Differential Diagnosis Mnemonics

-

Differential Diagnosis � Mnemonics

I

J

Differential Diagnosis Mnemonics Thomas J. Donnelly, MD Pulmonary and Critical Care Consultants Dayton, Ohio

Christopher C. Giza, MD Assistant Researcher Division of Neurosurgery University of California Los Angeles, California

HANLEY & BELFUS, INC. / Philadelphia

Publisher

HANLEY & BELFUS, INC . Medical Publishers 2 1 0 South 1 3th Street Ph i ladelphia , PA 1 9 1 07 ( 2 1 5) 546-7293; 800-962- 1 892 FAX (2 1 5 ) 790-9 3 3 0 Web site: http : //www. han leya ndbelfus.com

Note to the reader: Although the i nformation in this book has been carefully re­ viewed for correctness of dosage and ind ications, neither the authors nor the ed­ itors nor the publ isher can accept any legal responsibil ity for any errors or om issions that may be made. Neither the publ isher nor the ed itors make any warranty, expressed or i m pl ied , with respect to the material conta i ned here i n . Before prescribing a n y drug, the reader m ust review the manufacturer's current product i nformation (package i nserts) for accepted ind ications, absolute dosage recom mendations, and other i nformation perti nent to the safe and effective use of the product described .

library of Congress Cotolog ing-in-Publ icotion Dota Donnelly, T homos J, 1962Differential Diognosis Mnemonics / Thomas J. Donnelly, Christopher C. Gizo. p. ; cm. Includes bibliographical references and index. ISBN 1-56053-31 1·0 lalk paper) 1. Diagnosis, Differential. 2. Mnemonics. I. Giza, Christopher c., 1965II. Title. [DNlM: 1. Diagnosis, Differential-Term inology-English. 2. Association Learning-Terminology-English. WB 15 D685d 2000J RC71.5.D66 2001 616 07'5'014-dc21 99-088120

Differential Diagnosis Mnemonics

ISBN 1-5605 3-3 1 1 -0

© 200 1 by Hanley & Belfus, Inc. All rights reserved . No part of this book may

be reproduced , reused, republished , or transmitted in any form, or stored in a data base or retrieval system , without written permission of the publ isher.

Last digit is the print n umber: 9 8 7 6 5 4 3 2 1

CO NTENTS . . . . . . . : . . . . . . . . . . . . .

1 2 2 4 8

II. Pulmonary and Critical Care . . . . . . . . . . . . . . . . . . . . . . . . . .

1 1

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

How to Use This Book . . . . . . . . . . . . . . General Approach to Differential Diagnosis Thi n king About Differential Diagnoses . . . . Presenting and Discussing Cases . . . . . . .

. . . .

. . . .

. . . .

. . . .

. . . .

General Considerations General Approach to Pulmonary Med icine . . General Approach to Critical Care Med icine Chest X-Ray Interpretation . . . . . . . . . . . . . . Clinical Symptoms and Sig ns Chronic Cough . . . . . . . . . . . . . . . . . . . . Clubbing . . . . . . . . . . . . . . . . . . . . . . . . Dyspnea . . . . . . . . . . . . . . . . . . . . . . . . . Hemoptysis . . . . . . . . . . . . . . . . . . . . . . . Stridor Wheezing . . . . . . . . . . . . . . . . . . . . . . . Clinica l Conditions or Diagnoses ARDS - Diffuse Pulmonary Infiltrates . . . . . . . Acute Respi ratory Failure . . . . . Bronchiectasis . . . . . . . . . . . . . . . . . . . . . Cavitary and Cystic Lung Disease . . . . . . . . Interstitial Lung Disease . . . . . . . . . . . . . . . Mediastinal Mass . . . . Pleural Effusion . Pneumothorax . . . . . . . . ' . Pulmonary Hypertension . . . . . . . . . . . . . . Pulmonary I nfiltrate . . . . . . . . . . . . . . . . . . Pulmonary Nod ule . . . . . . , . . . Refractory Hypotension . . . . . . Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

.

.

.

.

.

.

.

.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

.

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . ..

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

. . . . . . . . . . . . . .

.

.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

III. HematolOgy and Oncology . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

.

.

. . . . . . . . . . . . . .

Genera.l Considerations Clinical Symptoms and Signs Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

.

1 1 13 14 16 18 19 21 23 24 27 29 30 31 33 . 36 38 42 ; 43 46 ! 48 50 52 55 56

Contents.

v

i

Bleed ing Diatheses . . . . . . Splenomegaly . . . . . . Clinical Conditions or Diagnoses Eosinophilia . . E ryth rocytosis . . . . . . . . . . . Hypercoagula ble States Lymphopenia Monocytosis . . . . . . . . . . . . . . . . . Neutropenia Neutrophilia . . . . . . Pa ncytopenia . . . . . . . . . . Throm botic Thrombocytopenic Throm bocytopenia . . . . . . . Thrombocytosis .. . . . . . . . . Tra nsfusion Reactions

. . . . . . .

60 61

. . . . . . .

63 65 66 68 70 71 73 75 76 77 80 81

. . . . . . . . . . . . . . . . . . . . . . . . Purpura . . . . . .

IV. Infectious Disease Clin ical Symptoms and Signs Fever of Un known Origin . . . . . Infections Causing Splenomegaly . . . Temperature/Pulse Dissociation . . Clinical Conditions or Diagnoses Acute Men ing itis . . . . AI DS/ Human I m m unodeficiency Virus Immu nodeficiency States Rheumatic Fever . . . . . . . . . . . Sexually Tra nsmitted Diseases .

.

.

.

.

.

.

.

.

.

.

V. Cardiology Clinical Symptoms and Signs Syncope . . . . . . . . . . . . . . . . . Clinical Conditions or Diagnoses Arrhyth mia Atrial Fi bril lation . . Congestive Heart Failure Hypotension Pericarditis . . . Restrictive Cardiac Disease VI. Endocrinology . . . . . . . . General Considerations Pituitary/Hypotha lamus Cli nical Symptoms and Signs Amenorrhea . . . . . . . . . . . . Gynecomastia Hirsutism . . . . . . . . . . vi •

Contents

.

.

.

. . . .

. . . .

. . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

83

. . .... . . . . . .

83 85 86

. . . . . . . . . . . . . . . . . . . . . . .

87 89 91 92 93

.

97 97 100 10 1 1 02 1 04 1 05 1 07 1 09 109 11 1 113 114

--

Cli nica l Conditions or Diagnoses Adrenal I nsufficiency . . . . . . . . . . . . Carcinoid Tumors .' . . . Hypercalcemia . . . . . . . . . . . . . . . Hyperphosphatemia Hyperprolacti nemia . . . . .. . . . . . . Hyperthyroidism . . . . . . . Hypoca lcemia Hypoglycemia . . . . . . . . . . . . . . . . Hypophosphatemia . . . . . . . Syndrome of I nappropriate Antidiuretic .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

VI I . Nephrology . . . . . . . General Considerations Cli nical Symptoms and Signs Edema . . . . . . . . . Hematuria . Hypertension . . . . . . . . . . Clinical Conditions or Diag noses Hyperka lemia . . Hypernatremia . Hypoka lemia . . . . . . . . . . Hyponatremia . . . . . . . . Neph rotic Syndrome . Renal Fa ilure . . . . . . Renal Stones

.

.

.

.

.

.

.

.

.

.

.

.

.

.

. . . . . .

.

. .

.

.

. . . . . . .

.

.

.

.

.

.

. . . .

.

.

.

.

.

.

.

.

.

.

.

. . . . . . . . . . . . . . . . . . . . . . . . Hormone secretion

.

.

.

.

.

131

.

. . . . . . . . . . . . . . . . . . . . . . . . . .

1 33 1 34 136

.

.

. . . . . . . .

.

.

.

.

. . . . . . . . . . . . . . . . . . . . . . . . . .

VI I I . Acid-Base General Considerations Arterial Blood Gas Interpretation . . . . . . . . . . . . . Clinical Conditions and Diagnoses Meta bolic Acidosis with a High Anioll Gap . . . Meta bolic Acidosis with a Normal Anion Gap . . . . . . . Low Anion Gap . . Meta bolic Alkalosis . . . . . . . . . . . . . . . . . . . . . Respi ratory Acidosis Respiratory Alkalosis .

.

.

.

.

.

.

.

.

.

.

.

1 38 1 40 1 43 1 46 1 49 1 50 152 1 55 1 55

. . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

.

IX. Gastroenterology .

Clinical Symptoms and Signs Abdom inal Pa in . . . . Dia rrhea . . . . . . Dysphagia . . . . . . . . . Hepatomega ly . . . Jaundice . . Nausea and Vom iting . .

1 16 1 17 1 19 1 20 1 21 1 22 1 24 1 25 1 27 129

1 60 1 63 165 166 167 1 68 1 69

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

.

.

.

. . . . . . Contents

.

]69 1 73 1 76 178 179 18 1 • vii

Clinical Conditions or Diagnoses Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 83 .

X. Rheumatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Clinical Symptoms and Signs Acute Monoarthritis . . . . . . . . . . . . . . . . . . . . . . . Inflammatory Polyarth ritis . . . . . . . . . . . . . . . . . . . Clinical Conditions or Diagnoses Calcium Pyrophosphate Di hydrate Deposition Disease CREST Syndrome . . . . . . . . . . . . . . . . . . . . . . . . Osteoa rthritis . . . Rheumatoid Arthritis . . . . . . . . System ic Sclerosis (Scleroderma) . . . . . . . . . . . . . . Systemic Lupus E rythematosus . . . . . . . . . . . . . . . . Vasculitis . Wegener's Granulomatosis . . . . . . .

.

.

.

.

.

.

XI. Neurology . . . . . . . . . . . .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

,

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

XII. Appendix . . . . . . . . . . . . . . . . . . . Acronym Dictionary viii •

Contents

.

.

.

.

.

.

.

.

.

.

.

.

.

1 87

. . . . . . . . . . 1 87 1 88 . . . . . . . . . .

. . . . . . . . . . . . . . . . . . .

.

.

.

.

.

.

.

.

.

.

. . . . . . . . . . . . . . . . . .

.

.

.

.

.

.

. . . . . . . . .

.

191 1 92 1 93 1 95 1 97 1 98 1 99 20 1 203

.

General Considerations How To Make a Broad Differential Diagnosis How To Make a "Working" Differential Diagnosis How To Do a Good Neurologic Exam ination . . Neurologic Exam ination Summa ry . Clinical Symptoms and Signs Altered Mental Status . . . . Ataxia . Autonomic Disorders Di plopia . . . . . . . Dizziness . . . . . . . . . . . . . . . . . . . . . . . . . . Headache . . . . . . . . Loss of Consciousness . Monocular Visual Loss Ptosis . . . . . . . Rig idity Tremor . . Weakness . . . . . . . . . Cl inical Conditions or Diagnoses Dementia . . . . Myelopathy . . . Neuropathy . . . . . . . . . . . . . . . . . . . . . . Seizure . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stroke . . . . . . . . . . . . . Neurology Glossary . . . . . .

.

.

.

. . . . . . . . . . . . . . . . . . . . . . .

.

.

.

.

.

.

.

.

.

.

.

.

203 204 207 213

215 218 222 . . . . . . . . . . 223 . . . . . . . . .. . . 226 229 . 233 237 239 24 1 243 246 .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

. .

.

.

.

.

.

.

.

.

.

.

. .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

249 25 1 253 259 262 267 271

-

PREFACE Generating a useful and complete differential diag nosis is a keystone of clinical medicine. Many texts exist which provide exhaustive lists of possible diagnoses for a particu lar com plaint. It is refining such lists into useful d ifferentials that is part of the "art" of med icine. Memorizi ng lists of diagnoses can be a daunting task, and a d ry one at that. By using mnemon ics as a framework, we wish to make learning differential d iagnoses more palatable and even enjoya ble. In ad. dition, we present an organizational a pproach to differential d iag nosis that is practical and easily learned . The mnemon ics presented here range from concise lists that may be committed to memory aher the first read, to more lengthy, com­ prehensive listings that can be looked up when needed . In al most all cases, the mnemonics themselves spell out something that refers to the symptom or diagno­ sis, increasing the l i kelihood of remembering it. Throughout a student's medical education, he or she receives countless little tips or "pearls" that a re of im mense practical worth but are ohen difficult to look up in the Iypical medical textbook . After each m nemon ic, we have i ncluded many pearls that refer to the symptom or condition descri bed . Some of these tips are j ust one-l i ners; others are small tables or outl i nes that help organ ize com­ monly referenced i nformation . We hope you find this to be a useful handbook that provides a sound organ­ i zational framework for a pproa c h i n g d i fferential d ia g noses. The m nemonic . format necessa rily led to some creative listi ngs, which should be easily remem­ bered as well as amusing . We welcome any suggestions or new m nemonics from our readers. Tom Don nelly Chris Giza

Preface.

ix

-

a

INTRODUCTION The purpose of this book is to help med ical students and clinicians form com pre­ hensive d ifferential d i a g noses for common i nternal med icine a nd neurology problems. It is an aid for organ izing diag nostic poss ibil ities qu ickly and effec­ tively in clinical situations. A number of excellent references provide comprehensive l ists of d ifferential diagnoses. This book was created with a similar pu rpose in mind, but we pre­ sent an a pproach based on mnemonics. The mnemonics are i ntended to pro­ vide simple fra meworks on which to construct differentia l diag noses . They a re not i ntended to be the sole source of i nformation, and pri mary texts should be read to fully understand d isease pathogenesis. It is doubtful that anyone can re­ mem ber every mnemonic i n this book. We hope that those for commonly en­ countered problems will be reta i ned ; the others can be referenced shou l d a particular problem a rise. Most students and residents are fa miliar with nu merous disease processes, but have difficu lty g iving an exhaustive d ifferential diagnosis from memory for a particular clinical entity. This problem often stems from the lack of a n organiza­ tiona l framework. Once d ifferential d iagnoses a re considered in terms of "cate­ gories" of i l l ness, they a re much easier to com plete . We have attem pted to identi fy a wide variety of clin ical scenarios and organize a d ifferential d iagno­ sis for each. Some entities a re common, such as anemia or renal failure, while others are more specialized, such as refractory hypotension. Having a complete list of possible diagnoses at the outset will lead to the correct diagnosis even in the most complex cases. Th is a pp roach encourages thorough ness i n eva l ua­ tions, so that d iag noses a re not missed . The mnemon ics range in length depending on the clin ical entity. Sometimes more than one has been included for brevity or organizational reasons. The best m nemon ics a re concise, perti nent words or ph rases constructed to reflect the pathogenesis of the problem. Others a re no more than sim ple words that help in remembering a list of possibilities . An explanatory section is included with each mnemonic to review pathogenesis or provide helpful i nformation . Some com­ monly used m nemon ics (a uthors generally u n known) are i ncl uded in deference to their history or for lack of a better replacement. F i nally, please forgive a ny "artistic" license taken in the creation of these m nemonics.

Introduction •

1 i

H ow to Use This Book The chapters are divided by organ system and presented with a common organi­ zational theme. A "General Considerations" section starts some chapters to pro­ vide an overview of differential diagnosis and clinical assessment pertinent to that particular system . Specific mnemonics, which are divided i nto two sections, follow. The first section , "Clinica l Symptoms and Sig ns, " l ists mnemon ics that refer to specific clinical complaints by the patient (e. g . , cough, headache), or to particular clinical signs detectable on careful physical exami nation (e. g . , jaundice, ataxia) . The second mnemonic section, "Clinical Cond itions and Diagnoses," lists d iffer­ ential diagnoses for clin icol conditions detected through the use of various d iag­ nostic tests (such as thrombocytopenia, hypernatremia), general mnemonics for broad diagnoses (e.g . , sexually transm itted disease, pneumothorax), and specific mnemonics that refer to a pa rticular d isorder (such as rheumatoid arthritis, AIDS). Thus, the first section is i ntended to help i n making a differential diagnosis list based primarily on the chief complaint or a significant clinical sign, aher the initial history and physica l . The second section is a i med at generati ng more specific differentials based u pon initial diagnostic testi ng and careful consideration of the overall clinical syndrome. Each section is listed alphabetically for ease of reference.

G eneral Approach to Differential Diag noses The d ifferential diagnosis for any medical problem can be thought of i n terms of categories of d isegse. The mnemon ic "MEDICINE DOC" may be used as a general a pproach to a ny patient: Meta bolic disease (e. g . , nutritional deficiency, dysli pidemias, porphyria) Endocrine disease (thyroid disease, diabetes) Drugs/ med ici nes (iatrogenic, accidental, self-administered) I n fections (e . g . , bacteria l , viral, fu ngal, mycobacterial, protozoa l , hel mi nthic) Congen ital a bnormalities (inherited a natom ic, immunologic and metabol ic disorders) Immunologic disease (collagen vascular diseases, asthma, acqui red immunodeficiency) Neoplasms (e. g . , primary, metastatic, paraneoplastic) Exotic ( "strange" diseases of unknown etiology such as sarcoid, histiocytosis X) Degenerative processes (e. g . , Alzheimer's, a myotrophic lateral sclerosis) Occu pational!envi ronmental exposures (e.g . , asbestos, hypersensitivity, trauma) Cardiovascular d iseases (e.g . , arrhythmias, atherosclerosis, pulmonary em­ bolus, congestive heart failure) 2 • Introduction

This list includes the primary etiologies for most medical problems. There is, of course, some overlap between categories: atherosclerosis i s both a cardio­ vascular and metabolic disease; both i nfections and collagen vascular diseases may cause ca rdiovascular disease; many of the "exotic diseases" may have an i m m u nolog ic basis, a n d many i m m unologic di seases are exotic. The redun­ dancy is necessary, however, si nce some entities a re difficult to classify or may be forgotten if a framework based solely on pathogenesis is used. For exam ple; where does one classify arrhyth mias or pulmonary embolus? Both a re common entities that have many causes. The cardiovascula� category helps you to re­ member these com mon problems in u nusual presentations. When faced with any clinical problem, you can use either the MEDICINE DOC m nemonic or another, more specific m nemonic to develop a differential diagnosis. For exa m ple, if a patient has renal fa ilure, you can construct a differ­ ential based on the categories in MEDICINE DOC or use the specific "I C HASE A RISING BUN," which lists specific ca uses of renal fa ilure: Pre-renal Intravascular vol ume depletion (dehydration, th ird spacing) Cardiac ca uses (CHF, MI, tamponade) Hepatorenal syndrome Arterial disease ( renal artery stenosis) Shock 'Eclampsia/obstetrical compl ications Pre-renal/Renal Acute tubular necrosis ( "ATN" in a sense, both " pre-" and "renal" in etiology) Renal Radiographic contrast and other toxi ns (drugs, rhabdomyolysis, hemolysis) I ntrarenal emboli (cholesterol, DIC) Scleroderma Interstitial nephritis Necrotizing vascul itis (polyarteritis nodosa , Wegener's) Glomerulonephritis Post-renal Bladder obstruction (usually prostatism, sometimes blood, pus, calcul i ) Ureteral obstruction (calcul i , retroperitoneal fi brosis, cancer) Necrosis of renal pa p i l lae (dia betes, sickle cell a nemia, NSAID a buse, i nfection) The two approaches provide fairly comprehensive lists of possibil ities, and there a re strengths and weaknesses for both . MEDICIN E DOC a l lows broad classification of disease processes, while I C HASE A RISING BUN l i sts spe­ cific causes of rena l fa ilure a n d organ izes them in p re-rena l , ren a l , a n d post­ renal categories . It is helpful to look at medical problems using both types of approach .

Introduction • 3

� inking About Differential Diagnoses Two thought processes are helpful in a pproaching differential d iag noses 1 . What is the most l i kely d iagnosis? This "gestalt" approach involves look­ ing at the entire picture first and form ulati ng a hypothesis to explain it. After re­ viewing a l l the data for a case, decide which d i agnosis is most l i kely. The th inking process from this point focuses on proving or disproving the hypothesis. This a pproach is helpful for more simple cases, although most clin icians use it to some extent i n all cases. Pay careful attention to a ny aspects that are i nconsis­ tent with the presum ptive diagnosis and be able to account for them . Avoid be­

coming fix,ated on a diagnosis and ignoring data that do not support it,

2 . What are the patient's problems? This a pproach focuses on the "pa rts" or individual aspects of the case. list all of the patient's problems and consider a d if­ ferential d iagnosis for each. Then, attempt to formulate a u nifying diag nosis that explains the data, creating a whole from the parts. This techn ique is helpful when faced with complex cases featuring multiple symptoms and large amounts of data. The m nemonic a pproach to differential diagnosis em phasizes sta rting with a com plete list of possibilities. Certain entities on the l ist wi l l be very uncommon and unl ikely in most circumstances, Common entities a re considered in the i n itial d ifferential diag nosis of a problem , but other aspects of 'a particu lar patient's case may di rect the work-up to more unusual entities. This approach is appropri­ ate as long as you do not ignore features that may be i nconsistent with the pre­ sumed diagnosis. Another a pproach to defi ning a long list of d iag nostic possibi l ities is to de­ velop a second or perhaps even a third list based on a second sign or symptom of the patient. If you assu me that the man ifestations of the d isease in question are secondary to one process, then you can limit the number of possibi lities by only pursu ing diag noses that a re on both l ists. Be careful using this a pproach, because patients may have more than one disease process at work, and impor­ tant diagnostic considerations may be eli m i nated prematurely. Aga i n , it is criti­ cal to always refer back to the com plete list of differential d iagnostic possibilities when all the features of a case do not add up to a coherent picture. Sources of Error in Differential Diagnosis

Decision ana lysis is a process that attempts to classify errors in medical rea­ soning, with the goal of i mproving the accuracy of differential diag nosis and en­ suring that a critical diag nosis is not m i ssed , Althoug h controversy exists i n a pplying decision analysis to clinical settings, i t i s worthwh ile to understa nd the sources of error. One a pproach focuses on fi rst outlin ing the basic steps in ar­ riving at a presum ptive diag nosis a nd then classifyi ng errors accord i n g to where they occur in those basic steps. The basic steps are: 1 , Triggering determ ining a d iagnostic possibil ity based on patient i nfor­ mation . -

4

• Introduction

-

2. Framing-establish ing the context within which the problem will be solved . 3 . Gathering a n d processi ng - reviewi ng a n d i nterpreting d iag nostic data ; selecting and d iscarding possible diagnoses 4 . Verifi cation - reaching a final diagnosis, the one that best fits all of the data . Errors occur at each of these steps: Triggeri ng errors may result from a lack of knowledge and associations . Consider the exa mple of a renal fa i lu re patient in whom hypotension develops shortly after beginning dialysis. Some clinicians may consider sepsis or hemor­ rhage (which a re plausi ble) , but most neph rolog ists would i m med iately th i n k of a perica rd. ial effusion and tamponade as being m uch more likely Triggering is an associative process that comes with experience . Framing errors occur when you do not th ink broadly enough i n considering the cause of a patient's problem . For exa mple, a patient with recurrent a bdomi­ nal pa in secondary to hyperca lcemia may undergo a n extensive gastroi ntesti nal work-up because the d ifferential d iag nosis of a bdominal discomfort was not framed broadly enough to i nclude metabolic or systemic disorders . This type of error demonstrates the importance of having a com plete list of diagnostic possibili­ ties prior to embarking on an extensive work-up. It also shows the value of framing the differential diagnosis i n two or more contexts (i e . , MEDIC I N E DOC and a mnemonic for a bdominal pa i n ) and then looking at the " i ntersection" of the sets . Broad framing and framing in mu ltiple contexts may decrease framing errors. Gathering and processing errors result from m isi nterpreting test results, not understanding the sensitivity or specificity of a test, or not knowing a particu lar disease preva lence or li kelihood i n a given patient. For exam ple, a slightly ele­ vated u rinary catechola m i ne in a 75-year-old patient with severe hypertension may lead a clinician to pursue a diagnosis of pheochromocytoma , even though this is a rare disease. It is much more l i kely that the catechola mine result is false positive, and the test probably should not have been ordered in the initial evalu­ ation of this patient. I ntrinsic renal d isease or renovascular d isease should be i n­ vestigated fi rst in this type of patient before looking for more un usual diag noses. (See "Other Sources of Diag nostic Error�' on the next page for additional d iscus­ sion of proba bil istic thinking . ) Verifi cation errors occur when some data supporting a particular diag nosis are obtai ned , and the patient is then assumed to have that diagnosis, even when other, contradictory data subsequently become available. Failing to account for all aspects of a case and inappropriately adhering to a presum ptive diagnOSis re­ sults i n premature closure. Consider a woman with fever, rash , anem ia, renal i n­ sufficiency, and a positive antin uclea r anti body test suggesting the diagnosis of systemic l upus erythematosus (SLE) If this patient also had a heart murmur and a negative double-stranded DNA test, these features are less easily explained by a simple d iagnosis of SLE (although not impossible). Presumptive immunosuppressive therapy of this patient for a d iag nosis of SLE cou ld be hazardous if the patient rea lly has subacute bacterial endocard itis as the cause of her m ultiple problems. There also a re "no-fault" errors. These occur when the patient's findings are highly atypical for the underlying disease, or the disease is extremely uncommon. Introduction • 5

An example of this type of error occurred when a young woman on birth con­ trol pills presented with dyspnea, chest pa i n , and a h i g h-probability V /Q sca n . Most clin icians would proba bly i n itiate a nticoagulation , as was done i n

this case, given this constellation o f findings. Subsequently, however, the pa­ tie nt develo ped card i ac ta m ponade d ue to hemorrh a g i c perica rd itis ( h e r actual problem) and h a d a prolonged i ntensive care course as a result o f the a n ticoagulation . An a rteriog ra m demonstrated a congenitally stenosed pul­ monary a rtery su bseg ment, which expla i ned the h ig h-proba bility V/Q sca n . This type of error i s unfortunate but, i n some cases, u navoida ble . N o matter how well we perform our duties, errors will occu r. This exa mple points to the fact that you must continue to be vigilant even when a diagnosis seems as­ sured. Note that p remature closure, a lthoug h u ndersta nd a b le in this case, was to the patient's detriment. The Importance of Probability in Differential Diagnosis

When evaluating the data as they apply to a list of diagnostic possibilities, it is helpful to consider probabilities. Always question : 1. How common is the diseaseq 2 . How common is the d isease in the relevant population , i . e. in the par­ ticu lar patient being eval uated2 3 . How com mon is a pa rticular symptom, sign, or la boratory result in the disease bei ng consideredq As you prog ress in medical education and gain fa miliarity with different dis­ eases, these questions become easier to answer. Baye's theorem is a mathemat­ ical relationship that can be helpful in assessing the proba bil ity of one disease versus another, g iven a particular find ing. Probabil ities can be calculated based on Baye's rule, which states that the l i keli hood of a disease in a patient with a g iven set of findings can be esti mated as the proportion of patients with the same findi ngs who also have the d isease. For example, the likeli hood of pneu­ monia in a person with fever, cough, and sputum is estimated by d ivid ing the n umber of people with fever, coug h , sputum , and pneumonia by the num ber of people with fever, coug h , and sputu m . The actual mathematica l calculation is complex, and there a re many criticisms of this type of ana lytical approach, but a few simple and useful poi nts can be offered : • Have a general idea of the prevalence a nd common symptoms of a particular disease. For exa mple, a young woman with fever, sweating, anxiety, tachycard ia, and hypertension may have a pheochromocytoma , but hyperthy­ roidism also is possible . The above symptoms are characteristic of both disorders; however, hyperthyroidism is much more likely to be the cause because it is more commo n . The find ing of exophthal mos may be seen in Grave's disease, but would not be cha racteristic of pheoch romocytoma , aga in pointing toward hy­ perthyroidism as the more likely cause. An evaluation a i med at hyperthyroidism, while keeping pheochromocytoma "on the back burner, " would be a ppropriate in this instance. Also, in the above setti ng, you should consider an anxiety disor­ der (even more common) as a possible cause of the patient's symptoms. 6 • Introduction

• The more specific a find ing is, the more helpful it wi ll be in establ ishing a l ist of l i kely diagnoses . Select one or two pivotal fi ndi ngs ( " pivots " ) of a pa­ tient's case for consideration of the differential diag nosis. Hypercalcemia, for ex­ a m pl e , is a good pivot because it has a fa i rly we l l-defi ned list of causes . Clubbing also might be helpful as its list of diag nostic possibil ities is rather l i m­ ited . Entities such as chest pa in or fatigue are more problematic because they are nonspecific and can occur in a large number of diseases . • When considering diagnostic possibilities, it is perhaps best to compare one symptom or finding (pivot) across multiple diseases, instead of seeking several sym ptoms or findi ngs for a single d isease This step-wise l i m itation of data analysis keeps the proba bil ities of a specific find ing in a specific d isease in the forefront. The difficu lty of this approach is the lack of specific data for the incidence and preva lence of signs and symptoms in specific d iseases. Also, the most proba ble d iagnosis based on one sym ptom may not be the most l i kely after all the data a re considered . The step-wise consideration of single pivots is mea nt to enhance, rather than replace, good cli nical judgment.

Other Sources of Diagnostic Error • Giving equal weight to pdsitive and negative findings. Often we focus on a positive la boratory test result and pursue a diagnosis based on it. Before giving too much weight to a positive resu lt, pay attention to a bsent su pportive el­ ements . This aspect of probabil istic reasoning often is neg lected . • Using the first informatian that comes to mind. This source of error has been termed the "availability heuristic . " An example is the i m mediate considera­ tion of myoca rdial infa rction as a possible diag nosis when a patient presents with ·chest pai n to the emergency room; pericarditis or pulmonary embolism may not come to mind as readily These latter d iag noses may not be considered ini­ tia lly, and the evaluation and treatment may be misd irected . • Laoking for evidence that supports an early worki ng hypothesis and ignoring contradictory data . An exam ple of this so-cal led confirmation bias is

seeking ischem ic changes on the EKG of a patient with chest pa in, while ignor­ ing more d iffuse cha nges which may be suggestive of perica rd itis.

• Believing in the chosen course of action and favoring evidence that supports it. Physicians may become too invested in a d iag nosis and conti nue

down the wrong pathway in pursuit because of overconfidence. Summary ofTypes of Errors

Triggering errors Framing errors Gathering and processing errors Verification errors No-fa ult errors Premature closure

Not giving equal weight to positive and negative findings The availability heuristic Confirmation bias Overconfidence/overreliance on a method or dogma

In troduction • 7

Ways to Avoid Errors

1. 2. 3 4.

Carefully compile information Pick one or two " pivots " Have a complete differential diagnosis for each pivot. Have at least a general sense of the prevalence of the disease in a g iven population and in the releva nt population for the patient being considered . 5 Have a general idea of the prevalence of a symptom in a particular disease. 6. Do not discard contradictory data when it becomes available. A careful accounting of unexplained aspects of the case is essentia l . 7 . Pay attention to what is not present, i . e , negative find ings . 8 . Know that differential d iag nosis is an im perfect science: You are fallible. The unexpected , unlikely, or atypical may occur.

f?e senting and Discussing Cases A few words a re i n order regarding case presentation and discussion . Case conferences a re inva lua ble teaching exercises. Lea rning to present cases in a concise and orderly man ner teaches the princi ples of differential d iag nosis. Case presentation em phasizes organ ization of data . Case discussion employs critical th inking and organization of diagnostic possibilities. Case Presentation

The key to case presentation is breVity. The traditional " H and P" (h istory and physica l) format is the best framework for discussion. Begin with a chief complaint (why the patient came for medical attention) and then proceed with an orga nized h istory and physica l exa m . The h istory should be d iscussed i n chronolog ical order to avoid confusion. Patients who have been il l for a long time or have been transferred from another hospital typically have extensive and complex his­ tories . It is the duty of the presenter to avoid overly long discussions of previous work-ups or presum ptive diagnoses. Focus on the essential features of the case. Tips on Presentation •

• •

•

Be brief and be thorough You shou ld be able to present most cases com­ pletely in 5 minutes or less. Even the most complex cases can be sum ma­ rized effectively in a brief presentation. Present the case in chronological order. Avoid cl uttering the h istory with laboratory resu lts, previous work-ups, or other physicians' presum ptive d iag noses. Follow the trad itional "H and P" format a . Chief complaint b. History of present ill ness

8 • In troduction

-

c. Past med ical history d. Med ications e. Fam ily history 1. Social h istory g Review of systems (brief) h. Physical exam • Focus on pertinent positive and negative elements. It usually is best, for the sake of teach ing, to omit laboratory resu lts from the i n itial presentation . This om ission emphasizes the i m portance of a careful clini­ cal eva luation to guide the ordering of laboratory tests . Sometimes the incl usion of la boratory tests is unavoidable since it may be the reason for adm ission or re­ ferral (e . g . , anemia). I n most cases, however, it is best to fi rst consider diagnos­ tic possibil ities and then ana lyze appropriately focused diag nostic testi n g . Note that a thorough h istory a n d physical examination should be performed on every patient, and the presenter should be prepa red to prOVide any informa­ tion if it is requested . However, an exha ustive list of all negative findings is un­ necessary. Describing a Symptom

When considering the differential diagnosis of a patient's sym ptom or chief complaint, it is essential to obtain a thorough history and accurately describe the problem . Ma ny com plai nts , such as chest or abdom inal pa i n , have nu merous causes, and a more specific description is req u i red to d i rect the work-u p . Consider the m nemon ic "COMPLAINS" : Compla int-what is the problem? Onset -when did it begin? Magn itude- how severe is it? Pattern - episodic? crescendo, decrescendo? constant? Location -where is it? does it radiate? Associated symptoms - are any other symptoms tempora l ly related to the complai nt? Im provements - what makes it better? Negative sti mul i -what makes it worse2 Simila r episodes in the past - has it ever ha ppened before2 Obtain ing these descri ptive features may reveal the cause of a sympto m . Consider the complaint of chest pa in: Compla int- chest pa in Onset- began 2 hours ago Magn itude- 1O/ 1 0 Pattern -crescendo, crush ing Location -substernal location radiating to the jaw and left a rm Associated symptoms - shortness of breath, diaphoresis, anxiety Improvements - rest, nitroglycerin Negative sti m u l i - exertion Similar episodes in the past- 5 years ago before coronary artery bypass grah In troduction • 9

Chest pa in has myriad causes, but the above h istory strongly points to angina . Consider a different set of featu res for chest pain Compla int- chest pain Onset- began 6 hours ago Magnitude- 1 0/ 1 0 Pattern - constant, sharp Location - su bsterna I location, nonrad iati ng Associated symptoms - i nabil ity to take a deep breath Im provements -sitting-up, leaning forward Negative stimuli - lyi ng flat Similar episodes in the past- no prior history In this instance, the chest pa in features a re suggestive of pericardial pa i n , and a different l ist of diagnostic possibilities should be considered . Case Discussion

1. Beg i n with a summary statement. After l i stening to the case, g ive a one-sentence s u m m a ry of the case . For exa m ple: "The case concerns a 44yea r-old male with a h i story of poorly control led d ia betes and i ntrave nous d rug a buse who presents with a 2-day h i story of fever, ras h , a nd decreasing u rine output . " The summary statement is a "gestalt, " or overa l l i m pression , of the case . It is helpful because a presentation often suggests a l i kely d iagno. sis, and the d i scussion can focus on provi ng or dis proving this presu m ptive d iagnos is. 2. N ext, make a problem list of the major cu rrent and past problems. I n the above example, a problem l ist could include: Fever Rash Decreasing urine output History of dia betes History of intravenous drug abuse 3 . Construct the differential diagnosis framework based on the categories of disease or by using m nemonics for specific entities on the problem l ist. 4. Na rrow the d iagnostic possibilities based on the h istory and physical exa m . 5 . Request specific la boratory o r imaging tests t o further na rrow down the diag nostic possibilities. Specific m nemonics may be used to consider the differ­ ential d iag nosis for certain la boratory abnormal ities . When new data is not consistent with the diseases being considered, always return to the original, complete differential to reconsider diagnostic possibilities. 6. Summa rize the data and prioritize diagnostic possibil ities.

1 0 • In troduction

»

III

PULMONARY AND CRITICAL CARE General Considerations

G eneral Approach to Pulmonary Disease Many d isorders have pulmona ry manifestations, and chest symptoms a re fre­ q uently the fi rst noticed by the patient (e . g . , cou g h , wheezi n g , shortness of breath) . The lung is a common "ta rget" organ for infection, drug toxicity, cardio­ vascular com promise, i m m u nologic disease, and neoplastic processes. I n ap­ proaching the patient with thoracic disease, think of the more common categories of illness, such as infection, neoplasm , toxic exposures, and cardiovascular dis­ ease. Also i m portant, but less common, a re the immunologic and "exotic" cate­ gories of disease, a mong which there is considerable overla p. Other categories of illness such as endocrine or metabolic diseases have less d i rect pul monary in­ volvement. We can apply the m nemonic "ME DICINE DOC": Metabolic (e.g . , a myloidosis, a lpha- l -antitrypsin deficiency) Endocrine (para neoplastic syndromes, neuroendocrine cell hyperplasia) Drugs/medici nes (e.g . , nitrofurantoi n , am iodarone, chemotherapy toxicity) Infection (e. g . , H IV-related , TB, bacterial pneumonia) Congenital (e . g . , bronchogenic cysts, Kartagener's, cystic fibrosis) I m munologic (e . g . , Goodpasture's, rheumatoid lung, asthma, BOOP, PIE) Neoplastic (primary lung, pleural and mediastinal tumors, metastatic disease) Exotic d i seases (e . g . , sarcoi d , eosi noph ilic g ra n u loma, LAM, interstitial d iseases) Degenerative (e.g . , COPD?, degenerative neuromuscular disease [ALS]) Occupational/environmental (e.g . , smoking, asbestosis, hypersensitivity) Cardiovascular (e . g . , PE, edema from CHF, VOD, pulmonary hypertension) Metabolic disorders cause multi-system disease, but the lung and chest usually a re not prominently i nvolved . Amyloidosis (also "exotic" and immunologic) may Pulmonary and Critical Care . 1 1

rarely present as parenchymal or vascular lung disease. Alpha- l -antitrypsin defi­ ciency ohen leads to em physema, especia lly in young smokers, and also cou ld be classified as an i nherited disorder. In addition, the lungs may be affected by ongoing metabol ic processes, such as pu lmonary edema from u remia or tachyp­ nea (Kussmaul breath ing) from diabetic ketoacidosis. The lung has little known endocrine function and so this category usually is not helpful i n formu lati ng d ifferential diag noses for chest disease. Lung cancer, pa rticula rly small cel l carcinoma, can cause para neoplastic syndromes such as SIADH and Cush ing's syndrome. Myxedema may be associated with pleural ef­ fusions. The rare entity of neu roendocrine cell hyperplasia may present as chronic obstructive lung disease. Drugs can cause hypersensitivity reactions. Exa mples include nitrofu rantoin and phenytoin . Also, certa i n chemothera peutic agents have wel l-known pul­ monary toxicities (methotrexate, cytoxa n , bleomyc i n , BC N U ) Amiodarone ca uses p u l monary fibrosis as well as other types of lung i n j u ry. I ntravenous d rug a b use and coca i n e a buse may ha ve a c ute a n d c h ron i c p u l m o n a ry manifestations . I n fectious processes of many types can involve the lungs - either prima rily, as in loba r bacterial pneumonia, or as part of a dissemi nated infection , such as asperg illosis in immunocomprom ised patients. Viruses, mycobacteria, hel minths, and other parasites ca n all cause pulmonary pathology. Certa i n infectious agents may be specifica l ly associated with chronic diseases, such as PC P in AIDS, or Bu rkholderia in cystic fibrosis. The category of congen ital lung d isorders i nc l udes a natomic, i m m u no­ logic, and metabolic abnormal ities. Anatomic disorders i nclude bronchogenic cysts, sequestration , and dysmotile cilia syndrome. Immu nodeficiency syndromes such as immunog lobulin deficiency or functional neutrophil disorders characteris­ tically present with recurrent si nopulmonary i nfections . Alpha-l-a ntitrypsin defi­ ciency pred isposes patients to panlobu lar em physem a . Cystic fi brosis is a com mon i n herited disease with prominent pulmonary involvement i ncluding bronchiectasis, chronic i nfections, and fi brotic changes . Immunologic disease may affect the lu ngs specifical ly, as in asthma, or pul­ mona ry i nvolvement may be only a part of a more widespread i m m u nologic process such as Goodpasture's or Wegener's. Virtually all collagen vascular dis­ eases can i nvolve the respiratory system. Exam ples include pulmonary fibrosis i n scleroderma, l u n g nodules in rheumatoid a rthritis, pleural effusions in SLE, a n d tracheal collapse in rela psing polychondritis. Neuroimmu nologic d isorders such as myasthen ia g ravis and Gu illa in-Ba rre may lead to respiratory muscle fa ilure. Tropical eosinoph ilia represents an immunolog ic response to the i nfectious agent filaria, and is treated with the a nti-fi larial agent d iethylca rbamazine. Allergic bronchopulmonary asperg il losis is another exa m ple of an infectious agent elicit­ ing an i ntense i nfla m matory response . Treatment is primari ly d i rected at modify­ ing the host response with steroids. Neoplastic disease may arise primarily in the lungs or metastasize from a d istant cancer. Neoplasms in other thoracic structures also can affect pulmonary function (e. g . , pleura l tumors, compression of a irways from lym ph nodes). 12 • Pulmonary and Critical Care

-

N umerous exotic conditions affect the lungs, i ncluding h istiocytosis X, sar­ coidos is, Iymphang ioleiomyomatosis, and eosinophilic lung d isease. Many of these diseases are thought to have an immu nologic basis. Degenerative diseases may ca use pul monary symptomatology secondari ly, as is the case with neuromuscu lar d isorders such as ALS . These disorders can lead to swa l lowi ng dysfu nction and aspiration or respiratory fa i l u re . Severe kyphoscoliosis can lead to a restrictive ventilatory defect. Emphysema also could be considered degenerative. I n normal aging, lung function slowly decli nes and is thus degenerative. In the category of occupational and environmental exposures, smoki ng-re­ lated lung d isease is very common Other agents that can cause lung disease are leg ion and i n cl ude asbestos, s i l i ca, coa l d ust, and beryl l i u m . Hyper­ sensitivity reactions include farmer's lung, bird-fa ncier's lung, and nu merous other entities Tra uma may lead to hemorrhage, pneumothorax, lung contusion , o r ini ury to other i ntrathoracic structures. Cardiovascular diseases may i nvolve the lu ngs secondari ly, ca using pul­ monary infiltrates and pul monary hypertenSio n . Abnorma l ities of the heart and aorta are i m portant considerations i n thoracic d isease. The vascul itides (classi­ fied under i m m u nologic d isease) and pulmonary veno-occl usive d iseases a re more rare. Pul monary embolism is very com mon, u nderd iag nosed, and may be insidious. The presentations of pulmonary embolism are myriad, and the dis­

order should be considered in the d ifferential for most thoracic problems.

G eneral Approach to Cri t i c al Care Medicine The care of critica lly i l l patients i s complex a n d requires a n organ ized a pproach for managing m u lti-system disease . Consider the m nemonic "MICU'S LIFE GOALS " : Med ications/ prophylaxis Invasions Cardiovascular Uri ne/renal Ski n/decubitis care Lu ngs Infectious disease F l uids/electrolytes/ nutrition Endocrine Gastroi ntestina l/l iver Oncolog ic/hematolog ic Analgesia/ neurologic Long-term prognosis Social/family Pulmonary and Critical Care • 13

--

Many of these patients are on numerous medications which may cause side effects such os fever, rash, and cytopenias Carefully review the patient's medi­ ci nes dai ly, with an eye towa rd disconti nuing unnecessa ry agents. Consider all hospitalized patients for some type of DVT prophylaxis, especial ly ICU patients. Many patients should be considered for stress ulcer/gastritis prophylaxis, as wel l . I nvasive procedures and i n-dwel l i ng l i nes and catheters a re common i n the ICU. These i nvasions, while often necessary, a re sou rces of iatrogenic compli­ cations, especially i nfection, and should be discontinued as soon as possi ble. A systematic approach i s then used to add ress the patie nt's problems : cardiac (e . g . , hemodyna m ics, d i u resis), u ri n a ry/renal (e . g . , fluid ba lance, BUN/c reati n i ne , dialysi s ) , skin (e . g . , ras h , decubitus care), l u ngs ( i ncluding ventilator management! , infectious disease (active or suspected i nfections, a n­ tibi otic thera py i n c l u d i n g treatment day!, fluids/electrolytes/nutrition ( IVFs, electrolyte disorders or replacement, enteral or parenteral nutrition!, endocrine (e . g . , diabetes, thyroid d isease, steroid thera py! , GI/liver (e.g . , gastroi ntestinal bleeding, d iarrhea/consti pation, ci rrhosis/hepatic dysfu nction , pancreatic dis­ ease!, oncologic/hematologic (e . g . , m a l i g n a ncies, cytopenias, coag ulopa­ thy! , and ana lgesia/anxiolysis/neurologic status (e . g . , pain ma nagement, coma, neurologic defiCits, psych iatric d isease). It is i m portant to reassess the long-term prognosis frequently so as to avoid futile care . Careful attention often is g iven to a patient's medical issues without consideration of the l i keli hood of surviva l or chance of mea n i ngful recovery. Along the same l i nes , socia l/fa m i l i a l issues a re of para mount i m po rta nce . Family mem bers often a re upset and concerned . They req u i re regular meeti ngs with the ICU physician to discuss med ical problems, treatment decisions, prog­ nosis, and end-of-life decisions.

C hest X-Ray Interpretati o n Reading a chest x-ray req u i res an organized a pproach and ca n be as easy as ABCDE F . . Common methods used em phasize sta rti ng on the outside and working in or starting i n the center and working out. The ABCDEF method * starts with a q u ick confi rmation of the fi l m 's qual itative aspects a nd then outli nes a checklist for interpretation . Initial review: AP or PA Body position Confi rm name Date Exposure Films for comparison * This mnemonic was adapted from one proposed by Robert Crauseman, MD. 1 4 • Pulmonary and Critical Care

•

Interpretation . Ai rway/Adenopathy Bones/Breast shadows Cardiac silhouette/Costophrenic angles Diaphragm/Digestive tract Edges/Extra-thoracic tissues Fields/Fa ilure Initia l ly, the reader should look at the film's projection (AP or PAl , then the body position (lordotic, rotated , etc ) , a nd then confirm the name of the pa­ tient, the date of the fi l m , and the type of exposure (over-penetrated or u nder­ penet rated) See if old films a re ava i la ble for a compa rison . Aga i n , using ABCDEF as your guide, review the releva nt structu res on the chest x-ray. Start by looking at the airway for width and focal narrowing . Then look for evidence of h i lar adenopathy or enlargement as m ight be seen with pulmonary artery hy­ pertension . Next, exa mine for breast shadows, which may affect the density in the lower lung fields, and ca refully review the bones for rib fractures or evi­ dence of lytic bone lesions. The cardiac silhouette as well as the costophrenic angles should be exam­ i ned for evidence of cardiac enlargement or pleu ra l effusions Look at the di­ aphragm to see if there is d iscrepancy in the height of the hemi-d iaphragms or evidence of free air under the diaphragm . The digestive tract then ca n be ana­ lyzed . With in the chest, look for evidence of esophageal enlargement or herni­ ation of the stomach as wel l as dilated loops of bowel below the diaphrag m . Look at the edges and extra-thoracic tissues. Particula rly, look a t the a pices for fibrosis or a pical d isease as wel l as pneumothoraces, which may occur a long the edges a pica lly, lateral ly, or at the base of the l u n g . Pleura l thickening or plaq ues may be present. Next, exa m i ne the extra-thoracic soft tissues on both the anterior and lateral projections. Final ly, assess the lung fields for evidence of a lveolar filling or interstitial processes. Evidence of cardiac fa i l u re may be seen i f there is a lveolar a i r space d isease with promi nent vascularity with o r without evidence o f pleural effusions.

,

Pulmonary and Critical Care •

15

..

C l inical Sym ptoms and Signs

CHRONIC COUGH GASPS AND COU G H

Gastroesophageal reflux disease Asthma Smoking/chronic bronchitis Post-infection Sinusitis/post-nasal drip Ace-inhibitor Neoplasm/l ower airway lesion Diverticulum (esophageal) Congestive heart failure Outer ear U pper airway obstruction G I - airway fistula Hypersensiti v ity/allergy N otes

I

1 . Cough is one of the most common complaints encountered by physicians. It is most often related to upper respiratory tract infections and/or smoki ng. A per­ sistent cough lasting longer than 2 weeks may ind icate a more serious disease. The above d ifferential for chronic cough refers to cases lasting severa l weeks i n which chest radiographs a re norma l . 2 . I n a smoker, a chronic cough may i ndicate chron ic bronchitis o r i t may herald the development of ca ncer, particularly when it involves an ai rway. Any change

i n the nature of a chronic cough i n a smoker warrants i nvestigation for pos­ sible neoplasm .

3 . Infections, the most common causes of cough , may be d ue to viral or bacte­

I

I

ria l pathogens; viral agents are the usual culprits . In addition, a post-infectious cough may a rise d ue to a cycle of i rritation and coughing, which further irritates 16 • Pulmonary and Critical Care

the throat. A post-infectious cough may lost several weeks aher the resol ution of the acute infectious process . Treatment consists of cough su ppressa n ts , ipra­ tropri um, and, occasionally, a course of inhaled steroids 4. Both pulmonary parenchymal and pleural d isease may present as a cough with or without dyspnea . A chest x-ray usua lly is the first test obtai ned after the history and physical in evaluating a chronic cough ( i .e . , a cough lasting longer than 2 to 3 weeks) . If the chest x-roy is negative, consider a more l imited differ­ ential diagnosis, as outlined by the GASPS AND COUGH mnemon ic. 5. Certa in historica l featu res may poi nt to the etiology of a chronic cou g h . Symptoms of heart burn or worsening cough i n recu mbency (e. g . , night) may in­ d icate gastroesophageal reflux. A cough that is worse in the evenings o r a childhood history of reactive airways disease may suggest asthma. Smoking-in­ duced chronic bronch itis and post-infection coug h from chronic i rritation a re very common and should be suspected when there is a history of smoking or an­ tecedent infection Nosal congestion or sensation of post-nasal drip may indi­ cate sin usitis as the cause of a coug h . Ra rely, persistent clear rhi norrhea may be secondary to a CSF leak, which should be considered if nasal drai nage and cough don't respond to treatment. ACE inhibitors, such as ca ptopri l , a re a common ca use of cough in pa­ tients on anti hypertensive therapy. A neoplasm in the lower a irway, which is not visible on x-ray, may be made manifest by cough. An esophageal diverticulum (e.g . , Zen ker's d iverticulum) causes hal itosis, reg u rgitation , and cough associ­ ated with eating. Patients with congestive heart failure may have an exacerba­ tion of reactive a i rways disease with coug h a nd/or wheeZi ng, often worse at nig ht. The presence of ear pain or ear disease should prompt an investigation of the outer ear canal and the ear dru m , as irritation in those a reas by hair, wax, or a foreign body may lead to sti m ulation of the vagus nerve and cough . The ea r canal should be exa m i ned in a l l patients presenting with coug h , as e(] r problems may be asymptomatic. The presence of stridor on physical exa m i nation or a palpable neck mass may indicate an upper airway problem as a cause of chron ic coug h . A gas­ trOintestinal-a i rway fistula, usua l ly tracheoesophagea l , cha racteristically causes cough wh i le eati ng. And finally, the occurrence of the cough after work or worsen ing of the cough during the work week may suggest an occupational cause leading to a hypersensitivity pneumonitis or an allergy. 6. Stud ies have shown that patients with cough lasti ng longer than 3 weeks who come to a pulmona ry special ist for evaluation almost i nvariably have one of four ca uses of chronic cough : gastroesophageal reflux, asth ma, smoking-in­ duced chronic bronch itis, or sinusitis/post-nasa l drip. The authors of these stud­ ies have suggested that a work-up for these four possible entities and/or empiric treatment of them will lead to resol ution of the cough in the g reat majority of cases. Adding the common entity of post-infectious cough to these four entities creates the mnemonic GASPS, which is a good start for d iagnosing the cause of chronic cough.

Pulmonary and Critical Care • 1 7

7 . Occasiona l ly, patients with pulmona ry fi brosis present with coug h and a negative x-ray. These patients usually have fine, "velcro" crackles on chest aus­ cultation, and a CT scan will reveal the i nterstitial d isease. 8 . Finally, for patients in whom all other causes of cough a re ruled out, a psy­ chogenic etiol ogy is possi ble. This d iagnosis req u i res exclusion of the other aforementioned etiolog ies.

CLU B B I NG CLU B

Cancer Liver disease U lcerative colitis B ronchiectasis (especially cystic fibrosis) N ote Clubbing has been observed in association with lung diseases si nce antiqu ity; however, its cause is unknown . It may be seen associated with cancers, particu­ la rly pulmona ry neoplasms, and when such an association exists, there usually is evidence of hypertrophic pul mona ry osteoa rthropathy. Clubbing also is ob­ served i n some cases of chronic l iver disease, as well as in inflam matory bowel disease, especially with ulcerative col itis. Clubbing is a very common symptom in patients with cystic fi brosis and in other patients with bronch iectasis. Other l u ng d iseases that have been assoc iated with clubbing i nclude lung a bscess and asbestosis. Less commonly, it has been seen in association with sarcoidosis and eosi noph ilic g ra nu loma . Clubbing is less commonly associated with pul­ monary fibrosis. It is not associated with COPD, the presence of clubbing should prompt an i nvestigation for other d iag noses . Clubbing may regress with treat­ ment of the underlying disease.

18 • Pulmonary and Critical Care

-

DYS P N EA S H E PANTS

Stress/anxiety/deconditioning H eart disease Emboli Pulmonary disease A nemia Neuromuscular disease Trachea/upper airway obstruction Sleep disorder N otes 1 . Dyspnea is defined as an a bnorma l ly uncomforta ble awareness of breath­ ing and has diverse causes. Patients' own descriptions of symptoms may include fatigue, heavy breath ing, weakness, chest tightness, wheezing, and other com­ plai nts . There a re four primary a natomic areas that i nfluence the sensation of breathing: Pulmonary/a irway stretch receptors, Aortic/carotid chemoreceptors, Neuromedullary chemoreceptors and Thoracic muscle stretch receptors ( " PANT" ) . I n put from these sites i nfluences the breathing pattern. For exa m ple, an acute exacerbation of COPD leads to lung hyperinflation and chest wall ex­ pansion, which i n tu rn sti mu lates pul monary and thoracic m uscle stretch recep­ tors, ulti mately leading to the sensation of dyspnea . Neuromuscular disease causes hypoventilation, al lowing CO2 to rise and O2 to fa l l . H igh pC02 and low p02 sti m u late aortic , carotid, and medullary chemoreceptors and ca use dyspnea . Alternatively, hypoxia from pul monary emboli sti m u lates aortic, carotid, and medulla ry chemoreceptors and causes dyspnea . 2 . The onset of dyspnea (acute, subacute, chron ic/progressive) as well as ex­ acerbants should be establ ished . Note that some patients with slowly prog res­ sive processes may g radually adapt by decreasing thei r physical activity, but compla i n of more acute symptoms at rest. Positional complai nts of dyspnea may be elicited, such as orthopnea (worsening i n the supine position - card iac d is­ ease, u pper airway obstruction, diaphragmatic paralysis! platypnea (shortness ' of breath when ass u m i ng an u pright position - ci rrhosis patients with intra pul­ monary shunts, pneumonectomy patients with i ntra-atrial shunts, patients with de­ ficient abdom inal m usculature!, trepopnea (dyspnea occurring in the right or left Pulmonary and Critical Care • 1 9

..

lateral decubitus position - heart disease , uni lateral pul monary d isease) , and

paroxysmal nocturnal dyspnea ( most often related to left ventricular fa ilure, but

may be seen with obstructive lung disease or sleep-disordered breath ing). 3 . I n addition to exertional and positional preci pita nts , q uestion the patient a bout occupational or environmental exposures, animal exposures, inhalational agents, and seasonal worsening. 4 . Stress, anxiety, and decond ition ing a re com mon causes of dyspnea , but often req u i re a n extensive i nvestigation to rule out more l ife-th reatening etiolog ies. 5 . Suspect heart disease or cardiac ischemia in patients at risk for or with a his­ tory of cardiac disease. A history of exertional symptoms, orthopnea, paroxysmal nocturnal dyspnea, or chest pa in may be present, as well as physical exa m i na­ tion findi ngs of edema , jugu lovenous distension , or card iac murmurs/gallops. I ntraca rdiac shunts also cause hypoxemia, CHF, and dyspnea . 6. Pulmonary emboli may present with acute dyspnea , chest pai n , or wheez­ ing . . Chronic, recurrent pulmonary emboli may be relatively "si lent" in itially and present as slowly progressive dyspnea . Evidence of lower extrem ity venous ob­ struction may not be present. 7. The category of primary pulmonary disease i ncl udes a i rway, interstitial and infiltrative, pleura l , and pulmonary vascular diseases (embolic d isease is consid­ ered separately a bove ) . Wheezing, coug h , and a worsening of symptoms in the evening in a younger person suggest reactive ai rways disease, while g radu­ ally prog ressive dyspnea and "velcro" crackles in an older patient suggest inter­ stitial pul monary fibrosis. Pri mary pulmonary hypertenSion is often seen in young women and may present as gradua lly progressive dyspnea with a paucity of physical find i ngs. 8. Anemia should be considered i n you n g , m enstruati ng women a n d i n pa­ tients with gastrOintestinal disease, chronic renal disease, or maligna ncy. 9. Neuromuscular diseases include myopathies, neuropathies, and diaphrag­ matic dysfunction . 1 0. Obstruction of the trachea or upper airways, may be subtle, and wheez­ i n g may be attri buted incorrectly to asth ma or COPD. Tu mors of the upper a i rway and vocal cord dysfu nction a re poss i ble etiolog ies. The flow-volume loop may show a cha racteristic pattern of obstruction. 1 1 . Sleep-disordered breathing is com mon i n obese patients, the elderly, and Pl tients with chronic heart and lung d isease. Heavy snori ng, jerky l i m b move­ m� nts while asleep, morn ing headaches, daytime hypersom nolence, and sexual dysfunction a re clues to the diagnosis. It is important to obtain i nformation from fa m i ly members and sleep partners as well as the patient . Sleep d istu rba nce can cause fatigue, exercise intolerance, and complaints of dyspnea . 1 2 . One of the most common clinical conundru ms is the differentiation of car­ diac from pulmonary dyspnea . Many patients have both hea rt and lung dis­ ease, and the relative contribution of each may be d ifficult to d iscern . The i m portance of a careful physical exa mi nation can not be overstated . Look ca re­ fully for the signs of C H F, including an S3 or S4 ga llop, rales, jugulovenous dis­ tension UVD ) , and peri phera l edema . S i g ns of pulmonary l i m itation i n clude 2 0 • Pulmonary a n d Critical Car£!

wheezing or reduced a i r entry, increased lung volumes, and hyperresonance to percuss ion . Note that JVD and pedal edema may be seen with cor pul monale, and they a re not always indicative of left-sided cardiac dysfunction . In additio n to the physical exa mination , a few simple measu rements may be The peak expiratory flow (PEF) is an easily obtai ned measure of a i r flow pful hel lim itation . A reduction in PEF « 200 L/m in) i ndicates obstruction and a likely pul­ monary etiology. The Pa02 also tends to be lower in pu lmonary dyspnea , a l­ though there is considerable overlap One g roup of investigators has suggested using a combination of both measures, PEF X Pa02 / 1 000, to differentiate be­ tween cardiac and pulmonary dyspnea . They have named this q uantity the dys­ pnea d ifferentiation i ndex (DDI) and use a cut-off of 1 3 to disti nguish between pulmonary and cardiac etiologies. A DDI < 1 3 ind icates a probable pulmonary etiology; values > 1 3 are suggestive of a cardiac etiology. Be careful to obta in a room air Pa02 and an accurate PEF (often tachypneic patients can not perform this test in itia lly) if these parameters a re being used . Another sim ple bedside parameter is the blood pressure response to the Valsalva maneuver. The a rterial pressure response to the Va lsa lva maneuver is abnormal in either systolic or d iastol ic dysfunction (see Cha pter V, Cardiology) . Norma lly, there is a decrease in the pulse am plitude and a narrowing of pulse pressure in response to stra i ning. In CHF this response is blunted, prod ucing a "square wave response . " A normal arterial response to Va lsalva suggests a pul­ monary etiology for dyspnea .

H E M 0 PTYS I S CAV I TAT E S

Congestive heart failure Airway disease/bronchiectasis Vasculitis/vascular mal f ormations I nfection (e.g., tracheobronchitis, anaerobes, fungi, T 8 ) Trauma Anticoagulation Tumo r Emb olism Sto mach (G I or nasal source) 'Pulmonarv and Critical Care • 2 1

N otes 1 . When a patient complains of blood in the sputu m , fi rst determine if the source is the lungs or ai rways (hemoptysis) and not the mouth , nose, pha rynx, or GI tract. The next steps are to q uantitate the a mount of blood and then consider possi ble etiolog ies . The d isease processes caus i n g hemoptysis often cause tissue necrosis, and the lung cavitates. Cavities, cystic cha nges, bronchiectasis, or alveolar ai rspace fi l l i ng on chest x-ray may ind icate a source of bleed i n g . Diffuse infiltrates suggest a more l i m ited d ifferential (e.g . , vascul itis with diffuse a lveolar hemorrhage, coagulopa thy, m i tra l stenos is) . Although an a l a r m i n g symptom, hemoptysis is often secondary to a benign etiology. Gross o r massive hemoptysis is most com monly caused by cancer, TB, or bronch iectasis. 2. Congestive heart failure often causes pink, frothy sputum , but rarely fra n kly bloody sputu m . Mitral stenosis is specifically associated with hemoptysis; ra rely, m itral regurg itation may cause expectoration of fra n k blood . 3 . Diseases of the a irways often cause hemoptysis, with tracheobronchitis as the most common cause of blood-ti nged sputum . Chronic a irway inflammation leads to bronchiectasis, which commonly causes hemoptysis. 4. Vasculitides, such as Wegener's granulomatosis or Goodpasture's d isease, are often characterized by fever, acute illness, and evidence of systemic involve­ ment, often renal dysfu nction . Arteriovenous ma lformations may cause hemop­ tysis and should be ruled out before biopsies a re ta ken . 5 . Certa in infections, such as TB, fungi , and a naerobic lung a bscess, are more likely to cause hemoptysis. Hemoptysis in these diseases is often seen in associ­ ation with cystic or cavitary lung d isease. Staphylococcal infection following i n­ fluenza characteristica l ly causes " rusty" or bloody sputu m . Rarely, Serratia marcescens lung infection causes redd ish sputu m that appears bloody. 6 . Trauma from thoracic injuries, in halations, pu l monary artery catheters, or en­ dotracheal tubes may cause va ria ble a mounts of airway bleed i ng . 7. Anticoagulation with coumad i n or heparin, or a bleed ing diathesis such as thrombocytopenia may precipitate bleed ing from the respiratory tract. Aga i n , the presence of blood does not necessarily indicate a malignancy or specific in­ fectious etiology, but be suspicious, si nce a nticoagu lation can " u n m ask" an occult lesion . 8 . Suspect tumors of the airway or parenchyma in smokers or patients with a known malignancy. 9 . Pulmonary emboli may cause tissue infa rction and hemoptysis. Ra rely, pul­ monary emboli cause cavitation. 1 0. Be careful to d iscri m i nate hemoptysis from stomach or other gastrointesti­ nal bleed i n g . N asopharyngeal bleed i n g may cause cough and be m isi nter­ preted as hemoptysis. The pH of hemoptysis is usua lly a l kaline, while that from the stomach is acidic. 1 1 . The treatment of hemoptysis usually i nvolves observation and perhaps maintaini ng the bleed ing source in the dependent position . If the hemoptysis is 22 • Pulmonary and Critical Care

maSSive (arbitrarily defined as > 500 ml/24 hours) , i ntu bation with a double­ lumen endotracheal tube is often required , with an attempt to isolate the hemor­ rhaging lung and prevent "soi l i n g " of the non bleed ing lung . The sou rce of massive bleed ing is usually the bronch ial a rterial system , and hemostasis may be obtained bronchoscopically, surgical ly, or by invasive radiologic procedure. 1 2 . A more comprehensive list of causes of hemoptysis is outlined below:

TRAC H EAL

Tracheobronchitis, Trauma, Tuberculosis, Thrombotic thrombocytopenic purpura Rupture of pulmonary artery (Swan-Ganz), Resin/paint production (trimeliitic anhydride), Rasmussen 's aneurysm Aspirated foreign body, A Ilergic bronchopulmonary aspergillosis, A naerobic/necrotic pneumonia Cancer, Cardiac (especiall y mitral stenosis) ' Crack coca i ne Heparin, Hemosiderosis (idiopathic pulmonary), Helminths (paragonimus, echinococcus) E NT/esophagus (pseudo-hemoptysis), Embolism (pulmonary, septic), Endometriosis A rteriovenous malformation, A rteritis/vasculitis, Amyloid Lung abscess, Left atrial myxoma, Lithiasis (broncholith), Lymphangioleiomyomatosis Also.· penicillamine and arterial bronchial fistula

STR I DO R WE TRA C H O R TR EAT

Wegener 's E piglottitis/supraglottitis Pulmonary and Critical Care • 23

Tracheobronchitis Relapsing pol y chrondritis Aspirated foreign body Cancer (endotracheal, metastatic, extrinsic compression) Hereditary (web, Ehlers-Danlos, Williams-Campbell, Mounier-Kuhn) Obstructive lung disease/"dynamic" compression Reidel 's thyroiditis/Radiation (fibrosing mediastinitis) Trauma/T racheostomy R hinoscleroma E motion/anxiety (vocal cord dysfunction) Amyloidosis Tracheopathia osteoplastica WH EEZI NG AST H MA

Asthma S mall airways disease Tracheal obstruction/l a rge airways disease H eart failure Mastocytosis/carcinoid A naphylaxis/A Ilergy N otes 1 . "All that wheezes is not asth ma" (Osler) . The mnemonic ASTHMA em pha­ sizes the maior causes of wheezi ng . Wheezi ng is ca used by a i rway narrow­ ing. The narrowing may be in the u pper a i rway (e . g . , laryngeal tumors, vocal cord dysfunction) , the large ai rways (e . g . , lung cancer, aspirated foreign body), or the small a i rways (e.g . , bronchiolitis, asth ma ) . When there is upper a i rway compromise, the wheezi ng sound is hea rd best over the trachea and is referred 24 • Pulmonary and Critical Care

to as stridor. Extra-p u l monary d i sorders a lso may ca use bronchoc 30% change per day in airfl ow • Nocturnal asthma • High amount of beta-agon ist use ( more than two ca n isters per m onth) . • Associated psych iatric d isease. Other factors i ncluding age, degree of obstruction , and race also ca ll be signif­ icant ind icators of high-risk asth ma . 3 . Small airways diseases a re a group of poorly understood entiti es d i sti nct from asthm a . As the name indicates, they cause narrowing and ObStruction of the small a i rways and consequent wheeZing . A relatively com mon p hysical ex­ amination find ing is an end-inspi ratory "squeak, " which probably c O rresponds to late opening of d istal airways. 4. Tracheal disease and large airway obstruction usually cause stritJ or, which may be d ifficult to differentiate from wheeZi n g . U pper airway lesions �an be de­ tected by physical examination (stridor over the upper ai rways) or Ch\l racteristic flow volume loops. A pa rticula rly common cause of upper ai rway W h eezi ng is vocal cord dysfu nction . These patients, often young women , typically h ave exer­ tiona I or emotionally ind uced wheeZing and shortness of breath whi� h may be severe. Characteristical ly, the wheeZing occurs with inspiration . The fI()w volume loop may show variabili ty in the i nspiratory phase. These patients oftE! n are mis­ diagnosed and treated im properly (often with steroids) as refractory Ci sth matics. Speech therapy and education are helpfu l . 5 . Extra-pulmonary disorders can cause bronchoconstriction . Heart f� i l u re may be made man ifest by wheezing or it may exacerbate normally q u i�scen t a i r­ ways hyperreactivity in certa in patients. A few un usual diseases (ma�tocytosis, carci noid syndrome) can produce h ista m i nic compounds that caus ras h , hy­ potension, and wheezi ng . Carcinoid tumors can cause wheeZi ng by two mech­ anisms: ( 1 ) airway obstruction by a bronchial carcinoid, and ( 2 ) prod ucti on of 5-H IAA, a bronchoconstrictor, which usually only causes wheeZing when the tumor i nvolves the liver (see Cha pter VI, Endocrinology, the Carcinoid secti on). 6. Anaphylaxis and allergy can cause bronchospasm and wheeZin g . It i s crit­ ical to identify environmenta l precipitants of wheeZing, as such knOW ledge can be life-savi ng. Avoidance of precipitants obviates the need for medic(:] tion s . Pulmonary and Critical t:are • 25

7. Pulmonary function tests a re essential in the diagnos is of a i rway obstruction and assessing the response to therapy. Inspect the flow volume loop with both i n­ spiratory and expiratory limbs for evidence of a large a i rway obstruction . Obtain lung vo,lume measurements: a n obstructive lung disease should show normal or increased lung volumes. Then a n assessment of simple spi rometry IFEV I , FVC) determines if obstruction is present. Occasional ly, a provocative test for asthma ; � needed ( i . e . , methacholine challenge test) when the d iagnosis is u ncerta i n . 8 . Below i s a more comprehensive list of the causes o f wheezi ng:

T H E AST H MATICS

Toxic fumes Hypersensitivity pneumonitis Eosinophilic disease Asthma Small airways disease Tracheal obstruction/l a rge airways disease Heart failure Mastocytosis/carcinoid A na phylaxis/Allergy Thromboembolism I nfection/bronchitis Cystic fibrosis/bronchiectasis Smoking/COPD

26 • Pulmonary and Critical Care

C l inical Conditions or Diagnoses

A C U T E R E S P I R AT O R Y D I ST R E S S SYN D R O M E­ D I F F U S E P U L M O N A RY I N F I LT R AT E S ARDS

Acute onset Ratio PaOiFi02 � 2 0 0 Diffuse infiltration Swan-Ganz wedge 1 8 mmHg
20 m m H g . I n nonca rd iogen ic pulmona ry edema, the pulmo m o ry capillary wedge pressure is usually < 20 mmHg. 4 . The therapy of ARDS is supportive, with special emphCll s i s o n identifying and treati ng the cause. There has been a great deal of intereslt i n steroid therapy for ARDS, and current data suggests a role 1 -2 weeks aher onset, du ring the so­ called fi broproliferative phase. Most stuQ ies have showm no sa luta ry effect of steroids when they were started early in the course of ARDS. F u rther studies are needed to confirm benefit later i n the course. 5. Here is a more comprehensive m nemonic for the causes of ARDS:

CA R D S ? H O PE I T' S N O T A R D S e N S disorders Aspiration (especiall y gastric) Radiation Drugs (i.e., heroin, morphine, barbiturate-s, etc.) S moke/toxic gas inhalation Hypotension/shock O2 Toxicity Pancreatitis Emboli (i.e., pulmonary, fat, amniotic fluicrj) I nfection/sepsis Transfusion reaction S urgery (especiall y cardiac) Near drowning O bstetrical emergencies (e.g., eclampsia , HELLP) Thermal injury/burns A Ititude sickness Renal failure D iffuse intravascular coagulation Systemic lupus erythematosus

28 • Pulmonary and Critical Care

A C U T E R E S P I R AT O R Y FA I L U R E A P E H I T I N T U BAT E D

Aspiration " White " X-Ra ys Pus Edema Hemorrhage I mmunologic Tumor " Black " X-Ra ys I nfarcted right ventricle Neurologic disease (drug overdose, botulism, CVA, Guillain Barre Tension pneumothorax U pper airway obstruction (anaphylaxis, foreign body 'aspiration) B ronchospasm (COPD exacerbation, asthma) Arrhythmia Tamponade Embolus (pulmonary, air, amniotic fluid, tumor) Diaphragmatic weakness (surgery/trauma, neurologic disease) N otes 1 . This m nemonic i ndicates the ma ior causes of acute respi ratory fa ilure . The fi rst part of the mnemonic, A P E H IT, ind icates the same processes causing pul­ monary i nfi ltrates. These processes lead to opacifications on the chest x-ray. The second half of the m nemonic, I NTU BATED, i n d icates etiolog ies in which the chest x-ray often d oes not show any i nfi ltrates. I n these entities, air space d is­ ease is not the cause of respi ratory fa ilure, and you m ust consider other causes of hypoxemia (e . g . , neurologic i m pairment leading to hyperventilation , tension Pulmonary and Critical Care • 29

pneumothorax , upper and lower a i rway obstruct.on , a nd vascular obstruction ) . Therefore, a common way to d ivide u p the causes :Jf acute respiratory failure i s by those that have "wh ite x-rays " (opacificaf ons) ane those that have "black x-rays" (clea r lung fields) . 2 . There are six primary mechan isms of hy poxertia : • Hyooventi lation • Low inspired fraction of oxyge n , • DiFusion impairment such as occurs at high a ltitude • Low m ixed venous oxygen . • V/0 m ismatch • Shunt Of these ca uses , the m ost i m porta n t o n es a re V/0 m i s'll atc h , s h u nt, a n d hypoventilation . 3 . The indications for emergent endotrach eal intLbation are. • Hypoxem ic respi ratory failure ( p02 < 60 rrm H g on > 60% oxygen) • Hypercarbic respiratory failu re (res pi ratory acidosis with a pH < 7 . 3 ) • Airway protection • I ncreasing intracranial p ressure

B R O N C H I E C TA S I S A SICK AI RWA Y

A irway/lesion/chronic obstruction S equestration I mmunodeficiency syndrome (especiall y immunogl o bulin abnormalities) Cystic fibrosis Kartagener 's syndrome/dysmotile ciliary syndromes A lIergic bronchopulm onary aspergill osis (ABPA) I nfection/I nflammation (e.g., tuberculosis, post-viral, whooping cough, coll a gen-vascula r disease) R eflux (aspiration)/R ecurrent i njury (heroin, toxic gas inhalation) Williams-Campbell and other congenital diseases (e.g., Marfan's, Mounier-K u n) A Ipha-I antitrypsin deficiency Yellow nail syndrome, Young syndrome h '

30 • Pulmonary and Critical C.are

s

N otes 1 . Bronchiectasis, a di lation of the ai rways, is usually a result of chronic endo­ bronchial inflammation . 2 . Hemoptysis may be a frequent feature of chronic bronchiectasis. 3 . Bronch iectasis leads to d i lation of bronchial arteries and i ncreased blood flow, which predisposes patients to bleed ing. 4. "Dry" bronchiectasis refers to predom i nantly u pper lobe d isease ( i . e . , sec­ ondary to TB or h i stoplasmosis). which usually dra i ns effectively. The ca rd i nal sym ptom is hemoptys is "Wet" bronchiectasis refers to lower lobe d isease , which is characterized by chron ic cough and purulent sputum . Exceptions to this rough classification include cystic fibrosis, which has prom i nent u pper lobe dis­ ease and thick, tenacious secretions. 5. A few diseases commonly cause bronchiectasis with an upper lobe predom­ inance. These can be remem bered by the m nemonic " FACT" ( F u n g i , ABPA, Cystic fibroSiS, TBI 6 . Ai rway lesions include tumors (benign and mal igna nt!. foreign body aspi ra­ tion , and bronchol iths. These airway lesions may cause chronic atelectasis and, ultimately, bronch iectasis.

C AV I TA R Y A N D C Y S T I C L U N G D I S EAS E WEIRD HOLES

Wegener 's Emboli (pulmonary, septic) I nfection (e.g . , anaerobes, Pn eumocvs tis carin ii, T B ) R heumatoid arthritis (necrobiotic nodules) Developmental cysts (bronchogenic, sequestration) Histiocytosis X Oncologic (primary or metastatic cancer) Left atrial myxoma ( LA M ) Environmental/occupational (silicosis, trauma) Sarcoidosis Pulmonary and Critical Care . 3 1

N otes 1 . The presence of cavities or cystic cha nges on the chest x-ray may be caused by necrotizing processes such as i nfections, vasculitides, i nfarction from emboli, or maligna ncy. Also consider certain developmental a nomal ies, occupational exposures, and u nusual primary l u ng diseases. 2 . Pul monary cavities primarily result from six sections of the "MEDIC I N E DOC" m nemon i c : ( 1 ) I nfectious , ( 2 ) Congenita l , ( 3 ) I m m u nolog i c , ( 4 ) Neo­ plastic, (5) Exotic, (6) Occupational/environmental exposures 3 . Infectious etiologies i nclude mycobacterial disease, fungal disease, necro­ tizi ng bacteria l i nfections, parasitic infections, and septic pulmonary embol i . Tuberculous cavities typica l ly occur i n the upper lobes, but can present i n a ny lo­ cation . They a re part of a chron ic disease process, so prior fi lms are helpful i n analyzing the progression of the disease. I n the a bsence o f superinfection , a i r­ fluid levels are uncommon in tuberculous cavities. Sputum analysis often is posi­ tive in active cavitary tubercu losis, as the organism load is relatively high with i n the cavity. Fungal diseases, such a s coccidiomycosis, blastomycosis, a n d h isto­ plasmosis, also can produce cavities Asperg illosis may couse on acute necrotizing pneumonia in i mmunocom pro­ m ised patients, or it may colonize pre-existi ng cavities, producing a visible fungal boll on chest radiography. Because invasive aspergillosis characteristically i nvolves blood vessels, thrombosis, i nfarction , and cavity formation often ensue. The char­ acteristic "crescent" sign is produced by i nfa rcted tissue within the fu ngal cavity. Vi rtually all bacterial i nfections can cause a pneumonia that may produce cavitary lung changes . Cavita ry cha nges a re more typical of a naerobes and g ra m-negative org a n i s m s . However, Staphylococcus aureus, Streptococcus pneumonia, and Legionella species all can produce cavitary l u ng changes. A ra re com pl ication of bacterial pneumon ia is pulmonary ga ngrene. The rad i o­ logic a ppearance can be characteristic, with i nfa rcted lung tissue floati ng with i n a parenchymal cavity. Surgery often is required for resolution. Pa rasitic i nfections should be suspected i n i n d ividuals with a pp ropriate travel and exposure history. Paragonim iasis is secondary to a l iver fluke and is endemic to Southeast Asia . Echi nococcus is associated with exposure to sheep, dogs, or wild hosts such as caribou or rei ndeer. A characteristic rad iologic a p­ pearance, the "water-li ly" sign, is produced when the encysted organ isms' mem­ branes detach from the adventitia and float with i n a cavity. Finally, septic pulmonary emboli most commonly occur as a result of tricuspid endocard itis or a peri pheral source . Multiple cavita ry lesions may be present, often in the lower lung zones where the blood supply is greater. 4. Congenital anomalies i nclude developmental cysts (e . g . , bronchogen ic) as well as pulmonary sequestration, and should be suspected in young adults pre­ senti ng with asymptomatic cavitary lung lesions. 5. I m m u nolog ic processes i nclude the vasculid ities and rheumatoid a rthritis. Wegener's granulomatosis is the most common immunologic disease that presents 32 • Pulmonary and Critical Care

.... I

with pulmonary cavities. Rheumatoid arthritis ca n cause lung nodules that fea­ ture central necrosis a n d eventua l ly cavitate. Ankylosing spondylitis and polymyositis also may feature a pical bullous disease. 6. Oncolog ic processes can produce cavities by two mechanisms: ( 1 ) obstruc­ tion of a bronchus with d istal suppurative i nfection, or (2) cavitation of the tumor mass secondary to outgrowi ng of the blood supply. Squamous cell carci nomas have a particu lar propensity to outg row their blood su pply a n d cavitate . Angiocentric lymphoma (lymphomatoid granulo matosis) is a n u n usual mal ig­ nancy that can cause multi ple lung masses which may cavitate. 7. Exotic diseases causing cysts i nclude histiocytosis X, LAM, and sarcoidosis. Younger patients who present with multiple lung cysts should be suspected of haVing these diseases. Histiocytosis X, also called eosinophilic granuloma , is a disease of smokers. lANI is related to tuberous sclerosis and occurs in young females. 8. Envi ronmental or occupational exposures may lead to cystic lung d isease. A common occupational cause of cystic lung disease is sil icosis, which occurs in hard rock m i ners . Also, rarely, multiple trauma patients develop acute cavitary lung d i sease of uncerta i n etiology. Presumably, the trauma leads to vascular iniury, resulting in the cavitary changes on x-ray. 9 . As with most respiratory problems, emboli are a possible, albeit rare, cause of cystic or cavita ry changes . Both pulmonary and septic e m boli can cause necrosis, infarction, and subsequent cavitation .

I N T E R ST I T I A L L U N G D I S EAS E IS IT I PF?

I PF Sarcoidosis I nhalational (pneumoconioses) Treatment-related (e.g., medications, radiation, chemotherapy) I mmunologic (collagen-vascular diseases) Post-inflammatory (e.g., infection, A R D S ) Familial Pulmonary and Critical Care • 33

N otes 1 . The lung interstiti u m is the a rea between the gas-exchanging alveolar epithe­ lium and the capi llary membra ne. Norma lly this space is very th i n and allows for effective gas exchange. When d iseases or toxins damage the in�-:: ' -titiu m , it may become i nfi ltrated with inflammatory cells and, ultimately, scar tissue. These interstitial lung d i seases produce an i m pa i rment in the d iffusion of oxygen and lead to respiratory sym ptomatology The chest rad iograph characteristically shows what is often called a reticular or li near pattern of i nfiltration . The term " d i ffuse pa renchym a l lung disease" m ay be more a ppropriate since these d iseases may involve the a i rways and a i rspaces i n addition to the interstiti u m . The m nemonic " I S IT IPF?" summarizes the pri mary causes of i nter­ stitial d isease. 2 . One of the m ost commonly encountered i n terstitial lung diseases is id io­ pathic p u l m o n a r y fi brosis, I PF . Sarcoidosis is a lso very common and has myriad systemic manifestations . Immunologic/collagen-vascular diseases have well-descri bed systemic features and pulmonary i nvolvement. Lung disease is oc­ casion a l ly the i n i tial f i n d i n g i n patients with collagen-vascular d iseases . Treatment-related causes m ust be ca refully considered si nce removal of the of­ fending agenr is critica l . A complete occupational and environmental histary is mandatory to exclude in halational lung d i sease . Avoidance of the i nciting agent is mandatory for the patient, and other persons at risk may be identified . Pulmonary i nfections, ARDS, and other lung i njuries may result i n post-inflamma­ tory fibrosis and permanent parenchymal changes. Finally, a number of unusual familial d iseases have associated interstitial lung d isease. 3 . The history a n d clin ical exam i nation sometimes suggest an etiology for inter­ stitial disease, such as a n exposure or an u nderlying disease. The chest rad io­ g ra ph may show characteristic patterns which may also suggest a n etiology. For exa m ple, certa i n diseases more commonly have predom inantly upper lobe i n­ volvement, incl u d i n g Ankylosing spondyl itis, PIE (chronic eosi noph ilic pneumo­ n i a ) , Infections (TB, h istoplasmosis), Coa l worker's pneu mocon iosis/s i l icosis, Eosinophilic granuloma (h istiocytosis X), and Sarcoidosis/berylliosis ( "APICES"). A predom i nantly lower lobe pattern of disease is seen i n asbestosis, alveolar pro­ tei nosis, I PF, collagen-vascular diseases, and chronic hypersensitivity pneumonitis. Nodu les suggest sarcoidosis, Wegener's, inhalational exposures ( pneumoco­ nioses). rheumatoid a rthritis, or lymphomatoid granulomatosis ("SWIRL"). The pres­ ence of pleural disease is unusual in interstitial lung disease, but may be seen i n asbestosis, Iymphongitic carcinomatosis, a n d collagen vascular diseases. Normal or increased lung volumes and cystic changes are seen in only a few diseases. Finally, lymphadenopathy is also unusual in i nterstitial lung disease and may in­ dicate sarcoidosis, amyloidosis, Iymphangitic carcinomatosis, or berylliosis. 4. Diffuse pa renchymal lung d isease most often leads to i ncreased lung elastic­ ity and a reductio n in lung volumes. Pulmonary function tests usua lly reveal a re­ strictive ventilatory defect. Occasionally i nterstitial disease is seen i n a patient 34 • Pulmonary and Critical Care

with normal or i ncreased lung volumes, a n d this narrows the differential con­ s i derably. The causes of I nterstitial lung d isease with normal or increased lung volumes are summarized by the m nemonic LET'S BRONC H : LAM, Eosinoph ilic g ranuloma ( h istiocytosis XL Talc injection ( i ntravenous drug a busel, Sarcoidosis, B ronchiectatic d iseases (e. g . , cystic fi brosis), Respi ratory bronch iol itis, Obliter­ a tive bronch iolitis, Neurofibromatosis, COPD + ILD, Hypersensitivity pneumon itis. (This m nemonic is adapted from one i nvented by Robert Shpi ner, MD . ) I n con­ trast to other causes of i nterstitial lung d isease, these diseases feature obstruction on pul monary function tests. Exceptions a re hypersensitivity pneumon itis and eosinoph i l ic g ra nuloma, which most often show restriction on pulmonary func­ tion testing despite normal or i ncreased lung volumes . 5 . There are a pproximately 1 80 known i nd ividual diseases that m a y b e associ­ a ted with interstitial lung d isease . The most frequently encountered are I PF, sar­ coidosis, and interstitial lung disease associated with collagen vascular diseases . The following m nemonic l ists many of the causes of i nterstitial lung d isease:

I HAVE BRO N C H E D A N I NTERSTITIAL LUNG

I diopathic pulmonary fibrosis (I PF) H ermansky-Pudlak syndrome A R D S recovery Veno-occlusive disease E nd-stage liver disease B ronchocentric granulomatosis R heumatoid arthritis and other collagen vascular diseases O rganic and inorganic dusts (occupational/ environmental) N iemann-Pick and Gaucher's diseases Congestive heart failure H ypereosinophilic syndrome Eosinophilic lung diseases (PIE syndromes) D rug exposures (e,g" amiodarone, gold, antibiotics, chemotherapy) Amyloidosis N eoplastic (Iymphangitic carcinomatosis, post-radiation therapy) Pulmonary and Critical Care • 35

Idiopa ltt--. ic p u lmonar y he m os ider osis Neuro f ib ro m atosis Tuber (Q l..J S s c lerosis Eosin granulo ma/his ti ocytosis X Renal C::>f�P hiluil icre/uremia Sarcoi d Trans b le�ntsisa tion ( G V H D ) I nfect i S (r esidua act ive infe ction of any type) Toxic 'ioc hllem icals (ga se s, f um es , va pors, ae r os ols, par � q ua t, rad iati or) ) Idiopa pereosi nop h ilic synd rome A Iveo''tail... icprhy o teinosi Lymp� a. ng io leiomyos mat o si s ( L Lympth a cy tic di so rd er s (e .g . , A M ) Iym ph oc ytic interstitia l p n pse udolymphoma, U I ce r � t i v e c oli tis an d ot he r geum onitis) . Nec r Q,ti :Z i n g va sculit i s (Weg e as tro intes tin al diseases Iy m p h o m atoid granulo m a ne r 's, Ch u rg-S tra u ss , s) Goo d � a. st ur e's dis e as e an d tosi he fln a rrh ag e sy nd ro me s ot he r pu l m onary of

M E D I AST I N A L M AS S C H E ;g T A L A R Ms

Cysts ( bro n chia l, pe ricar d ia l) H erni � � (B o chdalek , Mo rg ag ni) Es oplJ a ge al div ert i c ulu m Sch geni c tu mor s Ts (TwlJ..aan noTm's:a/neuro ter ato ma , th Ym o n a, thy r oid , and ter ri. ble I Y � Pt'lO rn a) 4

36 • �u lrr, ona ry and Critical Car e

A neurysms (aortic and pulmonary) Lymph node enlargement Adipose tissue Renal (intrathoracic kidney) Metastatic disease S plenosis/extramedullary hematopoesis N otes 1 . One of the most common disorders of the mediastinum is a moss. The fi rst step in evaluation is to determ i ne the compartment of the med iastinum i n which the mass is located : a nterior, midd le, or posterior. The most common anterior masses are the 4 Ts : thymona , thyroid moss, teratoma, terrible lymphoma . The most common middle masses a re vascular mosses, lymph node enlargements, or cysts ( perica rd i a l , bronchogen ic) . Posterior masses i nclude neurogenic tumors, hiatal hernias, or esophageal diverticu l i . 2 . A CT scan , followed b y biopsy when appropriate, is the usual approach to diag nosis. 3 . Ca uses of a med iastinal mass, by compartment, a re summa rized by the m nemonic below. There is some overlap in the categories as some entities can be found in more than one mediastinal compartment.

N ERVES A N D CH EST PARTS Pos terior Media s tin um

Neurogenic tumors Esophageal enlargement or diverticulum Renal (intrathoracic kidney) Vascular (e.g., descending aortic aneurysm) Extramedullary hematopoesis/splenosis Skeletal /spinal (e.g., vertebral osteophyte, menin g ocel e ) Middle Media s tin um

Adipose tissue ("fat pad") Nodes Dilated aortic root

Pulmonary and Critical Care • 37

Cysts (pericardial, bronchogenic) Hematoma (e.g., after surgery or line placement) Enlarged pulmonary arteries Stomach (hiatal hernia) Tumor (metastatic, primary) A n terior Media s tinum

Parathyroid mass Aortic arch aneurysm R ight ventricular enlargement Ts (teratoma, thymona, thyroid, terrible lymphoma) Subclavian catheter hematoma PLE U RAL E F FU S I O N P E H I T ? D E C U B , TA P

Pus Edema H emorrhage I mmunologic Tumor D ial ysis (peritoneal) Esophagus (Boerhaave's ) Chyle U rine B ile Total parenteral nutrition Ascites Pancreatic

38 • Pulmonary and Critical Care

-

N otes 1 . There a re many d ifferent types of fluid that may enter the pleural space . Si m i lar to pulmonary i nfi ltrates, pleural fluid may consist of pus, edema, hemor­ rhage, i m munologic reactions, or tumor cells (PE H IT) These are the major causes of fluid i n the pleural space. However, other types also may gain access, such as dialysis fluid, i nflam matory fluid from a ruptured esophagus, chyle from i n j ury to the thoracic duct, urine, bile, total parenteral nutrition (TPN), ascitic fluid, or pancreatic fluid (DECUB TAP) There even have been cases of CSF ( pleuro-d u ro fistu la) and stool (fecothorax) in the pleu ra l space . As with pul­ monary i nfiltrates, pulmonary embolism must be considered i n the differential d i­ ag nosis of a pleural effusion . 2 . When a pleural effusion is discovered, decubitus films should be obtained to see if the fluid flows freely. Thoracentesis should then be performed without delay on freely flowing fluid. Thoracentesis is indicated i n virtually all newly d iagnosed , free-floWing pleural effusions. Exceptions to this rule are when the clinical diagnosis is certain (e.g . , CHF) or there is only a small amount of fluid in the pleural space. 3 . Pleura l effusions a re broadly cate g orized as tro nsudates or exudates . Tra nsudates occur when syste m ic factors that infl uence the formation and a b­ sorption of pleural fluid are altered . The most common causes are leN ventricular fai lure, pul monary embolus, and cirrhosis. Others i nclude nephrotic syndrome, peritoneal dialysis, myxedema, atelectasis, and uri nothorax. Urinothorax is the only cause of an acidic transudate. 4. Exudates occur when local factors that i nfluence the formation and absorp­ tion of pleural fluids are altered . The most com mon causes a re bacterial pneu­ monia, malignancy, viral i nfection, and pulmonary embolus. Pulmonary embolus may cause either a transudate or an exudate depending on whether i nfarction and hemorrhage occurs. Ca ncer and hypothyroidism also may cause either a transudate or exudate. 5 . Criteria for an exudate are: a. Pleural fluid protein/serum protein > 0.5 b. Pleural fluid LDH/serum LDH > 0 . 6 c . Pleural fluid LDH > 2/3 o f the normal upper limit for seru m . Transudates have none o f these features. 6. If the fluid is exudative, the follOWing tests should be ordered : glucose, amy­ lase, cell count and differential , cultures, cytology, gram sta i n , and pH. Two or three cytologi C samples will rule out a malignancy in most cases. 7. A possible para pneumonic effusion should be tapped i m med iately. It is said to be "compl icated" if any of the follOWing are present: a. Gross pus b. Organisms visi ble on gram stain c . Glucose < 50 d. pH < 7 . 0 Complicated effusions usually require chest tube drainage. Pulmonary and Critical Care • 39

� TB pleuritis usual ly requires a pleural biopsy for d iag nosis due to the scarcity

of orgon isms in the fluid The flu id ohen ( but not always) lacks mesothelial cells. Ma king the d iagnosis of primary tu berculous pleuritis m ay be d i fficult, but i t should b e pursued agg ressively a s there i s a h igh i ncidence of progression to pulmonary parenchymal d isease. The diagnosis may be elusive: several new d i­ ag nostic stud ies a re ava i la ble. There is evidence that a n elevated adenosine dea m i nase level may be helpful i n establishing a d iagnosis of tuberculous pleu­ ritis . A second promising diag nostic test is a polymerase chain reaction assay specific for mycobacterial d isease. This test may be applied to sputum samples and has been used for ana lysis of pleural and other body flu ids. It has a high degree of sensitivity, with probably a lesser degree of specificity. 9. A low g lucose is characteristic of rheumatoid arthritis effusions. Other entities that may have a very low g lucose i nclude empyema, malignancy, tuberculosis, SLE , and esophageal rupture. 1 0 . B loody fl uid may be seen in many conditions, but an RBC count g reater than 1 00 , 000 suggests trauma, maligna ncy, pul monary embolism , post car­ d iac i n j u ry synd rome, or asbestos pleuritis ( I T B LE D - I ntravenous catheter, Tra u m a , BAPE [ benign asbestos pleural effusion ] , Lung ca ncer, E m bolism , Dressler's synd rome). 1 1 . A pleural fluid a mylase level occasiona l ly is helpfu l . The mnemonic AMY­ LASE UP (Adenocarci noma , Mycobacteria, Yorking (esophageal rupture), Liver disease, Acute pa ncreatitis, Serum hypera mylase m i a , Ectopic pregna ncy, U reteral obstruction, Pseudocyst) can help you remember related d isorders . Hydronephrosis and other d isease states that lead to an elevated serum a mylase also increase the pleural fluid a mylase level. The highest levels are seen in pan­ creatic d isease, and usua lly a re g reater than 2 0 . In other causes i ncluding cancer the pleu ral fl uid/serum a mylase level is usua l ly a bout 1 0 . Pancreatic pseudocysts typically have the h i g hest a mylase levels, often g reater than 1 00 , 000. Amylase isozyme ana lysis may be hel pfu l in pinpoi nting the cause of a h i g h pleural fl uid a mylase . A h i g h sal ivary i sozyme l evel indicates malig­ nancy, whereas a high pancreatic isozyme level ind icates pancreatic disease. The most common malignancies causing a high pleural fluid amylase are lung or ova rian carcinoma . This fact can be helpful i n differentiating lung carci noma from mesothelioma , because mesotheliomas do not make a mylase. 1 2 . A high percentage of eosinophils in the pleural space usually i ndicates the presence of air or blood . Eosi noph ils may accumulate aher a pneumothorax or hemorrhage into the pleural space. Other causes of pleural fluid eosinophilia in­ clude certa in d rugs such as dantrolene, pulmonary emboli , parasitic i nfections, funga l i nfections, and malignancies . Ben ign asbestos pleural effusion ( BAPE) is a compl ication of asbestos exposure that may occur 1 0- 1 5 years after the ini­ tial exposure. Because the pleural effusion is bloody, a high eosinophil cou nt may be seen with BAPE as wel l . The m nemonic BAPE ( B lood , Air, Parasites, Emboli) summarizes the primary causes of pleural fluid eosi nophilia 1 3 . Suspect the presence of lymphatic fluid i n the pleural space (chylothorax) when effusions re-accumu late ra pidly or have a m i l ky color. The fl uid is not always rrl k'y however, and may be turbid or bloody Cond tions that c:ommonly 40 • Pulmonary and Cntlcal Care

lead to the accum u lation of lymphatic fluid (chyle) i nclude trauma, maligna ncy (especially lymphoma ), chest surgery, coughing, vomiting, or straining. A great number of other cond itions may be associated with a chylothorax as wel l , in­ cluding LAM; yel low nail synd rome; i nfections lead ing to thoracic lymphade­ nopa thy, i ncluding tu bercu losis and fu ngal infections; filariasis; aortic a n d pul monary aneu rysms; and certa i n congen ital syndromes, for example Down's syndrome, Noonan 's syndrome, and Turner's syndrome. Some major etiologies of chylothorax a re summa rized by the m nemonic CHYLES - Cough/stra in/vom iting, Hereditary diseases, Yellow nail syndrome, Lymphoma/LAM/lymph node enlargement, Elephantiasis, Surgery/trauma . All of these cond itions lead to obstruction of lymphatics and/or i njury to the thoracic duct. A pleural fluid triglyceride level > 1 1 0 establishes the d iagnosiS of chylo­ thorax. A level at 50-- 1 1 0 is intermediate and may be ind icative of chylothorax. When the level is i ntermed iate , the pleural fl uid should be subm itted for elec­ trophoresis to look for the presence of chylomicrons. When a chylothorax is diag­ nosed, establish NPO for the patient, and in itiate TPN . Do not attempt aggressive chest tube dra inage, as th is may lead to nutritional depletion. The thoracic duct may then spontaneously hea l ; if it does not," surgical ligation may be ind icated . 1 4 . If the cause of a pleural effusion is not determi ned after thoracentesis, then pleural biopsy is usually the next diagnostic step. If pleural biopsy fa ils to yield a diag nosis, then consider a n open surgical proced ure . Bronchoscopy may be helpful if there is another confirmed pulmonary lesion or hemoptySiS, but the yield is qu ite low for an undiagnosed pleural effusion with an otherwise normal x-ray. 1 5 . A small n u m ber of exudative effusions elude d iag nosis even after open pleural biopsy. Experience shows that about two-thirds of these do not recur, and no d iagnosis is established . They are presumed to be a result of infection or other i nfla m matory process that has resolved . The rema i n i ng one-third of cases a re eventually found to have a specific d iagnosis. Ma lignancy, usually lymphoma, is the most com mon cause . A few patients eventually a re diagnosed with colla­ gen vascular diseases or other m iscella neous d iag noses . I n teresting ly, in the la rgest publi shed series, none of the patients with u nd iag nosed exudative pleural effusions who had surgical biopsy were ever found to have tuberculosis. 1 6 . Here is a longer list of the causes of pleura l effusions:

U H , D O C I ' L L N E E D M Y T A P S TAT

U rinothorax Hypothyroidism o rugs (e.g., nitrofurantoin, amiodarone, procarbazine, dantrolene, methylsergide) Ovarian hyperstimulation syndrome Collagen vascular disease Pulmonary and Critical Care • 4 1

I nfection (pneumonia, parapneumonic effusion, emphysema, T B ) Left ventricular failure Lymphangioleiomyomatosis N ephrotic syndrome Esophageal rupture E mbolism ( P E ) Dial y sis (peritoneal) Malignancy (primary, metastatic, Meig's syndrome) Yellow nail syndrome Trauma (hemothorax) Ascites (hepatic or pancreatic) Post-surgical SVC obstruction (or other great veins) Trapped lung Asbestos ( BA P E ) T PN P N E U M OT H O R AX C H EST PAI NS

Cystic lung disease (e.g., cystic fibrosis, LA M , histiocytosis X, bullous emphysema) H ereditary connective tissue diseases (Marfan's, Ehlers-Danlos, pseudoxanthoma elasticum) E ndometriosis (catamenial) S pontaneous Trauma

42 • Pulmonary and Critical Care

--

Pneumonia, PCP A Ititude, A Iveolar microlithiasis Iatrogenic (thoracentesis, central line, ventilator, postoperati v e) Neoplasm (rare-osteogenic carcinoma metastases) Scleroderma, Sarcoidosis N otes 1 . Pri mary or "spontaneous" pneumothorax commonly occurs i n tall, thin i ndivid­ uals and is usua lly d ue to rupture of apica l blebs . Smokers a re at i ncreased risk. 2. Treatment of a large pneumothorax i n itially i nvolves aspiration , often fol­ lowed by chest tube re-expansion . Recurrent pneumothorax can be treated with sclerosing agents (tetracycline or bleomycin) or surgically. A small pneumothorax can be followed by serial chest x-rays, because it may resolve without medica­ tions or treatment. 3 . Tensian pneumothorax is life threatening and can lead to cardiac a rrest. It may be a compl ication of mechanical venti lation. It is treated emergently with a large-bore needle placed in the pleural space

P U L M O N A RY H Y P E RTE N S I O N LV E D P

Left-sided failure Vascular disease/obstruction Extrinsic compression D esatu ration/hypoxia Pulmonary parenchymal disease

Pulmonary and Critical Care • 43

PA HTNS

P ulmonary pare nchymal disease/primary pulmonary hypertension A pnea/A noxia H eart failure Thromboembolism N euro m uscularlskeletal disease Scleroderma/va sculitis N otes 1 . The differential diag nosis for pulmonary hypertension (PA HTNS) is a "plumb­ i n g " problem. The h istory, physical examination , and chest x-roy guide you i n deter m i n i n g where the " block" in the plumbing is located ( i . e . , aorta , aortic valve, left ventricl e , m i tral valve, left atrium, large pul monary vei ns, pulmonary venules, pulmonary ca pi llaries, pul monary arterioles, pul monary arteries) . Also consider pulmona ry valve disease, right ventricular dysfunction, tricuspid valve disease, right atria l d isease, a nd subclavian vei n thrombosis. 2. Left ventricular fa ilure is the most common couse of pulmonary hypertension . I n left-sided fa ilure, t h e left ventricular end-d iastolic pressure (LVEDP) i s elevated . Thus, on i mporta nt first step is to assess left ventricular function to ru le-out a cardiac couse of pulmonary hypertension . The physical exam ination may detect on S4 or pulmonary edema , suggesting left ventricular fa ilure . Physical findings ind icative of pul monary hypertenSion of any couse i nclude jugulovenous distension, a right ventricular h eave, a loud P2, and a systolic pul monary murmur. 3 . Ca uses of left-sided failure (post-pulmonary ca pillary) i nclude systolic and diastol ic CHF, congeni tal heart disease, valvular heart disease, and atrial tumors . Vascular causes of pu l monary hypertenSion i nclude chronic thromboembol i , pri­ mary pulmonary hypertenSion , intravenous drug a buse, collagen-vascular diseases such as scleroderma/CREST, schistosom iasis, diet/weight-loss pills, sickle cell anemia, and pulmonary hypertenSion associated with cirrhosis. Pulmonary venous d i sease is ra re and, a lthough vascular, it is a post-pulmonary capilla ry process that may look like C H F. Extrinsic processes causing pul monary hypertenSion i n­ clude kyphoscoliosis, neuromuscular disease, a nd fibrosing med iasti n itis. Periodic oxygen desaturation caused by obstructive sleep a pnea or hypoventi lation syn­ dromes eventually couse pulmonary hypertenSion . Chronic hypoxia of any cause leads to pulmonary vascu lar constriction a n d , u lti mately, hypertenSion . F i nal ly, pulmonary parenchymal diseases such as COPD and interstitial lung disease destroy the capillary bed, leading to pul monary hypertension . 44 • Pulmonary and Critical Care

4. An echocardiogram demonstrates both LV and RV function , valvular function, and an estimate of pulmonary a rtery pressures; it is a good i n itia l noni nvasive test. Defin itive local ization of the "block" may require pul monary artery catheter­ ization to measure the pul monary capillary wedge pressure ( PCWPl. a reflec­ tion of left atrial pressure, and an ind icator of LVEDP. Pul mon()ry a ngiog ra phy may be necessary to rule out chronic pul mona ry embol i or other vascular ob­ structions. The mnemonic below l ists the causes of pulmonary hypertension and i nd icates the helpful diag nostic i nformation provided by the PA catheter.

I C H E C K PCWPS A N D LV E D PS

I nterstitial lung disease Chronic obstructive pulmonary disease Hyperthyroidism Emboli (chronic pulmonary emboli, intravenous drug abuse) Collagen-vascular diseases Kyphoscoliosis Primary pulmonary hypertension (including pulmonary capillary hemangiomatosis) Congenital heart disease Worms (e.g., schistosomiasis) Pulmonary veno-occlusive disease Sleep apnea A trial disease Neuromuscular disease Diet pills (aminorex) Liver disease/cirrhosis Val v ular heart disease Extrinsic compression of pulmonary vasculature (e.g., fibrosing mediastinitis) Diastolic inhibition/equalization (tamponade, constrictive pericarditis) Primary cardiomyopathy (dilated, restrictive, infiltrative) Sickle cell anemia Pulmonary and Critical Care • 45

P U L M O N A R Y I N F I LT R AT E A PE H IT?

Aspiration Pus Edema Hemorrhage I mmunologic Tumor N otes 1 . A pulmonary i nfiltrate is a com mon med ical problem . Although the potential etiologies are many, the composition of infiltrates is limited . A pulmonary i nfiltrate may be composed of: ( 1 ) aspirated food or oil, (2) pus ( infection ), ( 3 ) pulmonary edema or vascular leak, (4) hemorrhage, (5) certa i n immunolog ic processes including collagen vascular diseases, eosi noph i l ic lung diseases, BOOP, and alveolar protei nosis, and (6) tumor i nfi ltration . As the m nemonic suggests, always consider pulmonary embolism in the differential diagnosis of a new i nfi ltrate, particularly when risk factors a re present or the cli nical picture is unclea r. 2 . A patient's specific presenting symptoms can indicate the nature of the infi ltrate. For exa mple, fever and productive coug h may i nd icate an infectious etiology. On the other hand, a patient with rales and a history of congestive heart fa ilure most likely has pul monary edema . Hemoptysis may indicate an underlying pul­ monary hemorrhage syndrome, while the presence of certa i n systemic sym ptoms may point toward an i m munologic cause of the lung disease. F i nally, risk of lung cancer or characteristic radiographs may lead to a consideration of neoplasm . Pulmonary neoplasms often block an a irway, leading to a post-obstructive pneu­ mon ia, which may be recurrent ar fa i l to clear after appropriate thera py. Less commonly, neoplasms primarily i nvolve the a irspaces and cause an infiltrate (see below) Neoplasms can have the same effect by bleed ing i nto the a i rspaces. 3 . Commun ity-acq u i red , bacterial pneumon ia (CAP) is the most common cause of a pulmonary i nfi ltrate. The typical presenting features a re fever, coug h with purulent sputum , and a loba r i nfi ltrate. Multi-lobar disease is more serious and less common. With ti mely and effective antim icrobial therapy, clin ical and radio­ graphic i mprovement a re evident. Of course, there are exceptions to these rules dependi ng on host-specific factors (e . g . , the elderly) and the particular pathogen (e . g . , Legionella l , but they provide valuable g uidel i nes in assessing response. 46 • Pulmonary and Critical Care

4. A common cli nical problem is differentiating between CAP and other causes of ai r-space disease. When faced with a pulmonary i nfi ltrate, there are four pri­ mary considerations: Cli nical presentation , Underlying d i seases/risks, Rad io­ graphic a ppearance, and Expected response to thera py (CURE). The clin ical presentation of CAP usua l ly includes acute onset of fever, cough, and purulent sputu m . The a bsence of these features ar the presence of less typical findings (e.g . , prolonged course, hemoptysis, lymphadenopathy, disproportionate hypox­ emia) should prompt consideration of other entities. A particular patient's under­ lying diseases or risk factors (e . g . , AIDS, known mal ignancy, smoki ng/COPD, i mmobil ity/hypercoagulability, medications/drug use) pred ispose to speci fic pathogens or cond itions other than CAP. The radiographic pattern of the i nfil­ trate may suggest a specific diagnosis (e. g . , volu me loss, peripheral pattern, re­ cu rrence i n the sa me a rea) And, finally, has the patient had the expected response to therapy, or has the i nfiltrate persisted or increased in size? An a lgorithm based on these principa l considerations beg i ns with empi ric therapy for CAP when the rad iograph and symptoms a re reasona bly sugges­ tive. If the patient responds to treatment and radiographic clea ring occurs, then no further investigation is needed. If atypiccil features a re present, progression or recurrence occurs, or there is no i mprovement, then consider other etiologies. 5. When a pulmonary infiltrate progresses or fa ils to resolve after specific ther­ a pies, consider the causes of chronic pul monary infiltrates summarized by the mnemonic ALVEOLAR LI ST: Alveolar cell carcinoma, Lym phoma, Vasculitis, Eosi noph i l ic pneumonia, Orga nizing pneu mon ia, li poid pneumon i a , Alveolar protei nosis, Reflux/aspi ration, LIP/DIP (lymphocytic and desquamative i n tersti­ tial pneumonitis), Infection (e. g . , TB, fungi), Sarcoidosis, and Tracheobronchial obstruction. This m nemon ic refers to the fact that the ma iority of these entities show an alveolar-fi lling pattern on chest x-rays A few other etiologies may rarely cause a chronic alveolar i nfi ltrate, including amyloidosis, alveolar m icro­ l ithiasis, and si lent m itral stenosis. 6 . The fol lowing mnemonic offers a more deta i led summary of the causes of pul monary infiltrates:

CA N IT B E A PE?

CHF (pulmonary edema) Aspiration (e.g., food, oil , G E R D ) Neoplasm (airway obstruction, bronchoalveolar cell carcinoma, Iymphoproliferative disorders) I nfection (bacterial, fungal, viral, mycobacterial, protozoal, helminthic) T -cells/B-cells (LI P, sarcoidosis, hypersensitivity pneumonitis) Pulmonary and Critical Care . 4 7

BOOP (organizing pneumonia) Eosinophils (PIE syndromes) Alveolar hemorrhage (e.g., vasculitis, coagulopathy, focal processes) Protein (al v eolar proteinosis) Embolus (e.g., thromboemboli, tumor emboli, septic emboli) P U L M O N A RY N O D U L E A NODULE

Age N icotine O ld Films Doubling time U nderlying diseases Lymph nodes Examinations N otes 1 . The find i ng of a solitary pulmonary nodule is cause for concern. The potential etiologies are many, and same major causes a re summarized i n note number 1 1 . Even th is long l ist is not comprehensive, a nd so a more practical approach to the solitary pulmonary nodule is outli ned by the m nemonic A NODULE. 2. The most critical q uestions to answer a re whether or not the nodule repre­ sents a malignancy and if su rgery is i nd icated . Severa l historical elements i n­ crease the cha nce of a malignancy, and a stepwise approach also is outli ned by the m nemonic a bove. 3 . A.J1 age g reater than 35 i ncreases the cha nce of malignancy. Therefore, a more aggressive diag nostic strategy may be u ndertaken i n an older patient. 4. N icotine addicts (smokers) have a g reatly i ncreased i ncidence of broncho­ gen ic carcinoma . A smoking history mandates a more aggressive approach. 4 8 • Pulmonary and Critical Care

5 . One of the fi rst thi ngs to find out is whether or not old films a re available, to determine if the nodule is a new find i n g . A lesion that was present on an old fil m is much less likely to be malignant. 6 . The doubling time of a nodule may indicate whether or not it is l i kely to be malignant. Ma lignancies usually dou ble in size after 20 days but before 450 days. Benign lesions may g reatly i ncrease i n size i n less than 20 days and often are due to i nfections. Also, a ny lesion that does not double i n 450 days is much less likely to be malignant. 7. Consider the patient's underlying diseases. Is this patient a smoker with em­ physema and at i ncreased risk for cancer2 Does the patient have a known ma­ ligna ncy? Evidence of pneu monia a n d i n fecti o n ? Evidence of a collagen vascular disease or an i m munodeficiency syndrome? Ma ny h istorical features are ind icative of specific etiology for the nodule. 8 . Physical exam ination may reveal lymphadenopathy i ndicative of malignancy or i nfection . Also, if a lymph node is detected , th i s should be the fi rst site of biopsy. It will be easier to biopsy tha n the lung lesion and will esta bl ish stagi n g . 9 . F i nally, diag nostic examinations should b e undertaken . T h e choice o f tests depends, of course, on the patient and the a bove-mentioned risk factors, which will determine how aggressive the physician can be i n trying to identify whether or not the lesion is malig nant. Exam i nations i nclude CT scans, fine needle aspi­ ration of the lesion , bronchoscopy with biopsy, thoracotomy with biopsy, or, i n some cases, mediasti noscopy. Recent evidence h a s shown that PET sca n n i n g may b e a ble t o differentiate mal ig nant from ben ign lesions. 1 0. The finding of multi ple nodules ind icates different types of disease. The cat­ egories of disease to be considered i nclude developmental a bnormalities, infec­ tious d i seases, i m m u nolog ic d i seases, m etastatic neoplasms, and tra u matic i n j u ry, as well as i d i opath ic causes . I n AIDS patients, m u ltiple nodu les may occur secondary to PCP, tuberculosis, cryptococosis, CMV, Kaposi's sarcoma , lymphoma, and pyogenic organ isms (staph, strep) . 1 1 . Here is a partial list of causes of pulmonary nodules:

LEAVE T H AT C H EST A LO N E P L EA S E

lung cancer Embolism Aspirated foreign body Vasculitis Echinococcus Tumor metastasis Heart worm Amyloidoma Tuberculosis Pulmollary and Critical Care • 49

Coccidioides and other fungal diseases Hamartoma Enlarged pulmonary artery Sarcoidosis Teratoma Arteriovenous mal f ormation Lymphoma Organizing pneumonia/BOOP Necrobiotic nodules (rheumatoid arthritis) Eosinophilic granuloma Pseudotumor Localized anthrosilicosis End ot h e l i a I tumor (hemangiopericytoma) A telectasis (round) Sequestration Erythrocytes (hematoma) R E F R AC TO RY H Y P OT E N S I O N CRAS H I N G

Cardiovascular Respiratory Addison's/Acidosis Sepsis/toxic Hypocalcemia I naccurate reading Neurologic G I bleed/internal bleeding N otes 1 . Although there o re many causes of hypotension , when refractory hypoten­ sion is encountered, you must consider a very specific list of possible etiologies . 50 • Pulmonary and Critical Care

Turn to this list when a patient's blood pressure fa i ls to i ncrease despite use of i n­ travenous fluids or pressor agents . Many of these causes of refractory hypoten­ sion a re emergencies and require u rgent treatment. 2 . A s i m ple system for remembering the causes of refractory hypotension is summarized by the m nemonic CRASH ING, or by the m nemonic TERMINAL­ Toxic/drugs, E ndocri ne/electrolytes, Respi ratory, Myoca rd ial/vascular, Infec­ tion/sepsis, Neurolog ic, Artifact, Losing blood . 3 . Cardiovascular causes include right ventricular i nfarction , pul mona ry em­ bol ism, cardiac ta m ponade, a rryth m i a , and massive leh ventricula r i nfarction . Respiratory causes ohen are seen in patients on the ventilator and i nclude ten­ sion pneumothorax and auto-PEEP, which occurs when patients are over-venti­ lated or have severe a i rway obstruction. E ndocrine causes i nclude Add ison's disease, and systemic acidosis may cause hypotension. Sepsis/toxic causes i n­ clude bacterial septic shock, toxic shock, a na phylaxis, a n d d ru g overdose . Hypocalcemia may cause hypotension si nce vascular tone and pressor agents are ca lcium dependent. I naccurate blood pressure readings may result from poor blood pressure cuff fit, peripheral vas.cular disease, and venous obstruction (e. g . , superior vena cava syndrome), leading to a false impression of refractory hypotension . Neurologic causes i nclude CVA, spinal cord injury, and epidural anesthesia. GI bleeding may be occult, or blood loss may occur i n the thorax, retroperitoneal area , or a bdomen . 4. The following m nemonic lists specific causes o f refractory hypotension :

ALAR M , B P THAT'S D R O P P I N G

A rti f act (poor cuff fit, peripheral vascular disease, superior vena cava syndrome) Liver failure Arrhythmia Right ventricular infarct Massive left ventricular infarct B lood transfusion Pulmonary embolism Tamponade Hypocalcemia Addison's Tension pneumothorax � epsis Pulmonary and Critical Care . 5 1

Drugs/toxins (anaphyl a xis, drug overdose, snake venom) Rewarming hypothermia Occult blood l o ss Pancreatitis P EEP/auto-PEEP I ntubation (usually transient) Neurogenic (spinal cord injury, epidural anesthesia, dysautonomia) Gastrointestinal bleeding SARCO I DO S I S H I LAR N O D E S *

Hepatosplenomegal y I nterstitial fibrosis, pulmonary Lymphadenopathy A rth ra Ig ia/a rth ritis Renal·(calcium metabolism abnormalit i e s, nephrolithiasis) Neurologic involvement (unilateral facial paralysis, chronic meningitis, mass lesion) Ophthalmologic (uveitis, conjunctival granulomas, sicca syndrome) Diabetes insipidus/other pituitary deficiency Erythema nodosum/other skin lesion Sali vary gland enlargement, bil a teral *

Clinical characteristics

52 • Pulmonary and Critical Care

-

SARC O I D BLU ES * *

S kin rash A rthropathy/arthralgias Respiratory Central nervous system O ptic (uveitis, iritis) I ncidental finding on chest x-ray Dysrhythmia/cardiac dysfunction Bone marrow/spleen Lofgren's syndrome (erythema nodosum, fever, malleolar, join pain, hilar adenopathy) Uveoparotid fever (e.g., Heerfordt's syndrome) Ear, nose, and throat Syste m i c symptoms (fever, chills, myalgias, hypercalcemia) * *

Possible presentations

N otes 1 . Sarcoidosis is a m u ltisystem d i sease . Vi rtually any organ system may be i nvolved . • Pu lmonary i nterstitial i nvolvement (up to 1 00%) • Lymphadenopathy, hi lar/mediasti nal (75-90%) • Arthra lgia/arthritis ( 25-50%) • Bone ma rrow ( 1 5-40%), but rarely symptomatic beyond m i ld anem i a , neutropenia, a n d eosi noph ilia • Hepatomegaly/liver enzyme elevation ( 20-30%) • Ophthal molog iC (25%): uveitis (75-95% of eye cases) • Erythema nodosum (25%), skin lesions • Upper respi ratory tract (up to 20%) • Sal ivary gland, parotid enlargement, bi lateral ( 1 0%) • Splenomegaly (5- 1 0%) • Neurolog ic i nvolvement (5%): u n i lateral facial paralysis (most common ) , papi lledema , hearing a bnormal, hypotha lam ic/pitu itary lesion , chronic meningitiS , mass lesion , seizure • Cardiac disease (5%) arrhyth m ias, heart block , pericorditis, CHF • Renal ca bum meta bolism a bnormal , nephrolithiasIs (rare , < 5%) • Diobetes i nsipidus or other pituitary deficiency Pulmonarv and Cntical Care • 53

2 . Pul mona ry, ocular, lym ph node, and ski n cha nges a re the m ost com mon, clinically important features. 3 . Many cases are found inCidental ly on chest x-ray. In fact, this is one of only a few diseases in which a patient may have a ma rkedly a bnormal chest x-ray, but a ppear q u ite healthy. . 4 . The disease pathogenesis may be related to exaggerated helper T-cell activity. 5 . Hyperca lcemia is d ue to an i ncrease in 1 , 2 5-hydroxylase activity i n the g ranulomas. It often responds to steroid thera py. 6 . Certa in factors are associated with progressive d isease i n sarcoidosis, the presence of which may be reason for more agg ressive i n itial thera py. These factors i nclude c h ronic uveitis, chronic bone d isease, neph roca lci nosis, skin plaq ues, lupus pern io, and pulmonary i nfiltrates without nodu les ( "type 3 " pul­ monary sarcoidosis) .

54 • Pulmonary and Critical Care

--

IDI

H EM ATO L O G Y General Considerati ons

The d i fferential diagnosis for a hematolog ic disorder can be developed using the MEDICINE DOC categories: Metabolic (e.g . , a myloidosis, B 1 2 and folate deficiencies) E ndocrine (e.g . , para neoplastic synd romes, adrenal i nsufficiency, hypothyroidism) Drugs/med icines (e. g . , anti biotics, alcohol, chemotherapy toxicity) Infection (e.g . , HIV-related, TB, systemic i nfections) Conge n i ta l (e . g . , Fanco n i 's, c h ronic granu lomatous d i sease, prote i n C deficiency) Immunologic ( e . g . , hemolytic anemia, ITP, autoimmune neutropenia)

Neoplastic (e.g . , leukemia, lymphoma, metastatic disease) Exotic diseases (e. g . , sarcoid, porphyria, Wegener's)

Degenerative (?myelodysplasia; also premalignantl Occupational/environmental (e. g . , radiation, hydrocarbons, heavy metal poisoning) Ca rd iovascular (e . g . , i ntracard iac shunt, hypercoagula ble states causing DVT/PE) Problems considered in the hematology section primari ly i nvolve the bone marrow and ohen a re made manifest by a decrease or i ncrease i n one of the primary blood cell types: RBCs, WBCs, and platelets. Also i ncluded are a bnor­ mal ities of the spleen and disorders of coagulation .

Hematology • 55 ,

C l i n i ca l Sym ptoms and S i g ns

AN E M IA M CVS

pro blem M arrow ption/ de struct ion Cons um increase (hemodilution) Volume Stool/m e nstrual / occult losses N otes 1 . Anem i a is defi ned as a d rop in the hemoglobi n conce ntration . The fou r basic mech anisms a re l isted a bove. Exa m i nation o f the peri pheral smear and red cell indi ces ( i . e , mean cell volume [MCV] , RBC distribution width) is the first step in eval uation of a nemia . The MCV is the most helpful vrde\ to guide the & work-up . The m nemonic "MCVS" helps to na rrow down the ffer� ntial by clas­ sifyi ng an a nemia as microcytic, normocytic, or macrocytic . 2 . Marrow problems are characterized by a decrease i n production of RBCs. There may be a defiCiency in com ponents needed for normal RBC synthesis; the ma rrow may be i nvaded and replaced by an i nfiltrative process such as a ma­ lignancy ( " myelophthisic process"); or there may be primary marrow dysfunction (" myelodysplasia" ) . Marrow problems may be m icrocytic ( i . e . , processes that per­ turb hemogl obin production, such as i ron deficiency), narmocytic ( i . e . , myelo­ dysplasia), or macrocytic (i . e . , processes that i n terfere with R BC maturation , such as B 1 2 deficiency). 3 . Consum ption/destruction of eryth rocytes occurs in patients with a utoi m­ m u n e or neoplastic d i seases (hemolytic anem i a ) , m ec h a n i ca l heart valves, severe systemic ill nesses such as sepsis (DIC), or thrombotic thrombocytopenic purpura (TI P) RBCs are destroyed either by antibodies (autoi m mune disorders) or a n i ntravascular cause ( mecha n ical heart valve or blood vessel process) . I ntravascul ar i n j u ry i s called " microangiopathic, " and the periphera l smear fea­ tures damaged RBCs called "schistocytes . " Consum ptive/destructive processes are accompan ied by increased bone marrow activity and more reticulocytes i n t h e peripheral smear. S i nce the reticulocyte is a you n g , la rge RBC , there is a n

56 • Hema tology

i ncrease i n the Mev. Thus these processes usually are macrocytic, u nless there is concomitant marrow fa ilure l i . e . , iron deficiency from chronic hemolysis). 4. Volume increase causes hemod i lution and a decrease in hemoglobi n con­ centration . This situation is' encountered when dehydrated patients receive i ntra­ venous flu ids. Also, in acute blood loss, i ntravenous fluids may make the blood loss man ifest si nce the i n itial hemog lobin may be norma l . The MeV is u naf­ fected by volume increase and is usua lly normocytic. 5. Stool/menstrual/occult blood losses frequently are accompan ied by iron deficiency and a re com mon causes of m icrocytic a nem i a . Young women are often a nemic because of monthly menstrual blood loss. The other common cause of blood loss is occult GI bleed i n g lead i n g to hemoccult positive stools. Less commonly, occult blood loss occurs from an i nternal source, such as a retroperi­ toneal bleed . Retroperitoneal bleeding may occur after an i nvasive procedure or as a compl ication of a nticoagulation. In add ition to a drop in the hemoglobin , the BUN i ncreases from a bsorbed heme metabolites. 6 . The m nemonic below d ivides the anem ias into categories accord ing to the MeV: m icrocytic, normocytic, or macrocytic. .

IT'S A N E M IA'S B RA N D

ron deficiency Thalassemia S ideroblastic anemia

Microcytic

I

Usually Normocytic

Anemia of chronic disease Nephrogenic anemia (uremia) E ndocrine disorders Myelophthisis (marrow infiltration) I V fluids A plastic anemia S ickle cell anemia

Usually Macrocytic

B 1 2 deficiency Reticulocytosis/hemolysis Alcohol/cirrhosis N utritional deficiency (folate) D rugs (D NA synthesis inhibitors, D ihydrofol a te reductase inhibitors) Hematology • 57

--

exfol iative ski n diseases, hemod ialysis), and malabsorption. Drugs that i n­ h i bit dihydrolate reductase (e. g . , methotrexate, triamterene) or DNA metab­ olism (e . g . , 5-FU, hydroxyu rea , azath iopri ne, AZT, acyclovir) a lso cause a macrocytic anem i a . 1 0. The work-up o f anemia i ncludes ruli ng out occult blood loss (usually stool or menstrua l!, exa m i nation of the peripheral smear, checking for deficiencies (iron, folate, or B 1 2! , a reticulocyte count to assess marrow activity, a hemolysis work­ up (bilirubin, LDH , ha ptoglobin, serum free hemoglobi n ! , and possibly a bone marrow biopsy. 1 1 . The reticu locyte count is a n i nd ication of the ma rrow's capaci ty to make RBCs. Here is a slightly different mnemon ic for anemia [still based on MCV) that emphasizes the importance of the reticulocyte count:

IT'S A R ETICS D E F ECT

I ron deficiency Thalassemia S ideroblastic anemia

Microc ytic

Usually Normocytic

Aplastic anemia Renal failure Endocrine disorders Tumor/myelophthisis Illness/I nflammation (chronic disease) Cirrhosis (may cause macrocytosis or spur cell anemia) Sickle cell anemia Usually Ma crocytic

D rugs (D NA synthesis inhibitors, D ihydrofolate reductase inhibitors) EtOH Fol a te Erythroleukemia (Di Guglielmo's ) Cobalamin deficiency ( 8 1 2 ) TTP/hemol y sis

Hematology • 59

7. Microcyti c anemi as are due to a deficiency of one of the three ma jor con­ stitue nts of hemoglobin : iron, globi n, and porphyrin . Hemoglobi n compri s�s. 90% of the protein in the RBC , so microcytic cells are small and pale. Iron deflc le �cy is seen in states of chronic- blood loss (stool , menstrual, occult) . RBC destruction ( he m olysis) , or nutritiona l deficiency (vegetari an d iet) . The thalassemi� s are a d iver se group of d iseases re sulti ng i n defecti ve globi n cha i n prod uction . The side robla stic a nemi as are characterized by " ringed sideroblasts" in the marrow and abnormal porphyrin syn theSi s . They may be hered itary ( rare, X-linked) . acquire d (alcohol, isoniazi , lead). or idi opathic ( premali gnant) . . . 8 : Normocytic anem i a IS seen in many d ise ase states . The a nem i a of chron� c d i sea se is seen whenever th ere i s long-standi ng i nflamma tion or syste m i c d i S­ ea se . It is characteri zed by low serum iron and total iron-bind ing capa c i ty, but an e l evated or normal serum ferriti n . N ephrog eni c a nem i a is caused by re­ d U ce d erythropoetin levels a n d can b e ameliorated by erythro poeti n repla ce­ m e n t therapy. E ndocri ne di sorde rs ohen feature a normocytiC anemia because an y hormones affect R BC proliferati on , inclu ng thyroxine, glucocorticoids, di e stOsterone, a nd growth . � or mo ne. Less commonly, hypot hyroidism .causes m a c ro cytosis . Myelophth i s I s i s m arrow i nfi ltration by neoplasm , i nfect i on , or m eta bolic isease ( neoplas m s can d ca use anemia by a variety of mechan isms, I n c l u di ng myelop hthisis, hem olyti C ane mia, occult blood loss, nutr itional defi­ C i e n cy, or the effects of che �atherapy)·. Myelophthisic processes cause a nor­ m Ocyti c anem ia, and the peri pheral smear may show immature eryth rOi d forms a n ? , o ccasion ally, ma rked n eutrophi l i a ( "leu kemoid reaction " ) . I ntravenous l f U i d s cause a d ilutional decrea se i n hemoglobin conce ntrat ion and may u n ma sk nemia after acute blood loss . Apl a st i c a nem ia may be a primary a a r r o w failure or secondary to d rug tox icity. S kl e ce ll a nemi a , a hemogloic I n o Pathy, features abnormally shaped cells, but the MCV i s usually normal . �. MacrocytiC anemi as are usually a result of an i m pai rment of DNA repl ica­ hon . Often the LDH level is very high due to accelerated turnover in the marrow or P �ri pherally. B 1 2 ( cobala m i n ) deficiency can occur in several settings, i �­ u d �I l n g gastroi ntestina l disea se, c h ron i C nitrou s ox ide use , and, rarely, nutn­ tl o n a l deficiency. Both B 1 2 and folate are important cofactors in DNA syntheSi S , a nd a deficiency in either r�sults i n large, abnormal R BCs . Macrocytosi S also occ u rs w ith R BC destrud on le .g . , h emolytic anemia, TIP) because of compen­ sato ry reticulocytosis (see above) . A l cohol depresses bone m a rrow R B C production, causi ng anem ia , often m ac r c O ytic . Alcoholics may ha ve pri ma ry macrocytosis (usua lly modest) o.r sec­ on d a r y macrocytosis from folate and /or B 1 2 defi Ciency. Anemia in cirrhoti C pa­ e nts lI may be mic rocytic, norm ocytic, or macrocytic beca use of thei r myriad p rob l e ms including blood loss, nutriti onal deficiency, and the effects of chron ic d l seo se . L ess commo nly, c i rr h oti cs have a hem ol ytic anem ia ca l led s pur cell m l a t hat is caused by the a bnorm al li poprotein balance present in advanced r d l s ase The d a gn s l s s IT\ de when a ci rrhotic patient has eVi d ence of l � ,� � he mo lys� c s t er ac pur cha cells i n the periphe ral smear. r � lS l l s w i th . ' N u t r i tional defic i ency of folate i s seen i n starvation , cond itions w i th I n­ cre a Se d requ irements ( pregna ncy, ma l i g n a n cy, ch ron ic hemolys i s , chron ic

�

�

�

�:

58 . Hematology

B L E E D I N G D I AT H E S E S A PTT

A natomic abnormality (e.g., AVM , peptic ulcer) Plasma protein abnormality T hrombocytopenia/qualitative platelet abnormality Trauma N otes 1 . A bleed ing problem is most commonly related to an anatomic abnormality. Congenital a bnormalities such as an arteriovenous malformation or acquired de­ fects such as peptic ulcer disease a re com mon . Plasma protein abnorma lities are less common and may be made manifest with unexpected hemorrhage asso­ ciated with a m inor surgical procedu re . Thrombocytopenia has many causes and is relatively common, but qualitative platelet abnormalities a re rare. Finally, trauma is a common cause of hemorrhage and usually obvious, but excessive bleedi ng or bru ising aher minor trauma may i ndicate an occult bleedi ng diathesis. 2. The APTI, PT, platelet count, and bleeding time a re the primary laboratory studies obtained when i nvestigating a possible plasma protein abnormality or quali­ tative platelet defect. Other tests i ncluding thrombin time, fibrinogen assay, clot solu­ bility and lysis, and factor assays may be helpful in identifying specific deficiencies. Pri mary Hemostatic ( Platel et) D i so rd e rs

Platelet adhesion defects:

Von Willebrand's disease Bernard-Soulier syndrome (absence, dysfunction of Gp l b/IX)

Platelet aggregation defects

Glanzmann's thrombasthenia (absence, dysfunction of Gp l l b/llla)

Platelet release defects •

Decreased cyclooxygenase activity Drugs-aspirin, nonsteroidal anti-inflammatory agents Congenital

Platelet coagulant defect Scott's syndrome

Gp

=

glycoprotein.

60 • Hematology

•

• •

Granule storage pool defects Congenital Acquired Uremia Platelet coating (e.g . , penicillin or para proteins)

Relatio n s h i p Between Secondary Hemostatic Disorders and Coagu lation Test Abnormal ities

Prolonged partial thromboplastin time (PTI) No clinical bleed ing - factors XII, HMWK, PK Mild or rare bleeding - factor XI Frequent, severe bleeding- factors VIII and IX Prolonged prothrombin time (PT) Factor VII deficiency Vitamin K deficiency -early Warfarin anticoagulant ingestion Prolonged PTI a nd PT Factor II, V, or X deficiency Vitamin K deficiency- late Warfarin anticoagulant ingestion Prolonged thrombin time (TI) Mild or rare bleed ing- afibrinogenemia Frequent, severe bleeding -dysfibrinogenemia Heparin-like inhibitors or heparin adm i nistration Prolonged PT and/or PTI not corrected with normal plasma Specific or nonspecific inhibitor syndromes Clot solubility in 5 M urea Factor XIII deficiency Inhibitors or defective cross-linking Rapid clot lysis Alpho2 plasmin inhibitor HMWK

=

high-molecular-weight kininogen; PK

=

prekallikrein .

Both tables fram Handin R I : Bleeding and thrombosi s . I n Isselbacher KJ , et a l (eds) : Harrison's Principles of Internal Medicine, 1 3th ed . New York, McGraw-Hi l l , Inc . , 1994 , pp 3 17-3 2 2 ; with permission.

S P L E N O M E G A LY BA N T I 'S

B lood flow problem Anemia/erythrocyte problem Neoplasm/infiltrative disease Thyrotoxicosis I nfection Sarcoid/Systemic lupus erythematosus Hematology . 6 1

,..

N otes 1 . Banti's syndrome is the eponym used to describe congestive splenomegaly with hypersplen ism . Using " BANTI ' S " as your g u ide, the ca uses of spleno· megaly can be classified in six categories . Blood flow problems cause spleno· megaly by increased splenic vei n pressures and consequent congestion . Splenic vei n thrombosis (often secondary to pancreatitis), portal vei n thrombosis or ex· tri nsic compression, ci rrhosis, hepatic vein thrombosis (Budd-C h i a ri synd rome), and CHF all cause congestive splenomegaly Anemias secondary to erythro­ cyte abnormalities (e . g . , thalassemias, sickle cell d isease, hereditary spherocy­ tosis) cause splenomegaly because there is hyperplasia of the reticuloendothelial system associated with the destruction of the a bnormal RBCs . These diseases also may cause splenic i nfarction (i e , sickle cell). Neoplasms and infiltrative diseases d i rectly involve the spleen and lead to its enlargement. I n myeloproliferative syndromes and myeloph thisic processes, because of marrow hypofu nction, there may be compensatory extra medu l la ry h e matopoiesis causing splenomega ly. Thyrotoxicosi s is associated with splenomega ly beca use of thyroid hormone-ind uced lym phoid hyperplasia . Numerous i n fections, usually chronic, may ca use splenomega ly. Disorders of i m m u ne reg u lation such as sarcoidosis and SLE may feature splen omega ly. Other examples i nclude rheumatoid arthritis ( Felty's syndrome), serum sickness, and immune hemolytic anemias. 2. The deg ree of splenomegaly va ries with the d isease entity. Massive splenomegaly occurs in chron ic myelocytic leukemia, myelofibrosis with myeloid meta plasia, ha i ry cell leuke m i a , Gaucher's and N iema n n·Pick diseases , sa r· coidosis, thalassemia major, chronic malaria, congenital syphilis, leishmaniasis, and some cases of portal vein obstruction. These are chronic d iseases in which the spleen slowly enlarges. Rupture of the spleen may be seen in acute infec­ tious processes such as EBV mononucleosis, malaria , and typhoid fever. 3 . Here is a more com prehensive listi ng of the causes of splenomegaly:

HIS BIG SPLENIC MASS

Hepatic vein obstruction (Budd-Chiari) Infection S plenic vein thrombosis (e.g., pancreatitis) Berylliosis Infiltrative diseases (e.g., Gaucher's , amyloid, eosinophilic granulomatosis) Grave's diseas.e/hyperthyroidism 62

• Hematology

S LE/collagen vascular diseases

Portal vein obstruction Liver disease (cirrhosis) E rythrocyte abnormality (e.g., spherocytosis, sickle cell, thalassemia) Neoplasm (lymphoma, myeloproliferative disease, metastatic) I ron deficiency C HF (congestive splenomegal y ) Myeloproliferative disease A utoimmune-hemolytic anemia Sarcoidosis Serum sickness/drug reaction 4 . Always consider an occult, i nfectious etiology for splenomegaly si nce these

diseases a re likely to respond to appropriate thera py. There a re numerous infec­ tions associated with splenomegaly, many of which a re I �sted in Chapter IV (see " I nfections Causing Splenomegaly" ) .

C linica l Conditions or Diagnoses

EOSI NOPH I LIA ALLERG I C

Addison's (adrenal insufficiency) Lymphoma/malignancy L-tryptophan Eczema/skin diseases Respiratory diseases (asthma, allergic bronchopulmonary aspergillosis, P I E syndromes) Gastroenteritis I nfections (helminths, coccidioides mycosis) Collagen vascular diseases Hematology • 63

N otes 1 . Eosi noph ilia is defi ned as > 500 eosinophils/m icroliter of blood . E osino­ philia has d iverse disease associations, but "ALLERGIC" reactions are probably the most com mon . Allergic reactions to drugs, pol lens, micro-organisms, and other antigens can sti m ulate eosi noph ilia. 2 . Addison's disease frequently features a moderate eosinophi lia that resolves with admin istration of corticosteroids . Lymphoma is the malig nancy most com· monly associated with eosi noph i l i a , although associations with m a ny sol id tumors have been described . Tumor-associated eosinoph ilia is probably a result of i n terleu kin-5 secretion a n d often ind icates a widely d isse m i nated tu mor. Eosinophilic leukem ia is a rare hematolog ic neoplasm with dra matically h i g h eosinophil counts. L-tryptophan preparations from a single source were i m pli­ cated in the eosinoph il ia-mya lgia syndrome, a potentia lly fatal , m u ltisystem dis­ ease. Eczema a nd several other skin diseases ( e . g . , pem ph igus , mycosis fungoides) may be associated with eosi noph ilia . Several respiratory diseases feature eosi noph ilia, i ncluding asthma and the PIE ( pu l monary infiltrates with eosi noph ilia) syndromes . The PIE syndromes i n­ clude acute eosinoph i l ic pneumonia, chronic eosi noph ilic pneumon ia, Churg­ Strauss vasculitis, parasitic infestation ( i . e . , "tropica l" pneumonia), and al lerg ic bronchopulmonary asperg illosis (ABPA) The hypereosinophilic syndrome, a m ul­ tisystem disease, may cause eosi noph i l ic i nfiltration of any organ including the lungs. Drugs also can cause eosi noph ilia with pulmonary i nfiltration . Eosinoph i l ic gastroenteritis is cha racterized by eosinophilic infiltration of any portion of the gastrOintesti nal tract, peripheral eosi noph i l ia (75% of cases), and inflam matory d ia rrhea . I n fections with hel m i nths typically ca use eos i no­ p h i l ia , and cocc idioides mycosis is u n i q ue a mong fungal i nfections in its propensity to elicit eosinophilia . Collagen vascular diseases such as rheuma­ toid arthritis, eosinoph ilic fasci itis, allerg ic angi itis, sarcoidosis, and Wegener's granulomatosis also a re associated with eosi noph ilia. 3. The eponym Loeffler's has been a ppl ied to PIE syndromes, the id iopathic hy­ pereosinoph i lic syndrome, and to eosinophilic endocard itis . Loeffler originally descri bed tra nsient pulmonary i nfiltrates with eosinop h i l i a , which m ay have been related to ascariasis i nfestation . Although it has no specific definition, the name is sti l l u sed in cases of i d iopath ic, ben i g n pul monary i nfi ltrates with eosinophilia. 4. The cytokine IL-5 is an i m portant sti m ulator of eosinoph ils and is probably i n­ tegral in many or a l l causes of eosinoph i l i a . The folloWi ng mnemonic, empha­ sizing the role of IL-5 , lists the causes of eosi noph ilia:

64 • Hematology

P LASMA I L- F I V E RAG E

Parasites L-tryptophan Addison's Sarcoidosis Malignancy (e.g., Hodgkin's, CML, gastric, ovarian, lung, pancreatic cancers) A Ilergy/A topy (e.g., drugs, serum sickness, hay fever) Idiopathic hypereosinophilic syndrome Lung diseases/Loeffler's Fungal (A B PA, coccidioides mycosis) I gE hypersecretion (Job's syndrome) Vasculitis/collagen vascular disease Eczema/skin diseases Recovery from bone marrow transplant Angiogram/Atheromatous emboli ("cholesterol emboli") Gastroenteritis E ndomyocardial E RYT H R O C YTO S I S H I RBCS

H ypoxia/hypoventilation I nappropriate erythropoietin Relative polycythemia (stress, dehydration) Bone marrow disorder Carboxyhemoglobin/congenital hemoglobinopathies . Steroids/androgens Hematology • 65

N otes 1 . Eryth rocytosis or polycythemia ind icates an i ncrease i n n u m ber of erythro­ cytes i n a sample of blood, which may or may not be a reflection of total body red cells. It is i m portant to disti ngu ish between absolute erythrocytosis, a true i n­ crease in total body red cell mass, and relative erythrocytosis, which occurs with dehydration (increase in RBC concentration ) and stress . 2 . The basic mechanisms of erythrocytosis a re summarized by "HI RBCS . "

H Y P E R C OAG U LA B L E S TAT E S PT I N R S

P latelets Trauma 1 m m obo I ization/stasis Neoplasm RBCs Serum clotting factors N otes 1 . Nu merous d isorders may predispose patients to thrombosis. Frequently, the history and physical examination reveal a likely etiology. Factors predisposing to thrombosis include obesity, varicose veins, trauma, general anesthesia, i mmobi­ lization, maligna ncy, CHF, oral contraceptives, infection , preg nancy, neph rotic syndrome, and blood protein defects. 2 . -Leiden factor 5, a mutation in which factor 5 is resistant to activated protein C, is the most common i n herited hypercoagulable condition known. Homozygous ind ividuals are at high risk for recurrent thromboembolic events. The risk for het­ erozygotes is less clear.

66 • Hema tology

3 . Protei n deficiencies may be difficult to identify. Current tests only identi fy 1 0-20% of the cases of familial thrombosis. Serum levels of proteins C and S will be affected by large thrombi and warfarin a nticoagulation . Deficiencies may be congenital or acquired . Antithrombin (ATI-1 II , protein C, and protein S are the most common congenital conditions. The most common acquired defects are AT-III and antiphospholipid antibodies. 4. The "lupus anticoagulant" is an anti phospholipid antibody that prolongs the PTI by interfering with phosphol ipid in the laboratory assay. It does not cause clinical bleedi ng, but rather predisposes to thrombosis and mid-trimester abortion. 5 . Urinary AT-I I I loss proba bly causes hypercoagulabi lily in patients with the nephrotic syndrome. These patients are pred isposed to renal vei n thrombosis and pulmonary embolism. 6. High levels of homocystine predispose patients to arterial as well as venous thrombosis. Homocysti ne also may be an important factor in the development of atherosclerosis. 7. An important drug-related cause of hypercoagulabil ily is hepari n-associated thrombocytopenia. The features are arterial thrombosis with falling platelet counts. Even low doses of subcutaneous heparin can cause this syndrome. A heparin-ag­ gregation study is avai lable for laboratory confirmation in suspected cases . 8 . Here is a more comprehensive list of hypercoagulable states:

D VT , P E A N D C L O T S

D rugs (e.g., tamoxifen, heparin) Venous catheter (central) Trauma (endothelial in j ury) Prosthetic valves Erythrocytosis (polycythemia) A nticardiolipin/A ntiphospholipid antibodies Nephrotic syndrome/N eoplasm Dysfunctional platelets/Dysfibrogenemia CHF/Collagen vascular disease (e.g., 8eh 285) ind icates the presence of osmotically active �.olutes such as ma n n itol or g l ucose . Glucose a nd m a n n itol a re osmotically :lctive solutes, which cause water movement out of cells and a d i lution of the plasma. Hyponatremia ensues but, si nce plasma osmolality is i ncreased, clinical manifestations of hypotonicity a re absent. The low serum sod ium is, in a sense, appropriate, si nce a normal sodium level would lead to an even h igher osmo­ lal ity. Th is scena rio is com monly encountered in patients with hyperglycemia, in whom correction of the high glucose levels with insulin is accompanied by a rise in serum sod i u m . An osmotic diuresis causes free water loss, and hypernatremia may result after clea ring the osmotica lly active solute. 3. A pathologic sod i u m disorder is defi ned by a low serum osmolal ity « 2 80), the causes of which may be d ivided i nto hypovolem ic, euvolem ic, and hypervolemic etiologies as listed on pages 1 48- 1 49. 4 . A normal serum osmola lity ( 2 80-2 85) suggests pseudohyponatremia d ue to a measurement error, which can occur i n severe hyperlipidemia or hyperpro­ tei nemia . Th is type of error is less com mon with newer laboratory techniques . 5 . Once pseudohyponatremia from measurement errors a nd accu mu lation of osmotically active solutes is ruled out, then a true, patholog ic sodium disorder is present. The patient's volume status is then used to elucidate the cause . Edematous states and profound volume depletion a re usua l ly obVious, but i n some cases it may be difficult to distinguish between moderate volume depletion, normovolemia , and modest volume expansion by physical exam ination a lone. 146 • Nephrology

6. Hypovolemic hyponatremia indicates salt losses in excess of water losses If a hyponatremic patient appears to be clin ically volume depleted, then it should be determi ned whether the losses are extra-renal (sequestration or skin ) or renal (osmotically active solutes, diuretic therapy, urina ry salt wasti ng , dopamine infu­ sion or m i neralocorticoid deficiency) . Measurement of the urinary sodium estab­ l ishes the cause, with a h i g h u ri ne sod i u m (> 20 m mol/L) i nd icati ng renal losses, and a low urine sodium « 1 0 m mol/L) i ndicati ng renal sod ium conser­ vation and extra-renal losses. 7. Euvolemic hyponatremia is essential ly a result of excessive free water i ntake (with inadequate solute intake), or excessive ADH activity. Excessive, surreptitious, free water intake occurs with psychiatric illnesses. This condition may be d ifficult to d istinguish from SIADH, si nce patients do not acknowledge the problem . Other forms of th is i ntake imbala nce are "beer potomania," an excessive intake of hypo­ tonic fluids with little d ietary solute, and the "tea and toast" syndrome, in which elderly patients i nadvertently have a similar d ietary imbalance. The latter problem may be made man ifest when a d iuretic is prescribed to an elderly patient with a poor d iet. E levated ADH levels i n hibit the kid ney from excreting free water. The result is modest volume expansion (ohen clin ically inappa rent) and hyponatremia. The key feature of SIADH is a n i na ppropriately concentrated u ri n e i n the face of serum hypo-osmolal ity a n d normovolem i a . There a re many causes of SIADH, i ncluding drugs, neoplasms, and C N S d isorders . Some other states such as pai n , emotion , and the postoperative state may also temporarily i mpa i r water excretion , probably a s a result of an ADH-mediated mechanism . ADH i s proba bly i m po rta nt i n endoc r i n e causes o f hyponatremia such a s hypothy­ roidism and pure cortisol deficiency (Addison's disease usua lly results in hypov­ olemia and features salt-wasting). In SIADH , urine sod i u m usual ly exceeds 20 m mol/L un less fluid i ntake has been restricted . 8 . An i m portant d istinction to make in neurosurgical patients is between SIADH and cerebra l salt wasting (a hypovolemic state ) . Cerebral salt wasting is rela­ tively rare a nd may be re lated to elevated levels of atrial natr i u retic peptide (AN P). The diagnosis depends on establishing a reduction i n blood vol ume and ina ppropriate natriuresis. Volume restriction (as is appropriate in SIADH) may be hazardous in cerebral salt wasting si nce it can lead to cerebral ischem ia from vasospasm . The proper treatment is to mai ntain i ntravascular volume and correct hyponatremia with norma l sa line i nfusion . Dopa m i ne a lso sti m u lates ANP re­ lease and promotes natriuresis. 9 . A less well understood euvolemic state is "essential" hyponatremia or the "sick cell" syndrome. It is hypothesized that these patients have a reset serum "osmostat" « 2 8 0 m mol/L) and mai ntain a lower serum sodium due to reesta blishing the "normal" range of osmolality. Alternatively, it may also represent a state of elevated ADH activity secondary to an un known nonosmotic sti mulus. When osmolal ity is lowered sufficiently, osmotic inh ibition of ADH overcomes the nonosmotic stimulus. 1 0 . Hypervolem i c hyponatre m i a occurs with edematous states . Mec h a n i s­ tically, these conditions a re similar to the hypovolemic states in that the effective c i rculating volume is reduced and the kid ney conserves sod i u m ( u ri ne sod i u m < 1 0 m mol/L) . CHF is the most common cause o f hypervolemic hyponatremia, Nephrology . 1 4 7

b

and hyponatremia is associated with a poor prognosis Loss of plasma proteins (albuminuria , protei n-losing enteropathy) causes th i rd spacing of fluids, intravas­ cular depletion, and hyponatremia End-stage l iver disease impa i rs circu lation and plasma protein synthesis with consequent edema and hyponatremia . Renal fa ilure impairs the abil ity to excrete a normal volume of dilute u rine and results in hyponatremia and edema . Early in the course of renal failure, the volume expan­ sion may be modest, and patients may a ppear to have euvolemic hyponatremia . 1 1 . Treatment: In genera l , only severe , symptomatic hyponatremia and hypo­ natremia developing over 24 hours or less ( e . g . , patients with psychogenic polyd i psia, surgical and obstetric patients) should be treated with hypertonic so­ lution and more prompt correction . In the majority of patients, rapid correction

of hyponatremia i s hazardous and may lead to centra l nervous system damage (i . e . , centra l ponti ne myel i nolysis) A sta nda rd ru le is that the serum sodium should not be raised by more than 0.5 to 1 . 0 m mol/L per hour and no more than 1 2 mmol/L over 2 4 hours . Another maxim of hyponatremia treat­

ment is that the time for correction should approxi mate the ti m e course of devel­ opment ( i . e , ra pidly occurring hyponatremia should be corrected ra pidly, and more chronic conditions should be corrected gradually) . 1 2 . The following m nemonic separates hyponatremic conditions i nto four cate­ gories: pseudohyponatremia, and hypovolemic, euvolemic, and hypervolemic (edematous) states:

A S O D I U M WAT E R CA P E R Ps eudoh ypona tremia

A rtifactu a l Hypovolemic

S eq u estra t i o n , S k i n l o s s e s ( b u rn s a n d sweat i n g ) O s motic d i u re s i s D i u re t i c s I ntest i n a l l os s e s ( d i a rr h e a , vo m it i n g ) U ri n a ry s a l t wast i n g M i n e ra l ocort i c o i d d ef i c i e n cy Euvolemic

W at e r i n toxi c a t i o n A D H exce ss ( S I A D H ) T e m porary i m pa i rm e n t of water exc r e t i o n ( pa i n , e mot i o n , d ru g s , post-o p e rat ive ) E n d o c ri n e ( hypothyro i d i s m , p u re c o rt i c o l d ef i c i e n cy) R es et o s m ostat ( " s i ck ce l l " ) 148 • Nephrology

Hypervo/emic

C o n g est i ve h e a rt fa i l u re A l b u m i n u ria P rote i n- l o s i n g e n te ro p a t hy E n d-st a g e l ive r d i s e a s e ( c i rr h o s i s ) R e n a l fa i l u re

N E P H R OT I C SY N D R O M E MAD NEPH ROTICS M ed i cat i o n s/tox i n s/d r u g s A my l o i d o s i s D i a betes N eo p l a s m E n d oca rd i t i s/i nfect i o n s P ri m a ry g l o m e ru l a r d i s e a s e H e re d ita ry d i se a s e s R e n a l ve i n t h ro m bos i s O be s ity ( m o rb i d ) T hy ro i d d i s e a s e ( myxe d e m a a n d thyro i d it i s ) I nterstitia I neph ritis C h ron i c ref l u x/o b s t ruct i o n S L E , c o l l a g e n va s c u l a r d i s e a s e s

N otes 1 . Neph rotic synd rome is cha racterized by a l bu m i n u ria (> 3 . 5 g/d ) , hypo­ album inemia, and edema . Urinary loss of critical plasma proteins predisposes patients to thromboembolic events ( renal vein thrombosis, pul monary embolus), hyperlipidemia and accelerated atherosclerosis, vitamin D deficiency, and pro­ tein mal nutrition , as well as drug toxicity from decreased plasma protein binding . 2 . The majority of cases a re due to glomerular d isease (75%), including mem­ bra nous (40%), m i n imal change d isease, focal g lomeru losclerosis, membrane proliferative glumeruloneph ritis (GN), and mesang ioproliferative GN. Nephrology .

lL

149

3 . Systemic diseases, including diabetes mellitus, SLE, amyloidosis, drug reac­ tions, thyrOid disease, infections, and maligna ncy, as wel l as obesity, account for about 25% of cases. 4. Ma l i g n a nci es that may be assoc iated with nephrosis i nclude myelom a , Hodgkin's a n d non-Hodgkin's lymphomas, leukemia, a n d breast a n d GI tract carcinomas. 5. Drugs that cause the nephrotic synd rome i ncl ude gold, herO i n , penicil­ lamine, proben icid , captopril, and N SAIDs. 6 . Infections associated with the nephrotic syndrome include endocard itis, hepa­ titis B, shunt i nfections, syph ilis, and mala ria . 7. Evaluation of nephrotic syndrome includes 24-hour urine for protein and cre­ atine, serum albu m i n , cholesterol, and com plement. Rule out dia betes and SLE , as well as d rug exposure, u nderlyi ng maligna ncy, and infection If no systemic disease or exposure can be discovered , then a renal biopsy is ind icated .

R E N A L FA I L U R E BIG BUNS B l ood f l ow p ro b l e m ( p re-re n a l ) I n t r i n s i c re n a l d i s e a s e ( re n a l ) G I/i n te r n a l b l ee d i n g ( m eta b o l i s m o f h e m e ) B l a d d e r o u t l et o b s t r u ct i o n ( post-re n a l ) U retera l/c o l l ect i n g syst e m obstruct i o n ( p o st-re n a l ) N e p h rotox i n s (e . g . , d ru g s , r h a b d o myo lys i s , u ri c a c i d ) S te ro i d s (cata b o l i c states)

N otes 1 . An elevated blood urea nitrogen (BUN) level may indicate renal insufficiency (reduced GFR) or may occur secondary to increased catabolism of proteins (e.g . , steroid therapy) o r with i ncreased metabolism of heme products (e.g . , GI or other internal bleed ing). " BIG BUNS" prOVides a quick list of causes of a rising B U N . When renal i nsufficiency i s the cause o f a rising B U N , it is helpful to categorize etiolog ies as pre-rena l , renal, or post-rena l . Pre-renal azotemia occurs when renal blood is reduced and, as a consequence, renal fi ltration (GFR). Prerenal causes include volume depletion , heart failure, vascular disease, and shock. Renal 150 • Nephrology

causes of low urine output result from damage or disease of the renal parenchyma, including the g lomeru l i , i n terstitiu m , and tubules. Toxins, vasculitides, i nterstitial diseases, and primary g lomerulonephritides a re a mong the causes . Post-renal conditions that lead to low urine output a re characterized by on anatomic obstruc­ tion to u ri ne output. The most com mon of these is prostate enlargement, a lthough papillary necrosis, bilateral ureteral obstruction, and bladder outlet obstruction are possible causes. There is, of cou rse, overlap in etiologies (e. g . , CHF may pre­ cipitate ATNl , but this classification is useful in organ izing diagnostic possibil ities. 2. The following m nemonic l ists most of the causes of renal fa ilure accord ing to pre-rena l , renal, and post-renal mechanisms:

I CHASE A RISING B U N Pre-renal

I n t rava s c u l a r vo l u m e d e p l e t i o n ( d e hyd rat i o n , t h i rd spacing)

C a rd i a c ca u s e s ( C H F, M I , t a m p o n a d e ) H epatore n a l syn d ro m e A rte r i a l d i s e a s e ( r e n a l a rtery ste n o s i s ) S h ock E cl a m ps i a/obstetri ca l c o m p l i cat i o n s

Pre-renallRenal A cute tubular necrosis Renal

R a d i o g ra p h i c c o n t ra st a n d oth e r toxi n s ( d r u g s , r h a bd o myo l ys i s , h e m o l ys i s ) n t ra re n a l e m bo l i (ch o l e s t e ro l , D I C) S c l e ro d e r m a I n t e rst i t i a l n e p h ri t i s N ec roti z i n g vas c u l i t i s ( po lya rte r i t i s , n od o s a , Weg e n e r 's) G l o m e ru l o n e p h ri t i s

I

Pos t-renal

B l a d d e r obstruct i o n ( u s u a l ly p rostat i s m , s o m et i m e s b l oo d , p u s , ca l c u l i ) U rete ra l obstruct i o n (ca l c u l i , retro p e ri to n e a l fi b ros i s , ca n c e r) N ec r o s i s of re n a l p a p i l l a e ( d i a bete s, s i c k l e ce l l a n e m i a , N SA I D a b u se , i nfect i o n ) Nephrology .

151

br

3 . The usual approach again depends on the history and physical evaluation .

Frequently, prerenal causes a re obvious, such as C H F and ci rrhosis. Post-renal causes can be excluded in a ppropriate patients by placement of a Foley catheter. BUN and creati nine may further help to identify the pathogenesis I n pre-renal causes, BUN rises d isproportionately t o creati n i ne (often in a ratio of 2 0 : 1 or g reater) , while i n renal causes, creatine elevation usually is more pro­ nounced . Pre-existi ng renal disease may confound these para meters and is a common factor in low urine output. 4. When the etiology is sti ll in question, a renal u ltrasound is helpful to evaluate the collecting system for presence of obstruction and to assess renal size. Small, shrunken kidneys indicate long-standing d isease that is unlikely to be reversible. Normal or large kidneys may be ind icative of more acute disease. Certa i n sero­ logic tests and renal biopsy may be appropriate. Prompt renal biopsy is espeCially i m portant in cases of prog ressive renal i nsufficiency when i m m u nosuppressive therapy may preserve renal function (e. g . , vasculitis) . 5 . Hypocom plementemic renal failu re : "COMPS" Cryoglobulinemia Occult infection (endocarditis, "sh unt" nephritis) Membranoproliferative glomerulonephritis Post-streptococcal g lomerulonephritis Systemic lupus erythematosus Low complement levels a re occasionally helpful in the d ifferential diag nosis of glomerulonephritis, sign ificantly na rrowi ng the list of diag nostic possibil ities . The role of complement in glomerular i n jury and progression of renal insufficiency is not clear. In id iopath ic mem branoproliferative g lomeruloneph ritis, an antibody cal led C 3. nephritic factor is capable of inducing C 3 cleavage and proba bly causes the persistent depression of C 3 levels. This entity often is seen in associa­. tion with hepatitis B infection.

R E N A L S TO N E S OUCHS O xa l ate U rate C yst i n e H yp e rca l c e m i a S t ruvite

1 52 • Nephrology

N otes 1 . Kidney stones are among the most pa inful of afflictions, hence the mnemonic OUCHS. 2. Oxa late is a common com ponent of kid ney stones . Hyperoxa l u ria can occur i n mala bsorptive gastroi ntesti nal disorders, such as Crohn's disease and ulcerative colitis. Normally, free oxalate is bound by calci u m i n the gut and is not absorbed . Mala bsorbed fat binds calci u m , lead ing to free luminal oxa late. Free oxa late is read ily a bsorbed and then excreted in the urine. H igh levels of oxalate in the u rine precipitate calcium oXGJlate stone formation . 3 . Uric acid stones occu r with low pH a n d su persatu ration o f the urine with und issoc iated u ric aci d . Myeloprol iferative disease, chemotherapy, and Lesch­ Nyhan syndrome couse massive production and excretion of uric acid . In gout, dehydration, and id iopathic u ric acid l ithiasis, urine pH is usually low. U ric acid fac i l i tates heterogenous n ucleation of ca lci u m oxa late; th us, hyperuricosuria causes calciu m oxalate stones. 4. Cystine stones a re rare and a re seen in patients with hereditary cystinosis. 5. Hypercalcemia (e . g . , hyperparathyroidism, neoplastic hyperca lcemia) in­ creases urinary calci um concentration and precipitates calci u m stone formation. Hyperca lciuria may be id iopath ic or result from renal tubular d isease. I n distal renal tu bular acidosis, on al kaline urine and low uri nary citrate levels favor for­ mation of calcium phosphate stones. 6. Struvite stones (Mg N H4P04) occur mai nly in women and result from u rinary tract infections with u rease-prod ucing organisms (usually Proteus) . Struvite stones may grow quite large and fill the renal pelvis ("staghorn calculus").

Nephrology .

1 53

mID

ACID- BASE Genera l Considerations

A rte ria l B lood G a s I nte rpretation The interpretation of on a rterial blood gas can be sim pl ified by the steps out­ l i ned in the m nemonic "ABG READ" : Accurate ABG? ( Henderson-Hassel balch) Basic or acidic? (primary disorder) Go p/delta gop (onion gop) Respi ratory or metabol ic? Extreme disturbance? Appropriate compensation? Double or triple d isorder? F i rst, determine if the gas is accurate by determining the hydrogen ion concen­ tration [H+] using the Henderson-Hasselbolch equation :

A sim ple way to recall this relationship is to remember that [H+] increases as the pC02 increases or [HC03-] decreases The [H+] for a given pH can be de­ termined by either of the following methods: ( 1 ) Remember that at pH 7. 2-7 . 5 , every 0 1 u n i t change in pH changes [H+] concentration by . 1 0 m Eq/L i n the opposite direction . So, if [H+] for pH 7.4 is 40 m Eq/L, then [H+] for pH 7.5 is 30 mEq/L and [H+] for pH 7 . 3 is 50 mEq/L (2) With every 0 1 unit rise i n p H , multiply the preced ing [ H + ] b y 0 . 8 (e. g . , for a change i n pH from 7 . 4 to 7 . 5 , 40 mEq/L x 0 . 8 3 2 m Eq/L) . Conversely, for every 0 . 1 unit fa ll i n pH, mu ltiply the preced ing [H+] by 1 . 25 (e . g . , for a cha nge in pH from 7.4 to 7. 3 , 40 mEq/L x 1 . 25 50). The second method is slig htly more accurate, but either m ethod is usu­ a l ly sufficient for con f i r m i n g a ccu racy The follow i n g l i sts the [ H + ] for a g iven p H : =

=

Acid-Base • 1 55 (

pH 7. 8 , [H+] 1 6 .4 pH 7 . 7, [H+] 20 5 pH 7.6, [H+] 2 5 . 6 pH 7.5, [ H + ] 3 2 pH 7 . 4 , [ H+] 4 0 pH 7 . 3 , [ H + ] 5 0 pH 7 . 2 , [ H + ] 6 2 . 5 p H 7. 1 , [ H+] 78 5 pH 7.0, [ H+] 97.7 pH 6.9, [ H+] 1 2 2 . 1 The com ponents of the bica rbonate/ca rbon ic acid system a re always i n equ i librium i n the blood, a n d so pH, pC02, and [ HC0 3-] measured by venous blood chemistry should adhere to the constra ints of Henderson-Hasselba lch . If there is disagreement, then a la boratory or col lection error has occurred and repeat determination should be obtained . To assess the accuracy of oxygenation , add the p02 a n d pC02 . I f the tota l is g reater than 1 40 TORR (at sea level), then the patient was on su pplementa l oxygen or a la boratory error was made. The oxygen level decreases with age, which can be estimated by subtracting 1 TOR R from 80 for every yea r of age a bove 60 . So, an 80-yea r-old patient should have a p02 no less than 60 at sea level. After establishing the consistency of the values for pH, pC02, and [HC0 3-], look at the pH to establ ish if the primary or dominant d i sorder is basic or acidic. Si nce there is no over-com pensation for an acid-base d isorder, t h e pri­ mary disturbance is determi ned by the pH . Occasional ly, a chronic respi ratory acidosis or alka losis may have a normal pH in the a bsence of a m ixed disorder. Next, the serum anion gap, [Na+] - ([CI-] + HC0 3-1, is calculated to look for the p resence of u n m easu red a n ions, as occ u rs with the add ition of a ny strong acid to body fluids The anion gap can be altered i n the a bsence of a n acid-base disorder. A low seru m albumin or an i ncrease in u nmeasured cation, such as occurs with lithium ingestion or when certa i n paraproteins a re present i n m u ltiple myeloma, m a y decrease the g a p (see Low Anion G a p section) . On the other hand, meta bolic al ka losis may modestly i ncrease the a n i on gap. An i n­ crease in the a n ion gap usually ind icates the presence of a metabolic acidosis, but the normal a n ion gap va ries widely, with an averag e va lue of 1 0- 1 2 m Eq/L. Given the large number of factors that can affect the a n ion gap, previous electrolytes measurements from the patient may be helpful for comparison . With a high anion gap metabolic acidosis, there should be a close reci pro­ cal relationsh i p between the rise i n a n ion g a p a n d the decrease of serum [ HC03-] , cal led the delta gap. The delta gap is defined as (an ion gap - 1 2 ) . I n simple gap acidosis, a red uction i n serum [HC0 3-] by 1 0 i s associated with an i ncrease in anion gap of 1 0 . Addition of the va lue for delta gap to the mea­ sured [ HC0 3-] allows you to determ i ne the [HC0 3-] level that existed prior to the development of the gap acidosis. Thus, if delta gap + [ H C0 3-] is in the normal ra nge for serum [ HC0 3 -], then a simple an ion gap acidosis is present =

=

=

=

=

=

=

=

=

=

156 • Acid-Base

.

( i e . , the added acid has caused the expected drop in [ HC03-]) . If the value is outside the normal range, then another d isorder must have been present prior to the development of the gap acidosis. The following rules su mmarize the use of delta gap after a high anion gap is detected : 28

�

delta gap

+

[ HC03-]

�

2 3 , sim ple high gap acidosis

Delta gap

+

[HC03-]


60 (patient with pC02 TORR to have normal pH. of 60 should have pH of 20/ 1 0 x 0 0 3 0 .06 so predicted pH is 7 . 4 0 . 06 7 34) HC03 increases 33.5 mmol/L for each 1 0 mmHg increase in pC02. .

,=

,

=

Respiratory Decreased pC02 alkalosis

Decreased Acute HC03

Same rule as acute pH is higher respiratory acidosis than chronic (patient with pC02 alkalosis of 20 should have pH of 7 56) HC03 decreases 2 mmal/L for each 1 0 mmHg decrease in pC02.

Chronic Same rule as chronic Unusual for respiratory acidosis HC03- to fall (patient with pC02 to less than 1 5 mEq/L in of 20 should have pH of 7 46) absence of Table continued on next page. 1 58 • Acid-Base

S u m ma ry of the Pri mary Disturbances and Compensatory Responses for Acid-Base D i sorders (Con tinued)

Disorder

Compensatory Primary Disturbance Response

Type

Appropriate Response for a Single Disorder

Respiratory Decreased pC02 alkalosis lcont.) Icont ) Metabolic acidosis

accompanying Decreased Chronic HC03 decreases 4-5 mmol/L for metabolic HC03 lcont.) each 1 0 mmHg acidosis. Icont.) decrease in pC02. The pH is often normal . pC02 [ 1 5(HC03) Full compensation Decreased Decreased (hyperventila+ 8) ± 2 (patient HC03 pC02 tion) may take with metabolic acidosis and HC03 1 2-24 hours of 1 0 should have pC02 of [ 1 .5( 1 0) + 8) ± 2 23 ± 2 2 1 -25 TORR. pC02 last 2 digits of pH x 1 00. =

=

=

=

Metabolic Increased HC03 alkalosis

Increased pC02

Compensation pC02 0.9* less consistent (HC03) + 9 than for meta(patient with metabolic acidosis. bolic alkalosis and HC03 of 40 pC02 > 45 occurs in 25% should have pC02 of 0 . 9 * (40) + of cases. Rare to see pC02 9 45 TORR) > 55 TORR except in severe * range 0.6-0.9 alkalosis or superimposed respiratory alkalosis. =

=

=

After checking for a ppropriate compensation , decide if the d i sorder is simple or if a double or triple d isturba nce is present. Types of m ixed d isorders and clues to their presence QTe as follows: 1 . Metabolic a lkalosis + respi ratory alkalosi s - Both processes i n­ crease the pH . A decreased pC02 is seen with i n c reased HC0 3 A very high pH is possible because the a l kaloses sum mate. There is a m i ld elevation of a nion gap. Hypokalemia freq uently is p resent. Exa m ple preg nancy with vom iti ng . 2 . Respiratory acidosis + metabolic alkalosis- Both processes increase the HC03. Often there is a normal pH and a very high HC0 3 pC02 is h ig her tha n predicted on the basis of metabolic alkalosis alone. Example: COPD + d i­ uretic therapy. \

Acid-Base •

1 59

3 . Metabolic acidosis + respiratory acidosis- Both processes decrease the pH . pH is very low because the acidoses sum mate. Example: decom pen­ sated COPD + lactic acidosis 4. Metabolic acidosis + metabolic alkalosis- The two processes change the HC03 and the pC02 in opposite directions. The pH may be increased, de­ creased , or norma l , depending on the relative severity of the two processes . Consider this d iagnosis when the anion gap is increased, but the HC03 is not decreased. Example: DKA + vomiti ng . 5 . Metabolic acidosis + respiratory alka losis Both processes decrease the HC03 . Consider this diag nosis when a metabolic acidosis is accompanied by a pC02 that is lower than predicted, or when respiratory alkalosis is associated with an HC03 measurement lower than predicted . Example: sal icylate overdose . 6. Triple acid-base disturbance- triple distu rbances occur when a m ixed metabolic acidosis + meta bolic alkalosis is compl icated by either a respiratory acidosis or a respiratory a l kalosis. While m ixtu res of meta bol i c distu rba nces may occur, m ixed respiratory disturbances ca nnot occur by definition, because a person can never concu rrently over- and u nder-excrete CO2. The d iagnosis of a triple d isturbance is generally made in a patient with metabolic alkalosis and res­ pi ratory acidosis or alkalosis i n whom the anion gap is found to be sign ificantly increased (> 1 6) . Example: DKA + vomiting + obtundation/hypoventilation . -

Cl inica l Conditions and Diagnoses

M E TA B O L I C A C I D O S I S WITH A H IG H AN ION GAP KLU ES I K et o a c i d o s e s

Lactic acidoses U re m ia ( o rg a n i c a c i d s ) E thyl e n e g lyco l a n d t h e a l co h o l s S a l icylates

160 • Acid-Base

-

N otes 1 . This m nemonic lists the primary conditions i n which the anion gap, {[Na+] ­ ( [CI] + [ HC03])}, i ncreases . Because of electroneutrality, unmeasured anions m ust i ncrease as bicarbonate fa lls, lead ing to a widen i n g of the an ion gap. " KLUES" to the cause of an i ncreased an ion gap come from the history and lab­ oratory tests, i ncluding BUN, creati n i ne, glucose, lactate, seru m ketones, serum osmolality, and a toxin screen. 2. Ketoacidosis occu rs i n three settings: d iabetes, alcoholism, and malnutri­ tion ("DAM ! " ) . In diabetic ketoacidosis, acetoacetic and beta-hydroxybutyric acids are produced more ra pidly than they can be metabolized . They accumu­ late, causing a d rop i n plasma bicarbonate a n d a rise i n the a n ion g a p . Alcoholics m a y have poor food i ntake and vom iting associated with h i g h ethanol intake, causing ketoacidosis and an elevated an ion gap. T h e ketoaci­ dosis may be missed because the n. itroprusside test for ketones only detects ace­ toacetic acid and not beta-hyd roxybutyric acid, which tends to pr·edomi nate. Ma ln utrition alone may cause a modest ketoacidosis. Red uced ca rbohydrate levels cause low i nsul i n and high gl ucagon . These hormonal changes (also rele­ vant to DKA and alcoholic ketosis) favor glycolysis and ketogenesis. 3. Uremia is characterized by the accumulation of organic acids, which normally are excreted by the kidney. In acute renal failure, plasma bicarbonate falls by 1 to 2 mmol/L per day if impaired renal acid excretion is the sole cause of metabolic aci­ dosis. Greater rates of decline suggest the presence of an additional cause of acid production. In chronic renal failure, the bicarbonate tends to stabilize at levels of 1 2- 1 8 mmol/L and rarely falls below 1 0 m mol/L unless another disorder is present. 4. Lactic acidosis occurs when there is an i m balance between lactate produc­ tion and el i m i nation ("LACTIC") . During a naerobic conditions, glycolysis is ac­ celerated and pyruvate i ncreases . Pyruvate is in eq u i l ibrium with lactate; thus, lactate levels i ncrease. Si nce one proton is generated for each lactate molecule produced, acidosis is the result of lactate production . Because the l iver is the ma jor organ for meta bolizing lactate, severe liver d isease causes lactic acidosis. Lactate production is norma l , but meta bol ism is i mpa i red . With significant l iver dysfunction , the normal lactate load produced by the body is not metabolized , lactate accum ulates, and acidosis ensues . Selective dysfunction of m itochondria (e . g . , congenital disease, biguan ide toxicity) causes lactic acidosis i n the a bsence of other evidence of liver dysfunc­ tion. Lactate overproduction results from c;.i rcu latory fa i l u re . Tissue hypoxia, as occurs with cardiopulmonary grrest, �arbon monoxide poison ing and severe anem ia, leads to lactic acidosis. Vigorous exercise or muscular tetany as occurs with seizures may cause a tra n sient rise in lactate. System ic infection/sepsi s causes circulatory shock, org an hypoperfusion, a n d subsequent lactate produc­ tion . Lactic acidosis may complicate �ancers, such as leukemia and lymphoma, when tissue hypoxia is not i n evidence. Overproduction of lactate by the mal ig­ nant tissue may be a factor. Acid-Base . 1 6 1

Note that lactic acidosis a lso may contri bute to the severe acidosis seen with salicylate, methanol, or ethylene glycol poison ings. 5. Ethylene glycol and methanol a re converted to acidic m etabolites, which accumu late i n the bloe>d . An increase i n osmola r gap is characteristic, and prompt intervention is critical . Isopropyl alcohol causes a more modest increase in anion gap and serum osmolal ity. 6. Salicylates cause a characteristic in itial respiratory alkalosis by stimulating cen­ tral respi ration . The presence of respiratory alkalosis combined with an increased anion gap frequently occurs with sal icylate intoxication and should not be m issed . 7. Certain gastrOi ntestinal disorders have been reported to cause a gap acidosis secondary to accum ulation of D-Iactate. It is thought that certa in bacteria pro­ duce D-Iactate in the gut that is systemically a bsorbed . A special serum assay for D-Iactate is ava i lable, as it is not detected by the conventional assay. 8. Other drugs have been associated with a gap acidosis. Isoniazid causes re­ fractory seizu res and a subsequent lactic acidosis. Paraldehyde is rarely used , a nd its role i n ca using gap acidosis is not well documented , but it is remem­ bered beca use of the fa m i l i a r "MUD PILES" m nemonic ( m etha n oJ , u rem i a , DKA, paraldehyde, isopropyl a lcohol , lactic acid, ethylene g lycol , sal icylates). Propylene glycol, a d i luent used i n some intravenous medications (e. g . , nitro­ glyceri ne) , may rarely cause a secondary lactic acidosis. 9. When measured plasma osmolal ity exceeds the calculated osmolality [(2 x plasma No) + glucose/ 1 8 + BUN/2 .81, suspect ethylene g lycol or methanol toxicity. Ethanol intoxication and some cases of lactic acidosis or alcoholic keto­ sis also may feature a small "osmolal gap" (up to 1 0- 1 5 mOsm/kg ) .

DAM U LACT I C GAPS Ke toacidoses

D i a betic ketoa c i d o s e s A l c o h o l i c keto s i s M a l n utriti o n U re m ia

Organ ic acids

Lactic a cidoses

L ive r d i se a s e A rrest C a rbon m o n o x i d e p o i so n i n g T eta ny/s e i z u res ( rh a b d o myo l ys i s) I nfect i o n/s e p s i s C a ncer 1 62 • Acid-Base

b

O ther unmeas ured anions

G a stroi ntest i n a l d i s e a s e ( D- I a ctate) A l c o h o l s/a n t i-f reeze P ro py l e n e g lyco l/pa ra l d e hyde S a l icylates

M E TA B O L I C A C I D O S E S WITH A N O R MAL AN ION GAP GUT G a stroi ntesti n a l l o s s e s ( d i a r r h e a , pa n c re a t i c f i stu l a ) U ri n a ry l o s s e s T ota l p a r e n t e ra l n utrit i o n

N otes 1 . N ormal anion gap or hyperchloremic acidoses almost a lways result from

HC03 loss from the GI tract or from the kidney. As the a bove m nemon ic sug­

gests, GUT losses from d i a rrhea a re the most common cause. Uri nary losses from renal tubular disease a re less com mon . 2 . In both GI and renal disorders, sod i u m bica rbonate stores a re low, a nd sod ium chloride is reta i ned in excessive a mounts to preserve volume status. The urine net charge or u rinary anion gap, { ([Na] + [K] - [CI] }, is useful in d iffer­ entiating between renal and gastrointestinal causes of HC03 loss. Urinary acid­ ification results from the excretion of a m m o n i u m , N H4 + The p resence of the positive ion, N H4+, ind icates that other maior cations, [Na] + [K] , a re present in lower amounts when compa red to the maior anion, [Cl] . A negative u rine an ion gap i m pl ies the presence of N H4+ in the urine, ind icati ng appropriate rena l acid ification in response t o acidosis ( a s in GI losses) . A positive va lue ind icates a renal acidification defect (no N H4+ in the uri ne) . If the cause appears to be renal dysfu nction (positive urinary a n ion gap), then the serum potassium is help­ ful. Low potassium suggests an H+ secretion defect, whereas high values are consistent with deficient aldosterone action (Type IV renal tubular acido�i� rRTA] ) . Acid-Base • 1 63

bn

3 . I n rare cases, iatrogenic normal gap acidosis results fro m i ntravenous ad­

m i n i stration of TPN or acidic a m i no acid solutions, a m mon i u m ch loride or hy­ d rochloric acid . An apparent, normal gap acidosis is occasionally seen when a gap acidosis is accompanied by a pre-existing condition that lowers the anion gap, such as hypoalbuminemia or a cationic para protein (see Low Anion Gap section) 4. Respiratory alkalosis with reduced pC02 levels leads to a loss of bicar­ bonate. With rapid correction ( i . e , decreased respiratory rate), pC02 returns to norma l , but bica rbonate conservation and reclamation by the kidney takes 24 to 48 hours to return levels to norma l . A tra nsient non-gap acidosis occurs . 5 . In DKA, it is common to see a n incidental hyperchloremic acidosis i n the recovery phase. This phenomenon occurs because sodium ch loride is reta ined with vol u me repletion . The ketones (a source for regenerating bica rbonate) are lost i n the urine, and bicarbonate regeneration is slowed S i m i la rly, vigorous volume replacement in a dehyd rated patient suppresses aldosterone secretion . S i nce a ldosterone i ncreases bica rbonate regeneration a n d a bsorpti o n , the lower levels tend to mainta i n the hyperch loremic state. This "expa nsion acido­ sis" is the converse of the "contraction alkalosis" seen with vol ume depletion; the latter i s a h i g h a ldosterone state. The acidosis from vol u me replacement is rarely of cli nical sign ificance. 6 . A more comprehensive listing of causes of non-gap acidoses is listed below. The mnemonic em phasizes the i m portance of calculating the urine gap when the cause is u ncerta i n .

U R I N E G A P : N A + K-C L U retero s i g m o i do stomy R TA I ntest i n a l d i s e a s e ( d i a rr h e a ) N H 4+/T P N E a rl y re n a l fa i l u re G l u e s n i ff i n g (to l u e n e ) A I d osterone defi c i e n cy P a n c rea t i c f i stu l a N a C I i nf u s i o n ( "expa n s i o n " a c i do s i s ) A ft e r D KA o r res p i ratory a l ka l o s i s K+�s p a r i n g d i u reti cs C a rbon i c a n hyd ra s e i n h i bitors ( i m pa i rs u r i n e acid i f i cati o n ) L axative a b u se ( G I l o s s e s ) 1 64 • Acid-Base

L ow A N I O N G A P ALB U M I N A lb u m i n loss L ithium B ro m i n e U n m e a s u red cati o n s ( K, M g , C a l M ye l o m a (cati o n i c pa ra p rote i n ) I od i d e N a + u n d e resti m a t i o n/a rtifact

N otes 1 . A low seru m a l bu m i n is the most com mon cause of low a n ion gap The normal an ion gap is a pproximately 5- 1 2 . Because of this wide ra nge of normal and the many factors affecting the an ion gap, the clin ical usefulness of a low measured an ion gap has been questioned . Knowing the factors that affect the an ion gap is perhaps most useful when tryi ng to determine the sign ificance of modest changes in the anion gap (e.g . , an an ion gap of 1 6 may be sig nificant in a patient with a very low album i n ) . A reduction in the anion gap may also be due to laboratory error. 2 . A lower serum a n ion gap may be observed in conditions with an i ncrease in unmeasured cations, such as occurs with hyperkalem ia , hypercalcem ia , or hypermagnesemia . It may also be seen when there is an increase in unmeasured cations that are not normally present, such as with multiple myeloma, polyclonal g a m mopathy, or lith i u m . A l ow gap is seen with a decrease i n un measured anions (usually hypoalbuminemia). Sodium underestimation is much less likely to occur g iven new d i rect ion-selective techniques (a low gap was more common previously i n cases of hyperviscosity and severe hypernatremia). Chloride overes­ timation was formally seen i n cases of hypertriglyceridemia, but this also is less of a problem now. However, bromine and iodide may lead to ch loride overesti­ mation and thus reduce the anion gap. Bromine and iodide have slightly lower renal clearances than chloride. Electrolyte measurements do not disti nguish be­ tween brom ine or iodide and chloride, so a rise in brom ine or iodide is falsely measured as an ever g reater rise in ch loride. Other rarely reported causes of a low serum anion gap include renal transplantation and hyponatremia . 3 . Clea rly, there are many considerations i n calculating the a nion gap- partic­ ularly in a patient with m ultiple med ical problems. Take all of these factors into account when interpreting the a n ion gap. Acid-Base • 1 65

M E TA B O L I C A L K A L O S I S ALOOS A l d oste ro n e Lasix D e hyd rati o n O ve r-ve n ti l a t i o n S t 6 m a c h l os s e s

N otes 1 . Metabolic alkalosis is not a specific d isease; it is usually a response to NaCI and K+ deficit. Understanding the hormone aldosterone is the key to understanding most cases of meta bolic a l kalosis; hence, the m nemonic ALDOS . Aldosterone promotes renal acidification and concom itant bicarbonate regeneration and a b­ sorption . Pri mary hyperaldosteronism and other hypermi nera locorticoid states cause metabolic alkalosis. Simi larly, volume depletion causes a secondary i n­ crease in aldosterone, a lso promoting metabol ic al kalosis. With volu m e con­

traction, there is an increase in sod i um avidity due to aldosterone activity. Because of electroneutrality, anions must be reabsorbed with sodium; therefore, chloride is maximally reabsorbed , leaving very little chloride in the urine . For this reason, the measurement of urine chloride (see mnemonic next page) is helpful in determining the cause of metabolic alkalosis. 2 . The majority of m etabolic a lkalosis cases a re due to extracel lular fluid volume contraction and respond to saline admin istration . These so-called sali ne­ sensitive types com monly result from vom iting and d i u retic use. I n these i n­

stances, volume loss leads to renal sod ium conservation, necessitating maximal reabsorption of ch loride as an obligate an ion . Urine chloride is usua lly less than 1 0 mmoles/L in sali ne-sensitive metabolic alkalosis. Replacement of the volume deficit corrects the alkalosis. 3. Hyperminera locorticoidism (primary, Cush ing's syndrome, renal artery stenosis, malignant hypertension, J-G cell tumor, Bartter's syndrome, and licorice gluttony) is the other major mechan ism that can mai ntain metabolic alka losis. These condi­ tions a re sa l i ne-sensitive and typically have a urine ch loride concentration > 20 m moles/L. The patient's volume status helps to differentiate between a sa line-sen­ s itive cause (low volu me) and a saline-i nsensitive cause ( normal or increased vol u me) . Rarely, patients with extracellular fluid vol ume depletion have other causes for metabolic alkalosis ( mag nesium depletion, Bartter's syndrome). liddle's syndrome is a rare disorder in which patients appear to have hyperaldosteronism, 1 66 • Acid-Base

JI

but aldosterone levels are low. It is probably due to an i ntri nsic tubular defect and can be treated with trai mterene or amiloride, but not spi ronolactone. 4. The following m nemonic lists the specific causes of metabolic alkalosis :

R E N A L C L- E VA L R e covery from hype rca p n i a , orga n i c a c i d o s i s E mesis N a s o g a s t r i c s u ct i o n A l d oste ro n i s m L a s i x/ l o o p d i u re t i cs C ys t i c f i b r o s i s L ow K + , M g + + E xsa n g u i n a t i o n/m a s s ive t ra n sf u s io n ( c i t rate) V o l u m e d e p l et i o n A l ka l a i i n t a ke ( I V b i ca rb, m i l k-a l ka l a i ) L i d d l e's syn d ro m e

R E S P I R AT O R Y A C I D O S I S COPOS C a rd i a c a rrest o btu n dati o n P u l m o n a ry d i se a s e/a i r way obstruct i o n D ru g s/ove r d o s e S ke l eta l/n e u ro m u s c u l a r d i s e a s e

N otes 1 . Respi ratory acidosis represents a fa il u re of venti lation. Obstructive lung dis­ ease is the most common cause of both acute and chronic respi ratory acidosis, hence the mnemonic COPDS . Acid-Base • 1 67

2 . Common causes of hypoventi lation and subsequent respiratory acidosis in­ clude card iac arrest, obtu ndation, pul monary d isease or la rge a i rway obstruc­ tion, C N S-depress ing d rugs/overdose, and skeleta l /neuromuscular disease (e.g , ALS, myasthenia g ravis, advanced kyphoscoliosis).

R E S P I R AT O R Y A L K A L O S I S peo2 V E N TS P re g n a n cy C i rr h o s i s O 2 d ef i c i t

V e nt i l a t o r E mbolus N e u ro l og i c d i s e a s e T e m p e ratu re (fev e r, h ea t ) S a l i cylates/d ru g s

N otes 1 . I n contrast to respiratory acidosis, respi ratory alka losis is seconda ry t o hy­ perventi lation . Over-excretion of carbon d ioxide, PC02 V E NTS, accounts for the alkalosis. 2. Respi ratory center sti m u lation in pregnancy is due to increased production of progesterone, while in cirrhosis there probably is decreased meta bolism of substances that stim ulate the respiratory center. Hypoxia (02 deficit) also causes hyperventilation. Patients on mecha nical ventilators may have respiratory alka­ losis when the minute ventilation is i nappropriately high. Tachypnea and respira­ tory alkalosis is a very sensitive albeit nonspecific sign of pulmonary embolus. CNS injury or neurologic diseases also may cause hyperventilation . Temper­ ature elevations with fever or heat exhaustion sti mulate breath ing, and respira­ tory alkalosis is the initial acid-base a bnormality in salicylate overdose.

1 68 • Acid-Base

113

G ASTRO ENT EROLOGY Clinica l Sy m ptoms and Signs

A B D O M I N A L PA I N M EAN G U T M eta b o l i c E n d o c ri n e A bd o m i n a l N e u ro g e n i c G yn e c o l o g i c/g e n ita l ia U ri n a ry/r e n a l system T h o ra c i c

N otes 1 . "MEAN GUT" provides a simple outline for a pproaching abdomi nal pa i n . The most i m portant in itial decision i s whether u rgent surgical intervention o r d i­ ag nostic testi ng is ind icated . The history and physical exa m i nation and a few simple tests gUide the decision-making . It is essential to exclude extra-abdominal causes of pa i n ( i . e . , meta bolic, endocri nolog ic, neurolog ic, gynecolog ic, uro­ log ic, and thoracic) before embarking on expensive and invasive testi ng . 2 . Metabolic causes of a bdom inal pain include u remia , porphyria, C 1 esterase deficiency, Fami lial Mediterra nea n Fever, and poisons (e g . , heavy metals, en­ venomation, chemotherapy) . Endocrine causes include adrenal insufficiency, hy­ percalcemia , and diabetic ketoacidosis. Most of the i ntra-abdo m i na l etiologies Gastroenterology . 1 69

of pa i n a re listed i n the "PREP FOR SURGICAL APPE NDECTOMY?" m nemonic on page 1 72 . Neurogenic ca uses of pa i n incl ude herpes zoster, tabes dor­ salis, psychogenic pa i n , functional bowel d isease, a n d spinal rad i c u l itis. Gynecologic causes of pa i n - i mportant i n any female patient and especia lly those of menstruating age - a nd urologic causes of pai n , such as renal stones, pyelonephritis, and u rinary retention, also a re i ncluded in the differential for ap­ pend icitis . Finally, pa i n may be referred from thoracic problems such as pneu­ monia and myoca rd ial ischemia . Esophagea l d i sease usually causes chest d iscomfort, although patients may complain of a bdom inal symptoms. 3 . The in itial d iag nostic eva luation of a patient with acute a bdominal pa i n often includes CBC, urinalysis, a mylase a nd/or lipase, liver enzymes, a n d a b­ dominal x-rays, taken with the patient in the u pright position to eva luate for d i­ lated loops of bowel or free a i r. Other tests may be appropriate i n selected patients, such as serum electrolytes, BUN, creati n i ne, calcium, cosyntropin stim­ u lation testing for adrenal i nsufficiency, or a chest radiograph. 4 . Important tips for internists:

a. Be careful to exclude meta bolic derangements, systemic d i seases a n d extra-a bdominal processes, which m a y present with a bdom i nal pa i n . b. Rule out ectopic pregnancy i n a n y female o f menstruating age. Pelvic ex­ a m ination should be performed on virtually a l l women with acute a bdom i na l pa i n . Every woman o f reproductive a g e must have a pregnancy test. c. E lderly patients with acute a bdom i na l processes may have atypical pre­ sentations and should be ma naged with g reater caution. Mesenteric ischem ia, for example, may present with severe pai n and an unimpressive physical exam­ i nation ( i . e . , pa i n out of proportion to the clinical findi ngs) . Also, patients on cor­ ticosteroid therapy may have atypical presentations, as steroids may mask ( clinical findings . 5 . The location , d u ration, progression, and onset of pa i n (see ta ble) can be helpful in d ifferentiating between causes of a bdom inal pai n . There is consider­ a ble overlap, but a general time cou rse is often helpful in d iscerning the cause of abdom inal pai n . Relieving and aggravating factors a re helpful in local izing the source. For exa m ple, pa in relieved by the passage of bowel movements suggests the colon as a l i kely source. Pa i n i n itiated by swallowing implicates the esophagus, wh i le pain aggravated by a ny action that moves the abdomen sug­ gests periton itis (the patient usually prefers ta lie sti l l ) . On the other hand, with obstruction of a hollow viscus, patients usually move about in an attempt to seek relief, and movement does not make the pain worse.

1 70 • Gastroenterology

Pa i n Accordi n g to the Acuity of Onset

Abrupt-Gnset Pain ( instant) Gastrointestinal Causes

Nongastrointestinal Causes

Perforated ulcer Ruptured abscess or hematoma Intestinal infarct Ruptured esophagus

Ruptured or dissecti ng aneurysm Ruptured ectopic pregnancy Pneumothorax Myocardial infarction Pulmonary infarction Dissecting aneurysm

Rapid-Onset Pa in (minutes) Nongastrointestinal Causes

Gastrointestinal Causes

Ureteral colic Perforated viscus Strangulated viscus Renal colic EctopiC pregnancy Volvulus Pancreatitis Biliary colic Mesenteric infarct Diverticulitis Penetrating peptic ulcer H igh intesti nal obstruction Appendicitis (gradual onset more common) Gradual-Gnset Pain (hours) Gastrointestinal Causes

Nongastrointestinal Causes

Appendicitis Strangulated hernia Low intesti nal obstruction Cholecystitis Pancreatitis Gastritis Peptic ulcer Colonic d iverticulitis Meckel's diverticulitis Crohn's disease Ulcerative colitis Mesenteric lymphadenitis Abscess Intestinal infarct Mesenteric cyst

Cystitis Pyelitis Salpingitis Prostatitis Threatened abortion U rinary retention Pneumonitis

Gastroenterology . 1 7 1

b

6. Here is a m nemonic delineating the d ifferential diag nosis for a ppendicitis:

P R E P F O R S U R G I CA L A P P E N D ECTOMY? P ye l o n e p h r i t i s R e n a l sto n e E ctop i c p re g n a n cy P e lv i c i nf l a m matory d i s e a s e F o l l i c l e ru ptu re ( m i tt e l s ch m e rz ) O va r. i a n cyst t o rs i o n R u pt u re of c o r p u s l ut e a l cyst S p l e n i c ru ptu re U ri n a ry rete n t i o n R u ptu red a n e u rysm G a st r o e n t e r i t i s I nfarcted/i sch e m i c g ut Cro h n 's/u l c e rat ive co l i t i s A bs c e s s L ive r c a ps u l e d i st e n s i o n/i rrita t i o n A ppendicitis P a n creatit i s P e rforated u l c e r E s o p h a g e a I ru ptu re N o disease D i vert i c u l it i s E ndometriosis C h o l ecys t i t i s T wi sted bow e l O bs t ru cted bowel M ecke l 's d ive rt i c u l u m Y e rs i n ia/lym p h a d e n it i s

1 72 • Gastroenterology

D IA R R H EA SOILING S ec retory O s m ot i c I n f l a m matory L a xa t i ves (fact i t i o u s ) I sch e m i c N e u ro g e n i c G a st ro i ntesti n a l b l e e d i n g

N otes 1 . The pri mary mechan isms of d iarrhea (or apparent d iarrhea ) a re summa rized by the m nemonic SOI LING. Dia rrhea is defined as an i ncrease in daily stool weight above 200 grams per day. Si nce this is not a very easily obta ined mea­ sure, dia rrhea is here defined from the patient's perspective : an i ncrease in stool frequency and/or liqu idity. This defi nition includes hyperdefecation, which is an increase i n frequency without a n increase i n stool weig ht as occurs i n i rritable bowel syndrome, hyperthyroidism, and fecal i nconti nence. Also i ncluded is gas­ trointesti nal bleeding causing melena, which patients may describe as d ia rrhea . 2 . Secretory (watery) diarrhea is characterized by volu m i nous feca l output not necessa rily related to food inta ke, which fa i ls to i mprove with fasting. There is perturbation of normal fluid and electrolyte transport in the gut, and the result is watery stools with normal electrolyte concentrations and no increase in stool os­ molal ity. The classic exa m ples of secretory d ia rrheas are hormona l , including ca rci noid syndrome, Zol l i n ger-E l l ison , VIPoma, medullary thyroid carcinoma, and systemic mastocytosis. An exception is somatistati noma , in which the diar­ rhea is osmotic with steatorrhea secondary to inhi bition of pancreatic secretions and gall bladder motil ity. Bile salts stimulate colonic secretion, and processes that i ncrease bile salt delivery to the colon also cause secretory d iarrhea . Examples include: ileal bypass or resection ( reduced reabsorption), tru nca l vagotomy (ab­ normal transit), and after cholecystectomy (reduced storage capacity ) . 3 . Osmotic dia rrheas (such as pa ncreatitis, sprue, bacterial overgrowth , and Whi pple's d isease) a re cha racterized by bulky, g reasy, foul-smel l i n g stools, weight loss, and i mprovement i n diarrhea with fasti ng . This form of diarrhea re­ sults from an ingested solute that is not a bsorbed by the sma ll intestine /The un­ absorbed solute exerts an osmotic force and draws fluid i nto the i ntestinal lumen . The resultant i ncreased stool volume exceeds the colon's reabsorptive capacity, Gastroenterology .

tb

1 73

po;

a nd dia rrhea ensues. Stool analysis shows a gap between electrolyte concen­ trations and total stool osmolal ity d ue to the unabsorbed solute. 4. Inflammatory causes (infla m matory bowel disease, rad iation enterocolitis, eosinophilic gastroentereitis and certai n AI DS-associated infections) a re charac­ terized by fever, a bdominal pa i n , and blood and/or leukocytes in the stool. In these d i sorders there is i nfla mmation and i n j u ry to the i ntesti nal mucosa . The mechanism of dia rrhea may include mala bsorption or secretion due to disrup­ tion of normal mucosal functions. 5. Factitious dia rrhea from laxative abuse is osmotic and should be suspected in women with chronic dia rrhea , hypokalemia, and a h istory of psychiatric i l l­ ness . Certa i n prescri bed medications also can cause d i a rrhea , such as antacids, theophyl li ne, colch icine, digita lis, and antibiotics. 6 . Ischemia is not a common cause of d iarrhea , and the clin ical picture de­ pends on the deg ree of vascular comprom ise. Acute, fulminant ischemic colitis is due to complete vessel occlusion and features severe abdominal pa i n , bloody d ia rrhea , and rapid decompensation . Nonocclusive ischemia has a less severe course and usua lly resolves without intervention . Patients with nonocclusive is­ chemia have lesser deg rees of pain and bleed i ng , occ u rring over a longer period of time. Anorexia, vomiting, and diarrhea may be the primary complaints. 7. Neurogenic d isorders a re d isturbances of intestinal motility that often cause hyperdefecation or i nconti nence as o pposed to true d i a rrhea . The i rrita ble bowel syndrome (IBS) is a common a nd increasingly recog nized form of neuro­ genic diarrhea . IBS is characterized by alternating constipation and d iarrhea , as wel l as d iffuse a bdom inal pai n . I B S beg ins by early adulthood a n d should not be accepted as a diagnosis in a n older patient with recent-onset diarrhea . Other neurologic diseases (diabetes, cauda-equina syndrome, Shy-Drager) also can cause altered intestinal moti lity a nd diarrhea . 8. Gastrointestinal bleeding, when subacute, may cause frequent loose, black stools. Although not strictly d i a rrhea , patients may interpret it as such . Also, some of the other mechanisms of diarrhea may feature bleed ing, especially the infla mmatory etiologies and ischemia . 9 . The majority of cases of acute diarrhea « 7- 1 4 days in d u ration) a re i n­ fectious, the d iagnosis of which ca n be suspected by a history of recent travel, ingestion of unusual food (raw seafood or undercooked poultry products or ham. burgeri, or recent contact with people who have been sick. Infections by inva­ sive bacteria ( Campylobacter, Shigella, Salmonella, Aeromonas, certa i n Escherichia coli) a re often associated with bloody diarrhea . It is i m portant to ex­ clude other causes of bloody dia rrhea such as mesenteric ischemia and inflam­ matory bowel disease. Infections by noninvasive bacteria a nd protozoa ( Vibrio cholerae, enterotoxigenic E. coli, Klebsiella, Giardia, Cryptosporidia) typically produce watery diarrhea without blood . C. difficile rarely causes bloody diar­ rhea . Yersinia, which commonly infects the term inal i leum and cecum, often pre­ sents with watery d i a rrhea and right lower quadrant pa i n , which ca n m i m ic a ppend icitis and Crohn 's d isease. 1 0. A more comprehensive list of the causes of chronic diarrhea, organ ized pathophysiolog ically, follows: 1 74 • Gastroenterology

b

d

I RACE TO PASS LOTS O F WI LD 8 M , FI N D A CURE ! Isch emia

I sch e m i a

Secre tory

R ecta l v i l l o u s a d e n o m a A fte r c h o l ecystectomy (ch o l e rr h e i c ) C o l l a g e n o u s c o l i t i s ( l y m p h ocyt i c o r m i c ro s c o pi c co l it i s ) E n d oc r i n e (Zo l l i n g e r- E l l i s o n , V I Po m a , ca rc i n o i d , m e d u l l a ry t h y r o i d ca rc i n o m a , m a s tocyto s i s ) T ru n ca l va g otomy O be s i ty s u rg e ry ( i l e a l bypa s s o r resect i o n ) Osmo tic

P a n crea t i t i s (ch ro n i c p a n c r e a t i t i s w i t h steato r r h e a ) A beta l i p o p rote i n e m i a S o m atostati n o m a S h o rt-bowe l syn d ro m e L y m p h a n g i ecta s i a O ve rg rowth o f bacte r i a T ro p i c a l s p r u e S p r u e ( g l u te n -se n s itive)

o l es t ra/d i etet i c foods

F ru its/ca n d y (fru ctos e , s o r b i ta l )

W h i p p l e 's d i s e a s e I nfect i o n s ca u s i n g stea t o r r h e a ( I s o s p o ra , G i a rd i a , S t ro n g y l o i de s ) L a ctose i nt o l e r a n c e o r u g s ca u s i n g steato r r h e a (e . g . , c o l ch i c i n e , n eomyc i n ) Factitious o r "pseudo " diarrh ea

B leeding (melena) M u n ch a u s e n 's/ma l i n g e r i n g ( l a xa tive a b u s e )

Gastroenterology . 1 75

Ne urogenic or altered m o tility

F eca l i n c o n t i n e n c e o r i m pacti o n ( o b st i pati o n ) I rrita b l e bowe l N e u ro l og i c d i se a s e s (e . g . , a uto n o m i c n e u ropat. h i es , ca u d a e q u i n a syn d ro m e ) D i a betes m e l l it u s In flammatory

A I DS-a s so c i a t e d i nfect i o n s (ch ro n i c i nfecti o n s ) C ro h n 's d i s e a s e U l ce ra tive co l it i s R a d i a t i o n e nteroco l i t i s E os i n o p h i l i c g a stroente r i t i s

DYS P H AG I A BITES B l ocked e s o p h a g e a l l u m e n I n t r i n s i c n a rrow i n g o f t h e e s o p h a g u s T h roat/m o u t h d i se a s e ( o ro p h a ry n g e a l dys p h a g i a) E xt r i n s i c c o m p res s i o n of t h e e s o p h a g u s S m o ot h/S t r i a t e d m u s c l e d i s o rd e rs

N otes 1 . There are five primary mechanisms of dysphagia. Blockage of the esopha­ geal lumen results from i m pacted foreign bod ies and swa l lowing too large a food bolus. Processes that cause i ntrinsic narrowing of the esophagus i nclude

herpes virus and other opportu n istic i nfections, esophageal webs and rings, peptic strictures and caustic burns, ben ign and malignant tumors, and Croh n 's disease. Abnormal ities of the throat and mouth cause oropharyngeal dysphagia and i nclude pharyngeal weakness from stroke, lack of saliva from Sjogren's syn­ d rome and lesions affecting the tongue. Extrinsic compression of the esophagus may be caused by a thyroid mass, Zenker's diverticu lum, vascular a nomal ies, or 7 76 • Gastroenterology

mediasti nal tumors. Hiatal hernias predispose patients to both i ntrinsic narrow­ i n g (strictures from G E RD) a n d extri nsic com pression ( i ncarceration of a paraesophageal or sliding hernia). Disorders of smooth muscle (scleroderm a , achalasia, Chagas' disease, diffuse esophageal spasm o r " n utcracker" esopha­ gus) and striated muscle (neurom uscular d iseases, rabies, teta nus) cause motor dysphagia. 2. The symptom of dysphagia may be oropha ryngeal or esophagea l . Oro­ pharyngeal dysphag ia (throat and mouth etiologies) is suggested by a history of other oropharyngeal symptoms including nasal regurgitation , coughing on at­ tempting to swallow and concomitant speech d isturbances Patients with recent stroke are particularly likely to have oropharyngeal dysphagia . 3 . Esophageal dysphag ia is caused by the other fou r etiolog ica l g roups ( blockage, i ntri nsic, extri nsic, and smooth/striated m uscle) Blockage of the esophagea l l u me n , intrinsic narrowi ng, and extri nsic com pression cause me­ chanical obstruction, while diseases of smooth and striated muscle cause neuro­ muscular dysphag i a . Mecha nical and neuromuscular types of dysphagia can usually be d isti ngUished by a brief, but ca refu l , h istory focusing on the type of food i nd ucing dysphagia (solids, liquids) , the pattern of dysphagia ( i nterm ittent, constant and/or progressive), and whether heartburn is present 3 . Dysphagia for solid foods only: This sym ptom sug gests mecha n ical ob­ struction, as fluids a re a ble to traverse the partial ly obstructed esophagus more easily than solids If dysphagia for solid food is i nterm ittent, it may be due to a n esophageal (Schatzki) ring . With esophageal rings, the obstruction is m i l d , and only la rge food bol uses a re obstructed ; hence the intermittent nature of sym p­ toms. Prog ressive dysphagia with a h istory of heartburn suggests peptic esophag itis with or without a peptic stricture. ProgreSSive dysphagia for sol ids without a history of heartburn is characteristic of esophageal tumors. 5. Dysphagia for both solids and liquids: This symptom is cha racteristic of neu rom usc u l a r dys phagia ( m oti l i ty d i sorder), o r adva nced mecha nical ob­ struction preventing fluids from passi ng . ProgreSSive moti lity-type dysphagia is usua lly due to achalasia . Pseudoachalasia , due to tumor i nfi ltrating the myen­ teric plexus, is a rare cause of this symptom . I ntermittent, episodic moti lity-type dysphagia w i th a ssoc i a ted c h est pa i n may i n d i ca te d i ffuse esophageal spasm . In patients from South America , chagasic achalasia should be consid­ ered . Progressive dysphagia with severe associated hea rtburn is seen with scleroderm a . 6 . Physical examination should i nclude a search for cervical a n d supraclaVicu­ lar lym ph nodes and features of con nective tissue d isease . A barium esopha­ gram typically is the fi rst diagnostic test obta i ned . If a motil ity disorder is l i kely, esophageal manometry is obtained and, possi bly, an upper GI endoscopy to rule out pseudoachalasia . If mechan ical obstruction is seen on the barium study, an upper GI endoscopy with biopsy is ind icated . Thoracic CT is useful for d iag­ nosi ng the cause of extri nsic compression of the esophagus. 7>. Here is a comprehensive list of the causes of dysphagia :

Gastroenterology . 1 77

--

O H WH E N EATI N G BITES O ro p h a ry n g e a l dys p h a g i a (stroke, Sjog re n's, to n g u e p a r a l y s i s/i nj u ry) H e rp e s s i m p l ex/o p p o rt u n i st i c i nfect i o n s ( C M V, Ca n d i d a ) Web H i a t a l h e r n i a ( i n c a rc e rated) E so p h a g e a l s p a s m N ut c ra cke r e s o p h a g u s E xt r i' n s i c co m p re s s i o n (thyro i d m a s s , Z e n ke r 's d ive rti c u l u m , a n e u ry s m ) A ch a l a s i a T rypa n a s o m i a s i s ( C h a g a s ' d i se a s e ) I n f l a m m a t o ry bowel d i s e a s e ( C ro h n 's) N e u ro m u sc u l a r d i se a s e s ( myasth e n ia g ra v i s , p o l i o mye l i t i s , A LS, p o l y myo s i t i s ) G E R D /p e pt i c s t r i ct u re B u rn (ca u st i c i n g e s t i o n ) I m pa ct e d fore i g n body T u mo r E so p h a g e a l r i n g S c l e ro d e r m a

H E PAT O M E G A LY B I G H E PA T I C M A S S B u dd-C h i a ri syn d ro m e I nfect i o n s ( v i r a l h e p a t i t i s , E BV, We i l 's d i se a s e , T B , a m e b i c a bs c e s s , hyd a t i d cyst) G a u c h e r 's d i s e a s e/G I ycog e n stora g e d i s e a s e s

1 78 • Gastroenterology

,M

H epatic cysts ( p o l ycys t i c d i se a s e ) E xt ra m ed u l l a ry h e mato p o i e s i s ( i . e . , mye l o p ro l ife rative d iseases) P ri m a ry b i l i a ry c i rr h o s i s A my l o i d o s i s T oxi n s I ron ove r l o a d ( e . g . , h e m och romatos i s ) C o n g estive h e a rt fa i l u re M a l i g n a n cy (e . g . , h e pato m a , m etastat i c tu m o rs , I y m p h o p ro l i fe rat ive d i se a s e s , a d e n o m a ) A l co h o l S a rc o i d o s i s/g ra n u l o m at o u s h e p a t i t i s S ch i stoso m i a s i s (va s c u la r o bstru cti o n )

N otes 1 . A palpable l i ver, hepatomega ly, may i nd icate acute i nfection, toxic damage, infiltration , metabolic d isease, obstruction to bile d ra i nage, or vascu­ lar congestion/obstruction. A pa lpa ble liver may also be detected in patients with COPD where there is downwa rd d i splacement of the l iver and , rarely, when there is an a natomic anomaly (Riedel's lobe). 2. The evaluation of hepatomegaly depends upon the rapidity of enlargement and presenting historicol and clin ical features. In general, assess l iver enzymes, bilirubin, a nd hepatic synthetic function (prothrombin time, albumin), and follow up with i maging studies.

J�U N D I C E BILE B i l i a ry obstruct i o n I n h e rited d i so rd e rs o f b i l e meta b o l i s m L iver pa r e n c h ym a l d a m a g e ( i nfect i o n , tox i n s) E ryth ro cyte destruct i o n Gastroenterology .

&

1 79

N otes 1 . The pathophysiologic mechanisms of hyperbilirubinemia a re outli ned by the B I LE mnemonic ( 1 ) biliary obstruction (i e . , cholel ithiasis), ( 2 ) inherited disor­ ders of bile con i ugation or excretion ( i e , Gil bert's, Dubi n-Johnson , Crig ler­ Naiiar and Rotor syndrome), ( 3 ) liver parenchymal damage ( i nfection, toxins), and (4) erythrocyte destruction (hemolysis, ineffective erythropoiesis) . 2 . Jau nd ice results from hyperbi l i rubinemia and a ppears as yellowi ng of the skin and sclera . Other conditions may cause yellowing (carotenemia) or darken­ ing (Add ison's) of the ski n , but do not ca use scleral icterus. After obta i n i n g a serum bilirubin level and confi rming that skin pigmentation changes are due to iaund ice, the next step is to fractionate the bilirubin i n to unconi ugated ( " i ndi­ rect" )' and con iugated ("direct") fractions. 3. Uncon;ugafed hyperbilirubinemia rarely causes bilirubin levels g reater than 5 mg/d l ; order hemolysis labs (ha ptog lobi n , reticulocyte count, d i rect and indi­ rect a nti-globulin tests, etc . ) if a n other cause is not a pparent. Disorders that cause a predomi nantly unconi ugated hyperbil i rubinemia include eryth rocyte a b­ normalities, sepsis (decreased hepatic u ptake), C H F, and certain in herited con­ ditions (Gilbert's, Crigler-Naiiar types I and I I ) . 4. If t h e patient h a s a predomina ntly con;ugafed hyperbilirubinemia, the next step is to differentiate between liver parenchymal da mage and biliary obstruc­ tion . liver parenchymal i n i u ry ca uses very h i g h levels of tra nsa m i nases : AST (SGOT) and ALT (SGPT) Biliary obstruction has a lesser i ncrease iri transa m i­ nases and a more rema rka ble elevation of a l ka l i ne phosphatase (and 5 ' nu­ cleotidase, if obta i ned) If bil iary obstruction is suspected , then d ifferentiate between intra-hepatic and extra-hepatic biliary obstruction by i maging studies, often ultrasonography. Disorders that cause a predominantly coniugated hyper­ biliru binemia incl ude hepatocellular destruction ( i nfection , d rugs), bil iary obstruc­ tion (stones, anomal ies of the bile d uct, cancer, sclerosing cholangitis), and a few i nherited disorders of bile excretion (Dubinjohnson , Rotor) . 5 . Here is a more complete list of etiologies of iaundice :

I ' M P A G I N G M R S W H I P P L E S TA T I n fe c t i o n ( e . g . , v i ra l h e patit i s , s e p s i s , l e ptos p i ro s i s , Clonorchis, Ascariasis)

M ed i ca t i o n s/d r u g s P osto p e rat ive c h o l esta s i s A l p h a - 1 a n ti-tryps i n defi c i e n cy G a l l st o n e s 180 • Gastroenterology

b

I nj u ry/tra u m a ( h e m o b i l i a ) N eo p l a s m s ( e . g . , ch o l a n g i o c a rc i n o m a , p e r i a m p u l l a r y c a rc i n o m a , carc i n o m a h e a d o f pa n c r e a s ) G ra n u l o m a t o u s/i n f i l t ra t i ve d i s e a s e (e . g . , s a rc o i d o s i s ) M a l fo rm a t i o n o f t h e b i l ia r y t r e e (atre s i a , s t r i ct u re , c h o l e d o ch a l cyst, etc . ) R eye's syn d r o m e S c l e ros i n g ch o l a n g it i s W i l s o n 's d i s e a s e H e red i t a ry d i se a s e s ( G i l be rt 's , D u b i n-Jo h n s o n , R oto r syn d ro m e , C r i g l e r- N aj j a r) I ro n ove r l o a d P re g n a n cy-re l ated ( ch o l esta s i s of p reg n a n cy, p re-ec l a m ps i a , a c u te fatty l iver of preg n a n cy) P ri m a ry b i l ia ry c i rr h o s i s L a e n n e c 's c i r rh o s i s (a l co h o l i c ) . E ryth rocyte d e st r u ct i o n S ta rva t i o n/fa s t i n g TPN A u to i m m u n e h e patitis T oxi n s

N AU S EA A N D VO M I T I N G I VO M IT I n c re a s e d i nt r a c ra n ia l p r e s s u re/C N S d i se a s e Vascular O bstructive M et a b o l i c/tox i c I nfect i o u s T ra u m a t i c

Gastroenterology .

181

N otes 1 . Nausea and vom iting a re very common symptoms and may be associated with any of the causes of a bdominal pa in (see Abdominal Pa i n section ) . In fact, these symptoms often occu r together. When na usea and vom iting are the pri­ mary symptoms, however, a different prioritization of diag nostic possibil ities­ summa rized by the m nemonic I VOMIT (see a lso Pa n c reatitis section ) - is a ppropriate. Increased intracranial pressure, as occurs with intracerebral hem­ orrhage, can cause nausea and vom iting . Vascular etiolog ies i nclude mesen­ teric ischemia, myoca rd ial ischem i a , and m igraine headache. Obstruction of the GI tract (e.g . , adhesions, volvu lus, intussusception) and pseudo-obstruction (e. g . , scleroderma, gastroparesis) a re com mon causes of nausea and vom iti ng . Metabolic/toxic causes i n clude pregnancy, hyperca lce m i a , adrenal i nsuffi­ ciency, kid ney fai lure, d rugs, and diabetic ketoacidosis. Infectious etiologies in­ cl ude gastroenteritis, a ppendicitis, a bscess, Helicobacter pylori, sepsis, and mening itis. Finally, trauma to the abdomen, either extrinsic or related to surgery, a re easily recognized causes of nausea and vom iting . 2 . Seek a history of headaches or nE:uroiogical symptoms, as these may poi nt toward a eNS cause of nausea and vom iti n g . Abdom inal pa i n preceding the vom iting may help localize an i ntra-abdom inal i nflam matory process (e. g . , epi­ gastric pa i n with pancreatitis, right upper q uadrant pa i n with cholecystitis, right lower quadrant pain with append icitis). Undigested food in the vom itus may help localize the etiology to the stomach, but ca nnot d istinguish m echan ica l obstruction from gastroparesis. Fecu lent vom itus suggests bowel obstruction or fistula . 3 . In addition to perform ing a general physical examination, measure orthosta­ tic changes in pulse and blood pressure to estimate the degree of dehydration. Orthostatic changes may also be due to autonomic dysfunction in diabetic pa­ tients, or due to d rug therapy. 4 . Abdominal exam i nation should esta bl ish the presence or a bsence of d isten­ sion . An absence of bowel sounds on a uscultation may indicate an i leus or an i nfla mmatory condition with peritonitis. Pa l pation of the a bdomen helps d istin­ guish the two, as localized tenderness with guarding is present in i nflammatory cond itions. The local ization of pa i n a n d tenderness may i nd icate the organ system i nvolved .

OH GOD AM I SICK O bstet r i c a l ( p re g n a n cy, h y p e re m es i s g ra v i d a ) H yp e rca l ce m i a

1 82 • Gastroenterology

G a st r o e n t e r i t i s ( b a ct e ri a l a n d v i ra l ) O bstruct i o n ( a d h e s i o n s , vo l v u l u s , i nt u s s u scepti o n , peptic s t r i ct u r e s , tu m o rs ) D i a betes ( D KA, g a stropa res i s ) A d re n a l i n s uff i c i e n cy M ed i cati o n s ( o p i ates, a nt i b i ot i c s , N SA I D s , ch e m o t h e ra pe u t i c a g e n t s , a n t i a rrhyt h m i cs ) I n t ra-a b do m i n a l i n f l a m m a t o ry co n d it i o n s ( p a n crea t i t i s , ch o l ecysti t i s , a p p e n d i c i t i s , t ra u m a ) S c l e ro d e rma ( a n d oth e r p s e u d o-obst ru ct ive states) I sch e m i a ( m es e n t e r i c , myoca rd i a l ) e N S d i se a s e ( m i g ra i n e s , i n creased i nt r a c ra n i a l p re ss u re , m e n i n g i t i s , stroke) K id n ey fa i l u re

C l inica l Conditions or Diagnoses

P A N C R E AT I T I S VOMIT Vascular O bst ru ct ive M et a bo l i c/toxi c I nfect i o u s T ra u ma t i c

N otes 1 . The VOMIT m nemonic (see Nausea and Vomiting section) can be used to classify the causes of pancreatitis. Vosculor causes of pancreatitis include necrotizing Gastroen terologv . 1 83

-

vascul itis, atheroemboli, and TIP. Obstructive causes of pancreatitis incl ude bil­ iary disease/cholelithiasis, pancreas divisu m , ampullary malig na ncies . Crohn 's d isease, sphi ncter of Oddi dysfunction , Ascariasis infestation , duodenal divertic­ ulum and ( probably) cystic fibrosis. Metabolic/toxic processes causing pancre­ atitis include a lcohol, d rugs, renal fa ilure, acute fatty liver, scorpion sting, Reye's syndrome, hyperca lcemia, and hypertriglyceridem ia. Infectious causes of pan­ creatitis i nclude m u mps, other viral i nfections, Reye's syndrome (a lso a toxic/metabolic process) , Mycoplasma and Ascariasis (obstructs pancreatic out­ flow). Traumatic caus�s of pancreatitis include external trauma, ERCP, surgery, erosion of duodenal ulcer, and after renal transplantation (the latter a lso may be considered toxic/metabolic) . 2. The most com mon causes of acute pa ncreatitis a re ( 1 ) bil iary obstruction by gall stones, ( 2 ) alcohol toxicity (these fi rst two account for approximately 90% of cases), and ( 3 ) drugs, which account for a bout 5% of cases ( "BAD") . Other ia­ trogenic causes ( e . g . , ERCP, post-operative, and ca lcium a d m i n i stration) a re being increasingly recogn ized . 3 . An i m portant d iag nostic test is the a mylase level, a lthough a normal level does not rule out pancreatitis. The lipase level may have somewhat g reater sen­ sitivity and specificity in the diag nosis of acute pancreatitis. 4. Other non-pancreatic conditions wh ich cause an elevation of serum amylase include renal insufficiency, salivary gland disease, macroamylasemia, DKA, cer­ ta in tumors ( l u n g , esophagus, ova ri a n ) , bu rns, ectopic pregna ncy, and other intra-a bdominal disorders (perforated viscus, penetrati ng ulcer, peritonitis). 5. Serial measu res of serum amylase a re not helpful , and patients are best fol­ lowed clinical ly. Urine amylase esti mation is only helpful for making the diagno­ sis of macroamylasemia. In this cond ition , the a mylase com plex is too large to be filtered into the urine, and u rine levels a re low i n contrast to elevated serum levels. 6 . Ra nson's criteria for pa ncreatitis may be used for p rognosis. " H E LLO RANSON" lists these factors : Within 48 Hours On Admission Hyperglycemia Renal fa ilure (BUN i ncrease > 5 mg/dl) (Glucose > 200 mg/ dl) Anemia ( hematocrit d rop > 1 0 mg/dl) Elevated AST > 250 u/I No calciu m « 8 mg/dl) Leu kocytosis Sequestration (> 4 L fluid) (WBC > 1 6, 000/m m 3 ) LDH > 350 u/I Oxygen d rop ( P02 < 60 mmHg) No albumin « 3 . 2 g/d l) Older patients (Age > 55 years) Patients with only one of these factors have an i ncreased risk of complications; those with two risk factors may have a mortality rate as high as 2 0-30%; and those with six to seven risk factors have a nearly 1 00% morta lity rate. I n patients with gal lstone-assoc iated pancreatitis, the prog nosis is genera l ly better, a n d modified criteria have been proposed . Other ind icators o f poor prog nosis in­ cl ude acidosis (base deficit > 4 m mol/L), hypotension (BP < 90 mmHg), tachy­ cardia ( heart rate > 1 30), oliguria « 50 cc/hr) and hemorrhagic peritoneal fluid ("toxic broth"). An APACHE II score > 1 2 is a lso predictive of more severe disease, 184 • Gastroenterology

a lthough it is a com plex and seldom used calculation . The i m portance of risk stratification is that high-risk patients should be mon itored more closely and a re candidates for earlier interventional therapy (surgica l , radiolog ic, endoscopic) . 7. The treatment for pancreatitis is largely supportive , with fl u id resuscitation . and ana lgesia . The pancreas is rested by eli minating oral intake. Monitoring for complications ( i nfection , hemorrhage, hemodynamic collapse, respi ratory fa il­ ure, hypoca lcem ia, hyperglycem ia ) is critica l . There are no proven benefits for routine nasogastric suction, peritoneal lavage, administration of antibiotics, or therapy with other medications. In cases of gal lstone pancreatitis, i m med iate re­ mova l of stones in severely ill patients may improve outcome. Other invasive therapies a re reserved for severely ill patients with specific com plications (e . g . , a bscess, pseudocyst, phlegmon ) . 8 . The fo l lowi n g m n e m o n i c l i sts m o s t of t h e causes a n d a ssociations for pa ncreatiti s :

B A D PA N C R EATI T I S C RAS H ES H A R D B i l i a ry d i s e a s e (ch o l ed o ch o l it h i a s i s ) A lcohol D ru g s/tox i n s P a n c re a s d i vi s u m A m p u l l a ry m a l i g n a n cy ( a d e noca rc i n o m a o f t h e pa n c rea s , p r i m a ry a m p u l l a ry, etc . ) N ecrotiz i n g va s c u l it i s ( l u p u s , p o lya rte r i t i s n od o s a ) C ys t i c f i b ro s i s R eye's syn d r o m e E RC P A t h e ro e m b o l i T ra u ma I nfect i o n (vi ra l , p a r a s i t e s , bacte ria l ) TTP I d i o p at h i c/i n h e rited S u rg e ry ( posto p e rative pa n creati t i s , e s p e c i a l l y post card i o p u l m o n a ry bypa s s )

Gastroenterology . 1 85

--

C ro h n 's d i s e a s e R e n a l fa i l u re A c ute fatty l ive r of p re g n a n cy S co r p i o n st i n g H yp e rca l c e m i a E ros i o n o f d u o d e n a l u l c e r S p h i n ct e r of O d d i dysf u n c t i o n H y p e rt r i g lyce r i d e m i a A sca r i a s i s R e n a l t ra n s p l a n t D u o d e n a l d iv e rt i c u l u m

1 86 • Gastroenterology

13

R H EUMATOLOGY Clinical Sym ptoms and Signs

AC U T E M O N OA R T H R I T I S HIS G O UT FIT* H e m a rt h ro s i s ( c oa g u l o pathy, e . g . , h e m o p h i l i a ) I n fect i o n ( b a cteri a , [e . g . , g o n ococc u s ] , myc o b a cte r i a l , f u n g a l , Lym e d i s e a s e , v i ra l ) S ystem i c i l l n e s s ( R e i t e r 's , S L E , r h e u m a t o i d a rt h ri t i s , p s o ri a s i s , s a rc o i d , B e h ge t 's ) G o u t/ps e u do g o u t O steoa rt h r i t i s U l c e rative c o l i t i s/C ro h n's T ra u m a/fo re i g n body s y n ov i t i s F i b r i n d e p o s i t i o n ( pa l i n d ro m i c a rt h r i t i s ) I sch e m i c n ec ros i s T u m o r ( m et a s t a t i c , pri m a ry) *

Differential diagnosis

N otes 1 . Acute pa in and swelling i n a joint req u i res i m med iate eva l uation a n d , in almost all cases, im mediate arthrocentesis to rule out infection . Rheumatology .

1 87 .

2 . The age of the patient, history of other d isease or symptoms (gastroenteritis), fa m i ly h istory, and sexual h istory m ust be carefully evaluated . Physical exa m i na­ tion is performed to look for signs of infection (skin cha nges) o r evidence of other systemic ill ness. Consider cu lture of the throat, u rethra, and rectu m in indi­ viduals suspected of gonococcal infection 3. Examine joint fluid by g ram sta i n and polarized light i n itia lly, and send for a culture and cell count. Normal synovial fluid contains fewer than 1 1 0 cells/mm 3 , most of which a re mononuclea r. F l u id is cOhsidered " n o n i nflam matory" if i t conta ins less than 3000 cells/mm 3 As the cel l count increases, s o does the sus­ picion of i nfectio n . Effusions with more than 1 00 , 000 WBC/mm 3 a re con­ sidered septic, but there is a wide range of possible va lues . Careful exam i nation of fluid for crystals may esta blish a d iagnosis early and obviate the need for hos­ pital ization . The presence of crystals, however, does not exclude infection, and if there is sti ll a q uestion of infection , the patient should be adm itted for a ntibi­ otics until cu lture results a re ava i lable. (See ta ble i n I nfla m matory Polya rthritis section . ) 4 . A freq uent diag nostic dilemma i nvolves d ifferentiati ng i nfections from other acute i nfla m matory a rthritides . Patients should be admitted for i ntravenous anti bi­ otics while awa iting cu lture results. N SAIDs should be withheld initially to j udge the response to antibiotics alone.

I N F L A M M AT O R Y P O LYA R T H R I T I S A G G RAVAT E D S Y N OV I A L J T S * A d u lt Sti l l s ' d i s e a s e G o u t/ps e u d o g o u t G o n ococce m i a R h e u m a t o i d a rt h ri t i s A c u t e r h e u m a t i c feve r Vascu litis A my l o i d o s i s T u be rc u l o s i s E n d oca rd i t i s D e rmatomyo s i t i s/polymyo s i t i s

1 88 • Rheumatologv

b

S yste m i c l u p u s e ryt h e ma t o s u s Y e rs i n ia , Ca m py l o b a ct e r, S h i g e l l a ( Re i t e r 's) N o n-g o n ococca l u reth ritis ( R e ite r 's) O ve r l a p syn d ro m e s (e . g . , m i xed c o n n ective t i s s u e d i sease) V i ra l i nfe ct i o n s ( reactive) I n f l a m m a t o r y bowe l d i s e a s e A I DS Lyme d isease J uve n i l e r h e u m a t o i d a rt h r i t i s T re p o n e m a l i n fect i o n (syp h i l i s ) S a rc o i d o s i s Also: scleroderma, polymyalgia rheumatica, psoriasis, intestinal bypass surgery, hemochromatosis *

This m nemonic provides the differential diagnosis.

N otes 1 . A q U ick and easy etiolog ic way to look at i nfla m matory polyarthritis is as follows a . Infection - d irect infection of joint ( bacteria, syphilis, TB, etc . ) b. Crysta l-ind uced (gout, pseudogout) c. Immunologic ( RA, SLE, vasculitis, etc) d . Reactive - i n response to infection elsewhere in body (Reiter's synd rome, AIDS, etc . ) e . Id iopathic (ankylosing spondylitis) 2. Work-up of inflammatory polyarth ritis includes: a. Laboratory studies: CBC, E S R , C R P may help distinguish i nfla m ma tory from noninfla m matory conditions. b . Synovial fluid aspiration is a lways ind icated when either an i nfectious or crysta l-i nduced i nfla m matory a rthritis is being considered . Normal viscosi ty is such that when expressed from a syri nge, each d rop has a long ta i l or string attached . R BCs a re not generally seen i n synovial fl u id except i n a settinq of hemarthrosis or trauma.

Rheumatology . 1 89

Synovial F l u i d Characteristics

Noninflammatory Arthritis

Crystal-Induced Arthritis

Infectious Arthritis

Appearance W BC

Clear

Tu rbid, yel low 3000-50,000

Turbid, opaque > 50,000 cells/ml

Differential

Mostly mononuclear cells

Mostly PMNs

Mostly PMNs

Glucose

Normal (within 1 0- 1 5 mg/dl of serum values)

Normal or low

Low

Protein

Normal

Normal or high

High

Viscosity

Good , stri nging of fluid

Poor, no stri ng ing

Poor, no stringing

Crysta ls

No

Yes

No

Gram stain/ culture

Negative

Negative

Positive