or angiotensin- receptor blocker for control of blood pressure and blood volume. If the blood pressure is not controlled with this regimen, or if resting tachycardia is present, additional antihypertensive agents, including a b-blocker, should be administered. Therefore, the evidence shows that for patients admitted with ADHF, the discharge plan should address these following issues: details regarding medication, dietary sodium restriction, and recommended activity level; follow-up by phone or clinic visit early after discharge to reassess volume status; medication and dietary compliance; alcohol moderation and smoking cessation; monitoring of body weight, electrolytes, and renal function; and consideration of referral for formal disease management with a cardiologist.13,15 The discharge instructions and education should be made clear to both patient and family. While the patient is still in the hospital it is critical that exacerbating factors are addressed, near optimal volume status observed, and transition from intravenous to oral diuretic is successfully completed, as well as documenting LVEF at the time of discharge.16 However, there is no evidence to support that a repeat echocardiogram should be done, unless that information will alter the management.13,18 A repeat ECHO is often left to the discretion of the healthcare provider following the patient. Bottom line: After admission with ADHF, all patients should have regular clinic follow-up or close-case management to detect any decline in their clinical condition. TAKE-HOME POINTS: ACUTE DECOMPENSATED HEART FAIlURE 1. Classic presentation for ADHF exacerbation is worsening dyspnea, orthopnea, PND with associated edema and “fluid” weight gain. 2. Although no formal admission criteria exist, there are several criteria that help physicians determine whether eminent admission is necessary, such as respiratory distress, hypoxia, and concomitant acute medical illness. 3. The physical examination is the most critical assessment tool to establish the severity of an ADHF patient. 4. An increased BNP can help distinguish dyspnea due to heart failure from noncardiac causes. 5. Differential diagnosis of dyspnea includes both cardiac and pulmonary problems, such as acute myocardial infarction, pulmonary embolism, and pneumonia. 6. Heart failure can besystolic (pump failure) or diastolic (stiff ventricle) in etiology or most commonly a combination of both. 7. Different types of heart failure have varying long-term treatments. Systolic dysfunction is treated with ACE inhibitors (to prevent ventricular remodeling), b-blockers (to decrease cardiac workload), and diuretics (to reduce volume overload). In diastolic dysfunction, it is important to control HTN and the options of medication include diuretics, calcium channel blockers, b-blockers, and nitroglycerin. 8. The most common cause of diastolic and systolic CHF is coronary artery disease. 9. The most common cause for a CHF exacerbation is dietary noncompliance (too much salt intake) or medication noncompliance. 10. The assessment of CHF progression is made from the NYHA and American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines. NYHA offers the functional classification of CHF. Class I presents no limitation of activity and no symptoms with normal activity. Class II presents slight limitation of activity and comfortable at rest or with mild exertion. Class III presents a marked limitation of activity and comfortable only at rest. Class IV is confined to complete rest in bed or chair, as any physical activity brings on discomfort and symptoms present at rest. REFERENCES 1. The Criteria Committee of the New York Heart Association. 1994. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels, 9th ed. 253–56. Boston, MA: Little, Brown & Co. 2. Logeart, D., G. Thabut, P. Jourdain, C. Chavelas, P. Beyne, F. Beauvais, E. Bouvier, and A. C. Solal. 2004. “Predischarge B-Type Natriuretic Peptide Assay for Identifying Patients at High Risk of Re-admission After Decompensated Heart Failure.” Journal of the American College of Cardiology 43 (4): 635–41. 3. Troughton, R. W., C. M. Frampton, T. G. Yandle, et al. 2000. “Treatment of Heart Failure Guided by Plasma Amino Terminal Brain Natriuretic Peptide (N- BNP) Concentrations.” Lancet 355: 1126–30. 4. Ellison, D. H. 2001. “Diuretic Therapy and Resistance in Congestive Heart Failure.” Cardiology 96: 132–43. 5. Jain, P., B. M. Massie, W. A., Gattis , L. Klein , and M. Gheorghiade. 2003. “Current Medical Treatment for Exacerbation of Chronic Heart Failure Resulting in Hospitalization.” American Heart Journal 145: S3–S17. 6. Satpathy, C., T. K. Mishra, R. Satpathy, H. K. Satpathy, and E. Barone. 2006. “Diagnosis and Management of Diastolic Dysfunction and Heart Failure.” American Family Physician 73: 841–46. 7. Mueller, C., A. Scholer, K. Laule-Kilian, B. Martina, C. Schindler, P. Buser, M. Pfisterer, and A. Perruchoud. “Use of B-Type Natriuretic Peptide in the Evaluation and Management of Acute Dyspnea.” New England Journal of Medicine. 2004;350: 647–54. 8. Schrier, R. W. 2006. “Role of Diminished Renal Function in Cardiovascular Mortality. Marker or Pathogenetic Factor?” Journal of American College of Cardiology 47: 1–8. 9. Hunt, S. A., W. T. Abraham, M. H. Chin, A. M. Feldman, G. S. Francis, T. G. Ganiats, and M. Jessup. “ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult—Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2005;112: 1825–52. 10. Krumholz, H. M., Y. T. Chen, Y. Wang, V. Vaccarino, M. J. Radford, and R. I. Horwitz. 2002. “Predictors of Readmission among Elderly Survivors of Admission with Heart Failure.” American Heart Journal 139: 72–77. 11. Gohler, A., J. L. Januzzi, S. S. Worrel, K. J. Osterziel, G. S. Gazekkem, R. Dietz, U. Sieber. “A sytematic meta-analysis of the efficacy and heterogenity of disease management programs in congestive heart failure.J. of Cardiac Failure.” 2006: Vol. 12 12. American Heart Association. 2005. Heart Disease and Stroke Statistics: 2005 Update. Dallas, TX: American Heart Association. 13. Aurigemma, G. P., J. S. Gottdiener, L. Shemanski, J. Gardin, and D. Kitzman. 2001. “Predictive Value of Systolic and Diastolic Function for Incident Congestive Heart Failure in the Elderly: The Cardiovascular Health Study.” Journal of American College of Cardiology 37 (4): 1042–48. 14. Costanzo, M. R., M. E. Guglin, M. T. Saltzberg, M. L. Jessup, B. A. Bart, J. R. Teerlink, B. E. Jaski, et al. 2007. “Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure.” Journal of American College of Cardiology 49: 675–83. 15. Humphries, R. L. 2007.“Cardiac Emergencies.” In Current Diagnosis & Treatment: Emergency Medicine, 6th ed. 2007, edited by C. K. Stone and R. L. Humphries, Chapter 32. Philadelphia: McGraw-Hill. 16. Bashore, T. M., C. B. Granger, P. Hranitzky, and M. R. Patel. 2010. “Heart Disease.” In Current Medical Diagnosis & Treatment, edited by S. J. McPhee, M. A. Papadakis, and L. M. Tierney, Jr., Chapter 10. New York: McGraw-Hill Medical. http://www.accessmedicine.com/content.aspx?aID=3671 17. Jourdain, P., G. Jondeau, F. Funck, P. Gueffet, A. Le Helloco, E. Donal, J. F. Aupetit, et al. 2007. “Plasma Brain Natriuretic Peptide-Guided Therapy to Improve Outcome in Heart Failure. The STARS-BNP Multicenter Study.” Journal of American College of Cardiology 49: 1733–39. 18. Hansen, A., M. Haass, C. Zugck, C. Kruger, K. Unnebrink, R. Zimmerman, W. Kuebler, and H. Kuecherer. 2001. “Prognostic Value of Doppler Echocardiographic Mitral Inflow Patterns: Implications for Risk Stratification in Patients With Chronic Congestive Heart Failure.” Journal of American College of Cardiology 37: 1049–55. 19. Rafeal, C., C. Briscoe, J. Davies, Z. Ian Whinnett, C. Manistry, R. Sutton, J. Mayet, and D. P. Francis. 2007. “Limitations of the New York Heart Association Functional Classification System and Self-reported Walking Distances in Chronic Heart Failure.” Heart 93: 476–82.

Non-ST Segment ElevatedCHAPTER Myocardial Infarction 20 NOEL M. BAKER, MD CASE A 67-year-old woman with a history of stable angina, hypertension, and well- controlled type 2 diabetes mellitus is brought to the emergency department (ED) via ambulance for evaluation of a 1-hour history of severe substernal chest pain. On examination, she is diaphoretic and clutching her left chest. Blood pressure is 156/95 mm Hg and heart rate is 115 bpm. The physical examination is otherwise entirely unrevealing. The initial set of cardiac enzymes is negative. Her electrocardiogram (ECG) is shown in Figure 20.1. 07-OCT-1920 (76 yr) Male Caucasian I aVR V1 V4 II aVL V2 V5 III aVF V3 V6 FIGURE 20.1 ST segment depression in lateral (V4–V6) leads. Source: ST Segment Depression-KH. The Alan E. Lindsay ECG Learning Center in Cyberspace. Authored by: Frank G. Yanowitz, M.D., Professor of Medicine, University of Utah School of Medicine, Medical Director, ECG Department, LDS Hospital Salt Lake City, Utah. 253 1. What is the differential diagnosis for sudden onset chest pain? The differential diagnosis for sudden onset chest pain should include the most life-threatening and common conditions that elicit such pain. Cardiac causes should generally be ruled out first but etiologies involving the lungs, the gastrointestinal tract, and even the chest wall (i.e., muscles, bone, and skin) should be considered. Cardiac causes of acute chest pain include acute myocardial infarction, stable and unstable angina, aortic dissection, and pericarditis. Acute chest pain that originates from the lung or gastrointestinal tract includes pneumonia, pulmonary embolism, esophageal spasm, gastroesophageal reflux disease, and cholecystitis. For a complete differential diagnosis, see Table 20.1. Bottom line: There is a broad differential for chest pain, but given this patient’s history of presumptive coronary artery disease (CAD) as the underlying cause of her stable angina, there should be a high index of suspicion for ongoing myocardial ischemia. TABLE 20.1 System-Based Causes of Chest Pain Chest pain etiology Cardiac Pulmonary Gastrointestinal Chest wall Differential diagnosis Acute coronary syndrome: Unstable angina, NSTEMI, STEMI Aortic dissection Pericarditis Myocarditis Prinzmetal angina Pleuritis Pulmonary embolism Tension pneumothorax Pneumonia Peptic ulcer disease Esophageal spasm Gastrointestinal reflux disease Pancreatitis Cholecystitis, cholangitis Costochondritis Neuropathic pain (e.g., herpes zoster) Rib fracture 2. What is the most likely diagnosis, given the information presented? The history and ECG changes suggest that the patient is suffering from acute coronary syndrome. The spectrum of acute coronary syndromes includes unstable angina (UA), non-ST segment elevated myocardial infarction (NSTEMI), and ST segment elevated infarction (STEMI). The details that distinguish the three acute coronary syndromes are described in Table 20.2. From a pathophysiological perspective, UA involves a partially blocked coronary artery with some persisting blood flow to the myocardium. The result is chest pain without cardiac enzyme elevation due to minimal cardiac tissue necrosis. STEMIs involve a complete to near-complete blockage that results in transmural myocardial tissue infarction, which leads to ST changes (elevation) on the ECG. The pathophysiology of NSTEMI lies somewhere in-between that of UA and STEMI, with incomplete blockage of flow by a platelet-coated arterial thrombus resulting in subendocardial ischemia, ST segment depression or T-wave inversions on ECG, and positive cardiac biomarkers. Given the initial negative cardiac enzymes, the patient is potentially experiencing UA that may quickly evolve into an NSTEMI or STEMI. However, because the cardiac enzymes can take up to 6 hours to climb after an ischemic insult, our patient could well be experiencing an NSTEMI, with positive cardiac biomarkers on later testing. Therefore, serial trending of cardiac enzymes is critical.1,10 Bottom line: Although distinctly classified, acute coronary syndromes are a spectrum of disease involving progressive pathologic cardiac damage due to varying degrees of coronary artery blockage. TABLE 20.2 Acute Coronary Syndrome ECG changes Cardiac enzymes History UA ST depression or T-wave inversion Negative Acute angina at rest usually lasting <30 min NSTEMI ST depression or T-wave inversion Positive Acute angina at rest usually lasting <30 min STEMI ST elevation Positive Acute angina at rest usually lasting >30 min Abbreviations: UA, unstable angina; NSTEMI, non-ST segment elevated myocardial infarction; STEMI, ST segment elevated infarction; ECG, electrocardiogram. Adapted from Ref. [1]. 3. What acute interventions does the evidence suggest should be performed in the emergency department for this patient? The patient should be administered “MONAB” (Morphine, Oxygen, Nitroglycerin, Aspirin, and β-Blockers) therapy as follows: • Morphine may be given for analgesic properties, that is, to abate ischemia- derived pain. • Oxygen is routinely given to maintain oxygen saturation in the normal range. It is believed that supplemental oxygen will benefit the patient by increasing the amount of oxygen available to be delivered to the myocardial tissue. • Nitroglycerin dilates veins as well as arteries, thereby decreasing preload and afterload, respectively. The reductions in preload and afterload substantially reduce myocardial oxygen demand and therefore minimize myocardial ischemia. Additionally, nitroglycerin dilates coronary vessels and results in increased myocardial perfusion. • Aspirin acts by inhibiting platelet aggregation at the site of plaque rupture, the inciting event of acute coronary syndrome. • β-Blockers have proved to decrease mortality of patients with acute coronary syndrome by inhibiting β-adrenergic receptors on myocardial tissue. β-Blockers slow heart rate and contractility and thereby decrease myocardial oxygen demand. However, it is important to note that results from the COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) trial have demonstrated an increased risk of cardiogenic shock with use of intravenous β- blockers in a cohort of patients with hypotension or current congestive heart failure (CHF). Thus, even though β-blockers are standard treatment for NSTEMI/STEMI, physicians should take into account factors such as hypotension or presence of heart block before initiating β-blocker treatment.2 Bottom line: The administration of morphine, oxygen, nitroglycerin, aspirin, and β-blockers are standard of care for acute coronary syndrome. β-Blockers and nitroglycerin decrease the workload of the heart, thereby decreasing oxygen demand. Aspirin works at the site of blockage to decrease platelet aggregation. Oxygen supplementation is used to mitigate ischemia and morphine is used for pain relief. 4. Does the data suggest that this patient should receive a cardiac catheterization? Why or why not? Yes. This patient is at increased risk for an adverse outcome (e.g., myocardial infarction, death). Risk stratification is important in determining subsequent treatment for patients with UA/NSTEMI. Scoring systems such as the thrombolysis in myocardial infarction (TIMI) helps to determine which patients are low versus high risk for recurrent MI or death. Using a 7-point scoring system, the TIMI score allocates 1 point for each of the following characteristics: • Age ≥ 65 years or older. • ≥3 Risk factors for CAD. • History of CAD (stenosis > 50%). • ST segment changes on ECG. • ≥2 episodes of angina in the past 24 hours. • Positive cardiac biomarkers. • Aspirin use in the past 7 days. A higher score denotes higher risk for MI and death and greater benefit of using early invasive strategies (angiography and percutaneous coronary intervention [PCI]) and GP IIb/IIIa inhibitors.3 Patients with UA/NSTEMI who have high TIMI scores, diabetes, peripheral vascular disease (PVD), congestive heart failure, and older age are at increased risk of adverse events/outcomes. Our patient is older than 65, uses aspirin regularly, has ST segment changes on ECG, and has a history of diabetes. Therefore, she is at a high risk for adverse cardiac outcomes.1 As for timing of intervention with cardiac catheterization, The American Journal of Cardiology published a study regarding the relation of timing of cardiac catheterization (expeditive <24 hours, early 24–48 hours, or delayed >48 hours) in patients with UA/ NSTEMI to outcomes.4 The expeditive intervention was performed on higher risk patients and there was a noticeable increase in in- hospital mortality compared with those who received early or delayed treatment (who were of lower risk).4 On the other hand, at 6-month follow up, there was a decreased mortality risk in the expeditive group and a steady increased risk of mortality in those with delayed treatment. The results suggest that the early and late risks of cardiac catheterization are minimal in the early group (treatment within 24–48 hours) when compared with the expeditive and delayed groups. This supports the general idea that patients with NSTEMI should be treated and stabilized medically for a short period of time and then sent for cardiac catheterization between 24 and 48 hours. Immediate cardiac catheterization for those with NSTEMI should be reserved for those who are hemodynamically unstable.4 With respect to the type of treatment, trials such as the FRISC (Fragmin during Instability in Coronary Artery Disease) II and TACTICS-TIMI (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction) support more invasive techniques (i.e., PCI) in high-risk patients in lieu of conservative medical therapy (medical treatment and selective angiography). The trials report decreased MI, rehospitalization, and death in those with UA/NSTEMI who receive early invasive therapy. The TIMACS study showed that early invasive (within 24 hours) was not superior to delayed invasive therapy (>36 hours) in reducing MI, death.2 Unfortunately, the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology and AHA Guidelines) quality improvement study showed that those receiving early invasive therapy are typically not the high-risk patients who are proved to benefit most from the interventions. Instead, younger patients with less comorbidities and those treated by cardiologists were more likely to receive the early invasive therapy.5,11 Given the patient’s high risk for MI, the studies support treating with PCI after medical stabilization. If the patient’s symptoms and ECG changes support a progression to STEMI, intervention should be initiated immediately. Bottom line: Risk stratification is vital in determining a treatment plan for patients with UA/NSTEMI. Scoring systems, such as TIMI, and patient risk factors (e.g., PVD, diabetes, and CHF) allow us to determine who should receive early versus delayed invasive versus noninvasive treatment. Studies support that high-risk patients with NSTEMI should be medically stabilized and then treated with PCI within 24–48 hours. This will minimize the risk of in-hospital mortality with expeditive care and the 6-month mortality risk associated with delayed care. If the patient is unstable, then treatment with cardiac catheterization should commence as soon as possible. 5. What is the optimal time from door to catheterization laboratory for STEMI? 90 minutes. For reasons discussed earlier, the optimal time for high-risk patients with UA/NSTEMI is within the first 24–48 hours.1 CASE CONTINUED The patient is given morphine, atorvastatin, nitroglycerin, aspirin, metoprolol, and supplemental oxygen. Cardiac catheterization reveals a “culprit” lesion in the circumflex artery and a bare metal stent is placed. The post op note states that there were no complications perioperatively. The patient is sent to the medicine floor for post-PCI management/observation. Later in the day, you look in on the patient and note that she is complaining of some left-sided flank pain that is moderate in intensity. Her hemoglobin is stable and she is not tachycardic. A stat abdominal CT scan is ordered but prior to the scan, the nurse calls to tell you that the patient has become hypotensive. 6. What concerns should you have? The patient’s left-sided flank pain and sudden drop in blood pressure should raise the concern for a post-PCI complication, specifically retroperitoneal hematoma (RPH), and pseudoaneurysm rupture. 7. What are the potential complications of cardiac catheterization? Complications of cardiac catheterization can be a result of contrast use— contrast-induced renal failure, contrast-induced nephropathy—or can involve the access site, groin hematoma, RPH, AV (atrioventricular) fistulas, and pseudoaneurysms. There is also a risk for recurrent MI from stent occlusion following PCI. 9,13 Contrast-induced nephropathy as a result of adverse effect of iodine contrast used can rarely result in the need for dialysis (<1% of all patients undergoing PCI). Contrast-induced lactic acidosis can be a complication if the patient is taking metformin and the drug is not discontinued before surgery and for 48 hours status/post the procedure. Post-PCI myocardial infarction incidence is variable, 5%–30%, due to indeterminate level of increase in cardiac enzymes that unequivocally defines post-PCI MI, especially silent ones (without symptoms).6 The incidence of major bleeding complications s/p PCI ranges from 1% to 2%. The vascular complications are not common post-PCI, but if they do occur, they must be addressed urgently. RPHs have an incidence of 0.15%–0.44% post-PCI and should be suspected if the patient develops hypotension and/or a significant drop in hematocrit postprocedure. Patient symptoms that are also indicative of bleeding include groin, flank, abdominal, and back pain. Diagnosis can be made with a noncontrast abdominal CT scan. Management is usually conservative with discontinuation of antithrombotic agents and initiation of blood transfusion. Only 16% of patients with RPHs post-PCI require surgery. Pseudoaneurysms have incidence in the range of 0.5%–6.3%. Signs and symptoms include a new bruit at the access site, groin pain, or palpable mass. Diagnosis is via Doppler studies. Management ranges from careful watching to ultrasound-guided compression or surgical repair. AV fistula incidence post-PCI ranges from 0.2% to 2.1%. Diastolic and systolic bruits are suggestive. Diagnosis is by Doppler ultrasound. Management is similar to that for pseudoaneurysms.6 Bottom line: There are multiple complications of PCI. Although these complications are not very common, they can pose a significant threat to the health of the patient. Therefore, practitioners should be cognizant of them. 8. Are there patient-specific characteristics that suggest a patient is more susceptible to RPHs? Yes. A retrospective study that specifically looked for characteristics of persons who might be at increased risk for RPH found the following: those who are female, have lower body surface area (BSA) and higher femoral artery puncture site, were significantly more likely to develop an RPH. The reason behind this increased risk is thought to be related to the fact that females and persons with low BSA have smaller diameter blood vessels and increased risk of multiple puncture.7 Another study regarding bleeding risk post-PCI was focused on determining risk factors for bleeding complications and testing an algorithm for use in risk stratification. The study found that age, CHF classification, type of acute coronary syndrome, history of PCI, and extent of kidney damage are also factors that can be used to determine a patient’s risk of bleeding s/p PCI.8 Bottom line: The overall risk for RPH is low but the consequences of this vascular complication can be lethal. The study highlights the need for heightened clinical suspicion of certain patient’s status postcatheterization, as they are at increased risk for life-threatening vascular complications due to unalterable, inherent patient characteristics, and comorbidities. TAKE-HOME POINTS: NON-ST SEGMENT ELEVATED MYOCARDIAL INFARCTION 1. NSTEMI is an acute coronary syndrome characterized by ischemic changes on ECG and positive biomarkers, although cardiac enzymes may initially be negative. 2. Cardiac biomarkers should be serially tested due to delay in elevation. 3. All patients with UA/NSTEMI should be risk stratified to determine appropriateness for cardiac catheterization. 4. Patients with a high TIMI score benefit from an aggressive strategy of early catheterization. 5. For those with UA/NSTEMI who are hemodynamically stable, a period of medical stabilization followed by PCI within 24–48 hours appears to be optimal in reducing in-hospital and longterm follow-up adverse outcomes. 6. The bleeding risk s/p PCI, although rare, can be rapidly fatal if not immediately recognized. 7. There is a need for increased clinical suspicion and vigilance of certain patients, status postcatheterization, as they are at increased risk for life- threatening vascular complications due to unalterable, inherent patient characteristics (e.g., female gender and low BSA). REFERENCES 1. Sabatine, M. S., ed. 2008. Pocket Medicine. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2. Kumar, A., and C. P. Cannon. 2009. “Acute Coronary Syndromes: Diagnosis and Management, Part I.” Mayo Clinic Proceedings 84 (10): 917–38. 3. Antman, E. M., M. Cohen, P. J. Bernink, C. H. McCabe, T. Horacek, G. Papuchis, B. Mautner, R. Corbalan, D. Radley, and E. Braunwald. 2000. “The TIMI Risk Score for Unstable Angina/Non-ST Elevation MI: A Method for Prognostication and Therapeutic Decision Making.” JAMA 284 (7): 835–42. 4. Montalescot, G., O. H. Dabbous, M. J. Lim, M. D. Flather, and R. H. Mehta. 2005. “Relation of Timing of Cardiac Catheterization to Outcomes in Patients With Non–ST-Segment Elevation Myocardial Infarction or Unstable Angina Pectoris Enrolled in the Multinational Global Registry of Acute Coronary Events.” American Journal of Cardiology 95 (12): 1397–403. 5. Bhatt, D. L., M. T. Roe, E. D. Peterson, Y. Li, A. Y. Chen, R. A. Harrington, A. B. Greenbaum, P. B. Berger, C. P. Cannon, D. J. Cohen, C. M. Gibson, J. F. Saucedo, N. S. Kleiman, J. S. Hochman, W. E. Boden, R. G. Brindis, W. F. Peacock, S. C. Smith Jr, C. V. Pollack Jr, W. B. Gibler, and E. M. Ohman. 2004. “Utilization of Early Invasive Management Strategies for High-Risk Patients With Non-ST-Segment Elevation Acute Coronary Syndromes: Results From the CRUSADE Quality Improvement Initiative.” JAMA 292 (17): 2096–104. 6. Levine, G. N., M. J. Kern, P. B. Berger, D. L. Brown, L. W. Klein, D. J. Kereiakes, T. A. Sanborn, A. K. Jacobs, and American Heart Association Diagnostic and Interventional Catheterization Committee and Council on Clinical Cardiology. 2003. “Management of Patients Undergoing Percutaneous Coronary Revascularization.” Annals of Internal Medicine 139 (2): 123–36. 7. Farouque, H. M., J. A. Tremmel, F. Raissi Shabari, M. Aggarwal, W. F. Fearon, M. K. Ng, M. Rezaee, A. C. Yeung, and D. P. Lee. 2005. “Risk Factors for the Development of Retroperitoneal Hematoma After Percutaneous Coronary Intervention in the Era of Glycoprotein IIb/IIIa Inhibitors and Vascular Closure Devices.” Journal of the American College of Cardiology 45 (3): 363–68. 8. Mehta, S. K., A. D. Frutkin, J. B. Lindsey, J. A. House, J. A. Spertus, S. V. Rao, F. S. Ou, M. T. Roe, E. D. Peterson, and S. P. Marso. 2009. “Bleeding in Patients Undergoing Percutaneous Coronary Intervention: The Development of a Clinical Risk Algorithm From the National Cardiovascular Data Registry.” Circulation Cardiovascular Interventions 2 (3): 222–29. 9. Bhatt, D. L. 2010. “Controversies in Non-ST-Elevation Acute Coronary Syndromes and Percutaneous Coronary Interventions.” Cleveland Clinic Journal of Medicine 77 (2): 101–09. 10. Jaffe, A. S., L. Babuin, and F. S. Apple. 2006. “Biomarkers in Acute Cardiac Disease: The Present and the Future.” Journal of the American College of Cardiology 48 (1): 1–11. 11. Mehta, S. R., C. P. Cannon, K. A. Fox, L. Wallentin, W. E. Boden, R. Spacek, P. Widimsky, P. A. McCullough, D. Hunt, E. Braunwald, and S. Yusuf. 2005 “Routine Vs Selective Invasive Strategies in Patients With Acute Coronary Syndromes: A Collaborative Meta-Analysis of Randomized Trials.” JAMA 293 (23): 2908–17. 12. Mixon, T. A., and G. J. Dehmer. 2003. “Patient Care Before and After Percutaneous Coronary Artery Interventions. American Journal of Medical 115 (8): 642–51. 13. Smith, S. C. Jr., T. E. Feldman, J. W. Hirshfeld Jr, A. K. Jacobs, M. J. Kern, S. B. King, III, D. A. Morrison, W. W. O’Neil, H. V. Schaff, P. L. Whitlow, D. O. Williams, E. M. Antman, C. D. Adams, J. L. Anderson, D. P. Faxon, V. Fuster, J. L. Halperin, L. F. Hiratzka, S. A. Hunt, R. Nishimura, J. P. Ornato, R. L. Page, and B. Riegel. 2006. “ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention).” Circulation 113 (7): e166–e286.

ST Segment Elevation C HA pter Myocardial Infarction 21 Muneer A. HAMeer CASE A 45-year-old man with a history of poorly controlled type 2 diabetes mellitus (DM), hypertension (HTN), and hyperlipidemia presents to the emergency department (ED) for an evaluation of a 3-day history of severe but intermittent substernal chest pain. His chest pain is brought on by exertion and subsides quickly with rest. Over the last 2 hours, the pain has increased in severity and frequency and is now constant. His chest pain is accompanied by nausea, diaphoresis, and weakness. He denies fever, chills, shortness of breath, abdominal pain, recent trauma, long travel, or long periods of immobility. He has no family history of premature coronary heart disease. Workup in the ED reveals tachycardia (heart rate 130), tachypnea (respiratory rate 24), and an oxygen saturation of 90% on room air. The remainder of the physical examination is normal. The first set of cardiac enzymes is negative. Figure 21.1 shows his electrocardiogram (ECG). 1. What is the likely diagnosis and why? The most common cardiac causes of acute chest pain include stable and unstable angina, myocardial infarction (MI), aortic dissection, and pericarditis. Acute chest pain that originates from the lung or gastrointestinal tract includes pneumonia, pulmonary embolism, tension pneumothorax, pancreatitis, peptic ulcer disease, and cholecystitis. A more complete differential is given in Table 21.1. The most likely diagnosis in this case is an ST segment elevation myocardial infarction (STEMI) given the presence of risk factors for cardiovascular disease (HTN, DM, hyperlipidemia, and male gender), the characteristics of the chest pain (pain at rest, lasting for hours, and the association with nausea, diaphoresis, and weakness), and an ECG suggestive of an STEMI (≥1-mm ST segment elevations in limbs leads I, aVL, and V4 through V6; and ≥2-mm ST segment elevations 263 IV1 V2 II aVL V2V5 III aVF V3 V6 II FigurE 21.1 Initial electrocardiogram. Adapted from Ref. 1. in V1 through V3). The American College of Cardiology and American Heart Association (ACC/AHA) criteria2 for diagnosing STEMI on ECG include the presence of at least 1 of the following: 1. More than or equal to 1-mm ST segment elevation in at least 2 anatomically contiguous limb leads (aVL to III, including aVR), 2. More than or equal to 1-mm ST segment elevation in a precordial lead V4 through V6, 3. More than or equal to 2-mm ST segment elevation in V1 through V3, or 4. A new left bundle branch block. Note that the reciprocal ST segment depression in limb leads II, III, and aVF in this patient’s ECG make the diagnosis of STEMI more specific. Although the ST segment elevations in this patient’s ECG are remarkable and highly suggestive of an MI, the consideration of other etiologies of ST segment elevation is especially important when the diagnosis is not clear (Table 21.2). Approximately 10% of patients with chest pain and ST segment elevation on initial ECG do not have an acute coronary thrombotic occlusion.3 Non-MI causes of ST segment elevation are numerous and include pericarditis, coronary artery spasm, early repolarization, acute cholecystitis, acute TAblE 21.1 Causes of Chest Pain Chest pain Cardiac Pulmonary Gastrointestinal Chest wall Differential diagnosis Acute coronary syndrome: unstable angina, NSTEMI, and STEMI Aortic dissection Pericarditis Myocarditis Prinzmetal angina Pleuritis Pulmonary embolism Tension pneumothorax Pneumonia Peptic ulcer disease Esophageal spasm Gastrointestinal reflux disease Pancreatitis Cholecystitis, cholangitis Costochondritis Neuropathic pain (e.g., herpes zoster) Rib fracture Abbreviations: NSTEMI, non–ST segment elevation myocardial infarction; STEMI, ST segment elevation myocardial infarction. pancreatitis, intracranial hemorrhage, acute corpulmonale, Takotsubo cardiomyopathy (stress-induced cardiomyopathy), hyperkalemia, myocarditis, myocardial tumors, hypothermia, left ventricular hypertrophy, and bundle- branch blocks.4 Laboratory measurement of cardiac enzymes, including troponins and CK-MB (the myocardial isoenzyme of creatine kinase), although important, are not an essential component in the acute diagnosis of a STEMI and should not delay implementation of reperfusion therapy. Nevertheless, troponins have an increased specificity when compared with CK-MB in diagnosing MI. It is important to note, however, that serum troponins can be falsely elevated in patients with renal failure.5 The negative set of cardiac enzymes in this patient with a duration of MI of ~2 hours is likely explained by the fact that serum concentrations of CK-MB and troponins typically increase approximately 6 and 4 hours post-MI, respectively. If this patient’s MI had begun 3 days ago, then the cardiac troponins (which remain elevated for 7–10 days after the onset of an MI) would be elevated. On the other hand, his CK-MB levels (which persist for about 72 hours) might have normalized. TAblE 21.2 Differential Diagnosis of ST segment Elevation on ECG Life- threatening etiologies Other cardiovascular and nonischemic etiologies Other noncardiac etiologies MI Aortic dissection Pulmonary embolus Perforating ulcer Tension pneumothorax Boerhaave syndrome Pericarditis Atypical angina Early repolarization Wolff–Parkinson–White syndrome Hypertrophic cardiomyopathy LV hypertrophy with strain Brugada syndrome Myocarditis Hyperkalemia Bundle-branch blocks Prinzmetal’s (vasospastic) angina Gastroesophageal reflux and spasm Chestwall pain Peptic ulcer disease Panic attack Biliary or pancreatic pain Cervical disc or neuropathic pain Psychogenic pain Abbreviations: MI, myocardial infarction; LV, left ventricular. Adapted from the American College of Cardiology and American Heart Association (ACC/AHA) guidelines for the management of patients with ST-elevation myocardial infarction.2 Bottom line: Although the differential diagnosis for chest pain is broad, ST segment elevations on ECG in the presence of risk factors for coronary artery disease (e.g., diabetes, hyperlipidemia) indicate STEMI until proven otherwise regardless of cardiac enzyme levels. 2. Where is the lesion most likely located in this patient? The most common site of a STEMI is the anterior wall of the left ventricle, which is supplied by the left anterior descending (LAD) artery. In this patient, the extensive distribution of leads with ST segment elevation (lateral, septal, and anterior leads) suggests an occlusion of the LAD proximal to both the diagonal and the septal branches. Bottom line: The most common site of a STEMI is the anterior wall of the left ventricle, which is supplied by the LAD artery. 3. What are the clinical implications of the Q-wave versus Non–Q-wave categorization of a STEMi? Does this distinction have prognostic and/or therapeutic value? There had been a lot of debate on the therapeutic implications of Q-wave myocardial infarction (QWMI) versus non-Q-wave myocardial infarction (NQMI), all of which stemmed from the notion that NQMI had a poorer prognosis. In 1999, Phibbset al.6 noted that 9 published studies did not show any difference in post-MI course between these 2 categories of MI. In addition, there was no benefit of managing NQMI more invasively than QWMI. Phibbs et al. said that “since the characterization of an infarct as ‘non-Q’ conveys no therapeutic implications, the classification becomes irrelevant and should be discarded.” Bottom line: Although NQWMIs have traditionally been thought to have a worse prognosis than QWMIs, these have not been supported by the studies. 4. What factors allow physicians to risk-stratify patients with an STEMi? There is a considerable variability in mortality risk in patients with an acute myocardial infarction (AMI). The 2 most useful tools for the early risk stratification of patients with AMI include the Killip classification and the thrombolysis in myocardial infarction (TIMI) score. In 1967, Killip categorized patients with AMI into 4 classes depending on the clinical evidence of left ventricular heart failure.7 Ross et al.8 followed 1773 consecutive AMI patients hospitalized in 25 coronary care units in Israel for up to 1 year; and 1-year mortality rates are presented (Table 21.3) based on the Killip’s classification. The TIMI score was created specifically for STEMI and predicts the 30-day mortality at presentation of fibrinolytic-eligible patients with STEMI.9 The TIMI risk score and 30-day mortality rate can be calculated as shown in Tables 21.4 and 21.5. Bottom line: Early risk stratification of patients with AMI include the Killip classification, which is based on left ventricular function, and the TIMI score, which is based on various historical factors (e.g., diabetes, age) and clinical signs (e.g., hypotension, specific ECG changes). TAblE 21.3 Killip class I—No heart failure II—Heart failure Killip Classification and 1-Year Morality Rate of Acute Myocardial Infarction III—Severe heart failure IV—Cardiogenic shock 1-Year Description mortality (%) No clinical signs of cardiac 6 decompensation Rales, S3 gallop, and venous 24 hypertension Frank pulmonary edema 42 Hypotension (systolic pressure 60 <90 mm Hg) and evidence of peripheral vasoconstriction such as oliguria, cyanosis, and diaphoresis TAblE 21.4 TIMI Scoring for STEMI Risk factor Points Age > 75 y 3 Age 65–74 y 2 Diabetes mellitus, hypertension, or angina 1 Systolic BP < 100 mm Hg 3 Heart rate > 100 bpm 2 Killip’s class II–IV 2 Weight < 67 kg 1 Anterior ST-elevation or left bundle branch block 1 Time to treatment >4 h 1 Total points possible 0–14 TAblE 21.5 Mortality Rate at 30 Days TIMI Risk score 30-d Mortality rate (%) 0 0.8
1 1.6 2 2.2 3 4.4 4 7.3 5 12.4 6 16.1 7 23.4 8 26.8 >8 35.9 6. What does the evidence suggest should be the first step in management for STEMi? According to the ACC/AHA guidelines,2 the initial steps in management after the diagnosis of a STEMI include the following: 1. Portable chest x-ray: for all patients but should not delay revascularization therapy. 2. Oxygen: supplemental oxygen to all patients. 3. Nitroglycerin: patients with ongoing ischemic discomfort should receive sublingual nitroglycerin 0.4 mg every 5 minutes for a total of 3 doses, after which need for intravenous nitroglycerin should be assessed. Note that nitroglycerin should not be given to patients with systolic blood pressure less than 90 mm Hg, heart rate of less than 50 or more than 100, suspected right ventricular infarction, or usage of a phosphodiesterase inhibitor for erectile dysfunction within the last 24 hours. 4. Morphine sulfate: 2–4 mg intravenously with increments of 2–8 mg intravenously repeated at 5- to 15-minute intervals. 5. Aspirin: 162–325 mg chewed unless contraindicated or already taken by the patient. 6. Oral b-blocker: should be administered promptly to those without contraindication irrespective of concomitant revascularization therapy. 7. Implementation of revascularization: see options for revascularization given below. Bottom line: With few exceptions, all STEMI patients should receive a chest x- ray, oxygen, nitroglycerin, morphine sulfate, aspirin, β-blocker, and emergent revascularization therapy. 7. What does the evidence suggest are the options for revascularization? The ACC/AHA guidelines state that “all STEMI patients should undergo rapid evaluation for reperfusion therapy and have a reperfusion strategy implemented promptly after contact with the medical system.”2 Following are the options to achieve prompt and complete revascularization: 1. Pharmacotherapy (fibrinolysis): the approved fibrinolytic agents include streptokinase, alteplase, reteplase, and tenecteplase. Data from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trials seem to suggest that alteplase and reteplase have an advantage over streptokinase in achieving early coronary reperfusion.10,11 However, it is important to note that streptokinase is considerably cheaper than alteplase or reteplase.2 2. Percutaneous coronary intervention (PCI): this option involves the use of balloon angioplasty with or without an intraluminal stent. 3. Surgical measures: despite advances in operative interventions, it is frequently dificult to provide surgical intervention in a timely fashion, and so, this is a less favorable option in the acute setting. In general, “if the presentation is less than 3 hours (from onset of symptoms) and there is no delay in an invasive strategy, there is no preference of either strategy (fibrinolysis or PCI).”2 However, depending on the severity of the STEMI, the risk of fibrinolysis, and time required for transport to a skilled PCI laboratory, the choice is not always as clear-cut (see discussion below). Bottom line: Revascularization options include fibrinolytics, PCI, and coronary artery bypass surgery. 8. What does the evidence suggest should be the door-to-needle or door-to- balloon time? The purpose of establishing the door-to-needle and door-to-balloon time was to facilitate quick recognition and treatment of patients with acute STEMI. In patients who are undergoing fibrinolytic therapy, current ACC/AHA guidelines recommend a door-to-needle time of less than 30 minutes.2 The ACC/AHA guidelines for patients undergoing PCI recommend a door-to- balloon time of less than 90 minutes. A prospective cohort study of 43,801 patients undergoing PCI within the National Cardiovascular Data Registry assessed the incremental mortality benefit of reductions in door-to-balloon times of less than 90 minutes. This study showed that reductions in door-to-balloon times from 90 to 60 minutes and from 60 to 30 minutes were associated with 0.8% and 0.5% reductions in mortality, respectively.12 Therefore, this study advocates for an as-short-as-possible approach to the door-toballoon time. Bottom line: The ACC/AHA guidelines for patients undergoing PCI for a STEMI recommend a door-to-balloon time of less than 90 minutes. 9. What are the contraindications to thrombolytic therapy? According to the ACC/AHA guidelines, the list of relative and absolute contraindications to thrombolytic therapy includes those presented in Table 21.6. TAblE 21.6 Contraindications for Fibrinolysis in STEMI Absolute contraindications Relative contraindications Prior history of intracranial hemorrhage Cerebral arteriovenous malformation Malignant intracranial neoplasm Ischemic stroke within 3 mo Suspected aortic dissection Active bleeding (excluding menses) Significant closed-head or facial trauma within 3 mo Chronic, severe, poorly controlled hypertension BP > 180/110 mm Hg at presentation Ischemic stroke greater than 3 mo ago Dementia Prolonged (>10 min) CPR within less than 3 wk Major surgery within less than 3 wk Recent (within 2–4 wk) internal bleeding Pregnancy Active peptic ulcer Current anticoagulant use For streptokinase–anistreplase: prior exposure (more than 5 d ago) or prior allergic reaction to these agents Abbreviations: BP, blood pressure; CPR, cardiopulmonary resuscitation. Adapted from the American College of Cardiology and American Heart Association (ACC/AHA) guidelines for the management of patients with ST- elevation myocardial infarction.2 It is important to note that overdose or bleeding caused by thrombolytic agents can be treated with aminocaproic acid, which inhibits the conversion of plasminogen to plasmin. Bottom line: Absolute contraindications to thrombolytics include active bleeding, recent head trauma, intracranial bleeding, and suspected aortic dissection; and relative contraindications include recent history of internal bleeding and pathologically elevated blood pressure. CASE CONTiNuED Imagine that the above-mentioned patient presented initially to a hospital that did not have an interventional cardiology service; and the hospital with such facilities (as well as cardiothoracic surgery) was 3 hours away. 10. What does the evidence suggest regarding the choice of revascularization for patients presenting to a hospital without a skilled PCi laboratory? In such a situation, the patient needs to be triaged to fibrinolytic therapy (with door-to-needle time of less than 30 minutes) or immediately transferred to a skilled PCI laboratory with surgical backup. According to ACC/AHA guidelines, this decision depends on assessing 4 factors: the mortality risk of the STEMI, the risk of fibrinolytic therapy, the duration of symptoms at time of presentation, and the time to travel to a PCI-capable facility.13 The candidates for fibrinolytic therapy include: • Patients who present early after the onset of symptoms • Patients with low bleeding risk from fibrinolytic therapy • Patients in whom PCI cannot be done within 90 minutes of first medical contact Candidates for immediate transfer to PCI-capable facility include: • Patients with high-risk features such as extensive ST segment elevation, congestive heart failure, or shock • Patients with high bleeding risk from fibrinolytic therapy • Patients presenting more than 4 hours after the onset of symptoms If fibrinolytic therapy is chosen, then the decision to transfer to a PCI-capable facility after receiving thrombolytic therapy still needs to be considered, especially if the patient remains to be symptomatic and failure to re-perfuse is suspected. If immediate transfer to PCIcapable facility is chosen, it is important to consider the travel time to a PCI-capable facility because there may be an indication to start an anticoagulant plus antiplatelet regimen during the patient transfer. The CARESS-in-AMI trial showed that STEMI patients with high-risk features who were treated at a noninterventional center with half-dose reteplase (Retavase, Rapilysin) and abciximab (ReoPro) had improved outcomes if they were immediately transferred for PCI rather than managed at the local hospital with transfer only in the case of clinical deterioration.14 Overall, the ACC/AHA recommends that each facility in a community have written criteria to allow for the expeditious transfer of patients from non-PCI- capable to PCI-capable facilities. Bottom line: STEMI patients evaluated at a hospital without a skilled PCI laboratory should be triaged either to fibrinolytic therapy or immediately transferred to a hospital with a skilled PCI laboratory and surgical backup. 11. What does the evidence suggest regarding glycemic control in patients with a STEMi? There is randomized trial evidence supporting a mortality benefit to glycemic control in STEMI patients.13 However, the role of intensive versus conventional glycemic control is unclear given the lack of evidence on the optimal level to target when achieving glucose control in patients with a STEMI. In view of this, the ACC/AHA guidelines recommend treating glucose concentrations above 180 mg/dL with a focus on avoiding hypoglycemia.2 Bottom line: Evidence supports a mortality benefit for glycemic control in STEMI patients, although an optimal target level remains unclear. 12. What does the evidence suggest should be the management of arrhythmias that occur during the acute phase of a STEMi? According to the ACC/AHA guidelines, the first-line management of various arrhythmias that occur during the acute phase of a STEMI includes those listed in Table 21.7. 13. What are common medical complications of STEMi? Medical complications of STEMI are similar to those seen in non– STEMI (see Chapter 20). 14. What does the evidence suggest is effective in secondary prophylaxis for these patients? The ACC/AHA strongly recommend implementation of secondary prophylaxis interventions for all patients who survive the acute phase of a STEMI, which include patient education, lipid management, weight management, smoking cessation, antiplatelet therapy, use of an angiotensin-converting enzyme (ACE) inhibitor, use of β-blocker, blood pressure control, diabetes management, and physical activity.2 The specific interventions with the best evidence from multiple randomized trials or meta-analyses outlined in the ACC/AHA guidelines include: • Diet therapy low in saturated fats and cholesterol. • Increased consumption of omega-3 fatty acids, fruits, vegetables, and whole grains. • Patients with low-density lipoprotein (LDL) cholesterol of greater than equal to 100 mg/dL should be prescribed a statin on discharge with a goal LDL of 70 mg/dL. TAblE 21.7 Management of Arrhythmias in STEMI Arrhythmia Ventricular fibrillation Sustained polymorphic ventricular tachycardia Sustained monomorphic ventricular tachycardia associated with angina, pulmonary edema, or hypotension Sustained monomorphic ventricular tachycardia not associated with angina, pulmonary edema, or hypotension Ventricular premature beats Accelerate idioventricular rhythms Atrial premature beats Sustained atrial fibrillation/flutter with hemodynamic compromise Sustained atrial fibrillation/flutter without hemodynamic compromise Paroxysmal supraventricular tachycardia Bradyarrhythmias First-Line management Unsynchronized electric shock Unsynchronized electric shock Synchronized electric shock Amiodarone infusion and synchronized electric shock (with brief anesthesia) Check electrolyte levels (especially potassium and magnesium). No treatment unless they lead to hemodynamic compromise Observation Observation Synchronized electric shock (with brief anesthesia) and slowing ventricular rate with IV amiodarone β -Blocker (preferred) or IV diltiazem/verapamil Carotid sinus massage (IV adenosine, β-blocker, or diltiazem as alternatives) Treat with atropine or pacing if hemodynamic compromise Abbreviations: STEMI, ST segment elevation myocardial infarction; IV, intravenous. Adapted from the American College of Cardiology and American Heart Association (ACC/AHA) guidelines for the management of patients with ST- elevation myocardial infarction.2 • All STEMI patients should be evaluated for a history of cigarette smoking. • Lifelong daily dose of aspirin 75–162 mg orally. • Lifelong β-blocker therapy begun within a few days of event, if not started acutely. • ACE inhibitor prescribed at time of discharge for all patients without contraindications. • Post-STEMI patients without significant renal dysfunction or hyperkalemia, who are already receiving therapeutic doses of an ACE inhibitor, have a left ventricular ejection fraction of less than or equal to 40%, and have symptomatic heart failure or diabetes should be prescribed long-term aldosterone blockade. Bottom line: Secondary prophylaxis interventions for all patients who survive the acute phase of a STEMI include lipid management with a goal LDL of 70 mg/dL, smoking cessation, antiplatelet therapy, ACE inhibitor, β-blocker, and aggressive control of diabetes and HTN (if present). Cardiac rehabilitation, exercise, and a weight loss program are also frequently implemented. 15. is there a role for implantable cardioverter/ defibrillator in patients with a STEMi? According to the ACC/AHA guidelines, the role for implantable cardioverter/defibrillator (ICD) in patients with STEMI varies depending on the presence of ventricular arrhythmias and left ventricular ejection fractions (Table 21.8). TAblE 21.8 Role of ICDs in Patients With STEMI Clinical scenario ICD Indicated? Ventricular fibrillation or hemodynamically signifiYes cant sustained ventricular tachycardia more than 2 d after STEMI Left ventricular ejection fraction between 31% and Yes 40% with evidence of electrical instability (such as nonsustained ventricular tachycardia) and induc ible ventricular fibrillation/sustained ventricular tachycardia on electrophysiologic testing at least 1 mo after STEMI No spontaneous ventricular fibrillation/sustained No ventricular tachycardia more than 2 d after STEMI and left ventricular ejection fractions of greater than 40% at least 1 mo after STEMI Abbreviations: STEMI, ST segment elevation myocardial infarction; ICD, implantable cardioverter/defibrillator. Adapted from the American College of Cardiology and American Heart Association (ACC/AHA) guidelines for the management of patients with ST- elevation myocardial infarction.2 Bottom line: Specific criteria exist for ICD placement following a STEMI. 16. What is the evidence for or against the use of antioxidants in patients recovering from a STEMi? Although observational studies in the early 1990s suggested that lipidsoluble antioxidants such as vitamin E reduced the incidence of cardiovascular events such as STEMI,15–17 the ACC/AHA guidelines noted that there are no convincing well-controlled studies to support the use of antioxidants in patients recovering from a STEMI.2 17. What does the evidence suggest should be the role for psychiatry consultation in patients with AMi? The Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial in 2001 demonstrated that major depression occurs in up to 20% of patients with AMI.18 In addition, depressed patients were at greater risk for all-cause mortality, especially starting around 12 months after the acute event. In view of this, the ACC/AHA guidelines strongly recommend the psychosocial evaluation of all patients regarding the symptoms of depression and social support environment. In addition, ACC/AHA guidelines also note that the use of cognitive-behavioral therapy and selective serotonin reuptake inhibitors are reasonable choices in managing depression in patients with STEMI.2 However, despite these recommendations, no reduction in cardiovascular events or mortality was seen between the 2 groups in this trial. Bottom line: Depression is common following a STEMI and should be actively evaluated for and treated, although such treatment has not been shown to reduce cardiovascular events or mortality. TAKE HOME-POiNTS: ST SEgMENT ElEVATiON 1. ECG is one of the most important tools used for diagnosing STEMI. 2. Laboratory or imaging studies should not delay revascularization. 3. In general, the appropriate and timely use of either fibrinolysis or PCI is more important than the choice of therapy. 4. The recommended door-to-needle time for fibrinolytics is 30 minutes or less. 5. The recommended door-to-balloon time for PCI is 90 minutes or less. 6. Arrhythmias that occur during the acute phase of a STEMI should be promptly managed to prevent hemodynamic compromise. 7. Implementation of secondary prophylaxis interventions is strongly recommended, especially the use of a statin, aspirin, β-blocker, and ACE inhibitor. 8. Major depression is common in patients with STEMI, and psychiatry care should be established before discharge from the hospital. rEFErENCES 1. Nathanson, L. A., S. McClennen, C. Safran, and A. L. Goldberger. 2011. “ECG Wave-Maven: Self-Assessment Program for Students and Clinicians.” http://ecg.bidmc.harvard.edu/maven/mavenmain.asp. 2. Antman, E. M., D. T. Anbe, P. W. Armstrong, E. R. Bates, L. A. Green, M. Hand, and J. S. Hochman. 2004. “ACC/AHA Guidelines forthe Management of Patients With ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).” Journal of the American College of Cardiology 44: e1–e211. 3. Sharkey, S. W. 2008. “Electrocardiogram Mimics of Acute ST Segment Elevation Myocardial Infarction: Insights From Cardiac Magnetic Resonance Imaging in Patients With Tako-Tsubo (stress) Cardiomyopathy.” Journal of Electrocardiology 41(6): 621–25. 4. Jacobson, C. 2008. “Myocardial Infarction Mimics ST Segments.” AACN Advanced Critical Care 19(2): 245–48. 5. Bozbas, H., A. Yildirir, and H. Muderrisoglu. 2006. “Cardiac Enzymes, Renal Failure and Renal Transplantation.” Clinical Medicine & Research 4(1): 79–84. 6. Phibbs, B., F. Marcus, H. J. C. Marriott, A. Moss, and D. H. Spodick. 1999. “Q-Wave Versus Non-Q Waves Myocardial Infarction: A Meaningless Distinction.” Journal of the American College of Cardiology 33(2): 576–82. 7. Killip, T., and J. T. Kimball. 1967. “Treatment of Myocardial Infarction in a Coronary Care Unit. A Two-Year Experience With 250 Patients.” The American Journal of Cardiology 20: 457–64. 8. Ross, D., D. Leibowitz, R. Schwartz, A. T. Weiss, S. Behar, and H. Hod. 2010. “Combination of the Killip and TIMI Classifications for Early Risk Stratification of Patients With Acute ST Elevation Myocardial Infarction.” Cardiology 117(4): 291–95. 9. Morrow, D. A., E. M. Antman, A. Charlesworth, R. Cairns, S. A. Murphy, J. A. de Lemos, R. P. Giugliano, C. H. Mccabe, and E. Braunwald. 2000. “TIMI Risk Score for ST-Elevation Myocardial Infarction: A Convenient, Bedside, Clinical Score for Risk Assessment at Presentation.” Circulation 102 (17): 2031–37. 10. The GUSTO Investigators. 1993. “An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction.” The New England Journal of Medicine 329: 673–82. 11. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. 1997. “A Comparison of Reteplase With Alteplase for Acute Myocardial Infarction.” The New England Journal of Medicine 337: 1118–23. 12. Rathore, S. S., J. P. Curtis, J. Chen, Y. Wang, B. K. Nallamothu, A. J. Epstein, and H. M. Krumholz. 2009. “Association of Door-to-Balloon Time and Mortality in Patients Admitted to Hospital With ST Elevation Myocardial Infarction: National Cohort Study.” British Medical Journal 338: b1807. 13. Kushner, F. G., M. Hand, S. B. King, III, E. M. Antman, E. R. Bates, D. E. Casey, Jr, and J. S. Hochman, 2009. “Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/ AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update).” Journal of the American College of Cardiology 54: 2205–41. 14. Di Mario, C., D. Dudek, F. Piscione, W. Mielecki, S. Savonitto, E. Murena, and K. Dimopoulos. 2008. “Immediate Angioplasty Versus Standard Therapy With Rescue Angioplasty After Thrombolysis in the Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): An Open, Prospective, Randomised, Multicentretrial.” Lancet 371: 559–68. 15. Rimm, E. B., M. J. Stampfer, A. Ascherio, E. Giovannucci, G. A. Colditz, and W. C. Willett. 1993. “Vitamin E Consumption and the Risk of Coronary Heart Disease in Men.” The New England Journal of Medicine 328: 1450–56. 16. Stampfer, M. J., C. H. Hennekens, J. E. Manson, G. A. Colditz, B. Rosner, and W. C. Willett. 1993. “Vitamin E Consumption and the Risk of Coronary Disease in Women.” The New England Journal of Medicine 328: 1444–49. 17. Gey, K. F., P. Puska, P. Jordan, and U. K. Moser. 1991. “Inverse Correlation Between Plasma Vitamin E and Mortality From Ischemic Heart Disease in Cross-Cultural Epidemiology.” The American Journal of Clinical Nutrition 53: 326S–34S. 18. ENRICHD Investigators. 2001. “Enhancing Recovery in Coronary Heart Disease (ENRICHD) Study Intervention: Rationale and Design.” Psychosomatic Medicine 63: 747–55.

C H apter Aortic Dissection 22 Heeseop sHin, MD CASE A 60-year-old African American man with a history of hypertension that has not been closely followed by the medical community is evaluated for a 1-hour history of substernal chest pain that radiates to his back. He describes the sensation as a tearing pain and rates it as 10/10 in intensity. Vital signs are as follows: temperature, 98.3°F; heart rate, 95; blood pressure, 180/100 mm Hg; respiratory rate, 18; oxygen saturation is 98% on room air. Cardiopulmonary exam and electrocardiogram (ECG) are unrevealing. A chest x-ray (CXR) shows a widened mediastinum. 1. What is the likely diagnosis in this patient? The description of this patient’s chest pain (tearing, substernal, and radiating to the back) and his history of hypertension, normal ECG, and widened mediastinum on CXR are all classic for an aortic dissection, a medical and possibly surgical emergency with a high mortality rate. 2. What are the different types of aortic dissection? Classification of aortic dissection is based on the site of the intimal tear and the extent of the dissection. Early classification of the dissection is important as it determines management of the condition. Two classification schemes for aortic dissection exist: the DeBakey classification and the Stanford classification. The DeBakey classification is divided into three types, of which type III is further subdivided into two types. The more commonly used Stanford classification can be divided into two types.1 Table 22.1 and Figure 22.1 present a complete description of these classification schemes. Note that DeBakey type 279 TAblE 22.1 Description of the Debakey and Stanford Classification Schemes Classification scheme DeBakey classification Type I Type II Type IIIa Type IIIb Description Dissection present in both the ascending and the descending aorta Dissection present in the ascending aorta only Dissection extends proximally or distally and is localized above the diaphragm Dissection extends distally and below the diaphragm Stanford classification Type A Type B Dissection involves the ascending aorta Dissection does not involve the ascending aorta (and is distal to left subclavian artery) III III DeBakey A FigurE 22.1 Classification of aortic dissection. Reprinted from “Cardiovascular Surgery for Marfan Syndrome” by T. Treasure, 2000, Heart, 84: 674–678 with modification by the author. B Stanford I and II dissections and Stanford type A dissections all involve the ascending aorta and require surgical management (see Section 7). Bottom line: Two classification schemes exist for aortic dissections: the DeBakey classification and the Stanford classification. Dissections involving the ascending aorta require surgical management. 3. What is an aortic intramural hematoma and how does it relate to aortic dissection? In contrast to a classic aortic dissection, intimal tear is not present in aortic intramural hematoma (AIH). AIH arises from hemorrhage of the vasa vasorum in the media or microscopic tears in the intima.2 There is no communication between the hematoma and the lumen of the aorta. However, AIH may lead to a secondary tear, converting to dissection in 28%–47% of the patients. AIH may extend along the aorta, progress, regress, or reabsorb. The prevalence of AIH in patients with suspected aortic dissection is in the range of 21%–30%.3 Involvement of the ascending aorta is generally considered an indication for urgent surgery due to similar potential complications of a dissection in the same location. Conservative management is indicated for AIH of the descending aorta.4 Bottom line: AIH is caused by medial hematoma without an intimal flap. It may get converted to aortic dissection and is managed similarly. 4. Does the evidence suggest high-risk patients should undergo routine screening for aortic aneurysms? Patients can be divided into low, intermediate, and high risk for aortic dissection depending on their history and physical examination. Concerning historical features include presence of connective tissue disease (Marfan, Turner, Ehlers- Danlos, etc.), aortic valve disease, aortic aneurysm, family history of aortic dissection or aneurysm, and chest pain with abrupt onset, severe intensity, or tearing, sharp quality. Concerning exam features include pulse deficit, difference of >20 mm Hg in systolic blood pressure of two different limbs, focal neurologic deficit, and new aortic regurgitation murmur. A high risk patient has two or more of these features; an intermediate risk patient has one; and a low risk patient has none.2 All patients may be screened with an ECG and CXR. High risk patients should have an expedited imaging of the aorta via transesophageal echocardiogram (TEE), computed tomography (CT) scan, or magnetic resonance imaging (MRI) regardless of the ECG and CXR results. For intermediate and low risk patients, imaging of the aorta may be pursued if an alternate diagnosis is not established. Of note, if ST segment elevation is seen on ECG in a patient with suspected myocardial infarction, it should be treated as a primary cardiac event unless the patient is at high risk for aortic dissection, in which case urgent screening for potential dissection should occur.2 Bottom line: Patients can be divided into low, intermediate, and high risk depending on their historical and exam features. All patients may be screened with an ECG and a CXR. A high risk patient will need an expedited imaging of the aorta. For intermediate and low risk patients, imaging of the aorta may be pursued if an alternate diagnosis is not established. 5. What imaging modalities does the evidence suggest are useful for diagnosing aortic dissection? CXR, angiography, CT, MRI, and echocardiography can all play a role. See the discussion below and refer to Table 22.2. 5.1 X-ray A CXR is recommended in all patients presenting with acute chest pain, including those with suspected aortic dissection. An x-ray suggestive of aortic dissection would show a widened mediastinum. However, almost 20% of patients with dissection may have negative findings. Therefore, further imaging should be pursued even if the x-ray is normal in cases of suspected aortic dissection.5 5.2 Angiography Historically, angiography has been considered the gold standard for diagnosing aortic dissection with a sensitivity of 88% and specificity of 94%, corresponding to a negative predictive value of 84% and a positive predictive value of 96%, respectively.6 False negatives may occur when the false lumen is not opacified, when there is simultaneous opacification of the true and false lumen, and when the intimal flap is not displayed in the profile. In recent years, angiography has been replaced by the use of TEE, CT, and MRI.3 However, it may be useful in circumstances where definitive coronary evaluation is required or if other modalities are inconclusive. 5.3 Computed tomography CT was the most common initial diagnostic test performed in patients enrolled in the International Registry of Acute Aortic Dissection.7 Past studies show sensitivities of 90%–100% and specificity of 87%.7–10 However, these studies used conventional CT, which has largely been replaced by multidetector helical CT (MDCT), which reportedly has even better test characteristics, with recent studies showing sensitivities and specificities of 100%.11 However, a 2006 meta- analysis comparing MDCT, MRI, and TEE demonstrated equally reliable diagnostic values.12 Advantages of CT include near-universal availability and ability TAblE 22.2 American College of Radiology Appropriateness Criteria Radiologic procedure for Relative suspected aortic radiation dissection Rating Comments levela X-ray chest 9 Should be performed if readily > available at the bedside and does not cause delay in obtaining a CT or MRI. Alternative causes of chest pain may be discovered. Not the definitive test for aortic dissection. CTA chest and 9 abdomen Recommended as the definitive >>>> test in most patients with suspicion of aortic dissection. MRA chest and 8 abdomen with or without contrast Alternative to CTA for: None contraindication to CT (iodinated contrast), multiple prior chest CTA for similar symptoms, and in patients showing no signs of hemodynamic instability. Scanner availability and local expertise limit widespread use as there is potential for delay in diagnosis. See statement regarding contrast in text under “Anticipated Exceptions.” If skilled operator None readily available. US echocar8 diography (transesopha geal) Aortography 5 US echocar4 diography (transthoracic) >>> None Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; CTA, computed tomography angiogram; MRA, magnetic resonance angiogram Reprinted from “Acute Chest Pain—Suspected Aortic Dissection” by American College of Radiology, 1998. www.acr.org aRating Scale: 1, 2, 3, usually not appropriate; 4, 5, 6, may be appropriate; 7, 8, 9, usually appropriate. to image the entire aorta to distinguish other causes of chest pain, which have been reported in up to 21% of cases scanned for suspected aortic dissection.9 Disadvantages include the need for contrast and the inability to detect aortic insufficiency. 5.4 Magnetic resonance imaging Both the sensitivity and specificity of MRI for diagnosing aortic dissection have recently been reported to be 100%.8,12–14 MRI allows visualization of aorta without using ionizing radiation. Also, iodinated contrast is not administered. Its limitations include longer examination times and limited availability on an emergent basis. Also, patients with ferromagnetic materials such as cardiac pacemakers, aneurysm clips, orthopedic prosthesis, and other MRI incompatible devices cannot undergo MRI. MRI may be preferred in hemodynamically stable patients or those with chronic dissection. 5.5 Echocardiography Echocardiography has the advantage of being widely available and can be performed at the bedside in hemodynamically unstable patients. Transthoracic echocardiography has been found to have a sensitivity of 59%–85% and a specificity of 95%.15,16 It is useful in diagnosing dissection in the ascending aorta and can assess pericardial effusion, aortic regurgitation, and left ventricular function.14 However, its use is limited in distal dissections. In contrast, TEE can image almost the entire aorta. The sensitivity and specificity of monoplane and biplane TEE range from 90% to 100% and from 77% to 100%, respectively. Multiplanar TEE is much more accurate, providing sensitivity of 99% and specificity of 98%.16 Bottom line: CXR is recommended in all patients with suspected aortic dissection and a CT is typically the next step, although MRI can be performed if the patient is hemodynamically stable. In the presence of hemodynamic instability, a bedside TEE should be considered. 6. How does the evidence suggest acute aortic dissection be managed? Once acute aortic dissection is diagnosed, the initial management is determined by the patient’s hemodynamic status. For hypertensive or normotensive patients, the goal is to decrease the aortic wall stress by controlling heart rate and blood pressure. Intravenous (IV) beta blockers should be used for a target heart rate of <60 beats per minute. If beta blockers are contraindicated (asthma, acute CHF, COPD, etc.), IV calcium channel blockers can be used. If systolic blood pressure remains >120 after rate control, IV vasodilators should be added to reduce the pressure. The patient will then either be managed surgically (if the dissection involves the ascending aorta) or transition to oral medications and receive follow up as an outpatient. Outpatient imaging of the aorta via MRI or CT scan is reasonable at 1, 3, 6, and 12 months post dissection. If the lesion appears stable, imaging can be done annually thereafter.2 Patients who are hemodynamically unstable should receive IV fluids with a goal mean arterial pressure of >70 mm Hg. If necessary, IV vasopressors can be started as well. Also, surgery should be consulted. Re-evaluate the patient and the imaging studies to determine the cause of hypotension (e.g. pericardial tamponade, contained rupture, severe aortic insufficiency). The patient should receive surgery if the cause of hypotension is correctable to such intervention or if the dissection involves the ascending aorta. Otherwise, the patient will be managed medically to correct the hypotension while keeping the systolic blood pressure below 120 mm Hg. Once stable, the patient can transition to oral medications and receive follow up as an outpatient.2 As the patient is being prepared for surgery, the aortic valve can be evaluated via TEE if not done already. Presence of aortic regurgitation or dissection of aortic sinuses may require replacement of the aortic valve in addition to graft replacement of the ascending aorta.2 Bottom line: Normotensive and hypertensive patients should be rate-controlled and pressure-controlled via IV medications acutely. If the dissection involves the ascending aorta, the patient should receive surgery. 7. Why are dissections involving the ascending aorta managed surgically? Generally, type A dissections are managed surgically, while type B dissections are managed medically. The necessity for surgery in type A dissection is due to its propensity for possible lethal complications. Type A dissections can extend into the aortic root, causing aortic regurgitation in 41%–76% of cases.17,18 They can also extend into the coronary arteries, resulting in acute myocardial infarction in 7% of cases.19,20 Finally, a dissected aorta can rupture directly into the pericardium, leading to cardiac tamponade in about 10% of cases.15 In one study, outcomes of 464 patients with aortic dissections (62.3% with type A dissection) were evaluated. Overall inpatient mortality was 27.4%. Mortality of patients with type A dissection treated surgically was 26%. Alternatively, mortality of those who did not receive surgery (typically due to advanced age and/or comorbidities) was 58%. Mortality of patients with type B dissection treated medically was 10.7%. Alternatively, mortality for those who received surgery (20%) was 31.4%.19 Thus, surgery appears to substantially reduce mortality risk in patients with type A dissections, while medical treatment is a better alternative for those with type B dissections. The only exception to the rule that acute aortic dissections involving the descending aorta should be managed with medical treatment occurs in situations where lethal complications develop. These complications include progression of dissection leading to symptoms of malperfusion (renal, mesenteric, lower extremity, etc.), enlarging aneurysm, and blood pressure instability. Malperfusion occurs in up to one-third of acute aortic dissection cases and doubles the mortality.16 In these cases, medical management should be supplemented with surgical or endovascular intervention Bottom line: Dissections involving the ascending aorta may lead to complications such as aortic regurgitation, acute myocardial infarction and cardiac tamponade. Surgery decreases mortality in type A dissections. TAKE-HOME POiNTS: AOrTiC DiSSECTiON 1. Debakey type I, II and Stanford type A dissections involve the ascending aorta and require surgical management. 2. Although CXR is indicated for initial screening, it has a poor sensitivity and a negative result therefore does not rule out dissection. 3. In hemodynamically stable patients, CT or MRI scanning following CXR is indicated, but if hemodynamic instablility is present, then a bedside TEE is indicated. 4. Normotensive and hypertensive patients should be ratecontrolled and pressure-controlled via IV medications acutely. If the dissection involves the ascending aorta, they should receive surgery. Otherwise, they can transition to oral medications and follow up as an outpatient. 5. Hypotensive patients should be given IV fluids and evaluated for the etiology of their hypotension. If the etiology is correctable or if the dissection involves the ascending aorta, they should receive surgery. Once stable, they can transition to oral medications and follow up as outpatient. 6. Type A dissections should be managed with surgery while Type B dissections should be managed with medical treatment. The exception to this rule occurs in cases where Type B dissections are accompanied by lethal complications, in which case surgery should be considered. rEFErENCES 1. Erbel, R., F. Alfonso, C. Boileau, O. Dirsch, B. Eber, A. Haverich, H. Rakowski, 2001. “Diagnosis and Management of Aortic Dissection.” European Heart Journal 22 (18): 1642–81. 2. Hiratzka, L. F., G. L. Bakris, J. A. Beckman, R. M. Bersin, V. F. Carr, D. E. Casey, Jr, K. A. Eagle, et al. 2010. “ACCF/AHA/AATS/ACR/ASA/ SCA/SCAI/ SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients with Thoracic Aortic Disease.” Journal of the American College of Cardiology 55 (14): e27–e129. 3. Nienaber, C. A., and K. A. Eagle. 2003. “Aortic Dissection: New Frontiers in Diagnosis and Management: Part I: From Etiology to Diagnostic Strategies.” Circulation 108 (5): 628–35. 4. Evangelista, A., D. Mukherjee, R. H. Mehta, P. T. O’Gara, R. Fattori, J. V. Cooper, D. E. Smith. et al. 2005. “Acute Intramural Hematoma of the Aorta: A Mystery in Evolution.” Circulation 111 (8): 1063–70. 5. Eyler, W. R., and M. D. Clark. 1965. “Dissecting Aneurysms of the Aorta: Roentgen Manifestations Including a Comparison With Other Types of Aneurysms.” Radiology 85 (6): 1047–57. 6. Chirillo F., C. Cavallini, C. Longhini, P. Ius, O. Totis, A. Cavarzerani, A. Bruni, C. Valfré, and P. Stritoni. 1994. “Comparative Diagnostic Value of Transesophageal Echocardiography and Retrograde Aortography in the Evaluation of Thoracic Aortic Dissection.” American Journal of Cardiology 74 (6): 590–95. 7. Moore A. G., K. A. Eagle, D. Bruckman, B. S. Moon, J. F. Malouf, R. Fattori, A. Evangelista, et al. 2002. “Choice of Computed Tomography, Transesophageal Echocardiography, Magnetic Resonance Imaging, and Aortography in Acute Aortic Dissection: International Registry of Acute Aortic Dissection (IRAD).” American Journal of Cardiology 89 (10): 1235–38. 8. Sommer, T., W. Fehske, N. Holzknecht, A. V. Smekal, E. Keller, G. Lutterbey, B. Kreft, et al. 1996. “Aortic Dissection: A Comparative Study of Diagnosis With Spiral CT, Multiplanar Transesophageal Echocardiography, and MR Imaging.” Radiology 199 (2): 347–52. 9. Thoongsuwan, N., and E. J. Stern. 2002. “Chest CT Scanning for Clinical Suspected Thoracic Aortic Dissection: Beware the Alternate Diagnosis.” Emergency Radiology 9 (5): 257–61. 10. Ballal, R. S., N. C. Nanda, R. Gatewood, B. D’Arcy, T. E. Samdarshi, W. L. Holman, J. K. Kirklin, and A. D. Pacifico. 1991. “Usefulness of Transesophageal Echocardiography in Assessment of Aortic Dissection.” Circulation 84 (5): 1903–14. 11. Yoshida S., H. Akiba, M. Tamakawa, N. Yama, M. Hareyama, K. Morishita, and T. Abe. 2003. “Thoracic Involvement of Type A Aortic Dissection and Intramural Hematoma: Diagnostic Accuracy—Comparison of Emergency Helical CT and Surgical Findings.” Radiology 228 (2): 430–35. 12. Shiga, T., Z. Wajima, C. C. Apfel, T. Inoue, and Y. Ohe. 2006. “Diagnostic Accuracy of Transesophageal Echocardiography, Helical Computed Tomography, and Magnetic Resonance Imaging for Suspected Thoracic Aortic Dissection: Systematic Review and Meta-analysis.” Archives of Internal Medicine 166 (13): 1350–56. 13. Laissy J. P., F. Blanc, P. Soyer, P. Assayag, A. Sibert, D. Tebboune, L. Arrivé, et al. 1995. “Thoracic Aortic Dissection: Diagnosis With Transesophageal Echocardiography Versus MR Imaging.” Radiology 194 (2): 331–36. 14. Nienaber, C. A., Y. von Kodolitsch, V. Nicolas, V. Siglow, A. Piepho, C. Brockhoff, D. H. Koschyk, and R. P. Spielmann. 1993. “The Diagnosis of Thoracic Aortic Dissection by Noninvasive Imaging Procedures.” The New England Journal of Medicine 328 (1): 1–9. 15. Gilon, D., R. H. Mehta, J. K. Oh, J. L. Januzzi, E. Bossone, J. V. Cooper, D. E. Smith, et al. 2009. “Characteristics and In-hospital Outcomes of Patients With Cardiac Tamponade Complicating Type A Acute Aortic Dissection.” American Journal of Cardiology 103: 1029–31. 16. Henke, P. K., D. M. Williams, G. R. Upchurch Jr., 2006. “Acute Limb Ischemia Associated With Type B Aortic Dissection: Clinical Relevance and Therapy.” Surgery 140: 532–39. 17. Jex, R. K., H. V. Schaff, J. M. Piehler, T. A. Orszulak, F. J. Puga, R. M. King, G. K. Danielson, and J. R. Pluth. 1987. “Repair of Ascending Aortic Dissection. Influence of Associated Aortic Valve Insufficiency on Early and Late Results.” Journal of Thoracic Cardiovascular Surgery 93: 375–84. 18. Mazzucotelli, J. P., P. H. Deleuze, C. Baufreton, A. M. Duval, M. L. Hillion, D. Y. Loisance, and J. P. Cachera. 1993. “Preservation of the Aortic Valve in Acute Aortic Dissection: Long-Term Echocardiographic Assessment and Clinical Outcome.” The Annals of Thoracic Surgery 55: 1513–17. 19. Hagan, P. G., C. A. Nienaber, E. M. Isselbacher, D. Bruckman, D. J. Karavite, P. L. Russman, A. Evangelista, et al. 2000. “The International Registry of Acute Aortic Dissection (IRAD): New Insights Into an Old Disease.” Journal of the American Medical Association 283: 897–903. 20.Neri E., T. Toscano, U. Papalia, G. Frati, M. Massetti, G. Capannini, E. Tucci, et al. 2001. “Proximal Aortic Dissection With Coronary Malperfusion: Presentation, Management, and Outcome.” Journal of Thoracic Cardiovascular Surgery 121: 552–60.

Chap T er Atrial Fibrillation 23 Lisa Josephine GUpTa, MD CASE A 77-year-old woman is evaluated in the emergency department (ED) for a 1- week history of progressively worsening shortness of breath and palpitations. Her medical history is significant for many years of moderately well-controlled hypertension (HTN). Examination reveals an elderly woman in moderate respiratory distress with an irregularly irregular rapid heart rate. An electrocardiogram (ECG) is as shown below. II FigurE 23.1 ECG on initial presentation. Adapted with permission from Brown and Shah 2012. USMLE Step 1 Secrets, 3 ed. 1. What is the likely diagnosis? Atrial fibrillation. The tachycardia and irregular ventricular rate, in conjunction with the loss of atrial input to ventricular filling, contribute to the development of the typical symptoms of atrial fibrillation (dyspnea, palpitations) that are noted in this patient.1 Similar to this case, patients with atrial fibrillation may have symptoms of palpitations, shortness of breath, exercise intolerance, or malaise, although patients are often asymptomatic. The pathophysiology of atrial fibrillation is thought to involve scarring and dilatation of the left atrium, which in some way 289 disrupts action potential conduction and triggers atrial fibrillation. Underlying cardiac conditions such as hypertension (HTN), congestive heart failure (CHF), and valvular disease are seen in approximately 50% and 80% of patients with paroxysmal and persistent atrial fibrillation, respectively.2 It is believed that ectopic foci located in the left pulmonary veins or atria fire multiple wavelets of electrical activity in the atria incites the atria and propagates signals throughout in an irregular fashion. These foci are believed to have a reduced refractory period and high conduction velocity, allowing for more frequent signals.3 Over time, this increase in signaling throughout both atria may lead to the remodeling of the other myocytes’ refractory periods as well, leading to chronic atrial fibrillation.2 Additionaly, multiple triggers can activate these ectopic foci, such as hyperthyroidism, catecholamine surge, vagal stimulation, tachycardia, myocardial ischemia, physiologic stressors such as surgery, stimulants, and alcohol.3,4 This ectopic foci theory is supported by evidence that radioablation of these foci may eliminate atrial fibrillation. Medical management for atrial fibrillation focuses on ventricular rate control. Bottom line: Although often asymptomatic, patients with atrial fibrillation classically experience palpitations, dyspnea, and exercise intolerance. Atrial fibrillation is thought to result from abnormal electrical activity in the left atrium and has been linked to numerous cardiovascular conditions such as HTN, CHF, and valvular disease. 2. What does the evidence suggest should be the initial work-up for this patient with new-onset atrial fibrillation without a clear precipitating cause? Medical history should focus on conditions potentially causing left atrial dilatation (HTN, valvular disease, obstructive sleep apnea), pulmonary infections, deep vein thrombosis (DVT) or pulmonary embolism (PE), hyperthyroidism, and transient ischemic attack or stroke. Recent history regarding alcohol and caffeine consumption should also be obtained, because these can precipitate atrial fibrillation. As discussed earlier, the etiology of atrial fibrillation is broad, and thus diagnostic evaluation should be thorough. Table 23.1 lists commonly ordered tests for the diagnostic work-up of atrial fibrillation. TAblE 23.1 Diagnostic Evaluation of Atrial Fibrillation Suspected etiology Hyperthyroidism Work-up TSH Acute myocardial ischemia Hypokalemia Troponin Indication Threefold increase in patients with subclinical hyperthyroidism5 If suspected Electrolytes; renal function, hepatic function Potential contraindications to therapy1 Other dysrrhythmias Electrocardiogram Left atrial dilatation, valvular heart disease Echocardiography, Transesophageal echocardiography Pulmonary embolism D dimer, CT Scan Other cardiac arrhythmias are present similar to atrial fibrillation Left ventricular function; left atrial size Guide cardioversion decisions
If suspected (pulmonary embolism can cause atrial fibrillation acutely) 3. Does evidence suggest that patients with atrial fibrillation are at increased risk for stroke? Yes.6 Due to stasis of blood, patients with atrial fibrillation are at increased risk for thromboembolic events from atrial thrombi. Unfortunately, many patients with unknown atrial fibrillation are diagnosed only after experiencing a thromboembolic stroke. Atrial fibrillation has an increased relative risk of overall mortality ranging from 1.4 to 2.3, and the increased mortality is predominantly due to stroke.2 The annual risk of stroke among patients with atrial fibrillation is approximately 5% to 7% per year,6 with an average relative risk of stroke approximately 6 times greater than that of age-matched controls.2 On the contrary, atrial fibrillation without an identifying cause and without structural heart disease (“lone atrial fibrillation”) has a fourfold increase in stroke when compared with controls.7 This suggests that known underlying cardiac pathology further increases the risk of stroke in patients with atrial fibrillation. The Framingham Heart study, a large-scale ongoing cardiovascular study, has demonstrated that the attributable risk of stroke in patients with atrial fibrillation compared with controls clearly increases with age. In patients aged 50 to 59 years, 1.5% of annual strokes are due to atrial fibrillation. This increases to 23.5% in patients aged 80 to 89 years.7 In addition, when atrial fibrillation is combined with significant heart disease, risk of stroke increases. Patients with concomitant coronary artery disease will have a two to fivefold increase in stroke, whereas patients with concomitant heart failure will have a two to threefold increase.7 Bottom line: The complication of primary concern in patients with atrial fibrillation is thromboembolic stroke. Risk of stroke in patients with atrial fibrillation increases with age and coexisting cardiac disease. 4. What is the CHADS2 score? How does it affect clinical management of patients with atrial fibrillation? The CHADS2 score is a tool used to stratify stroke risk with aims to guide anticoagulation treatment in an effort to prevent strokes. The patient is given a score of 0–6 based on the presence or absence of specific criteria (Table 23.2). The recommendation for antiplatelet therapy and/or anticoagulation in atrial fibrillation is based on the relative risk for stroke implied by the CHADS2 score, as shown in Table 23.3.8 For example, the patient in this case has a history of HTN and is older than 75 years, so she has a CHADS2 score of 2, suggesting that antiplatelet and/or anticoagulation prophylaxis would be reasonable. Other high-risk factors for stroke not included in the CHADS2 score include a history of thromboembolism, presence of a prosthetic TAblE 23.2 CHADS2 Score Calculation Risk factor Points CHF 1 HTN 1 Age > 75 1 Diabetes 1 Stroke or TIA history 2 heart valve, and mitral stenosis.2 Presence of one or more of these risk factors may alter recommended therapy in patients with atrial fibrillation (Table 23.4). In the absence of antiplatelet and/or anticoagulation prophylaxis, the relative risk of stroke in patients with atrial fibrillation increases approximately 17-fold.2 Patients with atrial fibrillation who began coumadin therapy experienced a 61% risk reduction in stroke incidence when compared with placebo controls.9 Unfortunately, intracerebral bleed is a concern of coumadin use. At the time of this writing, two new agents, dabigatran (Pradaxa) and rivaroxaban (Xarelto), have been FDA-approved for anticoagulation in patients with atrial fibrillation.10, 11 Bottom line: CHADS2 score and other risk factors are useful in determining antiplatelet and/or anticoagulation prophylaxis in patients with atrial fibrillation. Coumadin use has been associated with a reduced risk of stroke incidence but may result in intracerebral bleed. TAblE 23.3 Annual Risk for Stroke in Patients Who Are Not receiving Antiplatelet or Anticoagulation Prophylaxis CHADS2 Untreated annual score risk for stroke (%) 0 1.9 1 2.8 2 4.0 3 5.9 4 8.5 5 12.5 6 18.2 Recommended therapy Aspirin Aspirin or OAC therapy OAC therapy OAC therapy OAC therapy OAC therapy OAC therapy OAC, oral anticoagulant. TAblE 23.4 Therapeutic Implications of Non-CHADS2 Risk Factors for Atrial Fibrillation Risk category No risk factors One risk factor Any high-risk factor or >1 risk factor Recommended therapy Aspirin Aspirin or OAC therapy OAC therapy 5. What does the evidence suggest are treatment options for this patient with symptomatic atrial fibrillation? If the patient is hemodynamically unstable, electrical cardioversion should be undertaken immediately. However, if the patient is hemodynamically stable, has minimal symptoms, or has been in atrial fibrillation for longer than 48 hours, medical management to control heart rate and to improve symptoms is indicated.9 Note that any patient with prolonged atrial fibrillation is likely to have an atrial thrombus, thus making cardioversion a dangerous option unles the patient has received antiplatelet and/or anticoagulation therapy for several weeks. In this case, the patient has been having symptoms for one week and therefore should not be acutely cardioverted. Her symptoms can be improved with ventricular rate control. This may be accomplished by intravenous administration with digoxin, β-blockers, such as metoprolol, or nondihydropyridine calcium channel antagonists, such as diltiazem. If rapid rate control is needed, intravenous administration can be considered for the majority of the drugs listed in Table 23.5. Bottom line: Ventricular rate control is the primary means for acute management of symptomatic atrial fibrillation. If the patient is hemodynamically unstable, immediate (electrical) cardioversion is indicated. 6. in what situation(s) is cardioversion indicated and what are the ways one can “cardiovert” a patient into normal sinus rhythm? The use of cardioversion to regain normal sinus rhythm may be elective or emergent and can be achieved by drugs or electrical shock. Emergent cardioversion is necessitated when the arrhythmia results in hypotension, acute heart failure, hemodynamic instability, or worsening angina or cardiac ischemia. However, there is an increased risk of thrombosis with cardioversion, especially when the patient has been in atrial fibrillation for greater than 48 hours. Ideally, anticoagulation should be started 3 to 4 weeks before the procedure. Because “atrial fibrillation begets atrial fibrillation”, cardioversion is most efficacious when the patient has been in atrial fibrillation for 7 days or less. The antiarrhythmic drugs with strongest evidence for cardioversion are dofetilide, flecainide, ibutilide, propafenone, and amiodarone.9 Direct current cardioversion is an electrical shock applied to the ventricle during the QRS component to normalize the rhythm via external chest electrodes or internal cardiac electrodes. For elective cardioversion, anticoagulation therapy should be used at least 3 weeks before the procedure and 4 weeks after the procedure.9 TAblE 23.5 Common Medications Used for Heart Rate Control in Patients With Atrial Fibrillation: Duration of Onset and Major Side Effects Drug Onset Major side effects Digoxin 60+ min Digitalis toxicity, heart block, bradycardia Diltiazem IV 5 min Diltiazem PO 4–6 h Verapamil IV 5 min Verapamil xxx PO Esmolol 5 min Metoprolol 5 min IV Metoprolol 4–6 h PO Sotalol 4–6 h Amiodarone Days Hypotension, heart block Hypotension, heart block, CHF Hypotension, heart block Hypotension, heart block, CHF Hypotension, heart block, asthma Hypotension, heart block, asthma Hypotension, heart block, asthma, CHF Torsades de Points, heart block, asthma, CHF Torsades, pulmonary fibrosis, hypothyroidism, skin discoloration Adapted from ACC/AHA/ESC Practice Guideline.9 Bottom line: The antiarrhythmic drugs with strongest evidence for cardioversion are dofetilide, flecainide, ibutilide, propafenone, and amiodarone. Direct current cardioversion can be used, but anticoagulation therapy should be applied for at least 3 weeks before the procedure if possible. 7. in terms of stroke prophylaxis, does the evidence support giving this patient high-dose coumadin or a combination of fixed low-dose coumadin and aspirin? What about high-dose coumadin and aspirin? High-dose coumadin. See table 23.6. 8. What is the recommended therapeutic iNr range for coumadin anticoagulation in atrial fibrillation? In patients who meet criteria for initiation of antiplatelet and/or anticoagulation prophylaxis, the goal is to maintain the INR between 2 and 3. However, at the time of this writing, coumadin is being supplanted by newer agents that do not require any blood monitoring, which constitutes an enormous improvement in the quality of life for patients. Examples of these newer agents include dabigatran (Pradaxa) and rivaroxaban (Xarelto). Dabigatran is a direct thrombin inhibitor, whereas rivaroxaban is a factor Xa inhibitor. Apart from not requiring routine blood work, these newer anticoagulants have very few drug–drug interactions relative to coumadin and require no dietary modifications. 9. As suggested by the evidence, what pharmacologic options are available to the noncardiologist for optimization of rate control in atrial fibrillation? Does strict rate control result in better outcomes? Numerous effective rate-controlling agents exist. Commonly used examples include diltiazem, verapamil, digoxin, metoprolol, and amiodarone. In cases where medications are ineffective, nonmedical management (e.g., ablation) should be considered. Prior goals for patients with atrial fibrillation included maintenance of resting heart rate at 60–80 beats per minute and 90–110 beats per minute with moderate exercise. However, recent evidence published in 2010 from the New England Journal of Medicine13 suggests no morbidity or mortality benefit in maintaining heart rate in a strict range. Additionally, maintaining strict goals of 60–80 beats per minute appears to be difficult to achieve.13 10. Does evidence suggest that restoring normal sinus rhythm is more effective than rate control with anticoagulation in patients with atrial fibrillation? In deciding whether to pursue rate control with anticoagulation versus restoration and maintenance of sinus rhythm, it is necessary to review the results of five trials (PIAF, AFFIRM, RACE, PAF II, and STAF trials) comparing these two strategies (Table 23.7).14–18 These trials demonstrate that survival is similar regardless of the strategy chosen.9 In fact, there appears to be a trend toward reduced survival and increased thromboembolism with the rhythm control strategy. This is thought to be due to proarrhythmia of antiarrhythmic agents and the inappropriate cessation of anticoagulation. Bottom line: Restoration of sinus rhythm does not reduce the risk of stroke in these patients. This patient must be maintained on coumadin (or other anticoagulation agent) regardless of strategy chosen. CASE CONTiNuED Our patient becomes hemodynamically unstable and severely symptomatic. 11. What does the evidence suggest should be the next step in management of this patient? According to the guidelines set out by the American Heart Association, patients with atrial fibrillation who experience hemodynamic instability, ongoing myocardial ischemia, symptomatic hypotension, angina, or heart failure and who do not respond to drug management require immediate direct current cardioversion.9 12. if the etiology of atrial fibrillation has not been determined by the time of discharge, does the evidence suggest there is any utility in discharging the patient on a 30-day Holter monitor or inserting an implantable loop recorder? Yes.19 The use of a Holter monitor can provide insight into the inciting event causing the patient’s atrial fibrillation. By identifying the initiation of the fibrillation activity, we can guide treatment. Initiating events, such as bradycardia or tachycardia, will help decide if vagolytic or β-blockers are appropriate therapy. Similarly, the identification of ectopic activity preceding the fibrillation will help with decisions regarding catheter ablation.19 In addition, patients taking an antiarrhythmic are at risk of converting their atrial fibrillation to atrial flutter as an effect of the drug. The use of a Holter monitor can help to identify this problem.19 13. Does the evidence suggest that there is a role for echocardiography in the management of patients with atrial fibrillation? Yes. The use of transesophageal echocardiography (TEE) is important in identifying a thrombus in the atria. Patients needing cardioversion can be evaluated by TEE for thrombus if they have not been on antiplatelet and/or anticoagulation prophylaxis. If no thrombus is found, then conversion is acceptable as long as unfractionated heparin is given beforehand and the patient remains on anticoagulation for 4 weeks.9 If a thrombus is found, then the patient will need to be on antiplatelet and/or anticoagulation prophylaxis for 3 weeks before and 4 weeks after conversion (as stated earlier). In addition, TEE can provide knowledge of the heart structure, and it is a valuable tool when looking for valvular heart disease, atrial size and function, and pericardial disease. TAKE-HOME POiNTS: ATriAl FibrillATiON 1. Atrial fibrillation is the most common arrhythmia. The ECG is characterized by the absence of P waves and an irregularly irregular ventricular rhythm. 2. Its frequency increases substantially with age. 3. Patients may have symptoms of palpitations, shortness of breath, exercise intolerance, or malaise, or be completely asymptomatic. 4. The cause of atrial fibrillation is usually due to underlying heart disease and may improve with treatment of the underlying condition. Other causes include hyperthyroidism, pulmonary embolism, pulmonary infections, and alcohol abuse. 5. The most feared complication of atrial fibrillation is stroke. 6. Urgent cardioversion is required in cases of hemodynamic instability. 7. The CHADS2 score can be used to guide anticoagulation therapy. 8. Holter monitoring can be helpful in identifying the etiology of atrial fibrillation, thereby guiding management decisions. 9. By detecting or ruling out the presence of left atrial thrombi, the TEE can help guide the use of cardioversion. rEFErENCES 1. Christine, L., G. David, and C. David. 2008. “In the Clinic Atrial Fibrillation.” Annals of Internal Medicine 149: ITC5-1. 2. Prystowsky, E. N, and A. L. Waldo. 2008. “Atrial Fibrillation, Atrial Flutter, and Atrial Tachycardia” In Hurst’s The Heart. 12 ed., edited by V. Fuster, R. A. O’Rourke, R. A. Walsh, P. Poole-Wilson, Assoc. editors: S. B. King, R. Roberts, I. S. Nash, and E. N. Prystowsky. 3. Allessie, M. A., P. A. Boyden, A. J. Camm, A. G. Kléber, M. J. Lab, M. J. Legato, M. R. Rosen, et al. 2001. “Pathophysiology and Prevention of Atrial Fibrillation.” Circulation 103 (5): 769–77. 4. Marchlinski, F. 2008. “The Tachyarrhythmias.” In Harrison’s Principles of Internal Medicine. 17 ed., edited by A. S. Fauci, E. Braunwald, D. L. Kasper, S. L. Hauser, D. L. Longo, J. L. Jameson, and J. Loscalzo. 5. Krahn, A. D., G. J. Klein, C. R. Kerr, et al. 1996. “How Useful is Thyroid Function Testing in Patients with Recent-Onset Atrial Fibrillation? The Canadian Registry of Atrial Fibrillation Investigators.” Archives of Internal Medicine 156: 2221. 6. Piktel, J. S. 2011. “Cardiac Rhythm Disturbances.” In Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 7 ed., edited by J. E. Tintinalli, J. S. Stapczynski, D. M. Cline, O. J. Ma, R. K. Cydulka, G. D. Meckler. 7. Wolf, P. A., R. D. Abbott, and W. B. Kannel. 1991. “Atrial Fibrillation as an Independent Risk Factor for Stroke. The Framingham Study.” Stroke 22: 983–8. 8. Gage, B. F., A. D. Waterman, W. Shannon, M. Boechler, M. W. Rich, and M. J. Radford. 2001. “Validation of Clinical Classification Schemes for Predicting Stroke: Results from the National Registry of Atrial Fibrillation.” Journal of the American Medical Association 285 (22): 2864–70. 9. Fuster, V., L. E. Rydén, D. S. Cannom, et al. 2006. “ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation).” European Heart Journal 27 (16): 1979–2030. 10. Cotton, D., D. Taichman, S. Williams, and P. Zimetbaum. 2010. “In the Clinic: Atrial Fibrillation.” Annals of Internal Medicine December 7, 2010 vol. 153 (11): ITC6-1. 11. Schulman, S., C. Kearon, A. K. Kakkar, P. Mismetti, S. Schellong, H. Eriksson, D. Baanstra, J. Schnee, and S. Z. Goldhaber. 2009. “Dabigatran Versus Coumadin in the Treatment of Acute Venous Thromboembolism.” NEJM 361 (24): 2342–52. 12. Gulløv, A. L., B. G. Koefoed, P. Petersen, T. S. Pedersen, E. D. Andersen, J. Godtfredsen, and J. Boysen. 1998. “Fixed Minidose Warfarin and Aspirin Alone and in Combination vs Adjusted-Dose Warfarin for Stroke Prevention in Atrial Fibrillation.” Archives of Internal Medicine 158: 1513–21. 13. Van Gelder, I. C., H. F. Groenveld, H. J. G. M. Crijns, Y. S. Tuininga, J. G. P. Tijssen, A. M. Alings, H. L. Hillege, et al. 2010. “Lenient versus Strict Rate Control in Patients with Atrial Fibrillation.” New England Journal of Medicine 362 (15): 1363–73. 14. Hohnloser, S. H., K. H. Kuck, and J. Lilienthal. Nov 25, 2000. “Rhythm or Rate Control in Atrial Fibrillation—Pharmacological Intervention in Atrial Fibrillation (PIAF): A Randomised Trial.” Lancet 356 (9244): 1789–94. 15. Wyse, D. G., A. L. Waldo, J. P. DiMarco, M. J. Domanski, Y. Rosenberg, E. B. Schron, J. C. Kellen, et al. 2002. “A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation.” New England Journal of Medicine 347 (23): 1825–33. 16. Brignole, M., C. Menozzi, M. Gasparini, M. G. Bongiorni, G. L. Botto, R. Ometto, P. Alboni, et al. Jun 2002. “An Evaluation of the Strategy of Maintenance of Sinus Rhythm by Antiarrhythmic Drug Therapy after Ablation and Pacing Therapy in Patients with Paroxysmal Atrial Fibrillation.” European Heart Journal 23 (11): 892–900. 17. Van Gelder, I. C., V. E. Hagens, H. A. Bosker, J. H. Kingma, O. Kamp, T. Kingma, S. A. Said, et al. December 5, 2002. “A Comparison of Rate Control and Rhythm Control in Patients with Recurrent Persistent Atrial Fibrillation.” New England Journal of Medicine 347 (23): 1834–40. 18. Carlson, J., S. Miketic, J. Windeler, A. Cuneo, S. Haun, S. Micus, S. Walter, and T. Ulrish. 2003. “Randomized Trial of Rate-Control Versus RhythmControl in Persistent Atrial Fibrillation.” Journal of the American College of Cardiology 41 (10): 1690–96. 19. Wijffels, M. C., and H. J. Crijns. 2002. “Non-Invasive Characteristics of Atrial Fibrillation: The Value of Holter Recordings for the Treatment of AF.” Card Electrophysiol Rev 6 (3): 233–38. Indications

Chapterfor Pacemaker Placement 24 Song Li, MD CASE A 70-year-old woman collapsed onto the floor while shopping at the grocery store. She remembers feeling lightheaded and unstable on her feet right before the fall. Bystanders saw her lying still on the floor and unconscious for about 20 seconds and then she regained consciousness fairly quickly without much confusion. She denies any tongue biting or incontinence, but reports a similar episode of collapse a week ago. She has no other medical problems herself, although she reports that her grandfather died suddenly without a known cause. Her electrocardiogram (ECG) on presentation is as shown in Figure 24.1. 1. Given this woman’s history and ECG results, what is the benefit of permanent pacemaker implantation? This patient has symptomatic third-degree heart block (note the “dropped” QRS complexes following nonconducted p waves) with syncopal features. There are multiple observational studies over the years suggesting that permanent pacing significantly improves survival in third-degree atrioventricular (AV) block, especially if the patient has had syncope.1–4 According to the American College of Cardiology/American Heart Association/Heart Rhythm Society(ACC/AHA/ HRS) 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities, permanent pacemaker implantation is indicated for II I FiGurE 24.1 ECG on initial presentation. Above ECG belongs to the public domain with no copyright restrictions. 307 third-degree and advanced second-degree AV block at any anatomic level associated with bradycardia with symptoms (including heart failure)or ventricular arrhythmias presumed to be due to AV block (Class I Level C).5 However, before making the decision to implant a pacemaker, it is important to look for and correct reversible causes of AV block such as electrolyte abnormalities, perioperative block from cardiac surgery, and drugs that depress conduction. Bottom line: Permanent pacemaker implantation improves survival in patients with symptomatic third-degree heart block and is recommended for this indication. 2. in general, when is a permanent pacemaker indicated? Two general principles can be helpful in deciding whether a pacemaker is indicated. First, a pacemaker is more likely to be indicated in patients with symptoms that are directly attributable to documented arrhythmias. For example, pathologic bradycardia that is directly responsible for symptoms such as frank syncope or near syncope, lightheadedness, fatigue, poor exercise tolerance, and confusional states (as opposed to intermittent vasovagal episodes) is a well- founded indication. Second, the likelihood and pace of progression of the conduction system disease is an important determinant for pacemaker placement. For example, diseases within the His-Purkinje system (e.g., Mobitz type II, bundle branch block) are generally more likely to progress quickly than diseases affecting the AV node (e.g., Mobitz type I) and thus are more likely to benefit from a permanent pacemaker. Since the first pacemaker was implanted in 1958, indications for pacemaker placement have expanded dramatically. The three most common indications for permanent pacing in the United States are sinus node dysfunction (SND) (58.8%), complete AV block (28.6%), and certain types of second-degree AV block (8.4%).6 All other indications are much less common and are detailed in the ACC/AHA/HRS 2008 Guidelines. Bottom line: Permanent pacemakers are most commonly implanted for SND and AV block. Correlation of symptoms with arrhythmias and the expected rapidity of disease progression are two important determinants of whether to place a pacemaker. 3. What is SND and what are the specific indications for pacemaker placement in SND? SND is a group of diseases including persistent sinus bradycardia, chronotropic incompetence, and paroxysmal or persistent sinus arrest with escape rhythm. Sinus bradycardia also frequently presents with paroxysmal atrial fibrillation, sometimes oscillating suddenly from one to the other, and is thus termed the tachycardia–bradycardia syndrome. Symptoms can be related to bradycardia, paroxysmal tachycardia, or both, with syncope being the most significant presentation. It is crucial to distinguish pathological bradycardia from physiological bradycardia in trained athletes who do not need pacemaker placement. The natural history of SND is highly variable. Most patients with SND who have experienced a syncopal event will have recurrent syncope, but the risk of sudden death is extremely low with or without pacemaker placement.7,8 Permanent pacemaker implantation is the only effective long-term treatment for SND. Although pacing may not improve survival for SND, it reduces the symptoms and improves quality of life.9 The specific indications for pacemaker placement in SND are summarized in Table 24.1 according to the ACC/AHA/HRS 2008 Guidelines. 4. What mode of pacing is best in SND? Various randomized trials have compared atrial or dual-chamber pacing with ventricular pacing in the setting of SND. The first of these trials, a small Danish study of 225 patients, suggested that atrial pacing compared with ventricular pacing reduced the incidence of atrial fibrillation, heart failure, thromboembolism, and lowered cardiovascular mortality.10 Subsequent larger studies, such as the Canadian Trial of Physiologic Pacing and the Mode Selection Trial in SND, showed that atrial or dual-chamber pacing reduced the incidence of atrial fibrillation but without significant benefit in terms of mortality or stroke.11,12 In addition, the Pacemaker Selection in the Elderly trial showed that dual-chamber pacing and ventricular pacing had no difference in terms of mortality, atrial fibrillation, or stroke in patients older than 65.13 In the newest large trial published in March 2011, the Danish Pacing Trial compared single-lead atrial pacing with dual-chamber pacing in 1415 patients with sick sinus syndrome and found no difference in occurrence of stroke, heart failure, or death from any cause.14 However, atrial pacing was associated with a higher incidence of paroxysmal atrial fibrillation (HR, 1.27; 95% CI, 1.03–1.56; P = .024) and a two-fold increased risk of pacemaker reoperation (HR, 1.99; 95% CI, 1.53–2.59; P < .001). Taken together, the existing evidence supports the use of dual-chamber pacing for SND. Bottom line: In patients with SND, dual-chamber pacing mode (DDDR) seems to have the best overall clinical outcome. 5. What are the different types of acquired AV block? AV block is classified as first-, second-, or third-degree (complete) heart block. The respective ECG patterns are shown in Figure 24.2. TAblE 24.1 Indications for Pacemaker Placement in SND Class I (Benefits >>> Risks) 1. Permanent pacemaker implantation is indicated for SND with documented symptomatic bradycardia, including frequent sinus pauses that produce symptoms. (Level of Evidence: C) 2. Permanent pacemaker implantation is indicated for symptomatic chronotropic incompetence. (Level of Evidence: C) 3. Permanent pacemaker implantation is indicated for symptomatic sinus bradycardia that results from required drug therapy for medical conditions. (Level of Evidence: C) Class IIa (Benefits >> Risks) 1. Permanent pacemaker implantation is reasonable for SND with heart rate less than 40 bpm when a clear association between significant symptoms consistent with bradycardia and the actual presence of bradycardia has not been documented. (Level of Evidence: C) 2. Permanent pacemaker implantation is reasonable for syncope of unexplained origin when clinically significant abnormalities of sinus node function are discovered or provoked in electrophysiological studies. (Level of Evidence: C) Class IIb (Benefits ≥ Risks) 1. Permanent pacemaker implantation may be considered in minimally symptomatic patients with chronic heart rate less than 40 bpm while awake. (Level of Evidence: C) Class III (Risks ≥ Benefits) 1. Permanent pacemaker implantation is not indicated for SND in asymptomatic patients. (Level of Evidence: C) 2. Permanent pacemaker implantation is not indicated for SND in patients for whom the symptoms suggestive of bradycardia have been clearly documented to occur in the absence of bradycardia. (Level of Evidence: C) 3. Permanent pacemaker implantation is not indicated for SND with symptomatic bradycardia due to nonessential drug therapy. (Level of Evidence: C) Abbreviation: SND, sinus node dysfunction. Adapted from the ACC/AHA/HRS 2008 Guidelines. 6. What are the specific indications for pacemaker placement in acquired AV block? Similar to pacing for SND, the indications for pacing in AV block expanded in the last 40 years without the benefit of randomized control trials, as no other effective treatment alternatives exist. As noted previously, nonrandomized studies on third-degree (complete) AV block strongly suggest that permanent pacing improves Abnormal prolongation of the PR interval (>0.20 seconds) First-degree AV block Type I (not shown): progressive prolongation of PR interval before a dropped beat, usually with narrow QRS Second-degree AV block (2:1) Type II: fixed PR intervals before and after dropped beats, usually with wide QRS Complete AV dissociation Third-degree AV block FiGurE 24.2 Types of atrioventricular block. Source: ECG adapted from http://www.cvpharmacology.com/clinical%20topics/arrhythmias-2.htm survival, especially if syncope has occurred. Therefore, the ACC/AHA/ HRS 2008 Guidelines classify symptomatic third-degree AV block as a Class I indication for permanent pacing.5 Asymptomatic third-degree AV block with (a) documented periods of asystole greater than or equal to 3.0 seconds, or (b) any escape rate less than 40 bpm or an escape rhythm that is below the AV node, or (c) atrial fibrillation and bradycardia with 1 or more pauses of at least 5 seconds or longer is also a Class I indication. Other asymptomatic third-degree AV block is a Class IIa indication for permanent pacing. Advanced second-degree AV block, which refers to the blocking of two or more consecutive p waves with some conducted beats, should be considered as third- degree AV block with regards to pacemaker indication.5 Otherwise, type I second-degree AV block usually does not progress to more advanced AV block and pacing is not indicated in asymptomatic patients (Class III). Pacing is more controversial for symptomatic type I second-degree AV block patients but is still probably indicated (Class IIa).15 Type II second-degree AV block, on the other hand, frequently and sometimes suddenly progresses to complete heart block and carries a compromised prognosis.16 Thus, type II second-degree AV block is an indication for pacemaker placement regardless of symptoms (Class I for symptomatic patients and Class IIa for asymptomatic patients). Isolated first-degree AV block has not been shown to benefit from pacemaker placement (Class III).5 One exception involves some patients with marked first- degree AV block (PR interval greater than 300 milliseconds) and hemodynamic impairment caused by incomplete atrial filling before atrial contraction. These patients often exhibit symptoms similar to those of “pacemaker syndrome” including fatigue, syncope, malaise, and hypotension. For this population of patients, a small observational study has suggested that pacing may improve symptoms and functional status by decreasing AV conduction time and is probably indicated (Class IIa).17 Bottom line: For acquired AV block, pacemaker placement is generally indicated in third-degree AV block, advanced second-degree AV block, and type II second-degree AV block regardless of the symptoms. Pacing is also probably indicated in symptomatic type I second-degree AV block and marked first- degree AV block with symptoms similar to those of pacemaker syndrome or hemodynamic compromise. Pacing is not indicated in asymptomatic type I second-degree AV block or asymptomatic first-degree AV block. ViGNETTE TWO A 71-year-old woman with a history of myocardial infarction (MI) 2 years earlier presents for evaluation of gradually worsening symptoms of dyspnea on exertion. Her dyspnea has now progressed to the point where she has to stop to catch her breath after walking for 100 feet. She also has to sleep on two pillows and sometimes awakens at night due to shortness of breath. However, she is comfortable at rest. She has not had a recurrent ischemic event since her MI and she is on optimal drug therapy for her congestive heart failure. An ECG showed sinus rhythm, left ventricular hypertrophy, and a QRS interval of 155 milliseconds. An echocardiogram showed a left ventricular ejection fraction (LVEF) of 25% and ventricular dyssynchrony. 1. Does the evidence suggest this patient is likely to benefit from pacemaker placement? Yes.18 Although cardiac pacing is most frequently used to treat arrhythmias, it can also be used to improve cardiac hemodynamics. Advanced heart failure patients often have delayed electrical conduction (e.g., left bundle branch block) and impaired electromechanical coupling, causing ventricular dyssynchrony and reducing the efficiency of contraction. This patient most likely developed worsening heart failure due to her earlier MI and her symptoms are now New York Heart Association (NYHA) Class III. Her advanced symptoms coupled with increased QRS interval and an LVEF of 25% makes her a candidate for biventricular pacing, which is also known as cardiac resynchronization therapy (CRT). The rationale for CRT is that it would improve contraction pattern, reduce metabolic costs, and potentially induce favorable reverse remodeling. A number of pivotal randomized control trials including MIRACLE, COMPANION, and CARE-HF have evaluated the effectiveness of CRT. The latest large meta-analysis by McAlister et al. published in 2007 evaluated the data from 14 earlier trials and showed that in patients with left ventricle systolic dysfunction (EF ≤ 35%), prolonged QRS duration, and NYHA class III or IV symptoms despite optimal medical therapy, CRT improved LVEF by 3% (95% CI, 0.9%–5.1%), quality of life by 8 points on the 105-point Minnesota symptom scale (95% CI, 5.6–10.4 points), and functional status (improvements of ≥1 NYHA class were observed in 59% of CRT recipients).18 In addition, CRT decreased hospitalizations by 37% (95% CI, 7%–57%), while all-cause mortality occurrence decreased by 22% (95% CI, 9%–33%). In the CARE-HF trial studying the same patient population, it was estimated that to prevent one death, 13 patients would need to be treated with CRT for 2 years or 9 patients for 3 years.19 However, it should be noted that approximately one-third of the patients randomized to CRT did not show a clinical response, and the underlying predictors of effectiveness remain unclear.20 Bottom line: Biventricular pacemaker (also known as cardiac resynchronization therapy) is indicated in patients who have LVEF ≤ 35%, QRS duration ≥ 0.12 seconds, sinus rhythm, and NYHA functional Class III or IV despite optimal medical therapy. TAKE-HOME POiNTS: iNDiCATiONS FOr PACEMAKEr PlACEMENT 1. Permanent pacemaker is most commonly implanted for SND and AV block. Correlation of symptoms with arrhythmias and progression of conduction system disease are two important determinants of potential benefits from pacemaker placement. 2. Permanent pacemaker implantation is indicated for SND with documented symptomatic bradycardia or symptomatic chronotropic incompetence. 3. In patients with SND, dual-chamber pacing mode (DDDR) seems to have the best overall clinical outcome. 4. For acquired AV block, pacemaker placement is generally indicated in third- degree AV block, advanced second-degree AV block, and type II second-degree AV block regardless of the symptoms. Pacing is also probably indicated in symptomatic type I second-degree AV block and marked first-degree AV block with symptoms similar to those of pacemaker syndrome or hemodynamic compromise. Pacing is not indicated in asymptomatic type I second-degree AV block or asymptomatic first-degree AV block. 5. Biventricular pacemaker (also known as cardiac resynchronization therapy) is indicated in patients who have LVEF ≤ 35%, QRS duration ≥ 0.12 seconds, sinus rhythm, and NYHA functional Class III or IV despite optimal medical therapy. rEFErENCES 1. Johansson, B. 1966. “Complete Heart Block. A Clinical, Hemodynamic and Pharmacological Study in Patients With and Without An Artificial Pacemaker.” Acta Medica Scandinavica Supplementum 451: 1–127. 2. Hindman, M. C., G. S. Wagner, M. JaRo, et al. 1978. “The Clinical Significance of Bundle Branch Block Complicating Acute Myocardial Infarction. 2. Indications for Temporary and Permanent Pacemaker Insertion.” Circulation 58 (4): 689–99. 3. Donmoyer, T. L., R. W. DeSanctis, and W. G. Austen. 1967. “Experience With Implantable Pacemakers using Myocardial Electrodes in the Management of Heart Block.” The Annals of Thoracic Surgery 3 (3): 218–27. 4. Edhag, O., and A. Swahn. 1976. “Prognosis of Patients With Complete Heart Block or Arrhythmic Syncope Who Were Not Treated With Artificial Pacemakers. A Long-term Follow-up Study of 101 Patients.” Acta Medica Scandinavica 200 (6): 457–63. 5. Writing Committee Members, A. E. Epstein, J. P. DiMarco, et al. 2008. “ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons.” Circulation 117 (21): e350–e408. 6. Birnie, D., K. Williams, A. Guo, et al. 2006. “Reasons for Escalating Pacemaker Implants.” The American Journal of Cardiology 98 (1): 93–97. 7. Rasmussen, K. 1981. “Chronic Sinus Node Disease: Natural Course and Indications for Pacing.” European Heart Journal 2 (6): 455–9. 8. Alt, E., R. Völker, A. Wirtzfeld, and K. Ulm. 1985. “Survival and Followup After Pacemaker Implantation: A Comparison of Patients With Sick Sinus Syndrome, Complete Heart Block, and Atrial Fibrillation.” Pacing and Clinical Electrophysiology 8 (6): 849–55. 9. Gregoratos, G. 2005. “Indications and Recommendations for Pacemaker Therapy.” American Family Physician 71 (8): 1563–70. 10. Andersen, H. R., J. C. Nielsen, P. E. Thomsen, et al. 1997. “Long-term Follow-up of Patients from a Randomised Trial of Atrial Versus Ventricular Pacing for Sick-Sinus Syndrome.” Lancet 350 (9086): 1210–6. 11. Kerr, C. R., S. J. Connolly, H. Abdollah, et al. 2004. “Canadian Trial of Physiological Pacing: Effects of Physiological Pacing During Long-term Follow-up.” Circulation 109 (3): 357–62. 12. Lamas, G. A., K. L. Lee, M. O. Sweeney, et al. 2002. “Ventricular Pacing or Dual-chamber Pacing for Sinus-node Dysfunction.” The New England Journal of Medicine 346 (24): 1854–62. 13. Lamas, G. A., E. J. Orav, B. S. Stambler, et al. 1998. “Quality of Life and Clinical Outcomes in Elderly Patients Treated With Ventricular Pacing as Compared With Dual-chamber Pacing. Pacemaker Selection in the Elderly Investigators.” The New England Journal of Medicine 338 (16): 1097–104. 14. Nielsen, J. C., P. E. B. Thomsen, S. Højberg, et al. 2011. “A Comparison of Single-lead Atrial Pacing With Dual-chamber Pacing in Sick Sinus Syndrome.” European Heart Journal 32 (6): 686–96. 15. Connelly, D. T., and D. M. Steinhaus. 1996. “Mobitz Type I Atrioventricular Block: An Indication for Permanent Pacing?” Pacing and Clinical Electrophysiology 19 (3): 261–4. 16. Dhingra, R. C., P. Denes, D. Wu, R. Chuquimia, and K. M. Rosen. 1974. “The Significance of Second Degree Atrioventricular Block and Bundle Branch Block. Observations Regarding Site and Type of Block.” Circulation 49 (4): 638–46. 17. Barold, S. S. 1996. “Indications for Permanent Cardiac Pacing in Firstdegree AV Block: Class I, II, or III?” Pacing and Clinical Electrophysiology 19 (5): 747–51. 18. McAlister, F. A., J. Ezekowitz, N. Hooton, et al. 2007. “Cardiac Resynchronization Therapy for Patients With Left Ventricular Systolic Dysfunction: A Systematic Review.” Journal of the American Medical Association 297 (22): 2502–14. 19. Cleland, J. G. F., J. Daubert, E. Erdmann, et al. 2006. “Longer-term Effects of Cardiac Resynchronization Therapy on Mortality in Heart Failure [The CArdiac REsynchronization-Heart Failure (CARE-HF) Trial Extension Phase].” European Heart Journal 27 (16): 1928–32. 20. Bax, J. J., and J. Gorcsan. 2009. “Echocardiography and Noninvasive Imaging in Cardiac Resynchronization Therapy: Results of the PROSPECT (Predictors of Response to Cardiac Resynchronization Therapy) Study in Perspective.” Journal of the American College of Cardiology 53 (21): 1933–43.

Chapter Aortic Stenosis 25 Samantha S. huq CASE A 75-year-old male smoker with a history of hypertension presents for evaluation of sudden onset of dizziness while climbing a flight of stairs. Further history is significant for several months of worsening substernal chest pain and shortness of breath with exertion. He also reports of easy fatigability. Review of systems is otherwise unrevealing. Workup in the emergency department is significant for bibasilar inspiratory crackles. His heart rate is regular with a normal S1, diminished S2, and a late peaking systolic murmur at the right upper sternal border which radiates to both carotids. Murmur intensity increases with passive leg raising. Carotid pulses are delayed and diminished. The examination is otherwise unrevealing. Echocardiogram reveals a preserved ejection fraction but a narrowed, heavily calcified aortic valve. The calculated valve area is 0.8 cm2 with a mean transvalvular gradient of 64 mm Hg and a jet velocity of 5 m/sec. 1. What is the most likely diagnosis and why? Severe aortic stenosis (AS). Given the patient’s age, with no other history of valve disease, a degenerative calcific change of the aortic valve is the likely cause. As seen with this patient, AS can cause presyncope or even syncope with exertion due to inability of the left ventricle to significantly increase cardiac output due to the fixed, stenotic aortic orifice. This, in combination with exertion-induced peripheral vasodilation, can cause cerebral hypoperfusion and dizziness, lightheadedness, or even syncope.1 AS may also cause angina, resulting from an imbalance between myocardial oxygen demand (increased afterload and ventricular wall stress) and supply (reduced coronary perfusion gradient). AS can also lead to symptomatic heart failure, typically from combined systolic and diastolic dysfunction.2 317 Other causes of angina, dyspnea, and presyncope include myocardial ischemia/infarction, congestive heart failure (CHF), pulmonary embolism, and an increase in metabolic demand (e.g., severe hyperthyroidism or anemia). Bottom line: Consider AS when symptoms of exertional presyncope, angina, and dyspnea are present. 2. What are the risk factors for the progression of AS in this patient? In a retrospective study in patients undergoing aortic valve replacement (AVR), male gender, advanced age, and smoking were found to be statistically significant risk factors for progression of AS in those with degenerative valve disease similar to this patient.3 Additional factors that have been identified as risk factors for AS progression are shown in Figure 25.1. Factors such as renal insufficiency has been found to accelerate and amplify the process of AS via multiple pathways such as altered mineral metabolism, inflammation, oxidative stress, pressure, and volume overload.4 Response to exercise testing also serves as a good measure for risk of AS progression. A study done with 125 asymptomatic AS patients (mean age 65 years) found that 72% of those who Risk factors for AS progression Hypercalcemia Cause of AS Renal Degree of insufficiency valve calcification Aortic jet Hypercholestervelocity and olemiavalve area Response to exercise testing FigurE 25.1 Risk factors for progression of aortic stenosis. became symptomatic within 12 months had symptoms during earlier exercise testing.4 The findings suggest that exercise testing is strongly related to the severity and progression of valvular stenosis. It is noteworthy that the rate of progression of the stenotic lesion and the time of onset of symptoms varies significantly among patients. Bottom line: Although a number of risk factors for progression of AS exist, this patient is at risk due to his advanced age, age-related degenerative calcific changes, gender, and history of smoking. 3. What does the evidence suggest is the appropriate diagnostic workup for suspected AS? Physical examination is the first step in identification of AS. A study done by Etchells et al. (n = 124) determined that physical examination findings can accurately rule in or out AS.5 Absence of a murmur over the right clavicle ruled out AS (likelihood ratio [LR], 0.10; 95% confidence interval [CI], 0.01, 0.44). However, if a murmur is heard over the right clavicle, the presence of three or four associated findings (e.g., slow carotid artery upstroke, reduced carotid artery volume, maximal murmur intensity at the second right intercostal space, and reduced intensity of the second heart sound) ruled in AS (LR, 40; 95% CI, 6.6, 240).5 Certain characteristics of the arterial pulse, apical impulse, heart tones, and murmur are suggestive of severe AS (Table 25.1).6 In addition to physical examination, certain historical findings help support the existence of AS (Table 25.2).5 Evidence suggests that although physical examination findings correlate with stenosis severity, echocardiogram is still needed to exclude severe obstruction reliably when AS is suspected.7 Echocardiogram has a higher sensitivity and specificity of 86% and 88%, respectively, when compared to physical examination.7 Echocardiogram provides key diagnostic information including information on valve anatomy and hemodynamics, which looks at three parameters including aortic jet velocity, mean transaortic pressure gradient, and valve area, the left ventricular response to chronic pressure overload, aortic dilation, and associated valve disease.8 By assessing these parameters, an echocardiogram is better able to determine the severity of AS when stenosis is present and exclude severe obstruction when it is absent.7 Bottom line: While a thorough history and physical examination provide valuable information, echocardiogram is the standard practice for evaluation of an AS when suspected. TAblE 25.1 Physical findings Arterial pulse Delayed carotid artery upstroke Reduced 74–80 65–67 2.3 0.3 carotid artery volume Brachioradial 97 62 2.5 0.04 delay Apical impulse Sustained apical 78 81 4.1 0.3 impulse Apical-carotid 97 63 2.6 0.05 delay Heart tone Absent A2 18–20 96–98 4.5 NSa Absent or 44–90 76–98 3.6 0.4 diminished A2 S4 gallop 29–50 57–63 NSa NSa Murmur Late peaking 83–90 72–88 4.4 0.2 Prolonged 83–90 72–84 3.9 0.2 duration Loudest over 58–75 41–73 1.8 0.6 aortic area Murmur trans90–98 22–46 1.4 0.1 mits to neck Diagnostic Characteristics of Examination Findings in Aortic Stenosis Sensitivity Specificity Positive Negative (%) (%) LR LR 31–90 68–93 3.7 0.4 Abbreviations: LR, likelihood ratio. aNS, not significant. TAblE 25.2 Diagnostic Characteristics of Historical Findings in Aortic Stenosis Clinical findings History of angina History of congestive Sensitivity Specificity Positive LR Negative LR (%) (%) (95% CI) (95% CI) 53 42 0.92 1.1 (0.51, 1.4) (0.57, 1.8) 67 46 1.2 0.73 (0.75, 1.7) (0.32, 1.3) heart failure 4. based on our patient’s echocardiogram findings, how should his AS be classified? What about based on his symptoms? The key determinants for classifying AS severity are aortic valve area, aortic jet velocity, and mean transvalvular gradient (Table 25.3).9 Based on the echocardiogram findings, this patient has severe AS. Symptoms of AS are typically insidious in onset, with most patients initially experiencing decreased exercise tolerance or dyspnea on exertion. Some patients become symptomatic with mild-to-moderate stenosis, especially if there is coexisting aortic regurgitation, while others do not become symptomatic until there is severe aortic valve obstruction.9 In addition to decreased exertional tolerance and dyspnea on exertion, this patient shows signs of more severe symptoms of AS such as angina, syncope, and heart failure, which are typically late manifestations of the disease process. With no other coexisting valvular disease, this patient would be classified as symptomatic with severe AS.9 Bottom line: Aortic valve area, aortic jet velocity, and mean transvalvular gradient can be used to classify the severity of AS. Although symptoms can vary among individuals, angina, syncope, and heart failure are all manifestations of severe AS. 5. based on evidence, how long can we expect this patient to survive without intervention? As a symptomatic patient with severe AS, the mortality rate for this patient from the onset of symptoms is approximately 25% at 1 year and 50% at 2 years.10 In one study, in patients with severe AS (n = 55) who had refused surgery, the average survival was 2 years with a 5-year survival rate of <20%.11 The onset of symptoms to death is 5 years for angina, TAblE 25.3 Echocardiographic Findings in Aortic Stenosisa AS severity Normal Mild Moderate Severe Critical Valve area (cm2) 3.0–4.0 >1.5 1.0–1.5 <1.0* <0.6 Aortic jet velocity (m/s) ≤ 2.0 2.6–3.0 3.0–4.0 >4.0 Variable Mean gradient (mm Hg) <5 <25 25–40 >40 Variable Abbreviations: AS, aortic stenosis. aSevere aortic stenosis is also considered to be present if the valve area indexed by body surface area is <0.6 cm2/m2. 3 years for syncope, and 1.5–2 years for heart failure.12 Given that the patient presents with syncope with past history of angina and heart failure symptoms (e.g., bibasilar inspiratory crackles), his lifespan may range from 1 to 3 years without intervention. Bottom line: Once a patient becomes symptomatic, he has significantly decreased life expectancy without intervention. 6. What does the evidence suggest as the recommended intervention for this patient? An AVR is the recommended intervention in a symptomatic patient.13 If this patient’s symptoms are a manifestation of severe AS (valve area <1 cm2 and aortic jet velocity >4 m/s), for optimal management, a valve replacement should be pursued at the earliest possibility.13 If, however, this patient is symptomatic with moderate AS (valve area between 1 and 1.5 cm2 or with a velocity between 3 and 4 m/s), a careful work up to exclude other causes such as coronary artery disease is recommended.12 If there are no other explanations for the symptoms, valve replacement surgery should be considered if the valve shows significant calcification even with moderate stenosis.12 Bottom line: In a symptomatic AS patient, with no other contraindications, the next step in treatment is AVR. 7. What is the evidence based indication for an AVr? Surgical replacement of the aortic valve is the only effective treatment for severe AS.14 It is noteworthy that age alone is not a contraindication for surgical AVR. Several studies have shown that AVR can be performed in the elderly with acceptable mortality and morbidity and postoperative quality of life (Table 25.4).12 Bottom line: AVR is recommended in a symptomatic, severe AS patient. 8. given this patient’s current health status, what perioperative risks are associated with doing an AVr now? At 75, this patient presents with symptomatic AS with a history of smoking and hypertension. He does not have any past surgical history. To assess the perioperative risk associated with performing an AVR, an algorithm for predicting operative outcomes, the Society for Thoracic Surgery equation score, can be used.16 At present, his risk of mortality is 1.163%.16 TAblE 25.4 Indications for AVR in Aortic Stenosis Class I: There is evidence and/or general agreement that AVR is indicated in patients with AS in the following settings Class IIa: The weight of evidence or opinion is in favor of the usefulness of AVR in patients with AS in the following setting Class IIb: The weight of evidence or opinion is less well established for the usefulness of AVR in patients with AS in the following settings Class III: There is evidence and/ or general agreement that AVR for AS is not useful in the following settings • Symptomatic severe AS • Severe AS in patients undergoing coronary artery bypass graft surgery or surgery on the aorta or other heart valves • Severe AS with a left ventricular ejection fraction less than 50% • Moderate AS in patients undergo- ing coronary artery bypass graft surgery or surgery on the aorta other than heart valves • Severe AS in asymptomatic patients who have an abnormal response to exercise such as the development of symptoms or hypotension • Severe AS in asymptomatic patients with a high likelihood of rapid progression (as determined by age, valve calcification, and coronary heart disease) • Severe AS in asymptomatic patients in whom surgery might be delayed at the time of symptom onset • Mild AS in patients undergoing coronary artery bypass graft surgery in whom there is evidence, such as moderate-tosevere valve calcification, that progression may be rapid • Extremely severe AS (aortic valve area less than 0.6 cm2, mean gradient greater than 60 mm Hg, and aortic jet velocity greater than 5.0 m/sec) in asymptomatic patients in whom the expected operative mortality is 1% or less • For the prevention of sudden cardiac death in asymptomatic patients who have none of the class IIa or IIb findings Adapted from American College of Cardiology/American Heart Association (ACC/ AHA) Guideline Summary.15 Abbreviation: AS, aortic stenosis; AVR, aortic valve replacement. 9. How would this patient’s perioperative risk change if he decides to wait for another 10 years during which he develops chronic obstructive lung disease and CHF with an ejection fraction of 30% post myocardial infarction? If this patient waits for 10 years, with the deterioration of his health condition, his perioperative risks of mortality, morbidity, ventilation time, renal failure, and need for reoperation would all increase. His risk of mortality would more than double to 2.850%.16 Although there are always risks associated with any procedure, waiting will only risk this patient’s perioperative risks (Table 25.5). Bottom line: Given his health status and risk factors (e.g., age, hypertension, smoking, symptomatic AS), waiting to perform an AVR will increase the perioperative risks of morality, morbidity, reoperation to name a few. 10. is there a significant difference in this patient’s mortality risk with transcatheter versus surgical AVr? Despite surgical AVR being the standard treatment for patients with severe, symptomatic AS, up to 30% of patients with severe AS are denied surgery because of advanced age or high surgical risk.17 Evidence suggests that in high- risk patients (defined as severe AS with an aortic-valve area of less than 0.8 cm2 plus either a mean valve gradient of at least 40 mm Hg or a peak velocity of at least 4.0 m/s) who are candidates for surgical AVR (n = 699), balloon- expandable transcatheter replacement and surgical AVR are associated with similar mortality at 30 days and 1 year.17 In addition, the two methods are associated with similar improvements in cardiac symptoms.17 Although the exact numbers for the hemodynamic parameters (i.e., aortic valve area, aortic TAblE 25.5 Estimated Perioperative Risks for AVR in This Patient16 Date performed Now (%) 10 Years later (%) Risk of mortality 1.163 2.850 Morbidity or mortality 10.945 19.611 Permanent stroke 1.187 1.187 Prolonged ventilation 5.142 12.415 Deep sternal wound infection 0.237 0.604 Renal failure 2.286 4.193 Reoperation 6.684 jet velocity and mean transvalvular gradient) are unknown in this case, as a symptomatic patient with severe AS, this patient’s mortality would be similar in either a transcatheter or a surgical valve replacement. Bottom line: Findings indicate that transcatheter replacement is an alternative to surgical replacement as it has similar mortality in a wellchosen, high-risk subgroup of patients with AS. 11. Does evidence suggest that a balloon aortic valvotomy should be considered in this patient? A balloon aortic valvotomy (BAV) should not be considered in this case as the patient is an adult with symptomatic, severe AS.18 While the procedure may serve as a bridge to surgery in hemodynamically unstable patients who are at high risk for AVR, according to the 2006 ACC/AHA guidelines, BAV is not a substitute for valve replacement in adults.18 The limitations of this procedure include the following:18 • Restenosis and clinical deterioration within 6 to 12 months with long-term outcomes resembling the natural history of untreated AS • Despite a moderate reduction in the trasvalvular pressure gradient, the post- procedure valve area rarely exceeds 1.0 cm2, leaving the patient with persistent severe AS • Serious complications such as stroke, aortic regurgitation, myocardial infarction, major access-related complications occur in approximately 10%–20% of patients Despite its limited use in adults, BAV is often used in children with congenital valvular aortic stenosis.18 Bottom line: Although BAV may be considered a bridge for hemodynamically unstable patients, it is not a substitute for AVR in symptomatic adults with severe AS. 12. What, if any, indications exist for the use of pharmacological agents for this patient? Pharmacologic agents should be avoided for this patient unless he has inoperable AS, in which case optimizing loading conditions such as hypertension and volume status can lead to fewer symptoms.19 Research is currently on-going for identifying medications that can delay the progress of AS.19 Some of the medications that have been researched include angiotensin converting enzyme (ACE) inhibitor, statins, and anti-inflammatory drugs. The potential effects of these agents are listed in Table 25.6. TAblE 25.6 Potential Pharmacologic Agents in Aortic Stenosis20–25 ACE inhibitor Indications for use include • ACE inhibitor lowers blood pressure. This reduces the pressure overload of the left ventricle, which may reduce the mechanical stress and strain on aortic valve.20 • By reducing pressure overload, ACE inhibitor may halt progression of left ventricular hypertrophy, apoptosis, and fibrosis, thus slowing the progression of ventricular systolic and diastolic dysfunction.20 Study findings • Retrospective analysis by Rosenhek et al. found that progression of AS was not delayed in patients maintained on ACE inhibitors.21 • In contrast, in a retrospective study with wide confidence intervals, O’Brian et al. found that ACE inhibitor treatment is associated with a 71% reduction in the progression of aortic valve calcification.22 Statins Indications for use include • Reduce cardiovascular events rather than AS progression but may be a potential valuable preventative treatment in these patients20 Study findings • Recent retrospective study suggests the delay of disease progression in AS through lipid lowering and anti-inflammatory actions of statins23 • In contrast, results of SALTIRE (Scottish aortic stenosis and lipid lowering therapy, impact on regression), first double-blind randomized controlled trial, showed that atorvastatin failed to halt the progression or induce regression of the valve disease process as measured by Doppler echocardiography or helical computed tomography22 Anti-inflammatory Study findings • Study in the scientific journal Circulation have shown that specific pathways of inflammation are important underlying factors in the development of AS. The most significant inflammation was seen in patients with narrowest valves on ultrasound examination with evidence of immune cells and upregulation of leukotriene pathway.20 Abbreviation: ACE, angiotensin converting enzyme. Bottom line: As of now there is no established disease modifying treatment available to retard the progression of the stenotic process. ACE inhibitors, statins, and anti-inflammatory drugs are potential and promising treatments that may have beneficial effects in patients with AS but definitive evidence from large clinical trials is awaited. 13. What is this patient’s likely prognosis? This patient has a good prognosis if AVR is performed. Medical management would worsen his prognosis, especially considering his risk factors of long- standing hypertension and tobacco use. Through its synergistic effect with AS, hypertension increases afterload by increasing systemic vascular resistance, thus exacerbating the symptoms associated with AS.23 An AVR would not only improve symptoms but will also help improve mortality. A cohort study in elderly patients with severe AS and several comorbidites showed that an AVR improves 1-year, 2-year, and 5-year survival.23 Five-year survival is increased by 46% relative to individuals medically managed.23 Based on this cohort study, this patient has a 5-year survival estimated at roughly 68% after AVR compared to 22% without AVR.23 Bottom line: This patient has a good prognosis after AVR. His estimated 5-year survival rate is roughly 68%, which is 46% higher than the survival rate without AVR. TAKE-HOME POiNTS: AOrTiC STENOSiS 1. When severe AS is suspected, echocardiogram is indicated as it has a higher sensitivity and specificity and therefore provides key diagnostic information. 2. AS can be classified using the following parameters: aortic valve area, aortic jet velocity, and mean transvalvular gradient. 3. Without intervention, the onset of symptoms to death is 1.5–2 years for heart failure, 3 years for syncope, and 5 years for angina. 4. In a symptomatic, severe AS patient, the primary treatment is AVR. 5. The Society for Thoracic Surgery equation score, which is an algorithm for predicting operative outcomes, is a useful tool used to predict perioperative risk. 6. With an AVR, the estimated 5-year survival rate is roughly 68%, which is 46% higher than the survival rate without AVR. 7. In a symptomatic adult with severe AS, there is no indication for a BAV. 8. Transcatheter replacement has similar mortality when compared to an AVR in high-risk patients with AS. 9. As of now, there is no established disease modifying treatment available to slow down the progression of the stenotic process. rEFErENCES 1. Julius, B. K., M. Spillmann, G. Vassalli, et al. 1997. “Angina Pectoris in Patients with Aortic Stenosis and Normal Coronary Arteries: Mechanisms and Pathophysiological Concepts.” Circulation 95: 892. 2. Hess, O. M., B. Villari, and H. P. Krayenbuehl. 1993. “Diastolic Dysfunction in Aortic Stenosis.” Circulation 87: 73–77. 3. Novaro, G. M., R. Katz, R. J. Aviles, et al. 2007. “Clinical Factors, but not C- Reactive Protein, Predict Progression of Calcific Aortic-Valve Disease: The Cardiovascular Health Study.” Journal of the American College of Cardiology 50: 1992. 4. Das, P., H. Rimington, and J. Chambers. 2005. “Exercise Testing to Stratify Risk in Aortic Stenosis.” European Heart Journal 26: 1309–13. 5. Etchells, E., V. Glenns, et al. 1998. “A Bedside Clinical Prediction Rule for Detecting Moderate or Severe Aortic Stenosis.” Journal of General Internal Medicine 13: 699–704. 6. McGee, S. 2001. Evidence-Based Physical Diagnosis. Philadelphia: W.B. Saunders Company. 7. Oh, J. K., C. P. Taliercio, et al. 1988. “Prediction of the Severity of Aortic Stenosis by Doppler Aortic Valve Area Determination: Prospective DopplerCatheterization Correlation in 100 Patients.” Journal of the American College of Cardiology 11: 1227–34. 8. Otto, C. M. 2006. “Valvular Aortic Stenosis.” Journal of the American College of Cardiology 47 (11): 2141–51. 9. Grimard, B. H., and J. M. Larson. 2008. “Aortic Stenosis: Diagnosis and Treatment.” American Family Physician 78 (6):717–24. 10. Carabello, B. A. 2002. “Evaluation and Management of Patients with Aortic Stenosis.” Circulation 105: 1746–50. 11. Frank, S., A. Johnson, and J. Ross Jr. 1973. “Natural History of Valvular Aortic Stenosis.” British Heart Journal 35: 41–46. 12. Carabello, B. A. 1997. “Timing of Valve Replacement in Aortic Stenosis.” Circulation 95: 2241–43. 13. Bonow, R. O., B. A. Carabello, K. Chatterjee, et al. 2008. “2008 Focused Update Incorporated into the ACC/AHA 2006 Guidelines for the Management of Patients with Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.” Circulation 118: e523. 14. Vahanian, A., H. Baumgartner, J. Bax, E. Butchart, R. Dion, G. Filippatos, et al. 2007. “Guidelines on the Management of Valvular Heart Disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology.” European Heart Journal 28: 230–36. 15. Arnaoutakis, G. J., T. J. George, et al. 2011. “Society of Thoracic Surgeons Risk Score Predicts Hospital Charges and Resource Use after Aortic Valve Replacement.” Journal of Thoracic Cardiovasc Surgery 142 (3): 650–55. 16. Online STS Risk Calculator. riskcalc.sts.org. Feb 2012. 17. O’Brian, S. M., D. M. Shahian, G. Filardo, et al. 2009. “The Society of Thoracic Surgeons 2008 Cardiac Surgery Risk Models: Part 2—Isolated Valve Surgery.” Annals of Thoracic Surgery 88: S23–42. 18. Smith, C. R., M. B. Leon, M. J. Mack, et al. 2011. “Transcatheter versus Surgical Aortic Valve Replacement in High-Risk Patients.” The New England Journal of Medicine 364: 2187–98. 19. Ferguson, J. J. III, E. P. Riuli, A. Massumi, et al. 1990. “Balloon Aortic Valvuloplasty.” Texas Heart Institute Journal 17 (1): 23–30. 20. Newby, D. E., S. J. Cowell, and N. A. Boon. 2006. “Emerging Medical Treatments for Aortic Stenosis: Statins, Angiotensin Converting Enzyme Inhibitors, or Both?” Heart 92: 729–34. 21. Rosenhek, R., F. Rader, N. Loho, et al. 2004. “Statins but not AngiotensinConverting Enzyme Inhibitors Delay Progression of Aortic Stenosis.” Circulation 110: 1291–95. 22. Cowell, S. J., D. E. Newby, R. J. Prescott, et al. 2005. “Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) Investigators—A Randomized Trial of Intensive Lipid-Lowering Therapy in Calcific Aortic Stenosis.” The New England Journal of Medicine 352: 2389–97. 23. Varadarajan, P., N. Kapoor, et al. 2006. “Survival in Elderly Patients with Severe Aortic Stenosis is Dramatically Improved by Aortic Valve Replacement.” The European Journal of Cardio-Thoracic Surgery 30: 722–27.

C HA pt E r Temporal Arteritis 26 ADEEL SHAHID, MD CASE A 72-year-old Caucasian woman with a history of polymyalgia rheumatica (PMR) presents to her physician with a chief complaint of newonset headache. The headache is unilateral and localized over the right temporal area. On specific questioning, she admits to temporal scalp tenderness while combing her hair and jaw pain while chewing her food. She has no history of migraine headache. 1. What is the most likely diagnosis and why? The most likely diagnosis is temporal arteritis (TA). Although patients with temporal arteritis may present with a host of complaints including anorexia, weight loss, arthralgia, diplopia, fatigue, fever, headache, jaw claudication, visual symptoms, or vertigo, the presence of most of these symptoms alone does not significantly increase the probability of temporal arteritis.1 Jaw claudication and diplopia are two symptoms that should significantly raise clinical suspicion of this condition, as they increase the probability of receiving a positive biopsy result considerably (Table 26.1) (positive LR = 4.2 and 3.4, respectively).1 Alternatively, the most important finding in ruling out the possibility of temporal arteritis is a normal erythrocyte sedimentation rate (ESR), as it has a negative LR of 0.2. This is thus the most useful finding, as a normal ESR makes a final diagnosis of temporal arteritis unlikely, although roughly 5% of patients with temporal arteritis may have a normal ESR.2 In comparison, the absence of any abnormality found on the temporal artery biopsy is associated with a negative LR of only 0.531 (Table 26.2). Bottom line: Temporal arteritis may be associated with a variety of symptoms and physical examination findings. Presence of headache, jaw claudication, diplopia, or prominent temporal arteries upon 331 palpation significantly increases the probability of diagnosis. The most useful finding in ruling out the temporal arteritis in a patient suspected of this condition is a normal ESR. 2. How common is temporal arteritis in patients seeking medical attention for headache? A patient presenting with headache is unlikely to have temporal arteritis in the absence of other signs or symptoms, with a positive LR of only 1.2. This only increases to 1.5 if the headache is localized to the temporal region.1 In a retrospective chart review of 736 patients older than 75 years, who sought medical treatment for their headaches at an outpatient neurology clinic, only 4 patients (0.6%) were found to have temporal arteritis. Tension headache was the most common diagnosis, and no patients had headaches related to a neoplasm or due to infectious etiology.3 Bottom line: Although tension headache is a more common diagnosis, temporal arteritis has significant enough morbidity to warrant its inclusion in the differential diagnosis of headache in older patients. 3. What other rheumatologic condition is commonly associated with temporal arteritis? Approximately 40%–60% of patients with temporal arteritis have symptoms of PMR, whereas approximately 15% of patients with PMR have temporal arteritis.4 4. How is temporal arteritis typically diagnosed? In accordance with the American College of Rheumatology, a patient is considered to have temporal arteritis if at least 3 of the following 5 criteria are met.5 1. Age of onset ≥ 50 years 2. New onset of localized headache 3. Temporal artery tenderness or decreased temporal artery pulse 4. ESR > 50 mm/h 5. Abnormal artery biopsy (vasculitis with predominantly mononuclear or granulomatous inflammation, usually with multinuclear giant cells) The aforementioned criteria set forth by the American College of Rheumatology diagnose temporal arteritis with 93.5% sensitivity and 91.2% specificity if 3 or more criteria are met. These criteria definitively characterize a patient as having temporal arteritis and patients meeting them should thus be treated. However, if the clinical index of suspicion is high, a patient should be treated for presumptive temporal arteritis, even if bilateral temporal artery biopsies are negative due to the possibility of blindness if treatment is delayed.5 Bottom line: The criteria proposed by the American College of Rheumatology diagnose temporal arteritis with relatively high sensitivity and specificity. However, due to the significant morbidity, a patient suspected of having temporal arteritis should be treated irrespective of biopsy results or fulfillment of other criteria. 5. Is it always necessary to obtain a temporal artery biopsy in patients suspected of having temporal arteritis? Because the sensitivity of a temporal artery biopsy in establishing the diagnosis of temporal arteritis is approximately 87% and the lack of timely treatment may result in significant morbidity, many clinicians feel that a biopsy may be forgone if the clinical index of suspicion is high. In addition, because a temporal artery biopsy will only establish the diagnosis 87% of the time, a patient may be treated for temporal arteritis even after a negative biopsy if clinical suspicion remains high.6 However, due to the significant morbidity of a prolonged course of corticosteroid therapy itself, most clinicians opt to confirm a suspected diagnosis of temporal arteritis by temporal artery biopsy to continue treatment.1 Bottom line: A temporal artery biopsy may not be necessary to initiate corticosteroid therapy if the clinical index of suspicion is high. However, most clinicians obtain a temporal artery biopsy to confirm the suspected diagnosis and warrant a prolonged course of corticosteroid therapy. 6. Does obtaining a temporal artery biopsy influence the management of temporal arteritis? In a 2006 retrospective audit of 44 patients who underwent temporal artery biopsy, 83.8% of patients had no change in their clinical management, despite receiving a negative temporal artery biopsy result. Of these patients, 58% continued to receive glucocorticoid therapy for more than 6 months despite the negative biopsy result, while the decision to cease glucocorticoid therapy was made before receiving the biopsy result in the remaining 42%.7 Bottom line: Receiving a negative temporal artery biopsy result only influences clinical management of patients suspected of having temporal arteritis approximately 16% of the time. 7. Does previous glucocorticoid therapy affect the results of a temporal artery biopsy in patients suspected of having temporal arteritis? Due to the potential for serious complications including permanent visual loss if left untreated, patients suspected of having temporal arteritis should be emergently treated with glucocorticoids. The initiation of treatment often precedes the temporal artery biopsy in these patients. A study conducted by Achkar et al. looked at the effect of previous glucocorticoid therapy on temporal artery biopsy findings in patients suspected of having temporal arteritis. The study found that the positivity rates of temporal artery biopsy were similar in both the control group (31% positive) and the glucocorticoid-treated group (35% positive), as the difference in percentages was not statistically significant (P = .4).8 However, even though histologic evidence of arteritis was still detectable in the biopsy specimens after 14 days of corticosteroid treatment, the authors found that prolonged corticosteroid therapy modified the histologic appearance of the specimen. This finding along with the possibility that a biopsy-negative patient may have received corticosteroids before initiation of this study suggest that the biopsy specimen should be obtained before or as soon after initiation of treatment as possible.8 Bottom line: Although glucocorticoid therapy may not impact temporal artery biopsy positivity, it has been found to impact histologic findings. Therefore, temporal artery biopsy should be performed as soon as possible, but initiation of glucocorticoid therapy should not be delayed in order to do so. 8. What do the data suggest should be the role of imaging in diagnosing temporal arteritis? Several small-scale studies have tested different imaging modalities in both diagnosing temporal arteritis as well as monitoring the response to therapy in patients with the disease. A study was conducted to establish the utility of high-resolution magnetic resonance imaging (MRI), in comparison to a reference standard for diagnosing temporal arteritis. It revealed that high resolution MRI had a sensitivity of 81% (95% CI 67–95), a specificity of 97% (95% CI 91–100), a positive LR of 26.6 (95% CI 3.8–184.8), and a negative LR of 0.20 (95% CI 0.10–0.41). The authors concluded that a positive MRI with an appropriate clinical picture and laboratory data consistent with temporal arteritis may be useful in diagnosis. However, the low sensitivity of the test would prevent a negative MRI from ruling out the diagnosis of temporal arteritis.9 In another study aimed at documenting evidence of arterial inflammation in patients with PMR, 13 patients with untreated PMR (but no known TA) and 6 controls with unrelated inflammatory diseases underwent PET scanning. Twelve of 13 PMR patients showed accumulation of marker in the aorta and its branches, whereas none of the controls did. In addition, 8 of the PMR patients who underwent treatment for their symptoms revealed decreased marker uptake on repeat PET scan that correlated with symptom remission and improved laboratory measures of inflammation, indicating that the quantity of 18- fluorodeoxyglucose accumulation in the vessels may be a measure of arterial inflammation and disease activity.10 Bottom line: Although high-resolution MRI and other imaging techniques have shown some promise in diagnosing and monitoring temporal arteritis in small- scale studies, they currently do not play a role in diagnosing or monitoring the disease. In addition, high-resolution MRI does not have a high enough sensitivity to replace temporal artery biopsy as the gold standard for diagnosing temporal arteritis. 9. What risk factors for blindness have been identified in patients with temporal arteritis? In a study of 174 patients with temporal arteritis prospectively monitored for the development of blindness, thrombocytosis and a history of transient visual ischemic symptoms were the risk factors most associated with the development of permanent visual loss (odds ratio 3.7 and 6.3, respectively).11 These findings were supported by a 1991 study that looked at medical records of 56 patients diagnosed with temporal arteritis and found that patients with visual loss, transient ischemic attack, or cerebrovascular accident had a significantly higher prevalence of thrombocytosis (P < .01) and a higher median platelet count (P < .001) than those without.12 Bottom line: The presence of thrombocytosis or a history of transient visual ischemic symptoms are the risk factors most associated with the development of permanent visual loss in patients with temporal arteritis. 10. How should a patient with temporal arteritis be managed? Patients suspected of having temporal arteritis should be treated immediately with high-dose corticosteroids, even in the absence of temporal artery biopsy. An initial dose of prednisone 40–60 mg should be given promptly. The initial dose is usually continued for 2–4 weeks and is subsequently reduced by a maximum of 10% of the total daily dose each week. Care should be taken not to taper the dose of corticosteroids too quickly as a relapse of symptoms may occur. For patients with recent or impending visual loss due to temporal arteritis, intravenous pulsed doses of methylprednisolone 1000 mg every day for 3 days should be given. High-dose steroids (60 mg prednisone/day) should be initiated immediately. Because thrombocytosis is a suggested risk factor for development of permanent visual loss in patients with temporal arteritis, patients suspected of having temporal arteritis who are found to have an elevated platelet count should be treated with glucocorticoids immediately, and antiplatelet therapy should also be considered.11 Bottom line: Glucocorticoid therapy should be initiated as soon as possible. TAKE-HOME POINTS: TEMPORAl ARTERITIS 1. Temporal arteritis is associated with significant morbidity and should be included in the differential diagnosis of any older patient presenting with persistent headache. 2. A normal ESR argues strongly against a diagnosis of temporal arteritis, although approximately 5% of patients with temporal arteritis will have a normal ESR. 3. Temporal artery biopsy is the current gold standard method for diagnosing temporal arteritis, although MRI appears to have an excellent diagnostic utility. 4. Patients in whom a diagnosis of temporal arteritis is highly suspected should be treated with glucocorticoid therapy as soon as possible regardless of biopsy results. 5. Glucocorticoid therapy may impact histologic findings on temporal artery biopsy. Biopsy should therefore be performed as soon as possible. 6. Risk factors mostly associated with blindness in patients with temporal arteritis include thrombocytosis and history of transient visual ischemic symptoms. REFERENCES 1. Smetana, G. W., and R. H. Shmerling. 2002. “Does This Patient Have Temporal Arteritis?” The Journal of the American Medical Association 287 (1): 92–101. 2. Wise, C. M., C. A. Agudelo, W. L. Chmelewski, and K. M. McKnight. 1991. “Temporal Arteritis With Low Erythrocyte Sedimentation Rate: A Review of Five Cases.” Arthritis and Rheumatism 34 (12): 1571–74. 3. Perez-Martinez, D., A. Puente-Munoz, and B. Anciones. 2008. “Headache Among Oldest Old (+75 years): Findings From 736 Consecutive Subjects in Outpatient Neurological Clinic.” Neurologia 23 (7): 436–40. 4. Cantini, F., L. Niccoli, L. Storri, C. Nannini, I. Olivieri, A. Padula, L. Bolardi, and C. Salvarani. 2004. “Are Polymyalgia Rheumatica and Giant Cell Arteritis the Same Disease?” Seminars in Arthritis and Rheumatism 33 (5): 294–301. 5. Hunder, G. G., B. A. Bloch, B. A. Michel, M. B. Stevens, W. P. Arend, L. H. Calabrese, S. M. Edworthy, et al. 1990. “The American College of Rheumatology 1990 Criteria for the Classification of Giant Cell Arteritis.” Arthritis and Rheumatism 33: 1122–28. 6. Niederkohr, R. D., and L. A. Levin. 2005. “Management of the Patient With Suspected Temporal Arteritis: A Decision-Analytic Approach.” Ophthalmology 112 (5): 744–56. 7. Lenton, J., R. Donnelly, and J. R. Nash. 2006. “Does Temporal Artery Biopsy Influence the Management of Temporal Arteritis?” The Quarterly Journal of Medicine 99 (1): 33–36. 8. Achkar, A., J. T. Lie, G. Hunder, W. O’Fallon, and S. Gabriel. “How Does Previous Corticosteroid Treatment Affect the Biopsy Findings in Giant Cell (Temporal) Arteritis?” Annals of Internal Medicine 120: 987–92. 9. Khoury, J. A., J. M. Hoxworth, M. Maziumzadeh, K. E. Wellik, D. M. Wingerchuk, and B. M. Demaerschalk. 2008. “The Clinical Utility of High Resolution Magnetic Resonance Imaging in the Diagnosis of Giant Cell Arteritis: A Critically Appraised Topic.” Neurologist 14 (5): 330–35. 10. Moosig, F., N. Czech, C. Mehl, E. Henze, R. A. Zeuner, M. Kneba, and J. O. Schröder. 2004. “Correlation Between 18-Fluorodeoxyglucose Accumulation in Large Vessels and Serological Markers of Inflammation in Polymyalgia Rheumatica: A Quantitative PET Study.” Annals of the Rheumatic Diseases 63: 870–73. 11. Liozon, E., F. Herrmann, K. Ly, P. Y. Robert, V. Loustaud, P. Soria, and E. Vidal. “Risk Factors for Visual Loss in Giant Cell (Temporal) Arteritis: A Prospective Study of 174 Patients.” American Journal of Medicine 111 (3): 211– 17. 12. De Keyser, J., N. De Klippel, and G. Ebinger. 1991. “Thrombocytosis and Ischaemic Complications in Giant Cell Arteritis.” British Medical Journal 303: 825. Venous c ha P ter Thromboembolism 27 Patrick koo, MD CASE A 45-year-old Caucasian male smoker with a history of uncontrolled hypertension presented for evaluation of sudden onset shortness of breath. Further history is significant for 3 days of right calf pain and intermittent left leg pain. He tried to use his remaining amoxicillin from a previous upper respiratory tract infection but his dyspnea has continued to worsen. He has had no history or

family history of clotting or bleeding disorders. He denies any recent long travel, long periods of immobility, fever, chills, chest pain, or abdominal pain. He denies intravenous drug use. Workup in the emergency department (ED) is significant for tachycardia (HR, 115), tachypnea (RR, 24), and an oxygen saturation of 82% on a 100% nonrebreather. The remainder of the physical examination is normal except for cool feet bilaterally. Pedal pulses are present bilaterally. 1. How do clinicians risk stratify patients for possible pulmonary embolism (PE)? Clinicians are not advised to go straight to imaging, as this will incur unnecessary cost and will expose the patient to radiation. There are simple diagnostic algorithms based on pretest probability that can be used before engaging in any additional testing.1 Calculating the Wells score and Geneva score are two commonly used methods for estimating the pretest probability of PE. Table 27.1 can be used to calculate (sum) the pretest probability: The Geneva score is also used to calculate the pretest probability, as shown in the chart below (Table 27.2): Given these two modalities to determine pretest probability, which is the better one? Each has its strengths and weaknesses. The Wells score relies more on the clinician’s judgment to determine whether another 341 TAblE 27.1 Wells’ Criteria Criterion Points value Clinical symptoms of DVT (leg swelling, pain with 3.0 palpation) Pulmonary embolism most likely diagnosis 3.0 Heart rate >100 1.5 Immobilization (3 d) or surgery in the previous 4 wk 1.5 Previous DVT/PE 1.5 Hemoptysis 1.0 Malignancy 1.0 TOTAL Pulmonary embolism likely = scan with CT >4.0 Pulmonary embolism unlikely = DO NOT scan ≤4.0 and check d-dimer (if < 500 pulmonary embolism is excluded. Scan if ≥ 500.41 Abbreviations: CT, computed tomography; DVT, deep-vein thrombosis; PE, pulmonary embolism. TAblE 27.2 Calculation of Geneva Score Criterion Points value Age 60–79 y 1.0 ≥80 y 2.0 Previous DVT or PE 2.0 Recent surgery (<4 wk ago) 3.0 Heart rate >100 bpm 1.0 PaCO2 <35 mm Hg2.0 35–39 mm Hg 1.0 PaO2 <49 mm Hg4.0 49–59 3.0 60–71 2.0 72–82 1.0 Chest x-ray Band atelectasis 1.0 Elevation of hemidiaphragm 1.0 TOTAL Low probability <5.0 Moderate probability 5.0–8.0 High probability >8.0 Abbreviations: DVT, deep-vein thrombosis; PE, pulmonary embolism. diagnosis is more likely. The Geneva score is less complex and is standardized. The Geneva score is based on arterial blood gas analysis and chest x-ray findings. However, the Wells score may be preferred more in the inpatient setting than in the ED because the Geneva score was derived from a study involving ED patients.3,4 The use of either scoring method was not affected by the experience of the assessing clinician.5,6 Bottom line: Wells and Geneva scores can be used to calculate the pretest probability to guide clinical management. If pretest probability is high, acquire a CT angiogram or ventilation-perfusion scan (renal failure). 2. Is the d-dimer a good diagnostic screening test in the workup for DVT and PE? d -Dimer has a high sensitivity but poor specificity (~25%) in the diagnosis of deep vein thrombosis (DVT). In other words, about 75% of the time an elevated d-dimer does not correlate with a patient having a positive finding of a DVT or PE. This is because many other conditions can give rise to an elevated d-dimer. However, because of its high sensitivity, a low d-dimer level has a good negative predictive value. Therefore, if the d-dimer is low in a patient with a low pretest probability of DVT or PE, a thrombotic event can be largely excluded. Thus, if your clinical suspicion (pretest probability) is low, getting a d-dimer may be helpful.2,7,8,9,10 There are a few different d-dimer tests available in the market today: automated and rapid microlatex d-dimer assay, ELISA assay, automated quantitative latex- based immunoassay, semiquantitative latex agglutination assays, etc. ELISA assay is the prototype, but it is not optimal in the emergency setting because the kits are designed for batch assays and the results take several hours to obtain. Semi-quantitative latex assays are more rapid, but their sensitivity is too low. Recently, rapid microparticle assays have been developed to have quick turnaround time and high sensitivity and negative predictive value. For example, a current second-generation microparticle latex immunoassay has a sensitivity of 96%, and a negative predictive value of 98%, and a turnaround time of less than 30 minutes.11 Bottom line: Because the d-dimer only has a good negative predictive value, it should only be used when clinical suspicion of DVT or PE is low but it is still necessary to rule out these conditions. 3. Does the evidence suggest an arterial blood gas (AbG) is diagnostically helpful? No. ABG results alone or in combination with other clinical variables such as arterial-alveolar gradient, PaO2, PaCO2, and tachypnea are of little diagnostic value. A normal arterial-alveolar gradient does not rule out PE. ABG data and other clinical variables mentioned earlier do not have sufficient negative predictive value, specificity, or likelihood ratios to be useful in management of patients with suspected PE.12 However, the fact that the ABG data are incorporated in the Geneva score to help calculate the pretest probability implies that the ABG may have some, albeit minimal, diagnostic utility. Bottom line: Arterial blood gas results should not be used to diagnose PE. 4. What systemic diseases need to be considered as a cause of DVT/PE? Systemic diseases may result in DVT or PE in a small percentage of affected patients and should thus be considered in suspected patients with recurrent, unprovoked events. These diseases include the categories of collagen vascular diseases, venous anomalies, and primary hypercoagulable states. More specifically, the following can be considered to cause the development of a DVT/PE: antithrombin III deficiency, protein C and S deficiencies, Factor V Leiden mutation, prothrombin 20210A mutation, increased factor VIII, hyperhomocysteinemia, antiphospholipid antibodies, inflammatory bowel disease, obesity, sepsis, myocardial infarction, congestive heart failure, and varicose veins.13,14 Bottom line: The above-mentioned diseases and hypercoagulable states can result in venous thromboembolic events (VTEs). They should be considered if the patient has a recurrent, unprovoked event. 5. What are the criteria for admission to floor versus unit in patients with PE? A patient with DVT or PE can be managed on a regular medical floor with one exception: pulmonary embolus with hemodynamic instability. According to the critical care admission guidelines, hemodynamic instability is defined as pulse <40 or >150 bpm, systolic arterial pressure <80 mm Hg or 20 mm Hg below the patient’s usual pressure, mean arterial pressure <60 mm Hg, diastolic arterial pressure >120 mm Hg, and respiratory rate >35 breaths/min.15 Bottom line: If the patient is hemodynamically unstable, admit to the intensive care unit. 6. What is the value of checking troponin and brain natriuretic (bNP) in patients with PE? Some studies have shown that troponin I levels in the setting of acute pulmonary embolism play an important role for risk assessment. Elevated troponin I levels are associated with higher risk for in-hospital mortality and complicated clinical course.16,17 A high mortality rate was also seen in hemodynamically stable patients with elevated troponin levels.18 Troponin T has also been shown recently to independently predict in-hospital and 1-year mortality in patients with acute PE. Elevated levels equate to a 4-fold higher risk of in-hospital and 3-fold higher risk of 1-year mortality.19 A high BNP level in patients with acute PE is associated with a higher risk of complicated in-hospital course and death. Even though a high BNP level is associated with a higher risk of an adverse outcome, the high negative predictive value of a normal BNP level is more useful to select patients who will not have a significant adverse event.20,21 Both BNP and NT-proBNP (N-terminal proBNP) are associated with right ventricular dysfunction in the setting of acute PE, and they are good for predicting all-cause in-hospital or short-term mortality. Recently, a study showed preliminarily that NT-proBNP levels higher than 500 ng/L could be used to show the burden of PE and to be a predictor of death.22,23 Most interestingly, both elevated brain natriuretic peptides and troponins may eventually be used for risk stratification of acute PE. A recent meta-analysis again reiterated that increased troponins and BNP is associated with increased risk of adverse outcomes.24 Bottom line: There are no guidelines in the use of troponin or BNP for PE management. One can use these tests for determining severity, but they will not alter VTE management. 7. Should one check a 2D echocardiogram in a hemodynamically stable patient with PE to look for a dilated right ventricle? Use of routine echocardiography is not recommended for diagnosis of PE. However, it is useful in identifying patients with poor prognosis after having a pulmonary embolic event. It can be used as a risk assessment tool. Appropriate therapeutic strategies can be used for those who are at high risk. High-risk patients are defined as those who have right ventricular hypokinesis, persistent pulmonary hypertension, a patent foramen ovale, or a free floating right heart thrombus. These patients may benefit from thrombolysis or embolectomy. In addition, the benefits of echocardiography include portability and low cost.25,26 Bottom line: While performing an echocardiogram in a hemodynamically stable patient with PE is of little diagnostic value, it can provide important prognostic information. 8. Should hypercoagulable investigations be done at the time of presentation or in an outpatient setting? There is no conclusive agreement on this question. In patients with their first thrombotic episode, it is worthwhile to argue that identification of any mutations for a thrombophilic state will not change the initial management with anticoagulation. Moreover, testing for these mutations in the acute setting can lead to a misdiagnosis, as a falsepositive result may be believed to be a true positive. One thing to keep in mind is that these mutations are rare. Thrombophilic testing is beneficial, however, in appropriate patients like in those with a family history of thrombophilia or recurrent of thromboembolism. This can be done in an outpatient setting to help improve understanding of the disease, guide long-term management, and identify other relatives with the same condition. As a guide to selecting the appropriate patient for further evaluation, the patient should be classified to be “weakly” or “strongly” thrombophilic on the basis of history. The term “strongly” thrombophilic implies that the patient had his/her first venous thromboembolic event before 50 years of age, has a history of recurrent thrombotic episodes, or has first-degree family members with venous thromboembolic events that occurred before 50 years of age.27 Bottom line: Hypercoagulable investigations should be done in an outpatient setting only in those with unexplained recurrent thromboembolic events or with a strong family history. 9. In patients with a large PE, does the addition of a thrombolytic to heparin improve outcome? What about using thrombolytics in massive lower extremity DVTs? In hemodynamically stable patients with a submassive PE, addition of a thrombolytic to heparin therapy improves the clinical course and can prevent clinical deterioration requiring the escalation of treatment during the hospital stay.28 Thrombolytic therapy for lower extremity DVT has shown better short- and long-term clinical outcomes compared with heparin therapy but at the expense of bleeding risk. It offers advantages in reducing post-thrombotic syndrome and maintaining venous patency after a DVT event.29,30 There have been rapid advances in technology and techniques to aid in removal of thrombus endovascularly at the specific site. This will reduce the bleeding risk substantially. Published expert consensus now urges clinicians to strongly consider using thrombolysis for patients with extensive acute proximal DVT.31 Bottom line: Thrombolytics used with anticoagulation improves outcomes in patients with large PE and in those with extensive proximal DVT. 10. What are the indications for placing inferior vena cava (IVC) filters? Have they been shown to prevent fatal PE or recurrent DVT? The indications for placing IVC filters are for the prevention of PE in patients when anticoagulant therapy is contraindicated, such as a recent history of a gastrointestinal bleed, when complications arise while being on anticoagulation, and when there is a recurrent PE episode despite therapeutic anticoagulation.32 One randomized controlled trial called the PREPIC (Prévention du Risque d’Embolie Pulmonaire par Interruption Cave) trial investigated whether permanent IVC filters prevent pulmonary embolism. Permanent filters prevented PE 8 years after placement, but no reduction in mortality risk was seen. There was also an increased incidence of DVT in those with the filter. In addition, the study was underpowered to detect PE episodes over a shorter time course. In general, there is a lack of retrievable filter trials.33 Bottom line: Inferior vena cava filters can be used for PE prevention if the patient failed anticoagulation therapy or if there is an acute bleeding episode. However, filters increase the incidence of DVT and have not been shown to reduce mortality. 11. If there is an underlying malignancy, is there superiority of one anticoagulation agent over another? Low-molecular-weight heparin (LMWH) such as enoxaparin (Lovenox) has been shown to be more favorable and superior in profile than unfractionated heparin (UFH) in several meta-analyses. LMWH demonstrated a 29% reduction in mortality compared with UFH in a most recent review.34,35 In addition, use of LMWH is associated with improved safety in cancer patients. Bottom line: LMWH is the anticoagulant of choice in patients with underlying malignancy. 12. What has the most predictive value in predicting risk of future clots—clinical story (e.g., presence of provoking factors) or results of hypercoagulable workup? Predictors that are helpful in foreseeing future recurrence of venous thromboembolism are as follows: the gender and age of the patient, the initial presentation (proximal or distal deep vein thrombosis or pulmonary embolism), and the associated conditions (thrombophilia, cancer, surgery, and others). In addition, at the time of anticoagulant treatment discontinuation, d-dimer levels and residual thrombus burden have been indicated as predictors of recurrent VTE.36,37 The predictive value for recurrent VTE events from the results of a hypercoagulable workup is variable. Some acquired and inherited hypercoagulable states such as homozygous Factor V Leiden, antiphospholipid syndrome, and antithrombin III deficiency carry a high recurrence rate. Therefore, they require lifelong anticoagulation therapy. 42 Bottom line: Clinical history including the description of the patient, features of the initial event, and associated conditions is the best predictor of risk for future VTE events. 13. How beneficial are graduated compression stockings for secondary prophylaxis of DVT? Graduated compression stocking and other mechanical methods of prophylaxis do not have bleeding potential, but they are less effective than anticoagulant- based options. They have been shown to reduce the risk of DVT in different patients. However, they are also less studied compared to the anticoagulants. No mechanical thromboprophylaxis option has been studied in a large enough sample to determine if there is a reduction in the risk of death or PE. The use of mechanical prophylaxis alone is only recommended in high-risk bleeding patients.38 Bottom line: Graduated compression stockings are less effective than prophylactic-dosed anticoagulation, and therefore, they are not recommended as the first-line option for the prevention of DVT in hospitalized patients. 14. How do clinicians determine when and how long to anticoagulate a patient with a DVT or PE? The initial treatment of a diagnosed or a high-clinical-suspicion (while awaiting imaging results) VTE includes subcutaneous low-molecularweight heparin (LMWH), intravenous unfractionated heparin (UFH), fixed-dose subcutaneous unfractionated heparin, or subcutaneous fondaparinux. After you have selected your anticoagulation of choice, complete the following below:39 1. Start a vitamin K antagonist (e.g., warfarin) at the same time with the anticoagulant. 2. Treat with the anticoagulant for 5 days and until the INR is ≥2.0 for 24 hours.40 3. Start early ambulation.41 4. Duration of long-term anticoagulation (Table 27.3) TAblE 27.3 Duration of Long-Term Anticoagulation Etiology Transient reversible risk factor VTE Unprovoked (idiopathic) VTE Second episode of unprovoked VTE Unprovoked distal DVT VTE and cancer Incidental asymptomatic VTE Duration 3 months 3 months, then evaluate after for riskbenefit ratio of long-term therapy Long-term 3 months only LMWH for 3–6 mo followed by indefinite Coumadin or LMWH or until cancer resolution 3 months, then evaluate after for risk benefit ratio of long-term therapy Abbreviations: DVT, deep-vein thrombosis; LMWH, low-molecular-weight heparin; VTE, venous thromboembolism. Bottom line: The length of anticoagulation is largely determined by whether the event was provoked or not. 15. Can a patient with a nonmassive PE can be managed at home or receive a short hospital stay (observation) and can be discharged home the following day? Yes, hemodynamically stable patients with nonmassive PE can be managed in an outpatient setting. Home treatment has been a standard management plan for DVT, but for PE, patients are traditionally admitted to the hospital to initiate bridging therapy with heparin and warfarin. These patients typically remain in the hospital for several days until the INR achieves therapeutic range. However, recent studies show that home treatment or early discharge from an observational unit is possible for the management of PE.43 Aujesky et al. developed a clinical prediction rule called PE severity index (PESI) to risk stratify patients to mortality and adverse outcomes.44 This model achieved better results than the Geneva score and is now recommended for risk stratification of patients for outpatient or observational unit management.45,46 However, more clinical trials are needed to verify the accuracy of the clinical prediction score.47 Outpatient or observational unit management is only practical if the monitoring of INR in the outpatient setting is intensified and if there is a method in place to prevent premature discontinuation of transitioning therapy.48 Bottom line: PE can be managed at home or in an observational unit with early discharge if the INR can be closely monitored, and premature discontinuation of bridging therapy can be prevented. 16. Is investigation of pulmonary embolism warranted in a patient presenting with chronic obstructive pulmonary disease (COPD) exacerbation? Yes, especially if a patient presents with an unexplained severe COPD exacerbation. In recent studies and meta-analysis, approximately 25% of patients hospitalized for severe COPD exacerbations of unclear etiology had a PE. Pretest probability using the Wells criteria or Geneva score needs to be determined for these patients.49,50 Bottom line: A diagnosis of PE should be considered in patients with unexplained COPD exacerbation severe enough to be hospitalized, especially in those who have an intermediate-to-high pretest probability of PE. TAKE HOME POINTS: PUlMONARY EMbOlISM 1. Use the Wells criteria to determine pretest probability. 2. Do not obtain a d-dimer level if your suspicion for a venous thromboembolic event is moderate to high as a low d-dimer will not sufficiently lower your posttest probability to alter the diagnostic workup. 3. If the patient is hemodynamically unstable, admit to the intensive care unit. 4. Consider obtaining a 2D echocardiogram for prognostic purposes (e.g., right heart function and pulmonary hypertension) but realize that this information is quite unlikely to change clinical management. 5. Perform a hypercoagulable evaluation as an outpatient if warranted; this should be done several weeks after warfarin has been discontinued. 6. Graduated compression stockings are not sufficient to provide prophylaxis against development of a DVT. 7. Inferior vena cava filters increase the incidence of DVT and have not been shown to reduce mortality. 8. LMWH (e.g., enoxaparin) is the treatment of choice in the setting of malignancy. 9. Determine if the event is provoked or not and treat accordingly. 10. 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Dec 2010. “Treatment of Low-Risk Pulmonary Embolism Patients in a Chest Pain Unit.” Critical Pathways in Cardiology 9 (4): 212–15. 47. Otero, R., et al. Jul 2010. “Home Treatment in Pulmonary Embolism.” Thrombosis Research 126 (1): e1–5. 48. van Bladel, E. R., et al. 2010. “Out of Hospital Anticoagulant Therapy in Patients with Acute Pulmonary Embolism is Frequently Practised but Not Perfect.” Thrombosis Research 126 (6): 481–85. 49.Tillie-Leblond, I., et al. 2006. “Pulmonary Embolism in Patients with Unexplained Exacerbation of Chronic Obstructive Pulmonary Disease: Prevalence and Risk Factors.” Annals of Internal Medicine 144 (6): 390–96. 50. Rizkallah, J., et al. 2009. “Prevalence of Pulmonary Embolism in Acute Exacerbations of COPD: A Systematic Review and Metaanalysis.” Chest 135 (3): 786–93.

Chapte R Syncope 28 Faith J. Ross, MD CASE A 56-year-old man with a history of hypertension presents to the emergency department (ED) for evaluation of an episode of syncope. The episode occurred while standing outside at work smoking a cigarette and was preceded by lightheadedness and palpitations. According to coworkers, he was unconscious for a “couple of minutes,” and they observed no abnormal jerking movements. He was not incontinent of urine. He has no known history of cardiac disease but does not see a doctor regularly. Blood pressure (BP) in the ED is 146/92 mm Hg, and orthostatic vitals are normal. Pulse is approximately 150 bpm. Electrocardiogram (ECG) reveals a supraventricular tachycardia. 1. What are some common causes of syncope? According to a large prospective study evaluating the diagnostic approach to syncope,1 some of the commonly identified causes of syncope are given in Table 28.1. TAblE 28.1 Causes of Syncope Cause Frequency (%) Vasovagal 41 Situational (cough, micturition, 15 defecation, and swallow) Arrhythmia 11 Orthostatic hypotension 10 Nonsyncopal episode 6 Structural cardiac or 5 cardiopulmonary disease Vertebrobasilar TIA 1 Idiopathic 11 Abbreviations: TIA, transient ischemic attack. 355 These numbers agree closely with earlier studies, except that in older studies, a greater number of cases (greater than 30% in some studies) went without definitive diagnosis.2 Clinical evaluation is crucial in determining the cause of syncope. History and physical examination alone identify a likely cause of syncope in 45% of cases in which a diagnosis is eventually assigned.2 Bottom line: The most common cause of syncope is a vasovagal response. 2. What factors allow physicians to risk-stratify patients with syncope? Which patients with syncope should be admitted? A prospective cohort study of 684 patients showed that although physician’s judgment was useful in identifying patients at high risk of serious outcome within 7 days, physicians tend to over-admit patients with syncope.3 The study identified 5 variables associated with increased risk of serious outcome within 7 days of initial presentation. These variables include systolic BP (SBP) less than 90 mm Hg at triage, shortness of breath, history of congestive heart failure (CHF), abnormal ECG—new changes or any abnormality if old baseline ECG was unavailable—and hematocrit less than 30. The San Francisco Syncope Rule (SFSR) uses these variables to determine which patients require admission.4 This initial derivation study of the SFSR indicated that the use of these variables has 96% sensitivity and 62% specificity for predicting serious 7-day outcomes.3 Serious outcomes addressed in the study included death, myocardial infarction, arrhythmia, pulmonary embolism, stroke, subarachnoid hemorrhage, significant hemorrhage, or any condition requiring return to the ED and hospitalization for an event thought to be related to atrial fibrillation. Use of the SFSR was estimated to decrease admission rate by 10% in the cohort studied without missing any serious outcomes.4 Application of this rule to patients designated as “low risk” (i.e., estimated by physicians to have <2% chance of 7-day serious outcome) had a 94% sensitivity and 52% specificity in predicting serious outcomes.4 These values were initially validated in multiple independent studies. More recent studies have failed to independently validate these findings in other populations. For example, 1 prospective study showed that 26% of serious outcomes in patients estimated to be low risk were not identified using the SFSR.5 However, the authors of the original study attribute this difference to incorrect application of the rule.6 Thus, the SFSR is likely a useful algorithm, but it may not be generalizable to all populations, and clinical judgment must still be used in determining which syncopal patients should be admitted. Other prognostic prediction rules exist but most deal with longterm outcomes, making them less useful in determining which patients should be admitted. The American College of Emergency Physicians Clinical Policies Subcommittee on Syncope recommends considering the following parameters when determining which syncopal patients should be admitted: • Older age and associated comorbidities • Abnormal ECG • Hematocrit less than 30 • History or presence of heart failure, coronary artery disease, or structural heart disease7 Other prediction rules exist, but deal more with long-term outcomes and are thus less useful in risk stratification at the initial point of care. 3. Do all syncopal patients require an ECG? Yes. Even though ECG identifies the cause of syncope in fewer than 5% of cases, it should be performed on all patients because it is easily available, noninvasive, inexpensive, and may detect life-threatening abnormalities such as Wolff–Parkinson–White syndrome in otherwise asymptomatic patients.7 Bottom line: An ECG should be performed on all patients with syncope. 4. Is echocardiogram indicated in the routine workup for syncope? Studies have shown that echocardiograms are clinically useful only in those patients for whom there is suspicion of cardiac disease based on history, examination, or ECG findings.8 One prospective study of patients presenting to the ED for evaluation of syncope (n = 67) showed that routine echocardiography failed to reveal any relevant abnormalities in a 1 of 67 patients without history of cardiac disease, suspected aortic stenosis, or ECG abnormality.9 Bottom line: Echocardiography is not recommended without some suspicion of cardiac abnormality by history, physical examination, or ECG. 5. Should head computed tomography be a routine part of the workup for syncope? No. Older studies suggest that computed tomography (CT) has a 4% diagnostic yield in syncopal patients, with almost all positive results occurring in patients with focal neurologic findings or history consistent with seizure.10 A more recent prospective study showed that 4% of patients who underwent neuroimaging for syncope had abnormal CT scans (2 subarachnoid hemorrhages, 2 cerebral hemorrhages, and 1 stroke). However, post hoc evaluation of these patients revealed that indications of neurologic disease (focal neurologic findings and new onset headache) or evidence of head trauma were present in all of the patients with abnormal CT scans. Furthermore, all of the patients with abnormal CT scans were older than 65 years.11 Retrospective chart reviews have come to similar conclusions. One set of investigators found that CT provided a diagnosis in only 2% of patients (who had a history suggestive of seizure or stroke).12 Another chart review found clinically significant findings on CT scans in only 1 of 44 patients.13 Bottom line: Indications for head CT in patients presenting with syncope include history or physical evidence of head trauma, neurologic signs or symptoms, use of warfarin, or age greater than 60 years.11 6. Is ambulatory ECG monitoring useful in providing a diagnosis in unexplained cases of syncope? In a review that examined 8 studies following patients undergoing ambulatory ECG external monitoring for at least 12 hours, correlation of symptoms with arrhythmia was found in only 4% of patients. However, in 15% of patients, symptoms occurred in the absence of arrhythmia, thus ruling out arrhythmia as a cause of syncope.14 A more recent prospective randomized comparison of Holter monitoring versus external loop recording obtained similar results.15 In patients with infrequent syncopal episodes, 24-hour Holter monitoring is less likely to be useful. In such cases, long-term implantable loop recording is more likely to be diagnostic. Analysis of pooled data from 4 studies with a total of 247 patients with syncope that remained unexplained after conventional investigation showed a correlation between arrhythmia and syncope in 34% of patients. Thus, implantable loop recording may be a useful investigational tool in patients with undiagnosed syncope, but its usefulness must be weighed against the risk of the implantation procedure and the high cost of the device.8 Bottom line: If symptoms occur in the absence of arrhythmias, ambulatory monitoring is more useful in excluding arrhythmias as the etiology. In contrast, implantable loop recording is more likely to be diagnostic, particularly in patients with infrequent recurrence of syncope. 7. How useful are routine laboratory studies in the diagnostic workup of syncope? Laboratory studies are rarely helpful in determining the cause of syncope. Laboratory abnormalities such as hyponatremia, hypoglycemia, hypocalcemia, or renal failure are identified in only 2%–3% of “syncopal” patients, but most of these patients suffer from seizures rather than true syncope. This is often suspected based on history. A complete blood count is unlikely to identify clinically significant bleeding in the absence of an appropriate history or positive fecal occult blood test.14 Low hematocrit has been found to be a useful indicator of risk of short-term serious outcome, and it is incorporated into various advisory groups’ recommendations for admission criteria.7 Bottom line: Routine use of laboratory tests is unlikely to reveal important diagnostic information. Laboratory tests are indicated to verify abnormalities that are suspected clinically. 8. Is neurovascular ultrasound helpful in diagnosing the cause of syncope? No. Very few studies addressing this issue exist most likely because anterior cerebral circulatory events are very unlikely to produce syncope. Although vertebrobasilar transient ischemic attack may cause syncope, it is an uncommon etiology and is generally accompanied by other distinguishing symptoms (e.g., diplopia and ataxia). A retrospective study of 140 patients showed that neurovascular imaging (transcranial Doppler and carotid ultrasonography) identified lesions that may have contributed to syncope in only 1.4% of the patients, and even in these patients, the lesions were not thought to be the primary cause of syncope. These patients also had focal neurologic symptoms as part of their syncopal episode or neurologic findings or bruits on physical examination.16 Bottom line: Although not thoroughly studied, neurovascular ultrasound likely has a very low diagnostic yield in determining the cause of syncope, and it should be considered only in patients with carotid bruits or focal neurologic signs or symptoms. TAKE-HOME POINTS: SYNCOPE 1. A vasovagal response is the most common cause (~60%) of syncope. 2. Use of the SFSR may help to identify patients at risk of serious short-term events, thereby allowing physicians to avoid unnecessary admission for low-risk patients without missing serious outcomes. However, because of recent concerns regarding the generalizability of this rule, clinical judgment should still be exercised in deciding which patients should be admitted. 3. According to the SFSR, syncopal patients with SBP less than 90 mm Hg at the time of triage, dyspnea, history of CHF, arrhythmia or new changes on ECG, or anemia with a hematocrit of less than 30% should be admitted. 4. According to the American College of Emergency Physicians, syncopal patients aged 65 years or older, those with an abnormal ECG, hematocrit of less than 30%, or history of heart disease should be admitted. 5. All syncopal patients should receive an ECG. 6. Echocardiography is clinically indicated only in those patients in whom cardiac disease is suspected based on history, examination, or ECG findings. 7. Head CT should be considered only in patients with a history of head trauma, neurologic signs or symptoms, use of warfarin, or age greater than 60 years. 8. Routine laboratory studies are typically not useful in the evaluation of syncope. 9. Ambulatory ECG monitoring is useful in ruling out arrhythmia as a cause of syncope in patients with undiagnosed syncope and frequent syncopal attacks. Implantable loop recording is more likely to be diagnostic but must be considered in the context of the risk of the implantation procedure and the cost of the device. 10. Neurovascular ultrasound has a low diagnostic yield and should only be considered in patients with carotid bruits or focal neurologic signs or symptoms. REFERENCES 1. Brignole, M., C. Menozzie, A. Bartoletti, et al. 2006. “A New Management of Syncope: Prospective Systematic Guideline-Based Evaluation of Patients Referred Urgently to General Hospitals.” European Heart Journal 27: 76–82. 2. Linzer, M., E. H. Yang, N. A. Estes III, P. Wang, V. R. Vorperian, and W. N. Kapoor. 1997. “Diagnosing Syncope. Part 1: Value of History, Physical Examination, and Electrocardiography. Clinical Efficacy Assessment Project of the American College of Physicians.” Annals of Internal Medicine 126 (12): 989–96. 3. Quinn, J. V., I. G. Steill, D. A. McDermott, M. A. Kohn, and G. A. Wells. 2005. “The San Francisco Syncope Rule vs Physician Judgment and Decision Making.” American Journal Emergency Medicine 23: 782–86. 4. Quinn, J. V., I. G. Steill, D. A. McDermott, M. A. Kohn, and G. A. Wells. 2004. “Derivation of the San Francisco Syncope Rule to Predict Patients With Short-Term Serious Outcomes.” Annals of Emergency Medicine 43: 5. Birnbaum, A., D. Esses, P. Bijur, A. Wollowitz, and E. J. Gallagher. 2008. “Failure to Validate the San Francisco Syncope Rule in an Independent Emergency Department Population.” Annals of Emergency Medicine 52: 151– 59. 6. McDermott, D., and J. Quinn. 2009. “Response to Failure to Validate the San Francisco Syncope Rule in an Independent Emergency Department Population.” Annals of Emergency Medicine 53: 693. 7. Huff, J. S., W. W. Decker, J. V. Quinn, et al. 2007. “Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Syncope.” Annals of Emergency Medicine 49: 431–44. 8. The Task Force on Syncope, European Society of Cardiology. 2004. “Guidelines on Management (Diagnosis and Treatment) of Syncope— Update 2004.” Europace 6: 467–537. 9. Sarasin, F. P., A. -F. Junod, D. Carballo, S. Slama, P. -F. Unger, and M. Louis-Simonet. 2002. “Role of Echocardiography in the Evaluation of Syncope: A Prospective Study.” Heart 88: 363–67. 10. Kapoor, W. N. 2000. “Syncope.” New England Journal of Medicine 343 (24): 1852–56. 11. Grossman, S. A., C. Fischer, J. L. Bar, et al. 2007. “The Yield of Head CT in Syncope: A Pilot Study.” Internal and Emergency Medicine 2: 46–49. 12. Pires, L. A., J. R. Ganji, R. Jarandila, and R. Steele. 2001. “Diagnostic Patterns and Temporal Trends in the Evaluation of Adult Patients Hospitalized With Syncope.” Archives of Internal Medicine 161: 1889–95. 13. Giglio, P., E. M. Bednarczyk, K. Wiess, and R. Bakshi. 2005. “Syncope and Head CT Scans in the Emergency Department.” Emergency Radiology 12: 44– 46. 14. Kapoor, W. N. 1922. “Evaluation and Management of the Patient With Syncope.” Journal of the American Medical Association 268: 2553–60. 15. Sivakumaran, S., A. D. Krahn, G. J. Klein, et al. 2003. “A Prospective Randomized Comparison of Loop Recorders Versus Holter Monitors in Patients With Syncope or Presyncope.” American Journal of Medicine 115: 1–5. 16. Schnipper, J. L., R. H. Ackerman, J. B. Krier, and M. Honour. 2005. “Diagnostic Yield and Utility of Neurovascular Ultrasonography in the Evaluation of Patients With Syncope.” Mayo Clinic Proceedings 80 (4):

Hypertensive Cha P t E r Emergency 29 ErEalda PrEndaj, Md CASE A 42-year-old man with a history of hypertension (HTN) presents to the emergency department (ED) for evaluation of a 2-week history of progressively worsening headache. He does not recall an abrupt onset of the headache. Three days prior to presentation, the patient started experiencing lightheadedness and nausea. Three hours before presentation, he began to experience sharp chest pain. Blood pressure (BP) on presentation is 232/146 mm Hg. The patient admits that he had not been taking his BP medication for the last year because he had lost his job and couldn’t afford it. Review of systems is negative for dyspnea, orthopnea, paroxysmal nocturnal dyspnea, prior headache, seizures, head trauma, or use of alcohol or illicit drugs. 1. What is the likely diagnosis? This patient presents with hypertensive urgency, which is defined as significantly elevated BP (>180/120 mm Hg) in the presence of symptoms such as severe headache or dyspnea, but without obvious end-organ damage.1,2 Note that while the patient’s BP is 232/146 mm Hg, there is no clear end-organ damage identified as of this time. Hypertensive urgency should not be confused with hypertensive emergency, which is severe BP elevation (>180/120 mm Hg) accompanied by objective evidence of end-organ damage.3 However, most end-organ damage is noted with systolic BPs exceeding 220 mm Hg. For quick reference, Table 29.1 lists the definitions of common terms related to the cases of severe HTN.4 Bottom line: The degree of BP elevation is not as important as the presence of symptoms or signs of end-organ dysfunction in determining whether a patient is presenting with hypertensive urgency or hypertensive emergency. 363 TAblE 29.1 Terms That Apply to Cases of Severe HTN Term Severe HTN Hypertensive urgency Hypertensive emergency Hypertensive crisis Malignant HTN (accelerated HTN) Definition BP > 180/120 mm Hg without symptoms (or with only mild headache) BP > 180/120 mm Hg with symptoms but no end-organ damage BP > 180/120 mm Hg with signs of end-organ damage Hypertensive urgency and/or hypertensive emergency Type of hypertensive emergency characterized by encephalopathy or nephropathy with accompanying papilledema Abbreviations: HTN, hypertension; BP, blood pressure. 2. What are the epidemiology and precipitating factors of hypertensive emergency? Of the more than 65 million Americans with HTN, 1 to 2% will have a hypertensive crisis over their lifetime.5 The incidence of hypertensive emergencies has been on the rise over the past four decades despite the increasing availability of effective antihypertensive treatments. As in the case with essential HTN, African Americans are affected more frequently than whites. In addition, men are affected two times more frequently than women,5,6 and the majority of cases occur in patients with preexisting HTN.7 Lack of BP control with adequate antihypertensive treatment is an important risk factor for hypertensive crisis. A case-control study by Shea et al.8 cited nonadherence to antihypertensive medications as a major precipitant of hypertensive emergencies. A retrospective study by Bender et al. reported similar findings regarding the lack of adequate antihypertensive treatment as a contributor to BP elevation.7 The most common reasons for inadequate treatment are summarized in Table 29.2.7 Bottom line: The demographics of hypertensive emergency closely mirror those of essential HTN. Medication nonadherence or simple lack of medication is a major precipitating factor of hypertensive emergency. 3. How may hypertensive emergency manifest clinically? The clinical presentation of hypertensive emergency is directly related to the particular organ that has been compromised. Manifestation may include acute heart failure, acute myocardial infarction, aortic dissection, TAblE 29.2 Reasons for Inadequate Antihypertensive Treatment in Patients With Hypertensive Urgency Reason for inadequate antihypertensive treatment Patients affected (%) Ran out of medication 16 Nonadherence to medication 12 Never initiated treatment 30 eclampsia, hypertensive encephalopathy, and stroke.2,9 Severe headache, dizziness, visual changes, or altered mental status may be a sign of neurological compromise. Signs of cardiovascular involvement include dyspnea, chest pain, signs of congestive heart failure, or a prominent apical pulse. Acute onset of oliguria or anuria may be a sign of renal involvement.9 A detailed study by Zampaglione et al.10 showed the presentation of hypertensive crisis in 449 patients over a 12-month period in 1 ED in Turin, Italy. The most frequent symptoms on presentation were chest pain (27%), dyspnea (22%), and neurological deficit (21%). Another detailed retrospective study by Martin et al. reviewed the records of 452 patients with hypertensive crisis in a university-affiliated hospital in Brazil, reported that of 179 patients presenting with hypertensive emergency, 48.3% presented with neurological deficits, 24.7% with dyspnea, 19.8% with headache, 17.6% with chest pain, and so forth.11 Bottom line: The clinical manifestation of hypertensive emergency depends on the end-organ dysfunction, which changes in prevalence based on the population studied. 4. How can one distinguish hypertensive emergency from hypertensive urgency? As mentioned above, patients in hypertensive crisis usually present with 1 or several symptoms, but the presence or absence of end-organ damage will determine whether the patient is in hypertensive urgency or hypertensive emergency. More than 75% of patients in hypertensive crisis will have hypertensive urgency.10 To distinguish between the two, a thorough history, physical examination, and pertinent laboratory tests are necessary.12 Zampiglione et al. reported that the most common signs and symptoms for hypertensive urgency are headache (22%), epistaxis (17%), lightheadedness (10%), chest pain (9%), dyspnea (9%), and so forth.10 In the study by Bender et al., the charts of 50 patients who presented to the ED with hypertensive urgency were reviewed and found that the most common presenting symptoms of this condition were headache (42%), dizziness (30%, the authors did not distinguish between lightheadedness and vertigo), visual changes (14%), and chest pain (14%).7 Compare the signs and symptoms of hypertensive urgency to those quoted above for hypertensive emergency and it is clear why one cannot rely only on presenting signs and symptoms. Bottom line: History, physical examination, and laboratory tests are required to distinguish between hypertensive urgency and hypertensive emergency. 5. Does the evidence suggest that this patient be admitted? Patients who show signs of end-organ damage should be admitted to the hospital, preferably to the intensive care unit (ICU), and treated with intravenous medications.1,2,13 In the case of hypertensive urgency, the decision to treat as an inpatient or outpatient is based on the patient’s presentation and likely adherence to medications. Oral medication is the treatment of choice, but if medication nonadherence was the precipitating factor for the hypertensive urgency, hospital admission should be considered. On the other hand, severe HTN is best treated on an outpatient basis with oral agents and close followup with the primary care physician or provider.13,14 The patient in the vignette most likely has hypertensive urgency, but acute myocardial infarction or other kinds of hypertensive emergency need to be ruled out before he can be safely discharged from the ED. In addition, as medication nonadherence was the precipitating factor for his hypertensive urgency, admission should be considered. Bottom line: If a patient presents with end-organ damage, he should be admitted to the ICU. In the case of severely elevated BP levels (e.g., diastolic BP > 120 mm Hg) and in the absence of end-organ damage, the decision to admit is made on a case-by-case basis. 6. What laboratory tests does the evidence suggest should be ordered for evaluation of severe HTN? The evidence supports obtaining basic laboratory test, urinalysis, and electrocardiogram (ECG).1,2,3,13 Chest x-ray should be performed if pulmonary edema, heart failure, or aortic dissection is suspected.2,9 A head computed tomography is indicated if history and/or examination suggest central nervous system involvement.2 Despite the presence of clear guidelines, an observational study by Karras et al.15 reported that the majority of patients with hypertensive emergency do not receive the recommended evaluation in the ED. In this study, 4 academic EDs were observed for 1 week, and a total of 423 patients were noted with severely elevated BP. The authors reported that serum chemistries were only performed in 73% of these patients, ECG in 53%, and urinalysis in 43%. Only 6% of patients were given the full assessment recommended in the seventh report of the Joint National Committee (JNC) [ECG, serum chemistries, chest x-ray, urinalysis, and fundoscopic examination].3 The outcomes of these patients are unknown as the study was not designed to evaluate for the outcome but rather to observe the common management practices in the ED. Bottom line: Serum chemistries, ECG, urinalysis, and fundoscopic examination are the standard tests used in the evaluation of severe HTN; however, additional tests such as chest x-ray and neuroimaging should be ordered based on history and physical examination. 7. What are the goals of therapy for management of bP in hypertensive emergencies? According to the Seventh Report of the JNC on prevention, detection, evaluation, and treatment of high BP,3 the initial reduction of mean arterial BP in the first hour should be no more than 25%. If the patient is stable, the BP can be further reduced to a systolic BP of approximately 160 mm Hg over the next 2–6 hours. If the patient remains stable, the BP can be reduced gradually toward normal over the next 24–48 hours. These recommendations are cited throughout the literature and are used as the guidelines for the initial management of hypertensive emergencies. Caution should be used to avoid excessive falls in BP, as this may precipitate renal, cerebral, or coronary ischemia. Hence, short-acting nifedipine is no longer considered to be acceptable in the initial management of hypertensive crises.3 For patients with ischemic stroke, different guidelines should be used in the management of BP, as there is a loss of cerebral autoregulation in the affected region, which makes it prone to hypoperfusion during BP reduction. Hence, aside from the cases of extreme BP elevation (systolic BP > 220 mm Hg or diastolic BP > 130 mm Hg), it is usually not recommended to lower BP immediately following an ischemic stroke.16 Bottom line: Although it is critical to lower the BP in patients with hypertensive emergency, it should be reduced in a slow and controlled manner to prevent organ hypoperfusion. 8. What are the pharmacological agents used to treat hypertensive crises? The choice of agent depends on the end-organ damage and comorbidities. Refer Table 29.3 for a list of the most common agents used to treat hypertensive crisis.1,2,5,12–14 Bottom line: Combined α/β-blockers, β-blockers, calcium channel blockers, and peripheral vasodilators are some of the most commonly TAblE 29.3 Risks and Benefits of Common Agents Used to Treat Hypertensive Crisis Drug Labetalol Advantages Intravenous (bolus and infusion) and oral forms Rapid onset of action Can be used in the case of increased intracranial pressure Can be used during pregnancy First line for hypertensive emergency Sodium nitroprusside Immediate onset of action Short duration Esmolol Nicardipine Can be discontinued rapidly Can be titrated accurately and quickly Can be adminis tered in bolus and infusion forms Very rapid onset of action Useful in the case of severe postoperative HTN Rapid onset of action Increases stroke volume and coronary blood flow Disadvantages Relatively long duration of action (3–6 h) Potential for bradycardia and bronchoconstriction Side effects of nausea, vomiting, dizziness, paresthesias, and scalp tingling Risk of thiocyanate and cyanide poisoning (particularly in patients with hepatic/renal insufficiency) Requires special handling to prevent light degradation Side effects of nausea, vomiting, and muscle twitching Risk of first-degree heart block Side effects of flushing, nausea, and pain at the infusion site Contraindicated in heart failure patients Side effects of tachycardia, headache, nausea, and
vomiting Drug Advantages Fenoldopam Increases renal perfusion and promotes dieresis (useful in the case of renal insufficiency) Peripheral vasodilator (acts on peripheral D1 receptors) Disadvantages Expensive Side effects of nausea, headache, and flushing used medications for hypertensive crises. Labetalol is one of the firstline agents for hypertensive emergency. Sodium nitroprusside is also a drug of choice for hypertensive emergencies because of its quick onset of action and short duration. 9. What are the common complications of hypertensive emergencies? How are they assessed and managed? The common complications of hypertensive emergencies are listed in Table 29.4. Bottom line: The choice of antihypertensive will often vary depending on the particular complication of the hypertensive emergency. TAblE 29.4 Common Complications of Hypertensive Emergency Complication Acute aortic dissection Drugs used to Description treat Occurs in Combination patients presenting with sharp, tearing chest pain Abrupt onset Transesophageal echocardiogram, CT, or MRI used to confirm diagnosis17 of vasodi lator and β-adrenergic antagonist17 Drugs to avoid Agents that increase the cardiac output (continued) TAblE 29.4 (Continued) Complication Hypertensive encephalopathy Renal insufficiency Description Manifestation of cerebral edema Patients may present with severe headache, nausea, vomiting, visual disturbances, confusion, and weakness2 Reversible if treated Results in coma/ death if untreated Caused by rapidly progressive hypertension14 Drugs used to treat Nicardipine, labetalol, fenoldopam5,14 Drugs to avoid Nitroprusside (decreases cerebral blood flow while increas ing the intracranial pressure)5,14 Fenoldopam, sodium nitroprusside, nicardipine2 Myocardial ischemia May be complicated by severe elevations in BP due to increase in oxygen requirements Intravenous nitroglycerine to improve coronary perfusion and β-blockers to lower heart rate and BP Angiotensin convertingenzyme inhibitors (in the presence of bilateral renal artery stenosis) Pure vasodi lator, for example, sodium nitroprusside (poses risk of reflex tachycardia)14 Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging. TAKE-HOME POINTS: HYPERTENSIVE EMERGENCY 1. Severely elevated BP is defined as systolic BP greater than 180 mm Hg or diastolic BP greater than 120 mm Hg. 2. Hypertensive urgency is defined as systolic BP greater than 180 mm Hg or diastolic BP greater than 120 mm Hg in the presence of symptoms but without end-organ dysfunction. 3. Hypertensive emergency is defined as systolic BP greater than 180 mm Hg or diastolic BP greater than 120 mm Hg in the presence of end-organ damage. 4. A thorough history, physical examination, and laboratory tests are required to differentiate between hypertensive urgency and hypertensive emergency. 5. Common clinical manifestations of hypertensive emergency include chest pain, dyspnea, and neurological deficits. 6. Treatment of hypertensive crisis (urgency or emergency) depends on the patient’s clinical presentation but some of the preferred agents are labetalol, sodium nitroprusside, nicardipine, and fenoldopam. REFERENCES 1. Aggarwal, M., and I. A. Khan. 2006. “Hypertensive Crisis: Hypertensive Emergencies and Urgencies.” Cardiology Clinics 24: 135–46. 2. Hebert, C. J., and D. G. Vidt. 2008. “Hypertensive Crises.” Primary Care: Clinics in Office Practice 35: 475–87. 3. National Institute of Health. 2003. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. http://www.nhlbi.nih.gov/guidelines/ hypertension/jnc7full.pdf 4. Sutters, M. 2010. “Systemic Hypertension.” In Current Medical Diagnosis & Treatment, edited by S. J. McPhee, M. A. Papadakis, and L. M. Tierney Jr. New York: McGraw-Hill, 387–411 http://www.accessmedicine.com/ content.aspx? aID=3177080 5. Marik, P. E., and J. Varon. 2007. “Hypertensive Crises: Challenges and Management.” Chest 131: 1949–62. 6. Bennett, N. M., and S. Shea. 1988. “Hypertensive Emergency: Case Criteria, Sociodemographic Profile, and Previous Care of 100 Cases.” American Journal of Public Health 78: 636–40. 7. Bender, S. R., M. W. Fong, S. Heitz, and J. D. Bisognano. 2006. “Characteristics and Management of Patients Presenting to the Emergency Department With Hypertensive Urgency.” Journal of Clinical Hypertension 8: 12–18. 8. Shea, S., D. Misra, M. H. Ehrlich, L. Field, and C. K. Francis. 1992. “Predisposing Factors for Severe, Uncontrolled Hypertension in an Inner-City Minority Population.” New England Journal of Medicine 327: 776–81. 9. Stewart, D. L., S. F. Feinstein, and R. Colgan. 2006. “Hypertensive Urgencies and Emergencies.” Primary Care: Clinics in Office Practice 33: 613–23. 10. Zampaglione, B., C. Pascale, M. Marchisio, and P. Cavallo-Perin. 1996. “Hypertensive Urgencies and Emergencies: Prevalence and Clinical Presentation.” Hypertension 27: 144–47. 11. Martin, J., E. Higashiama, E. Garcia, M. R. Luizon, and J. P. Cipullo. 2004. “Hypertensive Crisis Profile. Prevalence and Clinical Presentation.” Arquivos Brasileiros De Cardiologia 83: 131–36. 12. Rodriguez, M. A., S. K. Kumar, and M. De Caro. 2010. “Hypertensive Crisis.” Cardiology in Review 18: 102–07. 13. Chung, S. A., E. C. Hsiao, and M. J. Klag. 2006. “Hypertensive Urgency and Emergency.” In The Osler Medical Handbook. 2nd ed., edited by J. P. Piccini and K. R. Nilsson. Philadelphia, PA: Mosby-Saunders. 14. Gilmore, R. M., S. J. Miller, and L. G. Stead. 2005. “Severe Hypertension in the Emergency Department Patient.” Emergency Medicine Clinics of North America 23: 1141– 58. 15. Karras, D. J., L. K. Kruus, J. J. Cienki, M. M. Wald, W. K. Chlang, P. Shayne, J. W. Ufberg, R. A. Harrigan, D. A. Wald, and K. L. Hellpern. 2006. “Evaluation and Treatment of Patients With Severely Elevated Blood Pressure in Academic Emergency Departments: A Multicenter Study.” Annals of Emergency Medicine 47: 230–36. 16. Bhalla, A., C. D. A. Wolfe, and A. G. Rudd. 2001. “Management of Acute Physiological Parameters after Stroke.” Quarterly Journal of Medicine 94: 167– 72. 17. Khan, J. A., and C. K. Nair. 2002. “Clinical, Diagnostic, and Management Perspectives of Aortic Dissection.” Chest 122: 311–28.

cH apter Rhabdomyolysis 30 Jessica intravia, MHa CASE A 32-year-old man arrives in the emergency room (ER) complaining of severe calf pain and weakness. The day before, he ran a marathon during an August heat wave. He states that his pain seems to be worse than typical muscle soreness. His medical history is significant for hypertension and hyperlipidemia, which he manages with diet, exercise, and simvastatin. In addition, he reports an upper respiratory tract infection a few days ago for which he was prescribed azithromycin. On review of systems, he denies fever, chills, shortness of breath, chest pain, headache, or vision changes. Although he denies dysuria, he notes that his urine “was as dark as coke” this morning. On examination the patient is well appearing with normal vitals. Both calves appear to be swollen and are very tender. 1. What is the likely diagnosis and why? The differential diagnosis for myalgia and muscle weakness includes rhabdomyolysis, compartment syndrome, viral myositis, and inherited metabolic diseases such as muscular dystrophy. The causes of darkened urine include concentrated urine from dehydration, hematuria, hemoglobinuria from intravascular hemolysis, myoglobinuria from muscle breakdown, bile pigment from biliary tract obstruction, and drug side effects. Causative agents include levodopa, methyldopa, metronidazole, nitrofurantoin, iron sorbitol, and chloroquine. The absence of red blood cells in the urine suggests myoglobinuria as the likely cause of the urinary abnormalities.1 This patient is most likely experiencing rhabdomyolysis, which, in adults, is marked by a classical triad of muscle weakness, myalgia, and dark urine (note that all three rarely occur together in children).2 Calf edema and tenderness further support the diagnosis of rhabdomyolysis.3 Rhabdomyolysis is characterized by muscle necrosis and the release 373 of intracellular muscle constituents into the circulation.4 Severity can range from asymptomatic enzyme elevations to life-threatening electrolyte imbalances and acute kidney injury (AKI). Generally, rhabdomyolysis is not only due to muscle trauma (as is the situation in this marathon runner) but also due to muscle enzyme deficiencies, electrolyte abnormalities, infectious agents, drugs, toxins, and endocrinopathies such as inherited disorders of metabolism. It is also important to note that macrolide antibiotics (e.g., azithromycin) decrease the hepatic clearance of statins and that a major side effect of statin usage is myotoxicity. The hot, summer weather likely contributed to the marathon runner’s increased insensible losses, resulting in dehydration and increased risk of developing rhabdomyolysis. Bottom line: Consider the diagnosis of rhabdomyolysis in any patient who presents with signs and symptoms of muscle weakness, myalgia, and dark urine. 2. Based on the evidence, what laboratory tests should be ordered for this patient to confirm the diagnosis? The hallmark laboratory finding in rhabdomyolysis is an elevation in the muscle enzyme, creatine kinase (CK). Events in which metabolic demand and ATP requirements are increased (e.g., marathon running) can result in myocyte necrosis and release of CK into the bloodstream. CK levels greater than 5000 U/L usually indicate serious muscle injury. Serum CK levels are often greater than 10,000 U/L in patients with rhabdomyolysis.5 CK levels typically increase within 12 hours of the muscle insult, which peaks in 1–3 days and declines within 3–5 days.4 Bottom line: A serum CK greater than 5000–10,000 U/L is typically required to diagnose rhabdomyolysis. 3. What complications does evidence suggest are most commonly associated with rhabdomyolysis? Complications of rhabdomyolysis include electrolyte abnormalities and AKI. Hyperkalemia and hyperphosphatemia are often observed in patients with rhabdomyolysis because of potassium and phosphate release during muscle breakdown. Hypocalcemia can also occur with rhabdomyolysis. Hypocalcemia is believed to occur due to the release of intracellular phosphate from damage myocytes, thereby resulting in calcium phosphate precipitation in the damaged muscles. In addition, the decreased supply of ATP in myocytes may lead to sarcoplasmic sequestration of calcium.6 Although this may lead to hypocalcemia in early rhabdomyolysis, note that there is potential for the development of hypercalcemia once this sequestered calcium is released.7 It has been estimated that between 10% and 50% of patients with rhabdomyolysis will develop AKI.4 A chart review of 97 rhabdomyolysis patients (CK > 1000 U/L) in a New York ER found that 17.5% of patients developed AKI.8 Another chart review of 382 trauma patients demonstrated that a CK level greater than 5000 U/L is associated with an 18%–22% risk of developing AKI, a 6%–7% chance that dialysis will be required, and a 15%– 18% risk of mortality.9 AKI is caused by the toxic nonprotein heme pigment that is released during myoglobin breakdown. It may lead to kidney destruction via 3 mechanisms: tubular obstruction, proximal tubular injury, and renal ischemia.10 Additional factors such as hypovolemia, acidosis, and mild ischemia may increase this toxicity.7 Bottom line: Rhabdomyolysis is most commonly due to muscle trauma but may also be attributed to other causative factors. Complications include electrolyte abnormalities and AKI. 4. Does the evidence suggest that certain toxins and drugs may have contributed to the development of rhabdomyolysis in this patient? Yes. Toxins and drugs are a common contributing factor to rhabdomyolysis. Many studies have showed an increased risk of rhabdomyolysis in statin users such as this patient. In fact, cerivastatin (Baycol, Lipobay) was withdrawn from the US market in 2001 due to high reports of fatal rhabdomyolysis associated with its usage.11 In addition, certain drug–drug interactions can increase the risk of rhabdomyolysis by reducing the clearance of statins through the cytochrome P450 system. Such drugs include macrolide antibiotics, cyclosporine, gemfibrozil, azole antifungals, and certain protease inhibitors. The patient was finishing a course of azithromycin (a macrolide antibiotic) while on his prescribed simvastatin. One study found that combined statin–fibrate usage conferred a 12-fold increase in the risk of rhabdomyolysis.11 Rhabdomyolysis from statins occurs infrequently and unpredictably in an idiosyncratic way. The risk of rhabdomyolysis does not appear to diminish with longterm usage of statins or fibrates.11 Bottom line: Statins are a frequently encountered cause of rhabdomyolysis. Many drugs can increase the plasma levels of statins by inhibiting hepatic P450 clearance, thereby increasing the likelihood for side effects such as rhabdomyolysis. The risk of rhabdomyolysis does not appear to diminish with long-term usage of statins or fibrates. 5. Given our suspicion of rhabdomyolysis, what additional workup does the evidence suggest should be undertaken for this patient? There is mixed evidence concerning the predictive nature of abnormal laboratory values in the development of AKI in rhabdomyolysis. One chart review of 97 patients with rhabdomyolysis showed that in a multivariate logistic regression model, only creatinine and blood urea nitrogen were predictive for AKI and required for hemodialysis.8 In contrast, another historical cohort review of 157 patients showed that elevated levels of serum CK, serum potassium, serum phosphorus levels, and history on presentation of dehydration or sepsis were predictive of AKI.12 Serum potassium, phosphate, and uric acid levels may initially increase as myocytes lyse and release their contents. Hyperkalemia, hyperphosphatemia, and hyperuricemia can also occur secondary to AKI. Bottom line: Although patients should be screened for abnormal laboratory values following development of rhabdomyolysis, the predictive nature of these values is currently unclear. 6. Does the evidence suggest that this patient should be aggressively hydrated? Yes. Although there are no well-designed, placebo-controlled studies,6 the weight of observational and case control studies suggests that aggressive hydration is beneficial.13 In 1984, a study showed an unprecedented reduction in mortality and AKI for 7 patients treated with early hydration within 60 hours of rhabdomyolysis following crush injury.14 A second study of 21 patients in intensive care unit (ICU) confirmed the benefit of saline administration.15 Since then, intravenous (IV) hydration has become the standard of care and the placebo arm in many randomized controlled trials. IV fluids should be started as soon as possible and dehydration should be corrected to maintain urine output at 200–300 mL/h.16 Forced diuresis when started within 6 hours of admission has been reported to minimize the risk of AKI.10 Urine output should be maintained at 200–300 mL/h and IV fluids continued until myoglobinuria stops or CK levels drop to 1000 U/L.16 Following initial fluid resuscitation with saline, mannitol and bicarbonate are occasionally used. There are few data supporting the additional benefit of mannitol17 or bicarbonate,9 but they are considered to be protective by reducing intratubular heme pigment deposition.4 A retrospective review of over 2000 trauma patients suggests that neither mannitol nor bicarbonate reduces the risk of renal failure, dialysis, or mortality in patients with CK levels greater than 5000 U/L.9 Bottom line: Although there are no well-designed, placebocontrolled studies, aggressive saline hydration has become the standard of care and placebo arm in recent experiments. There is little evidence to support the additional benefit of mannitol or bicarbonate. CASE CONTINUED Laboratory evaluation is significant for hyperkalemia, hypocalcemia, and a CK concentration of 10,500 U/L (normal level <200 U/L). The urine is dark, with a specific gravity of 1.030. No red blood cells are found on microscopic examination of the urine. 7. Based on the evidence, how should this patient’s electrolyte abnormalities be managed? Evidence suggests that no intervention is necessary for this patient’s hypocalcemia.18 Although hypocalcemia may aggravate the arrhythmic effects of hyperkalemia, it does not need to be corrected unless symptomatic (tetany and seizures) or electrocardiogram (EKG) changes are seen.7 If hypocalcemia need to be addressed, calcium chloride or IV calcium gluconate can be used.7 For patients with severe rhabdomyolysis (CK > 60,000 U/L), potassium levels should be checked frequently due to the concern for cardiac arrhythmias.6 Cardiac monitoring and admission to the ICU should be considered if the potassium is greater than 6 mEq/L, rapidly increasing, or if there are severe EKG manifestations.6 Bottom line: Expect early hypocalcemia, potentially followed by hypercalcemia. Evidence suggests that there is no clear benefit in treating hypocalcemia unless the patient is symptomatic. Hyperkalemia should be monitored closely in severe rhabdomyolysis. TAKE-HOME POINTS: RHABDOMYOLYSIS 1. The classic triad of rhabdomyolysis is muscle weakness, myalgia, and dark urine. 2. Rhabdomyolysis is most often caused by muscle trauma but may also be caused by muscle enzyme deficiencies, electrolyte abnormalities, infectious agents, drugs, toxins, and endocrinopathies. 3. The hallmark of rhabdomyolysis is an elevation in serum CK greater than 5000–10,000 U/L. 4. Statin usage may increase the risk of rhabdomyolysis. The risk of rhabdomyolysis does not appear to diminish with long-term usage of statins or fibrates. 5. Certain drug–drug interactions can reduce the clearance of statins through the cytochrome P450 system and thus increase the risk of rhabdomyolysis. 6. AKI in rhabdomyolysis results in part from the toxic heme pigment of myoglobin, which damages tubular cells and has a propensity to precipitate and cause intraluminal obstruction. 7. Renal ischemia is typically a significant contributing factor to the development of AKI. Early aggressive fluid replacement appears to be nephroprotective. REFERENCES 1. Karis, C., and Triantafyllidis, G. 2002. “Index of Suspicion.” Pediatrics in Review 23: 25. 2. Cervellin, G., I. Comelli, and G. Lippi. 2010. “Review: Rhabdomyolysis: Historical Background, Clinical, Diagnostic, and Therapeutic Features.” Clinical Chemistry and Laboratory Medicine 48 (6): 749–56. 3. Knochel, J. P. 1990. “Catastrophic Medical Events With Exhaustive Exercise: White Collar Rhabdomyolysis.” Kidney International 38 (4): 709–19. 4. Huerta-Alardin, A., Varon, J., Marik, P. E. 2005. “Bench-to-Bedside Review: Rhabdomyolysis—An Overview for Clinicians.” Critical Care 9 (2): 158–69. 5. Miller, M. 2010. “Clinical Manifestations, Diagnosis, and Causes of Rhabdomyolysis.” UpToDate. 6. Bosch, X., E. Poch, and J. Grau. 2009. “Rhabdomyolysis and AKI.” The New England Journal of Medicine 361: 61–72. 7. Warren, J. D., P. C. Blumbergs, and P. D. Thompson. 2002. “Rhabdomyolysis: A Review.” Muscle & Nerve 25 (3): 332–47. 8. Fernandez, W. G., O. Hung, G. R. Bruno, S. Galea, and W. K. Chiang. 2005. “Factors Predictive of Acute Renal Failure and Need for Hemodialysis Among ED Patients With Rhabdomyolysis.” Annals Journal of Emergency Medicine 23 (1): 1–7. 9. Brown, C. V., P. Rhee, L. Chan, K. Evans, D. Demetriades, and G. C. Velmahos. 2004. “Preventing Renal Failure in Patients With Rhabdomyolysis: Do Bicarbonate and Mannitol Make a Difference?” Journal of Trauma 56 (6): 1191–96. 10. Zager, R. 1996. “Rhabdomyolysis and Myohemoglobinuric Acute Renal Failure.” Kidney International 49: 314–26. 11. Graham, D. J., Staffa, J. A., Shatin. D., Andrade, S. E., Schech, S. D., La Grenade, L., Gurwitz, J. H., Chan, K. A., Goodman, M. J., Platt, R. 2004. “Incidence of Hospitalized Rhabdomyolysis in Patients Treated With Lipid- Lowering Drugs.” The Journal of the American Medical Association 292 (21): 2585–90. 12. Ward, M. M. 1988. “Factors Predictive of Acute Renal Failure in Rhabdomyolysis.” Archives of Internal Medicine 148 (7): 1553–57. 13. Odeh, M. 1991. “The Role of Reperfusion-Induced Injury in the Pathogenesis of the Crush Syndrome.” The New England Journal of Medicine 324: 1417–22. 14. Ron, D., U. Taitelman, M. Michaelson, G. Bar-Joseph, S. Bursztein, and O. Better. 1984. “Prevention of Acute Renal Failure in Traumatic Rhabdomyolysis.” Archives of Internal Medicine 144 (2): 277–80. 15. Hornsi, E., M. F. Barreiro, J. M. Orlando, and E. M. Higa. 1997. “Prophylaxis of Acute Renal Failure in Patients With Rhabdomyolysis.” Renal Failure 19 (2): 283–88. 16. Sauret, J. M., G. Marinides, and G. K. Wang. 2002. “Rhabdomyolysis.” American Family Physician 65 (5): 907–12. 17. Karajala, V., W. Mansour, and J. A. Kellum. 2009. “Diuretics in AKI.” Minerva Anestesiologica 75 (5): 251–57. 18. Vanholder, R., M. S. Sever, E. Erek, and N. Lameire. 2000. “Rhabdomyolysis.” Journal of the American Society of Nephrology 11(8): 1553– 61. Chapter Endocarditis Vishal Joshi, MD anD anuraDha 31 subraManian, MD CASE A 32-year-old intravenous (IV) drug abuser presents to the emergency department (ED) for evaluation of a 1-week history of increasing shortness of breath, subjective fever, and fatigue. He used heroin the day before presentation. Physical examination reveals temperature, 101.2°F; HR, 112; RR, 16; O2 saturation, 92% RA (room air). Cardiac exam is significant for jugular venous distension (JVD) and a pansystolic high-pitched heart murmur in the left fourth intercostal space (parasternal region). Lung examination reveals bibasilar

crackles. A petechial rash is present on the lower extremities below the knees. A blood culture drawn in the emergency room triggers an alert finding. 1. Does this man have infectious endocarditis? Almost certainly. The criteria for diagnosing endocarditis have evolved with evidence-based medicine. The current standard for diagnosing endocarditis is the DUKE CRITERIA1, which was developed in 1994 and modified in 2000.2 Application of the Duke Criteria classifies suspected endocarditis into definite, possible, or rejected (Table 31.1). Major clinical criteria: 1. Positive blood cultures for organisms that are typically known to cause endocarditis. 2. Vegetations or prosthetic valve dehiscence or intracardiac abscess on echocardiogram. 3. Suspected endocardial damage (i.e., new regurgitant murmur). 4. Serological/culture evidence of infection with Coxiella burnetii. 381 TAblE 31.1 Definition of Infective Endocarditis According to the Modified Duke Criteria Definite Direct evidence based on histopathology Or Gram-positive stain from surgery or autopsy Or 2 major criteria Or 1 major and 3 minor criteria Or 5 minor criteria Possible 1 major and 1 or 2 minor criteria or 3 minor criteria Rejected Alternate diagnosis best explains symptoms or Resolution with 4 d or less of antibiotics or No pathological evidence of endocarditis after 4 d or less of antibiotics or Clinical criteria for definite or possible endocarditis not met Minor clinical criteria: 1. Fever. 2. Prosthetic heart valve, regurgitant flow, or history of IV drug abuse. 3. Vascular complications (emboli/hemorrhages). 4. Immunologic phenomenon (i.e., glomerulonephritis, Roth’s spots/Osler nodes). 5. Positive blood cultures are neither persistent nor of typical organism involved with infective endocarditis (IE). Bottom line: Clinical diagnosis of IE includes clinical, microbiological, and echocardiography. Surgical or autopsy data are also useful in making definitive diagnosis. 2. Are there other indicators suggestive of IE not included in the Duke Criteria? Yes. Pay attention toward the patient’s history: indwelling catheters/ IV drug abuse. Spleen enlargement, finger clubbing, thrombocytopenia, leukocytosis, and ESR > 50 have been shown to be independently and predictive of IE. Embolic events including intracranial hemorrhage have also been shown to be independently associated with endocarditis.3 Bottom line: Although the Duke Criteria tool is extremely useful for diagnosing IE, other data can also be used to increase or decrease the likelihood of proper diagnosis. 3. Can endocarditis be diagnosed in the absence of positive blood cultures? Absolutely. It is thought that the primary cause of negative blood cultures in approximately half of patients is antibiotic pretreatment, followed by fastidious organisms (i.e., very rare bacteria and bacteria that are difficult to culture) which occur in 15%–20% of patients.4 Bottom line: Positive blood cultures are not required for diagnosing IE. 4. Describe the epidemiology and risk factors of infectious endocarditis IE is more common in men than women. Most of the cases are in elderly patients, with more than half of all cases in patients over the age of 60 years.5 Diabetic and hemodialysis-dependent patients are at increased risk for IE.6 Incidence varies by location and is often based on incidence of IV drug use, rheumatic heart disease, and age of the population. The mitral and aortic valves are most commonly involved.7 Risk factors for infectious endocarditis are as follows: Injection drug use Rheumatic heart disease Prosthetic heart valves Structural heart disease Previous history of IE Hemodialysis Pregnancy Peritoneovenous shunts (for ascites) Ventriculoatrial shunts (for hydrocephalus) Bottom line: Intravenous drug abuse (IVDA), hemodialysis, and structural heart disease are the main risk factors for IE. 5. Which organisms most commonly cause infectious endocarditis? Staphylococcus aureus and other Gram-positive organisms are the predominant microbiological causes of IE. Polymicrobial, Gram-negative, and fungal organisms are more common in IVDA or patients with indwelling venous catheters. 6. What physical examination findings may be seen in infectious endocarditis? Vascular and immunological phenomena, including emboli to the brain, lung, spleen, and kidneys, remain fairly common with the initial TAblE 31.2 Microbiology of Native Valve IE Organism Percentage Staphylococcus aureus 31 Streptococcus viridans group 17 Enterococcus group 10 Coagulase-negative Staphylococcus 11 Streptococcus bovis 6 Other Streptococcus species 6 HACEKa 2 Fungal organisms 2 Culture-negative 10 Polymicrobial 1 Other 4 Adapted from 2781 patients in International Collaboration on Endocarditis – Prospective Cohort Study, Archives of Internal Medicine 2009.8 aHACEK = Haemophilus aphrophilus, Aggregatibacter actinomycetemcomitan (previously known as Actinobacillus actinomycetemcomitans), Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae (all fastidious Gram-negative bacilli). presentation of IE in 30% of patients. Macular, blanching, nonpainful, and erythematous lesions on the palms and soles (Figure 31.1). In 1899, Janeway lesions were first described as nontender lesions on the palms and soles. They may be hemorrhagic.10 It is thought that they are secondary to microemboli from cardiac vegetations, with neutrophilic microabscess formation.11 Painful, violaceous nodules on fingertips are shown in Figure 31.2. Osler’s nodes, first described in 1873, are classically described as painful nodular erythema found on the finger tips, toes, thenar eminences, and skin on lower part of the arm.10 They are thought to be a microemboli from cardiac vegetations, eliciting a secondary immunologic vasculitis,12 although this has been debated since first described.13 They resolve completely usually within hours to 4–5 days.14 Oval-shaped, hemorrhagic lesion of retina is shown in Figure 31.3. Roth’s spots: First described in 1872 and are classically known to be canoe- shaped linear hemorrhagic spots with a light central area of the retina.15 Exact mechanism remains to be unknown, but they are believed to be secondary to emboli and associated hypoxia leading to capillary rupture.16 Nonblanching, linear reddish-brown lesions under the nail bed. Picture of splinter hemorrhages: Splinter hemorrhages, a nonspecific finding found in some patients with IE. They are usually nontender,

FIgurE 31.1 Janeway lesions in a patient with Staphylococcus aureus endocarditis. Adapted from Ref. [9]. Available on MDCONSULT.com

FIgurE 31.2 Osler’s node in IE. Goldman: Cecil Medicine: Available on MDCONSULT WEBSITE. and are caused by engorgement of capillaries under the nail, but the etiology of the hemorrhages is unclear. Bottom line: The skin findings of IE are well described in the literature and may help with narrowing your differential diagnosis.

FIgurE 31.3 White, centered retinal hemorrhage (Roth’s spot) seen in an HIV- infected patient. These lesions do not progress. Ryan: Retina. Available on MDCONSULT. 7. Do blood cultures need to be collected before giving IV antibiotics? Collection of blood culture should ideally occur before the administration of antibiotics. 8. How many sets of blood cultures should be taken? Three sets of blood cultures from different venipuncture sites are considered to be sufficient for diagnosis. Repeated testing beyond 3 sets increases the likelihood of false-positive results and is not recommended.17 In acute IE : take samples over a period of 1 hour before antibiotic administration Subacute: take samples over 2–3 days before antibiotic administration. Bottom line: For both acute and subacute IE, repeated blood cultures are key factors that help with the diagnosis. 9. How much blood should be collected for culturing? Blood count of about 10– 20 cc is ideal because of the low grade of bacteria associated with IE. Bottom line: Given the low grade of bacteremia associated with IE, it is important to notify the person involved with blood collection to collect 10–20 cc of blood per sample. 10. Are inflammatory markers useful in the diagnosis or follow-up of IE? Markers of inflammation, including leukocytosis with left shift, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and procalcitonin are usually elevated with IE, but are considered to be nonspecific. It has been demonstrated that the normalization of CRP and white blood cell is a good predictor of a favorable late outcome (surgery, death) of IE. A high CRP and slow normalization have been found to be poor clinical predictors of therapy.18,19 Bottom line: Elevated inflammatory markers provide nonspecific but important information to help and support the clinical judgment. 11. What about suspicious echocardiogram findings? Echocardiography has been found to be sensitive but lacks specificity for diagnosing endocarditis. This means that abnormal positive echo may correlate with endocarditis, whereas a negative echo does not rule out endocarditis.20 Bottom line: A positive echocardiogram helps to diagnose IE, whereas a negative echocardiogram does not rule out IE. 12. When are blood cultures considered to be positive? According to the Duke Criteria, persistent bacteremia with an organism, with a high likelihood of IE, (refer to Table 31.2) is considered as the major criteria when positive in 2 separate blood cultures: Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus, or enterococci. Blood cultures are consistent with IE if there are1: Two positive cultures drawn more than 12 hours apart or Three (or a majority of four) separate cultures drawn within 1 hour Bottom line: Major criteria for diagnosing IE include persistent bacteremia. Blood cultures are important for diagnosing and managing IE. 13. Is an EKg useful? Baseline EKG is useful for staging and follow-up. Cardiac conduction abnormalities are known to be complications of IE.21 Heart block or conduction delay may provide an important clue for an extension of infection to the valve annulus and adjacent septum. Unstable conduction abnormalities are associated with increased mortality. Persistent conduction changes are correlated with poor prognosis22 and may be a indicative of embolization to the coronary circulation.23 Repeated EKG is generally performed as indicated based on the clinical judgment. Bottom line: Baseline and repeated EKGs are important to help stage and manage IE. Persistent or fluctuating EKGs are associated with a poorer prognosis. 14. Should a chest x-ray be ordered? Chest radiography may help with narrowing the differential diagnosis and evaluating for complications of IE. Serial chest x-ray is helpful to monitor the severity of the hemodynamic consequences of valvular regurgitation and response to treatment. Other complications of IE may also be visualized on x-ray, including septic emboli of the lungs and perivalvular abscesses. Bottom line: Chest radiography provides helpful clinical and diagnostical information for IE. 15. Is an echocardiogram indicated in suspected endocarditis Yes. A transthoracic echocardiogram (TTE) is indicated when suspicion of endocarditis is present. Close attention should be paid toward indentifying vegetations on valves, valvular dysfunction, shunts, and abscess. This will not only help with diagnosis but also with following the disease. Remember that this is a major criterion in the diagnosis of IE. Bottom line: Echocardiography provides invaluable information and should be ordered for all patients with suspected endocarditis. 16. Transthoracic or transesophageal echocardiogram? A noninvasive TTE is generally performed on suspicion of endocarditis. The sensitivity of transesophageal echocardiogram (TEE) to TTE is remarkably improved (range 87%–100%, vs. 30%–63%).24 The specificity of TEE is also superior because of improved spatial resolution and image quality25 (exception: tricuspid valve endocarditis, where TTE may be equivalent to TEE26). Current limitations of TEE include limited around the clock availability in many institutions and patients must be NPO 6 hours before the procedure. Bottom line: A negative TTE does not rule out endocarditis because of poor sensitivity. 17. When is a TEE indicated? A TEE is indicated if the image quality of a TTE is poor combined with a moderate to high suspicion of endocarditis.27 A TEE is superior to a TTE, if a prosthetic heart valve is present for detecting small vegetations.28 If a TEE is negative, and a strong clinical suspicion for endocarditis remains, a repeated study should be considered in 7 days. Suspicious echocardiographic findings may also represent previous valvular damage, thrombi, or degenerative valvular stranding.29 Bottom line: A TEE is indicated for any patient with a negative TTE but continued moderate–high suspicion for IE. 18. What does the evidence suggest should constitute empirical treatment? Treatment should be guided by blood cultures and sensitivities to the etiologic organism. However, until culture data are available, the current recommendations from The Sanford Guide to Antimicrobial Therapy 201030 are given in Table 31.3: Bottom line: Empirical treatment is targeted toward likely organisms. Ideally, treatment should be tailored by blood cultures and sensitivities when available. TAblE 31.3 Recommended Antimicrobial Therapy Type of IE Native valve, no Intravenous drug user (IVDU) Native valve, IVDU Prosthetic valve Empirical treatment Pen G or Ampicillin IV + Nafcillin or Oxacillin IV + Gentamicin IV Alternative: Vancomycin IV + Gentamicin IV OR Daptomycin Vancomycin IV; Alternative: Daptomycin IV Vancomycin IV + Gentamicin IV + Rifampin PO 18.1 Prophylaxis Prophylaxis for IE has been recommended by the American Heart Association (AHA) since 1955 in certain procedures. Although prophylaxis for IE is not considered to be very effective to prevent IE, it is recommended in high-risk patients undergoing high-risk procedures. On the basis of the available evidence, recent guidelines (2008) prophylaxis is now generally recommended for dental procedures only31: Patients for whom antibiotic prophylaxis is recommended are those with32: Prosthetic heart valve or valve repair. Previous IE. Some congenital heart diseases (CHDs): unrepaired cyanotic CHD, repaired CHD with new prosthetic first 6 months, and repaired CHD with residual defect near prosthesis. Congenital valve malformations. Cardiac transplant recipients with valvulopathy. Constructed pulmonary shunts. Hypertrophic cardiomyopathy with obstruction. Mitral valve prolapse with regurgitation or thickened valves. In the absence of active infection, prophylaxis is no longer recommended for aortic stenosis, mitral stenosis, asymptomatic mitral valve prolapse without mitral regurgitation (MR), or thickened mitral valve (MV) on echocardiogram. It is also not indicated in adolescent and young adults with native heart valve disease. No prospective, randomized, placebo-controlled studies exist on the efficacy of antibiotic prophylaxis to prevent IE in patients who undergo a dental procedure. However, prophylaxis for some dental procedure is reasonable. Antibiotic regimen for prophylaxis (given as a single dose 30–60 before procedure): ORAL: amoxicillin – 2 g × 1 dose IV: ampicillin, cefazolin, and ceftriaxone IV are all acceptable For Penicillin allergy: cephalexin PO, clindamycin PO, or azithromycin/clarithromycin PO, cefazolin IV, ceftriaxone IV, or clindamycin IV Bottom line: There have been no prospective, randomized placebo controlled trials for prophylaxis in dental procedures. Prophylaxis is recommended for high-risk patients undergoing high-risk procedures. Adapted from AHA 2007 guidelines and 2008 focused update to guidelines. Although previous guidelines supported prophylaxis for GU (genitourinary) and GI (gastrointestinal) procedures, the 2008 AHA/ACC guidelines recommended against this practice. 19. When is surgery indicated for IE? Surgery is potentially indicated in patients at high risk of complications. Specific echocardiographic features which identify patient at higher risk are summarized in Table 31.4: In severely ill patients with the above features, early cardiothoracic surgical consultation is generally recommended. Bottom line: Surgical intervention may be required for treatment and cure of IE. TAKE-HOME POINTS: ENDOCArDITIS 1. Diagnosis of endocarditis usually requires detailed history, physical, diagnostical, and microbiological/laboratory data to confirm. 2. A negative TTE does not rule out endocarditis. 3. Empirical treatment is targeted to likely organisms. 4. Therapy is tailored based on bacterial cultures and antibiotic sensitivities. Surgical intervention may be required for management and cure. TAblE 31.4 Echocardiographic features that suggest potential need for surgical intervention Vegetation Persistent vegetation after systemic embolization Anterior mitral leaflet vegetation, particularly with size >10 mm ≥1 embolic events during first 2 wk of antimicrobial therapy Increase in vegetation size despite appropriate antimicrobial therapy,† Valvular dysfunction Acute aortic or mitral insufficiency with signs of ventricular failure† Heart failure unresponsive to medical therapy† Valve perforation or rupture† Perivalvular extension Valvular dehiscence, rupture, or fistula† New heart block†,‡ Large abscess or extension of abscess despite appropriate antimicrobial therapy† Adapted from AHA IE guidelines 2005.33 Surgery may be required because of risk of embolization. †Surgery may be required because of heart failure or failure of medical therapy. ‡Echocardiography should not be the primary modality used to detect or monitor heart block. 5. Prophylaxis is no longer recommended for routine GU/GI procedures. It is still reasonable for high-risk patients undergoing some dental procedures. rEFErENCES 1. Durack, D. T., A. S. Lukes, and D. K. Bright. 1994. “New Criteria for Diagnosis of Infective Endocarditis: Utilization of Specific Echocardiographic Findings. Duke Endocarditis Service.” The American Journal of Medicine 96 (3): 200–9. 2. Li, J. S., D. J. Sexton, N. Mick, R. Nettles, V. G. Fowler, Jr, T. Ryan, T. Bashore, G. R. Corey. 2000. “Proposed Modifications to the Duke Criteria for the Diagnosis of Infective Endocarditis.” Clinical Infectious Diseases 30: 633– 38 3. Richet, H., C. J.-P. Casalta, F. Thuny, J. Mérrien, J.-R. Harlé, P.-J. Weiller, G. Habib, and D. Raoult. 2008. “Development and Assessment of a New Early Scoring System Using Non-Specific Clinical Signs and Biological Results to Identify Children and Adult Patients with a High Probability of Infective Endocarditis on Admission.” The Journal of Antimicrobial Chemotherapy 62: 1434–40. doi: 10.1093/jac/dkn423. JAC Advance Access published on December 1, 2008. 4. Naber, C. K., and R. Erbel. 2007. “Infective Endocarditis with Negative Blood Cultures.” International Journal of Antimicrobial Agents 30 (Suppl. 1): S32– S36. 5. Durante-Mangoni, E., S. Bradley, C. Selton-Suty, M. F. Tripodi, B. Barsic, E. Bouza, C. H. Cabell,.et al. 2008. “Current Features of Infective Endocarditis in Elderly Patients: Results of the International Collaboration on Endocarditis Prospective Cohort Study.” Archives of Internal Medicine 168: 2095. 6. Kourany, W. M., J. M. Miro, A. Moreno, G. R. Corey, P. A. Pappas, E. Abrutyn, B. Hoen, et al. 2006. “Influence of Diabetes Mellitus on the Clinical Manifestations of Prognosis of Infective Endocarditis: A Report from the International Collaboration on Endocarditis-Merged Database.” Scandinavian Journal of Infectious Diseases 38: 613. 7. Miro, J. M., I. Anguera, C. H. Cabell, A. Y. Chen, J. A. Stafford, G. R. Corey, L. Olaison, et al. 2005. “Staphylococcus aureus Native Valve Infective Endocarditis: Report of 566 Episodes from the International Collaboration on Endocarditis Merged Database.” Clinical Infectious Diseases 41: 507. 8. Murdoch, D. R., G. R. Corey, B. Hoen, J. M. Miró, V. G. Fowler, Jr, A. S. Bayer, A. W. Karchmer, et al. 2009. “Clinical Presentation, Etiology and Outcome of Infective Endocarditis in the 21st Century: The International Collaboration of Endocarditis- Prospective Cohort Study.” Archives of Internal Medicine 169: 463. 9. Sande, M. A., and L. J. Strausbaugh. Infective endocarditis. In: E. W. Hook, G. L. Mandell, J. M. Gwaltney, Jr., et al, eds. Current Concepts of Infectious Diseases. New York: Wiley Press; 1977 10. Marrie, T. J. 2008. “Osler's Nodes and Janeway Lesions.” American Journal of Medicine 121 (2): 105–6. 11. Tan, J. S., and A. Kerr Jr. 1979. “Biopsies of the Janeway Lesion of Infective Endocarditis.” Journal of Cutaneous Pathology 6: 124–29. 12. Alpert, J. S., H. F. Krous, J. E. Dalen, R. A. O’Rourke, and C. M. Bloor, 1976. “Pathogenesis of Osler’s Nodes.” Annals of Internal Medicine 85: 471–73. 13. Gunson, T., and F. Oliver. 2007. “Osler’s Nodes and Janeway Lesions.” Australasian Journal of Dermatology 48 (4): 251–55. 14. Yee, J., and C. McAllister. 1987. “Osler’s Nodes and the Recognition of Infective Endocarditis: A Lesion of Diagnostic Importance.” Southern Medical Journal 80: 753–57. 15. Silverberg, H. H. 1970. “Roth’s Spots” The Mount Sinai Journal of Medicine 37: 77–79. 16. Falcone, P. M., and W. I. Larrison. 1995. “Roth Spots Seen on Ophthalmoscopy: Diseases with Which They may be Associated.” Connecticut Medicine 59: 271–73. 17. Raoult, D., J. P. Casalta, H. Richet, M. Khan, E. Bernit, C. Rovery, S. Branger, et al. 2005. “Contribution of Systematic Serological Testing in Diagnosis of Infective Endocarditis.” Journal of Clinical Microbiology 43: 5238–42. 18. Heiro, M., H. Helenius, J. Sundell, P. Koskinen, E. Engblom, J. Nikoskelainen, and P. Kotilainen. 2005. “Utility of Serum C-Reactive Protein in Assessing the Outcome of Infective Endocarditis.” European Heart Journal 26 (18): 1873–81. Epub 2005 Apr 26. 19. Verhagen, D. W. 2008. “Prognostic Value of Serial C-Reactive Protein Measurements in Left-Sided Native Valve Endocarditis.” Archives of Internal Medicine 168 (3): 302–7. 20. Prendergast, B. D. 2002. “Diagnosis of Infective Endocarditis.” British Medical Journal 325: 845. 21. Meine, T. J., R. E. Nettles, D. J. Anderson, C. H. Cabell, G. R. Corey, D. J. Sexton, and A. Wang. 2001. “Cardiac Conduction Abnormalities in Endocarditis Defined by the Duke Criteria.” American Heart Journal 142 (2): 280–85. 22. Dinubile, M. J., S. B. Calderwood, D. M. Steinhaus, and A. W. Karcher. 1986. “Cardiac Conduction Abnormalities Complicating Native Valve Active Infective Endocarditis.” The American Journal of Cardiology 58 (13): 1213–17. 23. Ryu, H. M., M. H. Bae, S. H. Lee, J. H. Lee, J. H. Lee, Y. S. Kwon, D. H. Yang, et al. 2011. “Presence of Conduction Abnormalities as a Predictor of Clinical Outcomes in Patients with Infective Endocarditis.” Heart and Vessels. May; 26(3): 298–305, Epub 2010 Nov 5. 24. Jacob, S., and A. T. Tong. 2002. “Role of Echocardiography in the Diagnosis and Management of Infective Endocarditis.” Current Opinion in Cardiology 17 (5): 478–85. 25. Erbel, R., S. Rohmann, M. Drexler, S. Mohr-Kahaly, C. D. Gerharz, S. Iversen, H. Oelert, and J. Meyer. 1988. “Improved Diagnostic Value of Echocardiography in Patients with Infective Endocarditis by Transoesophageal Approach: A Prospective Study.” European Heart Journal 9: 43–53. 26. San Román, J. A., I. Vilacosta, J. L. Zamorano, C. Almería, and L. SánchezHarguindey. 1993. “Transesophageal Echocardiography in Right SidedEndocarditis.” Journal of the American College Cardiology 21 (5): 1226– 30. 27. Evangelista, A., and M. T. Gonzalez-Alujas. 2004. “Echocardiography in Infective Endocarditis.” Heart 90 (6): 614–17. 28. Reynolds, H. R., M. A. Jagen, P. A. Tunick, and I. Kronzon. 2003. “Sensitivity of Transthoracic Versus Transesophageal Echocardiography for the Detection of Native Valve Vegetations in the Modern Era.” Journal of the American Society of Echocardiography 16: 67–70. 29. Naber, C. K., and R. Erbel. 2007. “Infective Endocarditis with Negative Blood Cultures.” International Journal of Antimicrobial Agents 30 (Suppl. 1): S32–S36. Epub 2007 Sep 24. 30. Gilbert, D. N., R. C. Moellering, Jr., G. M. Eliopoulos, H. F. Chambers, and M. S Saag. 2009. The Sanford guide to Antimicrobial Therapy 2009. 39th ed. Sperryville: Antimicrobial Therapy Inc. 31. Nishimura, R. A., B. A. Carabello, D. P. Faxon, M. D. Freed, B. W. Lytle, P. T. O’Gara, R. A. O’Rourke,.and P. M. Shah. 2008. “ACC/AHA 2008 Guideline Update on Valvular Heart Disease: Focused Update on Infective Endocarditis: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.” Journal of the American College Cardiology 52 (8): 676–85. 32. Wilson, W., K. A. Taubert, M. Gewitz, P. B. Lockhart, L. M. Baddour, M. Levison, A. Bolger, et al. 2007. “Prevention of Infective Endocarditis: Guidelines from the American Heart Association: A Guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group.” Circulation 116 (15): 1736–54. Epub 2007 Apr 19. 33. Baddour, L. M., W. R. Wilson, A. S. Bayer, V. G. Fowler, Jr., A. F. Bolger, M. E. Levison, P. Ferrieri, et al. 2005. “AHA Scientific Statement Infective Endocarditis, Diagnosis, Antimicrobial Therapy, and Management of Complications: A Statement for Healthcare Professionals From the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: Endorse by the Infection Disease Society of America.” Circulation 111: e394–e434.

Chap T er Bacterial Meningitis 32 Tamer Fakhouri, mD CASE A 25-year-old man presents to the emergency department (ED) for evaluation of a 6-hour history of severe headache, fever, photophobia, and neck stiffness. On physical examination, the patient has nuchal rigidity and a temperature of 103.4°F. A lumbar puncture (LP) is performed, and cerebrospinal fluid (CSF) analysis reveals 2200 WBCs/μL, 90% of which are polymorphonuclear (PMN) cells. 1. What is the suspected diagnosis and why? This patient is presenting with signs and symptoms of systemic toxicity and meningeal irritation. A neutrophilic infiltrate in the CSF with many WBCs are specific findings for bacterial meningitis. Bottom line: Signs and symptoms of meningeal irritation along with a neutrophilic leukocytosis in the CSF are highly suggestive of bacterial meningitis. 2. What are the most reliable diagnostic signs of bacterial meningitis on physical examination? A nationwide prospective study of 696 cases conducted in the Netherlands in 2004 found that only 44% of patients with acute bacterial meningitis manifested the triad of fever, neck stiffness, and altered mental status.1 Approximately 95% of patients presented with at least 2 of the following 4 symptoms: headache, altered mental status as defined by a Glasgow Coma Score (GCS) under 14, fever, or neck stiffness. When considering each symptom individually, the presence of headache was found to be most sensitive, followed by neck stiffness, fever, and then altered mental status (Table 32.1). A systematic literature review in the Journal of the American Medical Association (JAMA) arrived at similar sensitivities for the above 395 TAblE 32.1 Sensitivity of Signs and Symptoms for Meningitis Symptom Sensitivity (%) Any 2 of the following: headache, neck 95 stiffness, temperature greater than 38°C, or altered mental status Headache 87 Neck stiffness 83 Temperature greater than 38°C 77 Altered mental status 69 findings. Notably, the presence of either headache, altered mental status, or fever was found to be 99% sensitive for acute bacterial meningitis, making the absence of these signs useful in assessing the need for LP.2 Signs of meningeal irritation, including the Kernig and Brudzinski signs, were found to have poor diagnostic accuracy for acute bacterial meningitis in a prospective study of 297 adult patients with suspected meningitis.3 The Kernig sign is assessed with the patient lying supine with knees and hips flexed to 90°. When the sign is positive, passive extension of the knee causes pain. Brudzinski’s sign is positive when flexion of the neck causes involuntary flexion of the hip and knee. Patients enrolled in the study were adults older than 16 years with clinically suspected meningitis. Clinical suspicion was based on symptoms including fever, headache, stiff neck, photophobia, nausea, and vomiting. In contrast, a prospective study of 54 febrile patients with recent-onset headache showed that jolt accentuation of headache was 97% sensitive for the presence of CSF pleocytosis.4 Jolt accentuation is evaluated by asking the patient to rapidly rotate his or her head laterally with a positive result based on worsening of the patient’s headache. The positive and negative likelihood ratios of jolt accentuation based on the study are 2.42 and 0.5, respectively. Bottom line: The presence of headache, altered mental status, or fever is approximately 99% sensitive for acute bacterial meningitis, making the absence of these signs useful in assessing the need for LP. 3. What CSF findings determine the need for antibiotic therapy? The variety of CSF chemistry and cytology findings among cases of acute bacterial meningitis is sufficiently wide to prevent the use of specific abnormalities in ruling out the disease.5 For example, in the Dutch National Study, 12% of patients with bacterial meningitis had no CSF findings predictive of meningitis.1 On the other hand, several individual findings have excellent specificity (at least 99%) in ruling in bacterial meningitis: A CSF glucose level <1.9 mmol/L, a CSF–blood glucose ratio <0.23, a CSF protein level >2.2 g/L, >2000 × 106/L CSF leukocytes, or >1180 × 106/L CSF PMN leukocytes.6 The sensitivity of CSF Gram stain has been estimated between 50% and 90% for all cases of bacterial meningitis and between 81% and 93% in patients with pneumococcal disease.5 Bottom line: Several CSF findings are extremely specific for bacterial meningitis. These include low CSF glucose, a low CSF–blood glucose ratio, a high CSF protein level, and markedly elevated CSF leukocytes or PMNs. 4. What factors in acute bacterial meningitis are associated with a poor outcome? In a retrospective cohort study of 269 patients with LP-proven bacterial meningitis, 3 factors on initial presentation to the emergency room were associated with elevated mortality or persistent neurologic deficit on hospital discharge: hypotension, altered mental status, and seizures, with odds ratios of 2.39, 7.26, and 4.94, respectively. The authors devised a prognostic model based on the presence of the abovementioned factors and showed an escalating risk of adverse outcomes for patients with 0 (9%), 2 (35%), or all 3 factors (57%).7 In the Dutch National Study, unfavorable outcomes were defined as a score of 4 or less on the Glasgow Outcome Scale (GOS) (Table 32.2). Risk factors strongly associated with poor outcomes include CSF WBC count under 1000, heart rate over 120, positive blood culture, and advanced age (Table 32.3).1 The mortality rate for pneumococcal infection was 30% versus 7% for meningococcal infection, and infection with Streptococcus pneumoniae was strongly associated with an TAblE 32.2 GOS Scoring for Unfavorable Outcomes in Meningitis GOS score Outcome 1 Death 2 Vegetative state 3 Severe disability (unable to live independently) 4 Moderate disability (unable to return to work or school) 5 Mild or no disability Abbreviation: GOS, Glasgow Outcome Scale. TAblE 32.3 Characteristics Associated with an Unfavorable Outcome Characteristics Odds ratio P Value Advanced age 1.19 .005 HR >120 bpm 2.67 .002 CSF WBC count 100–999 2.82 <.001 CSF WBC count <100 3.43 .001 Positive blood culture 2.24 .009 Abbreviations: HR, heart rate; CSF, cerebrospinal fluid; WBC, white blood corpuscles. unfavorable outcome (odds ratio 6.0). In addition, clinical factors associated with pneumoccocal infection such as otitis or sinusitis, immunocompromised status, and the absence of rash were also found to predict an unfavorable outcome. A prospective, multicenter observational study found that a delay in antibiotic administration greater than 3 hours was independently associated with mortality at 3 months with an odds ratio of 14.12.8 A retrospective study of 123 cases of acute bacterial meningitis also found delay of antibiotic administration to be associated with mortality with an odds ratio of 8.4. The same study found that patients undergoing computed tomography (CT) scan before LP were 5.6 times more likely to be treated with antibiotic therapy, later than 6 hours after presentation.9 Bottom line: The coexistence of hypotension, altered mental status, and/or seizures with confirmed bacterial meningitis is associated with elevated mortality or persistent neurologic deficit on hospital discharge. One study showed an escalating risk of adverse outcomes for patients with 0 (9%), 2 (35%), or all 3 factors (57%). 5. When should patients receive a screening CT scan to exclude mass lesion prior to lP? In the absence of clinical suspicion for an intracranial mass, current guidelines recommend against the use of CT given the risks inherent in delaying therapy for bacterial meningitis. When CT is warranted, empiric therapy should be initiated before diagnostic LP.10 A prospective study of 301 adults with suspected meningitis identified numerous clinical features that were associated with an abnormal finding on cranial CT (Table 32.4). The authors found that the absence of all of the abovementioned clinical features excluded abnormalities on CT with a negative predictive value of 97%. In the same study, patients undergoing CT prior TAblE 32.4 Clinical Features Associated with an Abnormal Head CT11 Risk P Feature ratio value Immunocompromised 1.8 .01 History of CNS disease 4.8 <.001 Seizure within 1 wk of presentation 3.2 <.001 Abnormal level of consciousness 3.3 <.001 Inability to answer 2 questions correctly 3.8 <.001 Inability to follow 2 commands correctly 3.9 < 0.001 Gaze palsy 3.2 .003 Abnormal visual fields 4.0 <.001 Facial palsy 4.9 <.001 Arm drift 4.0 <.001 Leg drift 4.4 <.001 Abnormal language 4.3 <.001 Abbreviations: CT, computed tomography; CNS, central nervous system. to LP experienced a significant delay in the mean time interval from ED presentation to admission (5.3 vs. 3 h, P < .001). There was also a trend toward increased mean time interval from ED presentation to the administration of empiric antibiotic therapy, although this was not statistically significant. A prospective study of 113 adults compared clinical history and findings from physical examination to noncontrast CT scan of the head in predicting lesions that would contraindicate LP. The overall clinical impression of the examining physician had high predictive value in identifying patients with contraindicating lesions (positive likelihood ratio [LR], 18.8; 95% confidence interval [CI], 4.8– 43). Three statistically significant predictors were papilledema (positive LR, 11.1; 95% CI, 1.1–115), focal neurologic examination (positive LR, 4.3; 95% CI, 1.9–10), and altered mentation (positive LR, 2.2; 95% CI, 1.5–3.2).12 Bottom line: In a patient with suspected bacterial meningitis, a head CT scan is not required unless there is clinical concern for an intracranial mass. When CT is warranted, empiric therapy should be initiated prior to performing a diagnostic LP. 6. What is the effect of antibiotic therapy on the diagnostic utility of lP? The administration of antibiotic therapy in the first few hours preceding LP appears to have limited effects on CSF chemistry and cytology.13 A study of 128 children with bacterial meningitis showed sterilization of the CSF within 2 hours in 3 of 9 cases of meningococcal meningitis, and within 4–10 hours in patients with pneumococcal meningitis.14 Bottom line: If an LP can be performed within the first few hours, the administration of intravenous antibiotics is unlikely to substantially reduce the diagnostic sensitivity of CSF analysis. 7. When should patients receive dexamethasone? Current guidelines for the treatment of bacterial meningitis in adults recommend the use of dexamethasone in patients with suspected or proven pneumoccocal meningitis beginning 10–20 minutes before their first dose of antibiotic therapy at a dose of 0.15 mg/kg q6h for 2–4 days. The timing of corticosteroid therapy was shown to be important in one study where the likelihood of an unfavorable outcome was much higher in patients given dexamethasone after receiving antibiotic therapy versus those who received dexamethasone before antibiotics.1 Thus, corticosteroids should only be started before or at the time of the first dose of antibiotics. Corticosteroids should be continued only if infection with S. pneumoniae is supported by the results of Gram stain, blood culture, or CSF culture, as data supporting its use in infection with other bacterial pathogens are not available.10 In a prospective, randomized, double-blind trial in 301 European patients with bacterial meningitis, adjuvant dexamethasone therapy, significantly, reduced overall mortality and unfavorable neurological sequelae.15 Patients receiving a 4-day course of dexamethasone therapy initiated 15–20 minutes before their first dose of antibiotics had a mortality rate of 7% versus 15% with placebo (relative risk (RR), 0.48; 95% CI, 0.24–0.96). Patients in the treatment group also had an improvement in the rate of any unfavorable outcome, defined in the study as death, focal neurologic deficit at 8 weeks, or hearing loss at 8 weeks (15% vs. 25%; RR, 0.59; 95% CI, 0.37–0.94). Importantly, significant differences in primary and secondary outcomes were only seen within the subset of patients with pneumococcal disease by culture. Differences between the treatment and placebo groups for patients with pneumococcal disease were as shown in Table 32.5. A recent Cochrane review of 18 studies showed significant protection against death (RR, 0.57; 95% CI, 0.40–0.81) and short-term neurological sequelae (RR, 0.42; 95% CI, 0.22–0.87) in adults treated with corticosteroids.16 Bottom line: In suspected or proven pneumoccocal meningitis, dexamethasone should be given before the first dose of antibiotic therapy. TAblE 32.5 Outcome Differences in Pneumococcal Meningitis Corticosteroid Placebo RR, P Outcome group group (95% CI) value All unfavorable 26% 52% 0.50 .006 outcomes (0.30–0.83) Death 14% 34% 0.41 .02 (0.19–0.86) Adapted from Ref [15]. In the subset of patients with pneumoccocal meningitis, there were significant differences in the rate of unfavorable outcome only in those with intermediate neurologic deficits defined by a GCS of 8–11. However, recent guidelines recommend against the use wwof the GCS in selecting appropriate candidates for adjuvant therapy to avoid delay in treatment.10 TAKE-HOME POINTS: bACTERIAl MENINGITIS 1. While the physical examination is helpful in ruling out bacterial meningitis, there are no clinical signs that have been shown to be specific for the disease. 2. By contrast, CSF chemistries and cytology have poor sensitivity but can be highly specific. 3. Patients should receive head CT before LP only if there is clinical suspicion for mass effect or bleed, and in this scenario, they should be treated empirically with broad-spectrum antibiotics before the LP is performed. 4. Dexamethasone should be administered at the time of the first dose of antibiotic therapy to patients with suspected or proven pneumococcal meningitis. REFERENCES 1. van de Beek, D., J. de Gans, L. Spanjaard, M. Weisfelt, J. B. Reitsma, and M. Vermeulen. 2004. “Clinical Features and Prognostic Factors in Adults with Bacterial Meningitis.” The New England Journal of Medicine 351 (18): 1849– 59. 2. Attia, J., R. Hatala, D. J. Cook, and J. G. Wong. 1999. “The Rational Clinical Examination: Does this Adult Patient Have Acute Meningitis?” The Journal of the American Medical Association 282: 175–81. 3. Thomas, K. E., R. Hasbun, J. Jekel, and V. J. Quagliarello. 2002. “The Diagnostic Accuracy of Kernig’s Sign, Brudzinski’s Sign, and Nuchal Rigidity in Adults with Suspected Meningitis.” Clinical Infectious Diseases 35 (1): 46– 52. 4. Uchihara, T., and H. Tsukagoshi. 1991. “Jolt Accentuation of Headache: The Most Sensitive Sign of CSF Pleocytosis.” Headache 31: 167–71. 5. Fitch, M. T., and D. van de Beek. 2007. “Emergency Diagnosis and Treatment of Adult Meningitis.” The Lancet Infectious Diseases 7: 191. 6. Spanos, A., F. E. Harrell, and D. T. Durack. 1989. “Differential Diagnosis of Acute Meningitis, an Analysis of the Predictive Value of Initial Observations.” The Journal of the American Medical Association 262: 2700. 7. Aronin, S. I., P. Peduzzi, and V. J. Quagliarello. 1998. “CommunityAcquired Bacterial Meningitis: Risk Stratification for Adverse Clinical Outcome and Effect of Antibiotic Timing.” Annals of Internal Medicine 129: 862–69. 8. Auburtin, M., M. Wolff, J. Charpentier, E. Varon, B. Mourvillier, F. Bruneel, J. D. Ricard, and J. F. Timsit. 2006. “Detrimental Role of Delayed Antibiotic Administration and Penicillin-Nonsusceptible Strains in Adult Intensive Care Unit Patients with Pneumococcal meningitis: The PNEUMOREA Prospective Multicenter Study.” Critical Care Medicine 34 (11): 2758–65. 9. Proulx, N., D. Fréchette, B. Toye, J. Chan, and S. Kravcik. 2005. “Delays in the Administration of Antibiotics are Associated with Mortality from Adult Acute Bacterial Meningitis.” QJM: An International Journal of Medicine 98 (4): 291–98. 10. Tunkel, A. R., B. J. Hartman, S. L. Kaplan, B. A. Kaufman, K. L. Roos, W. M. Scheld, and R. J. Whitley. 2004. “Practice Guidelines for the Management of Bacterial Meningitis.” Clinical Infectious Diseases 39: 1267. 11. Hasbun, R., J. Abrahams, J. Jekel, and V. J. Quagliarello. 2001. “Computed Tomography of the Head Before Lumbar Puncture in Adults with Suspected Meningitis.” The New England Journal of Medicine 345 (24): 1727–33. 12. Gopal, A. K., J. D. Whitehouse, D. L. Simel, and G. R. Corey. 1999. “Cranial Computed Tomography Before Lumbar Puncture: A Prospective Clinical Evaluation.” Archives of Internal Medicine 159 (22): 2681–85. 13. Blazer, S., M. Berant, and U. Alon. 1983. “Bacterial Meningitis. Effect of Antibiotic Treatment on Cerebrospinal Fluid.” American Journal of Clinical Pathology 80 (3): 386–87. 14. Kanegaye, J. T., P. Soliemanzadeh, and J. S. Bradley. “Lumbar Puncture in Pediatric Bacterial Meningitis: Defining the Time Interval for Recovery of Cerebrospinal Fluid Pathogens After Parenteral Antibiotic Pretreatment.” Pediatrics 108 (5): 1169–74. 15. De Gans, J., and D. van de Beek. 2002. “Dexamethasone in Adults with Bacterial Meningitis.” The New England Journal of Medicine 347: 1549. 16. van de Beek, D., J. de Gans, P. McIntyre, and K. Prasad. 2007. “Corticosteroids for Acute Bacterial Meningitis.” Cochrane Database of Systematic Reviews 7 (3): 191–200.

CHAPTER Cellulitis 33 BRANDON OLIVIERI, MD CASE A 65-year-old man with a history of chronic lymphedema of the left leg presents to the emergency department (ED) for evaluation of a painful, erythematous swelling of the left shin. The swelling and erythema began around the toes and has spread to mid-calf level. On examination, the patient is well appearing, afebrile, and alert and oriented. The skin on his left lower extremity is circumferentially erythematous, edematous, tender, and warm to the touch from his toes to mid-calf (Figure 33.1). Tenderness does not extend beyond the area of erythema. Foot examination is suggestive of tinea pedis infection in the interdigital spaces. 1. What is the likely diagnosis and why? Cellulitis. The history of chronic lymphedema and tinea pedis along with the presence of a warm, edematous, erythematous and tender lesion on his lower extremity are all very suggestive of cellulitis. Rarer, but potentially catastrophic conditions that can be difficult to distinguish from cellulitis include osteomyelitis and deep vein thrombosis (DVT). Other potential diagnoses include contact dermatitis, drug or foreign body reactions, venous stasis dermatitis, and gout. Because this patient is not displaying signs of systemic toxicity and the tenderness does not extend beyond the borders of the lesion, more serious diagnoses such as necrotizing fasciitis are unlikely (see Section 4). 2. What risk factors does the evidence suggest predispose to the development of cellulitis? In one case-control study involving 167 patients admitted to the hospital for cellulitis and 294 control subjects, it was found that the presence of lymphedema (odds ratio [OR], 71.2; 95% CI, 5.6–908) and a portal of entry for infectious agents (OR, 23.8; 95% CI, 10.7–52.5) were 403

FIGURE 33.1 Rash on presentation. Adapted from © Elsevier. Boon et al.: Davidson’s Principles and Practice of Medicine 20e—www.studentconsult.com. major risk factors for development of cellulitis by multivariate analysis.1 Venous incompetence, leg edema, and obesity were also associated with development of cellulitis (OR: 2.9, 2.5, and 2, respectively).1 The study also demonstrated that 61% of the cases of cellulitis were attributable to the presence of toe web intertrigo.1 A separate casecontrol study also found significantly higher rates of toe web intertrigo in patients with cellulitis compared with controls subjects.2 In a recent prospective case-control study involving 100 subjects with cellulitis and 200 control subjects matched for age and sex who were admitted to a university hospital, risk factors for cellulitis were found to include history of cellulitis (OR, 31.04; 95% CI, 4.15–232.20), presence of Staphylococcus aureus and/or b-hemolytic streptococci in the intertriginous areas (OR, 28.97; 95% CI, 5.47–153.48), presence of leg erosions/ulcers (OR, 11.80; 95% CI, 2.47–56.33), and prior saphenectomy (OR, 8.49; 95% CI, 1.62–44.52).3 In this study, tinea pedis interdigitalis was associated with cellulitis when concomitant toe web bacteria were excluded from the analysis (OR, 3.86; 95% CI, 1.32– 11.27).3 This indicates that while the presence of toe web dermatophytes may be an independent risk factor for cellulitis of the lower leg, the presence of bacteria in theses spaces appears to be an even larger risk factor. Although dermatophytes in the intertriginous spaces do not cause cellulitis, their presence weakens the epithelial barrier, providing a site of entry for bacterial pathogens. This is important because they appear to be a potentially treatable risk factor. Effective agents against dermatophytes include imidazoles (clotrimazole and miconazole), allylamines (terbinafine), and substituted pyridones (ciclopirox and olamine). Table 33.1 gives a comprehensive listing of cellulitis risk factors. Bottom line: The most significant risk factors for developing cellulitis appear to be lymphedema, a portal of entry site, prior history of cellulitis, and the presence of intertriginous S. aureus and/or b-hemolytic streptococci. An important treatable risk factor for cellulitis is tinea pedis interdigitalis. TABLE 33.1 Cellulitis Risk Factors and Associated Odds Ratios Risk Factor Odds Ratio Reference Lymphedema 71.2 [1] History of cellulitis 31.04 [3] S. aureus and/or 28.97 [3] b -hemolytic strepto cocci in the intertrigi nous areas Portal of entry 23.8 [1] Leg erosions/ulcers 11.80 [3] Prior saphenectomy 8.49 [3] Tinea pedis interdigitalis 3.86 [3] Venous incompetence 2.9 [1] Leg edema 2.5 [1] Obesity 2.0 [1] 3. When should patients with severe cellulitis receive imaging tests? What is the modality of choice? It can sometimes be difficult to differentiate a complicated case of cellulitis from more serious conditions such as osteomyelitis, necrotizing fasciitis, or a deep abscess. Therefore, the clinician must have a high level of suspicion for more serious diagnoses when approaching the patient with cellulitis. Imaging techniques have significant diagnostic utility in this setting. Although computed tomography (CT) scans and conventional radiographs can be a useful adjunct to clinical suspicion in diagnosing more complicated infectious processes, they have limitations. In one study of 65 patients with necrotizing soft tissue infections, only 29% of subjects had evidence of soft- tissue gas in CT scans or plain radiographs.4 In another study of 148 patients with necrotizing soft tissue infections, 27% of subjects had no evidence of soft- tissue gas in CT scans or plain radiographs.5 Magnetic resonance imaging (MRI) appears to be the modality of choice for diagnosing necrotizing fasciitis. In one retrospective review of 11 patients, MRI was found to have a sensitivity of 100%, a specificity of 86%, and an accuracy of 94% for the detection of necrotizing fasciitis.6 MRI also appears useful in diagnosing an underlying osteomyelitis. A systematic review of 16 studies of diagnostic test performance of MRI in patients with suspected osteomyelitis revealed that MRI was associated with 90% sensitivity and 82.5% specificity for osteomyelitis. MRI had better diagnostic test performance than plain radiography, 99m-Tc bone scanning, and white blood cell scanning.7 In some cases, a broad area that appears to be cellulitis can conceal a deep abscess. In the detection of such deep abscesses, bedside ultrasonography is a practical yet effective imaging modality, as it has been shown to have higher sensitivity and specificity (98% and 88%, respectively) than clinical examination alone (sensitivity of 86% and specificity of 70%).8,9 Bottom line: The clinician must maintain a high-level of suspicion for other serious diagnoses such as osteomyelitis, necrotizing fasciitis, or deep abscess. MRI is the imaging modality of choice for ruling out necrotizing fasciitis and may also be the preferred imaging modality for diagnosing osteomyelitis. Ultrasound is highly sensitive and reasonably specific for diagnosing a deep abscess. 4. How can one differentiate simple cellulitis from more severe infections? Simple cellulitis is often difficult to differentiate from more severe soft-tissue infections such as necrotizing fasciitis. Even though these conditions are rare, the clinician’s level of suspicion must remain high, as early debridement may be limb or life saving. To aid the clinician in diagnosis of necrotizing fasciitis, several algorithms have been developed. Traditionally, the diagnostic signs of necrotizing fasciitis have included skin necrosis, crepitus, and hemorrhagic bullae. However, in a retrospective review of 22 patients, it was found that these characteristic signs are only present late in the progression of necrotizing fasciitis, while early on, clinical features common to cellulitis (such as swelling, pain, and warmth to palpation) were the only significant clinical features.10 Wang et al. do note the key examination findings useful in distinguishing cellulitis from early necrotizing fasciitis. These include tenderness over normal appearing skin beyond affected area, pain out of proportion to physical findings, as well as lack of lymphangitis, all of which are supportive of early necrotizing fasciitis.10 In diabetics and other immunocompromised individuals, systemic symptoms of toxicity may not even be apparent. In one retrospective review of patient’s with necrotizing fasciitis, only 53% were febrile at presentation and 18% were hypotensive at presentation.11 Another algorithm for distinguishing cellulitis from more severe infections when diagnosis is equivocal is the LRINEC score, which takes into account the patient’s C-reactive protein (CRP) level, WBC count, hemoglobin concentration, and sodium, creatinine, and glucose concentrations.12 This scoring system is used to stratify patients into low, moderate, or high-risk categories to determine the need for further evaluation for necrotizing fasciitis (Table 33.2). In one observational study, a cohort of 89 patients who had been diagnosed with necrotizing fasciitis were retrospectively analyzed. It was found that many cases of this potentially catastrophic condition were initially missed, with physicians raising the diagnosis or suspicion of necrotizing fasciitis in only 13 (14.6%) patients on admission. However, when LRINEC scores were retrospectively calculated based on data available on admission, 80 (89.9%) of the 89 patients who went on to develop necrotizing fasciitis were found to have had a LRINEC score of ≥6, indicating increased suspicion for necrotizing fasciitis.12 Therefore, one can infer that 89.9% of the cases of necrotizing fasciitis in this study group may have been diagnosed earlier if a LRINEC score had been calculated on admission. Although the LRINEC score is reported to be sensitive even in early cases of necrotizing fasciitis, prospective studies coupling defined markers of severity to outcomes are lacking.12 TABLE 33.2 LRINEC Score Parameters Units CRP (mg/L) <150 0 150 or more 4 Total WBC count (per mm3) <15 0 15–25 1 >25 2 Hemoglobin (Hb) (g/dL) >13.5 0 11–13.5 1 <11 2 Sodium (Na) (mmol/L) 135 or more 0 <135 2 Creatinine (Cr) (μmol/L) 141 or less 0

141 2 Glucose (mmol/L) 10 or less 0 >10 1 Reproduced from Wong et al. The LRINEC score is calculated by summation of the 6 individual parameters mentioned earlier. The maximum score is 13; a score of 6 or greater should raise the suspicion of necrotizing fasciitis and a score of 8 or greater is strongly predictive of this disease. Bottom line: Necrotizing fasciitis is a clinical emergency that must be dealt with immediately but is often difficult to distinguish from cellulitis, so the clinician must maintain a high-level of suspicion. Studies have demonstrated several findings and algorithms to be effective in diagnosing necrotizing fasciitis, including pain over normal appearing skin, pain out of proportion of physical findings, and the LRINEC score. 5. Does the evidence support obtaining blood cultures or performing a biopsy in this patient? In a prospective study of 103 otherwise healthy patients with cellulitis, needle aspiration was performed on areas of cellulitis to isolate pathogenic organisms. Only 15 of 173 needle aspirates performed yielded pathogens, a yield of 8.7%.13 In a prospective study of 30 patients with cellulitis and multiple comorbidities, it was found that needle aspiration led to successful pathogen isolation in only 10% of cases.14 Because of the low yield of culture, it is thought that empiric treatment covering typical organisms should be given without attempts at culture (see Section 5). However, in a prospective microbiological evaluation of 87 patients with acute cellulitis, it was found that adult patients with concomitant diabetes mellitus or malignant disorders had a greater frequency of positive cultures, signifying that in these individuals it may be more rewarding to attempt aspiration and culture.15 Therefore, in these patients, as well as those with immunodeficiency or unusual precipitating injuries (animal bites or immersion injuries), wound cultures may be more fruitful.16 In a retrospective study of 553 patients admitted to a medical center for community acquired cellulitis with a total of 710 blood cultures (1.3 cultures per patient), there was only a significant patient-specific microbial strain isolated in 11 patients (2.0%).17 The cost of laboratory workup of the 710 culture sets was $36,050. A similarly designed study in children provided comparable results.18 Bottom line: In the uncomplicated cellulitis patient, blood cultures and biopsy of lesions appear to have low yield and are not cost effective. Therefore, in the typical cellulitis patient, these tests should not be ordered. 6. What organisms should be targeted when treating the patient with cellulitis? Traditionally, cellulitis was most often thought to be caused by Group A streptococci. However, a systematic review of the literature was recently published that involved 16 studies dating from 1975 to 1996 and a total of 808 cellulitis patients without concomitant infection or breaks in the skin.19 All of these patients had either needle or punch biopsy of their cellulitis, and although only 15.7%–16.0% of biopsies generated positive results, S. aureus outnumbered Group A streptococci by a ratio of 2:1.19 Based on data from the National Nosocomial Infections Surveillance (NNIS) System, currently 59.5% of all S. aureus nosocomial isolates are methicillin- resistant S. aureus (MRSA).20 Therefore, when treating cellulitis, the clinician must have a fair degree of suspicion for MRSA. In several case-control studies, risk factors consistently found to be independently associated with nosocomial MRSA infection include previous hospitalization in the past 12 months, longer length of stay, previous surgery, enteral feedings, and previous exposure to macrolide or levofloxacin antibiotics.†21–23 Empirical coverage for simple cellulitis should cover GAS and MSSA. Empirical coverage of MRSA should be added after considering the prevalence of MRSA in the region, patient’s individual risk factors, and the severity of the infection (as determined by inflammatory markers such as fever, white count, tachycardia, hypotension, and evidence of organ dysfunction).24–25 Bottom line: Treatment for cellulitis should cover group A streptococcus and S. aureus, with empirical coverage of MRSA based on risk factors, local prevalence, severity of infection, and persistence of infection despite treatment. TAKE-HOME POINTS: CELLULITIS 1. The differential for cellulitis should include necrotizing fasciitis, gout, contact dermatitis, vascular causes (DVT and venous stasis dermatitis), foreign body reactions, and cellulitis with concomitant osteomyelitis or deep abscess. 2. The major risk factors for cellulitis are lymphedema and a portal of entry site. An important treatable risk factor for cellulitis is tinea pedis in the interdigital spaces. 3. MRI is a useful imaging modality when attempting to rule out necrotizing fasciitis and osteomyelitis. Ultrasound is a practical and effective modality to rule out deep abscesses. 4. The clinician must hold necrotizing fasciitis with a high level of suspicion as it is often difficult to differentiate from cellulitis. Factors that may help to differentiate early necrotizing fasciitis from cellulitis include pain over normal- appearing skin, pain out of proportion to physical findings, and a high LRINEC score. 5. Treatment for cellulitis should cover group A strep and S. aureus, with empirical coverage of MRSA based on risk factors, local prevalence, severity of infection, and persistence of infection despite treatment. No studies specify the time frame of when surgery was conducted in relation to infection or what surgery was performed. All studies allude to recent surgery during the same hospital admission and refer specifically to surgical site infections. †Multiple retrospective studies refer to “previous exposure” to these antibiotics but do not specify a definite time frame. The studies note that previous exposure to these antibiotics leads to colonization with MRSA at some point, which then leads to infection later on. REFERENCES 1. Dupuy, A., H. Benchikhi, J. C. Roujeau, et al. 1999. “Risk Factors for Erysipelas of the Leg (Cellulitis): Case-Control Study.” British Medical Journal 318: 1591–94. 2. Roujeau, J., B. Sigurgeirsson, H. Korting, H. Kerl, and C. Paul. 2004. “Chronic Dermatomycoses of the Foot as Risk Factors for Acute Bacterial Cellulitis of the Leg: A Case-Control Study.” Dermatology 209: 301–7. 3. Bjornsdottir, S., et. al. 2005. “Risk Factors for Acute Cellulitis of the Lower Limb: A Prospective Case-Control Study.” Clinical Infectious Diseases 41: 1416–22. 4. McHenry, C. R., J. J. Piotrowski, D. Petrinic, et al. 1995. “Determinants of Mortality for Necrotizing Soft-Tissue Infections.” Annals of Surgery 221 (5): 558–65. 5. “Elliott, D. C., J. A. Kufera, and R. A. Myers. 1996. “Necrotizing Soft Tissue Infections. Risk Factors For mortality and Strategies for Management.” Annals of Surgery 224 (5): 672–83. 6. Schmid, M. R., T. Kossmann, and S. Duewell. 1998. “Differentiation of Necrotizing Fasciitis and Cellulitis using MR Imaging.” American Journal of Roentgenology 170 (3): 615–20 7. Felson, D. T., et al. 2007. “Magnetic Resonance Imaging for Diagnosing Foot Osteomyelitis: A Meta-Analysis.” Archives of Internal Medicine 167 (2): 125– 32. 8. Tayal, V. S., N. Hasan, H. J. Norton, et al. 2006. “The Effect of SoftTissue Ultrasound on the Management of Cellulitis in the Emergency Department.” Academic Emergency Medicine 13 (4): 384–88. 9. Squire, B. T., J. C. Fox, and C. Anderson. 2005. “ABSCESS: Applied Bedside Sonography for Convenient Evaluation of Superficial Soft Tissue Infections.” Academic Emergency Medicine 12 (7): 601–6. 10. Wang, Y. S., C. H. Wong, and Y. K. Tay. 2007. “Staging of Necrotising Fasciitis Based on the Evolving Cutaneous Features.” International Journal of Dermatology 46 (10): 1036–41. 11. Wong, C. H., H. C. Chang, S. Pasupathy, L. W. Khin, J. L. Tan, and C. O. Low. 2003. “Necrotizing Fasciitis: Clinical Presentation, Microbiology, and Determinants of Mortality.” The Journal of Bone and Joint Surgery. American 85-A (8): 1454–60. 12. Wong, C. H., L. W. Khin, K. S. Heng, et al. 2004. “The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) Score: A Tool for Distinguishing Necrotizing Fasciitis from Other Soft Tissue Infections.” Critical Care Medicine 32: 1535–41. 13. Epperly, T. D. 1986. “The Value of Needle Aspiration in the Management of Cellulitis.” The Journal of Family Practice 23 (4): 337–40. 14. Newell, P. M. and C. W. Norden. 1988. “Value of Needle Aspiration in Bacteriologic Diagnosis of Cellulitis in Adults.” Journal of Clinical Microbiology 26: 410–04. 15. Kielhofner, M. A., B. Brown, and L. Dall. 1988. “Influence of Underlying Disease Process on the Utility of Cellulitis Needle Aspirates.” Archives of Internal Medicine 148: 2451–52. 16. Stevens, D. L., et al. 2005. “Practice Guidelines for the Diagnosis and Management of Skin and Soft-Tissue Infections.” Clinical Infectious Diseases 41: 1373–406. 17. Perl, B., N. P. Gottehrer, D. Raveh, Y. Schlesinger, B. Rudensky, and A. M. Yinnon. 1999. “Cost-Effectiveness of Blood Cultures for Adult Patients with Cellulitis.” Clinical Infectious Diseases 29: 1483–88. 18. Berger Sadow, K., and J. M. Chamberlain. 1998. “Blood Cultures in the Evaluation of Children with Cellulitis.” Pediatrics 101: 1–4. 19. Chira, S., and L. G. Miller. 2010. “Staphylococcus aureus is the Most Common Identified Cause of Cellulitis: A Systematic Review.” Epidemiology and Infection 138(3): 313–7. 20. NNIS. 2004. “National Nosocomial Infections Surveillance (NNIS) System Report, data Summary from January 1992 Through June 2004, Issued October 2004.” American Journal of Infection Control 32 (8): 470–85. 21. Fernandez, C., et al. 1995. “Mortality Associated with Nosocomial Bacteremia Due to Methicillin-Resistant Staphylococcus aureus.” Clinical Infectious Diseases 21 (6): 1417–23. 22. Gold, H. S., et al. 2003. “Flouroquinolones and the Risk for Methicillin- Resistant Staphylococcus aureus in Hospitalized Patients.” Emerging Infectious Diseases 9 (11): 1415–22. 23. Graffunder, E. M., and R. A. Venezia. 2002. ”Risk Factors Associated with Nosocomial Methicillin-Resistant Staphylococcus aureus (MRSA) Infection Including Previous Use of Antimicrobials.” The Journal of Antimicrobial Chemotherapy (6): 999–1005. 24. Stevens, D. L. 2009. “Treatments for Skin and Soft-Tissue and Surgical Site Infections Due to MDR Gram-Positive Bacteria.” Journal of Infection 59 (S1): S32–39. 25. Abrahamian, F. M., D. A. Talan, and G. J. Moran. 2008. “Management of Skin and Soft-Tissue Infections in the Emergency Department.” Infectious Disease Clinics of North America 22 (1): 89–116.

Clostridium difficile CHAPTER Infection 34 JESÚS GUTIERREZ, MD, MPH CASE A 78-year-old female presents to the emergency department (ED) for evaluation of a 2-day history of profuse watery diarrhea, lower abdominal pain, and fever. The patient had been in Florida for a few days visiting family when she developed symptoms and was forced to cut her vacation short. Two weeks before her vacation, she was hospitalized for treatment of community-acquired pneumonia with levofloxacin. There is no recent travel history outside the country, sick contacts, or suspicious food consumed and no history of inflammatory bowel disease. Blood pressure (BP) in the ED is 110/70 (supine), temperature is 101.5°F, and WBC is 22,000 with a 25% bandemia. Her medications include levothyroxine, carvedilol, pantoprazole, aspirin, and pravastatin. 1. What is the likely diagnosis and why? Clostridium difficile infection (CDI). CDI should be suspected in patients with otherwise unexplained diarrhea who received antibiotics approximately 1 week (but sometimes up to 2 months) before onset of symptoms. For mild-to-moderate disease, diarrhea is usually the only symptom, with patients experiencing up to but usually considerably less than 10 bowel movements per day. Stools are usually watery with a characteristic foul odor, although mucoid or soft stools also occur. Gross blood in the stool is rare.1 In 1986, a prospective case- controlled study found that fever was present in 28% of cases, abdominal pain in 22%, and leukocytosis in 50%.2 Bottom line: Watery, foul smelling diarrhea and recent antibiotic use (up to 2 months) should raise concerns of CDI. 413 TABLE 34.1 Antimicrobial Agents Associated with Development of C. difficile Diarrhea and Colitis Frequently associated Fluoroquinolones Clindamycin Penicillins Cephalosporins Occasionally associated Macrolides Trimethoprim Sulfonamides Rarely associated Aminoglycosides Tetracyclines Chloramphenicol Metronidazole Vancomycin 2. What are the antibiotics most commonly associated with CDI? Antibiotic use is the most widely recognized risk factor for CDI. Virtually any antibiotic may be implicated, including brief courses of antibiotics that are given prophylactically before surgery.3 The use of broadspectrum antimicrobials and multiple antibiotic agents and increased duration of antibiotic therapy all contribute to the incidence of CDI.4 Historically, CDI has been associated with the use of cephalosporins, clindamycin, and broad-spectrum penicillins.5 More recently, in a large retrospective cohort study of hospitalized patients in Canada, the use of fluoroquinolones emerged as the most important risk factor for CDI6,7 (Table 34.1). Bottom line: Use of any antibiotic is considered to be a risk factor for CDI. In general, antibiotics with anaerobic coverage are more commonly associated with CDI. 3. Are proton pump inhibitors associated with higher risk of CDI? Although the evidence on this issue remains observational, research has shown a significant association between proton pump inhibitor (PPI) use and CDI. In a retrospective study of (170) hospital patients, a positive association between PPI use and CDI was indicated with an odds ratio (OR) of 2.5 (95% confidence interval (CI): 1.5–4.2).8 In addition, a cohort study of 1187 inpatients at a Montreal teaching hospital who received antibiotics showed that use of PPIs was associated with C. difficile diarrhea with an adjusted OR of 2.1 (95% CI 1.2– 3.5). At a similar hospital, 94 cases of C. difficile diarrhea and 94 matched controls using similar antibiotics found an adjusted OR of 2.7 (95% CI 1.4–5.2) with PPIs.9 A more recent systematic review of 12 studies (10 case–control and 2 cohort) containing a total of 2948 patients found that CDI was significantly associated with PPI use (pooled OR, 1.96; 95% CI, 1.28–3).10 Findings from this study indicated that PPI may be an emerging and potentially modifiable risk factor for CDI. Bottom line: The risk of CDI may be compounded by exposure to PPI therapy. This underscores the importance of vigilance in prescribing PPIs only when specifically indicated for therapy, particularly in hospitalized patients, those taking multiple antibiotics, and/or those suffering from multiple comorbidities. 4. How is the diagnosis of CDI made? The American College of Gastroenterology and the National Clostridium difficile Standards Group (UK) recommend testing for anyone with diarrhea who has received antibiotics within the previous 2 months and/or whose diarrhea began 72 hours or more after hospitalization.11,12 In addition, they recommend that diarrheal specimens should be tested by either toxin detection, using a neutralized cell cytotoxicity assay or an immunoassay that detects both toxins A and B. Although the neutralized cell cytotoxicity assay requires >3 days to receive results, special facilities, and specialized labor, it is the current gold-standard. Toxin enzyme immunoassays have significantly lower sensitivities in comparison. Planche et al. performed a systematic review of 18 studies with 8920 patients that compared rapid detection tests to a reference standard of neutralizable C. difficile toxin in cell culture and found varied sensitivities among the tests (76%–96%). Thus, these assays are less than ideal as sole diagnostic tests. This review recommends using a screening test such as toxin A and B ELISA or glutamate dehydrogenase (GDH) followed by cell cytotoxicity assay or culture.13 This two-step algorithm has been studied by Ticehurst et al., who found that this method has reasonably good sensitivity, specificity, and cost, although there is a 24–48 hour delay in the results.14 Moreover, this study reported a sensitivity of only 38% for toxin A and B ELISA. A second study of a two-step algorithm uses a bioassay for GDH as a screening tool. This is followed by testing of the screenpositive samples by a rapid toxin A/B assay. According to the authors, this algorithm allowed exclusion of CDI if the GDH screen was negative (87.3%). Further evaluation for toxins A and B allows diagnosis of another 4.7% within 4 hours. Thus, this algorithm eliminated the need for routine culture in 92% of stool samples.15 PCR is an attractive new option. With a reported sensitivity of 93.3%, it is more sensitive than and as rapid as toxin enzyme immunoassays.16 However, this test remains expensive and will not be widely available in the near term. Moreover, the new Infectious Diseases Society of America (IDSA) guidelines require more data on utility before this new test can be recommended for routine testing.17 Bottom line: Presently, no single test combines good sensitivity and specificity with a rapid turnaround time and low cost. However, the reports of the two-step method indicate that it has reasonably good sensitivity, specificity, and cost. Thus, a positive screening test for GDH should be followed by a confirmatory assay for toxins A and B. In the long term, however, PCR may become the method of choice for the diagnosis of CDI. 5. When should vancomycin therapy be recommended over metronidazole for CDI? The American College of Gastroenterology and the Hospital Infection Control Practices Advisory Committee recommends that oral metronidazole be used as first line therapy for CDI. This recommendation takes into consideration metronidazole’s historic equal efficacy to vancomycin, its lower cost, and the risk of developing vancomycinresistant enterococcal infections.11 The IDSA guidelines published in 1995 recommend the use of either metronidazole or vancomycin for 10 days. However, they also indicate that metronidazole may be preferred because of its lower price and to avoid vancomycin resistance in other nosocomial bacterial species.2 On the contrary, two recent observational studies have suggested that metronidazole’s efficacy is no longer as great as that suggested by previous randomized controlled trials.18,19 In addition, a recent prospective, double-blind, randomized clinical study indicated that the clinical cure rate with oral vancomycin in patients with severe CDI was significantly better than that for metronidazole (97% versus 76%; P < .02).20 Severity of disease was defined as the presence of pseudomembranes on colonoscopy or two of the following: (1) age over 60 years; (2) serum albumin less than 2.5 mg/mL; (3) leukocyte count greater than 15 000 cells/mL; and (4) temperature greater than 38.3°C. This area is under great debate and it seems unclear what the best approach is. The majority of decisions are based on severity of illness, failure of earlier antimicrobial therapy, and patient factors including pregnancy and breast feeding. Bottom line: There is mounting evidence that metronidazole is inferior to vancomycin, at least for patients with severe CDI. Thus, oral vancomycin should be considered a first-line therapy for patients with severe or fulminant infection whose gastrointestinal tract is functioning. However, more studies are needed to validate an approach to determine the severity of disease. 6. What are the options for patients who cannot tolerate oral therapy? Based on anecdotal evidence, intravenous (IV) metronidazole is an alternative therapy for critically ill patients who are unable to take oral antimicrobial agents.21–23 A retrospective review of 10 patients who received IV metronidazole for at least 2 days as the initial therapy for acute CDI when oral therapy was not possible showed that in the majority of patients, symptoms improved without subsequent complications that required surgical intervention.24 A randomized, prospective study of IV metronidazole is needed, but this treatment alone may be inadequate in patients with severe CDI, especially if adynamic ileus is present.25 Bottom line: IV metronidazole appears to be a suitable alternative for most patients who are unable to receive oral therapy. 7. What is the role of intracolonic vancomycin in treating CDI? In patients with severe manifestations of CDI, other methods to ensure effective antimicrobial concentrations at the site of infection should also be undertaken. At one institution, a successful treatment strategy for six patients with severe ileus included oral vancomycin administered by nasogastric tube, vancomycin administered to the colon via a retention enema, and IV metronidazole.26 Shetler et al. subsequently suggested that colonoscopic decompression combined with adjunctive intracolonic vancomycin (ICV) therapy could be used to treat severe pseudomembranous colitis associated with ileus and toxic megacolon. This approach was safe, feasible, and effective; it resulted in complete clinical resolution for four (57%) of seven patients and partial clinical resolution for one patient (14%).27 Bottom line: Together, these reports suggest that adequate concentrations of ICV can be delivered to the site of C. difficile toxin production and inhibit it. However, the issues of the efficacy, dosage, and duration of adjunctive ICV therapy remains to be addressed in future studies. 8. Is there a role of stool transplantation in the treatment of CDI? A recent review by van Nood et al.28 cited 159 cases in which stool transplantation was performed for treatment of recurrent CDI. Of these, 91% of patients were cured after one or two infusions. However, the reports vary significantly in the definition of cure, route of transplantation, origin of stool, and use of antibiotics for pretreatment. More recently, two case series of a total of 31 patients reported a 100% cure rate of recurrent CDI in patients undergoing stool transplantation through colonoscopes.29,30 Based on these reports, it appears that stool transplantation can be considered an effective therapy for patients with CDI. Further studies are needed to develop the best, most effective standardized treatment regimen. Bottom line: Although highly effective in small case studies, stool transplantation needs to be evaluated in larger prospective, controlled trials before it can be regarded as a standard treatment for recurrent CDI. 9. When is surgical consult/surgery indicated for CDI? If these approaches are unsuccessful and the patient’s clinical condition deteriorates, colectomy is the only life-saving alternative.31 According to Koss et al., surgical intervention in the form of subtotal colectomy, which can be lifesaving in fulminant or refractory CDI, is the procedure of choice because reports of hemicolectomy suggest increased mortality.32 However, the optimal timing of surgery is difficult to establish as there are no randomized trials to evaluate this issue. Observational studies suggest that survival is improved with prompt surgical intervention in patients with severe or fulminant infection.33,34 At the same time, clinical research groups are trying to identify objective parameters (i.e., white blood cell > 16 K, concurrent inflammatory bowel disease (IBD), operative therapy in last 30 days, history of intravenous immunoglobulin (IVIG) therapy disease) that will help to identify those patients most likely to benefit from surgery.35 However, even with surgery, hospital mortality among patients undergoing subtotal colectomy for severe CDI is high (48%).36 Bottom line: For now, the best course is to obtain a surgical consultation as soon as fulminant or refractory disease is suspected and to base a decision to operate on close monitoring of the patient’s clinical course. 10. What is the role of biotherapeutic (e.g., probiotics) approaches in treating CDI? Neither the IDSA nor the ACG endorse the use of probiotics in the prevention or treatment of CDI. However, there have been several placebo-controlled, double- blind trials examining their role. A 2006 meta-analysis by McFarland reviewed 31 studies. Twenty-five of these studies found that prophylactic probiotics significantly reduced the subsequent incidence of acute C. difficile diarrhea (RR 0.43; P < .001). The remaining six studies evaluated the efficacy of probiotics as treatment of CDI and prevention of recurrence.37 Although no single study showed significant reduction of recurrence, in aggregate, a significant therapeutic benefit was reported for S. boulardii (RR, 0.59; P = .005). A Cochrane Review found only four studies of sufficient quality for inclusion from 1966 to 2007. This review demonstrated modest benefit only of S. boulardii in both prevention of recurrence and cessation of diarrhea as an adjunct to antibiotic treatment. However, the review concluded that the evidence is not sufficient to recommend probiotic therapy as an adjunct to antibiotics in established CDI.38 More recently, a randomized trial in the UK analyzed a yogurt drink, which contained Lactobacillus casei, L. bulgaricus, and Streptococcus thermophilus, for the prevention of CDI in patients aged greater than 50 years who were prescribed antibiotics. They reported a highly statistically significant reduction in the risk of CDI in the probiotics group.39 However, this study enrolled a highly selected subgroup of patients and excluded those taking “high risk” or more than two recent courses of antibiotics. These are crucial limitations on the generalizability of this study. Bottom line: The potential usefulness of these agents in CDI prevention and treatment should not be dismissed. At this point, however, the number of well- done randomized controlled trials is not sufficient to recommend a specific approach. Further studies are necessary to optimize the type and dose of organisms used. TAKE-HOME POINTS: CLOSTRIDIUM DIFFICILE INFECTION 1. Watery, foul smelling diarrhea and previous antibiotic use (up to 2 months) should raise concerns of CDI. 2. The risk of CDI may be compounded by exposure to PPI therapy. 3. Diagnosis of CDI should be based on a two-step algorithm using a bioassay for GDH as a screening too followed by testing of the screen-positive samples by a rapid toxin A/B assay. In the long-term, PCR may become the test of choice for the diagnosis of CDI. 4. Metronidazole continues to be the first-choice treatment for mild and moderate CDI. However, based on recent evidence, oral vancomycin should be considered as a first-line therapy for patients with severe or fulminant infection whose gastrointestinal tract is functioning. 5. IV metronidazole and intra-colonic vancomycin should be considered in patients who cannot tolerate oral therapy and/or are suffering from adynamic ileus. 6. Although highly effective, stool transplantation needs to be evaluated in larger prospective, controlled trials before it can be regarded as a standard treatment for recurrent CDI. 7. Surgical consultation should be sought as soon as fulminant or refractory CDI is suspected. 8. There is no sufficient evidence to support the use of probiotics for CDI prevention or treatment. REFERENCES 1. Kelly, C. P., and J. T. Lamont. 1998. “ Clostridium difficile Infection.” Annual Review of Medicine 49: 375–90. 2. Gerding, D. N., M. M. Olson, L. R. Peterson, D. G. Teasley, R. L. Gebhard, M. L. Schwartz, and J. T. Lee, Jr. 1986. “Clostridium difficile-associated Diarrhea and Colitis in Adults: A Prospective Case-controlled Epidemiologic Study.” Archives of Internal Medicine 146: 95–100. 3. Dial, S., A. Kezouh, A. Dascal, A. Barkun, and S. Suissa. 2008. “Patterns of Antibiotic Use and Risk of Hospital Admission Because of Clostridium difficile Infection.” Canadian Medical Association Journal 179 (8): 767–72. 4. Bignardi, G. E. 1998. “Risk Factors for Clostridium difficile Infection.” Journal of Hospital Infection 40: 1–15. 5. Bartlett, J. G. 2002. “Antibiotic-associated Diarrhea.” The New England Journal of Medicine 346(5): 334–9. 6. Pepin, J., N. Saheb, M. A. Coulombe, M. E. Alary, M. P. Corriveau, S. Authier, M. Leblanc, et al. 2005. “Emergence of Fluoroquinolones as the Predominant Risk Factor for Clostridium difficile-associated Diarrhea: A Cohort Study During an Epidemic in Quebec.” Clinical Infectious Diseases 41: 1254– 60. 7. Pepin, J., L. Valiquette, and B. Cossette. 2005. “Mortality Attributable to Nosocomial Clostridium difficile-associated Disease During an Epidemic Caused by a Hypervirulent Strain in Quebec.” Canadian Medical Association Journal 173 (9): 1037–42. 8. Cunningham, R., B. Dale, B. Undy, and P. N. G. Gaunt. 2003. “Proton Pump Inhibitors as a Risk Factor for Clostridium difficile Diarrhea.” Journal of Hospital Infection 54: 243–5. 9. Dial, S., K. Alrasadi, C. Manoukian, A. Huang, and D. Menzies. 2004. “Risk of Clostridium difficile Diarrhea Among Hospital Inpatients Prescribed Proton Pump Inhibitors: Cohort and Case–control Studies.” Canadian Medical Association Journal 171 (1): 33–38. 10. Leonard, J., J. K. Marshall, and P. Moayyedi. 2007. “Systematic Review of the Risk of Enteric Infection in Patients Taking Acid Suppression.” American Journal of Gastroenterology 102 (9): 2047–56. 11. Fekety, R. 1997. “Guidelines for the Diagnosis and Management of Clostridium difficile-associated Diarrhea and Colitis.” American Journal of Gastroenterology 92 (5): 739–50. 12. Berrington, A., S. P. Borriello, J. Brazier, G. Duckworth, K. Foster, R. Freeman, F. K. Gould, et al. 2004. “National Clostridium difficile Standards Group: Report to the Department of Health.” Journal of Hospital Infection 56: 1–38. 13. Planche, T., A. Aghaizu, R. Holliman, P. Riley, J. Poloniecki, A. Breathnach, and S. Krishna. 2008. “Diagnosis of Clostridium difficile Infection by Toxin Detection Kits: A Systematic Review.” Lancet Infectious Diseases 8: 777–84. 14. Ticehurst, J. R., D. Z. Aird, L. M. Dam, A. P. Borek, J. T. Hargrove, and K. C. Carroll. 2006. “Effective Detection of Toxigenic Clostridium difficile by a Two-step Algorithm Including Tests for Antigen and Cytotoxin.” Journal of Clinical Microbiology 44(3): 1145–49. 15. Fenner, L., A. F. Widmer, G. Goy, S. Rudin, and R. Frei. 2008. “Rapid and Reliable Diagnostic Algorithm for Detection of Clostridium difficile.” Journal of Clinical Microbiology 46: 328–30. 16. Peterson, L. R., R. U. Manson, S. M. Paule, D. M. Hacek, A. Robicsek, R. B. Thomson, Jr., and K. L. Kaul. 2007. “Detection of Toxigenic Clostridium difficile in Stool Samples by Real-time Polymerase Chain Reaction for the Diagnosis of C. difficile-associated Diarrhea.” Clinical Infectious Diseases 45: 1152–60. 17. Cohen, S. H., D. N. Gerding, S. Johnson, C. P. Kelly, V. G. Loo, L. C. McDonald, J. Pepin, and M. H. Wilcox. 2010. “Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).” Infection Control and Hospital Epidemiology 31(5): 431–55. 18. Pepin, J., M. E. Alary, L. Valiquette, E. Raiche, J. Ruel, K. Fulop, D. Godin, and C. Bourassa. 2005. “Increasing Risk of Relapse After Treatment of Clostridium difficile Colitis in Quebec, Canada.” Clinical Infectious Diseases 40: 1591–7. 19. Musher, D. M., S. Aslam, N. Logan, S. Nallacheru, I. Bhaila, F. Borchert, and R. J. Hamill. “Relatively Poor Outcome After Treatment of Clostridium difficile Colitis with Metronidazole.” Clinical Infectious Diseases 40: 1586–90. 20. Zar, F. A., S. R. Bakkanagari, K. M. Moorthi, and M. B. Davis. 2007. “A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile-associated Diarrhea, Stratified by Disease Severity.” Clinical Infectious Diseases 45: 302–7. 21. Bolton, R. P., and M. A. Culshaw. 1986. “Faecal Metronidazole Concentrations During Oral and Intravenous Therapy for Antibiotic Associated Colitis due to Clostridium difficile.” Gut 27: 1169–72 22. Kleinfeld, D. I., R. J. Sharpe, and S. T. Donta. “Parenteral Therapy for Antibiotic-Associated Pseudomembranous Colitis.” Journal of Infectious Diseases 157(2): 389. 23. Gorshluter, M., A. Glasmacher, C. Hahn, F. Schkowski, C. Ziske, E. Molitor, G. Marklein, T. Sauerbruch, and I. G. H. Schmidt-Wolf. 2001. “Clostridium difficile Infection in Patients with Neutropenia.” Clinical Infectious Diseases 33: 786–91. 24. Friedenber, F., A. Fernandez, V. Kaul, P. Niami, and G. M. Levine. 2001. “Intravenous Metronidazole for the Treatment of Clostridium difficile colitis.” Diseases of the Colon & Rectum 44: 1176–80. 25. Guzman, R., J. Kirkpatrick, K. Forward, F. Lim, D. I. Kleinfeld, and S. T. Donta. 1988. “Failure of Parenteral Metronidazole in the Treatment of Pseudomembranous Colitis.” Journal of Infectious Diseases 158(5): 1146. 26. Olson, M. M., C. J. Shanholtzer, J. T. Lee, and D. N. Gerding. 1994. “Ten Years of Prospective Clostridium difficile-associated Disease Surveillance and Treatment at the Minneapolis VA Medical Center, 1982–1991.” Infection Control and Hospital Epidemiology 15(6): 371–81. 27. Shetler, K., R. Nieuwenhuis, S. M. Wren, and G. Triadafilopoulos. “Decompressive Colonoscopy with Intracolonic Vancomycin Administration for the Treatment of Severe Pseudomembranous Colitis.” Surgical Endoscopy 15: 653–59. 28. van Nood, E., P. Speelman, E. J. Kuijper, and J. J. Keller. 2009. “Struggling with Recurrent Clostridium difficile Infections: Is Donor Faeces the Solution?” European Surveillance 14 (34): pii=19316. 29. Yoon, S. S., and L. J. Brandt. 2010. “Treatment of Refractory/Recurrent C. difficile-associated Disease by Donated Stool Transplanted via Colonoscopy: A Case Series of 12 Patients.” Journal of Clinical Gastroenterology 44: 562–566. 30. Rohlke, F., C. M. Surawicz, and N. Stollman. 2010. “Fecal Flora Reconstitution for Recurrent Clostridium difficile Infection: Results and Methodology.” Journal of Clinical Gastroenterology 44: 567–70. 31. Lamontagne, F., A. C. Labbe, O. Haeck, O. Lesur, M. Lalancette, C. Patino, M. Leblanc, M. Laverdiere, and J. Pepin. 2007. “Impact of Emergency Colectomy on Survival of Patients with Fulminant Clostridium difficile colitis During an Epidemic Caused by a Hypervirulent Strain.” Annals of Surgery 245 (2): 267–72. 32. Koss, K., M. A. Clark, D. S. Sanders, D. Morton, M. R. B. Keighley, and J. Goh. 2004. “The Outcome of Surgery in Fulminant Clostridium difficile colitis.” Colorectal Disease 8: 149–54. 33. Ali, S. O., J. P. Welch, and R. J. Dring. 2008. “Early Surgical Intervention for Fulminant Pseudomembranous Colitis.” American Surgery 74: 20–26. 34. Hall, J. F., and D. Berger. 2008. “Outcome of Colectomy for Clostridium difficile colitis: A Plea for Early Surgical Management.” American Journal of Surgery 196: 384–88. 35. Greenstein, A. J., J. C. Byrn, L. P. Zhang, K. A. Swedish, A. E. Jahn, and C. M. Divino. 2008. “Risk Factors for the Development of Fulminant Clostridium difficile colitis.” Surgery 143: 623–29. 36. Longo, W. E., J. E. Mazuski, K. S. Virgo, P. Lee, A. N. Bahadursingh, F. E. Johnson. 2004. “Outcome After Colectomy for Clostridium difficile colitis.” Diseases of the Colon & Rectum 47 (10): 1620–26. 37. McFarland, L. V. 2006. “Meta-analysis of Probiotics for the Prevention of Antibiotic Associated Diarrhea and the Treatment of Clostridium difficile Disease.” American Journal of Gastroenterology 101: 812–22. 38. Pillai, A., and R. Nelson. “Probiotics for Treatment of Clostridium difficile- associated colitis in Adults.” Cochrane Database of Systematic Reviews 23(1): CD004611. 39. Hickson, M., A. L. D’Souza, N. Muthu, T. R. Rogers, S. Want, C. Rajkumar, and C. J. Bulpitt. 2007. “Use of Probiotic Lactobacillus Preparation to Prevent Diarrhoea Associated with Antibiotics: Randomised Double Blind Placebo Controlled Trial.” British Medical Journal 335 (7610): 80.

Latent Tuberculosis CHAPTER Infection 35 JESÚS GUTIERREZ, MD, MPH CASE A 65-year-old woman from Peru is admitted to the hospital for a laparoscopic cholecystectomy while visiting family in the US. Unfortunately, she suffers a perioperative cerebrovascular accident (CVA) and has to be placed in a nursing facility. She undergoes a subsequent tuberculin skin test (TST) and is found to have an induration of 12 mm in diameter. She denies any fever, chills, night sweats, cough, weight loss, shortness of breath, or any tuberculosis (TB) contacts. On physical examination, she is afebrile, her lungs are clear to auscultation bilaterally, and there is no lymphadenopathy appreciated. She received Bacillus Calmette-Guerin (BCG) vaccine as an infant. Chest radiograph is normal. Her medical history is remarkable for type II diabetes mellitus, which is well-controlled on metformin. 1. What is the most likely diagnosis in this patient? Given her positive TST, this patient appears to be infected with Mycobacterium tuberculosis. However, her lack of clinical symptoms or any other evidence of active disease points toward a latent TB infection (LTBI). There are approximately 10–15 million Americans with LTBI, who like the patient are asymptomatic and not infectious.1 However, they are at risk for progression to active disease and should thus be treated immediately to avoid spreading the disease to others.2 Bottom line: It is important to quickly diagnose and treat patients with LTBI, given the possibility of progressing to active TB disease. This is an important aspect of TB control in the United States. 2. What are the risk factors for LTBI? Given that this patient is originally from a country with high prevalence of TB and has been in the United States for less than 5 years, she is at moderate 423 risk for infection. Other groups with increased risk of LTBI include residents of a congregate living facility (e.g., nursing homes, prisons, homeless shelters), employees of long-term care facilities, hospitals and medical laboratories; high- risk racial and ethnic minorities, as defined locally; persons who have close contact with someone known or suspected to have active TB; and medically underserved or low-income populations.3 Bottom line: Knowledge and identification of a patient’s risk factors for latent or active TB infection is an important step in the diagnosis and subsequent management of the disease. 3. How should this patient’s TST results be interpreted? The 2000 American Thoracic Society guidelines recommend 3 cut-off levels for denoting a positive TST: ≥5 mm, ≥10 mm, and ≥15 mm of induration.4 When interpreting this result, the transverse diameter of induration should be measured in millimeters. This should be done across the arm, perpendicular to the long axis. Positive predictive value of the test increases as the risk of TB exposure becomes elevated. In patients at highest risk for progression to active TB if infected, ≥5 mm of induration is considered positive. For patients with an increased probability of recent infection or with other clinical conditions that increase the risk for progression to active TB, ≥10 mm of induration is considered positive. For the rest of patients, who are considered at low risk for TB, TST is not generally indicated. In these cases, an induration ≥15 mm is considered positive. Refer to Table 35.1 for a complete list of TST criteria. As mentioned above, this patient is considered to be at moderate risk for infection. Thus, in this case, an induration ≥10 mm is considered a positive result. Bottom line: The criteria for interpreting a TST varies depending on the patient’s health status and TB risk. 4. Should history of BCG vaccination impact the interpretation of TST results? No. A meta-analysis of 24 studies performed in 1993 found that only 1% of patients who had received BCG vaccination during infancy were TST positive 10 years after vaccination. However, if the vaccination was given later in life, a greater and more long-lasting effect was seen.5 Although earlier BCG vaccination increases the likelihood of a positive TST, this response varies with age at vaccination, number of years since vaccination, number of times vaccinated, and number of TST performed. This variation in response along with the need to detect all cases of TB has led to the recommendation that all patients with a positive TABLE 35.1 Criteria for a Positive TST Reaction ≥ 5 mm induration Reaction ≥ 10 mm induration Reaction ≥ 15 mm induration Persons with HIV infection Persons who are receiving immunosuppressive therapy Persons who have had recent close contact with person with infectious TB Persons with abnormal chest radiographs consistent with prior TB Recent immigrants (who have arrived within 5 years) from high-prevalence countries Injection drug users Residents and employees of high-risk congregate settings Mycobacterology laboratory personnel Persons with the following clinical conditions Silicosis Diabetes mellitus Chronic renal failure Leukemias and lymphomas Carcinomas of head or neck and lung Weight loss of ≥10% ideal body weight Gastrectomy and jejunoileal bypass Children younger than 4 years of age or infants, children, and adolescents exposed to adults in high-risk categories Persons with no risk factors Source: Adapted from Ref. [4]. TST should be regarded as true positives, regardless of the BCG status.6 Bottom line: BCG vaccination status should not be taken into con sideration when interpreting a TST result. 5. Has active TB infection been ruled out in this case? The key to the diagnosis of TB is a high index of suspicion. In this particular case, the patient is not complaining of any symptoms and her chest radiograph is normal. Therefore, although infected with the M. tuberculosis bacterium, she appears to be free of active disease at the moment. Current recommendations suggest that a symptom screen, physical examination, and chest radiograph (if available) should be used to exclude active TB in high- risk adults.4 Symptom screen generally includes prolonged cough (≥ 2–3 weeks), night sweats, fever, unintentional weight loss, and chest pain or shortness of breath. However, the predictive values of this screening approach have not been established. This is partly due to the differences in the symptom definitions that have been used and the rigor with which the screening is performed. In addition, the role of chest radiography in screening remains unclear. Routine chest radiography appears to have increased the sensitivity of screening in an extremely highrisk group of gold miners.7 However, its value has not been confirmed in a more generalized population with a lower prevalence of TB.8 For now, more accurate markers are needed to reliably rule out active TB disease. Bottom line: Active TB disease must be ruled out before diagnosing and treating LTBI. In addition to the history and physical examination, a symptom screen and chest radiograph should be performed in highrisk patients to exclude active disease. 6. What are the risk factors associated with progression of LTBI to active TB? The greatest risk of progression from LTBI to active TB occurs within the first 2 years after infection, when about half of the 5%–10% lifetime risk occurs.2 This risk is further increased in the following situations4,9: HIV infection IV drug users Persons with a history of untreated TB or inadequately treated TB, as evidenced, for example, by apical fibronodular changes on chest radiography End stage renal disease Diabetes mellitus Disorders requiring immunosuppressive therapy, including long-term corticosteroid use and TNFα inhibitors Malignancy Silicosis Gastrectomy or jejunoileal bypass Recent weight loss of more than 10% of ideal body weight Bottom line: Knowledge of risk factors for progression to active TB is important to identify patients who would benefit the most from targeted testing. 7. Would an Interferon γ release assay be useful in this case? Yes. According to the recently released CDC guidelines, Interferon γ release assays (IGRAs) are preferred to a TST in persons who have received BCG vaccination to increase specificity.10 However, the TST is still an acceptable test. IGRAs are also preferred in groups of patients who have historically low rates of returning to have their TSTs read.10 In general, IGRAs can be used in place of (but not in addition to) TSTs in all situations where testing is indicated, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs for infection control (e.g., those for health-care workers).10 This recommendation is based on the advantages that IGRAs have over TSTs (refer to Table 35.2 for a full comparison of the TST and IGRA). As mentioned above, IGRAs have very high specificity and are unaffected by earlier BCG vaccination or sensitization to nontuberculous mycobacteria.11,12 The sensitivity of IGRAs in active TB is ~75% to 90%, depending on the IGRA used.12 It is important to remember that as with the TST, a negative IGRA does not rule out TB infection and should be regarded as an adjunct and not a substitute for the clinical evaluation of those suspected of having TB. In addition, data are lacking in HIV-infected and other immunocompromised populations. In addition, there are limited data on the ability of IGRAs to predict future development of TB disease.13 Bottom line: IGRAs are preferred to TSTs in persons with a history of BCG vaccination. However, current recommendations indicate that either IGRAs or TSTs are acceptable tests for all situations where testing is indicated. 8. What does the evidence suggest would be a reasonable diagnostic approach to the patient at increased risk for TB infection? A reasonable diagnostic algorithm to follow is shown in Figure 35.1. 9. What is the treatment of choice for LTBI? All screened persons found to have LTBI should be offered treatment after active disease has been ruled out, regardless of age and BCG vaccination status. Guidelines from the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC) recommend isoniazid (INH) as the treatment of choice for LTBI in all groups including HIV-infected persons. This recommendation has been endorsed by the Infectious Disease Society of America (IDSA).4 For adults, the recommended duration of treatment is a minimum of 6 months, but a duration of 9 months is preferred. Note that completion of therapy is defined by total number of doses administered and not on duration of therapy alone. TABLE 35.2 Comparison of Tuberculin Skin Test and Interferon-Gamma Release Assay Estimated sensitivity (in patients with active TB) Sensitivity in immunocompromised individuals TST 70%–90% QTF gold 75%–80% Low (due to anergy) Estimated specificity (in healthy persons with no known TB disease/exposure) Cross-reactivity with BCG Cross-reactivity with nontuberculous mycobacteria Association between test-positivity and subsequent risk of active TB during follow-up Benefits of treating test-positives (based on randomized, controlled trials) Reliability (reproducibility) Inter-reader variability Boosting phenomenon Patient visits to complete testing protocol Time to obtain a result 50%–95% (variable; affected by BCG: lower when BCG given after infancy) Yes Limited data in immunocompromised populations; higher chance of indeterminate result in those with low CD4+ counts 95%–100% (not affected by BCG vaccination) No Yes Less likely Moderate-to strong positive association Insufficient evidence Yes No evidence Moderate Yes Yes 2 Limited evidence but may be high No No 1 48–72 h 24–48 h Abbreviation: QTF, QuantiFeron. Source: Adapted from Refs. 11–14. Rifampin daily for 4 months is an acceptable alternative to INH for patients intolerant to INH or exposed to patients with INH-resistant TB.16 This regimen was compared to 9 months of INH by a 2009 Is patient at increased risk for TB infection? No No further action necessary Yes TST/IGRA Positive Clinical evaluation chest x-ray Negative Contact with person with active TB? Yes No Repeat TST/IGRA 12 weeks after last contact No further action necessary Normal Abnormal findings or symptoms Positive Negative Start LTBI treatment Evaluate for active TB infection Go back to clinical Treatment is evaluation and chest continued for high X-ray risk persons No further action necessary FIGURE 35.1 Diagnostic approach to the patient at increased risk for TB infection. Sources: Adapted from Refs. 4 and 15. meta-analysis. This review found that the rifampin-based treatment was associated with decreased hepatotoxicity and improved compliance compared to the INH therapy. In addition, rifampin therapy appears to be more cost-effective than INH.17 This regimen was also recommended by ATS and CDC in their most recent guidelines.4 However, despite the advantages that rifampin monotherapy offers, the efficacy of this treatment has not been demonstrated in larger studies at this time. Standard INH monotherapy was also compared with short-term combination INH and rifampin therapy in a 2005 meta-analysis of 5 RCTs of variable quality involving 1926 patients.18 This meta-analysis found no difference in risk of active TB development and mortality between INH monotherapy for 6–12 months and combination therapy including rifampin and INH for 3 months. Both groups also showed similar rates of adverse events. However, this short-term combination therapy is not currently recommended by the CDC/ATS guidelines. It should also be noted that despite having similar efficacy as 9-month INH regimen in HIV-infected patients,19 a 2-month regimen of rifampin plus pyrazinamide is not recommended due to higher rates of hepatotoxicity among non-HIV-infected persons.20 Refer to Table 35.3 for more details regarding acceptable LTBI treatment regimens. TABLE 35.3 Treatment Regimens for LTBI Isoniazid Interval Daily Twice weekly Daily Twice weekly Rifampin Daily Duration Dosage of therapy (Maximum dose) 9 mo (270 doses 5 mg/kg in 12 mo) (300 mg) 9 mo (76 doses 15 mg/kg in 12 mo) (900 mg) 6 mo (180 doses 5 mg/kg in 9 mo) (300 mg) 6 mo (52 doses 15 mg/kg in 9 mo) (900 mg) 4 mo (120 doses 10 mg/kg in 6 mo) (600 mg) Source: Adapted from Ref. 4. Bottom line: The agent of choice for the treatment of LTBI is isoniazid. In certain circumstances, rifampin is an acceptable alternative. At this moment, there is insufficient evidence for other combinations. Revised guidelines advise against the use of rifampin with pyrazinamide. CASE CONTINUED The patient begins treatment with INH. 10. How should this patient be monitored after initiation of treatment? The most severe adverse effect of INH therapy is hepatotoxicity. Toxicity increases with age and alcohol use. Therefore, abstinence from alcohol should be advised for all patients under therapy, especially in patients over 35 years of age.21 The CDC guidelines recommend obtaining pretreatment laboratory studies (bilirubin and AST or ALT levels) for those patients at high risk of hepatotoxicity. They include patients with regular alcohol use, viral or alcoholic hepatitis, cirrhosis, HIV infection, and pregnant women up to 3 months postpartum.4 Monthly clinical monitoring is recommended for all patients. At each visit, patients should be screened for symptoms of hepatitis including nausea, vomiting, dark urine, jaundice, and abdominal pain. A brief physical examination should also be performed to screen for signs of hepatitis. Repeated laboratory studies are recommended only for those with abnormal baseline liver function tests, conditions associated with increased risk of hepatic disease, or signs or symptoms of hepatotoxicity.4 Up to 20% of patients taking INH will have an asymptomatic rise of liver enzymes.22 Discontinuation of INH treatment is recommended if transaminase levels reach 3 times the upper limit of normal in symptomatic patients or 5 times the upper limit of normal in asymptomatic patients.4 Bottom line: Monthly clinical monitoring is recommended for all patients on INH therapy with special focus on hepatotoxicity, as this is the most severe adverse effect of the drug. Laboratory studies are indicated only for those patients at high risk of hepatotoxicity. TAKE-HOME POINTS: LATENT TUBERCULOSIS INFECTION 1. Although asymptomatic and noninfectious, patient who are diagnosed with LTBI should be treated to avoid progression to active disease. 2. Interpretation of a TST should be made in the context of the patient’s health and TB risk. 3. BCG vaccination status should not be taken into consideration when interpreting a TST result. 4. Before diagnosis and treating LTBI, active TB disease should be ruled out with a symptom screen and chest radiography. 5. Current recommendations indicate that either IGRAs or TSTs are acceptable tests for all situations where LTBI testing is indicated. 6. The treatment of choice for LTBI is isoniazid for at least 6 months, although 9 months is preferred. In addition, rifampin monotherapy for 4 months is an acceptable alternative in some cases. 7. Monthly clinical monitoring is recommended for all patients on INH therapy with special focus on hepatotoxicity. Laboratory studies are only indicated for those patients at high risk of hepatotoxicity. REFERENCES 1. 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Centers for Disease Control and Prevention. 2000. “Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection.” MMWR Recommendations and Reports 49 (No. RR-6): 1–51. 5. Rodrigues L. C., V. K. Diwan, and J. G. Wheeler. 1993. “Protective Effect of BCG Against Tuberculous Meningitis and Miliary Tuberculosis: A Meta- analysis.” International Journal of Epidemiology 22 (6): 1154–58. 6. Rowland, K., and J. Barbara. 2006. “How Should We Manage a Patient with a Positive PPD and Prior BCG Vaccination? Journal of Family Practice 55 (8): 718–20. 7. Day, J. H., S. Charalambous, K. L. Fielding, R. J. Hayes, G. J. Churchyard, and A. D. Grant. 2006. “Screening for Tuberculosis Prior to Isoniazid Preventive Therapy Among HIV-infected Gold Miners in South Africa.” International Journal of Tuberculosis and Lung Disease 10: 523–9. 8. Mosimaneotsile, B., E. A. Talbot, T. L. Moeti, N. M. Hone, G. Moalosi, H. J. Moffat, E. J. Lee, and T. A. Kenyon. 2003. “Value of Chest Radiography in a Tuberculosis Prevention Programme for HIV-infected People, Botswana.” Lancet 362: 1551–52. 9. Jensen, P. A., L. A. Lambert, M. F. Iademarco, and R. Ridzon. 2005. “Guidelines for Preventing the Transmission of Mycobacterium Tuberculosis in Health-care Settings, 2005.” MMWR Recommendations and Reports 54 (RR-17): 1–141. 10. Mazurek, G. H., J. Jereb, A. Vernon, P. LoBue, S. Goldberg, and K. Castro. 2010. “Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection—United States, 2010.” MMWR Recommendations and Reports 59 (RR-5): 1–25. 11. Menzies, D., M. Pai, and G. Comstock. 2007. Meta-analysis: New Tests for the Diagnosis of Latent Tuberculosis Infection: Areas of Uncertainty and Recommendations for Research.” Annals of Internal Medicine 146: 340–54. 12. Pai, M., A. Zwerling, and D. Menzies. 2008. “Systematic Review: T-Cell- based Assays for the Diagnosis of Latent Tuberculosis Infection: An Update.” Annals of Internal Medicine 149: 177–84. 13. Pai, M., S. Kalantri, and K. Dheda. 2006. “New Tools and Emerging Technologies for the Diagnosis of Tuberculosis: Part I. Latent Tuberculosis.” Expert Review of Molecular Diagnostics 6(3): 413–22. 14. Nahid, P., M. Pai, and P. C. Hopewell. 2006. “Advances in the Diagnosis and Treatment of Tuberculosis.” Proceedings of the American Thorac Society 3: 103–10. 15. Jasmer, R. M., P. Nahid, and P. C. Hopewell. 2002. “Latent Tuberculosis Infection.” New England Journal of Medicine 347 (23): 1860–66. 16. Reichman, L. B., A. Lardizabal, and C. H. Hayden. 2004. “Considering the Role of Four Months of Rifampin in the Treatment of Latent Tuberculosis Infection.” American Journal of Respiratory and Critical Care Medicine 170 (8): 832–35. 17. Ziakas, P. D., and E. Mylonakis. 2009. “4 Months of Rifampin Compared with 9 Months of Isoniazid for the Management of Latent Tuberculosis Infection: A Meta-analysis and Cost-Effectiveness Study That Focuses on Compliance and Liver Toxicity.” Clinical Infectious Diseases 49 (12): 1883–89. 18. Ena, J., and V. Valls. 2005. “Short-Course Therapy with Rifampin plus Isoniazid, Compared with Standard Therapy with Isoniazid, for Latent Tuberculosis Infection: A Meta-analysis.” Clinical Infectious Diseases 40: 670– 76. 19. Gordin, F., R. E. Chaisson, J. P. Matts, C. Miller, M. de Lourdes Garcia, R. Hafner, J. L. Valdespino, et al. 2000. “Rifampin and Pyrazinamide vs Isoniazid for Prevention of Tuberculosisin HIV-Infected Persons: An International Randomized Trial.” Journal of the American Medical Association 283 (11): 1445–50 20. Centers for Disease Control and Prevention. 2003. “Update: Adverse Event Data and Revised American Thoracic Society/CDC Recommendations Against the Use of Rifampin and Pyrazinamide for Treatment of Latent Tuberculosis Infection—United States, 2003.” MMWR Recommendations and Reports 52 (31): 735–39. 21. Brown, M. O., and E. Howard. 2004. “Are Liver Function Tests Required for Patients Taking Isoniazid for Latent TB?” Journal of Family Practice 53 (1): 63–65, 68. 22. Nolan, C. M., S. V. Goldberg, S. E. Buskin. 1999. “Hepatotoxicity Associated with Isoniazid Preventive Therapy: A 7-year Survey from a Public Health Tuberculosis Clinic.” Journal of the American Medical Association 281 (11): 1014–18. C H apter Delirium 36 Hailun Wang, MD CASE An 83-year-old woman with a history of mild cognitive impairment (recent mini-mental state exam [MMSE] of 25/30) is suffering from an acute change in

her mental status. The patient currently resides in a nursing home. She has had multiple falls during the past year, which has left her very unsteady on her feet, and she has been using a walker for the past several months. The most recent fall, 8 weeks earlier, resulted in a hip fracture. Since returning from the hospital, the patient has been wheelchair bound. With the exception of toileting, the patient is predominantly immobile. Her son noticed a mild decrease from her baseline cognition after the fall but felt that his mom was stable until this past week. He reports that she has been lethargic but seems to “snap out of it” and at times even has increased energy and accelerated speech. He notes that she seems distracted and starts talking about unrelated topics during conversation. Upon arriving at the nursing home today, he found her yelling at the nursing staff that a strange man had come into her room to steal her clothing. The staff reports that she has been irritable and easily startled the past 2 days and has had to be restrained to prevent falls and injuries. 1. What is the most likely diagnosis and why? Given the patient’s acute (hours to days) presentation, the most likely diagnosis for the patient’s change in mental status is delirium likely superimposed on preclinical dementia. Although symptoms of delirium can overlap with those of dementia (e.g., Alzheimer’s), the key differences include acute onset (dementia develops over months to years), fluctuating course, and altered levels of consciousness. Psychomotor and emotional disturbances may also be present. Of note, dementia is the leading risk factor for delirium; two-thirds of delirium patients 435 have dementia. Delirium also contributes to worsening functional status, loss of independence, and poorer outcomes among patients with dementia. Dementia with Lewy bodies (DLB) may be difficult to differentiate from delirium as both can present with fluctuations and visual hallucinations. In fact, the initial manifestation of DLB in some patients may be delirium resulting from a systemic disturbance (e.g., infection). However, unlike DLB, delirium usually resolves within days to weeks after correction of the underlying cause. Primary psychiatric illnesses must also be considered, particularly depression in the elderly. This patient has no history of psychiatric illness (besides dementia) and there are no reports of dysphoria. Bottom line: Acute onset of symptoms, fluctuating course, and altered levels of consciousness can be used to distinguish delirium from dementia. 2. How does one diagnose delirium? Cognitive assessment using the MMSE and Confusion Assessment Method (CAM) can aid in the diagnosis of delirium. Although patients with delirium generally score lower on the MMSE, their deficits are predominantly related to attention (e.g., serial 7’s, spell WORLD backwards). The CAM includes an instrument and a diagnostic algorithm for identification of delirium in suspected patients. The instrument is used to assess severity and patterns of 9 cardinal features of delirium, which are listed in Table 36.1.1 On the other hand, the CAM algorithm for diagnosis of delirium is based on the presence of only 4 features TAblE 36.1 Cardinal Features of the Confusion Assessment Method Instrument and Diagnostic Algorithm CAM instrument 1 Lack of attention span 2 Disorganized thoughts 3 Altered LOC 4 Disorientation 5 Impaired memory 6 Psychomotor agitation 7 Perceptual disturbance 8 Altered sleep–wake cycle 9 Acute onset CAM algorithm features Acute onset/fluctuating course Lack of attention span Disorganized thoughts Altered LOC Abbreviations: CAM, Confusion Assessment Method; LOC, Level of Consciousness. TAblE 36.2 Statistical Performance of the Confusion Assessment Method Statistical measure Score (%) Sensitivity 94–100 Specificity 90–95 PPV 91–94 NPV 90–100 Abbreviations: PPV, Positive Predictive Value; NPV, Negative Predictive Value. (Table 36.1). Diagnosis of delirium according to CAM requires the presence of features 1, 2, and either 3 or 4. Statistical performance of the CAM is examined in Table 36.2.2,3 In addition, the CAM has convergent agreement with the MMSE.1 Bottom line: The CAM is a sensitive and specific test for diagnosing delirium. 3. Per the fourth edition of the Diagnostic and Statistical Manual, what are the diagnostic criteria for delirium? a. Disturbance of consciousness (e.g., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention. b. A change in cognition (such as memory deficit, disorientation, language disturbance) or the development of perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia. c. The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the day. d. There is evidence from the history, physical exam, or laboratory findings that the disturbance is caused by the direct physiological consequence of a general medical condition. Bottom line: Patients with delirium present with disturbances in consciousness and cognition, which develop over a short period of time and are the direct consequence of a general medical condition. 4. What are the ways to reduce risk factors for the development of delirium? Multicomponent interventions addressing issues such as orientation, early mobilization, and intervention for volume depletion and sleep deprivation are the most effective methods to prevent the onset of delirium.4 Since drug-induced delirium is the most preventable form of this condition, strategies for reducing the incidence of delirium also include adherence to prescription regimens and immediate consultation of the prescribing physician if symptoms occur. Bottom line: Multicomponent non-pharmacologic interventions are effective ways to prevent delirium. CASE CONTINUED The patient has no chronic medical conditions and is not on any medication. The patient has no known drug or toxin exposures. On physical exam, the patient is noted to be restrained in a wheelchair. She appears well-nourished and euvolemic but drowsy. Vital signs are within normal limits. Evaluation of the skin reveals no foci for infection and there are no signs of hepatic or renal failure (e.g., asterixis, spider angiomata, azotemia). Initial laboratory testing are all within normal limits with the exception of a mildly elevated WBC and a urine dipstick positive for leukocyte esterase and nitrites. 5. What is the likely cause of delirium in this patient? The most obvious underlying cause for this patient’s delirium is a urinary tract infection (UTI), as evidenced by her elevated WBC count and positive urine findings. It is important to note that the elderly often do not present classic features of a UTI (e.g., dysuria, increased frequency, suprapubic pain). Note that delirium in the elderly can result from a number of clinical and environmental factors, which are listed in Table 36.3. Bottom line: A wide spectrum of underlying medical, surgical, and environmental factors contribute to the risk of developing delirium 6. What does the data suggest would be an appropriate diagnostic workup for this patient? Delirium is a clinical syndrome and therefore there is no “gold standard” test for its diagnosis. There are many risk factors and potential causes for delirium. The history and exam should focus on pertinent risk factors (see answer to Section 3). In the elderly patient, it is particularly important to review all medications (including any recent changes), coexisting medical conditions, and symptoms and signs of infection. The physical exam should focus on vital signs, hydration status, and identifying potential sites of infection. A neurologic exam in a cooperative patient may help rule out focal neurologic disease. TAblE 36.3 Precipitating Factors for Delirium in the Elderlya Demographics Cognitive status Functional status Sensory impairment Decreased oral intake Drugs Neurologic diseases Systemic disturbances Surgery Environmental

65 y, male gender Dementia, cognitive impairment, hx of delirium, depression Functional dependence, immobility, low level of activity, hx of falls Visual, auditory Dehydration, malnutrition Psychoactive drugs (e.g., antidopaminergics), polypharmacy, alcohol abuse or withdrawal, benzodiazepine withdrawal, narcotics, anticholinergic drugs, toxins (e.g., methanol, salicylate) Stroke (especially in nondominant hemisphere), intracranial bleeding, meningitis, encephalitis Infections, hypoxia, shock, fever or hypothermia, anemia, uremia, thyrotoxicosis Orthopedic, cardiac, prolonged cardiopulmonary bypass, noncardiac surgery ICU, physical restraints, bladder catheter, multiple procedures, pain, emotional stress Prolonged sleep deprivation Adapted from Ref. [5]. aThis is an amalgamation of 2 tables from the “delirium in older patients” NEJM article with minor changes/additions. Laboratory testing: Focused testing should be performed based on the likely diagnoses. These include glucose, electrolytes,6 calcium, BUN/Cr,7 complete blood count, vitamin B12/folate, LFTs, TSH, and urinalysis. Drug levels and blood and urine toxicology screens should be ordered when appropriate. An ammonia level should be considered if hepatic encephalopathy is suspected. In the appropriate clinical setting, blood gases may be helpful, as many causes of delirium may lead to respiratory alkalosis or metabolic acidosis. A lumbar puncture and cerebrospinal fluid examination is indicated in febrile patients where meningitis is suspected.8 It is important to note that elderly patients are less likely to present with the classic symptoms of meningitis (e.g., fever and meningeal signs). A 1993 prospective cohort study done at Yale identified a BUN/Cr ratio >18 to be an independent predisposing risk factor for delirium with a relative risk of 2.0 (95% confidence interval [CI], 0.9–4.0). This study was limited by its small sample size, which could account for the widened CI. The elevated BUN/Cr may be indicative of low volume states such as dehydration or poor oral intake, which can predispose patients to delirium.6,7 A large prospective cohort study performed at Brigham & Women’s hospital9 established that abnormal electrolyte levels (Na, <130 or >150 mEq/L; K, <3.0 or >6.0 mEq/L; glucose, <60 or >300 mg/dL) were independent risk factors for postoperative delirium in a population of patients undergoing elective noncardiac surgery. The odds ratio observed in this study was 3.4 (95% CI, 3.6– 8.7).9 Bottom line: To determine the underlying cause for delirium, the physician should perform a detailed history and physical exam looking for probable etiologies and supplement with focused laboratory testing. 7. Does the data suggest that an electroencephalogram should be performed as part of the diagnostic workup of this patient? No. The role of electroencephalogram (EEG) in diagnosing delirium is limited due to its high false negative and positive rates of 17% and 22%, respectively.10 EEG is most useful when occult seizures are expected as the cause for the patient’s mental status changes or when the findings of all other diagnosis studies are unremarkable. An EEG may also help confirm metabolic and infectious CNS diseases with characteristic wave patterns (e.g., temporal lobe focal abnormality in herpes encephalitis). Of note, in almost all cases of delirium, EEGs show a generalized slowing pattern of brain wave activity. However, a normal EEG does not rule out delirium.11 Bottom line: Because of its low sensitivity and specificity, EEG is not indicated in the routine workup of delirium. 8. Does the data suggest that neuroimaging should be included in the workup of this patient? No. Neuroimaging (e.g., magnetic resonance imaging [MRI]) is of low clinical yield and is only necessary in patients with new focal neurologic signs, evidence of trauma, suspected encephalitis, or if workup reveals no clear cause for the delirium.12 If the cause of the patient’s delirium is reasonably obvious, or if the patient lacks evidence of trauma or focal neurologic disease, neuroimaging should not be routinely performed. Neuroimaging is also not performed during periods of lucidity.12 A 2008 systematic review in the Journal of Psychosomatic Research found that small sample sizes and other limitations of 10 structural MRI and/or computed tomography (CT) studies “preclude drawing any clear conclusions regarding neuroimaging findings in delirium.”13 Bottom line: Neuroimaging is not indicated in cases of suspected delirium unless the patient has new focal neurologic deficits or evidence of trauma. 9. What does evidence suggest should be included in the initial management of this patient? In patients with delirium, all underlying causes (e.g., UTI, in this case) and risk factors should be treated. In addition, supportive care is necessary to protect the patient’s airway, to maintain proper hydration/ nutrition, and to address the patient’s daily needs. The use of physical restraints should be minimized and care should be taken to prevent pressure ulcers and deep vein thrombosis. The presence of calendars, clocks, and familiar objects can help orient the patient and create a calm environment. Reduce nighttime interruptions by staff to encourage normal sleep–wake cycles and provide sufficient lighting during daytime hours to improve wakefulness.14 Bottom line: Treatment should focus on removing precipitating factors, supportive care, and efforts to reorient the patient. There may be a role for anti- psychotics if patient is acutely agitated with risk of hurting themselves. TAKE-HOME POINTS: DElIRIUM 1. Delirium should be suspected when a patient’s change in mental status is acute in onset, fluctuating, and accompanied by altered levels of consciousness. 2. Dementia is a risk factor for the development of delirium; acute changes in mental status should not be attributed to the progression of the patient’s dementia. 3. Although laboratory testing may help to identify the underlying etiologies responsible for the development of delirium, it should be targeted based on the history and physical findings. 4. Management of patients with delirium should include treatment of all precipitating factors, supportive care, and an attempt to reorient the patient. REFERENCES 1. Wei, L. A., M. A. Fearing, E. J. Sternberg, and S. K. Inouye. 2008. “Confusion Assessment Method (CAM): A Systematic Review of Current Usage.” Journal of the American Geriatrics Society 56 (5): 823–30. 2. American Psychiatric Association. 1994. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington DC: American Psychiatric Association. 3. Plaschke, K., R. von Haken, M. Scholz, et al. 2008. “Comparison of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) with the Intensive Care Delirium Screening Checklist (ICDSC) for Delirium in Critical Care Patients Gives High Agreement Rate(s).” Intensive Care Medicine 34: 431. 4. Bird Thomas, D., and L. Miller Bruce, “Dementia (Chapter).” In Harrison’s Principles of Internal Medicine. 17ed., edited by A. S. Fauci, E. Braunwald, D. L. Kasper, S. L. Hauser, D. L. Longo, J. L. Jameson, and J. Loscalzo, Chapter 365. http://www.accessmedicine.com/content .aspx?aID=2904052. 5. Inouye, S. K. 2006. “Delirium in Older Persons.” New England Journal of Medicine 354: 1157–65. 6. Inouye, S. K., C. Viscoli, R. Horwitz, L. Hurst, and M. Tinetti. 1993. “A Predictive Model for Delirium in Hospitalized Elderly Medical Patients Based on Admission Characteristics.” Annals of Internal Medicine 6: 474–81. 7. Marcantonio, E., et. al. 2006. ”Serum Biomarkers for Delirium.” Journal of Gerontology: Medical Sciences 12: 1281–86. 8. Inuoye, S. 1994. “The Dilemma of Delirium: Clinical and Research Controversies Regarding Diagnosis and Evaluation of Delirium in Hospitalized Elderly Medical Patients.” American Journal of Medicine 97: 278–88. 9. Marcantonio, E. R., L. Goldman, C. M. Mangione, et al. 1994. “A Clinical Prediction Rule for Delirium After Elective Non-Cardiac Surgery.” Journal of the American Medical Association 271: 134–39. 10. Trzepacz, T. T., R. P. Brenner, G. Coffman, et al. 1988. “Delirium in Liver Transplantation Candidates: Discriminant Analysis of Multiple Tests Variables.” Biological Psychiatry 24: 3–14. 11. Kwentus Joseph, A., H. Kirshner. “Delirium, Dementia, and Amnestic Syndromes (Chapter).” In Current Diagnosis & Treatment: Psychiatry. 2ed., edited by M. H. Ebert, P. T. Loosen, B. Nurcombe, J. F. Leckman, Chapter 14. http://www.accessmedicine.com/content.aspx?aID=3282796 12. Naughton, B. J., M. Moran, Y. Ghaly, and C. Michalakes. 1997. “Computer Tomography Scanning and Delirium in Elder Patients.” Academic Emergency Medicine 4: 1107. 13. Soiza, R., V. Sharma, K. Ferguson, et. al. 2008. “Neuroimaging Studies of Delirium: A Systematic Review.” Journal of Psychosomatic Research 65: 239– 48. 14. Millisen, K., J. Lemiengre, T. Braes, and M. D. Foreman. 2005. “Multicomponent Intervention Strategies for Managing Delirium in Hospitalized Older People: Systematic Review.” Journal of Advanced Nursing 52(1): 79–90. C HAP t ER Myxedema Coma 37 RAJASREE RAMACHANDRA PAI, MD CASE A 55-year-old woman with a history of type 2 diabetes mellitus, coronary artery disease, and hypothyroidism is evaluated in the emergency department for the sudden onset of confusion. Review of systems is unobtainable due to her altered mental status (AMS). It is unclear how compliant she has been with her medications. Her blood glucose is 56 mg/dL. She becomes moderately more alert after receiving a bolus of D5 normal saline with correction of her hypoglycemia to 155 mg/dL. Examination is significant for a heart rate of 55 bpm, temperature of 94.5°F, coarse facial features, coarse dry skin, macroglossia, hoarse voice, and generalized hyporeflexia. 1. What is the most likely diagnosis in this patient and why? Myxedema coma presents more commonly in middle-aged to elderly women and has a 9:1 female-to-male incidence ratio. Myxedema coma is uncommon,

occurring in less than 1% of patients with hypothyroidism.1 Signs and symptoms include AMS, hypoventilation, bradycardia, hypotension, hypothermia, constipation, and urinary retention. Periorbital edema, macroglossia, and generalized edema may also be seen. Electrolyte abnormalities, particularly hyponatremia, may occur due to excessive fluid retention.2 AMS, defective thermoregulation, and a precipitating event or illness are the three essential elements for diagnosis.3 Bottom line: AMS in patients with hypothyroidism should raise concern for myxedema coma, particular when history suggests a precipitating event. 443 2. What are the causes of myxedema coma? The most common causes of myxedema coma are patient nonadherence to thyroid medications and hypothermia. More than 90% of cases of myxedema coma occur during the winter months.4 This seasonal variation is attributed to the age-related loss of thermoregulation.5 Amiodarone, due to its high iodine content, alters thyroid function and can rarely precipitate myxedema coma. Hypothermia in myxedema coma, which occurs in approximately 65% of patients, lowers the threshold for encephalopathy. Other rare precipitants of myxedema coma include drugs such as amiodarone, narcotics, and anesthetics.3 Bottom line: The most common causes of myxedema coma are medication nonadherence and hypothermia. 3. What laboratory findings should confirm your suspicion of myxedema coma? One should expect a very high thyroid-stimulating hormone (TSH) concentration and very low triiodothyronine (T3) and thyroxine (T4) concentrations. Elevated creatine phosphokinase concentrations suggest the presence of rhabdomyolysis, which can occur in myxedema coma, as can myxedematous myopathy. Other laboratory abnormalities potentially seen include hypoglycemia, dyslipidemia, and anemia. Electrocardiogram may show a low-voltage sinus bradycardia. Given a reasonable index of suspicion, therapy with thyroid hormone can be started immediately while awaiting the results of TSH and T4 and T3 concentrations. In elderly patients, however, especially those with underlying cardiac disease, thyroid hormone therapy should be undertaken more cautiously because of the risk of inducing a dysrrhythmia. Bottom line: Expect impressively elevated TSH concentrations and very low concentrations of T4 and T3 in myxedema coma. CASE CONTINUED The patient was started on a high dose of oral levothyroxine (Synthroid) but was initially administered oral glucocorticoids. 4. Why were glucocorticoids administered to this patient before giving levothyroxine? Glucocorticoids should be administered until coexisting adrenal insufficiency is ruled out. This is important as thyroid hormone replacement may unmask adrenal insufficiency and cause adrenal crisis. Stress doses of steroid therapy should be initiated and continued until a random cortisol concentration is confirmed as normal.6 Intravenous (IV) methylprednisolone (50–100 mg) is usually given every 6 to 8 hours for several days, after which it is tapered and discontinued on the basis of clinical response. Such short-term glucocorticoid therapy is safe and can be discontinued when the patient has improved and the hypothalamic–pituitary–adrenal axis has been adequately assessed. Bottom line: Stress doses of steroids are indicated in myxedema coma until adrenal insufficiency is ruled out. 5. What are the predictors of poor outcome in myxedema coma? A study on factors associated with mortality of myxedema coma revealed that older age (age > 55 years), history of cardiac disease, and high-dose thyroid hormone replacement (T4 ≥ 50 μg/d or T3 ≥ 75 μg/d) were significantly associated with a fatal outcome within 1 month of treatment.7 Table 37.1 indicates the predictors of mortality associated with myxedema coma.7 Bottom line: The presence of comorbid conditions increases the mortality in myxedema coma. The etiology of the hypothyroidism is not a prognostic factor. Coma at presentation in myxedema is associated with high (73%) mortality. TAblE 37.1 Mortality Predictors in Patients with Myxedema Coma Predictors of mortality Mortality (%) Overall mortality with treatment 30–60 Age > 55 y 20 History of CAD 30 Nonadherence to levothyroxine 70 Coma at presentation (GCS < 7) 73 Previous diagnosis of hypothyroidism 70 Hypothermia with core body temp >80 of <90°F Abbreviations: CAD, coronary artery disease; GCS, Glascow Coma Score. 6. Do the data support starting this woman on IV rather than oral T3? No. A study by Holvey et al.8 suggests that patients who receive oral l-thyroxine show no outcome differences than those receiving IV thyroxine. Route of administration is a factor only in patients who are comatose according to reports available from recent studies.8 Bottom line: Route of T3 administration likely has little effect on outcome in myxedema coma. 7. T3 or T4: Which is more important in the management of myxedema coma? This is controversial. Some studies show that T3 more effectively crosses the blood-brain barrier.9 Additionally, in myedematous patients, peripheral conversion of T4 to T3 is typically impaired. Therefore, administering T3 seems like the intuitive way to proceed. However, in elderly patients and those with cardiac conditions, T3 administration can lead to arrhythmias and is also more likely to cause adrenal crisis. Although some data suggest that T3 is more effective, T4 is more commonly given to these patients due to the enhanced safety of its administration. Bottom line: T3 may be the most appropriate physiologic agent but T4 is generally administered because it is thought to be safer. 8. What are some of the complications to watch out for in myxedema coma? Data suggest that seizures (both focal and generalized), paralytic ileus, exudative pleural effusions and ascites, bradycardia, and bladder atony with urinary retention can occur in myxedema coma. The slower metabolism of drugs such as narcotics and subsequent carbon dioxide retention can lead to respiratory failure.10 Case reports have demonstrated status epilepticus in myxedematous patients with no history of seizure.11 9. Does the evidence suggest a role for supportive therapy? Yes. Data suggest that warm blankets, hypertonic saline for severe symptomatic hyponatremia,12 IV hydration with normal saline, and ventilatory support have a role in improving the outcome of myxedema coma.12 Since hypothyroidism on its own rarely results in myxedema coma, until proven otherwise the clinician should assume that some precipitating illness or stressor has triggered it. Thyroid hormone deficiency itself causes the derangement of renal tubular function, which results in impaired free water excretion and hyponatremia. Fluid restriction should therefore be undertaken, and in severe cases, hypertonic saline may need to be administered. IV antibiotics have a role if infection is the suspected precipitating event.12 Bottom line: Supportive care has a role in improving the outcome of myxedema coma. TAKE-HOME POINTS: MYXEDEMA COMA 1. Women with a history of hypothyroidism who present with AMS should raise concern for myxedema coma. 2. The most common cause of myxedema coma is a precipitating stressor in a patient with hypothyroidism who has been nonadherent with his medication for an extended period (typically years). 3. Hypothermia lowers the threshold of encephalopathy in myxedema coma and is a poor prognostic factor. 4. Stress-dose glucocorticoids should be given before the administration of thyroid hormones to minimize the risk of adrenal crisis. 5. T4 and T3 have equal efficacy in treating myxedema coma; nonetheless, T4 is generally recommended due to an improved safety profile. 6. The route of thyroid hormone replacement (IV vs. oral) does not appear to affect outcome. 7. Supportive therapy with warm blankets, saline, and glucose has a definite role in therapy. 8. Coma at presentation is a very poor prognostic sign. 9. The etiology of hypothyroidism is not a prognostic factor in myxedema coma. 10. Narcotics and sedatives should be avoided in myxedema coma, as their reduced metabolic clearance may precipitate respiratory failure. REFERENCES 1. Rehman, S. U., D. W. Cope, A. D. Senseney, and W. Brzezinski. 2005. “Thyroid Disorders in Elderly Patients.” South Med J 98: 543–549. 2. Wall, C. R. 2000. “Myxoedema Coma: Diagnosis and Treatment.” American Family Physician 62: 2485–90. 3. Wartofsky, L. 2006. “Myxedema Coma.” Endocrinology and Metabolism Clinics of North America 35: 687–698. doi: 10.1016/j.ecl.2006.09.003. 4. Bailes, B. K. 1999. “Hypothyroidism in Elderly Patients.” AORN Journal 69: 1026–30. 5. Ballester, J. M., and F. P. Harchelroad. 1999. “Hypothermia: An Easy-tomiss, Dangerous Disorder in Winter Weather.” Geriatrics 54: 51–52, 55–57. 6. Jordan, R. M. 1995. “Myxedema Coma. Pathophysiology, Causes and Factors Affecting Prognosis.” Medical Clinics of North America 79 (1): 185–94. 7. Yammamoto, T., J. Fukuyama, and A. Fujoysh. 1999. “Factors Associated With Mortality of Myxoedema Coma.” Thyroid 9: 1167–74. 8. Holvey, D. N., C. J. Goodner, J. T. Nicoloff, and J. T. Dowling. 1964. “Treatment of Myxedema Coma With Intravenous Thyroxine.” Archives of Internal Medicine 113 (1): 89–96. 9. Chernov, B. 1983. “T3 May Be a Better Agent Than T4 in the Critically Ill Hypothyroid Patient.” Society of Critical Care Medicine 11 (2): 99–104. 10. Orr, W. C., J. L. Males, and N. K. Imes. 1973. “Myxedema Coma with Respiratory Failure.” The American Review of Respiratory Disease 107: 842–45. 11. Jansen, H. J. 2006. “Myxedema and Epilepsy.” Netherlands Journal of Medicine 64: 205. 12. Nicoloff, J. T., and J. S. Lopresti. 1993. “Myxedena Coma. A Form of Decompensated Hypothyroidism.” Endocrinology and Metabolism Clinics of North America 22 (2): 279–90. 13. Galofré, J. C., and R. V. García-Mayor. 1997. “Densidad de incidencia del coma mixedematoso.” Endocrinologia 44: 103–4. 14. Rodríguez, I., and E. Fluiters. 2004. “Factors Associated With Mortality With Mytion.” Journal of Endocrinology 180: 347–50. doi: 10.1677/ joe.0.1800347. 15. Senior, R. M., Birge, S. J., Wessler, S., Avioli, L. V. 1971. “The Recognition and Management of Myxedema Coma.” JAMA 217(1): 61–65. 16. Koide, Y., K. Oda, K. Shimizu, A. Shimizu, I. Nabeshima, S. Kimura, M. Maruyama, and K. Yamashita. 1982. “Hyponatremia Without Inappropriate Secretion of Vasopressin in a Case of Myxedema Coma.” Endocrinologia Japonica 29 (3): 363–68. 17. Bazaria, S. 2005. “Amiodarone and the Thyroid.” American Journal of Medicine 118: 706–14. 18. Roberts, C., and P. W. Landerson. 2004. “Hypothyroidism.” Lancet 363: 793–803. Diabetic

Cha P ter Ketoacidosis 38 Vatsal Patel CASE An 18-year-old woman without significant medical history is brought to the emergency department (ED) this morning by her parents, who found her vomiting and moaning in pain, speaking incoherently, and poorly responsive. On initial evaluation, she has diffuse abdominal tenderness, an altered level of consciousness, and vomiting. Her parents deny prior drug or alcohol abuse or suicide attempts. She takes no prescribed or over-the-counter medications. On examination, she appears ill and pale. Temperature is 96.9°F, blood pressure is 80/40 mm Hg, pulse is 135 bpm, and respiratory rate is 38 breaths/min. Both axillae are dry. She has dried mucous membranes and sunken eyes. Cardiopulmonary examination is unrevealing apart from the tachypnea and tachycardia. Abdominal examination reveals hypoactive bowel sounds with diffuse tenderness and involuntary guarding. Laboratory workup is significant for glucose of 610 mg/dL, anion gap of 20, HCO3− of 7, Na of 130 meq/L, K of 6.0 meq/L, plasma ketones of 8 meq/L, leukocytes of 15,000 cells/μL, and BUN/Cr of 42/0.8. 1. What is the likely diagnosis in this patient and why? This patient has diabetic ketoacidosis (DKA), given the suggestive history and examination as well as the laboratory triad of hyperglycemia, anion gap metabolic acidosis, and ketonemia. Precipitating factors for DKA include poor compliance with or inadequate insulin regimen, new-onset diabetes (in 20%– 25% of cases), acute infections, myocardial infarction, stroke, acute pancreatitis, second-generation antipsychotics, mood stabilizers, sympathomimetics, glucocorticoids, and cocaine.1–3 The most likely precipitating factor in our patient is newonset type 1 diabetes mellitus (DM). Among type 2 diabetics, DKA occurs most often among obese African Americans but it has been shown to occur among Caucasians and Hispanics as well.2 449 In type 1 diabetes, moderately severe hyperglycemia (500–800 mg/dL in DKA) primarily occurs due to insulin deficiency. Other features of DKA include intravascular volume depletion from the hyperglycemia-associated osmotic diuresis, which contributes toward the tachycardia, dry axillae and mucous membranes, and mentation changes; high anion gap metabolic acidosis due to the production of large amounts of unmeasured anions (ketones) by the liver; Kussmaul pattern of breathing and abdominal pain from the metabolic acidosis; a concomitant metabolic alkalosis from vomiting and intravascular volume depletion; hyperkalemia primarily from the hyperglycemia-mediated solvent drag effect; dilutional hyponatremia from intracellular water shifting to the hyperosmotic extracellular fluid (ECF) compartment; an increased BUN/Cr ratio due to hypovolemia; and a mild leukocytosis from stress-induced demargination of WBCs. Bottom line: Patients with DKA often present with the triad of hyperglycemia, anion gap metabolic acidosis, and ketonemia. Physical examination findings suggestive of fluid depletion are strongly supportive of this condition as well as laboratory findings of mild leukocytosis, prerenal azotemia from hypovolemia, and dilutional hyponatremia. 2. What does the evidence suggest is our patient’s prognosis? Given our patient’s young age and absence of an underlying infection or other comorbidities, her prognosis is excellent provided that she receives appropriate treatment.4,5 The overall mortality rate of all age groups for DKA is 2%–5% and is mostly attributed to an underlying comorbidity rather than metabolic complications of DKA. Prognosis is worse at extremes of age and in the presence of complicating factors such as coma, hypotension, hypothermia, or oliguria at the time of diagnosis.1,4–6 The worst prognosis is seen in older patients with an underlying illness or comorbidity that likely precipitated the DKA, especially if they are not given timely treatment in an intensive care unit (ICU) setting. Early diagnosis and treatment are critical to reduce mortality. Bottom line: Complicating factors such as coma, hypothermia, underlying infection, oliguria, co-morbidities, or delayed ICU triage are all poor prognostic factors in patients with DKA. 3. Does the presence of hypokalemia and hypophosphatemia on initial presentation contribute to an increased mortality for this patient? Yes, hypokalemia is associated with increased mortality and is secondary to respiratory paralysis, cardiac arrest, or cardiac arrhythmias.7–9 Hypophosphatemia, while asymptomatic in most cases, can lead to altered mental status, diplopia, dysarthria, dysphagia, or even respiratory failure and myocardial depression in severe cases. Hypokalemia and hypophosphatemia should be closely monitored throughout insulin treatment because both can cause respiratory paralysis.8–11 Bottom line: The presence of hypokalemia and hypophosphatemia on initial presentation is associated with increased mortality. 4. Does the evidence suggest that this patient should undergo a diagnostic workup for infection? Although a workup for a triggering infection would almost certainly be performed, no clear evidence supports such a workup in the presence of a mild leukocytosis, which our patient has and which is typically seen in DKA. However, if the WBC count were greater than 25,000/μL or a band count greater than 10%, then further workup to look for infection would be evidence based.3,12 Bottom line: Further workup for infections in setting of leukocytosis in DKA is evidence based when WBC count is greater than 25,000/μL or band count is higher than 10%. 5. Does the evidence suggest that this patient would benefit from an arterial blood gas (ABG) measurement? No, it does not.7,13 However in practice, measuring ABGs is routinely performed in DKA to follow plasma CO2 levels, a marked increase in which may be a harbinger for respiratory collapse from respiratory muscle fatigue. Although there is no evidence to suggest that checking ABG10 leads to better outcomes, this measure is recommended by the American Academy of Family Practitioners.10 Bottom line: Although there is no clear data to suggest mortality is improved by monitoring ABGs, it is nonetheless currently the standard of care. 6. To what extent would measuring serum ketones help in management of this patient? The presence of elevated serum ketones is helpful diagnostically,7 and a progressive decline in serum ketones during treatment strongly suggests that the patient is responding favorably to insulin therapy, that is, resolution of ketoacidosis.7,14 Bottom line: Serum ketones help to confirm the diagnosis of DKA and a progressive decline suggests a favorable response to insulin therapy. 7. Does the evidence support aggressive hydration for this patient? Yes, the literature strongly supports aggressive intravenous (IV) hydration for this patient.7,15 Average fluid loss is 3–6 L in DKA.1,16–18 Fluids should be administered as soon as the diagnosis is established. The goal of the therapy is to replete ECF volume and restore renal perfusion without inducing cerebral edema or pulmonary edema secondary to rapid reduction in plasma osmolality. Most studies on hydration of DKA patients suggest that fluid management is best accomplished with 0.9% normal saline at an infusion rate of 10–15 mL/kg lean body weight/h (about 1000 mL/h in an average-sized person) for the first few hours.1,7 Once volume deficit is rectified, and the patient is stable in regards to blood pressure and mental status (typically when blood glucose reaches 250 mg/dL), fluids can be switched to 5% dextrose in 0.45% saline to minimize the risk of insulin-induced hypoglycemia.7,16,18 Bottom line: The evidence strongly supports aggressive hydration in DKA. The goal of therapy is to replete ECF volume and to restore renal perfusion without inducing complications like cerebral edema, pulmonary edema, or hypoglycemia. 8. Does the evidence suggest insulin should be given intravenously or subcutaneously in this patient? The literature suggests that insulin should be administered intravenously in this patient. If the patient is not in shock, both intramuscular and subcutaneous insulin therapy appear to be as effective as intravenous insulin therapy, but IV regular insulin still remains the standard of care.7,12,19 Two randomized controlled trials that looked at the efficacy and cost-effectiveness of subcutaneous rapid-acting insulin analogs (lispro and aspart) in the treatment of uncomplicated DKA demonstrated that duration of therapy until correction of hyperglycemia and resolution of ketoacidosis was the same with both intravenous and subcutaneous insulin therapies.20,21 In our patient, we will use IV regular insulin—the standard of care. Bottom line: IV insulin is the standard of care for patients with DKA, although if the patient is not in shock, the evidence suggests that both intramuscular and subcutaneous insulin therapies may be as effective as IV insulin. 9. In the presence of hypokalemia, does the evidence support administering insulin (and potassium) immediately or only after hypokalemia has been corrected? Does the evidence suggest insulin administration should be delayed in a setting of hypokalemia? The evidence suggests that insulin administration should be delayed in cases of severe hypokalemia until potassium is greater than or equal to 3.3 mEq/L.8,9,22 In some hyperglycemic patients with severe potassium deficiency, insulin administration may precipitate profound hypokalemia with an increase in mortality risk through arrhythmias, cardiac arrest, and respiratory failure.8,9,22 According to one review article, if the initial serum potassium is lower than 3.3 mEq/L, potassium replacement should begin immediately by an infusion of KCl at the rate of 40 mEq/h and insulin therapy should be delayed until potassium level is greater than or equal to 3.3 mEq/L. If the patient is not hypokalemic, potassium administration typically occurs after initiation of insulin therapy once serum potassium level falls below 5.3 mEq/L. To accomplish this, 20–30 mEq/L of potassium chloride is added to 1⁄2 Normal Saline. The goal is to maintain serum potassium between 4.0 and 5.0 mEq/L.8,9 Bottom line: With severe hypokalemia, insulin therapy should be delayed. If the patient is not hypokalemic, potassium is typically given after initiation of insulin therapy, to minimize the risk of insulininduced hypokalemia. 10. Does the evidence suggest bicarbonate, phosphate, and potassium replacements are indicated in this patient? The literature suggests that bicarbonate and phosphate supplementation should not be done routinely in the treatment of DKA. There no clear benefit of bicarbonate administration,23–25 although this remains a controversial issue.26 Slowed rate of recovery of ketosis, neurologic deterioration, and post-treatment metabolic alkalosis are all possible complications of bicarbonate administration.7,12 Although total body phosphate is universally low in patients with DKA, the clinical significance of this abnormality remains unknown. In most cases, hypophosphatemia is usually acute, self-limited, and not associated with adverse side effects.7 Prospective randomized trials of patients with DKA have failed to show any beneficial effects of phosphate replacement on the duration of ketoacidosis, dose of insulin required, rate of fall of serum glucose, or morbidity and mortality.7,27–29 On the other hand, the literature supports potassium supplementation because insulin administration has been known to unmask hypokalemia that has been associated with arrhythmias, cardiac arrest, respiratory muscle weakness—all leading to adverse outcomes.8,9 Although potassium supplementation is warranted, there are no randomized controlled clinical trials to demonstrate improved clinical outcomes with potassium supplementation. One concern for administering potassium is the risk for causing hyperkalemia in the presence of renal dysfunction.7 However, if the patient is urinating, potassium replacement can generally be administered safely. Bottom line: Typically, bicarbonate and phosphate administration should not be done and is not recommended in patients with DKA due to lack of clear benefit and associated mortality risks. Potassium replacement is highly recommended given the known mortality risks associated with hypokalemia. 11. Does the evidence suggest that monitoring the anion gap and bicarbonate levels results in better outcomes? No, there are no prospective randomized controlled data to show that anion gap and bicarbonate level monitoring leads to better clinical outcomes. However, several studies have shown that measurement of serum anion gap and bicarbonate to assess correction of ketoacidemia are among the better tests to gauge response to therapy.7 Closing of the anion gap is the single best measure to monitor resolution of DKA with insulin therapy!7 Ketonemia may persist for more than 36 additional hours even after resolution of DKA, since acetone takes longer time to eliminate through lungs.30,31 Because acetone is biochemically neutral, the patient does not have persistent ketoacidosis once anion gap normalizes.7 This is one of the reasons why anion gap is a better measure for assessment of ketoacidosis when compared with serum or urine ketones. Bottom line: Serum anion gap and bicarbonate help assess correction of ketoacidemia. However, there is no prospective randomized controlled data to show that use of these tests leads to better clinical outcomes. 12. What are some complications of DKA treatment that could occur in this patient? The complications of DKA treatment that could occur in this patient and ways to decrease the risk of their occurrence are listed in Table 38.1.7,12 TABlE 38.1 Potential Complications of DKA Treatment Complications Hypoglycemia Hyperglycemia Hypokalemia Cerebral and noncardiogenic pulmonary edema Hyperchloremic nonanion gap metabolic acidosis Preventative measures Administration of low dose insulin Coverage with subcutaneous insulin prior to discontinuing IV insulin Potassium replacement Avoiding overly aggressive fluid replacement and correction of plasma hyperosmolarity Avoiding overly rapid infusion of saline Abbreviations: DKA, diabetic ketoacidosis; IV, intravenous. CASE CONTINUED Six hours into the hospitalization course, our patient complains of a worsening headache. He is given some acetaminophen. Approximately, 1 hour later, he is noted to be obtunded. 13. What is likely occurring with the patient? What preventative measures does the evidence suggest should be taken to reduce the risk of this complication in our patient? Cerebral edema is primarily a complication seen in young children and almost all patients are younger than 20 years of age. It is associated with a 20%–40% mortality rate.7,16 Headache is the earliest clinical symptom. Symptoms can rapidly progress to lethargy, reduced consciousness, seizures, incontinence, pupillary changes, bradycardia, and respiratory arrest. Death occurs from brainstem herniation and consequent respiratory arrest. Symptom progression may be so rapid that papilledema is not seen,7 so very high level of clinical suspicion is required if the patient demonstrates neurologic deterioration through the course of treatment. Symptoms typically occur within 12–24 hours of initiation of treatment for DKA. However, in some patients, symptoms may be present before onset of therapy.7 Possible preventive measures in high-risk patients include gradual correction of fluid and sodium deficits (maximum reduction in plasma osmolality of 3 mOsmol/kg/h) and maintenance of a slightly elevated serum glucose until the patient is stable.7 Bottom line: If the patient complains of worsening headache during the course of treatment, evaluation for cerebral edema should be strongly considered. Gradual replacement of sodium and water is crucial to prevent this complication. Treatment of patients with cerebral edema induced during treatment of DKA is not evidence based; hence, this complication is best avoided. 14. When does the evidence suggest the patient can be safely discharged? What specific criteria should be met? There does not seem to be a general consensus on when patients with DKA should be discharged. In general, the DKA should have resolved and the patient should have transitioned from IV insulin to subcutaneous insulin with appropriate mentation before discharge can occur.7,11,22 TAKE-HOME POINTS: DIABETIC KETOACIDOSIS 1. DKA is an acute, life-threatening medical emergency that most commonly occurs in young DM I patients. It is characterized by triad of hyperglycemia, ketonemia, and anion gap acidosis. Clinical features of DKA include nausea, vomiting, abdominal pain, kussmaul respiration (deep, rapid breathing), fruity breath odor, hypotension (from volume depletion), tachycardia, altered mentation, and coma, if untreated. 2. Typical laboratory findings include hyponatremia, hyperkalemia despite total body potassium deficiency, anion gap metabolic acidosis, lowered bicarbonate, elevated serum ketones, and mild leukocytosis. Phosphate and magnesium levels may be low. 3. Further workup for infection in a setting of leukocytosis is evidence-based when the WBC count is greater than 25,000/μL or band count is higher than 10%. 4. Volume replacement, insulin therapy, and potassium supplementation are the mainstay of therapy. 5. Hypoglycemia, hyperglycemia, hypokalemia, cerebral and noncardiogenic pulmonary edema, and hyperchloremic nonanion gap metabolic acidosis are potential complications of DKA treatment. 6. There is no clear evidence that administered bicarbonate or phosphate results in any clinical benefit. Potassium supplementation is recommended given the known increased mortality risks from severe hypokalemia. 7. Hypertonic saline should typically not be administered in patients with hyponatremia. 8. There are no prospective randomized controlled clinical trial data to suggest any clinical benefit from performing an ABG. However, in practice, ABGs are routinely performed and monitored. 9. If the patient complains of worsening headache during the course of treatment, evaluation for cerebral edema should be strongly considered. Gradual replacement of sodium and water is crucial to prevent this complication. REFERENCES 1. Kitabchi, A. E., G. E. Umpierrez, M. B. Murphy, E. J. Barrett, R. A. Kriesberg, J. I. Malone, and B. M. Wall. 2001. “Management of Hyperglycemic Crises in Patients with Diabetes Mellitus.” Diabetes Care 24: 131. 2. Kitabchi, A.E., D. M. Nathan, J. I. Wolfsdorf, and J. E. Mulder. 2011. “Epidemiology and Pathogenesis of Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State.” http://www.uptodate.com/contents/epidemiology- andpathogenesis-of-diabetic-ketoacidosis-and-hyperosmolar-hyperglycemic- state. 3. Kitabchi A. E., B. D. Rose, D. M. Nathan, and J. E. Mulder. 2011. “Clinical Features and Diagnosis of Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State in Adults.” http://www.uptodate.com/contents/ clinical- features-and-diagnosis-of-diabetic-ketoacidosis-and-hyperosmolar- hyperglycemic-state-in-adults. 4. http://emedicine.medscape.com/article/118361-overview#a0156. 5. Kreisberg, R. A. 1987. “Diabetic Ketoacidosis: An Update.” Crit Care Clin. 3(4): 817–34. [PMID: 3139263]. 6. Malone, M. L., V. Gennis, and J. S. Goodwin. 1992. “Characteristics of Diabetic Ketoacidosis in Older Versus Younger Adults.” J Am Geriatr Soc. 40(11): 1100–4. [PMID: 1401693]. 7. Kitabchi, A. E., B. D. Rose, D. M. Nathan, and J. E. Mulder. 2011. “Treatment of Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State in Adults.” http://www.uptodate.com/contents/treatment-of-diabeticketoacidosis- and-hyperosmolar-hyperglycemic-state-in-adults. 8. Abramson, E., and R. Arky. 1966. “Diabetic Acidosis with Initial Hypokalemia. Therapeutic Implications.” JAMA 196(5): 401–3. [PMID: 5952215]. 9. Beigelman, P. M. 1973. “Potassium in Severe Diabetic Ketoacidosis.” Am J Med 54(4): 419–20. [PMID: 4633105]. 10. http://www.aafp.org/afp/2005/0501/p1705.html. 11. http://emedicine.medscape.com/article/767955-clinical. 12. Agabegi, S. S., and E. D. Agabegi. 2008. Step-Up Medicine. 2nd ed., 188– 90. Philadelphia, PA: Lippincott Williams & Wilkins. 13. Middleton, P., A. M. Kelly, J. Brown, and M. Robertson. 2006. “Agreement Between Arterial and Central Venous Values for pH, Bicarbonate, Base Excess, and Lactate.” Emerg Med J. 23(8): 622–4. [PMID: 16858095]. 14. Wiggam, M. I., M. J. O’Kane, R. Harper, A. B. Atkinson, D. R. Hadden, E. R. Trimble, and P. M. Bell. 1997. “Treatment of Diabetic Ketoacidosis using Normalization of Blood 3-Hydroxybutyrate Concentration as the Endpoint of Emergency Management. A Randomized Controlled Study.” Diabetes Care 20(9): 1347–52. [PMID: 9283776]. 15. Hillman, K. 1987. “Fluid Resuscitation in Diabetic Emergencies—A Reappraisal.” Intensive Care Med. 13(1): 4–8. [PMID: 3104431]. 16. Kitabchi, A. E., G. E. Umpierrez, J. M. Miles, and J. N. Fisher. 2009. “Hyperglycemic Crises in Adult Patients with Diabetes.” Diabetes Care 32(7): 1335–43. [PMID: 19564476]. 17. Rose, B. D., and T. W. Post. 2001. Clinical Physiology of Acid-Base and Electrolyte Disorders. 5th ed., 809–15. New York: McGraw-Hill. 18. Barrett, E. J., and R. A. DeFronzo. 1984. “Diabetic Ketoacidosis: Diagnosis and Treatment.” Hospital Practice 19: 89–95, 99–104. [PMID: 6425326]. 19. Fisher, J. N., M. N. Shahshahani, and A. E. Kitabchi. 1977. “Diabetic Ketoacidosis: Low-Dose Insulin Therapy by Various Routes.” New England Journal of Medicine 297(5): 238–41. [PMID: 406561]. 20. Umpierrez, G. E., K. Latif, J. Stoever, R. Cuervo, L. Park, A. X. Freire, and A. E. Kitabchi. 2004. “Efficacy of Subcutaneous Insulin Lispro Versus Continuous Intravenous Regular Insulin for the Treatment of Patients with Diabetic Ketoacidosis.” American Journal of Medicine 117(5): 291–6. [PMID: 15336577]. 21. Umpierrez, G. E., R. Cuervo, A. Karabell, K. Latif, A. X. Freire, and A. E. Kitabchi. 2004. “Treatment of Diabetic Ketoacidosis with Subcutaneous Insulin Aspart.” Diabetes Care 27(8): 1873–8. [PMID: 15277410]. 22. Umpierrez, G. E., M. B. Murphy, and A. E. Kitabchi. 2002. “Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome.” Diabetes Spectrum 15: 33. http://spectrum.diabetesjournals.org/content/15/1/28.full. 23. Morris, L. R., M. B. Murphy, and A. E. Kitabchi. 1986. “Bicarbonate Therapy in Severe Diabetic Ketoacidosis.” Annals of Internal Medicine 105(6): 836–40. [PMID: 3096181]. 24. Lever, E., and J. B. Jaspan. 1983. “Sodium Bicarbonate Therapy in Severe Diabetic Ketoacidosis.” American Journal of Medicine 75(2): 263–8. [PMID: 6309004]. 25. Latif, K. A., A. X. Freire, A. E. Kitabchi, G. E. Umpierrez, and N. Qureshi. 2002. “The Use of Alkali Therapy in Severe Diabetic Ketoacidosis.” Diabetes Care 25(11): 2113–4. [PMID: 12401775]. 26. Viallon, A., F. Zeni, P. Lafond, C. Venet, B. Tardy, Y. Page, and J. C. Bertrand. 1999. “Does Bicarbonate Therapy Improve the Management of Severe Diabetic Ketoacidosis?” Critical Care Medicine 27(12): 2690–3. [PMID: 10628611]. 27. Fisher, J. N., and A. E. Kitabchi. 1983. “A Randomized Study of Phosphate Therapy in the Treatment of Diabetic Ketoacidosis.” The Journal of Clinical Endocrinology and Metabolism 57(1): 177–80. [PMID: 6406531]. 28. Keller, U., and W. Berger. 1980. “Prevention of Hypophosphatemia by Phosphate Infusion During Treatment of Diabetic Ketoacidosis and Hyperosmolar Coma.” Diabetes 29(2): 87–95. [PMID: 6766411]. 29. Wilson, H. K., S. P. Keuer, A. S. Lea, A. E. Boyd III, and G. Eknoyan. 1982. “Phosphate Therapy in Diabetic Ketoacidosis.” Archives of Internal Medicine 142(3): 517–20. 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c hapte R Adrenal Insufficiency 39 RickindeR GRewal CASE A 61-year-old woman with a history of rheumatoid arthritis managed with daily prednisone presents for evaluation of a 2-day history of fever, productive cough, worsening shortness of breath, abdominal pain, and nausea. Vital signs are as follows: T 100.6°F, heart rate 114, respiratory rate 24 breaths/min, blood presure 85/50 mm Hg. On exam the patient appears confused and has decreased breath sounds and dullness to percussion at the right lung base. The patient appears confused. There are decreased breath sounds at the right lung base with dullness to percussion. Her skin is cool and clammy. A chest x-ray a right lower lobe infiltrate. The patient is admitted and given intravenous fluids and empiric antibiotic coverage. 1. What is the most likely diagnosis and why? Acute adrenal insufficiency (adrenal crisis) is the most likely diagnosis given the patient’s presumptive pneumonia, intestinal symptoms (abdominal pain, nausea), and the apparent septic physiology which likely reflects the inability of her adrenal glands to mount an effective response to the stress of the pneumonia. This patient is at an increased risk for adrenal crisis because of her chronic glucocorticoid therapy, which suppresses the secretion of corticotropin-releasing hormone from the hypothalamus and adrenocorticotropic hormone (ACTH) from the pituitary.1 When the patient is subjected to a stressful condition (e.g., pneumonia, as in this case), the body’s normal response to increase cortisol production is severely compromised.
The degree of suppression of the hypothalamic-pituitary-adrenal (HPA) axis is dependent on several factors including the dose and duration of glucocorticoid therapy and cannot be predicted in any given patient.2 461 Other risk factors for adrenal crisis include human immunodeficiency virus and chronic primary adrenal insufficiency. The causes of primary adrenal insufficiency include Addison’s disease, bilateral adrenal metastasis with the most common primary tumor originating from the lung, adrenal hemorrhage or necrosis (especially in the setting of meningococcal infections or coagulation disorders such as Waterhouse–Friderichsen syndrome), and adrenal infection or inflammation (e.g., tuberculosis) (Lamberts, S. W., H. A. Bruining, and F. H. de Jong. 1997. “Corticosteroid Therapy in Severe Illness.” The New England Journal of Medicine 337: 1285–92).2,3 Initial diagnosis of adrenal crisis is often delayed, as the various nonspecific symptoms of adrenal crisis (abdominal pain, nausea, diarrhea, and weakness) are common to a myriad of other conditions.2,4 Moreover, patients with adrenal crisis are typically treated with glucocorticoids rather than mineralocorticoids because at the supraphysiologic levels where glucocorticoids are administered, they exert mineralocorticoid actions on mineralocorticoid-sensitive tissues.5 It should be noted that there have been no clinical trials examining the efficacy of mineralocorticoid therapy alone in septic shock. Thus, the benefit of administering mineralocorticoids along with glucocorticoids in adrenal crisis remains unclear. Bottom line: Chronic glucocorticoid therapy suppresses the HPA axis and predisposes to adrenal crisis in the presence of severe physiologic stressors. 2. What does the evidence suggest would be an appropriate way to screen this patient for adrenal crisis? A reasonable way to screen patients suspected of adrenal crisis is to perform an ACTH (cosyntropin) stimulation test, as plasma cortisol response has significant diagnostic and prognostic values.6 Inadequate cortisol response (<9 μg/dL) has been associated with increased mortality.6 A recent meta-analysis has shown that the low-dose (1 μg) cosyntropin stimulation test is more sensitive than the high- dose (250 μg) cosyntropin stimulation test in diagnosing HPA insufficiency.7 This contradicts the findings of an earlier meta-analysis, which showed that the low-dose test was no more effective than the high-dose test.8 However, the low- dose test is associated with a variety of technical difficulties that include preparation of 1 μg cosyntropin and the stringent time requirements surrounding blood collection postcosyntropin stimulation.7 In addition, there are limited data on the use of the lowdose cosyntropin test in critically ill patients.9 Although the accurate diagnosis of adrenal crisis and immediate intervention is imperative in order to prevent death, evidence has shown that routine screening for adrenal insufficiency in all critically ill patients is not warranted.10 However, in the setting of unexplained hypotension that is not responsive to vasopressor therapy, one should be highly suspicious of adrenal crisis. Our patient is presenting in a rather typical fashion for adrenal crisis, as she is in hypotensive shock secondary to mineralocorticoid deficiency and resultant plasma volume depletion. The presentation of vascular unresponsiveness may also be exacerbated by an increase in prostaglandins (prostacyclin) as well as a decreased sensitivity to norepinephrine and angiotensin II.5 Therefore, due to the serious danger in the delay of treatment, initial screening should be performed for plasma concentration of sodium, potassium, bicarbonate, and total serum cortisol. Although evidence clearly supports that both low- and high-basal cortisol levels are associated with increased mortality in septic patients, 6,11 the magnitude of the cortisol response to ACTH appears to have more prognostic value than the basal cortisol level. Bottom line: The cosyntropin stimulation test has good diagnostic and prognostic predictive values in patients who are suspected of adrenal crisis. Vasopressor-resistant hypotension, in the appropriate setting, is concerned for adrenal crisis. 3. Does the evidence suggest that the insulin tolerance test is an appropriate diagnostic test to consider in this situation? Yes, the insulin tolerance test (ITT) would be appropriate to consider, as it is highly sensitive for detecting adrenal insufficiency (Erturk E., C. A. Jaffe, and A. L. Barkan. 1998. “Evaluation of the Integrity of the Hypothalamic-Pituitary- Adrenal Axis by Insulin Hypoglycemic Test.” The Journal of Clinical Endocrinology and Metabolism 83: 2350–54). In fact, the ITT is the current gold-standard method for examining abnormalities of the HPA axis. The underlying concept of the test is that in a patient with a normal HPA axis, the administration of insulin will cause hypoglycemia and thereby promote cortisol secretion. A failure of cortisol secretion in response to hypoglycemia indicates a faulty HPA axis and some form of adrenal insufficiency. However, there are practical difficulties with the ITT, including the risk of precipitating severe hypoglycemia or even adrenal crisis itself.12 Thus, availability of the test is largely limited to tertiary academic centers with the ability for specialized monitoring.13–15 In addition to the aforementioned limitations, there is a lack of correlative predictability in the relationship between the degree of induced hypoglycemia and maximum plasma cortisol response.16 Furthermore, the validity of the test is dependent on plasma glucose falling below 40 mg/dL, a range which is almost always symptomatic. Therefore, the test is relatively contraindicated in patients with epilepsy, cardiovascular, or cerebrovascular disease.17,18 Evidence shows that postcosyntropin serum cortisol levels correlate well with the peak cortisol levels obtained during the insulin-induced hypoglycemia test, thus making the cosyntropin stimulation test an appropriate substitute for the ITT.19 Bottom line: Although ITT is the gold standard for assessing the HPA axis, given its numerous practical difficulties, the cosyntropin stimulation test is a reasonable alternative. 4. What is the metyrapone test and how can it be used to distinguish primary adrenal insufficiency from secondary (pituitary) adrenal insufficiency? The metyrapone test has value in differentiating primary from secondary (pituitary) causes of adrenal insufficiency. Metyrapone inhibits the adrenal cortex enzyme 11 β-hydroxylase and, therefore, inhibits the conversion of 11- deoxycortisol (11-DOC) to cortisol. In patients with an intact HPA axis, the administration of metyrapone should increase pituitary secretion of ACTH, thus stimulating the adrenal glands to increase cortisol production (in the form of 11- DOC).4,12 In primary adrenal insufficiency, ACTH levels will be high and 11- DOC levels will be low following metyrapone administration due to inadequate adrenal function. In secondary (pituitary) adrenal insufficiency, neither ACTH nor 11-DOC levels will increase in response to metyrapone. Although the metyrapone test is nearly as sensitive as the ITT and more sensitive than the cosyntropin stimulation test,20,21 it is often not an ideal screening test for adrenal crisis due to practical limitations, which include complexity of the test and variable accuracy of 11-DOC assays. Although the occurrence is rare, the metyrapone test may, ironically, precipitate adrenal crisis.22 Additionally, the use of other drugs (e.g., phenytoin and rifampicin) may alter assay results by affecting metyrapone clearance.23 5. Based on the discussion provided in the above questions, how do the characteristics of the aforementioned screening tests compare to one another for the diagnosis of secondary (pituitary) adrenal insufficiency? Table 39.1 outlines the findings of a recent study by Giordano et al.24 that compares the diagnostic sensitivity, specificity, and accuracy of TABlE 39.1 Test Characteristics for the Diagnosis of Secondary (Pituitary) Adrenal Insufficiency.24 Diagnosis of secondary adrenal insufficiency Cut-off point Sensitivity (%) Specificity (%) Accuracy (%) ROC AUC PPV (%) NPV (%) High-dose cosyntropin stimulation Metyrapone test test ACTH 11-DOC Cortisol (pmol/L) (nmol/L) (μg/L) 17.3 144.3 21.1 71.4 64.3 71.4 100 82.4 82.4 87.1 74.2 77.4 0.82 0.68 0.76 100 75 76.9 81 73.7 77.8 Low-dose cosyntropin stimulation test Cortisol (μg/L) 17.3 73.3 80 76.7 0.74 78.6 75.0 Abbreviations: ACTH, adrenocorticotropic hormone; DOC, deoxycortisol; ROC AUC, Area under the Receiver Operating Characteristic Curve; PPV, Positive Predictive Value; NPV, Negative Predictive Value. the metyrapone test, the high-dose (250 μg) cosyntropin stimulation test, and the low-dose (1 μg) cosyntropin stimulation test in a group of patients with secondary (pituitary) adrenal insufficiency (not adrenal crisis) using ITT as the reference test.24 Evidence suggests that the metyrapone and high-dose or low- dose cosyntropin stimulation tests show similar sensitivity and specificity, although they are not as reliable (in terms of reproducibility and diagnostic sensitivity/specificity) as the ITT.24 However, it should be noted that the cut-off concentration of 11-DOC of 144 nmol/L used for the metyrapone test in this particular study was set very low, which may have inappropriately reduced its sensitivity. This idea is supported by several other studies that have shown the metyrapone test to be actually more accurate than either the high-dose or low- dose corticotropin stimulation tests.12 6. Does the evidence support starting empiric corticosteroid therapy in this patient while awaiting results of the diagnostic workup? Yes, evidence has shown that treatment with glucocorticoids (both intravenous and oral) significantly reduces mortality in vasopressorresistant septic shock patients.25 The effect was even more apparent in those with relative adrenal insufficiency, defined as an increase of less than 9 μg/dL from baseline to the highest measurement at 30 or 60 minutes in the cosyntropin stimulation test. Importantly, there was no increase in adverse events.25 If the results of the cosyntropin stimulation test show a peak cortisol greater than 20 μg/dL and an incremental cortisol response greater than 9 μg/dL at 30 minutes, the treatment should be discontinued.26 However, if the peak cortisol is less than 20 μg/dL or if the incremental cortisol response is less than 9 μg/dL, treatment should be continued. After the first 24 hours, the dose of glucocorticoids can be tapered gradually in the following days to avoid the increase in proinflammatory mediators and hemodynamic deterioration that can occur after abruptly discontinuing therapy.27 Further hydration with saline or dextrose will be dependent on laboratory results and clinical presentation of the patient. It is also important to rule out and treat possible infections that may have precipitated the adrenal crisis in the first place.28 Once the acute crisis has resolved, final confirmation of adrenal insufficiency and possible etiology may need to be evaluated.5 Bottom line: It is safer to administer hydrocortisone prophylactically rather than delay therapy in the adrenal crisis patient for which workup is still ongoing. 7. Does the evidence support starting empiric corticosteroid therapy in all septic shock patients, regardless of whether they are vasopressor-resistant or not? No, evidence has shown that the use of low-dose hydrocortisone does not decrease mortality in a general population of patients with septic shock (either vasopressor-responsive or vasopressor-resistant), regardless of the patient’s adrenal responsiveness to cosyntropin.29 In the previously cited study, there appeared to be an increased incidence of sepsis and septic shock in patients receiving low-dose hydrocortisone therapy. Before the initiation of this study, this effect had only been observed with high-dose glucocorticoid therapy, as the low-dose steroid study conducted by Annane et al.25 showed no increase in adverse events.25 Bottom line: Hydrocortisone therapy should be used only in septic shock patients, who are poorly responsive to fluid resuscitation and vasopressor therapy. 8. Does the evidence suggest there is an effective way to prevent a recurrent episode of adrenal crisis in this patient? No, there are currently no high-quality studies that have examined the prevention tactics for adrenal crisis. It is, however, generally accepted that during times of physiologic stress (illness, trauma, surgery, etc.), patients on chronic glucocorticoid therapy should increase their normal glucocorticoid dosage to compensate for the lack of the normal endogenous rise in cortisol production during the stress. Various recommendations on dosage and duration of glucocorticoid therapy in these patients for a variety of medical illnesses are available in the literature (Jung C. and W. J. Inder. 2008. “Management of Adrenal Insufficiency during the Stress of Medical Illness and Surgery.” The Medical Journal of Australia 188: 409–413).30 However, these are largely based on expert consensus rather than hard clinical endpoint data. Bottom line: Patients on chronic glucocorticoid therapy are often advised to increase their dosage during various stressors such as surgery or illness. The optimal dose, frequency, and duration of such therapy remain unclear. TAKE-HOME POINTS: ADRENAl INSUFFICIENCY 1. Chronic glucocorticoid therapy suppresses the HPA axis and, in the presence of severe physiologic stressors, predisposes to adrenal crisis. 2. Although the classic presentation of adrenal crisis is severe weakness, hypotension, and electrolyte disturbances such as hyponatremia and hyperkalemia, the diagnosis is often missed because the patients commonly present with nonspecific symptoms such as abdominal pain, nausea, and fatigue. 3. Because immediate intervention is urgent, rapid diagnostic testing, typically via the cosyntropin stimulation test, should be performed. 4. Empiric management while awaiting the results of the cosyntropin stimulation test should include aggressive hydration. Intravenous corticosteroids should be given if the hypotension is vasopressor resistant, although in vasopressorresponsive hypotension, particularly in sepsis, corticosteroids should not be given empirically. 5. Patients on chronic glucocorticoid therapy are generally advised to increase their dosage during a severe illness, although there is no evidence to support specific guidelines in therapy. REFERENCES 1. Salem, M., R. E. Tainsh, J. Bromberg, D. L. Loriaux, and B. Chernow. 1994. “Perioperative Glucocorticoid Coverage.” Annals of Surgery 219: 416–25. 2. Cooper, M. S., and P. M. Stewart. 2003. “Corticosteroid Insufficiency in Acutely Ill Patients.” The New England Journal of Medicine 348: 727–34. 3. Lam, K. Y., and C. Y. Lo. 2002. “Metastatic Tumours of the Adrenal Glands: A 30-Year Experience in a Teaching Hospital.” Clinical Endocrinology 56: 95– 101. 4. Taub, Y. R., and R. W. Wolford. 2009. “Wolford Adrenal Insufficiency and Other Adrenal Oncologic Emergencies.” Emergency Medical Clinics of North America 27: 271–82. 5. Bouillon, R. 2006. “Acute Adrenal Insufficiency.” Endocrinology and Metabolism Clinics of North America 35: 767–75. 6. Annane, D., V. Sebille, G. Troche, J. Raphael, P. Gajdos, and E. Bellissant. 2000. “A 3-Level Prognostic Classification in Septic Shock Based on Cortisol Levels and Cortisol Response to Corticotropin.” The Journal of the American Medical Association 283: 1038–45. 7. Kazlauskaite, R., A. T. Evans, C. V. Villabona, T. A. M. Abdu, B. Ambrosi, A. B. Atkinson, C. H. Choi, et al. 2008. “Corticotropin Tests for Hypothalamic- Pituitary-Adrenal Insufficiency: A Metaanalysis.” The Journal of Clinical Endocrinology and Metabolism 93: 4245–53. 8. Dorin, R. I., C. R. Qualls, and L. M. Crapo. 2003. “Diagnosis of Adrenal Insufficiency.” Annals of Internal Medicine 139: 194–204. 9. Kozyra, E. F., R. S. Wax, and L. D. Burry. 2005. “Can 1 μg of Cosyntropin be Used to Evaluate Adrenal Insufficiency in Critically Ill Patients?” The Annals of Pharmacotherapy 39: 691–8. 10. Jurney, T. H., J. L. Cockrell Jr., J. S. Lindberg, J. M. Lamiell, and C. E. Wade. 1987. “Spectrum of Serum Cortisol Response to ACTH in ICU Patients.” Chest 92: 292–95. 11. Sibbald, W. J., A. Short, M. P. Cohen, and R. F. Wilson. 1977. “Variations in Adrenocortical Responsiveness During Severe Bacterial Infections: Unrecognized Adrenocortical Insufficiency in Severe Bacterial Infections.” Annals of Surgery 186: 29–33. 12. Wallace, I., S. Cunningham, and J. Lindsay. 2009. “The Diagnosis and Investigation of Adrenal Insufficiency in Adults.” Annals of Clinical Biochemistry 46: 351–67. 13. Jones, S. L., P. J. Trainer, L. Perry, J. A. Wass, G. M. Bessser, and A. Grossman. 1994. “An Audit of the Insulin Tolerance Test in Adult Subjects in an Acute Investigation Unit Over One Year.” Clinical Endocrinology (Oxford) 41: 123–28. 14. Lange, M., O. L. Svendsen, N. E. Skakkebaek, J. Muller, A. Juul, M. Schmiegelow, and U. Feldt-Rasmussen. 2002. “An Audit of the InsulinTolerance Test in 255 Patients with Pituitary Disease.” European Journal of Endocrinology 147: 41–7. 15. Finucane, F. M., A. Liew, E. Thornton, B. Rogers, W. Tormey, and A. Agha. 2008. “Clinical Insights into the Safety and Utility of the Insulin Tolerance Test (ITT) in the Assessment of the Hypothalamo-Pituitary-Adrenal Axis.” Clinical Endocrinology 69: 603–7. 16. Lindholm, J. 2001. “The Insulin Hypoglycaemia Test for the Assessment of the Hypothalamic-Pituitary-Adrenal Function.” Clinical Endocrinology 54: 283– 86. 17. Oelkers, W. 1996. “Adrenal Insufficiency.” The New England Journal of Medicine 335: 1206–12. 18. Andrioli, M., F. P. Giraldi, and F. Cavagnini. 2006. “Isolated Corticotrophin Deficiency.” Pituitary 9: 289–95. 19. Hurel, S. J., C. J. Thompson, M. J. Watson, M. M. Harris, P. H. Baylis, and P. Kendall-Taylor. 1996. “The Short Synacthen and Insulin Stress Tests in the Assessment of the Hypothalamic-Pituitary-Adrenal Axis.” Clinical Endocrinology (Oxford) 44: 141–6. 20. Fiad, T. M., M. J. Kirby, S. K. Cunningham, and T. J. McKenna. 1994. “The Overnight Single-Dose Metyrapone Test is a Simple and Reliable Index of the Hypothalamic-Pituitary-Adrenal Axis.” Clinical Endocrinology 40: 603–9. 21. Annane, D., V. Maxime, F. Ibrahim, J. C. Alvarez, E. Abe, and P. Boudou. 2006. “Diagnosis of Adrenal Insufficiency in Severe Sepsis and Septic Shock.” American Journal of Respiratory and Critical Care Medicine 174: 1319–26. 22. Arlt, W., and B. Allolio. 2003. “Adrenal Insufficiency.” Lancet 361: 1881– 93. 23. Fluck, C. E. 2011. “Assessing the Function of the Human Adrenal Cortex.” In Diagnostics of Endocrine Function in Children and Adolescents. 4th ed., edited by M. B. Ranke, and P. E. Mullis, 50–78. Basel: Karger. 24. Giordano, R., A. Picu, L. Bonelli, M. Balbo, R. Berardelli, E. Marinazzo, G. Corneli, E. Ghigo, and E. Arvat. 2008. “Hypothalamus-PituitaryAdrenal Axis Evaluation in Patients with Hypothalamo-Pituitary Disorders: Comparison of Different Provocative Tests.” Clinical Endocrinology 68: 935–41. 25. Annane, D., V. Sebille, C. Charpentier, P. Bollaert, B. Francois, J. Korach, G. Capellier, et al. 2002. “Effect of Treatment with Hydrocortisone and Fludrocortisone Mortality in Patients with Septic Shock.” The Journal of the American Medical Association 288: 862–71. 26. Sakharova, O. V., and S. E. Inzucchi. 2007. “Endocrine Assessments During Critical Illness.” Critical Care Clinics 23: 467–90. 27. Keh, D., T. Boehnke, S. Weber-Cartens, C. Schulz, O. Ahlers, S. Bercker, H. Volk, W. Doecke, K. J. Falke, and H. Gerlach. 2003. “Immunologic and Hemodynamic Effects of “Low-Dose” Hydrocortisone in Septic Shock.” American Journal of Respiratory and Critical Care Medicine 167: 512–20. 28. Stewart, P. M., and N. P. Krone, 2011. “The Adrenal Cortex.” In Williams Textbook of Endocrinology. 12th ed., edited by S. Melmed et al., 479–544. Philadelphia: Elsevier Saunders. 29. Sprung, C. L., D. Annane, D. Keh, R. Moreno, M. Singer, K. Freivogel, Y. G. Weiss, et al. 2008. “Hydrocortisone Therapy for Patients with Septic Shock.” The New England Journal of Medicine 358: 111–24. 30. Coursin, D. B., and K. E. Wood. 2002. “Corticosteroid Supplementation for Adrenal Insufficiency.” The Journal of the American Medical Association 282: 236–40.

Heparin-Induced Chapter Thrombocytopenia 40 Lisa Josephine Gupta, MD CASE A 70-year-old woman with a history of osteopenia presents to the emergency department (ED) via ambulance after falling in her home. Her only complaint is of hip pain. Examination reveals an externally rotated right hip and imaging reveals an intertrochanteric fracture. Examination is otherwise unrevealing. She undergoes hip replacement surgery the following day and is started on heparin immediately following surgery. On the sixth postop day, she suddenly develops slurred speech and blurred vision. Preoperative platelet count is noted to have decreased from normal to 47,000. 1. What is the likely diagnosis and why? The most likely diagnosis in this patient is heparin-induced thrombocytopenia (HIT) owing to her rapid decline in platelet concentration following the addition of heparin. Patients with HIT are hypercoagulable because they produce antibodies against heparin-platelet factor-4 (PF-4) complexes, which bind to platelets and activate the coagulation cascade. The onset of neurologic symptoms 6 days post surgery suggests that this patient experienced a stroke due to the hypercoagulable state. As these symptoms were not present before heparin administration, this history is consistent with the diagnosis of HIT. Other possible causes of thrombocytopenia and thrombosis include adenocarcinoma, antiphospholipid antibody syndrome, infective endocarditis, paroxysmal nocturnal hemoglobinuria, post-transfusion purpura, pulmonary embolism, septicemia-associated disseminated intravascular coagulation, and thrombolytic therapy. Bottom Line: The diagnosis of HIT is likely if thrombocytopenia and thrombosis are observed following heparin administration. 471 2. What are the clinical signs of HIT? Thromboembolic events are serious complications of HIT and often include gangrene of the legs, stroke, acute myocardial infarction, deep vein thrombosis, and pulmonary embolism. In a retrospective chart review of patients with confirmed HIT antibodies, 61% experienced venous thrombosis while 18% experienced arterial thrombosis.1 Patients suspected of HIT should be monitored for signs of skin erythema and skin necrosis, thrombosis at a catheter site, and symptoms of neurologic deficits, chest pain, and leg pain. HIT can be a life- threatening problem if it affects the vital organs. Bottom Line: Thromboembolic events are a common complication in patients with HIT. 3. What factors increase the likelihood of a patient developing HIT? HIT is more likely to develop in the following: • Women • Postsurgical patients (especially cardiopulmonary2 and prostheses) • Patients who receive bovine heparin > porcine heparin > lowmolecular-weight heparin • Long duration of therapy 4. Describe the clinical-scoring scale (4Ts scale) for patients with HIT. A study conducted by Francis et al.3 demonstrated that despite the high rate of antibodies formed against heparin–PF4 complexes in patients receiving heparin following cardiac bypass surgery (>40% of patients were found to have HIT antibodies), very few develop adverse effects with the use of heparin. The appearance of antibodies alone, therefore, does not make a diagnosis of HIT. Clinical judgment is key in deciding on appropriate management.4 The 4Ts scale can aid in determining the likelihood of HIT in suspected patients before receiving an antibody test. The 4Ts scale is based on the following four factors: Thrombocytopenia, Timing, Thrombosis, oTher causes, with a 0–2 point score for each category. The pretest probability score is as follows: Low = 0–3, Intermediate = 4–5, High = 6–8. With a score of 3 or below, antibodies are unlikely and a cause for adverse events is not likely from heparin exposure. With high scores, antibodies are very likely and appropriate treatment should begin before antibody results are back. Intermediate scores are possibly HIT or possibly another cause and testing for antibodies can be very helpful (Table 40.1).5 TAblE 40.1 4Ts Scale 0 Points 1 Point 2 Points Thrombocytopenia Less than 30% fall in platelets or no more than 10,000 drop from baseline Timing of drop in platelets or other adverse event Less than 4 days (fall too early) and without heparin exposure Between 30 and 50% drop in platelet or a drop between 10,000 and 19,000 from baseline Greater than day 10 or timing unclear (missing drop in platelet counts) Thrombosis or other adverse events No thrombosis, no other adverse events Other possible causes of platelet drop Definite other possible causes/ explanations Progressive or recurrent thrombosis, erythematous skin lesions, and/or suspected new thrombosis but not yet proven Possibly other causes Greater than 50% drop in platelets or a drop greater than 20,000 from baseline Between day 5 and 10 of heparin exposure or less than day 1 if heparin given in last 100 days New throm bosis, skin necrosis, or acute systemic reaction after IV bolus No apparent other causes According to Denys,6 a low 4T score has good predictive value in ruling out HIT, but intermediate and high scores will require further evaluation. Bottom line: Use clinical judgment along with laboratory results and remember the 4Ts! (Thrombocytopenia, Timing, Thrombosis, and oTher) 5. What tests can be performed to confirm the diagnosis of HIT? 5.1 Serotonin release assay The premise of this test relies on the fact that platelet activation following antibody binding to heparin–PF4 complexes (if these antibodies are indeed present in the test serum) leads to a release of prothrombotic and procoagulant substances including serotonin. Thus, serotonin levels in a patient’s serum may be used to indicate platelet activation. Platelets from a normal donor are radiolabeled with 14C-serotonin. Patient’s serum is mixed with the radiolabeled platelets and both low- and high-concentration heparin are added. Serotonin release is measured. Despite the high sensitivity and specificity of this test, it is both labor-intensive and costly and, therefore, is not usually used despite the fact that it is considered the gold-standard test.7 5.2 Platelet aggregation Platelet aggregation studies are functional methods to determine whether a patient may have HIT. In these studies, normal donor platelets are combined with the patient’s test serum, and heparin is then added. If platelet aggregation occurs under these conditions, the test is considered positive. Platelet aggregation studies have 90% specificity but are not very sensitive.11 5.3 ELISA immunoassay In general, these are highly sensitive tests such that a negative test strongly rules out HIT. However, some of the available tests lack specificity. Additionally, depending on the particular hospital, these tests may not be offered in-house and may have a significant turn-around time. Bottom-line: Use both the functional and antigenic tests to get results with high sensitivity and specificity. Functional = Specific, Antigenic = Sensitive. 6. What does the evidence suggest should be the initial step in management of this patient? Discontinue heparin use, including treatment and heparin line flushes. Treatment with low-molecular-weight heparin (enoxaparin [Lovenox] and dalteparin [Fragmin]) should also be bypassed since these medications can react with anti- heparin–PF4 antibodies as well. Instead, nonheparin anticoagulant therapy should be started immediately since the possibility for new thromboses in these patients is high. Direct thrombin inhibitors and antifactor Xa agents have all proven to be effective in preventing new thromboses in patients with HIT.10 Lepirudin (Refludan), a direct thrombin inhibitor, is most widely used in the United States for suspected HIT.8 Bottom line: Immediately discontinue heparin use in patients with suspected HIT and replace with nonheparin anticoagulant agents to prevent the formation of new thromboses. 7. What anticoagulant treatment options are there for a patient with HIT? Lepirudin : Direct thrombin inhibitor Argatroban: Direct thrombin inhibitor Bivalirudin: Antithrombin Danaparoid: Anti-factor Xa (not used in United States).9 Fondaparinux (Arixtra): Anti-Factor Xa 8. What laboratory tests should be performed in patients with HIT? Platelet counts should be measured at least every other day in highrisk patients. Monitoring the platelet levels will allow tracking of the antibody reaction and to check if there is improvement with the new anticoagulant therapies. 9. Should a platelet transfusion be considered in this patient? No! Since anti-heparin–PF4 antibodies persist for up to 100 days after the last dose of heparin, platelet transfusion will simply increase the risk of thrombosis.4 10. Once the heparin is stopped, how long is the patient still at risk for further exacerbation of clinical manifestations? Patients are at 25% to 50% risk of developing thrombosis up to 30 days after heparin is stopped.1 After 100 days, the antibody should be gone. It is recommended for these patients to avoid heparin if possible. If heparin is required, antibodies should be checked before considering re-exposure. In addition, heparin should only be used for a short duration, and the patient should be switched to another anticoagulant as soon as possible.4 TAKE-HOME POINTS: HEPARIN-INDUCED THROMbOCYTOPENIA 1. HIT is caused by an immune reaction against the complex of PF-4 and heparin. 2. Correlate clinical suspicion of HIT with laboratory results, because unnecessarily changing from heparin can be dangerous if therapeutic anticoagulation is not rapidly achieved and costly. However, if you believe your patient has HIT, do not wait for laboratory results. 3. Remember the 4Ts: Thrombocytopenia, Timing, Thrombosis, and oTher causes. 4. Use both functional and antigenic laboratory tests to get the best sensitivity and specificity. 5. Immediately stop heparin and start another anticoagulant therapy such as l. 6. Risk factors include postsurgery, female, and long-term use of unfractionated heparin. 7. Clinical signs of stroke, pulmonary embolism, and myocardial infarction within 5–10 days of initiating heparin should be a red flag for HIT. 8. Platelet transfusion can make the situation worse!
9. Try to avoid future heparin use in these patients. REFERENCES 1. Warkentin, T. E., and J. G. Kelton. 1996. “A 14-year Study of HeparinInduced Thrombocytopenia.” American Journal of Medicine 101: 502– 7. 2. Burke, A. P., T. Mezzetti, A. Farb, E. R. Zech, and R. Virmani. 1998. “Multiple Coronary Artery Graft Occlusion in a Fatal Case of HeparinInduced Thrombocytopenia.” Chest 114: 1492–5. 3. Francis, J. L., G. J. Palmer III, R. Moroose, and A. Drexler. 2003. “Comparison of Bovine and Porcine Heparin in Heparin Antibody Formation after Cardiac Surgery.” Annals of Thoracic Surgery 75: 17–22. 4. Shantsila, E., G. Y. H. Lip, and B. H. Chong. 2009. “Heparin-Induced Thrombocytopenia.” Chest 135: 1651–64. 5. Zinkovsky, D. A., and M. S. Antonopoulos. 2008. “Heparin-Induced Thrombocytopenia: Overview and Treatment.” Pharmacy Therapeutics 33(11): 642–44, 647–51. 6. Denys, B., V. Stove, J. Philippe, and K. Devreese. 2008. “A Clinical- Laboratory Approach Contributing to a Rapid and Reliable Diagnosis of Heparin-Induced Thrombocytopenia.” Thrombosis Research 123: 137–45. 7. Harenberg, J., G. Huhle, C. Giese, L. C. Wang, M. Feuring, X. H. Song, and U. Hoffmann. 2000. “Determination of Serotonin Release From Platelets by Enzyme Immunoassay in the Diagnosis of Heparin-Induced Thrombocytopenia.” British Journal of Haematology 109(1): 182–6. 8. Warkentin, T. E., R. S. Greinacher, A. Koster, and A. M. Lincoff. 2008. “An Improved Definition of Immune Heparin-Induced Thrombocytopenia: American College of Chest Physicians Evidence-Based clinical Guidelines, 8th ed.” Chest 133(Suppl 6): 340S–380S. 9. Konkle, B. A. 2008. “Disorders of Platelets and Vessel Wall.” In Harrison’s Principles of Internal Medicine. 17th ed., edited by A. S. Fauci, E. Braunwald, D. L. Kasper, S. L. Hauser, D. L. Longo, J. L. Jameson, and J. Loscalzo, pp. 718. New York: McGraw-Hill. 10. Rauova, L., L. Zhai, M. A. Kowalska, G. M. Arepally, D. B. Cines, and M. Poncz. 2006. “Role of Platelet Surface PF4 Antigenic Complexes in Heparin- Induced Thrombocytopenia Pathogenesis: Diagnostic and Therapeutic Implications.” Blood 107: 2346. 11. Newman, P. M., and B. H. Chong. 2000. “Heparin-Induced Thrombocytopenia: New Evidence for the Dynamic Binding of Purified Anti- PF4-Heparin Antibodies to Platelets and the Resultant Platelet Activation.” Blood 96: 182.

Cha P ter Thrombocytopenia 41 Krishna Patel CASE A 55-year-old man with a 40-pack-year history of smoking and a distant splenectomy after a motor vehicle accident presented to the emergency department for evaluation of a 3-day history of productive cough, pleuritic chest pain, malaise, and subjective fever. Chest x-ray reveals a left lower lobe infiltrate. The patient is admitted and placed on empiric antibiotic coverage. Vitals on admission are as follows: temperature, 101.5°F; blood pressure, 134/72 mm Hg; heart rate, 105; and respiratory rate, 20. The following day, platelets are noted to have dropped from 160 K/μL to 48 K/μL. 1. What is the most likely diagnosis and why? Although this patient clearly has pneumonia, he has now developed thrombocytopenia. A normal platelet count in adults ranges from 150,000 to 450,000/μL. Thrombocytopenia is defined as a platelet count less than 150,000/ μL. However, it is important to keep in mind that approximately 2.5% of the normal population will have a platelet count lower than 150,000/μL. Although these patients are considered to be thrombocytopenic by definition, it is only when a patient is symptomatic that we would worry about treatment or cause. Thrombocytopenia is not usually clinically detectable until the platelet count has fallen below 100,000/μL, at which point petechiae, purpura, and mucosal bleeding may occur.1 Depending on the underlying cause of the thrombocytopenia, other symptoms such as fever or hypotension may be present as well. Spontaneous hemorrhage and severe bleeding do not typically occur until platelet counts are well below 50,000/μL.2 A dramatic reduction in the platelet count by 50%, despite remaining in the normal range, could be an indication of an underlying acute pathological condition as well (e.g., heparin- induced thrombocytopenia, infection, or sepsis).3 479 Overall incidence of thrombocytopenia is 13%–58% in intensive care unit (ICU) patients. Variation often depends on patient population and clinical settings.2,4 Bottom line: Thrombocytopenia is defined as a platelet count less than 150,000/ μL. Clinical symptoms of thrombocytopenia include petechiae, purpura, and mucosal bleeding. It is rare for such symptoms to manifest until the platelet count has fallen below 50,000/μL. CASE CONTINUED The next morning, the patient is noted to have a spontaneous nose bleed and scattered petechiae around the ankles. Morning labs reveal a platelet count of 12,000/μL. He is transferred to the ICU. 2. Does the presence of thrombocytopenia portend a worse prognosis for patients in the ICU? Yes. Regardless of the cause, thrombocytopenia has been shown to be an independent predictor of ICU mortality.3–8 It has been found that thrombocytopenia is associated with a 4- to 6-fold increase in mortality3,5,6 and a longer ICU stay.3–5,7 The relationship of thrombocytopenia and mortality is unlikely to be causal, because few critically ill patients die from fatal hemorrhage. More likely, thrombocytopenia is an indicator of severe homeostatic derangement and underlying pathology such as infection or disseminated intravascular coagulation (DIC). It has long been recognized that thrombocytopenia may be an early warning sign of sepsis, as demonstrated in this patient. Several studies underscore the relationship between thrombocytopenia and infection.3–8 The association between sepsis and thrombocytopenia may be attributed to platelet consumption, immune-mediated platelet destruction, or dilution secondary to excessive fluid resuscitation.8 Patients tend to die from the disease causing the thrombocytopenia rather than from the thrombocytopenia itself. Hence, the presence of thrombocytopenia in a critically ill patient should warrant an active search for the underlying pathology, as this often poses a much greater morbidity and mortality risk.6 Bottom line: Thrombocytopenia is an independent predictor of ICU mortality. However, mortality tends to be due to the underlying disease causing the thrombocytopenia rather than the thrombocytopenia itself. 3. According to the evidence, what are the most likely causes of thrombocytopenia in critically ill patients? Thrombocytopenia in critically ill patients is often multifactorial.4–6 The etiologies listed in Table 41.1 have emerged as some of the major contributors. TABlE 41.1 Causes of Thrombocytopenia in Hospitalized Patients Differential diagnosis Sepsis Disseminated intravascular coagulation Drug-induced 9.5% thrombocytopenia Relative incidence 52.4% 25.3% Heparin-induced 1.2% thrombocytopenia Immune 3.4% thrombocytopenia Massive blood loss 7.5% Thrombotic 0.7% microangiopathy Diagnostic clues Sepsis criteria, positive blood cultures Prolonged PT and aPTT, increased fibrin split products Normalization of platelet count after cessation of drug, recent new medication Use of heparin, venous or arterial thrombosis, positive HIT test, rebound of platelets after cessation of heparin Antiplatelet antibodies, normal or increased megakaryocytes in bone marrow aspirate Major bleeding, low hemoglobin, prolonged aPTT, and PT Shistocytes in blood smear, Coombs negative hemolysis, renal insufficiency Adapted from Ref. [5]. Bottom line: There are multiple etiologies of thrombocytopenia in hospitalized patients, the most common of which include sepsis, DIC, and drug induced thrombocytopenia. 4. Based on the evidence, what laboratory tests should be ordered for this patient? The initial evaluation of a thrombocytopenic patient should include a complete blood count (CBC) and peripheral blood smear. Examination of the blood smear should include estimation of platelet count, morphology, clumping, and other changes in the white blood cells or red blood cells (RBCs). A CBC and blood smear can help rule in diseases like acute leukemia, by examining for the presence of blast cells. Likewise, they can be used to identify bone marrow tumor invasion and fibrosis via the presence of teardrop RBCs or myeloid progenitors. Signs of increased peripheral platelet destruction that may be evidenced via blood smear include fragmented RBCs (schistocytes). If CBC and blood smear are inconclusive, more invasive testing such as bone marrow aspiration and biopsy should be considered to rule out myelodysplastic disorders or aplastic anemia. Bottom line: A CBC and peripheral blood smear are the gold-standard workup for thrombocytopenia. CASE CONTINUED In the ICU, the patient’s blood pressure drops to 100/70 mm Hg, heart rate is 98 bpm, respiratory rate is 22 breaths/min, and temperature increases to 39°C. His white blood cell count increases to 15,000 cells/ mm3 and his blood smear shows evidence of schistocytes. 5. Based on the evidence, what is the most likely cause for thrombocytopenia in this patient? The patient in this vignette meets the criteria for severe sepsis. Therefore, it is likely that the initial thrombocytopenia observed in this patient was an early sign of underlying infection, which eventually progressed to sepsis. As noted in Table 41.1, infection with progression to sepsis is the most common underlying cause of thrombocytopenia among critically ill patients. Sepsis is diagnosed in patients who meet the criteria for systemic inflammatory response syndrome (SIRS) with a proven or suspected microbial etiology. Note that the criteria for SIRS include two or more of the following conditions: • Fever (>38°C) or hypothermia (<36°C) • Tachypnea (>24 breaths/min) • Tachycardia (>90 bpm) • Leukocytosis (>12,000/μL) or leukopenia (<4000/μL) or >10% bands Severe sepsis is marked by evidence of organ dysfunction, including hematological instability (thrombocytopenia with a platelet count <80,000/μL) or cardiovascular instability, which includes hypotension defined by arterial systolic blood pressure <90 mm Hg or mean arterial pressure <70 mm Hg. If the patient’s hypotension does not respond to fluid resuscitation, then the patient will have progressed to septic shock. However, the patient in this vignette does not currently meet the criteria for septic shock.9 Bottom line: Underlying infection with progression to sepsis is one of the most common underlying pathologies behind thrombocytopenia in hospitalized patients. The criteria for sepsis include suspected microbial etiology along with 2 or more of the following conditions: fever or hypothermia, tachypnea, tachycardia, or leukocytosis or leukopenia. Presence of organ dysfunction defines severe sepsis. CASE CONTINUED Records indicate that the patient has a medical history of bipolar disease, which has been controlled with valproic acid for the past 8 months. 6. Does the evidence suggest that certain medications may contribute to the onset of thrombocytopenia among critically ill patients? Since thrombocytopenia can be due to many causes, drug-induced thrombocytopenia is often overlooked and the thrombocytopenia is falsely attributed to sepsis or other underlying conditions in acutely ill and hospitalized patients. There are hundreds of medications that can cause thrombocytopenia; Table 41.2 lists some of the more common agents. Notice that valproic acid is included within this list and thus may be contributing to the severity of thrombocytopenia in this patient. Bottom line: Since there are hundreds of drugs that can potentially cause thrombocytopenia, drug-induced thrombocytopenia should not be overlooked as a cause of thrombocytopenia in acutely ill or hospitalized patients. TABlE 41.2 Common Drugs Causing Thrombocytopenia Drug category Heparins Cinchona alkaloids Platelet inhibitors Antiarrhythmics Antirheumatic agents Antimicrobrials Anticonvulsants H2 Antagonists Analgesics Diuretic agents Immunosuppresants Common drugs implicated Unfractionated heparin, low-molecular weight heparin Quinine, quinidine Abciximab, eptifibatide, tirofiban Amiodarone, procainamide Gold salts Linezolid, rifampin, sulfonamides, vancomycin, piperacillin Carbamazeoine, phenytoin, valproic acid Cimetidine Acetaminophen, diclofenac, naproxen Chlorothiazide Fludarabine, oxaliplatin Adapted from Refs. [2,10,11]. 7. Based on the evidence, how should this patient be managed? Treatment should be directed at the etiology of the thrombocytopenia, which is why it is so important to identify the underlying pathology.6,8 The underlying pathology of thrombocytopenia in this patient is infection progressing to sepsis. Therefore, the patient should be started on broad-spectrum antibiotics until results of the blood cultures show a definitive causal organism. Supportive oxygen and intravenous fluids should be started as well. If the patient shows signs of worsening hypotension, then the use of vaso pressors should be considered.9 If the patient’s thrombocytopenia remains depressed, despite recovering from his infection, then drug-induced thrombocytopenia secondary to his use of cimetidine should be considered. Treatment for drug-induced thrombocytopenia includes immediate cessation of the offending agent. After drug discontinuation, bleeding symptoms should resolve within 1–2 days, and platelet count should recover within 4–10 days.2 Bottom line: Treatment for thrombocytopenia in hospitalized patients should be directed toward the underlying cause of thrombocytopenia. 8. Based on the evidence, should platelet transfusion therapy be considered for this patient? Treatment with platelet infusion therapy in critically ill patients continues to be a topic that remains controversial. Recent studies continue to show inconsistencies between current guidelines and the use of platelet transfusions.12 These guidelines indicate platelet transfusion therapy if there are signs of active hemorrhage or if the platelet count is less than 10,000–20,000/μL. However, they are based on the studies by the American Society of Clinical Oncology and may not be applicable to all critically ill patients who, unlike oncology patients, have normal bone marrow function.13 Benefits of platelet transfusion include reduced morbidity/mortality associated with minor and major bleedings.14 Transfusion therapy is contraindicated in thrombotic thrombocytopenic purpura (unless there is life-threatening hemorrhage) and heparin-induced thrombocytopenia. There are also risks associated with platelet transfusion, especially for critically ill patients, including alloimmunization, infection, allergic reaction, and transfusion-related acute lung injury.14 In this case, if the patient’s nose bleed stops and he shows no signs of worsening hemorrhage or dramatic reduction in platelet count, then platelet transfusion therapy can be held, especially because his bone marrow function is intact. However, it is important to realize that a sound argument can be made in support of starting platelet transfusion therapy. It is often up to the clinician to weigh the risks and benefits to the therapy in critically ill patients because there are few well- controlled studies that have evaluated this issue.13 Bottom line: Platelet transfusion therapy should only be considered in critically ill patients in the setting of active bleeding and severe thrombocytopenia (<10,000–20,000/μL). However, in most cases of thrombocytopenia with active bleeding, data supporting routine use of transfusions are lacking. 9. What does the evidence suggest with regards to prophylactic platelet transfusion therapy for thrombocytopenia before surgery? There is little overall evidence to help guide the use of prophylactic platelet transfusion therapy for surgical procedures, due to the large number of variables involved, which makes prophylactic platelet transfusion therapy a very controversial topic. Guidelines recommend that to undergo minor procedures like lumbar puncture, epidurals, gastroscopy and biopsy, insertion of indwelling catheters, transbronchial biopsy, and liver biopsy, platelet counts should be raised to at least 50,000/μL. Surgery in more delicate sites like the brain or eyes require a platelet count of at least 100,000/μL.14 However, there are few wellcontrolled studies that support the 50,000/μL platelet count as the cutoff for prophylactic therapy among critically ill patients, marking this as an area that requires additional study.13 Bottom line: Guidelines recommend that a patient should have a platelet count of at least 50,000/μL before undergoing surgical procedures. However, the use of prophylactic platelet transfusions before surgical procedures in critically ill patients continues to be a controversial topic. TAKE-HOME POINTS: THROMBOCYTOPENIA • Thrombocytopenia is defined as a platelet count less than 150,000/μL. • Clinical symptoms of thrombocytopenia include petechiae, purpura, and mucosal bleeding, like epistaxis. • The initial evaluation of a thrombocytopenic patient should include a CBC and peripheral blood smear. • Thrombocytopenia is often a marker of underlying pathologies such as infection, sepsis, and DIC. • Treatment of thrombocytopenia is based on the underlying etiology of the thrombocytopenia. • The possibility of drug-induced thrombocytopenia should not be overlooked. Patients suspected of drug-induced thrombocytopenia should undergo immediate drug discontinuation. • Indications for platelet transfusion therapy include active bleeding and a platelet count <10,000–20,000/μL. • Indications for prophylactic platelet transfusion therapy before surgical procedures include a platelet count of less than 50,000/μL. • Guidelines and indications for platelet transfusion therapy in critically ill patients continue to be a controversial topic in need of more evidence-based support. REFERENCES 1. Buckley, M. F., and J. W. James. 2000. “A Novel Approach to the Assessment of Variations in Human Platelet Count.” Journal of Thrombosis and Haemostasis 83: 480–84. 2. Priziola, J. L., and M. A. Smythe. 2010. “Drug-Induced Thrombocytopenia in Critically Ill Patients.” Critical Care Medicine 38 (6): S145–54. 3. Moreau, D. 2007. “Platelet Count Decline: An Early Prognositic Marker in Critically Ill Patients with Prolongs ICU Stays.” Chest 131: 1735–41. 4. Strauss, R., and M. Wehler. 2002. “Thrombocytopenia in Patients in the Medical Intensive Care Unit: Bleeding Prevalence, Transfusion Requirements, and Outcome.” Critical Care Medicine 30: 1765–71. 5. Levi, M., and M. Schultz. 2011. “Coagulation Biomarkers in Critically Ill Patients.” Critical Care Clinics 27: 281–97.http://Criticalcare.theclinics.com. 6. Vanderschueren, S., and A. D. Weerdt. 2000. “Thrombocytopenia and Prognosis in Intensive Care.” Critical Care Medicine 28: 1871–77. 7. Crowther, M. A., and D. J. Cook. 2005. “Thrombocytopenia in Medicalsurgical Critically Ill Patients: Prevalence, Incidence, and Risk Factors.” Journal of Critical Care 20: 348–53. 8. Hui, P., and D. J. Cook. 2011. “The Frequency and Clinical Significance of Thrombocytopenia Complication Critical Illness.” Chest 139: 271–78. 9. Munford, R. S. 2012. “Severe Sepsis and Septic Shock.” In Harrison’s Principles of Internal Medicine. 18th ed., edited by D. L. Longo, A. S. Fauci, D. L. Kasper, S. L. Hauser, J. L. Jameson, and J. Loscalzo, Chapter 271. New York: McGraw-Hill. http://www.accessmedicine.com/ content.aspx?aID=9105972. 10. Aster, R. H., and D. W. Bougre. 2007. “Drug-Induced Immune Thrombocytopenia.” The New England Journal of Medicine 357: 580–87. 11. Moulis, G. 2011. “Drug-Induced Immune Thrombocytopenia: A Descriptive Survey in the French PharmacoVigilance Database.” Platelets 1–5. 12. The Blood Observational Study Investigators on Behalf of the ANZICSClinical Trials Group. 2010. “Transfusion Practice and Guidelines in Australian and New Zealand Intensive Care Units.” Intensive Care Medicine 36: 1138–46. 13. Gajic, O., and W. H. Dzik. 2006. “Fresh Frozen Plasma and Platelet Transfusion for Nonbleeding Patients in the Intensive Care Unit: Benefit or Harm?” Critical Care Medicine 34.5: S170–73. 14. British Committee for Standards in Haematology. 2003. “Guidelines for the Use of Platelet Transfusions.” British Journal of Haematology 122: 10–23. 15. Kitchens, C. S. 2009. “Thrombocytopenia and Thrombosis in Disseminated Intravascular Coagulation (DIC).” Hematology: American Society of Hematology 240–47.

c h A pt E r Acute Renal Failure 42 Eric Addo CASE A 67-year-old woman with a history of systolic congestive heart failure (CHF) is evaluated for a 3-day history of progressively worsening fatigue and malaise. Before the onset of these symptoms, she experienced a 1-week history of vomiting and diarrhea, presumably from a viral gastroenteritis. She denies any recent changes to her medications and admits only to recent ibuprofen use. Several hours after admission, the patient becomes confused. 1. What is the most likely diagnosis and why? The patient’s recent history of vomiting and diarrhea is suggestive of volume depletion and places her at risk for ARF from renal hypoperfusion. The recent use of ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), is undoubtedly contributing to her ARF. Her confusion is likely due to her uremia. Note that while acute periods of prerenal azotemia are typically reversible with restoration of renal hemodynamics, this patient’s prolonged duration of hypovolemia is likely to have developed into acute tubular necrosis (ATN), which may be more refractory to mere fluid replacement (see Section 4). The diagnosis of ARF is traditionally made based on an elevation of serum creatinine concentration by ≥0.5 mg/dL or by an increase in creatinine concentration of ≥50% from baseline.2,3 There is an agedependent increase in development of ARF in patient’s over 60, likely due to decreased renal reserves.4 The patient’s presentation of ARF with a co-morbid condition, CHF, is increasingly common and portends a worse prognosis, particularly in the elderly.4–6 Bottom line: The classic presentation for ARF includes fatigue, malaise, and nausea. The diagnosis of ARF is even more likely in elderly patients presenting with CHF. 489 2. Is history alone a powerful enough diagnostic tool to make the diagnosis of ARF? Yes, oftentimes history alone may provide sufficient information to diagnose ARF (Table 42.1). Medication history, in particular, can be extremely helpful in suggesting the diagnosis of ARF. The findings of one case control study in which there was a 3- fold increase in relative risk of ARF in patients with recent NSAID compared to those without suggests that recent NSAID use has diagnostic value.5 Findings from another case control study in which the use of diuretics was associated with a 3-fold increase in relative risk of ARF suggests that diuretic use likewise has diagnostic value.5 Although history is a crucial component in diagnosing ARF, laboratory findings are clearly necessary to confirm the diagnosis. Bottom line: History is very helpful in diagnosing ARF. In particular, recent use of NSAIDs or diuretics has diagnostic value. CASE CONTINUED Laboratory workup reveals a creatinine of 4 mg/dL, potassium of 6 mg/dL, BUN of 38 mg/dL, and bicarbonate of 16 mmol/L. Phosphate and uric acid levels are both elevated. Urinalysis reveals dark granular casts, 2+ protein, and epithelial cell casts. Her AMS resolves within hours of admission. The resident caring for her is considering a nephrology consultation for emergent dialysis. 3. Based on the evidence, should this patient undergo hemodialysis at this time? No. Indications for emergent dialysis include refractory volume overload, refractory hyperkalemia, refractory metabolic acidosis, toxic ingestion, and uremic symptoms.6 At this time, no interventions have been attempted, so her signs are not clearly refractory, and her uremic symptoms (AMS) are resolving. Fluid overload is an important risk factor for adverse outcomes in ARF and should be managed with dialysis only after appropriate pharmacologic intervention.7 Of note, although loop diuretics may improve short-term outcomes in hypervolemic ARF, loop diuretics are not associated with long-term renoprotective effects.8 Because ARF in this patient is not associated with oliguria (<400 mL urine/d), which portends a more serious insult, she is predicted to have a better outcome.6 She should be managed with TABlE 42.1 Probable Causes of Acute Renal Failure Based on History Findings History obtained on review of systems Pulmonary Sinus, upper respiratory or pulmonary symptoms Cardiac Symptoms of heart failure Intravenous drug abuse, prosthetic valve or valvular disease Gastrointestinal Diarrhea, vomiting, or poor intake Colicky abdominal pain radiating from flank to groin Genitourinary Symptoms of benign prostatic hypertrophy Musculoskeletal Bone pain in the elderly Trauma or prolonged immobilization Skin Rash Constitutional symptoms Fever, weight loss, fatigue or anorexia Multiple sclerosis, diabetes mellitus or stroke Surgical history Recent surgery or procedure Medication history Angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics or acyclovir (Zovirax) Probable causes of acute renal failure Pulmonary-renal syndrome or vasculitis Decreased renal perfusion Endocarditis Hypovolemia Urolithiasis Obstruction Multiple myeloma or prostate cancer Rhabdomyolysis (pigment nephropathy) Allergic interstitial nephritis, vasculitis, systemic lupus erythematosus, atheroemboli or thrombotic thrombocytopenic purpura Malignancy or vasculitis Neurogenic bladder Ischemia, atheroemboli, endocarditis or exposure to contrast agent Decreased renal perfusion, acute tubular necrosis or allergic interstitial nephritis Source: Agrawal, M., and R. Swartz. April 1, 2000. “Acute Renal Failure.” American Family Physicians 61 (7): 2077–88. With permission. nondialytic supportive care, including potassium restriction, reduced fluid intake, sodium restriction (<2 g/d), and sodium bicarbonate supplementation if bicarbonate levels fall below 15–18 mmol/L.9 If the patient is refractory to treatment, it would be appropriate to consider hemodialysis. Bottom line: Patients with prerenal ARF generally do not require hemodialysis unless they display signs of refractory hypervolemia, uremia, acidemia, or electrolyte imbalances. CASE CONTINUED A nephrology consultation is performed and the attending requests urine and serum levels of kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and N-gelatinase associated lipocalin (N-GAL). Workup reveals high urinary levels of KIM-1 and IL-18, and low levels of N-GAL. Urine cytology shows the presence of dark granular casts, >5 WBC/HPF, and epithelial cell casts. Urinalysis and urine indices show 2+ protein, urine osmolality of 300 mOsm/kg, urine sodium of 45 mmol/L, and fractional excretion of sodium (FeNa) of 5%. 4. How does the evidence suggest urinary levels of KIM-1, Il-18, and N-GAl should be interpreted in this patient? The high urinary levels of KIM-1 suggest that she has ischemic ATN because the expression of KIM-1, a transmembrane protein in tubular epithelial cells, is substantially upregulated after ischemic or toxic insult.10,11 A unit increase in urinary KIM-1 compared with normal levels results in a 12 fold higher risk from baseline for ATN.12 The high levels of urinary IL-18, a cytokine whose expression is also upregulated with renal ischemia, suggests proximal tubular necrosis.13 The sensitivity of a high IL-18 for ARF is ~50%, with a somewhat higher specificity of 75%.14 Urinary levels of IL-18, an active cytokine in ischemic ARF, have been observed to increase in patients with ATN.15 Although a high urinary concentration of N-GAL has high sensitivity and specificity in diagnosing ARF in postoperative adults, the low levels of urine N- GAL in this woman does not serve to exclude the diagnosis of ARF.16 N-GAL is present in proximal tubular cells after ischemic insult and can be obtained from the urine.17 N-GAL is a very effective marker in adults following cardiac surgery.16 Recent clinical studies have measured the sensitivity and specificity of TABlE 42.2 Common Urinary Markers Indicative of ARF Urinary Type of Marker levels injury KIM-1 High Intrinsic renal Duration of injury 12 hours after initial insult20 IL-18 High Intrinsic renal N-Gal Low Prerenal, intrinsic renal, postrenal Urine Il-18 levels > 100 pg/ mL are associated with increased odds of AKI of 6.9 in the next 24 hrs.21 3 h after initial insult21 Sensitivity Specificity Too small Too small of a of a study to study be deterto be mined determined 50% 75% 69% 65% N-GAL for making a diagnosis of all-cause ARF (defined as increase of 50% or greater in creatinine levels-3 hours postsurgery compared with preoperative levels) to be 69% and 65%, respectively.18,19 Information regarding sensitivity, specificity, duration of injury, and type of injury indicative of urinary markers is illustrated in Table 42.2 below. Bottom line: Above and beyond serum creatinine levels, obtaining urinary levels of KIM-1, IL-18, and N-GAL may help the clinician determine the time of initial occurrence injury, nature of injury, and duration of ARF. 5. What does the evidence suggest regarding the etiology of ARF based on the urine indices and urinalysis of the patient? The dark (muddy brown) granular casts and urine indices suggest that her prerenal azotemia has progressed to ATN.22,23 Epithelial cells and low-grade proteinuria on urinalysis are indicative of intrinsic renal failure (most likely ATN).23 In ATN, tubular epithelial cells slough off from the basement membrane, resulting in the formation of dark granular casts.22 In addition, the urine osmolality of 300 mmol/kg coincides with an inability of the renal parenchyma to reabsorb sodium and water due to loss of epithelial cells. Thus, urine osmolality becomes isotonic with plasma osmolality, and fractional excretion of sodium generally exceeds 2%, as seen in this woman.22 Without the reabsorptive capacity of the kidney, urine sodium levels will exceed 40 mmol/L. Urine indices and urinalysis findings that are common in ATN can be seen in Table 42.3 below. Bottom line: Presence of dark granular casts, epithelial cell casts, and low-grade poteinuria are indicative of intrinsic renal etiology (ATN). Increased fractional excretion of sodium and an isotonic urine osmolality can signal a loss of reabsorptive renal capacity. 6. Does the evidence suggest a renal biopsy should be performed in this patient? No. Because this patient does not present with signs that suggest an atypical etiology of her ARF (e.g., acute glomeulonephritis, lupus nephritis, or acute interstitial nephritis), current evidence does not support a renal biopsy.24,25 Renal biopsy is recommended only when (1) noninvasive diagnostic methods have failed or (2) in patients whom are suspected to have pathological conditions separate from ATN (e.g., glomerulonephritis and vasculitis).26 However, in these select patients, renal biopsy may have substantial diagnostic value. For example, in a prospective study of 266 patients from a single center with various renal pathology (ARF, nephritic syndrome, chronic renal failure, etc.), management of patients with ARF was shown to be altered in 71% TABlE 42.3 The Most Important Urinary Variables in the Differential Diagnosis of Acute Renal Failure22 Urinalysis Specific gravity Osmolality (mmol/kg) Sodium (mmol/L) Fractional excretion of sodium (%) Fractional excretion of uric acid (%) Low- molecular-weight proteins Brush-border enzymes Renal (ATN) Abnormal 1·010 >300 >40 >2 >15 High High Source: Reprinted from The Lancet, 365, Lameire, N., W. V. Van Biesen, and R. Vanholder, “Acute Renal Failure,” 417−30, Copyright 2005, with permission from Elsevier. of cases after histologic results of renal biopsy, thereby indicating the importance of biopsy.27 Bottom line: Renal biopsy should be reserved for ARF cases that are refractory to initial therapy and for which the patient has an atypical pathology or presentation, such as glomerulonephritis or a vasculitis. 7. What does the evidence suggest regarding management for this patient’s ARF? The evidence suggests that volume replacement is the most effective prophylactic strategy to prevent further deterioration of renal function, but has little to no effect at restoring renal function after ATN develops.6 Loop diuretics are also not indicated in this patient. Loop diuretics have been shown to enhance diuresis after being administered in the first 24 hours of onset of oliguria, although no evidence supports that they restore renal recovery or benefit mortality.28 Oral bicarbonate or citrate can be administered to this patient in pill or liquid preparation but does not need to be given unless her bicarbonate is less than 15– 18 mmol/L.6,9 Elevated phosphate in this woman should be treated with dietary phosphate restriction, oral phosphate binders, or intravenous (IV) calcium gluconate followed by oral calcium carbonate. Management of her hyperkalemia should be based on the severity as well as the presence or absence of ECG changes.9 Treatment for the hyperkalemia may include glucose and insulin, binding resins, and correction of metabolic acidosis.6 In 15 randomized clinical trials with 1550 patients, there was no survival advantage of continuous renal replacement therapy over intermittent renal replacement therapy in ARF.29 The advantage of continuous renal replacement therapy over intermittent renal replacement therapy is the improved hemodynamic stability, effective acid/ base control, ability to administer unlimited nutritional support, and removal of inflammatory mediators, but overall outcomes are unchanged.30,31 Bottom line: IV fluids and treating underlying cause are proven to manage ARF in all patients. Acid base and electrolyte status should be assessed and treated. If renal replacement is indicated, continuous replacement is preferred over intermittent replacement for ease of administration, but no survival advantage has been documented between the 2 methods. Common management strategies in ARF are presented in Table 42.4. Other therapies are still being studied, but have no proven evidence for efficacy. 8. What preventative measures does the evidence suggest can be used for this patient with established ATN to prevent further deterioration in renal function? None. Clinical studies involving patients with established ATN have discounted the benefit of pharmacological therapy in prevention of ARF secondary to postischemic ATN.33 Rather, interventions tend to concentrate on preventing the initial development of ATN. Nonpharmacological intervention is recommended in patients at risk during periods of ischemia. Intravenous fluids, maintenance of adequate hemodynamic status, and removal of inciting factors such as nephrotoxic agents should be performed to reduce progression to ATN. Fluid repletion can continue at a rapid rate until systemic pressures normalize. Randomized controlled trials and meta-analysis have not determined an advantage between fluid repletion with isotonic saline versus a colloid containing solution such as albumin.34,35 Identification of individuals at high risk for ARF is tantamount. Most patients at risk for postischemic ATN are those with a period of prolonged hypotension, as in this case. Prolonged hypotension can be due to marked hypovolemia, sepsis, major surgery, or severe pancreatitis.33 Risk factors for ATN include heart failure, diabetes, TABlE 42.4 Acute Renal Failure Management in Inpatient Setting33 Exclude urinary tract obstruction by utilizing clinical suspicion Evaluate for presence of a prerenal state If evidence of intravascular depletion is present, restore intravascular volume Always consider the possibility of intrarenal causes that require early diagnosis Discontinue all potential nephrotoxins or drugs associated with AIN Search for and treat acute uremic complications such as hyperkalemia, acidosis, and volume overload Optimize nutritional status and avoid foods high in potassium and phosphorous Initiate renal replacement therapy before uremic, metabolic, or volume related complications develop IV calcium gluconate, phosphate restriction, and oral phosphate binders should be used for individuals with hyperphosphatemia. Source: Modified from Yarlagadda, S., and M. A. Perazella. Acute Renal Failure in the Hospital: Diagnosis and Management, Turner White Communication Inc. Wayne, PA. With permission of the author. or procedures such as cardiopulmonary bypass and abdominal aortic aneurysm repair. Bottom line: Pharmacologic interventions for prevention of ARF in patients with established ATN is lacking. IV fluids, maintenance of hemodynamic status, and removal of inciting factors are currently indicated for initial prevention of ATN development. TAKE-HOME POINTS: ACUTE RENAl FAIlURE 1. ARF is defined as an increase in creatinine ≥0.5 mg/dL or an increase in creatinine of greater than or equal to 50% from baseline concentration. 2. Risk factors for ARF include preexistent kidney disease, diabetes, advanced age, hypertension, peripheral artery disease, and heart failure. Patients hospitalized in the ICU are also at increased risk for developing ARF. 3. Clinical presentation and history of ARF can be a history of prior volume depletion, malaise, fatigue, uremia, postoperative, history of renal obstruction, and volume overload. 4. ARF has many causes that are categorized as prerenal, intrinsic renal, and postrenal. 5. Make sure before any diagnostic workup that a complete history of medications and possible exposure to nephrotoxins are obtained. 6. History and physical examination, renal ultrasonography, urine indices, urinalysis, and metabolic panel can elucidate the cause of renal failure. 7. Treatment of ARF includes IV fluids, treating underlying cause, correction of electrolyte imbalance, and dialysis if indicated is mainstay treatment. REFERENCES 1 . Parker, B. D., and J. H. lx. 2011. “Renal Disease.” In Pathophysiology of Disease. 6th ed., edited by S. J. McPhee, and G. D. Hammer. Chapter 16. New York: McGraw-Hill. 2. Sabatine, M. S. 2011. Pocket Medicine: Massachusetts General Hospital Handbook of Internal Medicine. 4th ed., 4–12. Phildelphia: Lippincott Williams & Willkins. 3. Moore, R. D., C. R. Smith, J. J. Lipsky, E. D. Mellits, and P. S. Lietman. 1984. “Risk Factors for Nephrotoxicity in Patients Treated with Aminoglycosides.” Annals of Internal Medicine 100: 352–57. 4. Molitoris, B. A., and W. F. Finn. 2001. ARF; A Companion to Brenner & Rector’s The Kidney, 169. Philadelphia: W.B. Saunders Company. 5. Huerta, C., and J. Castellsague. 2005. “Nonsteroidal Anti-Inflammatory Drugs and Risk of ARF in the General Population.” American Journal of Kidney Disease 45 (3): 531–39. 6. Thadhani, R., M. Pascual, and J. V. Bonventre. 1996. “ARF.” New England Journal of Medicine 334: 1448–60. 7. Yarlagadda, S., and M. A. Perazella. Acute Renal Failure in the Hospital: Diagnosis and Management, 51–58. Wayne, PA: Turner White Communication Inc. Resident Grand Rounds. 8. Tataw, J., and P. Saudan. 2011. “Diuretics in Acute Kidney Failure: Useful or harmful.” Revue Médicale Suisse 7 (284): 501–4. 9. Bellomo, R., T. Naka, and I. Baldwin. 2004. “Intravenous Fluids and AcidBase Balance.” Contributions to Nephrology 144: 105–18. 10. Ichimura, T., C. C. Hung, S. A. Yang, J. L. Stevens, and J. V. Bonventre. 2004. “Kidney Injury Molecule-1: A Tissue and Urinary Biomarker for Nephrotoxicant-Induced Renal Injury.” The American Journal of Physiology 286: 552–63. 11. Han, W. K., and J. V. Bonventre. 2004. “Biologic Markers for Early Detection of Acute Kidney Injury.” Current Opinion in Critical Care 10: 476– 82. 12. Molony, D., and J. Craig. 2009. Evidence Based Nephrology, 76–77. Wiley- Blackwell, West Sussex, UK. 13. Faubel, S. 2005. “The Role of IL-18 in Ischemic Acute Renal Failure.” National Institute of Diabetes and Digestive and Kidney Diseases. 14. Parikh, C. R., E. Abraham, M. Ancukiewicz, and C. L. Edelstein. 2005. “Urine IL-18 is an Early Diagnostic Marker for Acute Renal Injury and Predicts Mortality in the Intensive Care Unit.” Journal of the American Society of Nephrology 16: 3046– 52. 15. Parikh, C. R., A. Jani, V. Y. Melnikov, S. Faubel, and C. L. Eldestein. 2004. “Urinary Interleucin 18 is a Marker of Human Acute Tubular Necrosis.” American Journal of Kidney Diseases 43: 405–14. 16. Wagener, G., M. Jan, M. Kim, K. Mori, J. M. Barasch, R. N. Sladen, and H. T. Lee. 2006. “Association Between Increases in Urinary Neutrophil Gelatinase- Associated Lipocalin and Acute Renal Dysfunction After Adult Cardiac Surgery.” Anesthesiology 105 (3): 485–91. 17. Mishra, J., Q. Ma, A. Prada, M. Mitsnefes, K. Zahedi, J. Yang, J. Barasch, and P. Devarajan. 2003. “Identification of Neutrophil Gelatinase-Associated Lipocalin as a Novel Urinary Biomarker for Ischemic Renal Injury.” Journal of the American Society of Nephrology 14: 2534–43. 18. Mishra, J., C. Dent, R. Tarabishi, M. M. Mitsnefes, Q. Ma, C. Kelly, S. M. Ruff, et al. 2005. “Neutrophil Gelatinase Lipocalin (NGAL) as a Biomarker for Acute Renal Injury after Cardiac Surgery.” Lancet 365: 1231–38. 19. Waikar, S., K. D. Liu, and G. M. Chertow. 2008. “Diagnosis Epidemiology and Outcomes of Acute Kidney Injury.” Clinical Journal of the American Society of Nephrology 3 (3): 844–61. 20. Trof, R. J., and D. M. Francesco. 2006. “Biomarkers of Acute Renal Injury and Renal Failure.” Shock 26 (3): 245–53. 21. Chertow, G. M. 2008. “Diagnosis, Epidemiology and Outcomes of Acute Kidney Injury.” Clinical Journal of American Society of Nephrology 3 (3): 844– 61. 22. Lameire, N., W. V. Van Biesen, and R. Vanholder. 2005. “Acute Renal Failure.” Lancet 365: 417–30. 23. Agrawal, M., and R. Swartz. April 1 2000. “Acute Renal Failure.” American Family Physicians 61 (7): 2077–88. 24. Yarlagadda, S., and M. A. Perazella. Acute Renal Failure in the Hospital: Diagnosis and Management, 51–58. Wayne, PA: Turner White Communication Inc. Resident Grand Rounds. 25. Wilson, M. D. R., Turner, J. S. Cameron, C. S. Ogg, C. B. Brown, and C. Chantler. 1976. “Value of Renal Biopsy in Acute Intrinsic Renal Failure.” British Medical Journal 2: 459–61. 26. Post, T. W., and B. D. Rose. May 2011. “Diagnostic Approach to the Patient with Acute or Chronic Kidney Disease.” Up to Date 19:2. 27. Richards, N. T., S. Darby, A. J. Howie, D. Adu, and J. Michael. 1994. “Knowledge of Renal Histology Alters Patient Management in Over 40% of Cases.” Nephrology, Dialysis, Transplantation 9: 1255–59. 28. Shilliday, I. R., K. J. Quinn, and M. E. Allison. 1997. “Loop Diuretics in the Management of Acute Renal Failure: A Prospective Double-Blind, Placebo-Controlled, Randomized Study.” Nephrology, Dialysis, Transplantation 12: 2592–96. 29. Swartz, R. D., J. M. Messana, S. Orzol, and F. K. Port. 1999. “Comparing Continuous Hemofiltration with Hemodialysis in Patients with Severe ARF.” American Journal of Kidney Diseases 34 (3): 424–32. 30. Mehta, R. L. 1994. “Therapeutic Alternatives to Renal Replacement for Critically Ill Patients in ARF.” Seminars in Nephrology 14: 64–82. 31. De Vriese, A. S., R. C. Vanholder, M. Pascual, N. H. Lamiere, and F. A. Colardyn. 1999. “Can Inflammatory Cytokines be Removed Efficiently by Continuous Renal Replacement Therapies?.” Intensive Care Medicine 25 (9): 903–10. 32. Yarlagadda, S., and M. A. Perazella. “Acute Renal Failure in the Hospital: Diagnosis and Management.” Resident Grand Rounds 51–58. 33. Sanoff, S., and M. Okusa. May 2011. “Possible Prevention and Therapy of Postischemic Acute Tubular Necrosis.” 34. Finfer, S., R. Bellomo, N. Boyce, J. French, J. Myburgh, and R. Norton. 2004. “A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit.” The New England Journal of Medicine 350: 2247. 35. Bellomo, R., H. Morimatsu, C. French, L. Cole, D. Story, S. Uchino, and T. Naka. 2006. “The Effects of Saline or Albumin Resuscitation on Acid-Base Status and Serum Electrolytes.” Critical Care Medicine 34: 2891.

Acute Interstitial Ch A pter Nephritis 43 Aimee S. Ang, mD CASE A 63-year-old obese man with a history of coronary artery disease, hypertension, and diabetes mellitus presents for evaluation of a 2-day history of a pruritic, salmon-colored rash that is present diffusely over the back. He has also been feeling weak with vague diffuse body aches. Medications include aspirin, lisinopril, metoprolol, and metformin. He recently completed a 7-day course of ciprofloxacin for a urinary tract infection. He denies any recent history of travel or drug/seasonal allergies. On exam, the rash is erythematous, salmon colored, maculopapular, and diffusely present over the back (see Figure 43.1). Laboratory results are as follows: White blood cell: 17,900/ul Eosinophils: 10% Hemoglobin: 12.1 gm/dL Blood urea nitrogen: 119 g/dL Creatinine: 2.6 mg/dL Urinalysis: 2+ protein, 3+ blood, 1+ leukocytes, and 17% eosinophils. 1. What is the differential diagnosis for rash in this patient? In a patient with rash, possible causes include the following: 1. Allergies to drugs and external agents: Commonly, medications such as penicillins and cephalosporins can cause a characteristic urticarial rash. Sulfa drugs can cause erythema multiforme and Steven Johnson’s syndrome. External agents such as poison ivy can cause a localized dermatitis or an anaphylactic rash. 501

FigurE 43.1 Rash on presentation. 2. Infectious causes: A number of infectious agents, usually viruses, cause rashes. Measles can incite a rash from head to toe. Rocky Mountain spotted fever causes a centripetally spreading rash. Other potential causes include Lyme disease, Rubella, and postStreptococcal rash. 3. Connective tissue and autoimmune diseases including lupus (malar, butterfly- shaped, and discoid rash), psoriasis, and dermatomyositis (violaceous rash) should also be considered in this patient, although they are far more common in women. Because the occurrence of the rash is closely related to recent use of ciprofloxacin, drug allergy is the most likely cause. Bottom line: In patients presenting with a rash, consider allergic reactions, infections, and connective tissue diseases. A thorough history with emphasis on preceding illnesses, medications, and associated symptoms will guide you to the most likely differential. 2. What is the most likely diagnosis and why? The patient has a rash, eosinophilia, and acute kidney injury (AKI), all characteristics of acute interstitial nephritis (AIN). The AIN was almost certainly caused by the recent exposure to ciprofloxacin, as noted earlier. TAblE 43.1 Common Signs and Symptoms in AIN Oliguria 51% Arthralgia 45% Fever 30% Rash 21% Fever, arthralgia, and rash 8% Abbreviations: AIN, acute interstitial nephritis. Adapted from Ref. [4]. The classic clinical presentation of AIN includes fever, maculopapular rash, and eosinophilia. However, patients can be asymptomatic or can have other symptoms such as nausea, vomiting, arthralgia, and malaise. Timing of symptoms is usually 3–5 days post second exposure to the offending drug or 2 weeks post first exposure to the offending drug. Classic signs and symptoms of AIN include oliguria, arthralgia, fever, and rash, as shown in Table 43.1 based on a 2004 study by Clarkson et al. Note that in this study, the “classic triad” of fever, arthralgia, and rash was seen in <10% of patients with AIN. Bottom line: Whether or not patients present with classic symptoms, a history of recent infection or exposure to a new medication (particularly antibiotics, nonsteroidal anti-inflammatory drugs [NSAIDs], and proton pump inhibitors [PPIs]) should lead one to consider AIN as a possible cause of AKI. In patients with AIN, objective findings include AKI, proteinuria, pyuria with WBC casts, hematuria, and eosinophiluria. CBC may also reveal a peripheral eosinophilia. 3. What are the most common causes of AiN? 1. Drugs (71%): methicillin (most common in the past), penicillin and cephalosporins, sulfa drugs (sulfamethoxazole/trimethoprim, furosemide, thiazides), rifampin, and NSAIDS. 2. Infections (15%): Mechanism is not well understood. Causal agents include Legionella, Leptospira, Cytomegalovirus, Streptococcus, and Ebstein–Barr virus. 3. Idiopathic (8%). 4. Tubulointerstitial nephritis and uveitis (TINU) syndrome (5%). 5. Sarcoidosis (1%). Note that other autoimmune diseases (e.g., Sjogren’s syndrome, Systemic lupus erythematosus, and Wegener’s granulomatosis) can also result in interstitial nephritis). TAblE 43.2 Laboratory Features Associated with AIN Laboratory study Typical findings Urinalysis Proteinuria Pyuria Hematuria Renal tubular epithelial cells or casts Elevated urine major basic protein Eosinophiluria Serum chemistry profile Complete blood count Elevated BUN and creatinine Hyperkalemia or hypokalemia Hyperchloremic metabolic acidosis Fractional excretion of sodium Eosinophilia Liver function tests Miscellaneous Anemia Elevated serum transaminase levels Elevated serum IgE levels Expected range, diagnostic use, or value Present to variable degrees, usually <1 g per 24 h except in AIN associated with NSAIDs. Leukocytes or leukocyte casts. Red cell casts are rare in AIN. Nonspecific finding. Lacks adequate predictive value to confirm or exclude diagnosis. Positive predictive value 38% (95% CI, 15%–65%) Variable degree of renal injury. Variable based on severity of renal failure and associated electrolyte or fluid changes. Suggests tubulointerstitial injury. Usually greater than 1%. More often associated with b-lactam antibiotic-induced AIN. Variable. In patients with associated drug-induced liver injury. Abbreviations: AIN, acute interstitial nephritis; NSAIDs, nonsteroidal anti- inflammatory drugs; CI, confidence interval; BUN, blood urea nitrogen; IgE, immune globulin E. Adopted from Ref. [1]. Bottom line: Pharmacological agents, especially antibiotics, PPIs, and NSAIDS, are the most common cause of AIN. 4. based on the evidence, what diagnostic tests should be obtained to confirm the diagnosis of AiN in this patient? 1. CBC with differential may provide clues to the etiology of AIN. Peripheral eosinophilia is present in 23% of patients with AIN. 2. Urinalysis may show hematuria, mild proteinuria, and sterile pyuria. Eosinophiluria can differentiate AIN from other causes of renal failure but is not always present. Acute tubular necrosis (ATN) will show muddy brown casts. Acute glomerulonephritis may show red and white cell casts. 3. Serum chemistry may show elevated BUN and creatinine. 4. Wright or Hansel stain for eosinophiluria becomes positive when eosinophils account for more than 1% of urinary white cells. 5. FeNa is usually >1% in AIN because of tubular damage, but rarely greater than 2% is seen in ATN. 6. Ultrasonography may show swollen and echogenic kidneys. 7. Renal biopsy has a controversial role. See detailed discussion in question 5. Bottom line: Essential tests include CBC, chemistries, and urinalysis. Look for eosinophilia and AKI with pyuria and WBC casts in the urine (Table 43.2). 5. Does renal biopsy play a role in the diagnosis of AiN? Not necessarily. Although renal biopsy remains the diagnostic gold standard, it is typically required only if there is no improvement of symptoms and persistent renal dysfunction despite removal of the suspected offending agent and treatment with steroids. Hematuria, pyuria, and symptoms usually resolve within 2 weeks and complete recovery of renal function typically occurs within 6–8 weeks after discontinuation of the offending agents. If a biopsy is performed, histology typically reveals interstitial edema and marked interstitial infiltrates consisting of lymphocytes and monocytes. Eosinophils, plasma cells, and neutrophils may also be present. Bottom line: Renal biopsy is the gold standard for diagnosis of AIN, but it is typically reserved for patients with no improvement in renal function despite appropriate treatment. 6. What does the evidence suggest should be the initial step in management of this patient? Initial management involves discontinuation of the suspected agent and is the cornerstone of therapy. Supportive treatment for renal failure includes adequate hydration with intravenous (IV) fluids and correction of electrolyte abnormalities. Renal function should improve within 1–2 weeks after discontinuation, with complete recovery typically occurring within 6–8 weeks (Table 43.3). Bottom line: Discontinuation of the offending agent(s) and supportive therapy are the mainstay of management in patients with AIN. 7. According to the evidence, is steroid use beneficial in patients with AiN? Steroids are a controversial topic in AIN. Several small prospective studies demonstrated significantly improved renal function following steroid use.[5-8] In 2008, a multicenter retrospective study of 61 patients with biopsy proven drug- induced AIN demonstrated improved outcomes in patients who had early treatment with steroids.[2] Although the efficacy of steroids in AIN remains controversial, the standard of care is to typically administer them in cases of suspected AIN. Consideration to administer corticosteroids folllowing discontinuation of the putative offending medication should take into account not only rapidity and completeness of return of normal renal function but also TAblE 43.3 Supportive Care Measures in AIN Discontinue offending drug Hydrate adequately with IV fluids Monitor and correct electrolyte abnormalities Avoid volume depletion or overload Symptomatic relief for fever and systemic symptoms Symptomatic relief for rash Avoid use of nephrotoxic drugs Avoid use of drugs that impair renal blood flow Adjust drug dosages for existing level of renal function Abbreviations: IV, intravenous. Adapted from Ref. [4]. potential long-term benefits in avoiding interstitial fibrosis and eventual chronic kidney disease.[3] Bottom line: A number of small prospective and retrospective studies have suggested that steroids may be beneficial in AIN. Given their relative safety, steroids are therefore typically given in suspected cases. TAKE-HOME POiNTS: ACuTE iNTErSTiTiAl NEPHriTiS 1. In patients presenting with rash, consider allergies, infections, and connective tissue diseases. A good chronological history focused on medication changes and preceding infections is helpful before proceeding to objective findings. 2. Classic symptoms of AIN include fever, maculopapular rash, and eosinophilia. However, patients can be asymptomatic or present with nausea, vomiting, arthralgia, or malaise. 3. Objective findings associated with AIN include elevated BUN/ creatinine, proteinuria, pyuria with WBC casts, hematuria, and eosinophiluria. 4. Drugs are the most common cause of AIN, and commonly include NSAIDs, antibiotics, and PPIs. 5. Discontinuing offending agents and supportive therapy with IV fluids is the mainstay of management. 6. While the use of steroids remains somewhat controversial, glucocorticoids are nonetheless typically administered. rEFErENCES 1. Kodner, M., and A. Kudrimoti. 2003. “Diagnosis and Management of Acute Interstitial Nephritis.” American Family Physician 67: 2527–34. 2. González, E., E. Gutiérrez, C. Galeano, C. Chevia, P. de Sequera, C. Bernis, and E. G. Parra. 2008. “Early Steroid Treatment Improves the Recovery of Renal Function in Patients with Drug-Induced Acute Interstitial Nephritis.” Kidney International 73: 940–46. 3. Appel, G. B. 2008. “The Treatment of Acute Interstitial Nephritisi: More Data at Last.” Kidney International 73: 905–7. 4. Clarkson, M., L. Giblin, F. O’Connell, P. O’Kelly, J. Walshe, P. Conlon, Y. O’Meara, A. Dormon, E. Campbell, and J. Donohoe. 2004. “Acute Interstitial Nephritis: Clinical Features and Response to Corticosteroid Therapy.” Nephrology, Dialysis, Transplantation 19: 2778–83. 5. Baker, R. J., and C. D. Pusey. 2004. “The Changing Profile of Acute Tubulointerstitial Nephritis.” Nephrology, Dialysis, Transplantation 19: 8–11. 6. Buysen, J. G., H. J. Houthoff, R. T. Krediet, and L. Arisz. 1990. “Acute Interstitial Nephritis: A Clinical and Morphological Study in 27 Patients.” Nephrology, Dialysis, Transplantation 5: 94–99. 7. Laberke, H. G. 1980. “Treatment of Acute Interstitial Nephritis.” Klinische Wochenschrift 58: 531–32. 8. Galpin, J. E., J. H. Shinaberger, T. M. Stanley, M. J. Blumenkrantz, A. S. Bayer, G. S. Friedman, J. Z. Montgomerie, L. B, Guze, J. W. Coburn, and R. J. Glassock. 1978. “Acute Interstitial Nephritis due to Methicillin.” The American Journal of Medicine 65: 756–65.

Minimal Change Chapter Disease 44 Chika anekwe, MD CASE A 6-year-old boy with an unremarkable past medical history is evaluated for a 1 week history of facial swelling, which recently progressed to whole-body swelling. He has also been sleeping more than usual over this time period and has reported some abdominal pain. He has otherwise been in his usual state of good health and his mother denies any sick contacts. Physical exam reveals facial edema, ascites, scrotal edema, and pitting edema halfway up both legs. Examination is otherwise unremarkable. Urinalysis reveals massive proteinuria, and initial blood tests reveal hypoalbuminemia. The urine protein-to-creatinine ratio is 3.6 mg/mg (normal <0.5). 1. What is the likely diagnosis and why? Nephrotic syndrome, which is characterized by four clinical features: nephrotic range proteinuria (>50 mg/kg/d urine protein-to creatinine ratio, hypoalbuminemia (serum albumin <3 g/dL), edema, and hyperlipidemia. Only the former two features are required to make the diagnosis; the latter two features may not be present. The glomerular diseases that cause nephrotic syndrome can be classified as either idiopathic (primary), suggesting that they result from intrinsic disease of the kidney, or secondary, suggesting that they result from pathology extrinsic to the kidney. There are several subsets of idiopathic nephrotic syndrome, including focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), minimal change disease (MCD), and diffuse mesangial proliferation. In adults, the most common causes of primary nephrotic syndrome are FSGS and MN, whereas in children, the most common cause of primary nephritic syndrome is MCD. Diabetes mellitus is the most common cause of 509 secondary nephrotic syndrome in children and adults. Given that the patient in the vignette is a child who presents with nephrotic syndrome and no evidence of extrinsic renal pathology, this chapter will focus on idiopathic nephrotic syndrome due to MCD. Although MCD can occur in adults, it is typically a disease of childhood. More than 90% of cases occur between the ages of one and ten.1 Among children older than ten, MCD accounts for only 50% of primary nephrotic cases, with an increased incidence of FSGS in this age group.2 A presumptive diagnosis of MCD can be made based on clinical findings if the following criteria are present: patient is less than 6 years of age, absence of hypertension, absence of hematuria, normal complement levels, and normal renal function.1 To definitively diagnose MCD, histologic analysis must be obtained. MCD is characterized by diffuse foot process effacement on electron microscopy and minimal changes (hence the name) on light microscopy. Bottom line: Nephrotic syndrome is characterized by four clinical features: nephrotic range proteinuria (>50 mg/kg/d or >3.5 g/d), hypoalbuminemia, edema, and hyperlipidemia; only the former two features are required to make the diagnosis. In a patient younger than 6 years old who presents with normal complement levels, normal renal function, and an absence of hypertension and hematuria, a presumptive diagnosis of MCD can be made; definitive diagnosis is made by biopsy. 2. What does the evidence suggest should be the initial work-up for a patient suspected of having nephrotic syndrome? The initial evaluation of a patient with nephrotic syndrome suspected of having MCD includes the following: – Urinalysis and urinary protein/creatinine ratio obtained from first morning void (>2 is diagnostic) – Serum electrolyte, creatinine, blood urea nitrogen, cholesterol, albumin, and complement 3 levels – Purified protein derivative (PPD) level – Serology for hepatitis B, C, and HIV in high risk populations – Thorough review for lack of signs and symptoms to suggest that the nephrotic syndrome may be attributed to a secondary condition (i.e., malar rash, adenopathy, hepatosplenomegaly) For patients more than 10 years of age or with signs of systemic lupus erythematosus (SLE), the following may also be obtained: – Antinuclear antibody (ANA) level For patients over 12 years of age: – Renal biopsy Urinalysis with microscopy is used to identify urine sediment such as cellular casts or hematuria, which suggests glomerulonephritis rather than nephrotic syndrome. The first morning urine protein/creatinine ratio will most accurately quantify the degree of proteinuria.1,3,6 Urine samples collected later in the day when the patient is upright and active often contain nonpathologic false elevations in protein. PPD is typically placed due to concern that a patient who was previously exposed to TB may become immunocompromised enough to develop an active TB infection in the case that steroid treatment is indicated in that patient’s future management. HIV and hepatitis viral serologies can rule out common infectious causes of nephrosis. Complement 3 and ANA are obtained to screen for diseases that cause proteinuria and are associated with hypocomplementemia, such as MPGN and SLE. If these tests are positive, a renal biopsy is almost certainly indicated. Bottom line: Initial work up for a patient suspected of having nephrotic syndrome should include urinalysis, urine protein/creatinine ratio from first morning void, serum chemistries, lipid profile, albumin, complement levels, placement of a PPD, serology for HIV and hepatitis B and C in high risk populations, and thorough review for signs and symptoms suggesting a systemic etiology. 3. Does the evidence suggest that this patient should receive a renal biopsy? This remains unclear. Since such a high proportion of children presenting with idiopathic nephrotic syndrome have MCD, empiric steroid therapy should be initiated before proceeding to renal biopsy.4 However, renal biopsy should be performed before initiation of empiric therapy in patients with any of the following criteria:1 Age <1 year or >10 years Gross hematuria Marked elevation of serum creatinine Abnormal complement levels Extra-renal manifestations such as malar rash or purpura Renal biopsy is recommended for patients over the age of 12 because of the increased frequency of diagnoses other than MCD.3 In the adult population, there is a much higher incidence of nephrotic syndrome presenting as a result of a systemic disease such as diabetes mellitus, amyloidosis, or SLE. In addition, renal biopsy should be performed in patients with steroid-resistant nephrotic syndrome (SRNS), defined as those who do not respond to steroid therapy within 4 weeks.3 Following these guidelines will prevent performing unnecessary renal biopsies on a large percent of children presenting with nephrotic syndrome. Bottom line: Empiric steroid therapy should be initiated before proceeding to renal biopsy unless certain concerning features such as hypertension, young age, or gross hematuria are present. 4. Given a spot urine protein/creatinine ratio of 3.6, what is the degree of proteinuria in this patient? The urine protein/creatinine ratio is used to determine the degree of proteinuria since it is less cumbersome to obtain than the 24-hour urine protein collection. This test is more accurate when performed on the first morning void, as this eliminates false elevations in protein secondary to orthostatic effects. For a child under 2 years, a normal ratio is <0.5. For children over age two and adults, a normal ratio is <0.2, which is equivalent to <300 mg/d. Nephrotic range for a spot protein/creatinine ratio is >2 mg/mg or >3 g/d of protein. Thus, our patient with a urine protein/ creatinine ratio of 3.6 has nephrotic range proteinuria. Bottom line: Nephrotic range for a spot urine protein/creatinine ratio is >2 or >3 g/24 hours of protein. 5. How does the evidence suggest this patient should be treated? Initial therapy for childhood nephrotic syndrome is administration of corticosteroids. A standard regimen is as follows: prednisone 2 mg/kg per day for 6 weeks (maximum: 60 mg/d) followed by prednisone 1.5 mg/kg on alternate days for 6 weeks (maximum: 40 mg/d). No steroid taper is required at the conclusion of this initial therapy.5 Treatment is adjusted accordingly for patients with steroid-dependent or SRNS. Steroid-dependent patients are those who have a relapse, as determined by the urine protein/creatinine ratio, within 2 weeks of discontinuation of steroid therapy, while steroid resistant patients fail to respond to treatment within the initial 4 weeks of therapy. Symptomatic treatment is also important since some patients may not show response to steroids or response may take several weeks. Symptomatic treatment is primarily directed toward reducing the edema. Salt restriction is recommended, since renal retention of sodium is the primary mechanism of edema in patients with nephrotic syndrome. Although salt restriction may not reduce the edema significantly, it will reduce further fluid accumulation. Diuretics may be used cautiously in patients with severe edema and only if there is not significant intravascular volume depletion. Particularly in children, there is risk of precipitating acute renal failure or hypovolemic shock with the use of diuretics.6 The fractional excretion of sodium (FeNa) can be used to distinguish patients with adequate intravascular volume (FeNa >2%) from those with volume depletion.7 Albumin can also be administered to increase the intravascular oncotic pressure and thereby protect the intravascular compartment against volume contraction, although data demonstrating a benefit in morbidity or mortality is lacking.6
Nephrotic patients with severe hypoalbuminemia are at risk for thromboembolic complications. Although patients with nephrotic syndrome are at increased risk for clot formation, no clear guidelines exist regarding the use of anticoagulants. There have been no placebo controlled studies to assess efficacy of anticoagulation in children with nephrotic syndrome. Heparin, low molecular- weight heparin (e.g., Lovenox) and oral anticoagulation with warfarin are some therapeutic options. Preventative measures include mobilization, avoidance of hemoconcentration resulting from hypovolemia, and early treatment of sepsis.3 Prophylactic treatment with low-dose aspirin or dipyridamole may be considered in high risk patients (those with albumin concentration <2 g/dL, fibrinogen >6 g/L, or antithrombin III <70% of normal). However, prophylactic antiplatelet therapy or anticoagulation is not universally recommended because of the lack of clear outcome data in children.3 Children with nephrotic syndrome are at increased risk for both bacterial and viral infections because of the loss of immunoglobulins in the urine. Although prophylactic antibiotics or antiviral agents are not recommended, it is recommended that these children receive the pneumococcal and varicella vaccines.8 The hyperlipidemia that is induced by nephrotic syndrome will normally reverse with remission of the proteinuria. The optimal treatment of hyperlipidemia in children with persistent nephrotic syndrome is unknown. These patients may be treated with statin therapy based on the data on adults with nephrotic syndrome (which show what exactly?) and children with familial hypercholesterolemia.3 Bottom line: A 12-week steroid therapy regimen is the standard treatment for the initial presentation of nephrotic syndrome. Symptomatic treatment should also be administered as needed with salt restriction, diuretic therapy, early mobilization, antiplatelet therapy, or anticoagulation for thrombosis prophylaxis, pneumococcal and varicella vaccination, and/or statin therapy. 6. Should therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker be considered in this patient? Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy is recommended for nephrotic syndrome with persistent hypertension and can be considered in steroid-dependent or frequently relapsing nephrotic syndrome. Frequently relapsing nephrotic syndrome is defined as having two or more relapses within 6 months after initial therapy or four or more relapses in any 12-month period. Patients with steroid-resistant idiopathic nephrotic syndrome have a high risk of progression to end-stage kidney disease due to progressively worsening proteinuria, and therefore ACE inhibitors may be particularly beneficial in these patients. In addition, children with nephrotic syndrome and persistent hypertension are more likely to have chronic kidney disease with poor outcome.3 In addition to having an antihypertensive effect, inhibition of the renin– angiotensin system with ACE inhibitors or ARB has been shown to reduce progression of kidney disease, especially when such disease is associated with heavy proteinuria.9 These medications result in a reduction of proteinuria while having a protective effect on renal tubules and preserving glomerular filtration rate (GFR).9,10 Bottom line: ACE inhibitor or ARB therapy is recommended nephrotic syndrome with chronic hypertension and should also be considered in steroid- dependent or frequently relapsing nephrotic syndrome. 7. What are some complications of MCD? The major complications seen with idiopathic nephrotic syndrome in children are dyslipidemia, infections, thromboembolism, and hypovolemia. Therapy- associated growth complications may also result from prolonged glucocorticoid use. The two most common lipid abnormalities in the nephrotic syndrome are hypercholesterolemia and hypertriglyceridemia. Dyslipidemia is thought to result from an overproduction of hepatic lipoproteins by an unknown mechanism.11 Treating children with SRNS and persistent dyslipidemia with statins has been proposed in childhood dyslipidemia care guidelines; however randomized studies are lacking.12 Children with nephrotic syndrome are at increased risk of developing serious bacterial infections, especially with encapsulated bacteria. This increased risk of infection is thought to be due to reduced levels of serum immunoglobulins and alternative complement pathway factors B and D, impaired ability to make specific antibodies, and immunosuppressive therapy.13 In addition to upper respiratory infections and urinary tract infections, pneumonia, sepsis, meningitis, empyema, and peritonitis are some of the infectious complications seen in children with nephrotic syndrome.14 Limiting the degree of nephrosis and the accumulation of edema and ascitic fluid is the best way to reduce the risk of infection. Children with nephrotic syndrome have an increased risk for developing thromboembolism. Multiple factors are thought to contribute to the increased risk, namely urinary loss of antithrombin III and increased production of clotting factors such as fibrinogen.15 Thrombocytosis and platelet hyperaggregability are also found with nephrotic syndrome. Moreover, hemoconcentration, hyperviscosity, diuretic therapy, and relative immobilization and corticosteroid therapy may increase the risk of clot formation.16 Deep vein thrombosis, renal vein thrombosis, and pulmonary embolism are the most frequently encountered thrombotic events; however, axillary, subclavian, femoral, coronary, and mesenteric arterial thromboses have also been reported.16 Because of this increased risk, patients with massive proteinuria and severe hypoalbuminemia should be observed closely and, in the case of thrombosis, treated promptly with heparin followed by oral anticoagulant therapy.17 Prophylactic anticoagulation is not recommended except in cases of relapsing nephrotic syndrome with thrombosis.17 Despite an increase in extracellular fluid volume in nephrotic syndrome due to third spacing from the hypoalbuminemia, these patients are often intravascularly volume depleted. This may manifest in tachycardia, peripheral vasoconstriction, decreased GFR with oliguria, or elevated plasma renin, aldosterone, and norepinephrine. In such patients, diuretic therapy, sepsis, or diarrhea may lead to severe hypotension and possibly shock. Glucocorticoid therapy may impair growth and increase body mass index in proportion to dose and duration of therapy. The risk is considerably higher for children receiving therapy for more than 6 months.18 Recommendations are to monitor BMI and linear growth, provide counseling for weight control, and consider alternatives to glucocorticoid therapy for patients with short stature or obesity. Bottom line: The major complications related to idiopathic nephrotic syndrome in children are infection, thromboembolism, hypovolemia leading to renal insufficiency, and hypovolemia. The major complication of therapy is growth impairment. 8. What are the criteria for admission and should this patient be admitted in the hospital? With appropriate outpatient follow up and home care, hospitalization is likely not necessary for this patient. Hospitalization should be considered if a patient has edema that is severe enough to cause respiratory distress, if a patient has tense scrotal or labial edema, if serious complications develop (e.g., sepsis, peritonitis, pneumonia, thromboembolism,), or if patient adherence to their treatment regimen is in doubt.19 9. What is the likely prognosis for this patient? The key determinant of prognosis is the success of initial treatment with corticosteroid therapy, which is based on the relative reduction in proteinuria. Steroid-sensitive nephrotic syndrome (SSNS) is four times more common than SRNS, and although SSNS has a tendency to relapse in excess of 60% of cases, the long-term outcome is good.20 Over 90% of patients with MCD will respond to glucocorticoid therapy within 8 weeks.4 Almost all these patients have an excellent outcome with few developing end stage renal failure or renal insufficiency. It should be noted that under age one, and particularly in the first three months of life, nephrotic syndrome is likely due to gene mutation and may thus be resistant to steroids.21 Bottom line: The key determinant of prognosis is the success of initial treatment with corticosteroid therapy, which is determined by relative reduction in proteinuria. TAKE-HOME POINTS: MINIMAL CHANGE DISEASE 1. MCD can be diagnosed clinically in a child with nephrotic range proteinuria (>50 mg/kg/d or >3–3.5 g/d), hypoalbuminemia (serum albumin <3 g/dL), and edema. Biopsy is typically not necessary to make the diagnosis. 2. Empiric steroid therapy should be initiated before proceeding to renal biopsy unless certain concerning features such as hypertension, young age, or gross hematuria are present. 3. A 12-week steroid therapy regimen is the standard treatment for the initial presentation of nephrotic syndrome. 4. ACE inhibitor or ARB therapy is recommended for SRNS and nephrotic syndrome with chronic hypertension and can be considered in steroid-dependent or frequently relapsing nephrotic syndrome. 5. The major complications related to idiopathic nephrotic syndrome in children are infection, thromboembolism, hypovolemia leading to renal insufficiency, and hypovolemia. The major complication of therapy is growth impairment. 6. Hospitalization is not necessary except in the case of complications or to ensure appropriate compliance and follow up. 7. The key determinant of prognosis is the success of initial treatment with corticosteroid therapy, based on the relative reduction in proteinuria. REFERENCES 1. 1978. “Nephrotic Syndrome in Children: Prediction of Histopathology from Clinical and Laboratory Characteristics at Time of Diagnosis. A Report of the International Study of Kidney Disease in Children.” Kidney International 13: 159. 2. Cameron, J. S. 1987. “The Nephrotic Syndrome and its Complications.” American Journal of Kidney Diseases 10 (3): 157–71. 3. Gipson, D. S., S. F. Massengill, L. Yao, S. Nagaraj, W. E. Smoyer, J. D. Mahan, D. Wigfall, et al. 2009. “Management of Childhood Onset Nephrotic Syndrome.” Pediatrics 124 (2): 747–57. 4. 1981. “The Primary Nephrotic Syndrome in Children. Identification of Patients with Minimal Change Nephrotic Syndrome From Initial Response to Prednisone. A Report of the International Study of Kidney Disease in Children.” The Journal of Pediatrics 98: 561. 5. Ehrich, J. H., and J. Brodehl. 1993. “Long Versus Standard Prednisone Therapy for Initial Treatment of Idiopathic Nephrotic Syndrome in Children. Arbeitsgemeinschaft für Pädiatrische Nephrologie.” European Journal of Pediatrics 152 (4): 357–61. 6. Hogg, R. J., R. J. Portman, D. Milliner, K. V. Lemley, A. Eddy, J. Ingelfinger. 2000. “Evaluation and Management of Proteinuria and Nephrotic Syndrome in Children: Recommendations From a Pediatric Nephrology Panel Established at the National Kidney Foundation Conference on Proteinuria, Albuminuria, Risk, Assessment, Detection and Elimination (PARADE).” Pediatrics 105: 1242. 7. Kapur, G., R. P. Valentini, A. A. Imam, and T. K. Mattoo. 2009. “Treatment of Severe Edema in Children with Nephrotic Syndrome with Diuretics Alone— A Prospective Study.” Clinical Journal of American Society of Nephrology 4: 907. 8. Ulinski, T., S. Leroy, M. Dubrel, S. Danon, A. Bensman. 2008. “High Serological Response to Pneumococcal Vaccine in Nephrotic Children at Disease Onset on High-dose Prednisone.” Pediatric Nephrology 23: 1107. 9. Ellis, D., A. Vats, M. Moritz, S. Reitz, M. J. Grosso, and J. Janosky. 2003. “Long-Term Antiproteinuric and Renoprotective Efficacy and Safety of Losartan in Children with Proteinuria.” Journal of Pediatrics 143 (1): 89–97. 10. Yi, Z., Z. Li, X. C. Wu, Q. N. He, X. Q. Dang, and X. J. He. 2006. “Effect of Fosinopril in Children with Steroid-Resistant Idiopathic Nephrotic Syndrome.” Pediatric Nephrology 21: 967–72. 11. Joven, J., C. Villabona, E. Vilella, L. Masana, R. Alberti, M. Valles. 1990. “Abnormalities of Lipoprotein Metabolism in Patients with the Nephrotic Syndrome.” New England Journal of Medicine 323: 579. 12. Holmes, K., and P. Kwiterovich. 2005. “Treatment of Dyslipidemia in Children and Adolescents.” Current Cardiology Reports 7: 445–56. 13. McIntyre, P., and J. C. Craig. 1998. “Prevention of Serious Bacterial Infection in Children with Nephrotic Syndrome.” Journal of Peadiatrics and Child Health 34: 314–17. 14. Alwadhi, R., J. Mathew, and B. Rath. 2004. “Clinical Profile of Children with Nephrotic Syndrome not on Glucorticoid Therapy, But Presenting with Infection.” Journal of Paediatrics and Child Health 40: 28–32. 15. Mehls, O., K. Andrassy, J. Koderisch, U. Herzog, and E. Ritz. 1987. “Hemostasis and Thromboembolism in Children with Nephrotic Syndrome: Differences From Adults.” Journal of Pediatrics 110 (6): 862–67. 16. Citak, A., S. Emre, A. Sairin, I. Bilge, and A. Nayir. 2000. “Hemostatic Problems and Thromboembolic Complications in Nephrotic Children.” Pediatric Nephrology 14 (2): 138–42. 17. Lilova, M. I., I. G. Velkovski, and I. B. Topalov. 2000. “Thromboembolic Complications in Children with Nephrotic Syndrome in Bulgaria (1974–1996).” Pediatric Nephrology 15 (1–2): 74–78. 18. Emma, F., A. Sesto, and G. Rizzoni. 2003. “Long-Term Linear Growth of Children with Severe Steroid-Responsive Nephrotic Syndrome.” Pediatric Nephrology 18 (8): 783–88. 19. Cohen, E. P. 2010. “Nephrotic Syndrome.” Emedicine. 20. 1984. “International Study of Kidney Disease in Childhood. Minimal Change Nephrotic Syndrome: Deaths During the First 5 to 15 Years Observation.” Pediatrics 73: 497–501. 21. Hinkes, B. G., B. Mucha, C. N. Vlangos, R. Gbadesgesin, J. Liu, K. Hasselbacher, D. Hangan, F. Ozaltin, M. Zenker, and F. Hildebrandt, 2007. “Nephrotic Syndrome in the First Year of Life: Two Thirds of Cases are Caused by Mutations in 4 Genes (NPHS1, NPHS2, WT1, and LAMB2).” Pediatrics 119: e907. Hyponatremia from Syndrome of Inappropriate Antidiuretic Hormone Cha P t E r Secretion 45 Jonathan ShUPE, MD

CASE An 82-year-old woman with a history of hypertension and depression presents to the emergency department for evaluation of a 1-week history of worsening fatigue, headache, and mild confusion. She is a widow, lives in a retirement home, and is able to perform all activities of daily living. Medications include metoprolol and sertraline. Aside from her presenting symptoms, review of systems is unrevealing. Examination, including orthostatic vitals, is unremarkable. Laboratory workup reveals a plasma Na concentration of 120 mEq/L. A follow-up plasma osmolality is 265 mOsm/kg H2O. 1. What is the diagnosis? This woman has symptomatic hyponatremia. Hyponatremia, a plasma Na concentration of less than 135 mEq/L, is the most common electrolyte abnormality encountered in clinical practice and is particularly common in hospitalized patients.1 Severe hyponatremia, defined as a serum sodium <115 mEql/L, is associated with substantial morbidity and a mortality rate of up to 20% in hospitalized patients.2–4 Whether the hyponatremia plays a causal role in increasing mortality or is merely a marker for severe illness remains unclear. Bottom line: Hyponatremia is the most common electrolyte abnormality encountered in clinical practice and when severe is associated with substantial morbidity and mortality. 2. What is the diagnostic approach to a patient with hypotonic hyponatremia? The Hyponatremia Treatment Guidelines, outlined in the Journal of Medicine 2007, outline a diagnostic approach to hypotonic hyponatremia starting with clinical assessment of the patient’s effective circulating volume (ECV) status and urine sodium excretion as shown in Figure 45.1.5 519 2.1. Hypovolemic hyponatremia Patients appear hypovolemic on exam (e.g., orthostatic changes in blood pressure) and spot urine [sodium] is usually <30 mmol/L unless the kidney is the site of sodium loss, such as is the case with diuretic use, cerebral salt wasting, and mineralocorticoid deficiency.5,6 Hypovolemic hyponatremia results from the non-osmotic release of ADH via activation of high- and low-pressure baroreceptors in an attempt to maintain extracellular fluid (ECF) volume homeostasis. Hypovolemic hyponatremia should correct with infusion of isotonic saline because restoration of normal ECF volume will suppress further ADH secretion. 2.2. Euvolemic hyponatremia Patients appear euvolemic on exam and spot urine [sodium] should be ≥30 mmol/L unless there is a history of ingesting large volumes of fluid with a disproportionately low solute intake, such as is the case with beer potomania.5,6 Hyponatremia results in this euvolemic state due to overall fluid intake exceeding that of the kidney’s ability to excrete free water. When clinical assessment of ECF volume status is unclear or urine sodium is <30 mmol/L, volume expansion with isotonic saline may be helpful as in hypovolemic hyponatremia. In patients with low ECF volume, the serum sodium will begin to correct as discussed previously. Conversely, in patients with SIADH, the urine [sodium] will increase and serum sodium will decrease as free water is retained and the sodium load is excreted in a smaller volume of concentrated urine. Bottom line: In a patient appearing euvolemic on exam and with a urine [sodium] ≥30 mmol/L, the differential diagnosis would focus on causes of hypotonic euvolemic hyponatremia, including syndrome of inappropriate antidiuretic hormone secretion (SIADH). 2.3. Hypervolemic hyponatremia Patients appear hypervolemic on exam (e.g., edema, ascites) and spot urine [sodium] is typically <30 mmol/L. This picture results from a reduction in the ECV activation of the rennin–angiotensin–aldosterone system with secondary renal sodium conservation despite total body volume overload. 3. What is SIADH? SIADH was first described in patients with bronchogenic carcinoma in 1957 after plasma concentrations of antidiuretic hormone were found to be elevated when they should otherwise have been normal due to their euvolemic status.7 ADH secretion from the posterior pituitary is normally stimulated by (a) activation of osmoreceptors in the anterior hypothalamus due to increased plasma osmolality and/or (b) decreased Hyponatremia (SNa<135 mmol/L) Hypovolemia [TBW↓, TBNa↓↓] (orthostatic changes in BP, poor skin turgor, dry mucous membranes) Euvolemia [TBW↑, TBNa↔] Hypervolemia [TBW↑↑, TBNa↑] (edema, ascites) Renal losses (UNa>30 mmol/L) Mineralocorticoid deficiency Diuretic excess Salt-wasting Extrarenal losses (UNa<30 mmol/L) Diarrhea Vomiting Pancreatitis (UNa ≥30 mmol/L) Hypothyroid Glucocorticoid deficiency Pain SIADH (UNa<30 mmol/L) CHF Cirrhosis Nephrotic syndrome Renal failure Isotonic saline Water restriction Sodium and water restriction Normonatremia FIgurE 45.1 Algorithm for diagnostic and therapeutic approach to the hyponatremic patient as described in Hyponatremia Guidelines 2007.5 SNa, serum sodium; UNa, urine sodium; TBW, Total body water; TBNa, Total body sodium; SIADH, syndrome of inappropriate antidiuretic hormone; CHF, congestive heart failure. blood volume or pressure via activation of high- and low-pressure baroreceptors located in the aortic arch, carotid sinus, pulmonary vessels, and cardiac atria. When serum osmolality falls below the genetically determined osmostat threshold, ADH secretion is suppressed, resulting in excretion of maximally dilute urine and maintenance of the designated serum osmolality threshold. Failure to suppress ADH secretion in this context results in water retention and hyponatremia. 4. How is SIADH diagnosed? SIADH is a diagnosis of exclusion. The following are the essential criteria necessary for the diagnosis of SIADH according to the Hyponatremia Treatment Guidelines 20075: 1. Serum osmolality <275 mOsm/kg H2O 2. Urine osmolality >100 mOsm/kg H2O 3. Clinical euvolemia 4. Urinary sodium concentration >40 mmol/L with normal dietary salt intake 5. Exclusion of hypothyroidism, glucocorticoid deficiency, and diuretic use Bottom Line: Hyponatremia in a euvolemic patient with inappropriately concentrated urine and a high urine sodium concentration strongly suggests SIADH. 5. What are the clinical features of SIADH? The clinical features of SIADH depend on the severity of the associated hyponatremia and are consistent with other causes of hyponatremia. These include headache, lethargy, restlessness, confusion, coma, nausea, vomiting, and respiratory distress.8 Most patients with hyponatremia are asymptomatic, with symptoms usually occurring when serum sodium falls below 125 mEq/L or with a rapid drop in serum sodium.9 An observational study of 66 patients with hyponatremia found that those patients with serum sodium levels <125 mEq/L were found to have more neurological symptoms, including grand mal seizures in 9 (14%) of the patients.9 Bottom line: Neurologic symptoms predominate and depend on the severity of the associated hyponatremia, usually arising when serum sodium falls below 125 mEq/L. 6. What are the underlying causes of SIADH? Few studies have examined the distribution of underlying causes of SIADH. Identifying and treating the underlying cause is extremely important because doing so will often also correct the hyponatremia. Underlying causes of SIADH are as shown below. Malignancy Lung (small cell carcinoma, mesothelioma) Nasopharyngeal Gastrointestinal (stomach, duodenum, pancreas) Genitourniary tract (ureter, prostate, bladder, endometrium) Lymphoma Sarcoma Pulmonary Infection (tuberculosis, bacterial, and viral pneumonia, abscess, aspergillosis) Asthma Cystic fibrosis Positive pressure ventilation Vasculitis CNS Infection (meningitis, encephalitis, abscess, AIDS, rocky mountain spotted fever) Mass/bleed (tumor, subarachnoid hemorrhage, subdural hematoma, traumatic brain injury, hydrocephalus, cavernous sinus thrombosis) Other (vasculitis, multiple sclerosis, Guillain-Barre syndrome, Delerium tremens, Shy-Drager syndrome, acute intermittent porphyria) Drugs AVP analogs (desmopressin, oxytocin, vasopressin) Antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants) Antipsychotics (haloperidol, phenothiazines) Antiepileptics (levetiracetam, carbamazepine) Recreational drugs (MDMA, narcotics, nicotine) Chemotherapeutic agents (ifosfamide, cyclophosphamide, vincristine) Antibiotics (quinolones) Other (clofibrate, chlorpropramide, prostaglandins) Other Hereditary (mutation in vasopressin V2 receptor) Idiopathic Transient (general anesthesia, pain, stress, nausea, endurance exercise) 7. What is the prevalence of SIADH in patients with hyponatremia? A 1999 prospective study found SIADH as the most common etiology of hyponatremia in medical cancer patients, comprising 30%, followed closely by depletional state (29%) and diuretic use (14%).10 Other retrospective studies have suggested possible diagnosis of SIADH in 48% of general medical in- patients; however, generally accepted diagnostic criteria outlined in the Hyponatremia Treatment Guidelines 2007 were frequently not met.11,12 In a prospective, observational, noninterventional study focusing on elderly hospitalized patients with serum sodium ≤125 mEq/L, 73.6% of normovolemic patients were found to have SIADH, with etiology of the SIADH identified in only 46% of the patients. The etiology of hyponatremia in general was thought to be multifactorial in 51% of the patients.13 Bottom line: SIADH is the leading etiology of hyponatremia in the hospital setting. The underlying cause of SIADH is often difficult to ascertain. 8. What is the significance of appropriately diagnosing the underlying cause(s) of SIADH? SIADH-associated hyponatremia may be the initial presentation of underlying disease. A 2004 prospective study analyzed the etiology of neurological symptoms in 432 patients with small cell lung carcinoma (SCLC); SIADH was found in 30 (7%) patients.14 No recommendations or studies were found to support or refute radiological screening studies in patients presenting with SIADH-associated hyponatremia with no other clinical indication, including significant smoking history. Medications are a common cause of SIADH and discontinuing their use can effectively reverse hyponatremia is some cases.12,13,15 SSRIs are the most frequently associated pharmaceutical agent causing SIADH-associated hyponatremia. Reported incidences range from 0.5% to 32% and was most often associated with advanced age and concomitant use of diuretics.15–17 The time course of return to normal sodium concentrations upon discontinuation of the inciting drug ranges from 48 hours to 6 weeks, with most cases resolving within 2 weeks.15 Bottom line: Symptoms resulting from SIADH-associated hyponatremia may be the initial presentation of an underlying disease, such as SCLC. Thus, further diagnostic workup is almost always warranted. 9. How fast should hyponatremia be corrected? Overly rapid correction of serum sodium in patients with longstanding hyponatremia may be associated with severe neurologic sequelae such as central pontine myelinolysis.18,19 A multicenter questionnaire study of patients with severe hyponatremia (≤105 mmol/L), from the membership of the American Society of Nephrology, found that neurological sequelae after the treatment of severe chronic hyponatremia were associated with increases in sodium concentration that were >12 mmol/L over the first 24 hours and >18 mmol/L over the first 48 hours of therapy.20 No study has assessed whether the etiology of the hyponatremia, nor the methodology used to correct hyponatremia, changes susceptibility for producing osmotic demyelination as a result of overly rapid correction. In contrast to overly rapid correction, failure to correct in a timely fashion has its own consequences. A retrospective review of patients with serum sodium concentration of 115 mmol/L or less at a single tertiary teaching hospital demonstrated an overall trend toward increasing mortality with a slower rate of correction. The serum sodium at 48 hours was 127.1 ± 7.9 in survivors versus 118.8 ± 9.8 in nonsurvivors.4 These findings are consistent with those of previous studies showing that a correction rate of <0.7 mmol/L/hour was associated with high mortality.19 Rate of correction of hyponatremia is determined by acuity and severity of symptoms. The Hyponatemia Treatment and Guidelines 2007 suggest that patients with severe symptoms of hyponatremia, such as those with seizures or coma, may benefit from brief infusion of hypertonic saline and by increasing serum sodium by 2 to 4 mmol/L within the first 2 to 4 hours. However, limited data is available to support this recommendation. The goal of the rapid infusion is to have a change of sodium of 1 to 2 mmol/L per hour and the infusion should be stopped when any of the following 3 end points are reached:5 1. Marked improvement in symptomatology. 2. Serum sodium levels have reached a level >120 mmol/L. 3. Change of sodium >18 mmol/L in a 24-hour period. Strong emphasis is placed on correcting serum sodium to a safe range rather than to completely normal levels. Serum sodium should be checked every 2 to 4 hours to decrease the risk of too rapid a change in sodium levels during infusion with hypertonic (3%) saline and every 4 to 8 hours thereafter until serum sodium returns to normal. Rarely, loop diuretics may need to be given along with hypertonic saline to prevent volume overload.5 The rate of change should be slower for chronic symptomatic hyponatremia. The osmotic demyelination syndrome can usually be avoided by limiting correction to <10 to 12 mmol/L in 24 hours and to <18 mmol/L in 48 hours.20 There is no evidence that correction of serum sodium by >10 mmol/L in 24 hours or 18 mmol/L in 48 hours improves outcomes in patients with acute or chronic hyponatremia.5 Bottom Line: Given hypertonic 3% saline infusion for acute symptomatic hyponatremia with goal of increasing serum sodium by 1–2 mmol/L/hr and stopping once symptoms have resolved, serum sodium reaches 120 mmol/L or change in serum sodium is >18 mmol/L in 24-hour period. To avoid osmotic demyelination, syndrome correction of chronic symptomatic hyponatremia should be slower at a rate of <10–12 mmol/L in 24 hours and <18 mmol/L in 48 hours. 10. How does treatment of SIADH-associated hyponatremia differ from other causes of hyponatremia? Treating potential underlying causes and removing any inciting factors implicated in the onset of SIADH, such as medications, are important initial considerations when approaching a patient with suspected SIADH. As in other causes of severe hyponatremia, correction of acute symptomatic SIADH-associated hyponatremia is best accomplished with hypertonic 3% saline given via continuous infusion as described previously. This is because patients with euvolemic hypoosmolality, such as is the case with SIADH, will not respond to isotonic saline, and hyponatremia may even worsen. For patients with mild-to-moderate SIADH-associated hyponatremia, fluid restriction is the least toxic therapy and is the treatment of choice. The following points should be considered during fluid restriction:5 1. All fluids must be included in restriction, not only water. 2. The degree of restriction required depends on urine output plus insensible fluid loss. Fluids should be limited to 500 mL/day below the average daily urine volume. 3. Several days of restriction are usually necessary before a significant increase in plasma osmolality occurs. 4. Only fluid, not sodium, should be restricted. If hyponatremia does not resolve or if the patient is unable to tolerate water restriction, pharmacologic management is recommended.5 Bottom line: Consider the underlying pathophysiology of SIADH and stop or change any drugs known to be associated with SIADH. Hypertonic saline (3%) infusion may be indicated in acute severely symptomatic SIADH-associated hyponatremia, while normal saline (0.9%) is not recommended. Water restriction is the treatment of choice for mild-to moderate SIADH-associated hyponatremia. 11. What additional treatments are there for chronic asymptomatic hyponatremia caused by SIADH? A 1978 study of 10 patients with SIADH who had persistent hyponatremia despite severe water restriction compared effectiveness of demeclocycline versus lithium carbonate.21 Daily treatments with demeclocycline demonstrated restoration of serum sodium concentration within 5–14 days without restricting water and no serious adverse side effects were noted. In the same study, 0 of the 3 patients treated with lithium carbonate showed any change in serum sodium concentration and 2 of the patients experienced adverse CNS symptoms.21 It should be noted that demeclocycline can cause reversible azotemia and nephrotoxicity, especially in patients with cirrhosis.22 Bottom Line: If the hyponatremia doesn’t respond to fluid restriction, or if the patient is unable to tolerate fluid restriction, treatment with demeclocycline can be considered, keeping in mind its potential for nephrotoxicity. 12. Are arginine vasopressin-antagonists effective in treating SIADH-associated hyponatremia? A multicenter, randomized, placebo-controlled trial to assess efficacy and safety of a vasopressin receptor antagonist in patients with hyponatremia, demonstrated dose dependent sustained increase in renal free water clearance with significant improvement in serum osmolality and serum sodium.23 Significant dehydration was noted in patients receiving high doses of the drug.23 A randomized, double-blinded, placebo-controlled study to assess the efficacy and safety of different doses of satavaptan in SIADH demonstrated improvement of serum sodium concentration with the use of an arginine vasopressin (AVP)- antagonist. Responders (patients whose serum sodium levels normalized or increased by at least 5 mmol/L from baseline) were 79% in the 25 mg group, 83% in the 50 mg group, and 13% in the placebo group, all showing significant differences. No drug-related serious adverse events were recorded.24 A third study assessing the efficacy of intravenous conivaptan in treating euvolemic and hypervolemic hyponatremia demonstrated significant increase in area under the sodium-time curve during 4-day treatment as compared to placebo control, and treatment was well controlled.25 Although promising, clinical trials have not assessed whether vaptans can sufficiently raise serum sodium levels rapidly enough without the use of hypertonic saline in patients with acute severe hyponatremia. The rate of correction of serum sodium using AVP-antagonists is presumed to follow the same guidelines outlined in the Hyponatremia Treatment Guidelines 2007.5 Bottom Line: AVP-antagonists have been shown to safely normalize sodium levels in patients with mild-to-moderate hyponatremia caused by SIADH (Figure 45.2). However, no study has assessed their effectiveness in patients with acute severe hyponatremia. TAKE-HOME POINTS: HYPONATrEMIA FrOM SYNDrOME OF INAPPrOPrIATE ANTIDIurETIC HOrMONE SECrETION 1. Hyponatremia is the most common electrolyte abnormality encountered in clinical practice and is associated with substantial morbidity and mortality when severe. 2. Symptoms of hyponatremia depend on the severity of the hyponatremia. Neurological symptoms predominate when the serum sodium falls below 125 mEq/L. 3. SIADH is the leading etiology of hyponatremia in the hospital setting, comprising nearly one-third of all cases. SIADH-associated Hyponatremia Acute (<48 hours) or seizure, coma –Start hypertonic (3%) saline immediately with goal of 1–2 mmol/L/hr change in SNa –loop diuretic for volume overload –Check SNa every 2–4 hrs and adjust accordingly –Stop 3% saline when: 1: Symptoms improve 2: SNa>120 mmol/L 3: ∆Sna>18 mmol/L in 24-hours Mild-to-moderate Asymptomatichyponatremia with chronic hyponatremiano severe symptoms –Consider underlying cause and address correctable factors –Restrict fluids –Check SNa every 4–8 hrs –Demedclocycline therapy –AVP–anlagonist FIgurE 45.2 Algorithm for therapeutic approach to SIADH-associated hyponatremia. Adapted from Ref. [26] SNa, serum sodium; ΔSNa, change in serum sodium. 4. SIADH is characterized by hyponatremia in a euvolemic patient with inappropriately concentrated urine after hypothyroidism and glucocorticoid deficiency have been excluded. 5. Symptoms resulting from SIADH-associated hyponatremia may be the initial presentation of an underlying disease, such as SCLC. 6. Overly rapid correction of serum sodium in patients with longstanding hyponatremia is associated with neurologic sequelae and central pontine myelinolysis. 7. Hypertonic saline (3%) infusion may be indicated in acute symptomatic SIADH-associated hyponatremia, while normal saline (0.9%) is not recommended. Water restriction is the treatment of choice for mild-to-moderate SIADH-associated hyponatremia. rEFErENCES 1. Upadhyay, A., B. L. Jaber, and N. E. Madias. 2006. “Incidence and Prevalence of Hyponatremia.” American Journal of Medicine 119(7A): S30–S35. 2. Kennedy, P. G., D. M. Mitchell, and D. I. Hoffbrand. 1978. “Severe Hyponatremia in Hospital In-Patients.” British Medical Journal 2: 1251–3. 3. Gross, P., D. Reimann, J. Neidel, C. Doke, F. Prospert, G. Decaux, J. Verbalis, and R. W. Schrier. 1998. “The Treatment of Severe Hyponatremia.” Kidney International 53. 4. Nzerue, C. M., H. Baffoe-Bonnie, W. You, B. Falana, and S. Dai. 2003. “Predictors of Outcome in Hospitalized Patients with Severe Hyponatremia.” Journal of the National Medical Association 95: 335–43. 5. Verbalis, J. G., S. R. Goldsmith, A. Greenberg, R. W. Schrier, and R. H. Sterns. 2007. “Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations.” American Journal of Medicine 120: S1–S21. 6. Schrier, R. W. 2006. “Body Water Homeostasis: Clinical Disorders of Urinary Dilution and Concentration.” Journal of the American Society of Nephrology 17: 1820–32. 7. Schwartz, W. B., W. Bennett, S. Curelop, and F. C. Bartter. 1957. “A Syndrome of Renal Sodium Loss and Hyponatremia Probably Resulting from Inappropriate Secretion of Antidiuretic Hormone.” American Journal of Medicine 23: 529–42. 8. Patel, G. P., and R. A. Balk. 2007. “Recognition and Treatment of Hyponatremia in Acutely Ill Hospitalized Patients.” Journal of Clinical Therapy 29: 211–29. 9. Arieff, A. I., F. Llach, and S. G. Massry. 1976. “Neurological Manifestations and Morbidity of Hyponatremia Correlation with Brain Water and Electrolytes.” American Journal of Medicine 55: 121–29. 10. Berghmans, T., M. Paesmans, and J. J. Body. 1999. “A Prospective Study on Hyponatremia in Medical Cancer Patients: Epidemiology, Aetiology and Differential Diagnosis.” Support Care Cancer 8: 192–97. 11. Clayton, J. A., I. R. Le Jeune, and I. P. Hall. 2006. “Severe Hyponatremia in Medical in-Patients: Aetiology, Assessment and Outcome.” Quarterly Journal of Medicine 99: 505– 11. 12. Hannon, M. J., and C. J. Thompson. 2010. “The Syndrome of Inappropriate Antidiuretic Hormone: Prevalence, Causes and Consequences.” European Journal of Endocrinology 162: S5–S12. 13. Shapiro, D. S., M. Sonnenblick, I. Galperin, L. Melkonyan, and G. Munter. 2010. “Severe Hyponatremia in Elderly Hospitalized Patients: Prevalence, Aetiology and Outcome.” Internal Medicine Journal 40: 574–80. 14. Seute, T., P. Leffers, G. P. M. ten Velde, and A. Twijnstra. 2004. “Neurological Disorders in 432 Consecutive Patients with Small Cell Lung Carcinoma.” American Cancer Society 100: 801–6. 15. Jacob, S., and S. A. Spinler. 2006. “Hyponatremia Associated with Selective Serotonin-Reuptake Inhibitors in Older Adults.” Annals Pharmacotherapy 40: 1618–22. 16. Rosner, M. H. 2004. “Severe Hyponatremia Associated with the Combined Use of Thiazide Diuretics and Selective Serotonin Reuptake Inhibitors.” American Journal of the Medical Sciences 327: 109–11. 17. Adverse Drug Reactions Advisory Committee. 2003. “Hyponatremia with SSRIs.” Australian Adverse Drug Reactions Bulletin 22: 10. 18. Sterns, R. H., J. E. Riggs, and S. S. Schochet. 1986. “Osmotic Demyelination Syndrome Following Correction of Hyponatremia.” New England Journal of Medicine 314: 1535–42. 19. Ayus, J. C., R. K. Krothapalli, and A. I. Arieff. 1987. “Treatment of Symptomatic Hyponatremia and its Relation to Brain Damage.” New England Journal of Medicine 317: 1190–95. 20. Sterns, R. H., J. D. Cappuccio, S. M. Sliver, and E. P. Cohen. 1994. “Neurologic Sequelae After Treatment of Severe Hyponatremia: A Multicenter Perspective.” Journal of the American Society of Nephrology 4: 1522–30. 21. Forrest, J. N., C. Malcolm, C. Hong, G. Morrison, M. Bia, and I. Singer. 1978. “Superiority of Demeclocycline Over Lithium in the Treatment of Chronic Syndrome of Inappropriate Secretion of Antidiuretic Hormone.” New England Journal of Medicine 298: 173–77. 22. Miller, P. D., S. L. Linas, and R. W. Schrier. 1980. “Plasma Demeclocycline Levels and Nephrotoxicity: Correlation in Hyponatremic Cirrotic Patients.” Journal of the American Medical Association 243: 2513–15. 23. Wong, F., A. T. Blei, L. M. Blendis, and P. J. Thuluvath. 2003. “A Vasopressin Receptor Antagonist (VPA-985) Improves Serum Sodium Concentration in Patients with Hyponatremia: a Multicenter, Randomized, Placebo-Controlled Trial.” Journal of Hepatology 37: 182–90. 24. Soupart, A., P. Gross, J. Legros, S. Alfoldi, D. Annane, H. M. Heshmati, and G. Decaux. 2006. “Successful Long-Term Treatment of Hyponatremia in Syndrome of Inappropriate Antidiuretic Hormone Secretion with Satavaptan (SR121463B), an Orally Active Nonpeptide Vasopressin V2-Receptor Antagonist.” Clinical Journal of the American Society of Nephrology 1: 1154– 60. 25. Zeltser, D., S. Rosanksy, H. van Rensburg, J. G. Verbalis, and N. Smith. 2007. “Assessment of the Efficacy and Safety of Intravenous Conivaptan in Euvolemic and Hypervolemic Hyponatremia.” American Journal of Nephrology 27: 447–57. 26. Ellison, D. H., and T. Berl. 2007. “The Syndrome of Inappropriate Antidiuresis.” New England Journal of Medicine 356: 2064–72. Ch A p T er Hypernatremia 46 AlexAndriA ThornTon, Md CASE An 82-year-old man with long-standing dementia is brought into the emergency department by his family for evaluation of a 1-day history of increased confusion and lethargy and a 3-day history of nonbloody diarrhea. His diarrhea has stopped today, but the family reports he has barely left his bed to eat or drink. Family reports no recent falls. His vital signs are T 99.2°F; BP 112/74 mm Hg (supine), 92/64 mm Hg (sitting); HR 90 (supine), 116 (sitting); RR 14; O2 sat = 99% on room temperature; Wt 150 lbs (70 kg). On physical examination, you find a lethargic elderly man who opens his eyes in response to voice. Upon awakening, he is mildly confused but is clearly speaking full sentences. He has dry mucus membranes and decreased subclavicular skin turgor but normal forearm skin turgor. Capillary refill is 3 seconds. Laboratory testing is significant for a serum sodium concentration of

170 mEq/L. 1. What are the primary signs and symptoms of hypernatremia and how reliable are the physical exam findings? Hypernatremia is defined as an increase in plasma sodium concentration above 145 mEq/L. Severe hypernatremia is a potentially life-threatening electrolyte abnormality that requires rapid assessment and treatment. Symptoms of hypernatremia are primarily due to CNS dysfunction from the osmotic shift of intracellular fluid to the extracellular compartment, which causes cell shrinkage. Symptoms are more prominent with large or rapid increases in sodium concentration. The most common early symptoms are headache, nausea, lethargy, and weakness.1 More severe consequences of hypernatremia include altered mental status, delirium, or coma. Seizures occur rarely. If the hypernatremia develops rapidly, increased tension on bridging cerebral veins from cerebral shrinkage 531 can predispose to venous rupture and intracerebral hemorrhage. Elderly patients may often have few symptoms until the sodium concentration is >160 mEq/L. In a study of 150 hypernatremic elderly patients matched to 300 controls, the classic signs of hypernatremia and dehydration were unreliably present.2 Only three exam findings were present in more than 60% of the hypernatremic patients. These signs were orthostasis (sensitivity [sens] = 61.5%, specificity [spec] = 50.6%), abnormal forearm skin turgor (sens = 68.3%, spec = 67.8%), and abnormal subclavicular skin turgor (sens = 73.3%, spec = 79.0%). In patients with both hypernatremia and volume depletion, findings of tachycardia (sens = 17.8%, spec = 94.0%) and dry mucus membranes (sens = 49.0%, spec = 87.8%) were not sensitive for detecting hypernatremia. As a result, physical exam findings for hypernatremia have a low sensitivity and are relatively nonspecific. Interestingly, patients with hypovolemic hypernatremia (as in our patient) often do not look as hypovolemic as they do in other states of dehydration, as the shift
of fluids from the intracellular to the extracellular space protects intravascular volume status longer.3 Bottom Line: Bedside physical assessment of hydration status in patients with hypernatremia has a low sensitivity and specificity. Out of all physical exam findings, subclavicular skin turgor is the most sensitive and specific. 2. How does the thirst mechanism (response) guard against hypernatremia across a person’s lifetime? Defenses against hypernatremia include the thirst mechanism, which increases free water uptake, and the release of antidiuretic hormone (ADH), which increases renal-free water reabsorption.1 Studies have shown that when plasma osmolarity of humans is increased by as little as 1%–2%, thirst is heightened.4,5 Thirst is such a potent stimulus that it is extraordinarily rare to see hypernatremia in patients with an intact thirst mechanism and adequate access to free water, even if the patient has a near total absence of ADH. It has been demonstrated that thirst drive decreases over a lifetime as evidenced by a 24- hour water deprivation study comparing older to younger men.6 The study results showed that older men had greater increases in plasma osmolality, sodium concentration, and vasopressin levels compared with their younger counterparts.6 A study in which volunteers were administered 5% saline showed that younger individuals drank nearly twice as much as older individuals in response to a similar intravenous infusion.7 In addition, decreasing renal function and total body water with advancing age compound the susceptibility for healthy older individuals to develop hypernatremia compared to their younger counterparts.8 Thus, these studies suggest that physicians should be proactive about water balance problems in hospitalized elderly patients by paying close attention to fluid intake and losses. It is also important for physicians to educate the caregivers of the elderly about the importance of monitoring fluid intake in their loved one, especially during periods of illness. The patient in the vignette is not only elderly, but has a history of dementia and so is at high risk of developing a dysnatremia. Bottom Line: Thirst drive in humans is exquisitely sensitive and is activated with an increase in plasma osmolarity of as little at 1%–2%. However, thirst drive decreases with increasing age, suggesting that physicians should be especially vigilant when monitoring water balance in elderly patients. 3. What does the evidence indicate regarding the epidemiology of hypernatremia? Hypernatremia is a common and often severe electrolyte disorder, with the highest prevalence in the elderly and the debilitated. Studies have shown that the incidence of hypernatremia in hospitalized patients ranges somewhere between 0.3% and 5.5%.9,10 A large cohort study of 15,187 newly hospitalized patients older than 60 years of age calculated the incidence rate of hypernatremia to be 1.1%, with 43% of patients hypernatremic on admission and the remaining 57% developing hypernatremia post-admission. A large percentage of the patients who ultimately developed hypernatremia post-admission showed rapid onset, with 50% of patients developing hypernatremia within the first 8 days of admission.11 While the study identified more than 40 causal factors of hypernatremia, the most frequent primary causes were complications of recent surgery (21%), febrile illness (20%), infirmity (11%), and diabetes mellitus (11%).11 A more recent prospective cohort study of general medical–surgcal patients showed that the prevalence of hypernatremia was 1% of patients at risk (n = 8517).12 This study went on to show that the prevalence of hospital-associated hypernatremia has an age distribution that parallels the age distribution of hospitalized patients. This implies that hospitalacquired hypernatremia affects patients of various ages, often as the result of inappropriate intravenous fluid prescriptions. In the intensive care unit, dysnatremias are even more prevalent than in the general patient wards. Two earlier studies found a hypernatremia prevalence rate of ~9% in patients hospitalized in the ICU13,14. A more recent study demonstrated an incidence rate of 7.4% per 100 days of ICU admission,15 underscoring the importance of the need for physicians to be familiar with the management of this common but complex disorder. Bottom Line: Hypernatremia has a prevalence of approximately 0.3%–5.5% depending on the population studied. Hypernatremia in hospitalized patients has an age of distribution similar to that of the overall population. This differs from outpatient hypernatremia, which more often affects the elderly. 4. What is the mortality rate associated with hypernatremia and are there any prognostic indicators for mortality? Past studies in adults have shown that hypernatremia is associated with a significant risk of in-house mortality, ranging from ~42% to 60%.11,16 The bulk of the mortality risk is not directly associated with the hypernatremia itself, but rather the clinical situation from which the hypernatremia arose. For example, Palevsky et al. found in their study of hypernatremic hospitalized patients that the mortality rate was 41%, but hypernatremia was judged to contribute to mortality in only 16% of patients.12 However, additional evidence supports that hypernatremia is an independent risk factor for poorer prognosis. Funk et al. demonstrated increased mortality odds ratios (ORs) for patients with borderline ([Na+] = 146–150), mild ([Na+] = 151–155), and severe hypernatremia ([Na+] > 155). The study controlled for the severity of illness by using two severity of illness scales (SAPSII-Simplified Acute Physiology Score II and LODS-Logistic Organ Dysfunction System) and considering length of ICU and hospital stay. The ORs and 95% CIs shown in Table 46.1 demonstrate that hypernatremia is an independent risk factor for mortality in critically ill patients.17 According to a 2006 study by Chassagne et al., level of consciousness at the time when hypernatremia is diagnosed has been shown to be the most powerful prognostic indicator of mortality risk (OR = 2.3%, 95% CI = 1.01–5.2).2 Mandal et al. demonstrated that lower mean systolic and diastolic blood pressure both on admission (P < .05) and throughout the hospital course (P < .001) were significant predictable factors TAblE 46.1 Association of Hypernatremia Severity and Mortality Hypernatremia Classification Odds Ratio 95% CI Borderline (Na+ = 146–150) 1.48 1.36–1.61 Mild (Na+ = 151–155) 2.32 1.98–2.73 Severe (Na+ > 155) 3.64 2.88–4.61 for high mortality.16 Low diastolic blood pressure (<60 mm Hg) and hypernatremia were especially correlated with mortality risk. Individuals enrolled in this study were divided into two groups: expired and surviving patients. Low diastolic blood pressure in combination with hypernatremia was found in 67% of the expired group versus 19% of the survivor group (P < .001). This study also supports decreased level of consciousness (consisting of confusion, obtundation, and speech abnormality) as a significant predictor of mortality (P < .05). In light of the strong association of level of consciousness with increased mortality in hypernatremic patients, the patient in the vignette with lethargy and confusion should be monitored extremely closely. Despite being orthostatic, the patient has been tenuously able to maintain his blood pressure at rest, despite his extreme volume loss from diarrheal illness. Based on his weight and a total body water percentage of 50% typical of elderly men, he has lost at least 7.5 liters of free water. The patient’s severely high serum sodium of 170 mEq/L is also worrisome, as the OR for mortality more than doubles in severe versus borderline hypernatremia. Bottom Line: Hypernatremia is associated with a significant risk of mortality (42%–60%), but contributes to mortality in only a minority of patients. Hypernatremia is an independent risk factor for mortality. Decreasing level of consciousness is a prognostic factor for mortality. Low mean systolic and diastolic blood pressures also predict high mortality. 5. What is the Androgue and Madias formula for correcting dysnatremias and how is its accuracy in managing patients with hypernatremia? The Adrogue and Madias formula was first published in 1997 in the Journal of Intensive Care Medicine and again in the New England Journal of Medicine in 2000 with the goal of simplifying the management of serum sodium abnormalities. The formula calculates the impact that a single liter of any chosen fluid will have on the patient’s plasma sodium concentration (Table 46.2). Adrogue and Madias Formula: Change in Serum Sodium = ([Na+] Infused − [Na+] serum)/(TBW + 1)18 The advantages of the Adrogue and Madias formula are ease of use, applicability with fluids of differing tonicities, and not needing to plan the fluid prescription over several days. Only one study has examined the accuracy of the Adrogue and Madias formula in planning a fluid prescription for hypernatremia. Liamis et al. found a nonsignificant difference between predicted and achieved serum sodium concentrations TAblE 46.2 Impact on Serum Sodium Concentration with Various IV Solutions ∆ per L of fluid in a 70 kg elderly male with Na+ = Fluid Na+ content 170 mEq/L 0.9% saline (NS) 154 mEq/L −0.4 mEq Na+/L Lactated Ringers 130 mEq/L −1.1 mEq Na+/L (LR) 0.45% saline 77 mEq/L −2.6 mEq Na+/L (1/2NS) Dextrose 5% in 0 mEq/L −4.7 mEq Na+/L water (D5W) after IV fluid administration after 24 and 36 hours,19 suggesting that the Adrogue and Madias formula is accurate for planning fluid prescriptions in hypernatremic patients. After creating an individualized fluid prescription for the patient, serial sodium measurements should be taken and therapy tailored as appropriate. No studies exist regarding the frequency of serial [Na+] measurements, but q1-4hours based on the patient’s clinical state is generally recommended. Bottom Line: The Adrogue and Madias formula for planning fluid prescriptions for dysnatremias has been validated in one study by Liamis et al. Still, the Adrogue and Madias formula can only approximate fluid correction so serial sodium measurements should be followed. 6. How does the correction rate of hypernatremia correlate with 30-day mortality? The guidelines for management of hypernatremia suggest that chronic hypernatremia or hypernatremia of unknown duration be corrected slowly at a rate of <0.5 mEq/L/h over a period of 2–3 days, though there are no prospective studies in humans to substantiate this claim. The current recommendations are based predominately on animal studies showing the rate of cerebral osmotic adaption and a tradition of safety at this correction rate.20 A recent retrospective chart review study demonstrated that although 90% of patients had their [Na+] corrected at a rate of <0.5 mEq/L/h, only 27% of patients were eunatremic within 72 hours, suggesting that the majority of hypernatremic patients are being undertreated. Inadequate correction of [Na+] by 72 hours was shown to be an independent predictor of 30-day mortality. Additionally, the study demonstrated that patients with slow correction rates (<0.25 mEq/L/h) during the first 24 hours of treatment were more likely to be uncorrected at 72 hours and had significantly higher 30 day mortality risk (HR = 2.63, P = .02).21 Bottom Line: While a correction rate of <0.5 mEq/L/h over 2–3 days is the current standard of care for hypernatremia of a chronic or unknown duration, overly slow rates (<0.25 mEq/L) of correction and lack of correction by 72 hours have been demonstrated to increase 30-day mortality risk. Recommended fluid correction rate should, therefore, be between 0.25 and 0.5 mEq/L for chronic or unknown duration of hypernatremia. 7. Does the evidence support one route of fluid administration over another for fluid repletion in hypernatremia? There are no available studies to support one route over another. The consensus opinion is to permit patients to drink or use a nasogastric feeding tube to correct hypernatremia if tolerated as free water can be administered rather than having to infuse larger volumes of hypotonic intravenous solutions. As the risk of cerebral edema increases with larger volumes of infusate, the goal should be to restrict the amount of fluid repletion to that necessary to correct the hypernatremia. Often, the patient is unable to tolerate enteral fluid repletion. In these instances, parenteral fluids should be administered. There is no data showing either superiority or inferiority for intravenous over enteral repletion. Bottom Line: There is no data to support a route of fluid administration for hypernatremia, though consensus opinion favors enteral repletion if tolerated by the patient. 8. Is there any available evidence to support specific hospital admission and discharge criteria for hypernatremia? A thorough literature search did not reveal any studies that looked at specific admission and discharge criteria for patients with hypernatremia. Thus, one should rely on clinical judgment when making this decision. Experts and clinical logic suggest that symptomatic patients with hypernatremia should be admitted. Asymptomatic patients with a new onset diagnosis and [Na+] > 150 mEq/L should probably also be admitted simply to expedite the diagnostic workup. Admission to the ICU should strongly be considered for symptomatic patients or for patients with [Na+] > 160 mEq/L.22,23 Consider discharge if patients have a [Na+] < 150 mEq/L and are no longer symptomatic, assuming adequate follow up is assured and the cause of the hypernatremia is addressed. Consider discharge of chronically hypernatremic patients if they are asymptomatic and at their baseline, even if their [Na+] is greater than 150 mEq/L.23 Close follow up should be guaranteed. Bottom Line: There are currently no studies that examine admission or discharge criteria for hypernatremia and outcome. Consider admitting all symptomatic and newly diagnosed asymptomatic patients with [Na+] > 150 mEq/L. Asymptomatic patients with [Na+] < 150 mEq/L or chronically hypernatremic patients at baseline can often be discharged with close follow up. TAKE-HOME POINTS: HYPERNATREMIA 1. Hypernatremia is defined as [Na+] > 145 mEq/L and is due to an abnormality in water homeostasis causing a deficit of water compared to sodium. 2. Symptoms of hypernatremia are predominantly CNS in origin and include headache, nausea, lethargy, and weakness followed late by altered mental status, delirium, or coma. Physical exam findings overall have poor sensitivity and specificity, but subclavicular and forearm skin turgor and orthostasis are present in more than 60% of patients. 3. Though thirst drive is exquisitely sensitive and protects against hypernatremia, it typically decreases with age. Decreased thirst drive, renal function, and potentially access to free water place the elderly at increased risk for hypernatremia. 4. Hypernatremia has a prevalence of approximately 0.3%–5.5%. Hypernatremia in the inpatient population occurs at a younger age distribution than that of the community. 5. Hypernatremia carries a substantial risk of mortality (42%–60%), though directly contributes to mortality in only a minority of the cases. Diminishing level of consciousness is a prognostic indicator for mortality. Low mean systolic and diastolic blood pressures also portend a poor prognosis. 6. The Adrogue and Madias formula for dysnatremias has been validated as a simple but accurate method of planning fluid therapy for hypernatremia, though serial electrolytes must still be monitored. 7. Overly slow rates (<0.25 mEq/L) of correction and lack of correction by 72 hours have been demonstrated to increase 30 day mortality. Serum sodium correction rate should be somewhere between 0.25 and 0.5 mEq/L for chronic or unknown duration of hypernatremia, though the optimal rate of correction has never been determined experimentally. 8. There is a lack of data supporting enteral versus parenteral fluid therapy in hypernatremia, though current opinion is to use the gastrointestinal tract for fluid therapy if the patient can tolerate it. 9. There is a lack of studies examining specific admission and discharge criteria for patients with hypernatremia. Some reasonable guidelines for admission include admitting symptomatic patients and patients with new onset hypernatremia with [Na+] > 150 mEq/L. Consider discharge of asymptomatic patients with [Na+] < 150 mEq/L or chronic hypernatremics when at baseline. REFERENCES 1. Reynolds, R. M., P. L. Padfield, and J. R. Seckl. 2006. “Disorders of Sodium Balance.” British Medical Journal 332 (7543): 702–5. 2. Chassagne, P., L. Druesne, C. Capet, J. F. Menard, and E. Bercoff. 2006. “Clinical Presentation of Hypernatremia in Elderly Patients: A Case Control Study.” Journal of the American Geriatrics Society 54 (8): 1225–30. 3. Goff, D. A., and V. Higinio. 2009. “Hypernatremia”. Pediatrics in Review 30 (10): 412. 4. Fitzsimons, J. T. 1976. “The Physiological Basis of Thirst.” Kidney International 10: 3–11. 5. McKinley, M. J., and A. K. Johnson. 2004. “The Physiologic Regulation of Thirst and Fluid Intake.” Physiology 19 (1): 1–6. 6. Phillips, P. A., B. J. Rolls, J. G. Ledingham, M. L. Forsling, J. J. Morton, M. J. Crowe, and L. Wollner. 1984. “Reduced Thirst After Water Deprivation in Healthy Elderly Men.” New England Journal of Medicine 311: 753–59. 7. Dyke, M. M., K. M. Davis, B. A. Clark, L. C. Fish, D. Elahi, and K. L. Minaker. 1997. “Effects of Hypertonicity on Water Intake in the Elderly: An Age Related Failure.” Geriatric Nephrology and Urology 7: 11–16. 8. Steen, B., B. Isaksson, and A. Svanborg. 1979. “Body Composition at 70 and 75 Years of Age. A Longitudinal Population Study.” Journal of Clinical Gerontology 1: 185–200. 9. Long, C. A., P. Marin, A. J. Bayer, H. G. M. Shetty, and M. S. J. Pathy. 1991. “Hypernatremia in an Adult Inpatient Population.” Postgraduate Medical Journal 67(789): 643–5. 10. Lukitsch, I. V., and V. E. Batuman. 2010. “Hypernatremia.” eMedicine .medscape.com. 11. Snyder, N. A., D. W. Feigal, and A. I. Arieff. 1987. “Hypernatremia in Elderly Patients.” Annals of Internal Medicine 107: 309–18. 12. Palevsky, P. M., R. Bhagrath, and A. Greenberg. 1996. “Hypernatremia in Hospitalized Patients.” Annals of Internal Medicine 124: 197–203. 13. Polderman, K. H., W. O. Schreuder, R. J. Strack van Schijndel, and L. G. Thijs. 1999. “Hypernatremia in the Intensive Care Unit: an Indicator of Quality of Care?” Critical Care Medicine 27: 1105–8. 14. Lindner, G., G. C. Funk, C. Schwarz, N. Kneidinger, A. Kaider, B. Schneeweiss, L. Kramer, and W. Druml. 2007. “Hypernatremia in the Critically Ill is an Independent Risk Factor for Mortality.” American Journal of Kidney Diseases 50: 952–57. 15. Stelfox, H. T., S. B. Ahmed, F. Khandwala, D. Zygun, R. Shahpori, and K. Laupland. 2008. “The Incidence of Intensive Care Unit Acquired Hyponatremia and Hypernatremia in Medical-Surgical Intensive Care Units.” Critical Care 12: 162. 16. Mandal, A. K., M. G. Saklayan, N. M. Hillman, and R. J. Markert. 1997. “Predictive Factors for High Mortality in Hypernatremic Patients.” American Journal of Emergency Medicine 15: 130–2. 17. Funk, G. C., G. Lindner, W. Druml, B. Metnitz, C. Schwarz, P. Bauer, and P. G. H. Metnitz. 2010. “Incidence and Prognosis of Dysnatremias Present on ICU Admission.” Intensive Care Medicine 36: 304–11. 18. Adrogue, H. J., and N. E. Madias. 2000. “Hypernatremia.” The New England Journal of Medicine 342 (20): 1493–99. 19. Liamis, G., M. Kalogirou, V. Saugos, and M. Elisaf. 2006. “Therapeutic Approach in Patients with Dysnatraemias.” Nephrology Dialysis Transplantation 21: 1564–9. 20. Lien, Y. H., J. I. Shapiro, and L. Chan. 1990. “Effect of Hypernatremia on Organic Brain Osmoles.” Journal of Clinical Investigation 85: 1427–35. 21. Alshayeb, H. M., A. Showkat, F. Babar, T. Mangold, and B. M. Wall. May 2011. “Severe Hypernatremia Correction Rate and Mortality in Hospitalized Patients.” American Journal of Medical Sciences 341 (5): 356–60. 22. Morris, J. E. 2011. “Fluid, Electrolyte, & Acid–Base Emergencies.” In Current Diagnosis & Treatment: Emergency Medicine. 6th ed., edited by C. K. Stone and R. L. Humphries, Chapter 42. Retrieved October 2, 2011 from http://www.accessmedicine.com/content.aspx?aID=3112714. 23.Mueller, L. 2011. “Hypernatremia.” In Rosen and Barkin’s 5-Minute Emergency Medicine Consult. 4th ed., edited by Jeffrey Schaider and Peter Rosen, 555. Philadelphia, PA: Lippincott Williams & Wilkins. Index

A ABCD2 score, 75 components of, 76 risk stratification for stroke, 76 Ablation, 297 Acephalic migraine, 88 Acute aortic dissection, 369 Acute asthma exacerbation, 160 treatment of, 164–166 Acute chest pain, 263 Acute coronary syndrome (ACS), 230 spectrum of, 255 standard of care for, 256 Acute decompensated congestive heart failure BNP concentration and, 244–245 criteria exist to admitting CHF patient, 245– 246 diagnosis, 241 discharge plan, 247–248 NYHA classification system, 242–243 parameters, monitoring during patient admission, 247 physical examination and chest x-ray, 243–244 treatment for, 246–247 ultrafiltration, treating with, 246–247 Acute hepatitis B virus (HBV), 24 follow-up, 31 patients exposed to and recovered from, 30 post-exposure treatment algorithm, 29 requiring adjustment of medications, 27 risk of progression to chronic HBV, 30 serologic diagnosis of, 24–25 three routes of transmission for, 24 treatment with vaccination, 28 Acute hepatitis C virus (HCV), 24 follow-up, 31 patients exposed to and recovered from, 30 requiring adjustment of medications, 27 risk of progression to chronic HBV, 30 serologic diagnosis of, 25–26 three routes of transmission for, 24 treatment with interferon, 27–28 Acute interstitial nephritis (AIN) causes of, 503, 505 confirmation tests for, 505 diagnosis, 502–503 initial management of, 506 laboratory features associated with, 504 renal biopsy in, role of, 505 signs and symptoms of, 503 steroids for, 506–507 supportive care measures in, 506 Acute kidney injury (AKI), 374–375, 502 Acute lower gastrointestinal bleed (LGIB) causes of, 1–2 first step in patient management with, 3–4 Acute myocardial infarction (AMI), 231–232, 267 Acute myocardial ischemia, 291 541 Acute renal failure (ARF) causes based on history findings, 491 diagnosis, 489–490 hemodialysis, 490–492 history as diagnostic tool, 490 management of, 495 preventative measures, 496–497 renal biopsy, recommendation of, 494–495 risk factor for, 490 urine cytology etiology of ARF based on, 493–494 IL-18, 492–493 KIM-1, 492–493 N-GAL, 492–493 Acute Respiratory Distress Syndrome (ARDS), 56 Acute spinal cord compression cauda equina syndrome (CES), 106 causes of, 103 dexamethasone usage in, 108–109 differential diagnosis, 101–102, 103–105 initial diagnostic imaging modality, 109–111 signs and symptoms, 107–108 Acute tubular necrosis (ATN), 493–494, 496–497, 505 Acute viral hepatitis acute HBV and HCV infections diagnostic imaging studies for, 26–27 liver function tests (LFTs) in, 26 patients exposed to and recovered from, 30 requiring adjustment of medications, 27 risk of progression to chronic HBV, 30 serologic diagnosis of, 24–26 three routes of transmission for, 24 treatment with interferon, 27–28 classic symptoms for, 24 diagnosis, 23 follow-up, 31 fulminant liver failure and, 28–29 post-exposure treatment algorithm, 29 ultrasonography for, 26–27 Antifactor Xa agents, 474 Antiplatelet therapy, 95, 235, 292 for prevention of TIA, 77–78 Antithrombotic treatment, 94 Aortic dissection aortic intramural hematoma (AIH) and, 281 classification of, 280 diagnosis, 279 imaging modalities, 281–284 initial management, determination of, 284–285 radiologic procedure for, 283 screening for, 281–282 type A and type B dissections, management, 285–286 types of, 279–280 Aortic intramural hematoma (AIH), 281 Aortic stenosis (AS) aortic valve replacement (AVR) assessing perioperative risk associated with performing, 322 estimated perioperative risks for, 324 indication for, 322, 323 intervention, 322 transcatheter replacement, mortality risk with, 324–325 balloon aortic valvotomy (BAV), 325 diagnosis, 317–318 echocardiographic findings in, 321 life expectancy without intervention, 321– 322 pharmacologic agents in, 325–326 physical examination, 319–320 prognosis, 327 risk factors for progression of, 318–319 Aortic valve replacement (AVR), 322 assessing perioperative risk associated with performing, 322 estimated perioperative risks for, 324 indication for, in aortic stenosis, 322, 323 intervention, 322 transcatheter replacement, mortality risk with, 324–325 Aphasia, 89 Argatroban, 475 Arginine vasopressin-antagonists Atrial fibrillation (continued) risk for stroke with, 291–292 transesophageal echocardiography (TEE), use of, 302 treatment options, 294, 295 trials evaluating rate control versus rhythm control in, 298–301 The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial, 298 Atrioventricular (AV) block, 308 types of, 309, 311–312 Atrioventricular fistulas, 260 Azithromycin, 374, 375 Azole antifungals, 375 Adrenal hemorrhage, 462 Adrenal insufficiency appropriate way to screen for, 462–463 diagnosis, 461–462 empiric corticosteroid therapy, 465–466 insulin tolerance test (ITT) for, 463–464 metyrapone test to distinguish, 464 prevention of, 466–467 screening tests, characteristics of, 464–465 septic shock patients, 466 Adrenocorticotropic hormone (ACTH) stimulation test, 462 Adrogue and Madias formula, 535–536 AFA-SAK 2 study, 296 Aggrenox, 78 Aggressive intravenous (IV) hydration, 452 β-Agonists, 182 Airway, Breathing, Circulation, Disability, and Exposure (ABCDE), 91 Airway hyper-responsiveness (AHR), 162 Albumin, 513 Albuterol, 164, 182 Aldosterone, 11 Allergic asthma, 162 Allylamines, 405 American Academy of Family Practitioners, 451 Amiodarone, 294, 295, 297 Amphetamines, 73 Ampicillin/sulbactam, 193, 206 Angiography for aortic dissection, 282 lower gastrointestinal bleed (LGIB), 5 Angiotensin-converting enzyme (ACE) inhibitor, 79, 243, 248, 273, 275, 326, 514 Angiotensin receptor blocker (ARB) therapy, 514 Anti-inflammatory drugs, 326 Antiarrhythmic drugs, 294 Antibodies to hepatitis C virus (anti-HCV), 25 Anticholinergic agents, 181 effective for SIADH-associated hyponatremia, 527 Arrhythmias management, in STEMI, 273, 274 Arterial blood gas (ABG), 343–344 measurements, 164, 168, 451 Aspartate aminotransferase (AST), 26 Aspergillus fumigates, 215 Aspirin, 77, 269 versus anticoagulant therapy, 296 Asthma exacerbation causes of, 162 diagnosis, 160–161 epidemiology of, in US, 161 follow-up with primary care provider, 169–171 need for hospitalization reassessment of exacerbation severity after 1 hour of treatment, 167 response to initial therapies, 166–167 nonpharmacological interventions, 168–169 pathophysiology of allergic asthma, 162 pharmacologic treatment of, 164–166 respiratory distress with hypoxemia, differential diagnosis for, 159 severity of, 163–164 symptoms and signs, 163 ways to monitor the progression, 167–168 Atrial fibrillation aspirin versus anticoagulant therapy, 296 cardioversion, use of, 294–295 CHADS2 score, 292–293 diagnosis, 289–290 diagnostic evaluation of, 291 ECG on initial presentation, 289 Holter monitor, use of, 302 initial work-up for, 290–291 INR range for coumadin anticoagulation in, 295, 297 management, 302 medications used for heart rate control, 295 optimization of rate control in, 297 restoration of sinus rhythm, 297 B B-type natriuretic peptide (BNP) concentration, 244–245 BacillusCalmette-Guerin (BCG) vaccination, 424–425 Bacterial meningitis antibiotic therapy, administration of, 399–400 cerebrospinal fluid (CSF) findings, 396–397 computed tomography for, 398–399 dexamethasone, use of, 400–401 diagnosis, 395 risk factors associated with poor outcomes, 397–398 signs of, on physical examination, 395–396 Bacterial peritonitis (BP). See Spontaneous bacterial peritonitis (SBP) Balloon aortic valvotomy (BAV), 325 Barium enema, 5 Benzodiazepines, 235 Beta-blockers, perioperative. See Perioperative beta-blockers Bicarbonate, 376 administration, complications of, 453 measurement of, 454 Bipolar disease management of, 484 medications to, 483 platelet transfusion therapy, 483–485 prophylactic platelet transfusion therapy for, 485 Bivalirudin, 475 Biventricular pacemaker, 312 Blatchford score, 17–18 Blindness, risk factors for, 337 β-Blockers, 236, 269, 275, 284, 302 Blood smear, examination of, 481–482 Brain natriuretic (BNP), 344 Broca’s aphasia, 89 Bronchodilators, 169 use of, 181–182 Bumetanide (Bumex), 246 Cephalosporin, 68, 194, 206, 414, 501, 503 Cerebral edema, risk of, 537 Cerebral osmotic adaption, rate of, 536 Cerebral pulmonary edema preventive measures for, 455 risk reduction for, 455–456 CHADS2 score, 292–293 Chest infection, 141, 142 Chest pain causes of, 265 cocaine-induced. See Cocaineinduced chest pain differential diagnosis for, 263–266 system-based causes of, 254 Chest x-ray (CXR) for acute decompensated CHF, 243–244 for aortic dissection, 282, 283 for community-acquired pneumonia (CAP) diagnosis, 190 for infective endocarditis (IE), 388 for nosocomial pneumonia diagnosis, 217–218 Chlamydia pneumoniae, 190 Chlamydia psittaci, 190 Chronic asymptomatic hyponatremia, by SIADH, 526 Chronic glucocorticoid therapy, 461 Chronic obstructive pulmonary disease (COPD) exacerbation antibiotics, use of, 184 bronchodilators, use of, 181–182 classification systems for, 179–180 corticosteroids, use of, 183 diagnosis, 177–178 noninvasive positive pressure ventilation (NPPV), use of, 184–185 oxygen therapy, 183–184 with pCO2, 181 PE in patients presenting with unexplained, 350 potential triggers for, 178 prognosis, during hospitalization, 181 spirometry, diagnostic value of, 180 theophylline treatment, 182–183 workup for, 179 Chronic primary adrenal insufficiency, 462 Ciprofloxacin, use of, 502 Community-acquired pneumonia (CAP) complications of, 195–196 diagnosis, 189 imaging modality for, 190 pathogens causing, 190 risk factor reduction (smoking cessation), 194–195 scoring systems for prognosticating outcomes in, 190–193 treatment for (outpatient, hospitalized patient, ICU patients), 193–194 Complete blood count (CBC), 168, 217, 359, 481–482, 504, 505 Complicated pleural effusion antibiotic therapy for, 206, 208 bacteriology of, 206 categorization of parapneumonic effusions, 207 causes of, 205–206 diagnosis, 199–200 diagnostic thoracentesis, performing, 203 etiologies of, 205–206 imaging studies, 201–203 indications for tube thoracostomy, 208 intrapleural tissue plasminogen activator (tPA) and DNase in, 208–209 physical examination in detecting and identifying, 200–201 pleural space anatomy, 201 surgical interventions, 209 test results, 204–205 Computed tomography (CT) for aortic dissection, 282–284 for bacterial meningitis, 398–399 for cellulitis, 406 for complicated pleural effusion, 201–203 for ischemic colitis, 47 for ischemic stroke, 90–91 in patients presenting with syncope, 357–358 for spontaneous bacterial peritonitis (SBP), 65–66 for transient ischemic attack (TIA), 73–74 Confusion Assessment Method (CAM), for diagnosing delirium, 436–437 Congestive heart failure (CHF), 178, 206, 241, 290, 356. See also Acute decompensated congestive heart failure Continuous renal replacement therapy, advantage of, 495 Controlled hypoventilation technique, 169 Corticosteroids, 109, 169, 400, 465–466, 512, 515 inhaled, 165 systemic, 165 use of, 183 Coumadin, 293, 295 Coxiella burnetii, 190 Creatine kinase (CK), 374 Creatine phosphokinase, 444 CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology and AHA Guidelines), 258 Crystalloids, use of, 16 CURB-65 score, for CAP risk stratification, 190–191 Cyclosporine, 375 Cytochrome P450 system, 375 IVC filters increases the incidence of, 347 screening test for, 343 systemic diseases in, 344 thrombolytic therapy for lower extremity, 346 Delirium, 142 appropriate diagnostic workup for, 438–440 cause of, 438 Confusion Assessment Method (CAM), 436–437 diagnosis, 435 diagnostic criteria for, 437 electroencephalogram (EEG) for, 440 initial management, 441 laboratory testing, 439 multicomponent non-pharmacologic interventions, 437–438 neuroimaging, 440–441 precipitating factors for, in elderly, 439 risk factor for, 435–436 ways to reducing risk factors for, 437–438 Dementia with Lewy bodies (DLB), 436 Depression, 276 Dermatomyositis, 502 Dermatophytes, 405 Dexamethasone, 108, 400 Dextrose, hydration with, 466 Diabetes, 79, 90, 509–510 Diabetic ketoacidosis (DKA) aggressive hydration for, 452 arterial blood gas (ABG) measurement, benefit from, 451 complications of, 454–455 diagnosis, 449–450 insulin for, 452 potential complications of, 455 preventative measures for, 455–456 prognosis, 450 serum anion gap, measurement of, 454 serum ketones, measurement of, 451–452 specific criteria, 456 supplements for, 453–454 workup for infection, 451 Diastolic arterial pressure, 344 Digoxin, 295, 297 Diltiazem, 294, 297 Diltiazem IV, 295 Diltiazem PO, 295 Direct thrombin inhibitors, 474 Disseminated intravascular coagulation (DIC), 480, 481 Diuretics, 246 Dofetilide, 294 Doxycycline, 194 Drug-induced thrombocytopenia, 481 Duke Criteria, 381–382 Dyslipidemia, 514 Dysnatremias, 533–534 Dyspnea, causes of, 159, 161 Enoxaparin (Lovenox), 347, 474 Enterobacter spp., 215 Enterobacteria, 206 Eosinophiluria Hansel stain for, 505 Wright stain for, 505 Epinephrine, 57–58 Escherichia coli, 67, 178, 215 Esmolol, 295, 368 Esophagogastroduodenoscopy (EGD), for peptic ulcer disease (PUD), 13 The European Stroke Prevention Study (ESPS-2), 77, 81 European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT), 77–78, 81 Euvolemic hyponatremia, 520 C C-13 urea breath test, 11 C-reactive protein (CRP), 387 Calcium channel blockers (CCB), 235–236 Cancer, 206 Candida, 215 Carbapenem, 206 Cardiac catheterization, complications of, 259 Cardiac causes, of acute chest pain, 263 Cardiac enzymes, 233 Cardiac events in orthopedic surgery, 146–147 risk factors and predictors of, in perioperative history, 144 Cardiac resynchronization therapy (CRT), 312 Cardioversion, use of, 294–295 CARESS-in-AMI trial, 272 Carotid atherosclerosis, 73 Carotid endarterectomy, 79, 83, 84 Catecholamines, 115, 244 Cauda equina syndrome (CES), 106 Cefepime, 193 Cefotaxime, 68, 193 Ceftazidime, 68, 193 Ceftriaxone, 193 Cellulitis diagnosis, 403 imaging modality for, 406 necrotizing fasciitis, diagnosis of, 406–408 obtaining blood cultures/performing biopsy, 408–409 risk factors for development of, 403–405 treatment for, 409–410 Cirrhosis, 33 Citrate, 495 CK-MB (the myocardial isoenzyme of creatine kinase), 265 Clindamycin, 222, 414 Clinical-scoring scale, 472–473 Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, 77, 80 Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, 77, 80 Clostridium difficile infection (CDI) antibiotic use, 414 colectomy for, 418 diagnosis, 413 intracolonic vancomycin role in treating, 417 IV metronidazole, alternative therapy for, 417 metronidazole/vancomycin, use of, 416 PCR method, 415–416 probiotics role in treating, 418–419 proton pump inhibitor (PPI) use and, 414– 415 stool transplantation role in treating, 417–418 surgical intervention, 418 Cocaine, 73 Cocaine-induced chest pain acute myocardial infarction (AMI) and, 231–232 causes of, 230 characteristics, 231 diagnosis, 229 due to myocardial ischemia (MI), 232 imaging studies, 233–235 patients with, monitored in observation unit, 232–233 treatments for, 235–236 β-blocker use, 236 Colonoscopy, for acute lower gastrointestinal bleed (LGIB), 4–5 COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) trial, 256 D d-dimer tests, 343 Dabigatran (Pradaxa), 293, 297 Dalteparin (Fragmin), 474 Danaparoid, 475 Dark granular casts, 494 DeBakey classification, 279–280 DECREASE-IV (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) trial, 120–121 Deep abscess, 406 Deep vein thrombosis (DVT) duration of long-term anticoagulation, 348 graduated compression stocking for, 348 E Echocardiogram for cocaine-induced chest pain, 234 for infective endocarditis (IE), 387–388, 391–392 Echocardiography for aortic dissection, 283, 284 in aortic stenosis (AS), 321 for pulmonary embolism (PE), 345 Edema, 509 Electrocardiogram (ECG) for atrial fibrillation, 289 benefit of permanent pacemaker implantation, 307 for cocaine-induced chest pain, 234–235 for infective endocarditis (IE), 387–388 myxedema coma, 444 STEMI diagnosing on, 264, 266 for syncope, 357 for transient ischemic attack (TIA), 75 Electroencephalogram (EEG), for delirium, 440 Electrolyte abnormalities, 374 ELISA assay, 343, 474 Empyema, 200 Endocarditis. See Infective endocarditis (IE) Endoscopic therapy, for upper gastrointestinal bleeding (UGIBs), 56–58 Endotracheal intubation (ETI), 168–169 Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial, 276 F Femoral head replacement, 138 Fenoldopam, 369 First Multicenter Intrapleural Sepsis Trial (MIST 1), 209 Flecainide, 294 Fluoroquinolones, 193, 194, 414 Fondaparinux (Arixtra), 475 Forrest classification, 57 4Ts scale. See Clinical-scoring scale Fractional excretion of sodium (FeNa), 513 Francisella tularensis, 190 FRISC (Fragmin during Instability in Coronary Artery Disease) II trial, 258 Furosemide (Lasix), 246 G Gait ataxia, 107 Gastrointestinal (GI) hemorrhage, 2 Gelofusine, 16 Gemfibrozil, 375 Geneva score, 341–343 Glasgow Outcome Scale (GOS), for unfavorable outcomes in meningitis, 397 Glasgow–Blatchford bleeding score (GBS), 54–55 Global initiative for Chronic Obstructive Lung Disease (GOLD), 180 Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trials, 269–270 Glomerular filtration rate (GFR), 514 Glucocorticoids, 445, 515 treatment with, 462, 465–466 Glycemic control, in STEMI patients, 273 Graduated compression stocking, 348 Hepatitis B e-antigen (HBeAg), 24, 25 Hepatitis B surface antibody (HBsAb), 25 Hepatitis B surface antigen (HBsAg), 24, 25 Hepatitis B vaccine, 28 Hepatitis C virus recombinant immunoblot assay (HCV RIBA), 25 Hepatitis C virus ribonucleic acid (HCV RNA), 25 Hepatotoxicity, 430 Hip fracture cardiac events in perioperative history, risk factors and predictors, 144 current treatment for, 138 delayed surgery and increased mortality in, 139–141 epidemiology of, in US, 135–138 major complications of, 141, 142 preoperative cardiac testing, 143–146 risk factors for, 136 risk of cardiac death and nonfatal MI, 146–147 steps to follow for noncardiac surgery, 145–146 Holter monitor, use of, 302, 358 Hospital-acquired pneumonia (HAP), 213–224 Human immunodeficiency virus, 462 11 β-Hydroxylase, 464 Hypercarbia, 183 Hyperchloremic nonanion gap, preventive measures for, 455 Hypercholesterolemia, 514 Hypercoagulable, 471 Hyperglycemia, 93, 183 Hyperkalemia, 374, 377 management of, 495 risk for causing, 454 Hyperlidemia, 78–79 Hyperlipidemia, 509 induced by nephrotic syndrome, 513 Hypernatremia Adrogue and Madias formula for, 535–536 correction rate of, 536–537 definition of, 531 epidemiology of, 533–534 Hyponatremia (continued) hypovolemic, 520 SIADH-associated, 520–521 arginine vasopressin-antagonists effective for, 527 causes of, 522–523 clinical features of, 522 diagnosis of, 521–522 prevalence of, 523 treatment of, 525–526 Hypophosphatemia, 453 versus hypokalemia, 450–451 Hypothalamic-pituitary-adrenal (HPA) axis, degree of suppression, 461 Hypothermia, in myxedema coma, 444 Hypotonic hyponatremia, diagnostic approach to, 519 Hypovolemic hypernatremia, 532 Hypovolemic hyponatremia, 520 H H2-receptor blockers, 14 HACEK group, 387 Haemophilus influenza, 178, 206, 214 Haldane effect, 183 Hansel stain, for eosinophiluria, 505 Headache, in older patients, 334 The Health Assessment Program, in UK, 12 Healthcare-associated pneumonia (HCAP), 213–224 Helicobacter pylori infection, 9 characteristics of diagnostic tests for, 12 H2 blockers in treating, 14 NSAID use and, 11 peptic ulcer disease with, 58 treatment in patients with PUD, 12–13 Hematemesis, symptom of UGIB, 13 Hematochezia, 4 Hemodynamic instability, 344 Hemophilus influenzae, 190, 222 Heparin, 513 risk of, 475 Heparin-induced thrombocytopenia (HIT), 481 anticoagulant treatment options, 475 clinical-scoring scale, 472–473 clinical signs of, 472 confirmation tests for, 473–474 developing factors for, 472 diagnosis, 471 heparin, risk of, 475 laboratory tests, 475 management of, 474 platelet transfusion, need for, 475 Hepatitis B core IgM antibody (HBcAb IgM), 24, 25 fluid repletion in, 537 hospital admission and discharge criteria for, 537–538 mortality rate, 534 prognostic indicators, for mortality, 534–535 signs and symptoms of, 531–532 thirst mechanism (response) guard against, 532–533 Hyperphosphatemia, 374 Hypertension, 79 Hypertensive crisis, 364 pharmacological agents used to treating, 367–369 Hypertensive emergency cases of severe HTN, 364 clinical manifestation of, 364–365 complications of, 369–370 diagnosis, 363 epidemiology and precipitating factors of, 364 goals of therapy for BP management in, 367 and hypertensive crisis, 364 risks and benefits of agents used to treating, 367–368 and hypertensive urgency, 365–366 laboratory tests, 366–367 patient admission, 366 reason for inadequate anti hypertensive treatment, 365 Hypertensive encephalopathy, 370 Hypertensive urgency, 363, 364 Hyperthyroidism, 291 Hypertriglyceridemia, 514 Hypervolemic hyponatremia, 520 Hypoalbuminemia, 509 Hypocalcemia, 374, 377 Hypoglycemia, 92 Hypokalemia, 291 insulin administration for, 453 vs hypophosphatemia, 450–451 Hyponatremia, 443 chronic asymptomatic, by SIADH, 526 correction for, 524–525 diagnosis of, 519 euvolemic, 520 hypervolemic, 520 hypotonic, diagnostic approach to, 519 I Ibuprofen, use of, 489 Ibutilide, 294 Idiopathic nephrotic syndrome, subsets of, 509 IL-18, urinary levels of, 492–493 Imidazoles, 405 Imipenem, 193 Immune thrombocytopenia, 481 Implantable cardioverter/defibrillator (ICD) role, in patients with STEMI, 275–276 Infective endocarditis (IE) antimicrobial therapy, 389 blood cultures, collection of, 386, 387 chest x-ray for, 388 definition of, 382 diagnosis of, 381–382 Duke Criteria, 381–382 echocardiogram findings, 387 EKG, for staging and follow-up, 387–388 empirical treatment, 389 epidemiology and risk factors of, 383 inflammatory markers, 387 microbiology of native valve, 384 other indicators, 382 physical examination findings in, 383–386 diagnostic tests, 46–47 epidemiology, 44 long-term complications of, 48–49 marginal artery of Drummond, 45 occlusive and nonocclusive ischemia, 45–46 pathological findings, 47 three acute indications for surgery, 48 treatment, 47–48 Ischemic stroke antithrombotic treatment, 94 complications, 95 diagnosis, 87–88 initial management, 91–93 modified Rankin Scale (mRS), 94, 97 neurologic event, 89 noncontrast computed tomography (CT) scan for, 90–91 occurrence, 89–90 options for addressing thrombosed vessel, 93–94 pharmacologic interventions, 95–96 prognosis, 96–97 recombinant tissue plasminogen activator (rtPA), 93 indications and contraindications for, 94 rehabilitation, 94 risk factors for, 90 Isoniazid (INH), 427–430 positive blood cultures, 383 prophylaxis for, 390 Staphylococcus aureus, 383 surgical intervention, 391 transesophageal echocardiogram (TEE) for, 388–389 transthoracic echocardiogram (TTE) for, 388 Inferior mesenteric artery (IMA), 45 Inferior vena cava (IVC) filters placement, indications for, 347 Influenza vaccination, 194 Inhaled corticosteroids (ICS), for asthma exacerbation, 165 Inhaled ipratropium and albuterol, 182 Inhaled ipratropium bromide, 165 Inhaled magnesium sulfate and heliox, 166 Insulin, 452, 463 Insulin tolerance test (ITT), 463–464 Interferon γ release assays (IGRAs), 426– 427 and tuberculin skin test (TST), comparison of, 428 Intra-arterial thrombolysis technique, in acute ischemic stroke, 93 Intracolonic vancomycin (ICV) therapy, 417 Intrapleural fibrinolytics, use of, 208–209 Intrapleural tissue plasminogen activator (tPA) and DNase, 208–209 Intravascular volume depletion, 450 Intravenous (IV) albumin administration, to patients with SBP, 68 Intravenous ciprofloxacin, 39 Intravenous methylprednisolone, 445 Intravenous metronidazole, 417 Intravenous pantoprazole, 14 Intrinsic renal failure, indication of, 493 Ipratropium, 182 Ipratropium bromide, 165 Ischemic colitis antibiotics role in treatment, 48 causes of, 44 clinical symptoms of, 46 colonic blood supply influencing the onset of, 44–45 diagnosis, 43–44, 47 J Janeway lesions, 384, 385 The Journal of Clinical Endocrinology and Metabolism, 463 JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial, 78, 82 K Ketorolac, 10 Killip classification, 267–268 KIM-1, urinary levels of, 492 Klebsiella pneumoniae, 178, 190 Klebsiella spp, 67 L Labetalol, 368 β-Lactam antibiotics, 193 Lactobacillus bulgaricus , 419 Lactobacillus casei, 419 Latent tuberculosis infection (LTBI) BCG vaccination, 424–425 diagnosis, 423 interferon γ release assays (IGRAs), 426–427 monitoring, after INH therapy, 430–431 reasonable diagnostic algorithm, 429 risk factors for, 423–424 risk of progression from, to active TB, 426 TB infection, ruled out before diagnosis and treating, 425–426 treatment for, 427–430 tuberculin skin test (TST) criteria for interpreting, 424, 425 and interferon γ release assays (IGRAs), comparison of, 428 Left anterior descending (LAD) artery, 266 Legionella pneumophila, 215 Legionella species, 190 Lepirudin, 475 Levothyroxine (Synthroid), 444 Lhermitte’s phenomenon, 107 Linezolid, 193, 206 Lipid abnormalities, in nephrotic syndrome, 514 Liver function tests (LFTs), 26, 504 LODS-Logistic Organ Dysfunction System, 534 Loop diuretics, 495 Lovenox, 513 Low diastolic blood pressure, 535 Low-molecular-weight heparin (LMWH), 347 Lower gastrointestinal bleed (LGIB) acute, 1–2, 3–4 barium enema and, 5 colonoscopy for, 4–5 etiologies of, by age, 2 hematochezia, indicator of, 4 intervention, in ruling out UGIB, 4 physical examination findings and blood loss volume, 3 severity of intestinal bleeding, 2–3 sources and frequencies, 2 visceral angiography, 5 Lower respiratory tract cultures, for nosocomial pneumonia, 218–219 LRINEC score, 407, 408 Lumbar metastases, 107 Lupus, 502 Lymphedema, 403, 405 M Macrolide antibiotics, 375 Macrolides, 193, 194 Magnetic resonance imaging (MRI) for acute spinal cord compression, 109–111 for aortic dissection, 283, 284 for cellulitis, 406 for spontaneous bacterial peritonitis (SBP), 66 for temporal arteritis (TA), 336–337 for transient ischemic attack (TIA), 73–74 Malignant hypertension (HTN), 364 Malignant spinal cord compression dexamethasone usage in, 108–109 signs and symptoms of, 107–108 Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH) trial, 77, 80 Mannitol, 376 Massive blood loss, 481 Mean arterial pressure, 344 Measles, 502 The Medical Journal of Australia, 467 MEDICS, 88 Meningeal irritation, signs and symptoms of, 395 Merci Retriever, 94 Methicillin, 503 Methicillin-resistant Staphylococcus aureus (MRSA), 193, 206, 214, 215, 409– 410 Methylxanthines, 183 Metoprolol, 294, 297 Metoprolol IV, 295 Metoprolol PO, 295 Metronidazole, 416 Metyrapone test, 464 Minimal change disease (MCD). See also Nephrotic syndrome in childhood, 510 complications for, 514–515 presumptive diagnosis of, 510 Ministrokes. See Transient ischemic attack (TIA) Modified Rankin Scale (mRS), 94, 97 “MONAB” (Morphine, Oxygen, Nitroglycerin, Aspirin, and β-Blockers) therapy, 256 Moraxella catarrhalis, 178, 190 Morphine, 246 Morphine sulfate, 269 Multidetector helical CT (MDCT), 282 Multidrug-resistant (MDR) bacteria, 215, 221–222 Myalgia, diagnosis for, 373 Mycobacterium tuberculosis, 206, 423 Mycoplasma pneumoniae, 190 Myocardial infarction (MI), 116 Myocardial ischemia, 370 cocaine-induced, 232 Myxedema coma causes of, 444 complications for, 446 diagnosis, 443 glucocorticoids for, 445 laboratory findings for, 444 management of, 446 mortality predictors in patients with, 445 predictors of, 445 supportive therapy, role for, 446–447 T3 administration, Route of, 446 criteria for admission in hospital, 515–516 degree of proteinuria for, 512 determinant of prognosis, 516 diagnosis, 509–510 initial evaluation of, 510–511 renal biopsy, recommendations for, 511–512 therapy recommendations for, 514 treatment for, 512–513 Nephrotoxic agents, 496 Neuroimaging, for delirium, 440–441 Neurovascular imaging, for transient ischemic attack (TIA), 74 Neurovascular ultrasound, 359 New York Heart Association (NYHA) functional classification, 242, 243 Nicardipine, 368 Nitroglycerin, 235, 269 Nocardia, 206 Non-osmotic release of ADH, 520 Non-ST segment elevated myocardial infarction (NSTEMI), 254–260 acute coronary syndromes and, 255–256 “MONAB” therapy, 256 optimal time, 258 risk stratification, 257–258 Noncardiogenic pulmonary edema, preventive measures for, 455 Noncontrast computed tomography (CT) scan, for ischemic stroke, 90–91 Noninvasive positive pressure ventilation (NPPV), 169, 184–185 Nonocclusive ischemia, 46 Non–Q-wave myocardial infarction (NQMI) versus Q-wave myocardial infarction (QWMI), 267 Nonsteroidal anti-inflammatory drugs (NSAIDs), 10, 503 risk of ARF with, 490 use of, 489 Non–variceal UGIB (NV-UGIB), 14, 17 Norfloxacin, 69 North American Symptomatic Carotid Endarterectomy Trial (NASCET), 79, 83, 84 Nosocomial pneumonia antibiotic therapy, 219–220 clinical and bacteriologic approaches, 219, 220 de-escalation of antibiotic therapy, 223 diagnosis, 213–214, 216–217 discontinuation of antibiotics, 223 empiric antibiotic therapy, 221–222 etiologies, in hospitalized patients, 214–216 Gram stain of endotracheal aspirates, 218 laboratory tests and imaging results, 217–218 lower respiratory tract cultures, 218–219 mortality rate, 216 prevention of bacterial, 223–224 N N-GAL, urinary levels of, 493 N-terminal proBtype natriuretic peptide concentration, 244 Nasogastric tube (NGT) placement in management of acute UGIB, 18–19 National Institutes of Health Stroke Score (NIHSS), 92 Necrosis, 462 Necrotizing fasciitis, diagnosis of, 406–408 Negative Gram stain of tracheal aspirates, in patients with VAP, 218 Neisseria meningitides, 190 Nephrotic range proteinuria, 509 Nephrotic syndrome O Occlusive and nonocclusive ischemia, 45–46 Octreotide, 38 Open reduction with internal fixation (ORIF), 138 Oral bicarbonate, 495 Oral norfloxacin, 39 Osler’s nodes, in IE, 384, 385 Osteomyelitis, 406 Oxygen therapy for asthma exacerbation, 165 for COPD, 183–184 P Pacemaker placement, indications for AV block, types of, 309, 311–312 benefit from, 312–313 dual-chamber pacing mode (DDDR) in SND, 309 ECG on initial presentation, 307 general principles, 308 permanent pacemaker implantation, 307–308 in sinus node dysfunction (SND), 308–309, 310 PAF II trial, 299–300 Parapneumonic pleural processes, classification of complicated parapneumonic effusions, 200 empyema, 200 uncomplicated parapneumonic effusions, 200 PE severity index (PESI), 349 Peak expiratory flow (PEF) relationship, to severity of asthma exacerbation, 163 Penicillins, 414, 501, 503 Penumbra, 90, 92, 94 Peptic ulcer disease (PUD) crystalloids, use of, as first step in fluid resuscitation, 16 diagnosis, 9–10 esophagogastroduo-denoscopy (EGD) for, 13 H. pylori infection diagnostic tests for, in patients with UGIB, 11–12 NSAID use and, in etiology of, 11 treatment of, 12–13 H2-receptor blockers role in treating, 14 immediate intervention in patients with active UGIB, criteria for, 16–18 medications contributing to risk of, 11 NGT placement, in management of acute UGIB, 18–19 PPI therapy for, 14–15 predictors of UGIB in absence of hematemesis, 13 red blood cell transfusion, criteria for, 15–16 risk factors for, 9 risk of stomach bleeding with different NSAIDs, 10 Peptic ulcer disease, 58 Percutaneous coronary intervention (PCI), 270 Perioperative beta-blockers benefits in orthopedic surgery, 115–116 DECREASE-IV trial, 120–121 excess mortality in hip fracture causes of, 123 no evidence in reducing, 124 other interventions, 124 Proton pump inhibitor (PPI) for PUD, 12, 14–15, 58 use and CDI, 414–415 Pseudoaneurysms, 260 Pseudomonas aeruginosa, 178, 215 Psoriasis, 502 Pulmonary embolism (PE), 206, 291 choosing home management/ observational unit admission with early discharge, 349–350 criteria for admission to intensive care unit, 344 d-dimer tests in, 343 duration of long-term anticoagulation, 348 echocardiography, 345 indications for placing IVC filters for prevention of, 347 methods for estimating the present probability of, 341–343 systemic diseases in, 344 thrombolytics used with anticoagulation, 346 troponin and brain natriuretic (BNP) in, 344–345 with unexplained COPD exacerbation, 350 Pulse oximetry, 159, 163, 168 Purified protein derivative (PPD), 511 Pyridones, 405 initiation of, use in advance of surgery, 124 PeriOperative ISchemic Evaluation (POISE) trial, 116, 117–120 results in reduced in-hospital mortality among high-risk patients, 121–123 and risk of death, 122 use of, 116–117 PeriOperative ISchemic Evaluation (POISE) trial, 116, 117–120 Permissive hypercapnia technique, 169 Pharmacotherapy (fibrinolysis), 269–270 Phenytoin, 464 PIAF (pharmacologic intervention in atrial fibrillation) trial, 298 Piperacillin/tazobactam, 193 Plasma osmolarity, 532 Platelet aggregation, 474 Platelet hyperaggregability, 515 Platelet transfusion therapy, 484–485 Pleural effusion. See Complicated pleural effusion Pneumococcal meningitis, 400–401 Pneumococcal vaccination, 194–195 Pneumonia severity index (PSI)/patient outcomes research team (PORT) score, 191, 192 Poison ivy, 501 Polymyalgia rheumatica (PMR), 334 Postcosyntropin serum cortisol levels, 464 Postischemic ATN, risk for, 496 Potassium deficiency, 453 Potassium supplementation, 454 Prednisone, 337, 512 Preoperative cardiac testing, 143–146 PREPIC (Prévention du Risque d’Embolie Pulmonaire par Interruption Cave) trial, 347 Prerenal azotemia, acute periods of, 489 Probiotics role, in treating CDI, 418–419 Propafenone, 294 Prophylactic platelet transfusion therapy, for thrombocytopenia, 485 Prophylactic treatment, 513 Prophylaxis, for infective endocarditis (IE), 390 Prostaglandins, 463 Q Q-wave myocardial infarction (QWMI) versus non–Qwave myocardial infarction (NQMI), 267 R RACE trial, 299 Randomized Aldactone Evaluation Study (RALES), 242 Ranitidine, 14 Ranitidine bismuth citrate (RBC), 14 Rapid infusion, goal of, 525 Rash, diagnosis for, 501–502 Rate control versus rhythm control in atrial fibrillation, trials evaluating, 298–301 Recombinant tissue plasminogen activator (rtPA), 93 Relapsing nephrotic syndrome, definition of, 514 Renal biopsy diagnosis of AIN, 505 nephrotic syndrome, 511–512 recommendation of, 494–495 Renal failure, supportive treatment for, 506 Renal insufficiency, 370 Renal tubules, 514 Renin–angiotensin system, inhibition of, 514 Respiratory distress with hypoxemia, differential diagnosis for, 159 Respiratory rate, 344 Retroperitoneal hematoma (RPH), 259, 260 Revascularization options, 269–270 Revised Cardiac Risk Index (RCRI), 121–122 Rhabdomyolysis, 233 aggressive hydration, 376–377 AKI development in, 376 complications of, 374–375 diagnosis, 373–374 electrolyte abnormalities, management of, 374, 377 laboratory tests, 374 toxins and drugs, contributing to, 375 Rifampin, 222, 428–430, 464, 503 Rivaroxaban (Xarelto), 293, 297 Rockall score, 16–17, 53–54 Rocky Mountain spotted fever, 502 Roth’s spots, 384 Ruptured esophageal varices antibiotics, 39 bleeding risk for, 34 causes, 33 for upper GI bleed, 34–35 coagulopathy, 37 diagnosis, 33, 35 failure of treatment to control active bleeding, 38–39 follow-up, 40 general principles of management hemodynamic stability, 35 identifying and correcting the cause of bleeding, 36–37 preventing nonhepatic complications, 36 Ruptured esophageal varices ( continued) management, 39 pathogenesis, 33–34 pharmacotherapy, 38 risk for, 39 signs and symptoms of, 34 transfusion requirement, 37 transjugular intrahepatic portosystemic shunt (TIPS) procedure, 36 variceal bleeding, 35 vasopressin and somatostatin, 38 S Saline, hydration with, 466 Salt restriction, 512–513 San Francisco Syncope Rule (SFSR), 356 SAPSII-Simplified Acute Physiology Score II, 534 Secondary bacterial peritonitis (BP), 65 Secondary prophylaxis interventions, in patients with STEMI, 273–275 Semi-quantitative latex agglutination assays, 343 Sepsis, 481 causes of, 482–483 Septic shock patients, 466 Serial measurements of lung function, 168 Serotonin release assay, 473–474 Serratia marcescens, 215 Serum alanine aminotransferase (ALT), 26 Serum anion gap, measurement of, 454 Serum-ascites albumin gradient (SAAG), 64 Serum chemistry profile, 504, 505 Serum electrolytes, 168 Serum ketones, presence of, 451 Serum sodium concentration, impact on, 536 Severe community-acquired pneumonia (SCAP) score, 191 classification algorithm, 193 Severity of asthma, 163–164 Short-acting β-agonist (SABA), 164 Short-term glucocorticoid therapy, 445 SIADH-associated hyponatremia, 520–521 arginine vasopressin-antagonists effective for, 527 clinical implications of Q-wave versus Non–Q-wave categorization, 267 common site of, 266–267 contraindications for fibrinolysis in, 270–271 depression in, 276 diagnosing, on ECG, 264, 266 door-to-balloon time, 270 glycemic control in, 273 implantable cardioverter/defibrillator (ICD) role, 275–276 medical complications of, 273 options for revascularization, 269–270 psychiatry care, before discharge, 276 risk stratification of patients with AMI, 267–268 secondary prophylaxis interventions, implementation of, 273–275 steps in management after diagnosis of, 269 STAF trial, 300–301 Stanford classification, 279–280 Staphylococcus aureus, 67, 109, 178, 190, 214, 222, 383, 387, 405, 409 Statins, 326 Steroid-resistant nephrotic syndrome (SRNS), 512 Steroid-sensitive nephrotic syndrome (SSNS), 515 Steroids, for acute interstitial nephritis (AIN), 506–507 Stool antigen testing, 11 Stool transplantation role, in treating CDI, 417–418 Streptococcus boulardii, 419 Streptococcus bovis, 387 Streptococcus milleri, 206 Streptococcus pneumonia, 190, 193 Streptococcus pneumoniae, 178, 206, 214, 222, 397–398 Streptococcus pyogenes, 190 Streptococcus thermophilus, 419 Stress testing, 234 The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, 78, 82 Stroke, risk of, in patients with atrial fibrillation, 291–292 Sudden onset chest pain, differential diagnosis for, 254 Sulfa drugs, 501, 503 Superior mesenteric artery (SMA), 45 Symptomatic treatment, 512 Syncope ambulatory ECG monitoring, 358 causes of, 355–356 ECG for, 357 indications for head CT, 357–358 laboratory tests, use of, 358–359 neurovascular ultrasound, 359 SFSR, use of, 356 Systemic corticosteroids, administration of, 165 Systemic inflammatory response syndrome (SIRS), criteria for, 482 Systemic lupus erythematosus (SLE), signs of, 510–511 Systolic arterial pressure, 344 Thrombocytopenia bipolar disease management of, 484 medications to, 483 platelet transfusion therapy, 483–485 prophylactic platelet transfusion therapy for, 485 blood pressure drops, causes of, 482–483 causes of, 480–481 definition of, 479 diagnosis, 479–480 drugs causing, 483 laboratory tests for, 481–482 predictor of ICU mortality, 480 prophylactic platelet transfusion therapy for, 485 Thrombocytosis, 337, 515 Thromboembolic complications, risk for, 513 Thromboembolic stroke, 291–292 Thrombolysis in myocardial infarction (TIMI) score, 257, 267, 268 Thrombolytic therapy, 346 Thrombotic microangiopathy, 481 Thyroid hormone deficiency, 446–447 Thyroid-stimulating hormone (TSH), 444 Total hip arthroplasty (THA), 138, 139 Transesophageal echocardiogram (TEE) for infective endocarditis (IE), 388–389 for transient ischemic attack (TIA), 75 Transesophageal echocardiography (TEE) in patients with atrial fibrillation, 302 Transfusion therapy, risks for, 484–485 Transient ischemic attack (TIA) antiplatelet therapy, 77–78 cardiac evaluation, 75 carotid endarterectomy, 79, 83 defined, 72 diagnosis, 71–72 etiologies, 72–73 imaging studies, 73–74 noninvasive neurovascular imaging for, 74 risk factor modifications, 78–79, 82 risk stratification for stroke, in near future, 75–76 symptoms of, 72 treatment for hyperlidemia, hypertension, and diabetes, 78–79 Transient neurologic deficits (TIA), 89 Transjugular intrahepatic portosystemic shunt (TIPS) procedure, 36 Transthoracic echocardiogram (TTE), for infective endocarditis (IE), 388 Tripod position, 160 Troponin T, 345 Troponins, 265 Tuberculin skin test (TST) criteria for interpreting, 424, 425 and interferon γ release assays (IGRAs), comparison of, 428 Tubulointerstitial nephritis and uveitis (TINU) syndrome, 503 pharmacological treatment for, 58 PPI therapy, reducing the risk of rebleeding, 58 predictors of, without hematemesis, 13 Rockall Score, 53–54 secondary to PUD, 9 Urinalysis, 504 with microscopy, 511 Urinary markers indicative, of ARF, 493 Urinary tract infection (UTI), 142, 438 Urine cytology ATN to prevent deterioration in, 496–497 etiology of ARF based on, 493–494 IL-18, 492–493 KIM-1, 492 N-GAL, 493 Urine osmolality, 494 Urine protein/creatinine ratio, use of, 512 causes of, 522–523 clinical features of, 522 diagnosis of, 521–522 prevalence of, 523 treatment of, 525–526 Sinus node dysfunction (SND) dual-chamber pacing mode (DDDR) in, 309 explanation of, 308–309 indications for pacemaker placement in, 308–309, 310 Skeletal disease, 104–105 Society for Thoracic Surgery equation score, 322 Sodium nitroprusside, 368 Somatostatin, 38 Sotalol, 295 Spinal abscess, 103 Spinal cord compression, defined, 102. See also Acute spinal cord compression Spinal hemorrhage, 103 Spinal tumor, 104 Spironolactone, 11, 242 Splinter hemorrhages, 384 Spontaneous bacterial peritonitis (SBP) characteristics of ascitic fluid in diagnosis of, 66 diagnosis, 63 etiology of, 67 initial step in diagnosis and management, 63–64 IV albumin administration to patients with SBP, 68 performing imaging studies, 65–66 primary prophylaxis, 69 prognosis of, 68–69 secondary BP, 65 treatment for, 68 typical causative organisms for, 67–68 Spot protein/creatinine ratio, nephrotic range for, 512 Stable angina, 263 ST-segment elevation myocardial infarction (STEMI), 255 antioxidants, use of, 276 arrhythmias management in, 273, 274 candidates for fibrinolytic therapy/ immediate transfer to PCIcapable facility, 272 T TACTICS-TIMI (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative StrategyThrombolysis in Myocardial Infarction) trial, 258 Temporal arteritis (TA) diagnosis, 331–335 glucocorticoid therapy, 336 headache, in older patients, 334 imaging modalities, 336–337 management of, 337–338 polymyalgia rheumatica (PMR), symptoms of, 334 risk factors for blindness, 337 sensitivity and likelihood ratios (LRs) in, 332–333 temporal artery biopsy for diagnosing, 335–336 Tension headache, 334 Theophylline treatment, 182–183 Thirst mechanism, against hypernatremia, 532 Thoracentesis, 203–205 Thoracic metastases, 107 Thoracoscopy, 209 U Ultrafiltration, 246–247 Ultrasonography for acute HBV and HCV infections, 26–27 for acute interstitial nephritis (AIN), 505 for cellulitis, 406 Uncomplicated parapneumonic effusions, 200 Unfractionated heparin (UFH), 347 UNLOAD trial, 246 Unstable angina (UA), 255, 263 Upper gastrointestinal bleed (UGIB), 1, 4, 34–35. See also Peptic ulcer disease (PUD) administering blood transfusions, 55–56 aggressive fluid resuscitation, 52–53 alarm features for, 10 Blatchford score, in triaging UGIB patients, 17–18 diagnosis, 51–52 at discharge, referred for H. pylori testing, 58–59 endoscopy, need for, 56–58 Forrest classification, 57 Glasgow–Blatchford bleeding score (GBS), 54–55 initial management, 52 NGT placement, in management of acute UGIB, 18–19 V Vancomycin, 193, 206, 416 Variceal bleeding, 35 Vascular unresponsiveness, presentation of, 463 Vasopressin, 38 Vasovagal response, 356 Venous thromboembolism 2D echocardiogram for prognostic purposes, 345 arterial blood gas (ABG) and, 343–344 choosing home management with early discharge, patients with nonmassive PE, 349–350 criteria for admission to intensive care unit, in patients with PE, 344 d-dimer tests and, 343 duration of long-term anticoagulation, 348 graduated compression stocking, 348 hypercoagulable investigations, in outpatient setting, 346 indications for placing IVC filters for prevention of PE, 347 low-molecular-weight heparin (LMWH), 347 PE in patients presenting with unexplained COPD exacerbation, 350 predicting risk of future clots, 347–348 pretest probability of PE, 341–343 systemic diseases, as cause of DVT/ PE, 344 thrombolytic therapy, 346 troponin and brain natriuretic (BNP), 344–345 Ventilator associated pneumonia (VAP), 213–224 Verapamil, 297 Verapamil IV, 295 Verapamil PO, 295 Viridans streptococci, 387 Vitamin E, 276 W Water balance problems, 532–533 Wells score, 341–343 Whole-spine MRI, in suspected metastatic spinal cord compression, 109–111 Wright stain, for eosinophiluria, 505 Z Zoledronic acid, 124